TW201127956A - Dual variable domain immunoglobulins and uses thereof - Google Patents

Dual variable domain immunoglobulins and uses thereof Download PDF

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Publication number
TW201127956A
TW201127956A TW099136250A TW99136250A TW201127956A TW 201127956 A TW201127956 A TW 201127956A TW 099136250 A TW099136250 A TW 099136250A TW 99136250 A TW99136250 A TW 99136250A TW 201127956 A TW201127956 A TW 201127956A
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Taiwan
Prior art keywords
seq
amino acid
acid sequence
binding
chain amino
Prior art date
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TW099136250A
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English (en)
Inventor
Tariq Ghayur
Susan E Morgan-Lappe
Edward B Reilly
Gillian A Kingsbury
Andrew Phillips
Jieyi Wang
Randy L Bell
Suzanne M Norvell
ying-chun Li
jun-jian Liu
Hua Ying
zhi-hong Liu
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Abbott Lab
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Application filed by Abbott Lab filed Critical Abbott Lab
Publication of TW201127956A publication Critical patent/TW201127956A/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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201127956 六、發明說明： 【發明所屬之技術領域】 本發明係關於多價及多特異性結合蛋白、其製備方法， 且特定言之係關於其用於診斷、預防及/或治療急性及慢 性發炎疾病、癌症及其他疾病之用途。 本申請案主張2009年1〇月23曰申請之美國申請案第 12/605,094號之優先權，其内容以引用的方式併入本文 中。美國申請案第12/605,094號為主張2009年4月28日申請 之美國臨時申請案第61/230，191號及美國申請案第 12/431，460號之優先權的部分接續申請案，該美國申請案 第12/605,094號為主張2008年4月29日申請之美國臨時申嗜 案第61/125,834號、2008年7月8曰申請之美國臨時申請案 第61/134,283號、2008年10月23日申請之美國臨時申請案 第61/197,191號及2〇08年11月12曰申請之美國臨時申請案 第61/199,009號之優先權的非臨時申請案，其内容以引用 的方式併入本文中。 【先前技術】 此項技術中已知經工程改造蛋白質，諸如能夠結合兩個 或兩個以上抗原之多特異性抗體。該等多特異性結合蛋白 可使用細胞融合、化學結合或重組DN A技術產生。 已使用四源雜交瘤技術（參看Milstein，C.及A.C. Cuello (1983) Nature 305(5934)··537-40)基於表現具有雙特異性抗 體之所要特異性之鼠類單株抗體（mAb)的兩種不同融合瘤 細胞株之體細胞融合產生雙特異性抗體。因為所得雜交融 151681.doc 201127956 合瘤（或四源雜交瘤）細胞株内兩種不同免疫球蛋白（Ig)重 鍵及輕鏈隨機配對，所以產生多達10種不同Ig種類，其中 僅一者為功能性雙特異性抗體。錯配副產物之存在及產率 顯著降低意謂需完善純化程序。 亦可藉由使兩種不同mAb化學結合來產生雙特異性抗體 (參看 Staerz，U.D.等人，（1985) Nature 314(6012): 628- 31)。此方法不產生均質製劑。其他方法已使用使兩種不 同mAb或較小抗體片段化學結合（參看Brennan，M.等人， (1985) Science 229(4708): 81-3)。 籲 用於產生雙特異性抗體之另一方法為將兩個親本抗體用 異雙功能交聯劑偶合’但所得雙特異性抗體具有顯著分子 異質性’因為交聯劑與親本抗體的反應並非定點反應。為 獲得更具均質性之雙特異性抗體製劑，已使兩個不同Fab 片段在其鉸鏈半胱胺酸殘基處以定點方式化學交聯（參看
Glennie，M.J.等人，（1987) J. Immunol. 139(7): 2367-75)。 但此方法產生Fab，2片段，而非完全IgG分子。 已開發出多種其他重組雙特異性抗體形式（參看籲
Kriangkum，J.等人，（2001) Biomol. Eng· 18(2): 31-40)。其 中’串聯單鏈Fv分子及微型雙功能抗體、及其多種衍生物 最為廣泛使用。慣常自兩個識別不同抗原的單鏈Fv(scFv) 片段開始建構此等分子（參看Economides, A.N.等人，（2003)
Nat. Med. 9(1): 47-52)。串聯scFv 分子（taFv)表示以另一肽 連接子簡單連接兩個scFv分子的簡單形式。此等串聯scFv 分子中存在的兩個scFv片段形成單獨摺疊實體。可使用多 151681.doc 201127956 種連接子連接兩個seFv片段且連接子長度為至多63個殘基 (參看 Nakanishi，K.等人，（2001) Ann. Rev Im_〇1 19: 423-74)。儘官親本scpv片段在細菌中通常可以可溶形式表 現，然而，通常觀測到串聯scFv分子在細菌中形成不溶聚 集體因此，慣常應用再摺疊方案或使用哺乳動物表現系 統產生可溶串聯scFv分子。在最近研究中，報導由轉殖基 因兔及牛活體内表現針對CD28及黑素瘤相關蛋白聚糖之 串聯 scFv(參看 Gracie，J.A·等人，（1999) J. Clin. lnvest. 104(10)· 1393-401)。在此構築體中，兩個SCFV分子由chi 連接子連接，且可見雙特異性抗體的血清濃度高達1 〇 〇 mg/L。使用多種策略，包括改變結構區域順序或使用具有 不同長度或可撓性之中間連接子以允許在細菌中可溶性表 現。少數研究現已報導使用極短Ala3連接子或富含甘胺酸/ 絲胺酸之長連接子在細菌中表現可溶串聯scFv分子（參看
Leung, B.P.專人，（2〇〇〇) j. immun〇i. 164(12): 6495-502 ; Ito，A.等人，（2003) J. Immunol. 170(9): 4802-9 ; Karni，A 專人，（2002) J· Neuroimmunol. 125(1-2): 134-40)。在另一 最近研究中，使用含有長度為3或6個殘基的隨機化中間連 接子之串聯scFv譜系的噬菌體呈現，以增濃在細菌中以可 溶性或活性形式產生之彼等分子。此方法致使串聯scFv* 子與ό個胺基酸殘基之連接子分離（參看Arndt, Μ.及j Krauss (2003) Methods Mol. Biol. 207: 305-21)。不清楚此 連接子序列是否表示可溶性表現串聯％!^分子的通用解決 方案。然而’此研究證明串聯scFv分子之噬菌體呈現與定 151681.doc 201127956 向突變誘發之組合為增濃可以活性形式在細菌中表現之此 等分子的有效工具。 雙特異性微型雙功能抗體（Db)利用微型雙功能抗體形式 進行表現。藉由使連接VH區域與VL區域之連接子長度減 小至約5個殘基，由scFv片段產生微型雙功能抗體（參看 Peipp，M.及 T. Valerius (2002) Biochem. Soc. Trans. 30(4): 5 07-1 1)。此連接子尺寸的減小便利於兩個多肽鏈藉由VH 區域與VL區域交叉配對進行二聚。藉由在同一細胞内表 現兩個具有結構VHA-VLB及VHB-VLA(VH-VL組態）或 VLA-VHB及VLB-VHA(VL-VH組態）之多肽鏈產生雙特異 性微型雙功能抗體。過去已產生多種不同雙特異性微型雙 功能抗體，且其中多數在細菌中以可溶性形式表現。然 而，最近比較研究證明，可變區域之定向可影響活性結合 位點之表現及形成（參看Mack，M.等人，（1995) Proc. Natl. Acad. Sci. U S A 92(15): 7021-5)。然而，細菌中之可溶性 表現代表優於串聯scFv分子的重要優勢。然而，因為單個 細胞内表現兩種不同多肽鏈，所以無活性均二聚體可與活 性雜二聚體一起產生。此需要執行額外純化步驟，以獲得 雙特異性微型雙功能抗體的均質製劑。一種迫使產生雙特 異性微型雙功能抗體之方法為產生杵臼結構（knob-into-hole)的微型雙功能抗體（參看Holliger，P.，Τ· Prospero及& Winter (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-8.18)。此方法已關於針對HER2及CD3之雙特異性微型雙 功能抗體得以證實。在抗HER2或抗CD3可變區域中，藉由 151681.doc 201127956 將Val37換為Phe且Leu45換為Trp在VH區域中引入大杵狀結 構，且藉由使Phe98突變為Met且Tyr87突變為Ala在VL區域 中產生互補臼狀結構。藉由使用此方法，雙特異性微型雙 功能抗體之產量可自親本微型雙功能抗體的72%增至杵臼 結構微型雙功能抗體的超過90%。重要的是，產品收得率 僅由於此等突變而略微降低。然而，若干構築體觀測到抗 原結合活性降低。因此，此相當精細的方法需要分析多種 構築體以鑑別產生結合活性無改變之雜二聚分子的彼等突 變。此外，該方法需要突變修飾免疫球蛋白序列之恆定 區，從而形成抗體序列的非原生及非天然形式，此可導致 免疫原性提高、活體内穩定性差以及不良藥物動力學。 單鏈微型雙功能抗體（scDb)表示改良雙特異性微型雙功 能抗體樣分子之形成的替代策略（參看Holliger，P.及G. Winter (1997) Cancer Immunol. Immunother. 45(3-4): 128-30 ; Wu，Α·Μ·等人，（1996) Immunotechnology 2( 1):第 21-30頁）。藉由以長度為約15個胺基酸殘基之額外中間連接 子連接兩個形成微型雙功能抗體之多肽鏈產生雙特異性單 鏈微型雙功能抗體。因此，分子量對應於單體單鏈微型雙 功能抗體（50-60 kDa)之所有分子均為雙特異性的。若干研 究已證明，雙特異性單鏈微型雙功能抗體以可溶性及活性 形式表現於細菌中，其中絕大多數經純化分子以單體形式 存在（參看 Holliger, P.及 G. Winter (1997) Cancer Immunol. Immunother. 45(3-4): 128-30 ; Wu，Α·Μ·等人，（1996)
Immunotechnol. 2(1): 21-36 ; Pluckthun，A.及 P. Pack 151681.doc 201127956 (1997) Immunotechnol· 3(2): 83-105; Ridgway，J.B.等人， (1996) Protein Engin. 9(7): 617-21)。因此，單鏈微型雙功 能抗體組合串聯scFv(所有單體均為雙特異性）及微型雙功 能抗體（在細菌中可溶性表現）之優勢。 新近已將微型雙功能抗體融合於FC產生更多4樣分子， 即聯微型雙功能抗體（參看Lu，D.等人，（2004) J. BioL Chem. 279(4): 2856-65)。此外，已描述在igG重鏈中包含 兩個Fab重複單元且能夠結合四個抗原分子的多價抗體構 築體（參看 WO 0177342A1，及 Miller，K.等人，（2〇〇3) J. Immunol. 170(9): 4854-61) 〇 此項技術中需要能夠結合兩個或兩個以上抗原的經改良 多價結合蛋白。美國專利申請案第11/507,050號提供新賴 結合蛋白家族，該等結合蛋白能夠以高親和力結合兩個或 兩個以上抗原且稱為雙重可變區域免疫球蛋白
IgTM)。本發明進一步提供能夠結合兩個或兩個以上抗原之 新穎結合蛋白。 【發明内容】 本發明係關於能夠結合兩個或兩個以上抗原之多價結人 蛋白。本發明提供能夠以高親和力結合兩個或兩個以上抗 原之新穎結合蛋白家族。 在一實施例中，本發明提供包含多肽鏈之結合蛋白，其 中該多肽鍵包含VDl-(Xi)n_VD2-C-(X2)n，其中VD1為第 一可變區域，VD2為第二可變區域，（^為怪定區域，幻表 不胺基酸或多肽，X2表示Fc區，且n為〇或i。在一實施例 151681.doc 201127956
中，結合蛋白中之VD1及VD2為重鏈可變區域。在另一實 施例中，重鏈可變區域係選自由以下組成之群：鼠類重鏈 可變區域、人類重鏈可變區域、CDR移植重鏈可變區域及 人類化重鏈可變區域。在又一實施例中，VD1與VD2能夠 結合相同抗原。在另一實施例中，VD1與VD2能夠結合不同 抗原。在又一實施例中，C為重鏈恆定區域。舉例而言，XI 為連接子，其限制條件為XI不為CH1。舉例而言，XI為選自 由以下組成之群的連接子：AKTTPKLEEGEFSEAR(SEQ ID NO: 1) ； AKTTPKLEEGEFSEARV(SEQ ID NO: 2)； AKTTPKLGG(SEQ ID NO: 3) ； SAKTTPKLGG(SEQ ID NO: 4) ； SAKTTP(SEQ ID NO: 5) ； RADAAP(SEQ ID NO: 6)； RADAAPTVS(SEQ ID NO: 7) ； RADAAAAGGPGS(SEQ ID NO: 8) ； RADAAAA(G4S)4(SEQ ID NO: 9) ； SAKTTPKLE EGEFSEARV(SEQ ID NO: 10) ； ADAAP(SEQ ID NO: 11)； ADAAPTVSIFPP(SEQ ID NO: 12) ； TVAAP(SEQ ID NO: 13) ； TVAAPSVFIFPP(SEQ ID NO: 14) ； QPKAAP(SEQ ID NO: 15) ； QPKAAPSVTLFPP(SEQ ID NO: 16) ； AKTTPP (SEQ ID NO: 17) ； AKTTPPSVTPLAP(SEQ ID NO: 18)； AKTTAP(SEQ ID NO: 19) ； AKTTAPSVYPLAP(SEQ ID NO: 20) ； ASTKGP(SEQ ID NO: 21) ； ASTKGPSVFPLAP (SEQ ID NO: 22) ； GGGGSGGGGSGGGGS(SEQ ID NO: 23)； GENKVEYAPALMALS(SEQ ID NO: 24) ； GPAKELTPLKEAKVS (SEQ ID NO: 25) ； GHEAAAVMQVQYPAS(SEQ ID NO: 26)。在一實施例中，X2為Fc區。在另一實施例中，X2為 151681.doc 201127956 變異Fc區。 在一實施例中，本文所揭示之結合蛋白包含多肽鏈，其 中該多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為第 一重鏈可變區域，VD2為第二重鏈可變區域，C為重鏈恆 定區域，XI為連接子，其限制條件為XI不為CH1，且X2 為Fc區。 在一實施例中，結合蛋白中之VD1及VD2為輕鏈可變區 域。在一實施例中，輕鍵可變區域係選自由以下組成之 群：鼠類輕鏈可變區域、人類輕鏈可變區域、CDR移植輕 鏈可變區域及人類化輕鏈可變區域。在一實施例中，VD1 及VD2能夠結合相同抗原。在另一實施例中，VD1與VD2 能夠結合不同抗原。在一實施例中，C為輕鏈恆定區域。 在另一實施例中，XI為連接子，其限制條件為XI不為 CL1。在一實施例中，XI為選自由以下組成之群的連接
子：AKTTPKLEEGEFSEAR(SEQ ID NO: 1) ; AKTTPKLEE GEFSEARV(SEQ ID NO: 2) ； AKTTPKLGG(SEQ ID NO: 3) ； SAKTTPKLGG(SEQ ID NO: 4) ； SAKTTP(SEQ ID NO: 5) ； RADAAP(SEQ ID NO: 6) ； RADAAPTVS(SEQ ID NO: 7) ; RADAAAAGGPGS(SEQ ID NO: 8) ; RADAAAA(G4S)4 (SEQ ID NO: 9) ； SAKTTPKLEEGEFSEARV(SEQ ID NO: 10) ； ADAAP(SEQ ID NO: 11) ； ADAAPTVSIFPP(SEQ ID NO: 12) ； TVAAP(SEQ ID NO: 13) ； TVAAPSVFIFPP(SEQ ID NO: 14) ； QPKAAP(SEQ ID NO: 15) ； QPKAAPSVTLFPP (SEQ ID NO: 16) ； AKTTPP(SEQ ID NO: 17) ； AKTTPPSVTPLAP 131681.doc -10- 201127956 (SEQ ID NO: 18) ； AKTTAP(SEQ ID NO: 19) ； AKTTAPSVYPLAP (SEQ ID NO: 20) ； ASTKGP(SEQ ID NO: 21) ； ASTKGPSVFPLAP (SEQ ID NO: 22) ； GGGGSGGGGSGGGGS(SEQ ID NO: 23)； GENKVEYAPALMALS(SEQ ID NO: 24) ； GPAKELTPLKEAKVS (SEQ ID NO: 25) ； GHEAAAVMQVQYPAS(SEQ ID NO: 26)。在一實施例中，結合蛋白不包含X2。
在一實施例中，可變重鏈及可變輕鏈包含相同連接子。 在另一實施例中，可變重鏈及可變輕鏈包含不同連接子。 在另一實施例中，可變重鏈與可變輕鏈皆包含短（約6個胺 基酸）連接子。在另一實施例中，可變重鏈與可變輕鏈皆 包含長（大於6個胺基酸）連接子。在另一實施例中，可變重 鏈包含短連接子且可變輕鏈包含長連接子。在另一實施例 中’可變重鏈包含長連接子且可變輕鏈包含短連接子。 在一實施例中，本文所揭示之結合蛋白包含多肽鏈，其 中該多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為第 一輕鏈可變區域，VD2為第二輕鏈可變區域，c為輕鏈恆 定區域’ XI為連接子，其限制條件為XI不為CH1，且X2 不包含Fc區。 在另一實施例中，本發明提供包含兩個多肽鏈之結合蛋 白’其中該第一多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其 中VD1為第一重鏈可變區域，為第二重鏈可變區域， C為重鏈值定區域，X1為連接子，其限制條件為χι不為 cm，且X2為Fc區；且該第二多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為第一輕鏈可變區域，VD2為第二輕鏈 151681.doc 201127956 可變區域’ c為輕鏈恆定區域，X1為連接子，其限制條件 為XI不為CH1，且X2不包含Fc區。在一特定實施例中，雙 重可變區域（DVD)結合蛋白包含四個多肽鏈，其中前兩個 多肽鏈分別包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為第 一重鏈可變區域’ VD2為第二重鏈可變區域，c為重鏈恆 定區域，XI為連接子，其限制條件為χι不為CH1，且Χ2 為Fc區；且後兩個多肽鏈分別包含vD1_(xl)n_VD2_c_ (X2)n，其中VD1為第一輕鏈可變區域，VD2為第二輕鏈可 變區域，C為輕鏈恆定區域，χι為連接子，其限制條件為鲁 XI不為CH1 ’且X2不包含fc區。該雙重可變區域（dvd)蛋 白質具有四個抗原結合位點。 在另一實施例中’本文所揭示之結合蛋白能夠結合一或 多個目標。在一實施例中，目標係選自由細胞激素、細胞 表面蛋白、酶及受體組成之群。在另一實施例中，結合蛋 白能夠調節一或多種目標之生物功能。在另一實施例中， 結合蛋白能夠中和一或多個目標。本發明之結合蛋白能夠 結合選自由以下組成之群的細胞激素：淋巴介質、單核球鲁 激素、多肽激素、受體或腫瘤標誌物。舉例而言，本發明 之DVD-Ig能夠結合以下中之兩者或兩者以上：cD_2〇、 CD-19、CD-80、CD-22、CD-40、CD_3、人類表皮生長因 子受體2(HER-2)、表皮生長因子受體(EGFR)、胰島素樣生 長因子1，2(IGF1，2)、胰島素樣生長因子受體（IGF1R)、巨 噬細胞刺激蛋白受體酪胺酸激酶（R〇N)、肝細胞生長因子 (HGF)、間葉細胞-上皮過渡因子（c_met)、血管内皮生長 151681.doc -12- 201127956 因子（VEGF)、果蠅δ同系物4(DLL4)、神經纖毛蛋白 1 (NRP1)、胎盤生長因子（PLGF)、及v-erb-b2禽類紅血球胚 細胞白血病病毒致癌基因同系物3(ErbB3)(亦參看表2)。在 一特定實施例中，該結合蛋白能夠結合選自由以下組成之 群的目標對：CD-20 與 CD-19 ; CD-20 與 CD-80 ; CD-20 與 CD_22 ; CD-20與 CD-40 ; CD-3 與 HER-2 ; CD-3 與 CD-19 ; EGFR與 HER-2 ; EGFR與 CD-3 ; EGFR與 IGF1，2 ; EGFR與 IGF1R ; EGFR 與 RON ; EGFR 與 HGF ; EGFR 與 c-MET ; HER-2 與 IGF1，2 ; HER-2 與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ； VEGF 與 HER-2 ； VEGF 與 CD-20 ； VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD-20 與 CD3 ; DLL-4 與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2與 ErbB3 ; c-Met與 ErB3 ; PLGF與 HER-2 ; HER-2與 HER-2。 在一實施例中，能夠結合CD-20及CD-19之結合蛋白包 含選自由SEQ ID NO· 112及SEQ ID NO. 114組成之群的 DVD重鏈胺基酸序列；及選自由SEQ ID NO. 113及SEQ ID NO. 11 5組成之群的DVD輕鏈胺基酸序列❶在一實施例 中，能夠結合〇0-20及00-19之結合蛋白包含8丑(^10>^0. 112之DVD重鏈胺基酸序列及SEQ ID NO·· 113之DVD輕鏈 胺基酸序列。在另一實施例中，能夠結合CD-20及CD-19 之結合蛋白具有反定向且包含SEQ ID NO. 114之DVD重鏈 胺基酸序列及SEQ ID NO: 11 5之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-20及CD-3(序列1)之結合蛋 151681.doc •13- 201127956 白包含選自由SEQ ID NO. 116及SEQ ID NO. 118組成之群 的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 117及SEQ ID NO. 119組成之群的DVD輕鏈胺基酸序列。在一實施例 中，能夠結合CD-20及CD-3(序列1)之結合蛋白包含SEQID NO. 116之DVD重鏈胺基酸序列及SEQ ID NO: 117之DVD 輕鏈胺基酸序列。在另一實施例中，能夠結合CD-20及 CD-3(序列1)之結合蛋白具有反定向且包含SEQ ID NO. 118之DVD重鏈胺基酸序列及SEQ ID NO: 119之DVD輕鏈 胺基酸序列。 在一實施例中，能夠結合CD-20及CD-80之結合蛋白包 含選自由SEQ ID NO. 120及SEQ ID NO. 122組成之群的 DVD重鏈胺基酸序列；及選自由SEQ ID NO. 121及SEQ ID NO. 123組成之群的DVD輕鏈胺基酸序列。在一實施例 中，能夠結合CD-20及CD-80之結合蛋白包含SEQ ID NO. 120之DVD重鏈胺基酸序列及SEQ ID NO: 121之DVD輕鏈 胺基酸序列。在另一實施例中，能夠結合CD-20及CD-80 之結合蛋白具有反定向且包含SEQ ID NO. 122之DVD重鏈 胺基酸序列及SEQ ID NO: 123之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-20及CD-22之結合蛋白包 含選自由SEQ ID NO. 124及SEQ ID NO. 126組成之群的 DVD重鏈胺基酸序列；及選自由SEQ ID NO. 125及SEQ ID NO. 127組成之群的DVD輕鏈胺基酸序列。在一實施例 中，能夠結合CD-20及CD-22之結合蛋白包含SEQ ID NO. 124之DVD重鏈胺基酸序列及SEQ ID NO: 125之DVD輕鏈 151681.doc -14- 201127956 胺基酸序列。在另一實施例中，能夠結合CD-20及CD-22 之結合蛋白具有反定向且包含SEQ ID NO. 126之DVD重鏈 胺基酸序列及SEQ ID NO: 127之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-20及CD-40之結合蛋白包 含選自由SEQ ID NO. 128及SEQ ID NO. 130組成之群的 DVD重鏈胺基酸序列；及選自由SEQ ID NO. 129及SEQ ID NO. 1 3 1組成之群的DVD輕鏈胺基酸序列。在一實施例 中，能夠結合CD-20及CD-40之結合蛋白包含SEQ ID NO. 128之DVD重鏈胺基酸序列及SEQ ID NO: 129之DVD輕鏈 胺基酸序列。在另一實施例中，能夠結合CD-20及CD-40 之結合蛋白具有反定向且包含SEQ ID NO. 130之DVD重鏈 胺基酸序列及SEQ ID NO: 131之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列1)及HER-2(序列1) 之結合蛋白包含選自由SEQ ID NO. 132及SEQ ID NO. 134 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 133及SEQ ID NO. 135組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列:1)及HER-2(序列1)之 結合蛋白包含SEQ ID NO. 132之DVD重鏈胺基酸序列及 SEQ ID NO: 133之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合CD-3(序列1)及HER-2(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 134之DVD重鏈胺基酸序列及 SEQ ID NO: 135之DVD輕鏈胺基酸序歹ij。 在一實施例中，能夠結合CD-2(序列1)及CD-19之結合蛋 白包含選自由SEQ ID NO. 136及SEQ ID NO. 138組成之群 151681.doc -15- 201127956 的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 137及SEQ ID NO. 139組成之群的DVD輕鏈胺基酸序列。在一實施例 中，能夠結合CD-3(序列1)及匸0-19之結合蛋白包含8丑(^10 NO. 136之DVD重鏈胺基酸序列及SEQ ID NO: 137之DVD 輕鍵胺基酸序列。在另一實施例中，能夠結合CD-3(序列 1)及CD-19之結合蛋白具有反定向包含SEQ ID NO. 138 之DVD重鏈胺基酸序列及SEQ ID NO: 139之DVD輕鏈胺基 酸序列。 在一實施例中，能夠結合EGFR(序列2)及HER-2(序列1) 之結合蛋白包含選自由SEQ ID NO· 140及SEQ ID NO. 142 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 141及SEQ ID NO. 143組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及HER-2(序列1)之 結合蛋白包含SEQ ID NO. 140之DVD重鏈胺基酸序列及 SEQ ID NO: 141之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及HER-2(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 142之DVD重鏈胺基酸序列及 SEQ ID NO: 143之DVD輕鏈胺基酸序列。
在一實施例中，能夠結合EGFR(序列2)及CD-3(序列1)之 結合蛋白包含選自由SEQ ID NO· 144及SEQ ID N〇. 146組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID N〇. 145 及SEQ ID NO· 147組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列2)及CD-3(序列1)之結合蛋 白包含SEQ ID NO. 144之DVD重鏈胺基酸序列及seQ ID 151681.doc -16- 201127956 NO: 145之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列1)及CD-3(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 146之DVD重鏈胺基酸序列及SEQ ID NO: 147之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF 1，2之結合 蛋白包含選自由SEQ ID NO. 148及SEQ ID NO· 150組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 149及 SEQ ID NO. 151組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合EGFR(序列2)及IGF 1，2之結合蛋白包含 SEQ ID NO. 148之DVD重鏈胺基酸序列及SEQ ID NO: 149 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 EGFR(序列2)及IGF 1，2之結合蛋白具有反定向且包含SEQ ID NO. 150之DVD重鏈胺基酸序列及SEQ ID NO: 151之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列1) 之結合蛋白包含選自由SEQ ID NO. 152及SEQ ID NO. 154 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 153及SEQ ID NO. 155組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列1)之 結合蛋白包含SEQ ID NO. 152之DVD重鏈胺基酸序列及 SEQ ID NO: 153之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 154之DVD重鏈胺基酸序列及 SEQ ID NO: 155之DVD輕鏈胺基酸序列。 I51681.doc 201127956 在第二實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 1)之結合蛋白包含選自由SEQ ID NO. 156及SEQ ID NO-158 組成 之群的 DVD重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 157及SEQ ID NO. 159組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 1)之結合蛋白包含SEQ ID NO. 156之DVD重鏈胺基酸序列 及SEQ ID NO: 15 7之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 158之DVD重鏈胺基酸序列及 SEQ ID NO: 159之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合EGFR(序列2)及IGF1R(序列 1)之結合蛋白包含選自由SEQ ID NO. 160及SEQ ID NO. 162組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 161及SEQ ID NO. 163組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 1)之結合蛋白包含SEQ ID NO. 160之DVD重鏈胺基酸序列 及SEQ ID NO: 161之DVD輕鍵胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 162之DVD重鏈胺基酸序列及 SEQ ID NO: 163之DVD輕缝胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 1)之結合蛋白包含選自由SEQ ID NO. 164及SEQ ID NO-166 組成 之群的 DVD 重鏈 胺基酸 序列； 及選自 由 SEQ ID NO. 165及SEQ ID NO. 167組成之群的DVD輕鍵胺基酸序 151681.doc 201127956 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 1) 之結合蛋白包含SEQ ID NO. 164之DVD重鏈胺基酸序列 及SEQ ID NO: 165之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 166之D VD重鏈胺基酸序列及 SEQ ID NO: 167之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列2) 之結合蛋白包含選自由SEQ ID NO_ 168及SEQ ID NO. 170 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 169及SEQ ID NO. 171組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列2)之 結合蛋白包含SEQ ID NO. 168之DVD重鏈胺基酸序列及 SEQ ID NO: 169之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 170之DVD重鏈胺基酸序列及 SEQ ID NO: 171之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合EGFR(序列2)及IGF1R(序列 2) 之結合蛋白包含選自由SEQ ID NO. 172及SEQ ID NO. 174組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 173及SEQ ID NO. 175組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 2)之結合蛋白包含SEQ ID NO. 172之DVD重鏈胺基酸序列 及SEQ ID NO: 173之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列2)之結合蛋白具 151681.doc • 19- 201127956 有反定向且包含SEQ ID NO. 174之DVD重鏈胺基酸序列及 SEQ ID NO: 175之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合EGFR(序列2)及IGF1R(序列 2)之結合蛋白包含選自由SEQ ID NO. 176及SEQ ID NO. 178組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 177及SEQ ID NO. 179組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 2)之結合蛋白包含SEQ ID NO. 176之DVD重鏈胺基酸序列 及SEQ ID NO: 177之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 178之DVD重鏈胺基酸序列及 SEQ ID NO: 179之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及IGF1R(序列 2)之結合蛋白包含選自由SEQ ID NO· 180及SEQ ID NO. 1 82組成之群的DVD重鍵胺基酸序列；及選自由SEQ ID NO. 181及SEQ ID NO. 183組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 2)之結合蛋白包含SEQ ID NO· 18之DVD重鏈胺基酸序列 及SEQ ID NO: 181之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF 1R(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 182之DVD重鏈胺基酸序列及 SEQ ID NO: 183之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列3) 之結合蛋白包含選自由SEQ ID NO. 184及SEQ ID NO. 186 151681.doc -20- 201127956 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 185及SEQ ID NO. 187組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及IGF1R(序列3)之 結合蛋白包含SEQ ID NO. 184之DVD重鏈胺基酸序列及 SEQ ID NO: 185之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 186之DVD重鏈胺基酸序列及 SEQ ID NO: 187之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合EGFR(序列2)及IGF1R(序列 3)之結合蛋白包含選自由SEQ ID NO. 188及SEQ ID NO. 190組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 189及SEQ ID NO. 192組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 3)之結合蛋白包含SEQ ID NO. 188之DVD重鏈胺基酸序列 及SEQ ID NO: 189之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 190之DVD重鏈胺基酸序列及 SEQ ID NO: 191之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合EGFR(序列2)及IGF1R(序列 3)之結合蛋白包含選自由SEQ ID NO. 192及SEQ ID NO. 194組成之群的DVD重鏈胺基酸序列；及選自由SEQ id NO· 193及SEQ ID NO. 195組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 3)之結合蛋白包含SEQ ID NO. 192之DVD重鏈胺基酸序列 151681.doc • 21 - 201127956 及SEQ ID NO: 193之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF 1R(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 194之DVD重鏈胺基酸序列及 SEQ ID NO: 195之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及IGF1R(序列 3)之結合蛋白包含選自由SEQ ID NO_ 196及SEQ ID NO. 198組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 197及SEQ ID NO. 199組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及IGF 1R(序列 3)之結合蛋白包含SEQ ID NO. 196之DVD重鏈胺基酸序列 及SEQ ID NO: 197之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及IGF1R(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 198之DVD重鏈胺基酸序列及 SEQ ID NO: 199之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及RON(序列1)之 結合蛋白包含選自由SEQ ID NO. 200及SEQ ID NO. 202組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 201 及SEQ ID NO. 203組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列2)及RON(序列1)之結合蛋 白包含SEQ ID NO. 200之DVD重鏈胺基酸序列及SEQ ID NO: 201之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列2)及RON(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 202之DVD重鏈胺基酸序列及SEQ ID NO: 203之DVD輕鏈胺基酸序列。 151681.doc •22· 201127956 在第二實施例中，能夠結合EGFR(序列2)及RON(序列1) 之結合蛋白包含選自由SEQ ID NO. 204及SEQ ID NO. 206 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 205及SEQ ID NO. 207組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及RON(序列1)之結 合蛋白包含SEQ ID NO. 204之DVD重鏈胺基酸序列及SEQ ID NO: 205之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合EGFR(序列2)及RON(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 206之DVD重鏈胺基酸序列及SEQ ID NO: 207之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合EGFR(序列2)及RON(序列1) 之結合蛋白包含選自由SEQ ID NO. 208及SEQ ID NO. 210 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 209及SEQ ID NO. 211組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及RON(序列1)之結 合蛋白包含SEQ ID NO. 208之DVD重鏈胺基酸序列及SEQ ID NO: 209之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合EGFR(序列2)及RON(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 210之DVD重鏈胺基酸序列及SEQ ID NO: 211之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及RON(序列1) 之結合蛋白包含選自由SEQ ID NO. 212及SEQ ID NO. 214 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 213及SEQ ID NO. 215組成之群的DVD輕鏈胺基酸序列。 151681.doc •23· 201127956 在一實施例中，能夠結合EGFR(序列2)及RON(序列1)之結 合蛋白包含SEQ ID NO. 212之DVD重鏈胺基酸序列及SEQ ID NO: 21 3之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合EGFR(序列2)及RON(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 2 14之DVD重鍵胺基酸序列及SEQ ID NO: 215之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及HGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 216及SEQ ID NO· 218組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 217 及SEQ ID NO. 2 19組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列2)及HGF(序列1)之結合蛋 白包含SEQ ID NO. 216之DVD重键胺基釀序列及SEQ ID NO: 2 1 7之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列2)及HGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 218之DVD重鏈胺基酸序列及SEQ ID NO: 219之DVD輕鏈胺基酸序列。
在一實施例中，能夠結合EGFR(序列1)及c-MET之結合 蛋白包含選自由SEQ ID NO. 220及SEQ ID NO. 222組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 221及 SEQ ID NO. 223組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合EGFR(序列1)及c-MET之結合蛋白包含 SEQ ID NO. 220之DVD重鏈胺基酸序列及SEQ ID NO: 221 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 EGFR(序列1)及c-MET之結合蛋白具有反定向且包含SEQ 151681.doc •24- 201127956 ID NO. 222之DVD重鏈胺基酸序列及SEQ ID NO: 223之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及IGF1，2之結合 蛋白包含選自由SEQ ID NO· 224及SEQ ID NO. 226組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 225及 SEQ ID NO. 227組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合HER-2(序列1)及IGF 1,2之結合蛋白包含 SEQ ID NO. 224之DVD重鏈胺基酸序列及SEQ ID NO: 225 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 HER-2(序列1)及IGF1,2之結合蛋白具有反定向且包含SEQ ID NO. 226之DVD重鍵胺基酸序列及SEQ ID NO: 227之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及IGF1R之結合 蛋白包含選自由SEQ ID NO. 228及SEQ ID NO. 230組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 229及 SEQ ID NO· 231組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合HER-2(序列1)及IGF1R之結合蛋白包含 SEQ ID NO. 228之DVD重鏈胺基酸序列及SEQ ID NO: 229 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 HER-2(序列1)及IGF1R之結合蛋白具有反定向且包含SEQ ID NO. 230之DVD重鏈胺基酸序列及SEQ ID NO: 231之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合RON(序列1)及HGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 232及SEQ ID NO· 234組 15I681.doc -25- 201127956 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO· 233 及SEQ ID NO. 235組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合RON(序列1)及HGF(序列1)之結合蛋 白包含SEQ ID NO. 232之DVD重鏈胺基酸序列及SEQ ID NO: 23 3之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合RON(序列1)及HGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 234之DVD重鏈胺基酸序列及SEQ ID NO: 235之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及EGFR(序列2) 之結合蛋白包含選自由SEQ ID NO. 23 6及SEQ ID NO. 23 8 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO-237 及 SEQ ID NO. 239組成 之群的 DVD輕鏈 胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及EGFR(序列2)之 結合蛋白包含SEQ ID NO. 236之DVD重鏈胺基酸序列及 SEQ ID NO: 237之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及EGFR(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 238之DVD重鏈胺基酸序列及 SEQ ID NO: 239之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及HER-2(序列1) 之結合蛋白包含選自由SEQ ID NO. 240及SEQ ID NO. 242 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 241及SEQ ID NO. 243組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及HER-2(序列1)之 結合蛋白包含SEQ ID NO. 240之DVD重鏈胺基酸序列及 15168I.doc •26- 201127956 SEQ ID NO: 241之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及HER-2(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 242之DVD重鏈胺基酸序列及 SEQ ID NO: 243之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及CD-20之結合 蛋白包含選自由SEQ ID NO. 244及SEQ ID NO. 246組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 245及 SEQ ID NO. 247組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合VEGF(序列1)及CD-20之結合蛋白包含 SEQ ID NO. 244之DVD重鏈胺基酸序列及SEQ ID NO: 245 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 VEGF(序列1)及CD-20之結合蛋白具有反定向且包含SEQ ID NO. 246之DVD重鏈胺基酸序列及SEQ ID NO: 247之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及IGF1,2之結合 蛋白包含選自由SEQ ID NO· 248及SEQ ID NO. 250組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 249及 SEQ ID NO· 251組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合VEGF(序列1)及IGF1,2之結合蛋白包含 SEQ ID NO. 248之DVD重鏈胺基酸序列及SEQ ID NO: 249 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 VEGF(序歹，U)及IGF 1,2之結合蛋白具有反定向且包含SEQ ID NO. 250之DVD重鏈胺基酸序列及SEQ ID NO: 251之 DVD輕鏈胺基酸序列》 151681.doc •27· 201127956 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列1) 之結合蛋白包含選自由SEQ ID NO. 252及SEQ ID NO. 254 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 253及SEQ ID NO. 255組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列1)之 結合蛋白包含SEQ ID NO. 252之DVD重鏈胺基酸序列及 SEQ ID NO: 253之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 254之DVD重鏈胺基酸序列及 SEQ ID NO: 255之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及HGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 256及SEQ ID NO. 25 8組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 257 及SEQ ID NO. 259組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合VEGF(序列1)及HGF(序列1)之結合蛋 白包含SEQ ID NO. 256之DVD重鏈胺基酸序列及SEQ ID NO: 25 7之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合VEGF(序列1)及HGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 258之DVD重鏈胺基酸序列及SEQ ID NO: 259之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及HGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 260及SEQ ID NO. 262 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 261及SEQ ID NO. 263組成之群的DVD輕鏈胺基酸序列。 151681.doc •28· 201127956 在一實施例中，能夠結合VEGF(序列1)及HGF(序列1)之結 合蛋白包含SEQ ID NO. 260之DVD重鏈胺基酸序列及SEQ ID NO: 261之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合VEGF(序列1)及HGF(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 262之DVD重鏈胺基酸序列及SEQ ID NO: 263之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及HGF(序列1) 之結合蛋白包含選自由SEQ ID NO· 264及SEQ ID NO. 266 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO-265及 SEQ ID NO. 267組成 之群的 DVD輕鏈 胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及HGF(序列1)之結 合蛋白包含SEQ ID NO. 264之DVD重鏈胺基酸序列及SEQ ID NO: 265之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合VEGF(序列1)及HGF(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 266之DVD重鏈胺基酸序列及SEQ ID NO: 267之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列1)及HGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 268及SEQ ID NO. 270 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO-269 及 SEQ ID NO. 271組成 之群的 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及HGF(序列1)之結 合蛋白包含SEQ ID NO. 268之DVD重鏈胺基酸序列及SEQ ID NO: 269之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合VEGF(序列1)及HGF(序列1)之結合蛋白具有反定向 if' 151681.doc -29- 201127956 且包含SEQ ID NO. 270之DVD重鏈胺基酸序列及SEQ ID NO: 271之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及RON(序列1)之 結合蛋白包含選自由SEQ ID NO. 272及SEQ ID NO. 274組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 273 及SEQ ID NO. 275組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合VEGF(序列1)及RON(序列1)之結合蛋 白包含SEQ ID NO. 272之DVD重鏈胺基酸序列及SEQ ID NO: 273之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合VEGF(序列1)及RON(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 274之DVD重鏈胺基酸序列及SEQ ID NO: 275之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及NRP1(序列1) 之結合蛋白包含選自由SEQ ID NO. 276及SEQ ID NO. 278 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 277及SEQ ID NO. 279組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及NRP1(序列1)之 結合蛋白包含SEQ ID NO. 276之DVD重鏈胺基酸序列及 SEQ ID NO: 277之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及NRP1(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 278之DVD重鏈胺基酸序列及 SEQ ID NO: 279之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合RON(序列2)及HGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 280及SEQ ID NO. 282組 151681.doc -30- 201127956 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 281 及SEQ ID NO. 282組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合RON(序列2)及HGF(序列1)之結合蛋 白包含SEQ ID NO. 280之DVD重鏈胺基酸序列及SEQ ID NO: 28 1之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合RON(序列2)及HGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 282之DVD重鏈胺基酸序列及SEQ ID NO: 2 83之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合RON(序列2)及EGFR(序列2)之 結合蛋白包含選自由SEQ ID NO. 2 84及SEQ ID NO. 2 86組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 285 及SEQ ID NO. 287組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合RON(序列2)及EGFR(序列2)之結合蛋 白包含SEQ ID NO. 284之DVD重鏈胺基酸序列及SEQ ID NO: 285之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合RON(序列2)及EGFR(序列2)之結合蛋白具有反定向且 包含SEQ ID NO. 286之DVD重鏈胺基酸序列及SEQ ID NO-287 之 DVD輕鏈 胺基酸序列。
在一實施例中，能夠結合RON(序列2)及VEGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 288及SEQ ID NO. 290組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 289 及SEQ ID NO. 291組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合RON(序列2)及VEGF(序列1)之結合蛋 白包含SEQ ID NO. 2 88之DVD重鏈胺基酸序列及SEQ ID 151681.doc •31 · 201127956 NO: 289之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合RON(序列2)及VEGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 290之DVD重鏈胺基酸序列及SEQ iD Ν〇: 291之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及HER-2(序列〇 之結合蛋白包含選自由SEQ ID NO. 292及SEQ ID Να 294 組成之群的DVD重鏈胺基酸序列；及選自由SEQ iD NQ 293及SEQ ID NO. 295組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及HER-2(序列丨）之 鲁 結合蛋白包含SEQ ID NO. 292之DVD重鏈胺基酸序列及 SEQ ID NO: 293之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列1)及HER-2(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 294之DVD重鏈胺基酸序列及 SEQ ID NO: 295之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及CD-3(序列1)之 結合蛋白包含選自由SEQ ID NO. 296及SEQ ID NO. 298組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 297 籲 及SEQ ID NO. 299組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列1)及CD-3(序列1)之結合蛋 白包含SEQ ID NO. 296之DVD重鏈胺基酸序列及SEQ ID NO: 297之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列1)及CD-3(序列1)之結合蛋白具有反定向且 包含SEQ ID NO· 298之DVD重鏈胺基酸序列及SEQ ID NO: 299之DVD輕鏈胺基酸序列。 151681.doc •32- 201127956 在一實施例中，能夠結合EGFR(序列1)及IGF1R之結合 蛋白包含選自由SEQ ID NO. 300及SEQ ID NO. 302組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 301及 SEQ ID NO. 303組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合EGFR(序列1)及IGF1R之結合蛋白包含 SEQ ID NO. 3 00之DVD重鏈胺基酸序列及SEQ ID NO: 301 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 EGFR(序歹U)及IGF1R之結合蛋白具有反定向且包含SEQ ID NO. 302之DVD重鏈胺基酸序列及SEQ ID NO: 303之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及RON(序列1)之 結合蛋白包含選自由SEQ ID NO. 304及SEQ ID NO. 306組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 305 及SEQ ID NO. 307組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列1)及RON(序列1)之結合蛋 白包含SEQ ID NO. 304之DVD重鏈胺基酸序列及SEQ ID NO: 3 05之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列1)及RON(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 306之DVD重鏈胺基酸序列及SEQ ID NO: 3 07之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及RON(序列2)之 結合蛋白包含選自由SEQ ID NO. 308及SEQ ID NO. 3 10組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 309 及SEQ ID NO. 3 11組成之群的DVD輕鏈胺基酸序列。在一 151681.doc -33- 201127956 實施例中，能夠結合EGFR(序列1)及RON(序列2)之結合蛋 白包含SEQ ID NO. 308之DVD重鏈胺基酸序列及SEQ ID NO: 3 09之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列1)及RON(序列2)之結合蛋白具有反定向且 包含SEQ ID NO. 3 10之DVD重鏈胺基酸序列及SEQ ID NO: 3 11之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及HGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 312及SEQ ID NO. 3 14組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 313 及SEQ ID NO. 3 15組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合EGFR(序列1)及HGF(序列1)之結合蛋 白包含SEQ ID NO· 312之DVD重鏈胺基酸序列及SEQ ID NO: 3 1 3之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合EGFR(序列1)及HGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 314之DVD重鏈胺基酸序列及SEQ ID NO: 3 15之DVD輕鏈胺基酸序列。
在一實施例中，能夠結合EGFR(序列1)及c-MET之結合 蛋白包含選自由SEQ ID NO. 316及SEQ ID NO. 3 18組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 31 7及 SEQ ID NO. 319組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合EGFR(序列1)及c-MET之結合蛋白包含 SEQ ID NO. 316之DVD重鏈胺基酸序列及SEQ ID NO: 317 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 EGFR(序列1)及c-MET之結合蛋白具有反定向且包含SEQ 151681.doc -34- 201127956 ID NO. 318之DVD重鏈胺基酸序列及SEQ ID NO: 319之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及VEGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 3 20及SEQ ID NO. 3 22 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 321及SEQ ID NO. 323組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及VEGF(序列1)之 結合蛋白包含SEQ ID NO. 320之DVD重鏈胺基酸序列及 SEQ ID NO: 321之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列1)及VEGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 3 22之DVD重鏈胺基酸序列及 SEQ ID NO: 323之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合NRP1(序列2)及VEGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 324及SEQ ID NO. 326 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 325及SEQ ID NO. 327組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合NRP1(序列2)及VEGF(序列1)之 結合蛋白包含SEQ ID NO. 324之DVD重鏈胺基酸序列及 SEQ ID NO: 3 25之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合NRP1(序列2)及VEGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 326之DVD重鏈胺基酸序列及 SEQ ID NO: 3 27之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-2(序列2)及CD-20之結合蛋 白包含選自由SEQ ID NO. 328及SEQ ]:D NO. 330組成之群 151681.doc -35- 201127956 的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 329及SEQ ID NO. 331組成之群的DVD輕鍵胺基酸序列。在一實施例 中，能夠結合CD-3(序列2)及CD-20之結合蛋白包含SEQID NO. 328之DVD重鏈胺基酸序列及SEQ ID NO: 329之DVD 輕鏈胺基酸序列。在另一實施例中，能夠結合CD-3(序列 2)及CD-20之結合蛋白具有反定向且包含SEQ ID NO. 330 之DVD重鏈胺基酸序列及SEQ ID N〇: 331之DVD輕鏈胺基 酸序列。 在一實施例中，能夠結合CD-3(序列2)及HER-2(序列1) 之結合蛋白包含選自由SEQ ID NO: 332及SEQ ID NO: 3 34 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO: 333及SEQ ID NO: 335組成之群的DVD輕鍵胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及HER-2(序列1)之 結合蛋白包含SEQ ID NO. 332之DVD重鏈胺基酸序列及 SEQ ID NO: 333之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合CD_3(序列2)及HER-2(序列1)之結合蛋白具 有反定向且包含SEQ ID NO: 334之DVD重鏈胺基酸序列及 SEQ ID NO: 335之DVD輕鏈胺基酸序列。
在一實施例中，能夠結合CD-2(序列2)及CD-19之結合蛋 白包含選自由SEQ ID NO. 336及SEQ ID NO. 338組成之群 的DVD重鍵胺基酸序列；及選自由SEQ ID NO. 337及SEQ ID NO. 339組成之群的DVD輕鏈胺基酸序列。在一實施例 中’能夠結合€〇-3(序列2)及0〇-19之結合蛋白包含8叫1〇 NO· 336之DVD重鏈胺基酸序列及SEQ ID NO: 337之DVD 151681.doc • 36- 201127956 輕鏈胺基酸序列。在另一實施例中，能夠結合CD-3(序列 2)及CD-19之結合蛋白具有反定向且包含SEQ ID NO. 338 之DVD重鏈胺基酸序列及SEQ ID NO: 339之DVD輕鏈胺基 酸序列。 在一實施例中，能夠結合CD-3(序列2)及EGFR(序列2)之 結合蛋白包含選自由SEQ ID NO. 340及SEQ ID NO. 342組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 341 及SEQ ID NO. 343組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合CD-3(序列2)及EGFR(序列2)之結合蛋 白包含SEQ ID NO. 340之DVD重鏈胺基酸序列及SEQ ID NO: 341之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合CD-3(序列2)及EGFR(序列2)之結合蛋白具有反定向且 包含SEQ ID NO· 3 42之DVD重鏈胺基酸序列及SEQ ID NO: 3 43之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3 (序列2)及EGFR(序列1)之 結合蛋白包含選自由SEQ ID NO. 344及SEQ ID NO. 346組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO· 345 及SEQ ID NO. 347組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合CD-3(序列2)及EGFR(序列1)之結合蛋 白包含SEQ ID NO. 344之DVD重鏈胺基酸序列及SEQ ID NO: 345之DVD輕鏈胺基酸序列《在另一實施例中，能夠 結合CD-3(序列2)及EGFR(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 346之DVD重鏈胺基酸序列及SEQ ID NO: 347之DVD輕鏈胺基酸序列。 151681.doc -37· 201127956 在一實施例中，能夠結合EGFR(序列1)及IGF1，2之結合 蛋白包含選自由SEQ ID NO. 348及SEQ ID NO. 3 50組成之 群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 349及 SEQ ID NO. 351組成之群的DVD輕鏈胺基酸序列。在一實 施例中，能夠結合EGFR(序列1)及IGF1，2之結合蛋白包含 SEQ ID NO. 348之DVD重鏈胺基酸序列及SEQ ID NO: 349 之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 EGFR(序列1)及IGF 1,2之結合蛋白具有反定向且包含SEQ ID NO. 350之DVD重鏈胺基酸序列及SEQ ID NO: 351之 DVD輕鏈胺基酸序列。 在一實施例中，能夠結合DLL-4(序列1)及PLGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 3 52及SEQ ID NO. 354 組成之群的DVD重鏈胺基酸序列；及選自由seQ ID NO. 353及SEQ ID NO. 355組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合DLL·4(序列1)及PLGF(序列1)之 結合蛋白包含SEQ ID NO. 352之DVD重鏈胺基酸序列及 SEQ ID NO: 353之DVD輕鍵胺基酸序列。在另一實施例 中’能夠結合DLL-4(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 354之DVD重鏈胺基酸序列及 SEQ ID NO: 355之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及PLGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 356及SEQ ID NO. 358 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 357及SEQ ID NO. 359組成之群的DVD輕鏈胺基酸序列。 151681.doc -38 - 201127956 在一實施例中，能夠結合VEGF(序列1)及PLGF(序列1)之 結合蛋白包含SEQ ID NO. 356之DVD重鏈胺基酸序列及 SEQ ID NO: 357之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 358之DVD重鏈胺基酸序列及 SEQ ID NO: 359之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 3 60及SEQ ID NO. 362組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 361及SEQ ID NO. 363組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含SEQ ID NO. 3 60之DVD重鏈胺基酸序列 及SEQ ID NO: 361之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 362之DVD重鏈胺基酸序列及 SEQ ID NO: 3 63之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 3 64及SEQ ID NO-366組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 365及SEQ ID NO. 367組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含SEQ ID NO. 3 64之DVD重鏈胺基酸序列 及SEQ ID NO: 365之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列1)之結合蛋白具 151681.doc -39- 201127956 有反定向且包含SEQ ID NO. 3 66之DVD重鏈胺基酸序列及 SEQ ID NO: 367之DVD輕鏈胺基酸序列》 在第四實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 368及SEQ ID NO. 370組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 369及SEQ ID NO. 371組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 1)之結合蛋白包含SEQ ID NO. 368之DVD重鏈胺基酸序列 及SEQ ID NO: 369之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 3 70之DVD重鏈胺基酸序列及 SEQ ID NO: 371之DVD輕鏈胺基酸序列》 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列1) 之結合蛋白包含選自由SEQ ID NO. 372及SEQ ID NO_ 374 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 373及SEQ ID NO. 375組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列1)之 結合蛋白包含SEQ ID NO. 372之DVD重鏈胺基酸序列及 SEQ ID NO: 373之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 374之DVD重鏈胺基酸序列及 SEQ ID NO: 375之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含選自由SEQ ID NO. 376及SEQ ID NO· 151681.doc -40- 201127956 3 78組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 377及SEQ ID NO. 379組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 376之DVD重鏈胺基酸序列 及SEQ ID NO: 377之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 378之DVD重鏈胺基酸序列及 SEQ ID NO: 3 79之DVD輕鏈胺基酸序歹ij。 在第三實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含選自由SEQ ID NO. 3 80及SEQ ID NO. 382組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 381及SEQ ID NO. 383組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 380之DVD重鏈胺基酸序列 及SEQ ID NO: 381之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 3 82之DVD重鏈胺基酸序列及 SEQ ID NO: 3 83之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含選自由SEQ ID NO· 3 84及SEQ ID NO. 386組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 385及SEQ ID NO. 387組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 384之DVD重鏈胺基酸序列 151681.doc -41 - 201127956 及SEQ ID NO: 3 85之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 386之DVD重鏈胺基酸序列及 SEQ ID NO: 387之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及ErbB3(序列1) 之結合蛋白包含選自由SEQ ID NO. 388及SEQ ID NO. 390 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 389及SEQ ID NO. 391組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及ErbB3(序列1)之 結合蛋白包含SEQ ID NO. 388之DVD重鏈胺基酸序列及 SEQ ID NO: 3 89之DVD輕鏈胺基酸序歹ij。在另一實施例 中，能夠結合EGFR(序列1)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 390之DVD重鏈胺基酸序列及 SEQ ID NO: 391之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及ErbB3(序列1)之 結合蛋白包含選自由SEQ ID NO. 3 92及SEQ ID NO. 3 94組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 393 及SEQ ID NO. 3 95組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列1)及ErbB3(序列1)之結合蛋 白包含SEQ ID NO. 392之DVD重鏈胺基酸序列及SEQ ID NO: 3 93之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列1)及ErbB3(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 394之DVD重鏈胺基酸序列及SEQ ID NO: 395之DVD輕鏈胺基酸序列。 151681.doc -42- 201127956 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列2) 之結合蛋白包含選自由SEQ ID NO. 3 96及SEQ ID NO. 398 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 397及SEQ ID NO. 399組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列2)之 結合蛋白包含SEQ ID NO. 396之DVD重鏈胺基酸序列及 SEQ ID NO: 397之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 398之DVD重鏈胺基酸序列及 SEQ ID NO: 399之DVD輕鏈胺基酸序歹|J。 在第二實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含選自由SEQ ID NO. 400及SEQ ID NO. 402組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 401及SEQ ID NO_ 403組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含SEQ ID NO. 400之DVD重鏈胺基酸序列 及SEQ ID NO: 401之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 402之DVD重鏈胺基酸序列及 SEQ ID NO: 403之DVD輕鏈胺基酸序歹|J。 在第三實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含選自由SEQ ID NO.. 404及SEQ ID NO. 406組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 405及SEQ ID NO. 407組成之群的DVD輕鏈胺基酸序
S 151681.doc -43- 201127956 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含SEQ ID NO. 404之DVD重鏈胺基酸序列 及SEQ ID NO: 405之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 406之DVD重鏈胺基酸序列及 SEQ ID NO: 407之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含選自由SEQ ID NO. 408及SEQ ID NO. 410組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 409及SEQ ID NO. 411組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 2)之結合蛋白包含SEQ ID NO. 408之DVD重鏈胺基酸序列 及SEQ ID NO: 409之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 410之DVD重鏈胺基酸序列及 SEQ ID NO: 411之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及ErbB3(序列2) 之結合蛋白包含選自由SEQ ID NO. 412及SEQ ID NO. 414 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 413及SEQ ID NO. 415組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列1)及ErbB3(序列2)之 結合蛋白包含SEQ ID NO. 412之DVD重鏈胺基酸序列及 SEQ ID NO: 413之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列1)及ErbB3(序列2)之結合蛋白具 15168l.doc -44 - 201127956 有反定向且包含SEQ ID NO. 414之DVD重鏈胺基酸序列及 SEQ ID NO·· 415之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及ErbB3(序列2)之 結合蛋白包含選自由SEQ ID NO. 416及SEQ ID NO. 4 18組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 417 及SEQ ID NO. 419組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列1)及ErbB3(序列2)之結合蛋 白包含SEQ ID NO. 416之DVD重鏈胺基酸序列及SEQ ID NO: 41 7之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列1)及ErbB3(序列2)之結合蛋白具有反定向且 包含SEQ ID NO. 418之DVD重鏈胺基酸序列及SEQ ID NO: 419之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列2) 之結合蛋白包含選自由SEQ ID NO. 420及SEQ ID NO. 422 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 421及SEQ ID NO. 423組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列2)之 結合蛋白包含SEQ ID NO. 420之DVD重鏈胺基酸序列及 SEQ ID NO: 421之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 422之DVD重鏈胺基酸序列及 SEQ ID NO: 423之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO· 424及SEQ ID NO. 151681.doc -45- 201127956 426組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 425及SEQ ID NO. 427組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 424之DVD重鏈胺基酸序列 及SEQ ID NO: 425之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 426之DVD重鏈胺基酸序列及 SEQ ID NO: 427之DVD輕鏈胺基酸序列》 在第三實施例中，能夠結合VEGF(序列1)及DLL-4(序列 鲁 2)之結合蛋白包含選自由SEQ ID NO. 428及SEQ ID NO. 430組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 429及SEQ ID NO. 431組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 428之DVD重鏈胺基酸序列 及SEQ ID NO: 429之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 43 0之DVD重鏈胺基酸序列及 ® SEQ ID NO: 431之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列1)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 432及SEQ ID NO. 433組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 434及SEQ ID NO. 435組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 432之DVD重鏈胺基酸序列 151681.doc -46- 201127956 及SEQ ID NO: 43 3之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 434之DVD重鏈胺基酸序列及 SEQ ID NO: 435之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列2) 之結合蛋白包含選自由SEQ ID NO. 43 6及SEQ ID NO. 43 8 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 437及SEQ ID NO. 439組成之群的DVD輕鏈胺基酸序列。 在一實施例十，能夠結合VEGF(序列2)及DLL-4(序列2)之 結合蛋白包含SEQ ID NO. 436之DVD重鏈胺基酸序列及 SEQ ID NO: 437之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 438之DVD重鏈胺基酸序列及 SEQ ID NO: 43 9之DVD輕鏈胺基酸序歹|J。 在第二實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 440及SEQ ID NO. 442組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 441及SEQ ID NO. 443組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 440之DVD重鏈胺基酸序列 及SEQ ID NO: 441之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 442之DVD重鏈胺基酸序列及 SEQ ID NO: 443之DVD輕鍵胺基酸序列。 151681.doc -47· 201127956 在第三實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 444及SEQ ID NO. 446組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 445及SEQ ID NO. 447組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 444之DVD重鏈胺基酸序列 及SEQ ID NO: 445之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 446之DVD重鏈胺基酸序列及 ® SEQ ID NO: 447之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 448及SEQ ID NO. 450組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 449及SEQ ID NO. 451組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 448之DVD重鏈胺基酸序列 及SEQ ID NO: 449之DVD輕鏈胺基酸序列。在另一實施例 ® 中，能夠結合VEGF(序列2)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 450之DVD重鏈胺基酸序列及 SEQ ID NO: 451之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列2) 之結合蛋白包含選自由SEQ ID NO. 452及SEQ ID NO. 454 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 453及SEQ ID NO· 455組成之群的DVD輕鏈胺基酸序列。 151681.doc -48- 201127956 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列2)之 結合蛋白包含SEQ ID NO. 452之DVD重鏈胺基酸序列及 SEQ ID NO: 453之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 454之DVD重鏈胺基酸序列及 SEQ ID NO: 45 5之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO_ 456及SEQ ID NO. 458組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 457及SEQ ID NO. 459組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO· 456之DVD重鏈胺基酸序列 及SEQ ID NO: 45 7之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL·4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 458之DVD重鏈胺基酸序列及 SEQ ID NO: 459之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 460及SEQ ID NO. 462組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 461及SEQ ID NO. 463組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO_ 460之DVD重鏈胺基酸序列 及SEQ ID NO: 461之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列2)之結合蛋白具 151681.doc • 49- 201127956 有反定向且包含SEQ ID NO. 462之DVD重鏈胺基酸序列及 SEQ ID NO: 463之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含選自由SEQ ID NO. 464及SEQ ID NO. 466組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 465及SEQ ID NO. 467組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 2)之結合蛋白包含SEQ ID NO. 464之DVD重鏈胺基酸序列 及SEQ ID NO: 465之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 466之DVD重鏈胺基酸序列及 SEQ ID NO: 467之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列1) 之結合蛋白包含選自由SEQ ID NO. 468及SEQ ID NO. 470 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 469及SEQ ID NO. 471組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列1)之 結合蛋白包含SEQ ID NO. 468之DVD重鏈胺基酸序列及 SEQ ID NO: 469之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 470之DVD重鏈胺基酸序列及 SEQ ID NO: 471之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 472及SEQ ID NO. 151681.doc -50- 201127956 474組成之群的DVD重鍵胺基酸序列；及選自由SEQ ID NO. 473及SEQ ID NO. 475組成之群的DVD輕鍵胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 472之DVD重鏈胺基酸序列 及SEQ ID NO: 473之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 474之DVD重鏈胺基酸序列及 SEQ ID NO: 475之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 476及SEQ ID NO. 478組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 477及SEQ ID NO. 479組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 476之DVD重鏈胺基酸序列 及SEQ ID NO: 477之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 478之DVD重鏈胺基酸序列及 SEQ ID NO: 479之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO_ 480及SEQ ID NO. 482組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 481及SEQ ID NO. 483組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 480之DVD重鏈胺基酸序列 151681.doc -51 - 201127956 及SEQ ID NO: 481之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 482之DVD重鏈胺基酸序列及 SEQ ID NO: 483之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列1) 之結合蛋白包含選自由SEQ ID NO. 484及SEQ ID NO. 486 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 485及SEQ ID NO. 487組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL_4(序列1)之 鲁 結合蛋白包含SEQ ID NO. 484之DVD重鏈胺基酸序列及 SEQ ID NO: 485之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 486之DVD重鏈胺基酸序列及 SEQ ID NO: 487之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 488及SEQ ID NO. 490組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID ^ NO. 489及SEQ ID NO. 491組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 488之DVD重鏈胺基酸序列 及SEQ ID NO: 489之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 490之DVD重鏈胺基酸序列及 SEQ ID NO: 491之DVD輕鏈胺基酸序列。 151681.doc •52· 201127956 在第三實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 492及SEQ ID NO. 494組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 493及SEQ ID NO. 495組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 492之DVD重鏈胺基酸序列 及SEQ ID ΝΟ·_ 493之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 494之DVD重鏈胺基酸序列及 SEQ ID NO: 495之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 496及SEQ ID NO. 498組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 497及SEQ ID NO. 499組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 496之DVD重鏈胺基酸序列 及SEQ ID NO: 497之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 498之DVD重鏈胺基酸序列及 SEQ ID NO: 499之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列1) 之結合蛋白包含選自由SEQ ID NO. 500及SEQ ID NO. 502 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 501及SEQ ID NO. 503組成之群的DVD輕鏈胺基酸序列。 151681.doc •53· 201127956 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列1)之 結合蛋白包含SEQ ID NO. 500之DVD重鏈胺基酸序列及 SEQ ID NO: 501之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 502之DVD重鏈胺基酸序列及 SEQ ID NO: 5 03之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 5 04及SEQ ID NO. 506組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 505及SEQ ID NO. 507組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 504之DVD重鏈胺基酸序列 及SEQ ID NO: 5 05之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 506之DVD重鏈胺基酸序列及 SEQ ID NO: 5 07之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及DLL-4(序列 1)之結合蛋白包含選自由SEQ ID NO. 5 08及SEQ ID NO. 5 10組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 509及SEQ ID NO. 511組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 1)之結合蛋白包含SEQ ID NO. 508之DVD重鏈胺基酸序列 及SEQ ID NO: 5 09之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列1)之結合蛋白具 151681.doc -54- 201127956 有反定向且包含SEQ ID NO. 51 0之DVD重鏈胺基酸序列及 SEQ ID NO: 5 11之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列3) 之結合蛋白包含選自由SEQ ID NO. 512及SEQ ID NO. 514 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 513及SEQ ID NO. 51 5組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列3)之 結合蛋白包含SEQ ID NO. 5 12之DVD重鏈胺基酸序列及 SEQ ID NO: 5 13之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 514之DVD重鏈胺基酸序列及 SEQ ID NO: 51 5之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 516及SEQ ID NO. 5 1 8組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 517及SEQ ID NO. 519組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 516之DVD重鏈胺基酸序列 及SEQ ID NO: 5 17之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 51 8之DVD重鏈胺基酸序列及 SEQ ID NO: 5 19之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 5 20及SEQ ID NO. 151681.doc -55- 201127956 522組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 521及SEQ ID NO· 523組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 520之DVD重鏈胺基酸序列 及SEQ ID NO: 521之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 522之DVD重鏈胺基酸序列及 SEQ ID NO: 523之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 524及SEQ ID NO. 526組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 525及SEQ ID NO. 527組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 524之DVD重鏈胺基酸序列 及SEQ ID NO: 525之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 526之DVD重鏈胺基酸序列及 SEQ ID NO: 527之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列3) 之結合蛋白包含選自由SEQ ID NO· 528及SEQ ID NO. 530 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 529及SEQ ID NO. 531組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合.VEGF(序列2)及DLL-4(序列3)之 結合蛋白包含SEQ ID NO. 528之DVD重鏈胺基酸序列及 151681.doc • 56· 201127956 SEQ ID NO: 5 29之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 53 0之DVD重鏈胺基酸序列及 SEQ ID NO: 531之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO_ 532及SEQ ID NO. 534組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 533及SEQ ID NO. 535組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 532之DVD重鏈胺基酸序列 及SEQ ID NO: 533之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 534之DVD重鏈胺基酸序列及 SEQ ID NO: 535之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 536及SEQ ID NO. 538組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 537及SEQ ID NO. 539組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 536之DVD重鏈胺基酸序列 及SEQ ID NO: 537之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 538之DVD重鏈胺基酸序列及 SEQ ID NO: 5 39之DVD輕鏈胺基酸序列。 I51681.doc -57- 201127956 在第四實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 540及SEQ ID NO-542 組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 541及SEQ ID NO. 543組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 5 40之DVD重鏈胺基酸序列 及SEQ ID NO: 541之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 542之DVD重鏈胺基酸序列及 SEQ ID NO: 543之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列3) 之結合蛋白包含選自由SEQ ID NO· 544及SEQ ID NO. 546 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 545及SEQ ID NO. 547組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列3)之 結合蛋白包含SEQ ID NO. 544之DVD重鏈胺基酸序列及 SEQ ID NO: 545之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 546之DVD重鏈胺基酸序列及 SEQ ID NO: 547之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 548及SEQ ID NO. 550組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 549及SEQ ID NO. 552組成之群的DVD輕鏈胺基酸序 151681.doc -58 · 201127956 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 548之DVD重鏈胺基酸序列 及SEQ ID NO: 549之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 5 50之DVD重鏈胺基酸序列及 SEQ ID NO: 551之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 5 52及SEQ ID NO. 5 54組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 553及SEQ ID NO. 555組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 552之DVD重鏈胺基酸序列 及SEQ ID NO: 5 53之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 5 54之DVD重鏈胺基酸序列及 SEQ ID NO: 555之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含選自由SEQ ID NO. 556及SEQ ID NO-558 組成 之群的 DVD 重鏈胺基酸序列； 及選自由 SEQ ID NO. 557及SEQ ID NO. 559組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 3)之結合蛋白包含SEQ ID NO. 5 56之DVD重鏈胺基酸序列 及SEQ ID NO: 557之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列3)之結合蛋白具 • 59· 151681.doc 3 201127956 有反定向且包含SEQ ID NO. 558之DVD重鏈胺基酸序列及 SEQ ID NO: 559之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列4) 之結合蛋白包含選自由SEQ ID NO. 560及SEQ ID NO. 562 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 561及SEQ ID NO. 563組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列4)之 結合蛋白包含SEQ ID NO. 560之DVD重鏈胺基酸序列及 SEQ ID NO: 561之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 5 62之DVD重鏈胺基酸序列及 SEQ ID NO: 5 63之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 5 64及SEQ ID NO. 566組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 565及SEQ ID NO. 567組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 564之DVD重鏈胺基酸序列 及SEQ ID NO: 5 65之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 566之DVD重鏈胺基酸序列及 SEQ ID NO: 5 67之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 568及SEQ ID NO. 151681.doc -60- 201127956 570組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 569及SEQ ID NO. 571組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 568之DVD重鏈胺基酸序列 及SEQ ID NO: 5 69之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 570之DVD重鏈胺基酸序列及 SEQ ID NO: 571之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 572及SEQ ID NO. 574組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 573及SEQ ID NO. 575組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 572之DVD重鏈胺基酸序列 及SEQ ID NO: 573之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 574之DVD重鏈胺基酸序列及 SEQ ID NO: 5 75之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列4) 之結合蛋白包含選自由SEQ ID NO. 576及SEQ ID NO. 578 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 577及SEQ ID NO. 579組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列4)之 結合蛋白包含SEQ ID NO. 576之DVD重鏈胺基酸序列及 151681.doc • 61 · 201127956 SEQ ID NO: 577之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 578之DVD重鏈胺基酸序列及 SEQ ID NO: 5 79之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列2)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 5 80及SEQ ID NO. 582組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 581及SEQ ID NO. 583組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL_4(序列 4)之結合蛋白包含SEQ ID NO. 580之DVD重鏈胺基酸序列 及SEQ ID NO: 581之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 582之DVD重鏈胺基酸序列及 SEQ ID NO: 583之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列2)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 5 84及SEQ ID NO. 586組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 585及SEQ ID NO. 587組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 584之DVD重鏈胺基酸序列 及SEQ ID NO: 5 85之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 586之DVD重鏈胺基酸序列及 SEQ ID NO: 587之DVD輕鏈胺基酸序列。 151681.doc -62- 201127956 在第四實施例中，能夠結合VEGF(序列2)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO· 5 88及SEQ ID NO· 5 90組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 589及SEQ ID NO. 591組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 588之DVD重鏈胺基酸序列 及SEQ ID NO: 589之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO· 590之DVD重鏈胺基酸序列及 SEQ ID NO: 591之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列4) 之結合蛋白包含選自由SEQ ID NO. 592及SEQ ID NO. 594 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 593及SEQ ID NO. 595組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列4)之 結合蛋白包含SEQ ID NO. 592之DVD重鏈胺基酸序列及 SEQ ID NO: 5 93之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO· 594之DVD重鏈胺基酸序列及 SEQ ID NO: 595之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列3)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 5 96及SEQ ID NO. 598組成之群的DVD.重鏈胺基酸序列；及選自由SEQ ID NO. 597及SEQ ID NO. 599組成之群的DVD輕鏈胺基酸序 151681.doc -63- 201127956 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 596之DVD重鏈胺基酸序列 及SEQ ID NO: 597之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 598之DVD重鏈胺基酸序列及 SEQ ID NO: 599之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列3)及DLL-4(序列 4)之結合蛋白包含選自由SEQ ID NO. 600及SEQ ID NO. 602組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID ® NO· 601及SEQ ID NO. 603組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO· 600之DVD重鏈胺基酸序列 及SEQ ID NO: 601之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列4)之結合蛋白具 有反定向且包含SEQ ID NO. 602之DVD重鏈胺基酸序列及 SEQ ID NO: 603之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列3)及DLL-4(序列 ® 4)之結合蛋白包含選自由SEQ ID NO· 604及SEQ ID NO. 606組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 605及SEQ ID NO. 607組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及DLL-4(序列 4)之結合蛋白包含SEQ ID NO. 604之DVD重鏈胺基酸序列 及SEQ ID NO: 605之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及DLL-4(序列4)之結合蛋白具 15I681.doc -64 - 201127956 有反定向且包含SEQ ID NO. 606之DVD重鏈胺基酸序列及 SEQ ID NO: 607之DVD輕鍵胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列1) 之結合蛋白包含選自由SEQ ID NO. 608及SEQ ID NO. 610 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 609及SEQ ID NO. 611組成之群的DVD輕鏈胺基酸序歹ij。 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列1)之 結合蛋白包含SEQ ID NO. 608之DVD重鏈胺基酸序列及 SEQ ID NO: 609之DVD輕鏈胺基酸序歹ij。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 610之DVD重鏈胺基酸序列及 SEQ ID NO: 611之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及ErbB3(序列 1)之結合蛋白包含選自由SEQ ID NO. 612及SEQ ID NO. 6 14組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 613及SEQ ID NO. 615組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 612之DVD重鏈胺基酸序列 及SEQ ID NO: 6 13之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 614之DVD重鏈胺基酸序列及 SEQ ID NO: 615之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HER-2(序列1)及ErbB3(序列 1)之結合蛋白包含選自由SEQ ID NO. 616及SEQ ID NO. 151681.doc -65- 201127956 61 8組成之群的DVD重鏈胺基酸序列；及選自由SEq id NO· 617及SEQ ID NO. 619組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 616之DVD重鏈胺基酸序列 及SEQ ID NO: 617之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 618之DVD重鏈胺基酸序列及 SEQ ID NO: 619之DVD輕鏈胺基酸序列。 在第四實施例中’能夠結合HER-2(序列1)及ErbB3(序列 籲 1)之結合蛋白包含選自由SEQ ID NO. 620及SEQ ID NO. 622組成之群的DVD重鏈胺基酸序列；及選自由SEq id NO. 621及SEQ ID NO. 623組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 1)之結合蛋白包含SEQ ID NO. 620之DVD重鏈胺基酸序列 及SEQ ID NO: 621之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列1)之結合蛋白具 鲁 有反定向且包含SEQ ID NO. 622之DVD重鏈胺基酸序列及 SEQ ID NO: 623之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列2) 之結合蛋白包含選自由SEQ ID NO. 624及SEQ ID NO. 626 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 625及SEQ ID NO· 627組成之群的DVD輕鏈胺基酸序列β 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列2)之 結合蛋白包含SEQ ID NO_ 624之DVD重鏈胺基酸序列及 151681.doc -66· 201127956 SEQ ID NO: 625之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 626之DVD重鏈胺基酸序列及 SEQ ID NO: 627之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及ErbB3(序列 2)之結合蛋白包含選自由SEQ ID NO. 628及SEQ ID NO. 630組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID ^ NO. 629及SEQ ID NO. 631組成之群的DVD輕鏈胺基酸序 列。在一實施例中’能夠結合HER-2(序列1)及ErbB3(序列 2)之結合蛋白包含SEQ ID NO. 628之DVD重鏈胺基酸序列 及SEQ ID NO: 629之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 630之DVD重鏈胺基酸序列及 SEQ ID NO: 631之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HER-2(序列1)及ErbB3(序列 φ 2)之結合蛋白包含選自由SEQ ID NO. 632及SEQ ID NO. 634組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 633及SEQ ID NO. 635組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列i)及ErbB3(序列 2)之結合蛋白包含SEQ ID NO. 632之DVD重鏈胺基酸序列 及SEQ ID NO: 63 3之DVD輕鍵胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 634之DVD重鏈胺基酸序列及 SEQ ID NO: 63 5之DVD輕鏈胺基酸序列。 151681.doc • 67·
S 201127956 在第四實施例中，能夠結合HER-2(序列1)及ErbB3(序列 2)之結合蛋白包含選自由SEQ ID NO. 636及SEQ ID NO. 638組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 637及SEQ ID NO. 639組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 2) 之結合蛋白包含SEQ ID NO. 636之DVD重鏈胺基酸序列 及SEQ ID NO: 63 7之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 638之DVD重鏈胺基酸序列及 SEQ ID NO: 639之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列3) 之結合蛋白包含選自由SEQ ID NO_ 640及SEQ ID NO. 642 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 641及SEQ ID NO. 643組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列3)之 結合蛋白包含SEQ ID NO. 640之DVD重鏈胺基酸序列及 SEQ ID NO: 641之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 642之DVD重鏈胺基酸序列及. SEQ ID NO: 643之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3) 之結合蛋白包含選自由SEQ ID NO. 644及SEQ ID NO. 646組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 645及SEQ ID NO. 647組成之群的DVD輕鏈胺基酸序 151681.doc -68 - 201127956 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 644之DVD重鏈胺基酸序列 及SEQ ID NO: 645之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 646之DVD重鏈胺基酸序列及 SEQ ID NO: 647之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3)之結合蛋白包含選自由SEQ ID NO. 648及SEQ ID NO. 650組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 649及SEQ ID NO. 651組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 648之DVD重鏈胺基酸序列 及SEQ ID NO: 649之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 650之DVD重鏈胺基酸序列及 SEQ ID NO: 651之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3)之結合蛋白包含選自由SEQ ID NO. 652及SEQ ID NO_ 654組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 653及SEQ ID NO. 655組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合EGFR(序列2)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 652之DVD重鏈胺基酸序列 及SEQ ID NO: 65 3之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合EGFR(序列2)及ErbB3(序列3)之結合蛋白具 151681.doc -69- 201127956 有反定向且包含SEQ ID NO. 654之DVD重鏈胺基酸序列及 SEQ ID NO: 655之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列3) 之結合蛋白包含選自由SEQ ID NO. 65 6及SEQ ID NO. 65 8 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 657及SEQ ID NO. 659組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列3)之 結合蛋白包含SEQ ID NO. 656之DYD重鏈胺基酸序列及 SEQ ID NO: 657之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 658之DVD重鏈胺基酸序列及 SEQ ID NO: 659之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及ErbB3(序列 3)之結合蛋白包含選自由SEQ ID NO. 660及SEQ ID NO. 662組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 661及SEQ ID NO. 663組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 660之DVD重鏈胺基酸序列 及SEQ ID NO: 661之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 662之DVD重鏈胺基酸序列及 SEQ ID NO: 663之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HER-2(序列1)及ErbB3(序列 3)之結合蛋白包含選自由SEQ ID NO. 664及SEQ ID NO. 151681.doc -70- 201127956 666組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO_ 665及SEQ ID NO. 667組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 664之DVD重鏈胺基酸序列 及SEQ ID NO: 665之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 666之DVD重鏈胺基酸序列及 SEQ ID NO: 667之DVD輕鍵胺基酸序列。 在第四實施例中，能夠結合HER-2(序列1)‘及ErbB3(序列 3)之結合蛋白包含選自由SEQ ID NO. 668及SEQ ID NO. 670組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 669及SEQ ID NO. 671組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及ErbB3(序列 3)之結合蛋白包含SEQ ID NO. 668之DVD重鏈胺基酸序列 及SEQ ID NO: 669之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及ErbB3(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 670之DVD重鏈胺基酸序列及 SEQ ID NO: 671之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及PLGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 672及SEQ ID NO. 674 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO-673 及 SEQ ID NO. 675 組成之群的 DVD 輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列1)及PLGF(序列2)之 結合蛋白包含SEQ ID NO. 672之DVD重鏈胺基酸序列及 151681.doc • 71 - 201127956 SEQ ID NO: 673之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 674之DVD重鏈胺基酸序列及 SEQ ID NO: 675之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 676及SEQ ID NO. 678組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 677及SEQ ID NO. 679組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含SEQ ID NO· 676之DVD重鏈胺基酸序列 及SEQ ID NO: 677之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 67 8之DVD重鏈胺基酸序列及 SEQ ID NO: 679之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 680及SEQ ID NO. 682組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 681及SEQ ID NO. 683組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 680之DVD重鏈胺基酸序列 及SEQ ID NO: 681之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 682之DVD重鏈胺基酸序列及 SEQ ID NO: 683之DVD輕鏈胺基酸序列。 151681.doc -72- 201127956 在第四實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 684及SEQ ID NO. 686組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 685及SEQ ID NO. 687組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列1)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 684之DVD重鏈胺基酸序列 及SEQ ID NO: 685之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 6 86之DVD重鏈胺基酸序列及 SEQ ID NO: 687之DVD輕鏈胺基酸序列。在一實施例中， 能夠結合VEGF(序列2)及PLGF(序列2)之結合蛋白包含選 自由SEQ ID NO. 688及SEQ ID NO. 690組成之群的DVD重 鏈胺基酸序列；及選自由SEQ ID NO. 689及SEQ ID NO. 691組成之群的DVD輕鏈胺基酸序列。在一實施例中，能 夠結合VEGF(序列2)及PLGF(序列2)之結合蛋白包含SEQ ID NO. 688之DVD重鏈胺基酸序列及SEQ ID NO: 689之 DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 VEGF(序列2)及PLGF(序列2)之結合蛋白具有反定向且包 含SEQ ID NO. 690之DVD重鏈胺基酸序列及SEQ ID NO: 691之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 692及SEQ ID NO. 694組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 693及SEQ ID NO. 695組成之群的DVD輕鏈胺基酸序 151681.doc -73- 201127956 列。在一實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 692之DVD重鏈胺基酸序列 及SEQ ID NO: 693之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 694之DVD重鏈胺基酸序列及 SEQ ID NO: 695之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 696及SEQ ID NO. 698組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 697及SEQ ID NO. 699組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 696之DVD重鏈胺基酸序列 及SEQ ID NO: 697之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 698之DVD重鏈胺基酸序列及 SEQ ID NO: 699之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 700及SEQ ID NO· 702組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 701及SEQ ID NO. 703組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列2)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 700之DVD重鏈胺基酸序列 及SEQ ID NO: 701之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列2)及PLGF(序列2)之結合蛋白具 151681.doc • 74· 201127956 有反定向且包含SEQ ID NO. 702之DVD重鏈胺基酸序列及 SEQ ID NO: 703之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及PLGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 704及SEQ ID NO. 706 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 705及SEQ ID NO· 707組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合VEGF(序列3)及PLGF(序列2)之 結合蛋白包含SEQ ID NO. 704之DVD重鏈胺基酸序列及 SEQ ID NO: 705之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 706之DVD重鏈胺基酸序列及 SEQ ID NO: 707之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 708及SEQ ID NO. 710組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 709及SEQ ID NO. 711組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 708之DVD重鏈胺基酸序列 及SEQ ID NO: 709之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 710之DVD重鏈胺基酸序列及 SEQ ID NO: 711之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 712及SEQ ID NO. 151681.doc -75- 201127956 714組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 713及SEQ ID NO. 715組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 712之DVD重鏈胺基酸序列 及SEQ ID NO: 713之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 714之DVD重鏈胺基酸序列及 SEQ ID NO: 715之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 716及SEQ ID NO-718組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 717及SEQ ID NO. 719組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合VEGF(序列3)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 716之DVD重鏈胺基酸序列 及SEQ ID NO: 717之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合VEGF(序列3)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 718之DVD重鏈胺基酸序列及 SEQ ID NO: 719之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及PLGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 720及SEQ ID NO. 722 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 721及SEQ ID NO. 723組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及PLGF(序列2)之 結合蛋白包含SEQ ID NO. 720之DVD重鏈胺基酸序列及 151681.doc -76· 201127956 SEQ ID NO: 721之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 722之DVD重鏈胺基酸序列及 SEQ ID NO: 723之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 724及SEQ ID NO. 726組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO_ 725及SEQ ID NO. 727組成之群的DVD輕鏈胺基酸序 列。在一實施例中’能夠結合HER-2(序列1)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 724之DVD重鏈胺基酸序列 及SEQ ID NO: 725之DVD輕鍵胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 726之DVD重鏈胺基酸序列及 SEQ ID NO: 727之DVD輕鏈胺基酸序列。 在第三實施例中’能夠結合HER-2(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 728及SEQ ID NO. 730組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 729及SEQ ID NO. 731組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列i)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 728之Dvd重鏈胺基酸序列 及SEQ ID NO: 729之DVD輕鍵胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO_ 730之DVD重鏈胺基酸序列及 SEQ ID NO: 731之DVD輕鏈胺基酸序列。 151681.doc •77- 201127956 在第四實施例中，能夠結合HER-2(序列1)及PLGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 732及SEQ ID NO-734 組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 733及SEQ ID NO. 735組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及PLGF(序列 2)之結合蛋白包含SEQ ID NO. 73 2之DVD重鏈胺基酸序列 及SEQ ID NO: 733之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 734之DVD重鏈胺基酸序列及 SEQ ID NO: 73 5之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合PLGF(序列1)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 736及SEQ ID NO. 738 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 737及SEQ ID NO. 739組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合PLGF(序列1)及VEGF(序列2)之 結合蛋白包含SEQ ID NO. 736之DVD重鏈胺基酸序列及 SEQ ID NO: 73 7之DVD輕鏈胺基酸序歹ij。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 738之DVD重鏈胺基酸序列及 SEQ ID NO: 73 9之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 740及SEQ ID NO-742 組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 741及SEQ ID NO. 743組成之群的DVD輕鏈胺基酸序 151681.doc -78- 201127956 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含SEQ ID NO. 740之DVD重鏈胺基酸序列 及SEQ ID NO: 741之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 742之DVD重鏈胺基酸序列及 SEQ ID NO: 743之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 744及SEQ ID NO. 746組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO_ 745及SEQ ID NO. 747組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含SEQ ID NO· 744之DVD重鏈胺基酸序列 及SEQ ID NO: 745之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 746之DVD重鏈胺基酸序列及 SEQ ID NO: 747之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含選自由SEQ ID NO. 748及SEQ ID NO. 750組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO_ 749及SEQ ID NO. 751組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 2)之結合蛋白包含SEQ ID NO· 748之DVD重鏈胺基酸序列 及SEQ ID NO: 7钧之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列2)之結合蛋白具 151681.doc •79· 201127956 有反定向且包含SEQ ID NO. 75 0之DVD重鏈胺基酸序列及 SEQ ID NO: 751之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合PLGF(序列1)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 752及SEQ ID NO. 754 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 753及SEQ ID NO. 755組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合PLGF(序列1)及VEGF(序列3)之 結合蛋白包含SEQ ID NO. 752之DVD重鏈胺基酸序列及 SEQ ID NO: 753之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 754之DVD重鏈胺基酸序列及 SEQ ID NO: 75 5之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含選自由SEQ ID NO. 756及SEQ ID NO. 758組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 757及SEQ ID NO. 759組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含SEQ ID NO. 75 6之DVD重鏈胺基酸序列 及SEQ ID NO: 757之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 75 8之DVD重鏈胺基酸序列及 SEQ ID NO: 759之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含選自由SEQ ID NO. 760及SEQ ID NO. 151681.doc -80 - 201127956 762組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 761及SEQ ID NO. 763組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含SEQ ID NO_ 760之DVD重鏈胺基酸序列 及SEQ ID NO: 761之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 762之DVD重鏈胺基酸序列及 SEQ ID NO: 763之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含選自由SEQ ID NO_ 764及SEQ ID NO. 766組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 765及SEQ ID NO. 767組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合PLGF(序列1)及VEGF(序列 3)之結合蛋白包含SEQ ID NO. 764之DVD重鏈胺基酸序列 及SEQ ID NO: 765之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合PLGF(序列1)及VEGF(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 766之DVD重鏈胺基酸序列及 SEQ ID NO: 767之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及PLGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 768及SEQ ID NO. 770 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 769及SEQ ID NO. 771組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HER-2(序列1)及PLGF(序列1)之 結合蛋白包含SEQ ID NO. 768之DVD重鏈胺基酸序列及 151681.doc 81- 201127956 SEQ ID NO: 769之DVD輕鏈胺基酸序歹ij。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 770之DVD重鏈胺基酸序列及 SEQ ID NO: 771之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及PLGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 772及SEQ ID NO. 774組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 773及SEQ ID NO. 775組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及PLGF(序列 籲 1)之結合蛋白包含SEQ ID NO. 772之DVD重鏈胺基酸序列 及SEQ ID NO: 773之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 774之DVD重鏈胺基酸序列及 SEQ ID NO: 775之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HER-2(序列1)及PLGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 776及SEQ ID NO. 778組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 779及SEQ ID NO. 781組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及PLGF(序列 1)之結合蛋白包含SEQ ID NO. 776之DVD重鏈胺基酸序列 及SEQ ID NO: 777之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 7678之DVD重鏈胺基酸序列 及SEQ ID NO: 779之DVD輕鏈胺基酸序列。 151681.doc • 82 - 201127956 在第四實施例中，能夠結合HER-2(序列i)及plGF(序列 1)之結合蛋白包含選自由SEQ ID NO. 780及SEQ ID NO-782組成 之群的 DVD 重鏈胺基酸序列； 及選自由 SEQ ID NO· 781及SEQ ID NO· 783組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及PLGF(序列 1)之結合蛋白包含SEQ ID NO. 780之DVD重鍵胺基酸序列 及SEQ ID NO: 78 1之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及PLGF(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 782之DVD重鏈胺基酸序列及 SEQ ID NO: 783之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列2)之 結合蛋白包含選自由SEQ ID NO· 784及SEQ ID NO. 786組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 785 及SEQ ID NO. 787組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列1)及VEGF(序列2)之結合蛋 白包含SEQ ID NO. 784之DVD重鏈胺基酸序列及SEQ ID NO: 785之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列1)及VEGF(序列2)之結合蛋白具有反定向且 包含SEQ ID NO. 786之DVD重鏈胺基酸序列及SEQ ID NO: 787之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HGF(序列1)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 788及SEQ ID NO. 790 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 789及SEQ ID NO. 791組成之群的DVD輕鏈胺基酸序列。 151681.doc -83- 201127956 在一實施例中，能夠結合HGF(序列1)及VEGF(序列2)之錄 合蛋白包含SEQ ID NO. 788之DVD重鏈胺基酸序列及SEQ ID NO: 789之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列2)之結合蛋白具有反定向 且包含SEQ ID NO. 790之DVD重鏈胺基酸序列及SEQ ID NO: 791之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HGF(序列1)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 792及SEQ ID NO. 794 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID Ν〇· 793及SEQ ID NO. 795組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列2)之結 合蛋白包含SEQ ID NO. 792之DVD重鏈胺基酸序列及SEQ ID NO: 793之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列2)之結合蛋白具有反定向 且包含SEQ ID NO. 794之DVD重鏈胺基酸序列及SEQ ID NO: 795之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合HGF(序列1)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 796及SEQ ID NO· 798 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO-797 及 SEQ ID NO. 799組成 之群的 DVD輕鏈 胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列2)之結 合蛋白包含SEQ ID NO· 796之DVD重鏈胺基酸序列及SEQ ID NO: 797之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列2)之結合蛋白具有反定向 151681.doc 84· 201127956 且包含SEQ ID NO. 798之DVD重鏈胺基酸序列及SEQ ID NO: 799之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列3)之 結合蛋白包含選自由SEQ ID NO. 800及SEQ ID NO. 802組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 801 及SEQ ID NO. 803組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列1)及VEGF(序列3)之結合蛋 白包含SEQ ID NO. 800之DVD重鏈胺基酸序列及SEQ ID NO: 801之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列1)及VEGF(序列3)之結合蛋白具有反定向且 包含SEQ ID NO. 802之DVD重鏈胺基酸序列及SEQ ID NO: 803之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HGF(序列1)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 804及SEQ ID NO· 806 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 805及SEQ ID NO. 807組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 804之DVD重鏈胺基酸序列及SEQ ID NO: 805之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 806之DVD重鏈胺基酸序列及SEQ ID NO: 807之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HGF(序列1)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO· 808及SEQ ID NO. 810 151681.doc •85- 201127956 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 809及SEQ ID NO. 811組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列1)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 808之DVD重鏈胺基酸序列及SEQ ID NO: 809之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 810之DVD重鏈胺基酸序列及SEQ ID NO: 811之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合HGF(序列1)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 812及SEQ ID NO. 814 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 813及SEQ ID NO. 815組成之群的DVD輕鏈胺基酸序列》 在一實施例中，能夠結合HGF(序列1)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 812之DVD重鏈胺基酸序列及SEQ ID NO·· 813之DVD輕鏈胺基酸序列β在另一實施例中，能 夠結合HGF(序列1)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 814之DVD重鏈胺基酸序列及SEQ ID NO: 815之DVD輕鏈胺基酸序列。
在一實施例中，能夠結合HGF(序列2)及VEGF(序列1)之 結合蛋白包含選自由SEQ ID NO. 816及SEQ ID NO. 818組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 817 及SEQ ID NO. 819組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列2)及VEGF(序列1)之結合蛋 白包含SEQ ID NO. 816之DVD重鏈胺基酸序列及SEQ ID 151681.doc -86 - 201127956 NO: 817之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列2)及VEGF(序列1)之結合蛋白具有反定向且 包含SEQ ID NO. 818之DVD重鏈胺基酸序列及SEQ ID NO: 819之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HGF(序列2)及VEGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 820及SEQ ID NO· 822 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 821及SEQ ID NO. 823組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列1)之結 合蛋白包含SEQ ID NO. 820之DVD重鏈胺基酸序列及SEQ ID NO: 821之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 822之DVD重鏈胺基酸序列及SEQ ID NO: 823之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HGF(序列2)及VEGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 824及SEQ ID NO. 826 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 825及SEQ ID NO. 827組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列1)之結 合蛋白包含SEQ ID NO. 824之DVD重鏈胺基酸序列及SEQ ID NO: 825之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 826之DVD重鏈胺基酸序列及SEQ ID NO: 827之DVD輕鏈胺基酸序列。 151681.doc -87 - 201127956 在第四實施例中，能夠結合HGF(序列2)及VEGF(序列1) 之結合蛋白包含選自由SEQ ID NO. 828及SEQ ID NO. 83 0 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 829及SEQ ID NO. 831組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列1)之結 合蛋白包含SEQ ID NO. 828之DVD重鏈胺基酸序列及SEQ ID NO: 829之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列1)之結合蛋白具有反定向 且包含SEQ ID NO. 83 0之DVD重鏈胺基酸序列及SEQ ID NO: 831之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列2)之 結合蛋白包含選自由SEQ ID NO. 832及SEQ ID NO. 834組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO· 833 及SEQ ID NO. 835組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列2)及VEGF(序列2)之結合蛋 白包含SEQ ID NO. 832之DVD重鏈胺基酸序列及SEQ ID NO: 833之DVD輕鏈胺基酸序列。在另一實施例中’能夠 結合HGF(序列2)及VEGF(序列2)之結合蛋白具有反定向且 包含SEQ ID NO. 834之DVD重鏈胺基酸序列及SEQ ID NO: 835之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HGF(序列2)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 836及SEQ ID NO· 83 8 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO· 837及SEQ ID NO. 839組成之群的DVD輕鏈胺基酸序列。 151681.doc -88 - 201127956 在一實施例中，能夠結合HGF(序列2)及VEGF(序列2)之結 合蛋白包含SEQ ID NO. 836之DVD重鏈胺基酸序列及SEQ ID NO: 83 7之DVD輕鏈胺基酸序列。在另一實施例中’能 夠結合HGF(序列2)及VEGF(序列2)之結合蛋白具有反定向 且包含SEQ ID NO. 838之DVD重鏈胺基酸序列及SEQ ID NO: 839之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HGF(序列2)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 840及SEQ ID NO. 842 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 841及SEQ ID NO. 843組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列2)之結 合蛋白包含SEQ ID NO. 840之DVD重鏈胺基酸序列及SEQ ID NO: 841之DVD輕鏈胺基酸序列。在另一實施例中’能 夠結合HGF(序列2)及VEGF(序列2)之結合蛋白具有反定向 且包含SEQ ID NO. 842之DVD重鏈胺基酸序列及SEQ ID NO: 843之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合HGF(序列2)及VEGF(序列2) 之結合蛋白包含選自由SEQ ID NO. 844及SEQ ID NO. 846 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 845及SEQ ID NO. 847組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列2)之結 合蛋白包含SEQ ID NO. 844之DVD重鏈胺基酸序列及SEQ ID NO: 845之DVD輕鏈胺基酸序列。在另一實施例中’能 夠結合HGF(序列2)及VEGF(序列2)之結合蛋白具有反定向
S 151681.doc • 89 - 201127956 且包含SEQ ID NO. 846之DVD重鏈胺基酸序列及SEQ ID NO: 847之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列3)之 結合蛋白包含選自由SEQ ID NO. 848及SEQ ID NO. 850組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 849 及SEQ ID NO. 851組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合HGF(序列2)及VEGF(序列3)之結合蛋 白包含SEQ ID NO. 848之DVD重鏈胺基酸序列及SEQ ID NO: 849之DVD輕鏈胺基酸序列。在另一實施例中，能夠 結合HGF(序列2)及VEGF(序列3)之結合蛋白具有反定向且 包含SEQ ID NO. 850之DVD重鏈胺基酸序列及SEQ ID NO: 8 5 1之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HGF(序列2)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 852及SEQ ID NO. 854 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 853及SEQ ID NO. 855組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 852之DVD重鏈胺基酸序列及SEQ ID NO: 853之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 854之DVD重鏈胺基酸序列及SEQ ID NO: 855之DVD輕鏈胺基酸序列。 在第三實施例中，能夠結合HGF(序列2)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 856及SEQ ID NO. 85 8 151681.doc -90- 201127956 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 857及SEQ ID NO. 859組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 8 5 6之DVD重鏈胺基酸序列及SEQ ID NO: 857之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 858之DVD重鏈胺基酸序列及SEQ ID NO: 859之DVD輕鏈胺基酸序列。 在第四實施例中，能夠結合HGF(序列2)及VEGF(序列3) 之結合蛋白包含選自由SEQ ID NO. 860及SEQ ID NO. 862 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 861及SEQ ID NO. 863組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合HGF(序列2)及VEGF(序列3)之結 合蛋白包含SEQ ID NO. 860之DVD重鏈胺基酸序列及SEQ ID NO: 861之DVD輕鏈胺基酸序列。在另一實施例中，能 夠結合HGF(序列2)及VEGF(序列3)之結合蛋白具有反定向 且包含SEQ ID NO. 862之DVD重鏈胺基酸序列及SEQ ID NO: 863之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含選自由SEQ ID NO. 864及SEQ ID NO-866 組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 865及SEQ ID NO. 867組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含SEQ ID NO. 864之DVD重鏈胺基酸序列 151681.doc -91 - 201127956 及SEQ ID NO: 865之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及HER-2(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 866之DVD重鏈胺基酸序列及 SEQ ID NO: 867之DVD輕鏈胺基酸序列。 在第二實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含選自由SEQ ID NO. 868及SEQ ID NO. 870組成之群的DVD重鏈胺基酸序列；及選自由SEQ id NO. 869及SEQ ID NO. 871組成之群的DVD輕鏈胺基酸序 列》在一實施例中，能夠結合HER-2(序列1)及HER-2(序列 _ 2)之結合蛋白包含SEQ ID NO. 858之DVD重鏈胺基酸序列 及SEQ ID NO: 869之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及HER-2(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 870之DVD重鏈胺基酸序列及 SEQ ID NO: 871之DVD輕鏈胺基酸序列》 在第三實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含選自由SEQ ID NO. 872及SEQ ID 874組成之群的DVD重鏈胺基酸序列；及選自由SEQ lE) % NO. 873及SEQ ID NO. 875組成之群的DVD輕鏈胺基峻序 列。在一實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含SEQ ID NO. 872之DVD重鏈胺基酸序歹,】 及SEQ ID NO: 873之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及HER-2(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 874之DVD重鏈胺基酸序歹,〗及 SEQ ID NO: 875之DVD輕鏈胺基酸序列。 151681.doc -92- 201127956 在第四實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含選自由SEQ ID NO. 876及SEQ ID NO-878 組成 之群的 DVD 重鏈 胺基酸 序列； 及 選自由 SEQ ID NO. 877及SEQ ID NO. 879組成之群的DVD輕鏈胺基酸序 列。在一實施例中，能夠結合HER-2(序列1)及HER-2(序列 2)之結合蛋白包含SEQ ID NO. 876之DVD重鏈胺基酸序列 及SEQ ID NO: 877之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合HER-2(序列1)及HER-2(序列2)之結合蛋白具 有反定向且包含SEQ ID NO· 878之DVD重鏈胺基酸序列及 SEQ ID NO: 8 79之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-19(序列2) 之結合蛋白包含選自由SEQ ID NO. 880及SEQ ID NO. 882 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 881及SEQ ID NO. 883組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-19(序列2)之 結合蛋白包含SEQ ID NO. 880之DVD重鏈胺基酸序列及 SEQ ID NO: 881之DVD輕鏈胺基酸序列。在另一實施例 中’能夠結合CD-3(序列2)及CD-19(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 8 82之DVD重鏈胺基酸序列及 SEQ ID NO: 883之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列3)及CD-19(序列2) 之結合蛋白包含選自由SEQ ID NO. 884及SEQ ID NO. 886 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 885及SEQ ID NO. 887組成之群的DVD輕鏈胺基酸序列。 151681.doc -93- 201127956 在一實施例中，能夠結合CD-3(序列3)及CD-19(序列2)之 結合蛋白包含SEQ ID NO. 884之DVD重鏈胺基酸序列及 SEQ ID NO: 885之DVD輕鏈胺基酸序列。在另—實施例 中，能夠結合CD-3(序列3)及CD-19(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 886之DVD重鏈胺基酸序列及 SEQ ID NO: 887之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-19(序列3) 之結合蛋白包含選自由SEQ ID NO. 888及SEQ ID NQ 89() 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID Να 889及SEQ ID NO. 891組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-19(序列3)之 結合蛋白包含SEQ ID NO. 888之DVD重鏈胺基酸序列及 SEQ ID NO: 889之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合CD-3(序列2)及CD-19(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 890之DVD重鏈胺基酸序列及 SEQ ID NO: 891之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列3)及CD-ls>(序列3) 之結合蛋白包含選自由SEQ ID NO· 892及SEq m Να 8料 組成之群的DVD重鏈胺基酸序列；及選自由seq 893及SEQ ID NO. 895組成之群的DVD輕鏈胺基酸序列。 在一實施例中’能夠結合CD-3(序列3)及cr)_19(序列3)之 結合蛋白包含SEQ ID NO. 892之DVd重鏈胺基酸序列及 SEQ ID NO: 893之DVD輕鏈胺基酸序列。在另—實施例 中’能夠結合CD-3(序列3)及CD-19(序列3)之結合蛋白具 151681.doc • 94· 201127956 有反定向且包含SEQ ID NO. 894之DVD重鏈胺基酸序列及 SEQ ID NO: 895之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-l9(序列^ 之結合蛋白包含選自由SEQ ID NO. 896及SEQ ID NO. 898 組成之群的DVD重鏈胺基酸序列；及選自由SEQ id 897及SEQ ID NO. 899組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列2)及CD-19(序列丨）之 結合蛋白包含SEQ ID NO. 896之DVD重鏈胺基酸序列及 ^ SEQ ID NO: 897之DVD輕鏈胺基酸序列。在另—實施例 中，能夠結合CD-3(序列2)及CD-19(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 898之DVD重鏈胺基酸序列及 SEQ ID NO: 899之DVD輕鏈胺基酸序列。 在一實施例中’能夠結合CD-3(序列3)及CD-1 9(序列1) 之結合蛋白包含選自由SEQ ID NO. 900及SEQ ID NO. 902 組成之群的DVD重鏈胺基酸序列；及選自由SEQ id NO, • 901及SEQ ID NO. 903組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列3)及CD-19(序列丨）之 結合蛋白包含SEQ ID NO. 900之DVD重鏈胺基酸序列及 SEQ ID NO: 901之DVD輕鏈胺基酸序列。在另—實施例 中，能夠結合CD-3(序列3)及CD-19(序列1)之結合蛋白具 有反定向且包含SEQ ID NO. 9032之DVD重鏈胺基酸序列 及SEQ ID NO: 903之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列2) 之結合蛋白包含選自由SEQ ID NO. 904及SEQ ID NO. 906 151681.doc •95- 201127956 組成之群的DVD重鏈胺基酸序列；及選自由SEQ iD 905及SEQ ID NO. 907組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列2)之 結合蛋白包含SEQ ID NO. 904之DVD重鏈胺基酸序歹,〗& SEQ ID NO: 9〇5之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合CD-3(序列4)及CD-19(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 906之DVD重鏈胺基酸序歹^ & SEQ ID NO: 907之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列3) 之結合蛋白包含選自由SEQ ID NO. 908及SEQ ID N〇. 9lQ 組成之群的DVD重鏈胺基酸序列；及選自由SEQ id N() 909及SEQ ID NO. 911組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列3)之 結合蛋白包含SEQ ID NO. 908之DVD重鏈胺基酸序列及 SEQ ID NO: 909之DVD輕鏈胺基酸序列。在另一實施例 中，能夠結合CD-3(序列4)及CD-19(序列3)之結合蛋白具 有反定向且包含SEQ ID NO. 910之DVD重鏈胺基酸序列及 SEQ ID NO: 911之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序歹〇 之結合蛋白包含選自由SEQ ID NO. 912及SEQ ID NO. 9l4 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID ]sr(X 913及SEQ ID NO. 915組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列1)之 結合蛋白包含SEQ ID NO. 912之DVD重鏈胺基酸序列及 151681.doc •96· 201127956 SEQ m NO: 913之DVD輕鏈胺基酸序列。在另_實施例 中，能夠結合CD-3(序列4)及CD_19(序列1}之結合蛋白具 有反定向且包含SEQ ID NO. 914<DVD重鏈胺基酸序列及 SEQ ID NO: 915之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合CD-3(序列4)及CD-19(序列1) 之結合蛋白包含SEQ ID NO_ 916之DVD重鏈胺基酸序列及 SEQ ID NO. 917之DVD輕鏈胺基酸序列。 在一實施例中’能夠結合CD-3(序列2)及CD-19(序列2) 之結合蛋白包含選自由SEQ ID NO, 918及SEQ ID NO. 920 組成之群的DVD重鏈胺基酸序列；及選自由SEq id NO. 91999及SEQ ID NO_ 921組成之群的DVD輕鏈胺基酸序 列。在一實施例中’能夠結合CD-3(序列2)及CD-19(序列 2)之結合蛋白包含SEQ ID NO. 91 8之DVD重鏈胺基酸序列 及SEQ ID NO: 919之DVD輕鏈胺基酸序列。在另一實施例 中’能夠結合CD-3(序列2)及CD-19(序列2)之結合蛋白具 有反定向且包含SEQ ID NO. 920之DVD重鏈胺基酸序列及 SEQ ID NO: 921之DVD輕鏈胺基酸序列。 在一實施例中，能夠結合小鼠mCI)-3及小鼠mCD-19之 結合蛋白包含選自由SEQ ID NO. 922及SEQ ID NO. 924組 成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO· 923 及SEQ ID NO. 925組成之群的DVD輕鏈胺基酸序列。在一 實施例中，能夠結合mCD-3及mCD-19之結合蛋白包含SEQ ID NO. 922之DVD重鏈胺基酸序列及SEQ ID NO: 923之 DVD輕鏈胺基酸序列。在另一實施例中，能夠結合mCD_3 151681.doc -97· 201127956 及mCD-19之結合蛋白具有反定向且包含SEQ ID NO· 924 之DVD重鏈胺基酸序列及SEQ ID NO: 925之DVD輕鏈胺基 酸序列。 在另一實施例中，能夠結合小鼠mCD-3及小鼠mCD-19 之結合蛋白包含選自由SEQ ID NO. 926及SEQ ID NO. 928 組成之群的DVD重鏈胺基酸序列；及選自由SEQ ID NO. 927及SEQ ID NO. 929組成之群的DVD輕鏈胺基酸序列。 在一實施例中，能夠結合mCD-3及mCD-19之結合蛋白包 含SEQ ID NO· 926之DVD重鏈胺基酸序列及SEQ ID NO: 927之DVD輕鏈胺基酸序列。在另一實施例中，能夠結合 mCD-3及mCD-19之結合蛋白具有反定向且包含SEQ ID NO. 928之DVD重鏈胺基酸序列及SEQ ID NO: 929之DVD 輕鏈胺基酸序列》 在另一實施例中，本發明提供包含多肽鏈之結合蛋白， 其中該多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中；VD1 為自第一親本抗體或其抗原結合部分獲得之第一重鏈可變 區域；VD2為自第二親本抗體或其抗原結合部分獲得之第 二重鏈可變區域；C為重鏈恆定區域；（XI)n為連接子，其 限制條件為（Xl)n不為CH1，其中該（Xl)n存在或不存在； 且（X2)n為Fc區，其中該（X2)n存在或不存在。在一實施例 中，結合蛋白中不存在Fc區。 在另一實施例中，本發明提供包含多肽鏈之結合蛋白， 其中該多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中，VD1 為自第一親本抗體或其抗原結合部分獲得之第一輕鏈可變 1516Sl.doc -98- 201127956 品域VD2為自第二親本抗體或其抗原結合部分獲得之第 輕鍵可變區域；C為輕鏈怪定區域；（χΐ)η為連接子，其 限制條件為（X丨）η不為CH丨’其中該（X丨 >存在或不存在； 且（Χ2)η不包含卜區，其中該（Χ2)η存在或不存在。在一實 施例中，結合蛋白中不存在（χ2)η。 在另一實施例中，本發明之結合蛋白包含第一多肽鏈及 第一多肽鏈，其中該第一多肽鏈包含第一 VD1_(xl)n_VD2_ φ C_(X2)n，其中VD1為自第一親本抗體或其抗原結合部分 獲得之第一重鏈可變區域；VD2為自第二親本抗體或其抗 原結合部分獲得之第二重鏈可變區域；c為重鏈恆定區 域；（Xl)n為連接子’其限制條件為（χι)η不為cm，其中 該（Xl)n存在或不存在；且（X2)n*Fc區，其中該（χ2)η存在 或不存在；且其中該第二多肽鏈包含第二VD1_(xl)n VD2_ C (X2)n其中VD1為自第一親本抗體或其抗原結合部分 獲得之第一輕鏈可變區域；VD2為自第二親本抗體或其抗 φ 原結合部分獲得之第二輕鏈可變區域；C為輕鏈恆定區 域，（X1 )n為連接子，其限制條件為（X 不為】，其中 該（Xl)n存在或不存在；且（χ2)η不包含^區，其中該（χ2)η 存在或不存在。在另一實施例中，結合蛋白包含兩個第一 夕狀鍵及兩個第·一多狀鍵。在另一實施例中，第二多狀中 不存在（Χ2)η。在另一實施例中，若第一多肽中存在以 區’則Fc區係選自由原生序列Fc區及變異序列Fc區組成之 群。在另一實施例中’ Fc區係選自由來自IgGl、Ig(}2、 IgG3、IgG4、IgA、IgM、IgE及IgD的 FC區組成之群。 15I681.doc ·99· 201127956 在另一實施例中，本發明之結合蛋白為能夠結合兩個抗 原且包含四個多肽鏈之DVD-Ig，其中第一多肽鍵及第三 多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為自第一
親本抗體或其抗原結合部分獲得之第一重鏈可變區域； VD2為自第·一親本抗體或其抗原ί吉合部分獲得之第二重鍵 可變區域；C為重鏈恆定區域；（χ1)η為連接子，其限制條 件為（Χ1)η不為CH1 ’其中該（χι)η存在或不存在；且（χ2)η 為Fc區，其中該（Χ2)η存在或不存在；且其中第二多肽鏈 及第四多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中VD1為 自第一親本抗體或其抗原結合部分獲得之第一輕鏈可變區 域，VD2為自第二親本抗體或其抗原結合部分獲得之第二 輕鏈可變區域；c為輕鏈恆定區域；（χι)η為連接子，其限 制條件為（χι)η不為cm，其中該（χι)η存在或不存在；且 (Χ2)η不包含Fc區，其中該（又2)11存在或不存在。
本發明提供一種藉由預選親本抗體製備DVD-Ig結合蛋 白之方法在貫細*例中，製備能夠結合兩個抗原之雙重 可變區域免疫球蛋白之方法包含以下步驟：a)獲得能夠結 合第-抗原之第-親本抗體或其抗原結合部分；b)獲得能 夠結合第二抗原之第二親本抗體或其抗原 結合部分；c)建 構包含VDl-(Xl)n_VD2心(χ2)η之第一多狀鍵及第三多狀 鍵’其中VD1為自該第—親本抗體或其抗原結合部分獲得 之第-重鏈可變區域；VD2為自該第二親本抗體或其抗原 結合部分獲得之第二重鏈可變區域，· C為重鏈值定區域； (X1)n為連接子，其限制條件為（Xl)n不為CH1，其中該 151681.doc •100· 201127956 (Xl)n存在或不存在；且（X2)r^Fc區，其中該（χ2)η存在或 不存在；d)建構包含vD1_(xl)n_VD2_c_(X2)n之第二多肽 鏈及第四多肽鏈，其中VD1為自該第一親本抗體或其抗原 結合部分獲得之第一輕鏈可變區域；VD2為自該第二親本 抗體或其抗原結合部分獲得之第二輕鏈可變區域；C為輕 鏈恒定區域；（xi)n為連接子，其限制條件為（χι)η不為 CH1 ’其中該（Χ1)η存在或不存在；且（Χ2)η不包含Fc區， φ 其中3亥（X2)n存在或不存在；e)表現該第一多肽鏈、該第二 多肽鏈、該第三多肽鏈及該第四多肽鏈；從而產生能夠結 合該第一抗原及該第二抗原之雙重可變區域免疫球蛋白。 在另一實施例中，本發明提供產生能夠結合兩個抗原且 具有所要特性之雙重可變區域免疫球蛋白之方法，其包含 以下步驟：a)獲得能夠結合第一抗原且具有至少一種由雙 重可變區域免疫球蛋白展現之所要特性的第一親本抗體或 其抗原結合部分；b)獲得能夠結合第二抗原且具有至少一 φ 種由雙重可變區域免疫球蛋白展現之所要特性的第二親本 抗體或其抗原結合部分；c)建構包含VD1_(xl)n_VD2_c_ (X2)n之第一多肽鏈及第三多肽鏈，其令：vm為自該第 一親本抗體或其抗原結合部分獲得之第一重鏈可變區域； VD2為自該第二親本抗體或其抗原結合部分獲得之第二重 鏈可變區域；c為重鏈恆定區域；（χι)η為連接子，其限制 條件為（Χ1)η不為CH1，其中該（χι)η存在或不存在·，且 (Χ2)η為Fc區，其中該⑽時在或不存在；幻建構包含 VDl-(Xl)n.VD2_C-(X2)n之第二多肽鏈及第四多肽鍵，其 151681.doc • 101 - 201127956 中，VD1為自該第一親本抗體或其抗原結合部分獲得之第 一輕鏈可變區域，· VD2為自該第二親本抗體或其抗原結合 部分獲得之第二輕鏈可變區域；c為輕鏈恆定區域；（χι)η 為連接子’其限制條件為（χι)η不為CH1，其中該（χι)η存 在或不存在；且（Χ2)η不包含以區，其中該（χ2)η存在或不 存在；e)表現該第一多肽鏈、該第二多肽鏈、該第三多肽 鍵及該第四多肽鏈；從而產生能夠結合該第一抗原及該第 二抗原且具有所要特性之雙重可變區域免疫球蛋白。 在-實施例中’本文所揭示之第—多肽鏈及第二多狀鍵 的VDI係自相同親本抗體或其抗原結合部分獲得。在另一 實施例中’本文所揭示之第一及第二多肽鏈的彻係自不 同親本抗體或其抗原結合部分獲得。在另一實施例中，本 文所揭示之第-多肽鏈及第二多狀鍵的彻係自相同親本 抗體或其抗原結合部分獲得。在另一實施例中，本文所揭 π之第夕狀鏈及第二多肽鍵的VD2係自不同親本抗體或 其抗原結合部分獲得。 在貫知例中，第一親本抗體或其抗原結合部分與第二 親本抗體或其抗原結合部分為相同抗體。在另—實施例 中第i本抗ϋ或其抗原結合部分與第二親本抗體或其 抗原結合部分為不同抗體。 貫&例中，第一親本抗體或其抗原結合部分結合第 -抗原’且第二親本抗體或其抗原結合部分結合第二抗 原。在-特定實施例中’第一抗原與第二抗原為相同抗 原在另實施例中，親本抗體結合同一抗原上之不同抗 151681.doc 201127956 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp He Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro 195 200 205
Leu Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 316 <211〉 246 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 401 - 151681·序列表.doc 201127956 <400〉 316
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Pro Glu Leu Val Arg Pro Gly Ala Ser Val Lys 130 135 140
Trp Ser Cys Pro Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Leu His 145 150 155 160
Trp Val Lys Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Met 165 170 175 -402-
151681·序列表.doc 201127956 lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Pro Asn Phe Lys 180 185 190
Asp Lys Ala Thr Leu Asn Val Asp Arg Ser Ser Asn Thr Ala Tyr Asn 195 200 205
Leu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Thr Tyr Gly Ser Tyr Val Ser Pro Leu Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Ser Val Tyr Val Ser Ser 245 <210〉 317 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 317
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 151681-序列表.doc -403 - 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Met Met Ser Gin Ser Pro Ser Ser Leu Thr Val Ser Val 115 120 125
Gly Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gin Ser Leu Leu Val 130 135 140
Thr Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gin 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Thr Ser Val Lys Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Asp Gly Thr Lys Leu Glu 210 215 220 lie Lys Arg 225 <210〉 318 404-
151681-序列表.doc 201127956 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 318
Gin Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Arg Pro Gly Ala 15 10 15
Ser Val Lys Trp Ser Cys Pro Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Lys Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp 35 40 45
He Gly Met lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Pro 50 55 60
Asn Phe Lys Asp Lys Ala Thr Leu Asn Val Asp Arg Ser Ser Asn Thr 65 70 75 80
Ala Tyr Asn Leu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr 85 90 95
Tyr Cys Ala Thr Tyr Gly Ser Tyr Val Ser Pro Leu Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Tyr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr 130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp •405- 151681·序列表.doc 201127956 145 150 155 160
Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp 165 170 175
He Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu 180 185 190
Lys Ser Arg Leu Thr lie Ser He Asp Thr Ser Lys Thr Gin Phe Ser 195 200 205
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys 210 215 220
Val Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly Thr 225 230 235 240
Met Val Thr Val Ser Ser 245 <210〉 319 <211〉 227 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 319
Asp He Met Met Ser Gin Ser Pro Ser Ser Leu Thr Val Ser Val Gly 1 δ 10 15
Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gin Ser Leu Leu Val Thr 20 25 30
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gin Gin •406- 151681·序列表.doc 201127956 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Thr Ser Val Lys Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Asp Gly Thr Lys Leu Glu He 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin Ala 130 135 140
Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Glu Thr Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe 180 185 190
Thr He Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Phe Cys Gin 195 200 205
His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu 210 215 220 151681·序列表.doc -407- 201127956 lie Lys Arg 225 <210〉 320 〈211〉 248 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 320
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 φ
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125 •408· 151681·序列表.doc 201127956
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie 165 170 175
Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg 180 185 190
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr 210 215 220
Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser
<210〉 321 <211> 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 321
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 •409 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp He Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro -410-
151681·序列表.doc 201127956 原決定基。在另—實施例中，第一抗原與第二抗原為不同 抗原。在另一實施例中，第一親本抗體或其抗原結合部分 結合第一抗原之效能不同於第二親本抗體或其抗原結合部 分結合第二抗原之效能。在另一實施例中，第一親本抗體 或其抗原結合部分結合第一抗原之親和力不同於第二親本 抗體或其抗原結合部分結合第二抗原之親和力。
在另一實施例_，第一親本抗體或其抗原結合部分及第 二親本抗體或其抗原結合部分係選自由人類抗體、cdr移 植抗體及人類化抗體組成之群。在—實施財，抗原結合 部分係選自由以下組成之群：Fab片段；F(ab，)2片段即 包含兩個在鉸鏈區由二硫橋鍵連接的Fab片段之二價片 段，由VH及CH1區域組成之Fd片段；由抗體單臂之乂[及 VH區域組成之Fv片段；㈣片段；分離互補決定區 (CDR)，單鏈抗體；及微型雙功能抗體。 在另一實施例中，本發明之結合蛋白具有至少一種由第 -親本抗體或其抗原結合部分或第二親本抗體或其抗原結 合部分展現之所要特性。或者，第—親本抗體或其抗原結 合部分及第二親本抗體或其抗原結合部分具有至少一種由 雙重可變區域免疫球蛋白展現之所要特性。在一實施例 中’所要特性係選自-或多種抗體參數。在另—實施例 卜抗體參數係選自由以下組成之群：抗原特異性、對抗 原之親和力、效能、生物功能、抗原決定基識別性、穩定 性、溶解度、生產效率、免疫原性、藥物動力學、生物可 用性、組織交叉反應性及直系同源抗原結合性。在一實施 I516Sl.doc • 103 · 201127956 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 322 〈211〉 248 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 322
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly -411 - 151681-序列表.doc 201127956 115 120 125
Pro Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser 130 135 140
Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser 145 150 155 160
Gly Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu 165 170 175
Glu Trp He Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro 180 185 190
Ser Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin 195 200 205
Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr 210 215 220
Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin 225 230 235 240
Gly Thr Met Val Thr Val Ser Ser 245 <210> 323 〈211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 323
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -412-
151681·序列表.doc 201127956 5 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Tlir Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gl)r Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190 •413· 151681·序列表.doc 201127956
Pro Glu Asp He Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro 195 200 205
Leu Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 324 <211〉 251 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 324
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Gin lie Ser Pro Ala Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Glu Leu Pro Tyr Tyr Arg Met Ser Lys Val Met Asp Val Gin 100 105 110 •414·
15168〗-序列表doc 201127956
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 145 150 155 160
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 180 185 190
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 325 <211〉 221 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 415- 151681·序列表 201127956 <400〉 325
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Tyr Phe Ser Ser Tyr 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Leu Gly Ser Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin •416- 151681-序列表doc 201127956 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 326 <211> 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 326
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val -417- 151681.序列表.doc 201127956 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser 145 150 155 160
Tyr Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ser Gin He Ser Pro Ala Gly Gly Tyr Thr Asn Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Glu Leu Pro Tyr Tyr Arg Met Ser Lys Val Met Asp Val 225 230 235 240
Gin Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 327 <211> 221 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 418- 151681-序列表.doc 201127956 <400> 327
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Tyr Phe Ser Ser 130 135 140
Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175 -419 151681-序列表.doc 201127956
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Leu Gly Ser Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 2l〇 215 220 <210> 328 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 328
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 •420 151681-序列表.doc 201127956 例中’結合蛋白為多價結合蛋白。在另一實施例中，結合 蛋白為多特異性結合蛋白。本文所述之多價及或多特異性 結合蛋白具有所要（尤其由治療觀點來看）特性。舉例而 言’多價及或多特異性結合蛋白可（1)相較於二價抗體由表 現抗體所結合之抗原的細胞較快内化（及/或分解代謝）； (2)為促效劑抗體；及/或誘導表現多價抗體能夠結合之 抗原之細胞的細胞死亡及/或細胞凋亡。提供多價及或多
特異性結合蛋白之至少一種抗原結合特異性的「親本抗 體」可為由表現抗體所結合之抗原的細胞内化（及/或分解 代謝）之抗體；及/或可為促效劑、誘導細胞死亡及/或誘導 細胞凋亡之抗體，且如本文所述之多價及或多特異性結合 蛋白可展現一或多種此等特性之改良。此外，親本抗體可 能缺乏任何一或多種此等特性，但在建構為如本文所述之 多價結合蛋白時可具有此等特性。 在另實施例中，如表面電漿子共振所量測，本發明
。。蛋白對—或多個目標之締合速率常數（Kon)選自由 4’，成1之群·至少約1〇2 Μ·1^ ;至少約1〇3 Μ_、·ι ;至少 10 M S，至少約1〇5 Μ·、·丨；及至少約1〇6 Μ、1。在一 _中如表面電漿子共振所量測，本發明之結合蛋白 J目標之缔合速率常數(Κ〇η)為：1〇2 M'V1至1〇3 Μ·ν 1〇3 M^s-U ]04 A/f., ., 4 Μ 8 -〇4^-〇5M-V；^〇5m-, 在另—實施例中，如表 對一或多個目標具有選自 面電漿子共振所量測，結合蛋白 由以下組成之群的解離速率常數 151681.doc •104- 201127956
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His 145 150 155 160
Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie Gly Ala lie 165 170 175
Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe Lys Gly Lys 180 185 190
Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser 210 215 220
Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr 225 230 235 240
Thr Val Thr Val Ser Ala 245 <210〉 329 <211〉 219 <212〉 PRT <213〉人造序列 421 · 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400> 329
Gin He Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Gin lie Val Leu Ser Gin Ser Pro Ala He Leu Ser Pro Ser Pro Gly 115 120 125
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 130 135 140
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 145 150 155 160
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser -422- 151681-序列表.doc 201127956 165 170 175
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Arg Val Glu Ala Glu 180 185 190
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 195 200 205
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215
<210> 330 <211〉 246 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 330
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys -423 - 151681-序列表.d〇c 201127956 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser 130 135 140
Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 145 150 155 160
Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly 165 170 175
Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245
<210〉 331 <211〉 219 <212〉 PRT 151681-序列表.doc -424- 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 331
Gin lie Val Leu Ser Gin Ser Pro Ala He Leu Ser Pro Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 115 120 125
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 130 135 140
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 145 150 155 160 151681-序列表.doc 201127956
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 165 170 175
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 180 185 190
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 195 200 205
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 <210〉 332 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 332
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 426-
151681-序列表.doc 201127956
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg He 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 333 151681·序列表.doc . 427 - 201127956 <211〉 220 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 333
Gin He Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 130 135 140
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -428-
151681-序列表.doc 201127956 160 145 150 155
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 180 185 190
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 195 200 205
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 334 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400 334
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr -429- 151681-序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val 130 135 140
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met 145 150 155 160
His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr 165 170 175 lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp 180 185 190
Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr 225 230 235 240
Leu Thr Val Ser Ser 245 -430- 151681·序列表.doc 201127956 (Koff):至多約 ΙΟ,3 s-i · 5 客的 1Λ.4 , , ，至夕約10 S·丨；至多約1〇·5 ! · 及至多約10·6 S·1。在—杳谂仓丨Λ ， ’ 也實施例t，如纟面電襞子共振 測，本發明之結合蛋白斜一七夕如 丨里 贪白對或多個目標之解離速率常數 (Koff)為.10 S 至 1〇 4 s'l ; 1〇-4 s-l 至 1〇.5 q > 5 S 至 10 S ;或1〇-53.1 至 1〇·6〆。 在另一實施例中’妹人恭占科 Α °D蛋白對一或多個目標之解離常數
(KD)選自由以下組成之群：至多約1〇-7 至多約1〇8 M. 至多約WM;至多約至多約Η)、；至多約1〇·12μ; 及至多約10 13 Μ。在—實施例中’本發明之結合蛋白對其 ： 10-7 Μ5.ι〇·«Μ; 10.8 Μ^ι〇-^Μ · l〇-y 河至 10_1U Μ ; 1〇.1〇至 1〇-1 ΙΟ·12 Μ至 ΙΟ·13 Μ。 Μ ; 10·11 Μ至 ΙΟ·12 Μ ;或 在另-實施例中，本文所述之結合蛋白為另外包含選自 由乂下，且成之群之試劑的結合物：免疫黏附分子、顯影 劑、治療劑及細胞毒性劑。在一實施例中，顯影劑係選自 由以下組成之群：放射性標記物、酶、螢光標記物、發光 標記物、生物發光標記物、磁性標記物及生物素。在另— 實施例中，顯影劑為選自由以下組成之群的放射性標記 物：3H、14C、35S、9〇Y、99Tc、",Ιη、125ι、⑴工、177Lu、 166 τ τ -p, 1 5 3 ci # ° m。在又一實施例中，治療劑或細胞毒性劑係 選自由以下組成之群：抗代謝物、院基化劑、抗生素、生 長因子、細胞激素、抗血管生成劑、抗有絲分裂劑、蒽環 Μ素（anthracycline)、毒素及細胞凋亡劑。 在另一實施例中，本文所述之結合蛋白為結晶結合蛋白 且以晶體形式存在。在一實施例中，晶體為無載劑醫藥控 151681.doc -105· 201127956 <210> 335 <211〉 220 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 335
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr 130 135 140 431 · 151681 -序列表.doc 201127956
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie 145 150 155 160
Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe 195 200 205
Thr Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg 210 215 220 <210〉 336 <211> 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 336
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60 432-
151681-序列表.doc 201127956
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser TFir Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser Val Lys 130 135 140 lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr Trp Met Asn 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Gin lie 165 170 175
Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys 180 185 190
Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg 210 215 220
Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Thr Val Ser Ser - 433 - 151681-序列表.doc 245 201127956 <210〉 337 <211〉 224 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 337
Gin He Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 115 120 125
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp •434-
151681·序列表.doc 201127956 130 135 140
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin He Pro Gly Gin Pro Pro 145 150 155 160
Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn He His 180 185 190
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 195 200 205
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 338 <211〉 249 <212〉 PRT <213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 338
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe -435- 151681·序列表.doc 201127956 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro 130 135 140
Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 145 150 155 160
Arg Tyr Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu 165 170 175
Trp lie Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin 180 185 190
Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr 195 200 205
Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 210 215 220
Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly 225 230 235 240 436-
151681·序列表.doc 201127956
Gin Gly Thr Thr Leu Thr Val Ser Ser 245 <210> 339 <211〉 224 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 339
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 100 105 110
Thr Val Ala Ala Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met 115 120 125 151681·序列表.doc -437 - 201127956
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser 130 135 140
Ser Val Ser Tyr Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro 145 150 155 160
Lys Arg Trp He Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala 165 170 175
His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser 180 185 190
Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser 195 200 205
Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 220 <210> 340 <211〉 244 〈212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述··合成多肽 <400〉 340
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45 151681·序列表.doc -438- 201127956
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140 lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn 195 200 205
Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu 210 215 220
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val -439- 151681·序列表.doc 201127956 225 230 235 240
Thr Val Ser Ala <210〉 341 <211〉 220 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 341
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly •440·
151681-序列表.doc 201127956 制釋放晶體。在另一實施例中，結晶結合蛋白具有比該結 合蛋白之可溶對應物長的活體内半衰期。在另一實施例 中’結晶結合蛋白保留生物活性。 在另一實施例中，本文所述之結合蛋白經糖基化。舉例 而言’糖基化為人類糖基化模式。 本發明之一態樣係關於編碼任一種本文所揭示之結合蛋 白的經分離核酸。另一實施例提供包含本文所揭示之經分 離核酸的載體，其中該載體係選自由以下組成之群： pcDNA ; pTT(Durocher等人，7/wc/ek dczA 2002, 第30卷，第2號）；pTT3(具有額外多個選殖位點之ρΤΤ);
pEFBOS(Mizushima，S.及Nagata，S·，（1990) izcW 第 18 卷，第 17 號）；pBV ; pJV ; pcDNA3.1 TOPO ; pEF6 TOPO及pB J。在一實施例中，載體為美國專 利申請案第61/021，282號中揭示之載體。 在另一態樣中，宿主細胞經本文所揭示之載體轉型。在 一實施例中，宿主細胞為原核細胞。在另一實施例中，宿 主細胞為大腸桿菌。在相關實施例中，宿主細胞為真核細 胞。在另一實施例中，真核細胞係選自由原生生物細胞、 動物細胞、植物細胞及真菌細胞組成之群。在另一實施例 中，宿主細胞為哺乳動物細胞，包括（但不限於）CHO、 COS ; NS0、SP2、PER.C6 ;或真菌細胞，諸如釀酒酵母 (Saccharomycescerevisiae);或昆蟲細胞，諸如 Sf9。 在一實施例中，例如具有不同特異性之兩個或兩個以上 DVD-Ig係在單個重組宿主細胞中產生。舉例而言，抗體 151681.doc -106- 201127956 115 120 12δ
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 130 135 140 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 145 150 155 160
Lys Tyr Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 180 185 190
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 195 200 205
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210〉 342 <211〉 244 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 342
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu •441 - 151681-序列表.doc 201127956 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Tyr lie 165 170 175
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp Lys 180 185 190
Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 210 215 220 442-
151681-序列表.doc 201127956
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr Leu 225 230 235 240
Thr Val Ser Ser <210〉 343 <211〉 220 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 343
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 •443· 151681-序列表.doc 201127956
Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie 145 150 155 160
Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe 195 200 205
Thr Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg 210 215 220 <210> 344 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 344
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 -444 -
151681-序列表 _doc 201127956
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asti Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser 130 135 140
Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr Tyr 145 150 155 160
Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp lie Gly 165 170 175
His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser 180 185 190
Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe Ser Leu Lys 195 200 205
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val Arg -445- 151681-序列表.doc 201127956 210 215 220
Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser <210〉 345 <211〉 220 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 345
Gin He Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro -446 - 151681·序列表,doc 201127956 100 105 110
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 130 135 140
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 145 150 155 160
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 180 185 190
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 195 200 205
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg 210 215 220
<210〉 346 〈211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 346
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 l〇
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly -447- 151681-序列表.doc 201127956 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala He Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr lie 165 170 175
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp Lys 180 185 190
Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205 -448-
151681-序列表.doc 201127956
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 210 215 220
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr Leu 225 230 235 240
Thr Val Ser Ser <210> 347 <211> 220
〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 347
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95 -449 151681-序列表.doc 201127956
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie 145 150 155 160
Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Gly Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe 195 200 205
Thr Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg 210 215 220 <210〉 348 <211〉 245 <212> PRT <213〉人造序列 <220〉 〈223〉人造序列之描述：合成多肽 <400> 348
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 •450·
151681-序列表.doc 201127956 混合物之表現已稱為 〇lig〇cl〇nicsTM(Merus B.v·, The Netherlands);美國專利第 7 262 〇28號；第 7 429 486號。 本發明之另一態樣提供製造本文所揭示之結合蛋白的方 法’包含在足以產生結合蛋白的條件下在培養基中培養任 一種亦為本文所揭示之宿主細胞。在一實施例中，此方法 產生之50%至75°/。結合蛋白為雙重特異性四價結合蛋白。 在一特定實施例中’此方法產生之75%至9〇〇/。結合蛋白為 φ 雙重特異性四價結合蛋白。在一特定實施例中，所產生之 90%至95%之結合蛋白為雙重特異性四價結合蛋白。 一貫施例知:供釋放結合蛋白之組合物，其中該組合物包 含調配物’該調配物又包含本文所揭示之結晶結合蛋白， 及一種成分，及至少一種聚合載劑。舉例而言，聚合載劑 為選自由以下組成之群中之一或多者的聚合物：聚（丙烯 酸）、聚（氰基丙烯酸酯）、聚（胺基酸）、聚（酐）、聚（縮 肽）、聚（酿）、聚（乳酸）、聚（乳酸_共_乙醇酸）或pLGA、聚 φ (b_羥基丁酸酯）、聚（己内酯）、聚（二氧環己酮）、聚（乙二 醇）、聚（（羥丙基）甲基丙烯醯胺）、聚[(有機）磷氮烯]、聚 (原酸酯）、聚（乙烯醇）、聚（乙烯。比咯啶酮）、順丁烯二酸 酐-烷基乙烯基醚共聚物、氧化異丙烯多元醇類、白蛋 白、海藻酸鹽、纖維素及纖維素衍生物、膠原蛋白、血纖 維蛋白、明膠、玻尿酸、寡醣、甘胺基聚糖、硫酸多醣、 其摻合物及共聚物。舉例而言，該成分係選自由白蛋白、 蔗糖、海藻糖、乳糖醇、明膠、羥丙基環糊精、曱氧基 聚乙二醇及聚乙二醇組成之群。另一實施例提供治療哺乳 151681.doc -107· 201127956
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 130 135 140
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asp He Asn 145 150 155 160
Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met Gly Trp Met 165 170 175
Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe Gin Gly Arg 180 185 190
Val Thr Met Thr Arg Asn Thr Ser He Ser Thr Ala Tyr Met Glu Leu -451 · 151681-序列表.doc 201127956 195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr 225 230 235 240
Val Thr Val Ser Ser 245 <210> 349 <211〉 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 349
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 δ 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu •452· 151681·序列表.doc 201127956 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly 115 120 125
Gin Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn 130 135 140
Asn His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu 145 150 155 160
Leu He Tyr Asp Asn Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe 165 170 175
Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu 180 185 190
Gin Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser 195 200 205
Leu Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 210 215 220
Gly 225 <210〉 350 <211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 •453· 151681·序列表.doc 201127956 <400〉 350
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu 130 135 140
Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr 145 150 155 160
Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp lie 165 170 175 -454 151681-序列表.doc 201127956
Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 180 185 190
Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe Ser Leu 195 200 205
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val 210 215 220
Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly Thr Met 225 230 235 240
Val Thr Val Ser Ser 245 <210> 351 <211〉 226 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 351
Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly Gin 1 5 10 15
Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn Asn 20 25 30
His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 lie Tyr Asp Asn Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser 50 55 60 -455- 151681-序列表.doc 201127956
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu Gin 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu 85 90 95
Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser 130 135 140
Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Phe Cys Gin His 195 200 205
Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu He 210 215 220
Lys Arg 225 <210〉 352 •456- 151681-序列表.doc 201127956 <211> 240 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 352
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu 115 120 125
Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys lie 130 135 140
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr He Asn Trp -457· 15168卜序列表.doc 201127956 145 150 155 160 Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly Trp lie Tyr 165 170 175 Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala 180 185 190
Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser 195 200 205
Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val Arg Asp Ser 210 215 220
Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val Ser Ser 225 230 235 240 <210〉 353 <211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 353
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly -458-
151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser 115 120 125
Leu Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu 130 135 140
Asn Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser 165 170 175
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys 195 200 205
Lys Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu 210 215 220 lie Lys Arg 225 151681 -序列表.doc - 459 - 201127956 <210> 354 <211> 240 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 354
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140 • 460·
151681-序列表.doc 201127956 動物之方法’纟包含向該哺乳動物投與有效量之本文所揭 示之組合物的步驟。 本發明亦提供包含本文所揭示之結合蛋白及醫藥學上可 接受之載劑的醫藥組合物。在另一實施例中，醫藥組合物 包含至少一種用於治療病症之額外治療劑。舉例而言，額 外藥劑係選自由以下組成之群：治療劑、顯影劑、細胞毒 性劑、血管生成抑制劑（包括（但不限於）抗vegf抗體或 VEGF-trap)、激酶抑制劑（包括（但不限於）kdr及τΐΕ-2抑 制劑）、協同刺激分子阻斷劑（包括（但不限於）抗…」、抗 Β7.2、CTLA4-Ig、抗CD20)、黏附分子阻斷劑（包括（但不 限於）抗LFA」抗體、抗E/L選擇素抗體、小分子抑制劑）、 抗細胞激素抗體或其功能片段（包括（但不限於）抗比_18、 抗TNF、及抗il-6/細胞激素受體抗體）、曱胺喋呤 (methotrexate)、環孢靈（cycl〇sp〇rin)、雷帕黴 ^ (rapamycin)、FK506、可偵測標記物或報導體、tnf拮抗 劑、抗風濕藥、肌肉鬆弛劑、麻醉藥、非類固醇消炎藥： (NSAID)、止痛劑、麻醉劑、鎮靜劑、局部麻醉劑、神經 肌肉阻斷劑、抗微生物劑、抗牛皮癬藥、皮質類固醇、同 化類固醇、紅血球生成素、免疫、免疫球蛋白、免疫抑制 劑、生長激素、激素替代藥物、放射性藥物、抗抑鬱劑、 抗精神病藥、興奮劑、哮喘藥物、p促效劑、吸入類固 醇、腎上腺素或類似物、細胞激素及細胞激素拮抗劑。 在另一態樣中，本發明提供治療罹患本文所揭示之結合 蛋白能夠結合之該（等）目標為有害的病症之人類個體之方 151681.doc -108- 201127956
Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn Trp lie Ser Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Tyr He Ser Pro Asn 165 170 175
Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly 210 215 220
Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 225 230 235 240 <210> 355 〈211〉 227 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 355
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 •461 - 151681-序列表.doc 201127956
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin 195 200 205
Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg •462·
151681·序列表.doc 201127956 225 <210〉 356 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 356
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly 463 - 151681-序列表.doc 201127956 130 135 140
Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp 145 150 155 160
Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp 165 170 175
He Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys 180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala 195 200 205
Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe 210 215 220
Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Leu Thr Val Ser Ser 245 <210〉 357 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 357
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr -464-
151681-序列表-doc 201127956 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Yal Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205 •465- 151681-序列表doc 201127956
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225 <210〉 358 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 358
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110 -466-
151681-序列表.doc 201127956
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr 165 170 175 ❿
Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe 180 185 190
Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr 210 215 220
Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210> 359 〈211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 467- 151681-序列表.doc 201127956 <400> 359
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser 130 135 140
Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr -468-
15168N 序列表.doc 201127956 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225
<210> 360 <211〉 252 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 360
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
Tyr He Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys -469- 151681-序列表doc 201127956 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn 145 150 155 160
Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp 180 185 190
Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp 225 230 235 240
Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 361 <211〉 233 <212〉 PRT -470·
151681·序列表.doc 201127956 法，包含向人類個體投盥 ― 仅〇奉文所揭不之結合蛋白，從而抑 制人類個體中該（等）目桿之法,w V寸彡日知之活性，且緩解多種症狀中之一 種或實現治療。舉例而言，哕、戌、广么 ° 及病症係選自包含以下之群： 關節炎、骨關節炎、青少年愒性關γ ^ ^ 干k r生關即炎、敗血性關節炎、 萊姆關節炎（Lyme arthritis)、牛古癍Μ火c ^ 干反餺〖生關即炎、反應性關 節炎、脊椎關節病、全身性紅斑狼瘡症、i羅恩氏病
(Crohn’s disease)、潰癌性結腸炎、發炎性腸病、胰島素依 賴性糖尿病、甲狀腺炎、哮喘、過敏性疾病、牛皮癖、皮 膚炎硬皮病、移植物抗宿主疾病、器官移植排斥反應、與 器官移植有關之急性或慢性免疫疾病、肉狀瘤病、動脈粥 樣硬化、散播性血管内凝血、川崎氏病（Kawasaki，s disease)、格雷氏病（Grave，s disease)、腎病症候群、慢性 疲勞症候群、韋格納氏肉芽腫病（Wegener，s granulomatosis)、亨偌-絲奇恩賴紫癜（Hen〇ch Sch〇eniein purpurea)、腎顯微性血管炎、慢性活動型肝炎、葡萄膜 炎、敗血性休克、中毒性休克症候群、敗血症症候群、惡 病質、感染性疾病、寄生蟲病、後天免疫缺乏症候群、急 性橫貫性脊髓炎、亨廷頓氏舞蹈病（Huntingt〇n,s chorea)、 帕金森氏病（Parkinson’s disease)、阿兹海默氏病 (Alzheimer's disease)、中風、原發性膽汁性肝硬化、溶血 性貧血、惡性病、心臟衰竭、心肌梗塞、艾迪森氏病、偶 發性I型多腺體分泌不足症及II型多腺體分泌不足症、施密 特氏症候群（Schmidt’s syndrome)、成人（急性）呼吸窘迫症 候群、脫髮、斑形脫髮、血清陰性關節病、關節病、萊特 151681.doc -109- 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 361
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp He Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp 145 150 155 160 471 _ 151681·序列表.doc 201127956
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr 165 170 175
Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly 210 215 220
Val
Gin Gly Thr Lys 225
Glu lie Lys Arg 230 <210> 362 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 362
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 472- 151681-序列表.doc 201127956
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly 130 135 140
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr He Asn Trp Val Lys Leu Ala 165 170 175
Pro Gly Gin Gly Leu Glu Trp He Gly Trp He Tyr Pro Gly Ser Gly 180 185 190
Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr lie 195 200 205
Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser 210 215 220
Glu Asp Thr Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val Ser Ser •473- 151681 -序列表.doc 201127956 245 250 <210〉 363 <211〉 233 <212> PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 363
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys •474·
151681-序列表.doc 201127956 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210> 364 <211> 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 364
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie -475- 151681-序列表.doc 201127956 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn 145 150 155 160
Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp 180 185 190
Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220 151681-序列表.doc -476- 201127956
Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp 225 230 235 240
Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 365 <211〉 226 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 365
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110 -477· 151681-序列表.doc 201127956
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser 130 135 140
Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He 210 215 220
Lys Arg 225 <210> 366 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 366
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 -478
151681 -序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly 130 135 140
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr He Asn Trp Val Lys Leu Ala 165 170 175
Pro Gly Gin Gly Leu Glu Trp lie Gly Trp lie Tyr Pro Gly Ser Gly 180 185 190
Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr lie •479· 151681-序列表.doc 201127956 195 200 205
Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser 210 215 220
Glu Asp Thr Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val Ser Ser 245 250 <210> 367 <211〉 226 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 367
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp -480-
151681-序列表.doc 201127956 爾氏病（Reiter's disease)、牛皮癬性關節病、潰瘍性結腸炎 關卽病、腸病性滑膜炎、披衣菌（chlamydia)、耶氏桿菌 (yersinia)及沙門氏菌（salmonella)相關之關節病、脊椎關 節病、動脈粥樣瘤病/動脈硬化、異位性過敏、自體免疫 大皰病、尋常天疱瘡、葉狀天疱瘡、類天疱瘡、線狀IgA 病、自體免疫溶血性貧血、庫姆氏陽性溶血性貧血 (Coombs positive haemolytic anaemia)、後天惡性貧血、青 少年惡性貧血、肌痛腦炎/皇家自由病（R〇yal Free Disease)、慢性皮膚黏膜念珠菌病、巨細胞動脈炎、原發 性硬化性肝炎、原因不明性自體免疫肝炎、後天免疫缺乏 疾病症候群、後天免疫缺乏相關疾病、B型肝炎、C型肝 炎、常見變異性免疫缺乏（常見變異性低7球蛋白血症）、擴 張性心肌病、雌性不孕症、卵巢功能衰竭、卵巢早衰、纖 維變性肺病、原因不明性纖維性肺泡炎、發炎後間質性肺 病、間質性肺炎、結締組織病相關之間質性肺病、混合結 締組織病相關之肺病、全身性硬化症相關之間質性肺病、 類風濕性關節炎相關之間質性肺病、全身性紅斑狼瘡症相 關之肺病、皮肌炎/多發性肌炎相關之肺病、休格連氏病 相關之肺病（Sjogren's disease associated lung disease)、僵 直性脊椎炎相關之肺病、血管炎擴散性肺病、含鐵血黃素 沈積症（haemosiderosis)相關之肺病、藥物誘發之間質性肺 病、纖維化、放射性纖維化、閉塞性細支氣管炎、慢性嗜 伊紅血球性肺炎、淋巴球浸潤性肺病、感染後間質性肺 病、痛風性關節炎、自體免疫性肝炎、丨型自體免疫性肝 151681.doc •110- 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225 <210> 368 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •481 - 151681·序列表.doc 201127956 <400〉 368
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr 165 170 175 •482 151681-序列表.doc 201127956
Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe 180 185 i9〇
Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr 210 215 220
Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 369 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 369
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 483 - 151681-序列表.doc 201127956
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr 165 170 175
Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190 Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205 Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 370 484· 151681 ·序列表.doc 201127956 <211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 370
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly 130 135 140
Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp -485- 151681-序列表.doc 201127956 145 150 155 160
Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp 165 170 175 lie Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys 180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala 195 200 205
Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe 210 215 220
Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Leu Thr Val Ser Ser 245 <210〉 371 <211〉 233 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 371
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie •486· 151681-序列表.doc 201127956 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220 487· 151681·序列表.doc 201127956
Ser Gly Thr Lys Leu Glu He Lys Arg 225 230 <210〉 372 〈211〉 242 <212〉PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 372
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Lys 115 120 125 -488- 151681·序列表.doc 201127956
Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr 130 135 140
Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 145 150 155 160
Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser 165 170 175
Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie 180 185 190
Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu 195 200 205
Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 210 215 220
Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ala
<210〉 373 <211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 373
Asp He Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 •489 151681* 序列表.doc 201127956
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp He Leu Leu Thr Gin Ser Pro Val 115 120 125
He Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 130 135 140
Ser Gin Ser He Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn 145 150 155 160
Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser Gly 165 170 175
He Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Ser lie Asn Ser Val Glu Ser Glu Asp He Ala Asp Tyr Tyr Cys Gin •490· 151681-序列表.doc 201127956 炎（經典自體免疫或類狼瘡性肝炎）、2型自體免疫性肝炎 (抗LKM抗體肝炎）、自體免疫介導之低血糖症、b型胰島 素抗性伴發黑色棘皮病、副甲狀腺低能症、與器官移植有 關之急性免疫疾病、與器官移植有關之慢性免疫疾病、骨 性關節病、原發性硬化性膽管炎、1型牛皮癬、2型牛皮 癬、特發性白血球減少病、自體免疫性嗜中性球減少症、 NOS型腎病、血管球性腎炎、腎顯微性血管炎、萊姆病 φ (lyme disease)、盤狀紅斑狼瘡、特發性或NOS型雄性不育 症、精子自體免疫、多發性硬化症（所有次型）、交感性眼 炎、結締組織病繼發之肺循環血壓過高、古巴士德氏症候 群（Goodpasture’s syndrome) '結節性多動脈炎之肺表現形 式、急性風濕熱、類風濕性脊椎炎、史提爾氏病（suufs disease)、全身性硬化症、休格連氏症候群、高安氏病 (Takayasu’s disease)/動脈炎、自體免疫性血小板減少症、 特發性血小板減少症、自體免疫性甲狀腺病、甲狀腺機能 • 亢進症 '甲狀腺腫性自體免疫性甲狀腺低能症（橋本氏病 (Hashimoto’s disease))、萎縮性自體免疫性甲狀腺低能 症、原發性黏液水腫、晶狀體源性葡萄膜炎、原發性血管 炎、白斑病急性肝病、慢性肝病、酒精性肝硬化、酒精誘 發之肝損傷、膽汁鬱滯、特質性肝病、藥物誘發之肝炎、 非酒精性脂肪變性肝炎、過敏症及哮喘、；6群鏈球菌（gbs) 感染、精神障礙（例如抑鬱症及精神分裂症）、Th2型及τΜ 型介導之疾病、急性及慢性疼痛（不同形式之疼痛）、及諸 如肺癌、乳癌、胃癌、膀胱癌、結腸癌、胰腺癌、卵巢 151681.doc 201127956 195 200 205
Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 2i〇 215 220
Leu Lys Arg 225 <210> 374 <211〉 242 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多狀 <400〉 374
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 9Ϊ5
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly •491 · 151681-序列表.doc 201127956 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu Ser 130 135 140
Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr Tyr Trp Ser 145 150 155 160
Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He Gly Glu He 165 170 175
Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val 180 185 190
Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu Lys Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Lys 210 215 220
Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210> 375 <211> 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -492- 151681-序列表.doc 201127956 <400> 375
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly 145 150 155 160
Gin Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175 -493 151681-序列表.doc 201127956
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225
<210〉 376 <211〉 249 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 376
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80 494-
151681·序列表.doc 201127956
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125
Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro 130 135 140
Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 145 150 155 160
Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu 165 170 175
Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro 180 185 190
Phe Thr Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val 195 200 205
Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr 210 215 220
Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ala 245 <210〉 377 495 · 151681 -序列表.doc 201127956 <211〉 234 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 377
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie 115 120 125
Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg 130 135 140
Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn lie His -496· 151681-序列表.doc 201127956 145 150 155 160
Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr 165 170 175
Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp 195 200 205
lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe 210 215 220
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 <210> 378 <211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 378
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gl}r Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr -497. 151681-序列表doc 201127956 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu 130 135 140
Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser 145 150 155 160
Phe Ser Gly Tyr Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly 165 170 175
Leu Glu Trp He Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn 180 185 190
Pro Ser Leu Lys Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn 195 2⑻ 205
Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly 225 230 235 240 498-
151681·序列表.doc 201127956
Arg Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 379 <211〉 234 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 379
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Glu Met Thr Gin Ser Pro 115 120 125 -499- 151681-序列表.doc 201127956
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Asn Cys Arg 130 135 140
Ser Ser Gin Ser Val Leu Tyr Ser Ser Ser Asn Arg Asn Tyr Leu Ala 145 150 155 160
Trp Tyr Gin Gin Asn Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Gin Gin Tyr Tyr Ser Thr Pro Arg Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 380 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 380
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30 -500-
151681·序列表.doc 201127956 癌、則列腺癌及直腸癌之癌症及造血性惡性病（白血病及 淋巴瘤）、無β脂蛋白血症、手足發紺、急性及慢性寄生或 感染過程、急性白血病、急性淋巴母細胞白▲病（all)、 急性骨髓白血病（AML)、急性或慢性細菌感染、急性膜腺 炎、急性腎衰竭、腺癌、心房異位搏動、Ams癡呆複合 症、酒精誘發之肝炎' 過敏性結膜炎、過敏性接觸性皮膚 炎、過敏性鼻炎、同種異體移植排斥反應、心卜抗胰蛋白 酶缺乏、肌肉萎縮性側索硬化、貧血、心絞痛、前角細胞 退化、抗cd3療法、抗磷脂症候群、抗受體過敏反應、主 動脈及周邊動脈瘤、主動脈剝離、動脈性高血壓、動脈硬 化、動靜脈瘺、共濟失調、心房纖維性顫動（持續性或陣 發性）、心房撲動、房室傳導阻滞、B細胞淋巴瘤、骨移植 物排斥反應、骨髓移植（BMT)排斥反應、束枝傳導阻滯、 伯基特淋巴瘤（Burkitt’s lymphoma)、燒傷、心律不整、心 臟頓抑症候群、心臟腫瘤、心肌病、心肺繞道發炎反應、 軟骨移植排斥反應、小腦皮質退化、小腦病症、奮亂性或 多灶性房性心動過速、與化學療法有關之病症、慢性髓細 胞白血病（CML)、慢性酒精中毒、慢性發炎性病變、慢性 淋巴細胞性白血病（CLL)、慢性阻塞性肺病（c〇PD)、慢性 水揚酸中毒、結腸直腸癌、充企性心臟衰竭、結膜炎、接 觸性皮膚炎、肺原性心臟病、冠狀動脈疾病、庫賈氏病 (Creutzfeldt-Jakob disease)、培養物陰性敗血症、囊腫性 纖維化、細胞激素療法相關之病症、拳擊員癡呆、脫趙勒 疾病、出血性登革熱（dengue hemorrhagic fever)、皮膚 151681.doc •112- 201127956
Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr He Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125
Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro 130 135 140
Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 145 150 155 160
Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu 165 170 175
Trp Leu Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro 180 185 190
Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val 195 200 205
Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr -501 · 151681-序列表.doc 201127956 210 215 220
Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ala 245 <210〉 381 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 381
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie -502- 151681·序列表.doc 201127956 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val 115 120 125 lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 130 135 140
Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn 145 150 155 160
Gly Ser Pro Arg Leu Leu He Lys Tyr Ala Ser Glu Ser He Ser Gly 165 170 175 lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Ser lie Asn Ser Val Glu Ser Glu Asp He Ala Asp Tyr Tyr Cys Gin 195 200 205
Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 210 215 220
Leu Lys Arg 225 <210> 382 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 382
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin - 503 - 151681-序列表.doc 15 201127956
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu 130 135 140
Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser 145 150 155 160
Phe Ser Gly Tyr Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly 165 170 175
Leu Glu Trp lie Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn 180 185 190 -504- 151681-序列表doc 201127956
Pro Ser Leu Lys Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn 195 200 205
Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly 225 230 235 240
Arg Gly Thr Leu Val Thr Val Ser Ser 245
〈210〉 383 <211〉 227 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 383
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80 505 - 151681-序列表.doc 201127956
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly 145 150 155 160
Gin Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225 <210〉 384 <211〉 242 <212> PRT <213〉人造序列 •506-
151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 384
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr He Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Lys 115 120 125
Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr 130 135 140
Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val 145 150 155 160
Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser •507_ 151681-序列表.doc 201127956 165 170 175
Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie 180 185 190
Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu 195 200 205
Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr 210 215 220
Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ala <210> 385 <211> 234 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 385
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val -508
151681·序列表.doc 201127956 50 55 * 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie 115 120 125
Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly Glu Arg 130 135 140
Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn lie His 145 150 155 160
Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr 165 170 175
Ala Ser Glu Ser He Ser Gly He Pro Ser Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp 195 200 205 lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe 210 215 220
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 509- 151681·序列表d〇c 201127956 <210> 386 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 386
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu Ser 130 135 140 -510- 151681-序列表.doc 201127956 k、皮膚病病狀、糖尿病（diabete、diabetes mellitus)、糖 尿病性動脈硬化病、泛發性路易體疾病（Diffuse body disease)、擴張型充血性心肌病、基底神經節病症、 中年唐氏症候群（Down's Syndrome in middle age) '由阻斷 CNS多巴胺受體之藥物誘發的藥物誘發之運動障礙、藥物 敏感、濕疹、腦脊髓炎、心内膜炎、内分泌病 '會厭炎、 EB病毒感染（epstein-barr virus infection)、肢端紅痛症、 參錐體外及小腦病症、家族性噬血性淋巴組織細胞瘤病、胚 胎胸腺移植排斥反應、弗里德賴希氏共濟失調 (Friedreich's ataxia)、功能性周圍動脈病症、真菌性敗血 症、氣性壞疽、月潰瘍、腎小球腎炎 '任何器官或組織的 移植物排斥反應 '革蘭氏陰性敗血症（gram negative sepsis)、革蘭氏陽性敗血症、胞内生物體引起之肉芽腫、 毛細胞白血病、哈洛弗登-史巴茲氏蒼白球色素退化症 (Hallerrorden-Spatz disease)、橋本氏甲狀腺炎（hashim〇t〇，s φ thyroiditis)、枯草熱、心臟移植排斥反應、血色素沈著 症、血液透析、溶血性尿毒癥候群/溶栓性血小板減少性 紫癜、出血、A型肝炎、希氏束心律不整（His bundle arrythmias)、HIV 感染 /HIV 神經病、霍奇金病（H〇dgkin，s disease)、過動性運動病症、過敏反應、過敏性肺炎、高 血壓、運動不足運動病症、下丘腦-垂體-腎上腺轴評估、 特發性艾迪森氏病、特發性肺纖維化、抗體介導之細胞毒 性、衰弱、嬰兒脊髓性肌萎縮症、主動脈發炎、a塑流 感、電離輻射曝露、虹膜睫狀體炎/葡萄膜炎/視神經炎、 151681.doc -113- 201127956
Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr Tyr Trp Ser 145 150 155 160
Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Glu lie 165 170 175
Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val 180 185 190
Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu Lys Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Lys 210 215 220
Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser
<210〉 387 <211> 234 <212> PRT 〈213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 387
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30 •511 · 151681-序列表.doc 201127956
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Glu Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr He Asn Cys Arg 130 135 140
Ser Ser Gin Ser Val Leu Tyr Ser Ser Ser Asn Arg Asn Tyr Leu Ala 145 150 155 160
Trp Tyr Gin Gin Asn Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Gin Gin Tyr Tyr Ser Thr Pro Arg Thr Phe -512- 151681-序列表.doc 201127956 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 388 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 388
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
Ser Arg Val Thr He Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Gin -513- 151681-序列表,doc 201127956 115 120 125
Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr 130 135 140
Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr Tyr Trp Thr 145 150 155 160
Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp lie Gly His lie 165 170 175
Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Leu 180 185 190
Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe Ser Leu Lys Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val Arg Asp Arg 210 215 220
Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly Thr Met Val Thr Val 225 230 235 240
Ser Ser <210> 389 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 389
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly • 514- 151681·序列表-doc 201127956 5 10 15
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin Ala 130 135 140
Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe 180 185 190 •515· 151681·序列表.doc 201127956
Thr lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Phe Cys Gin 195 200 205
His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225 <210〉 390 <211〉 242 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 390
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp He Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser He Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95 •516 151681·序列表.doc 201127956
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 Π0
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu Ser 130 135 140
Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr Tyr Trp Ser 145 150 155 160
Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Glu lie 165 170 175
Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val 180 185 190
Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu Lys Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Lys 210 215 220
Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210〉 391 <211〉 227 <212〉 PRT <213〉人造序列 517· 151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 391
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly 145 150 155 160
Gin Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly •518· 151681-序列表.doc 201127956 165 170 175
Va.1 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220
lie Lys Arg 225 <210> 392 <211> 245 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 392
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu -519· 151681·序列表.doc 201127956 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Val 115 120 125
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser 130 135 140
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser Trp lie 145 150 155 160
Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr He Ser Ser 165 170 175
Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser 195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr 210 215 220
Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 • 520· 151681·序列表.doc 201127956 缺血再灌注損傷、缺血性中風、青少年類風濕性關節炎、 青少年脊髓性肌萎縮症、卡波西氏肉瘤（Kap〇si,s sarcoma)、腎臟移植排斥反應、退伍軍人病（iegi〇neiia)、 利什曼體病（leishmaniasis)、麻風病、皮質脊髓系統病 變、脂性水腫、肝移植排斥反應、淋巴水腫、癔疾、惡性 淋巴瘤、惡性組織細胞增多病、惡性黑素瘤、腦膜炎、腦 膜炎球菌血症、代謝性/特發性疾病、偏頭痛、粒線體多 系統病症、混合結締組織病、單株球蛋白症、多發性骨趨 瘤、多系統退化（曼切、代哲因-托馬斯、史德爾格及馬查 多-約瑟夫（Mencel Dejerine-Thomas Shi_Drager and Machado-Joseph))、重症肌無力、禽細胞内分枝桿菌 (mycobacterium avium intracellulare)、結核分枝桿菌 ⑶/〇—)、骨髓發育不良症候群、心 肌梗塞、心肌缺血病症、鼻咽癌、新生兒慢性肺病、腎 炎、腎病、神經退化性疾病、I型神經原性肌肉萎縮、嗜 中性球減少性發熱、非霍奇金淋巴瘤（n〇n_H〇dgkins lymphoma)、腹主動脈及其分支閉塞、閉塞性動脈病症、 okt3療法、睪丸炎/副睪丸炎、睪丸炎/輸精管復通術 (vasectomy reversal procedure)、器官腫大、骨質疏鬆症、 騰腺移植排斥反應、騰腺癌、副腫瘤症候群/惡性高血飼 症、副甲狀腺移植排斥反應、骨盆腔炎疾病、常年性鼻 炎、心包疾病、周邊動脈粥樣硬化疾病、周邊血管疾病、 腹膜炎、惡性貧金、卡氏肺囊蟲肺炎（pneumocystis carinii pneumonia)、肺炎、POEMS症候群（多發性神經病、器官 151681.doc .114* 201127956 <210> 393 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 393
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu He 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala 130 135 140 151681-序列表.doc -521 - 201127956
Ser Gin Gly lie Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly 165 170 175
Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin 195 200 205
Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225 〈210〉 394 <211〉 245 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 394
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 151681-序列表.doc •522- 201127956
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glri Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 130 135 140
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 145 150 155 160
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 165 170 175
Gl)r Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 180 185 190
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 195 200 205
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 523 - 151681-序列表」〇c 201127956 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 395 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 395
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu - 524-
151681-序列表doc 201127956 115 120 125
Gly Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly 145 150 155 160
Gin Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225
<210〉 396 <211> 244 <212> PRT 〈213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 396
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser He Tyr •525· 151681-序列表.doc 201127956 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140
He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val He 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn 195 200 205 • 526- 151681·序列表.doc 201127956
Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu 210 215 220
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ala
<210〉 397 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 397
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95 -527 151681-序列表.doc 201127956
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160
lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 2i〇 215 220 <210〉 398 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 398
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin i 5 10 15 •528
151681·序列表.doc 201127956
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr Ser Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr He 165 170 175
Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met • 529· 151681-序列表.doc 201127956 195 200 205
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser <210> 399 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 399
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr • 530- 151681-序列表.doc 201127956 腫大、内分泌病、單株球蛋白症及皮膚變化症候群）、灌 注後症候群、泵後症候群、MI心切開術後症候群、子癎前 症、進行性核上性麻痹、原發性肺高血壓、放射性療法、 雷諾現象（Raynaud’s phenomenon)及疾病、雷諾病 (Raynoud’s disease)、雷弗素姆氏病（Refsum，s disease)、規 則性QRS波狹窄型心動過速、腎血管性高血壓、再灌注損 傷、限制型心肌病、肉瘤、硬皮病、老年性舞蹈病、路易 體型老年癡呆（Senile dementia of Lewy body type)、血清 陰性關節病、休克、鐮形細胞性貧血、皮膚同種異體移植 排斥反應、皮膚變化症候群、小腸移植排斥反應、實體腫 瘤、特異性心律不整、脊椎共濟失調、脊髓小腦退化、鏈 球菌肌炎、小腦結構病變、亞急性硬化性全腦炎、昏厥、 心血管系統梅毒、全身性過敏、全身性發炎反應症候群、 全身發作型青少年類風濕性關節炎、τ細胞或FAB ΑΙχ、 毛細管擴張、血栓閉塞性血管炎、血小板減少症、中毒、 移植、外傷/出血、III型過敏反應、IV型過敏、不穩定型 心絞痛、尿毒癥、尿膿毒病、蓴麻疹、心臟瓣膜病、靜脈 曲張血g炎、靜脈疾病、靜脈血栓形成、心室纖維性顫 動、病毋及真菌感染、病毒性腦炎/無菌性腦膜炎、病毒 相關之嗜血細胞症候群、韋尼克-科爾薩科夫症候群 (Wefnieke-Korsakoff syndr〇me)、威爾遜氏病（Wils〇n’s disease)、任何器官或組織的異種移植物排斥反應、急性 冠狀動脈症候群、急性特發性多發性神經炎、急性發炎性 脫髓勒性多發性神經根神經病、急性局部缺血、成人史提 151681.doc -115- 201127956 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp He Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205
lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg 210 215 220 <210> 400 <211〉 251 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述·•合成多狀 <400> 400
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -531 - 151681·序列表.doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser He Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val 130 135 140
Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser 145 150 155 160
Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly 165 170 175
Leu Glu Trp Leu Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn 180 185 190 -532- 151681·序列表.doc 201127956
Thr Pro Phe Thr Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser 195 200 205
Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie 210 215 220
Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250
<210〉 401 〈211〉 228 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 401
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80 •533 · 151681-序列表.doc 201127956
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Leu Leu Thr Gin Ser Pro 115 120 125
Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser.Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Ser He Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210〉 402 〈211〉 251 <212> PRT <213〉人造序列 534-
151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 402
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser He Tyr Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly •535- 151681-序列表.doc 201127956 165 170 175
Leu Glu Trp Val Ser Tyr He Ser Ser Ser Ser Ser Thr He Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys 195 200 205
Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp He 225 230 235 240
Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210〉 403 <211〉 228 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 403
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly .536· 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin 130 135 140
Ala Ser Glrv Asp He Thr Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Phe Thr lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Asn Cys 195 200 205
Gin Gin Cys Glu Asn Phe Pro lie Thr Phe Gly Gin Gly Thr Arg Leu 210 215 220
Glu He Lys Arg 225 •537 - 151681-序列表.doc 201127956 <210> 404 <211〉 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 404
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val 130 135 140 151681-序列表.doc -538- 201127956
Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser 145 150 155 160
Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly 165 170 175
Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn 180 185 190
Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser 195 200 205
Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie 210 215 220
Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250
〈210〉 405 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 405
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30 • 539- 151681·序列表.doc 201127956
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg -540-
151681-序列表.doc 201127956 爾氏病（adult Still’s disease)、斑形脫髮、全身性過敏反 應、抗磷脂抗體症候群、再生不全性貧血、動脈硬化、異 位性濕疹、異位性皮膚炎、自體免疫性皮膚炎、與鏈球菌 感染有關之自體免疫病症、自體免疫性腸病、自體免疫性 聽力損失、自身免疫淋巴組織增生症候群（ALps)、自體免 疫性心肌炎、自體免疫性印巢早衰、瞼炎、支氣管擴張、 大皰性類天疱瘡、心血管疾病、災難性抗磷脂症候群、乳 糜瀉、頸椎關節強硬、慢性局部缺血、瘢痕性類天疱瘡、 具有夕發性硬化症風險之臨床單一症候群（cis)、結膜 炎、兒童期初發型精神病症、慢性阻塞性肺病（COPD)、 淚囊炎、皮肌炎、糖尿病性視網臈病變、糖尿病、椎間盤 突出症、椎間盤脫垂、藥物誘發之免疫性溶血性貧血、心 内膜炎、子宮内膜異位、眼内炎、上鞏膜炎、多形性紅 斑、重症多形性紅斑、妊娠期類天疱瘡、格-巴二氏症候 群（Guillain-BarrS syndrome)(GBS)、枯草熱、休斯症候群 (Hughes syndrome)、特發性帕金森氏病、特發性間質性肺 炎、IgE介導之過敏症、免疫性溶血性貧企、包涵體肌 炎、感染性眼部發炎疾病、發炎性脫髓鞘疾病、發炎性心 臟病、發炎性腎病、IPF/UIP、虹膜炎、角膜炎、乾燥性 角膜結膜炎、庫斯毛爾氏病（Kussmaul disease)或庫斯毛 爾-米爾氏病（Kussmaul-Meier disease)、蘭德里麻療 (Landry's paralysis)、朗格罕氏細胞組織細胞增多病 (Langerhan’s cell histiocytosis)、網狀青斑、黃斑變性、顯 微性多血管炎、白赫鐵列夫症（morbus bechterev)、運動神 151681.doc • 116- 201127956 210 215 220 <210〉 406 <211〉 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 406
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr tys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val F^e Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val -541 · 151681·序列表.doc 201127956 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser lie Tyr Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ser Tyr He Ser Ser Ser Ser Ser Thr lie Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys 195 200 205
Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie 225 230 235 240
Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210> 407 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 407
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn -542- 151681·序列表.doc 201127956 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205 - 543 - 151681·序列表.doc 201127956 lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg 210 215 220 <210〉 408 〈211〉 244 〈212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 408
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125 151681·序列表 doc -544- 201127956
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140 lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser lie Asn Lys Asp Asn Ser Lys Ser .Gin Val Phe Phe Lys Met Asn 195 200 205
Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu 210 215 220
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ala
<210〉 409 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400〉 409
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 • 545 151681-序列表,doc 201127956
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp He Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp He Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Leu Leu Thr Gin Ser Pro 115 120 125
Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Aig Leu Leu He Lys Tyr Ala Ser Glu Ser lie Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys •546- 151681·序列表.doc 201127956 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225
<210> 410 <211> 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 410
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro F)he Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly • 547- 151681-序列表.doc 201127956 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr Ser Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie 165 170 175
Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser <210〉 411 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -548 - 151681·序列表.doc 201127956 <400〉 411
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin 130 135 140
Ala Ser Gin Asp lie Thr Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Glu Thr 165 170 175 -549 151681-序列表.doc 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Phe Thr He Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Asn Cys 195 200 205
Gin Gin Cys Glu Asn Phe Pro He Thr Phe Gly Gin Gly Thr Arg Leu 210 215 220
Glu lie Lys Arg 225 <210> 412 <211> 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 412
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 550- 151681·序列表.doc 201127956 經元病症、黏膜類天疱瘡、多器官衰竭、重症肌無力、骨 髓發育不良症候群、心肌炎、神經根病症、神經病、非A 非B型肝炎、視神經炎、骨質溶解、卵巢癌、少關節型 JRA(pauciarticular JRA)、周邊動脈閉塞性疾病（pA〇D)、 周邊血管疾病（PVD)、周邊動脈疾病（PAD)、靜脈炎、結節 性多動脈炎（或結節性動脈周圍炎）、多軟骨炎、風濕性多 肌痛、白髮症、多關節型JRA、多發性内分泌缺乏症候 群、多發性肌炎、風濕性多肌痛（PMR)、泵後症候群、原 發性帕金森氏症、刖列腺癌及直腸癌及造血性惡性病（白 血病及淋巴瘤）、前列腺炎、純紅血球發育不全、原發性 腎上腺機能不全、復發性視神經脊趙炎、再狹窄、風濕性 心臟病、sapho(滑膜炎、痤瘡、腺皰病、骨肥厚及骨炎）、 硬皮病、繼發性澱粉樣變性病、休克肺、鞏膜炎、坐骨神 經痛、繼發性腎上腺機能不全、聚矽氧相關之結締組織疾 病、史奈登-威爾金森皮膚病（sneddon-wilkinson dermatosis)、強直性脊椎炎、史蒂芬-瓊森症候群（Steveils_ Johnson syndrome，SJS)、全身性發炎反應症候群、顳動 脈炎、弓形蟲性視網膜炎、中毒性表皮壞死溶解、橫貫性 脊髓炎、TRAPS(腫瘤壞死因子受體）、1型過敏反應、π 型糖尿病、蓴麻疹、尋常性間質性肺炎（UIP)、血管炎、 春季結膜炎、病毒性視網膜炎、沃格特-小柳-原田症候 群（Vogt-Koyanagi-Harada syndrome)( VKH症候群）、濕式 黃斑變性、傷口癒合、耶氏桿菌及沙門氏菌相關之關節 病。 151681.doc 117 201127956
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser 130 135 140
Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr Tyr 145 150 155 160
Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp He Gly 165 170 175
His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser 180 185 190
Arg Leu Thr He Ser He Asp Thr Ser Lys Thr Gin Phe Ser Leu Lys 195 200 205
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val Arg 210 215 220
Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser <210> 413 551 · 151681-序列表.doc 201127956 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 413
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu •552-
151681-序列表.doc 201127956 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro 195 200 205
Leu Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 414 <211〉 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 414
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr He Ser He Asp Thr Ser Lys Thr Gin Phe • 553 · 151681-序列表.doc 201127956 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr Ser Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie 165 170 175
Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Arg Gly Asp Phe Asp Ala Phe Asp He Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser 151681·序列表.doc -554- 201127956 <210〉 415 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 415
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp He Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn 130 135 140 - 555 · 151681-序列表.doc 201127956
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205 lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg 210 215 220 <210〉 416 <211> 247 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 416
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60 •556· 151681·序列表.doc 201127956
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser 145 150 155 160
Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie 165 170 175
Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser • 557 - 151681·序列表.doc 245 201127956 <210〉 417 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 417
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp He Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser -558-
151681·序列表doc 201127956 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asri Leu Leu 145 150 155 160
He Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 418 〈211〉 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 418
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val - 559- 151681-序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asa Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 145 150 155 160
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Ser Tyr He Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr lie Ser Arg Asp 'Asn Ala Lys Asn Ser Leu Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 225 230 235 240 560-
151681-序列表 _doc 201127956 在一實施例中，可以本發明之組合物及方法治療或診斷 之疾病包括（但不限於）原發性及轉移性癌症，包括乳癌、 結腸癌、直腸癌、肺癌、口咽癌、下嚥癌、食道癌、胃 癌、胰腺癌、肝癌、膽囊癌及膽管癌、小腸癌、尿道癌 (包括腎癌、膀胱癌及尿道上皮癌）、雌性生殖道癌（包括子 宮頸癌、子宮癌及卵巢癌、以及絨膜癌及妊娠滋養細胞疾 病）、雄性生殖道癌（包括前列腺癌、精囊癌、睪丸癌及生 殖細胞腫瘤）、内分泌腺癌（包括曱狀腺癌、腎上腺癌及垂 體腺癌）及皮膚癌，以及金管瘤、黑素瘤、肉瘤（包括骨路 及軟組織產生之肉瘤以及卡波西氏肉瘤）、腦腫瘤、神經 腫瘤、眼腫瘤及腦膜腫瘤（包括星形細胞瘤、神經膠質 瘤、膠質母細胞瘤、視網膜胚細胞瘤、神經瘤、神經母細 胞瘤、神經鞘瘤及腦膜瘤）、由諸如白血病及淋巴瘤（霍奇 金淋巴瘤及非霍奇金淋巴瘤）之造血性惡性病引起的實體 腫瘤。 在一實施例中，本發明之抗體或其抗原結合部分在單獨 使用或與放射療法及/或其他化學治療劑組合使用時可用 於治療癌症或用於預防自本文所述之腫瘤轉移。 在另一態樣中，本發明提供治療罹患病症之患者的方 法’其包含在投與如上文所述之第二藥劑之前、同時或之 後投與本文所揭示之任一結合蛋白的步驟。在一特定實施 例中，第二藥劑係選自由以下組成之群：布地奈押 (b-n〇side)、表皮生長因子、皮質類固醇、環抱靈：： 氮確胺吡咬㈣fasalazine)、胺基水揚酸鹽、6疏基嗓吟、 151681.doc -118· 201127956
Thr Met Val Thr Val Ser Ser 245 <210〉 419 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 419
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe. Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125 -561 · 151681-序列表.doc 201127956
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Thr Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205 lie Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Arg 210 215 220 <210〉 420 <211> 248 <212〉 PRT 〈213>人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 420
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45 151681·序列表.doc -562- 201127956
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie 165 170 175
Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg 180 185 190
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr 210 215 220
Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin -563- 151681·序列表doc 201127956 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 421 <211〉 225 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 421
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu •564- 151681-序列表.doc 201127956 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin 130 135 140
Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr 195 200 205
Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys 210 215 220
Arg 225
<210> 422 <211〉 248 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 422
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr • 565 - 151681-序列表.doc 201127956 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 130 135 140
Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala 145 150 155 160
Tyr Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp 165 170 175 lie Gly T3fr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys 180 185 190
Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala 195 200 205 151681·序列表 d〇c -566- 201127956
Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245
<210〉 423 <211〉 225 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 423
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95 -567 151681-序列表.doc 201127956
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225 <210> 424 <211〉 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 568-
151681-序列表.d〇c 201127956 <400〉 424
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr 145 150 155 160
Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr • 569 · 151681-序列表.doc 201127956 180 185 190
Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys 195 200 205
Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp 225 230 235 240
Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 425 <211〉 232 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 425
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly He Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser •570· 151681-序列表-doc 201127956 硫唑嘌呤（azathioprine)、甲硝噠唑（metronidazole)、脂質 加氧酶抑制劑、美沙拉嗓（mesalamine)、奥沙拉嗪 (olsalazine)、巴柳氮（balsalazide)、抗氧化劑、凝血脂素 抑制劑、IL-1受體结抗劑、抗IL-1 β mAb、抗IL-6或IL-6受 體mAb、生長因子、彈性蛋白酶抑制劑、。比σ定基_ σ米嗤化 合物、TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL- 12、IL-13、IL-15、IL-16、IL-18、IL-23、ΕΜΑΡ-ΙΙ、GM-籲 CSF、FGF及PDGF之抗體或促效劑、CD2、CD3、CD4、 CD8、CD-19、CD25、CD28、CD30、CD40、CD45、 CD69、CD90或其配位體之抗體、甲胺喋呤、環孢靈、 FK506、雷帕徽素、撤紛酸嗎琳乙酿（myC〇phen〇iate mofetil)、來氟米特（leflunomide)、NSAID、布洛芬 (ibUprofen)、皮質類固醇、潑尼龍（prednis〇1〇ne)、磷酸二 醋酶抑制劑、腺苷促效劑、抗血栓劑、補體抑制劑、腎上 腺素激導劑、IRAK、NIK、IKK、P38、MAP激酶抑制 • 劑、IL·1!3轉化酶抑制劑、TNFa轉化酶抑制劑、T細胞信 號傳導抑制劑、金屬蛋白酶抑制劑、柳氮磺胺吼啶、硫唑 嘌呤、6-酼基嘌呤、血管收縮素轉化酶抑制劑、可溶性細 胞激素受體、可溶性P55 TNF受體、可溶性p75 TNF受體、 sIL-IRI、SIL-1RII、sIL_6R '消炎性細胞激素比“几· 、IL-11、IL-13及 TGFp。 在一特定實施例中，本文所揭示之醫藥組合物係藉由至 少一種選自以下之模式投與患者：非經腸、皮下、肌肉 内、靜脈内、關節内、支氣管内、腹内、囊内、軟骨内、 151681.doc •119· 201127956 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser 165 170 175
Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230
<210〉 426 <211〉 255 〈212〉 PRT 571 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 426
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly 130 135 140
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala 145 150 155 160 572·
151681-序列表.doc 201127956
Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr lie His Trp Val Lys Gin Ala 165 170 175
Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr lie Ser Ser Tyr Asn Gly 180 185 190
Ala Thr Asn Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr 195 200 205
Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser 210 215 220
Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val 225 230 235 240
Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 427 <211〉 232 <212〉 PRT <213〉人造序列
<220> 〈223>人造序列之描述：合成多肽 <400〉 427
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45 151681·序列表.doc -573- 201127956
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Val Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly He Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Val Pro Trp Thr Phe Gly Gly 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 151681-序列表.doc -574- 201127956 225 230 <210> 428 <211> 255 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 428
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val -575- 15168丨-序列表.doc 201127956 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr 145 150 155 160
Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr 180 185 190
Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys 195 200 205
Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp 225 230 235 240
Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 429 <211〉 225 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 429
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr •576·
151681·序列表.doc 201127956 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin 130 135 140
Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr 195 200 205 151681-序列表.doc • 577- 201127956
Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys 210 215 220
Arg 225 <210> 430 <211> 255 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 430
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 -578-
151681·序列表.doc 201127956
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly 130 135 140
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr lie His Trp Val Lys Gin Ala 165 170 175
Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr lie Ser Ser Tyr Asn Gly 180 185 190
Ala Thr Asn Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr 195 200 205
Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser 210 215 220
Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val 225 230 235 240
Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 431 <211〉 225 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 579· 151681-序列表.doc 201127956 <400> 431
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie -580-
151681-序列表.doc 201127956 腔内、體腔内、小腦内、腦室内、結腸内、子宮頸内、胃 内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸 膜内、前列腺内、肺内、直腸内、腎内、視網膜内、脊椎 内、滑膜内、胸内、子宮内、膀胱内、快速注射、經陰 道、經直腸、經頰、舌下、鼻内及經皮。 w 本發明之一態樣提供至少一種針對至少一種本發明之結 合蛋白的抗個體基因型抗體。抗個體基因型抗體包括含= 以下分子之任何蛋白質或肽，該分子包含免疫球蛋白I子 之至少一部分，諸如（但不限於）重鏈或輕鏈之至少—個互 補決定區（CDR)或其配位體結合部分、重鏈或輕鏈可變 區、重鏈或輕鏈恆定區、構架區或其可併入本發明之結合 蛋白中的任何部分。 本發明提供改良結合蛋白之特徵的方法，該方法包含以 下步驟.（a)在改變之前測定結合蛋白之特徵；（勾改變重 鏈及/或輕鏈之（X1)1的長度及/或序列，藉此提供經改變之 重鏈及/或輕鏈；及（b)測定包含經改變之重鏈及輕鏈的經 改變之結合蛋白之經改良特徵。本發明亦提供改良結合蛋 白之特徵的方法’該方法包含以下步驟：（a)在改變之前測 定結合蛋白之特徵；（b)改變第—多肽鏈及第二多肽鍵使得 VDl-(Xi)n.VD2-C.(X2)n ^ % VD2-(X1 )n.VD1 .c.(X2)n , 藉此提供經改變之重鏈及輕鏈；及⑷測定包含經改變之重 鏈及輕鏈的經改變結合蛋白之經改良特徵。 在另一態樣中，本發明提供改良結合蛋白之特徵的方 法’該方法包含以下步驟··⑷在改變之前測定結合蛋白之 151681.doc 201127956 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225
<210> 432 <211〉 248 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 432
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys •581 · 151681-序列表.doc 201127956 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie 165 170 175
Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg 180 185 190
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr 210 215 220
Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245
<210> 433 <211〉 232 <212〉 PRT 582- 151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 433
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie G-ln Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr 145 150 155 160 583 · 151681-序列表-doc 201127956
Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser 165 170 175
Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu He Lys Arg 225 230 <210> 434 <211> 248 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 434
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 -584· 151681·序列表 doc 201127956
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 130 135 140
Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala 145 150 155 160
Tyr Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp 165 170 175 lie Gly Ίγτ lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys 180 185 190
Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala 195 200 205
Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser -585- 151681-序列表.doc 245 201127956 <210〉 435 <211> 232 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 435
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr He Ser Cys Arg -586· 15168卜序列表.doc 201127956 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly lie Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Va.l Pro Trp Thr Phe Gly Gly 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 436 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 436
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr He His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie - 587 - 151681-序列表.doc 201127956 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly He 165 170 175
Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe 210 215 220 588- 151681-序列表.doc 201127956
Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 437 <211〉 225 <212> PRT <213〉人造序列 <220〉
〈223>人造序列之描述：合成多肽 <400〉 437
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 -589- 151681-序列表.doc 201127956
Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin 130 135 140
Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser 195 200 205
Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225 〈210〉 438 〈211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 438
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 •590
151681-序列表.doc 201127956 特徵；（b)改變第一多肽鏈及/或第二多肽鏈使得重鏈及/或 輕鏈之VD1或VD2中僅一者之序列得以改變；及（c)測定包 含經改變重鏈及輕鍵的經改變結合蛋白之特徵。在一實施 例中，特徵係選自由以下組成之群：與目標蛋白之結合、 自宿主細胞之表現產量、活體外半衰期、活體内半衰期、 穩疋性、溶解度、及改良之效應功能。在另一實施例中， 經改變之重鏈的（XI)!之長度增加。在另一實施例中，經 改變之重鏈的（XI)丨之長度減少。在另一實施例中，經改 變之輕鏈的（X1) 1之長度增加。在另一實施例中，經改變 之輕鍵的（X1) 1之長度減少。在另一實施例中，經改變重 鏈之（XI),包含選自由SEQ ID NO:21或22組成之群的胺基 酸。在另一實施例中，經改變輕鏈之（XI),包含選自由SEq ID N 0:13或14組成之群的胺基酸。在另一實施例中，經改 變重鏈之（Χ1)ι為SEQ ID NO:22且經改變輕鏈之（χι)ι為 SEQ ID NO: 14。在另一實施例中，經改變重鏈之（X J) 1為 SEQ ID NO:21且經改變輕鏈之（ΧΙ)ι為SEQ ID NO:14。在 另一實施例中，經改變重鏈之（Xl)^ SEQ ID NO:22且經 改變輕鏈之（XI) 1為SEQ ID NO: 13。在另一實施例中，經 改變重鍵之（Χ1)ι為SEQ ID NO:21且經改變輕鏈之（χι)ι為 SEQ ID ΝΟ:13。 【實施方式】 本發明係關於能夠結合兩個或兩個以上抗原之多價及/ 或多特異性結合蛋白。特定言之，本發明係關於雙重可變 區域免疫球蛋白（DVD-Ig)及其醫藥組合物，以及用於製備 -121 - 151681.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 130 135 140
Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr lie 145 150 155 160
His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr 165 170 175 lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe Lys Gly 180 185 190
Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu -591 - 151681-序列表 _doc 201127956 195 200 205
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245
<210〉 439 <211〉 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 439
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro -592· 151681-序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225 <210> 440 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -593 - 151681·序列表.doc 201127956 <400〉 440
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
He Ser Asp Tyr Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175 -594
151681-序列表.doc 201127956
Leu Glu Trp Val Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 441 <211〉 232 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 441
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60 15168 丨·序列表.doc -595- 201127956
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser 165 170 175
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu He Lys Arg 225 230 <210〉 442 596- 151681·序列表.doc 201127956 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 442
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val 130 135 140
Lys Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr -597- 15168U 序列表.doc 201127956 145 150 155 160
Ser Phe Thr Ala Tyr Tyr He His Trp Val Lys Gin Ala Pro Gly Gin 165 170 175
Gly Leu Glu Trp He Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr Asn 180 185 190
Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser 195 200 205
Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 443 <211〉 232 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 443
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -598- 151681-序列表.doc 201127956 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly lie Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Ala Glu Asp Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Val Pro Trp Thr Phe Gly Gly 210 215 220 151681-序列表.doc - 599- 201127956
Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 444 <211〉 252 <212〉 PRT 〈213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 444
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 •600·
15168卜序列表.doc 201127956 該等DVD-Ig之核酸、重組表現载體及宿主細胞。本發明 亦涵蓋使用本發明DVD-Ig活體外或活體内偵測特異性抗 原之方法。 除非本文另外定義，否則關於本發明使用之科技術語將 具有一般熟習此項技術者通常所瞭解之含義。術語之含義 及範疇應為清晰的，然而，若存在任何隱含歧義則本文 中所提供之定義優先於任何字典或外來定義。此外，除非 上下文另外要求，否則單數術語應包括複數且複數術語應 包括單數。在本申請案中，除非另外說明，否則使用 「或」意謂「及/或」。此外，使用術語「包括 (including)」以及其他形式，諸如「includes」及 「included」不具有限制性。同樣，除非另外特別說明， 否則諸如「元件」或「組件」之術語涵蓋包含一個單元之 元件及組件及包含一個以上次單元之元件及組件。 一般而言，本文所述之關於細胞及組織培養、分子生物 學、免疫學、微生物學、遺傳學以及蛋白質及核酸化學及 雜交所使用的命名法及其技術為此項技術中所熟知及常用 之命名法及技術。除非另外說明，否則一般根據此項技術 中熟知之習知方法及如本說明書全文所引用及論述之多種 一般性及更為具體之參考文獻所描述執行本發明之方法及 技術。酶促反應及純化技術係根據製造商說明書，如此項 技術中通常所實現或如本文所述來執行。本文所述之關於 分析化學、合成有機化學及醫學及醫藥化學所使用之命名 法及其貫驗至程序與技術為此項技術中所熟知及常用之命 151681.doc •122· 201127956
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 445 〈211〉 225 <212〉 PRT 〈213>人造序列 〈220> 〈223>人造序列之描述：合成多肽 <400〉 445
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15 -601 151681 -序列表.doc 201127956
Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg 100 105 110
Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin 130 135 140
Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 180 185 190
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser -602· 151681-序列表.doc 201127956 195 200 205
Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225
<210> 446 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 446
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin -603 - 151681-序列表.doc 201127956 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val 130 135 140
Lys Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Ser Phe Thr Ala Tyr Tyr He His Trp Val Lys Gin Ala Pro Gly Gin 165 170 175
Gly Leu Glu Trp He Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn 180 185 190
Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser 195 200 205
Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 447 <211> 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 • 604·
151681-序列表.doc 201127956 <400〉 447
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro 165 170 175 -605 151681-序列表.doc 201127956
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225
<210> 448 〈211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 448
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 606-
151681·序列表.doc 201127956
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly He 165 170 175
Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe 210 215 220
Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 449 151681-序列表.doc - 607 - 201127956 <211> 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 449
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr -608- 151681-序列表.doc 201127956 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser 165 170 175
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 450 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 450
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val • 609- 151681-序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 .125
Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr lie 145 150 155 160
His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp He Gly Tyr 165 170 175
lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe Lys Gly 180 185 190
Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu 195 200 205
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240 610- 151681-序列表.doc 201127956 名法及程序與技術。使用標準技術來進行化學合成、化與 分析、醫藥製備、調配及傳遞，以及患者之治療。 本發明可較輕易地理解，所選擇之術語定義如下。 如本文所用之術語「多肽」係指胺基酸之任何聚合鏈。 術語「肽」及「蛋白質」可與術語多肽互換使用且亦係指 胺基酸之聚合鏈。術語「多肽」涵蓋原生或人工蛋白質、θ 蛋白質片段及蛋白質序列之多肽類似物。多肽可為單體或 聚合體。除非上下文另有相反說明，否則本文中使用「多 肽」意欲涵蓋多肽及其片段及變異體（包括變異體之片 段）。就抗原多肽而言，多肽片段視情況含有多肽之至少 -個相鄰或非線性抗原決定基。該至少—個抗原決定基二 段之確切邊界可使用此項技術中之_般技術確定。該片尸 包含至少約5個相鄰胺基酸’諸如至少約叫固相鄰胺^ 酸、至少約15個相鄰胺基酸，或至 土 乂主夕約20個相鄰胺基酸。 多肽之變異體係如本文所述。 ^ h離蛋白質」或「經分離多肽」係指該蛋白質 或多肽基於其起源或射來源而不與其原生狀態中所 之天然締合組分締合；實質上 a新.丄 个曰叫物種之其他蛋 白質，由不同物種之細胞表現； 货 乂在自然界中不存在。因 此，以化學方式合成或在不同於其 隹因 έ姑士人、天起源之細胞的細胞 系統中合成之多肽將與其天然 τ 〇組分「分離 柹 項技術中熟知之蛋白質純化技 離」使用此 實質上不含天然締合組分。 仃刀離，亦可使蛋白質 如本文所用之術語「回收係 收」係才曰例如使用此項技術熟知 151681.doc -123· 201127956
Val Thr Val Ser Ser 245 <210〉 451 〈211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 451
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Val Met Thr Gin Ser Pro 115 120 125 -611- 151681·序列表.doc 201127956
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly lie Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp. Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Val Pro Trp Thr Phe Gly Gly 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 452 <211〉 246 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 452
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val.Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30 -612-
151681·序列表.doc 201127956
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 1：L0
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser Trp lie His 145 150 155 160
Trp Val Arg*Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie 165 170 175
Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp -613· 151681-序列表.doc 201127956 210 215 220
Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210> 453 <211> 225 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 453
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 614-
151681·序列表.doc 201127956 100 105 110
Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin 130 135 140
Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser 195 200 205
Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys 210 215 220
225 <210> 454 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 454
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly •615- 151681-序列表.doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser 130 135 140
Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr 145 150 155 160 lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp He Gly 165 170 175
Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190 -616 - 151681·序列表.doc 201127956
Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met 195 200 205
Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245
<210> 455 <211〉 225 〈212〉 PRT 〈213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400〉 455
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 617· 151681·序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225 <210〉 456 <211〉 253 <212〉 PRT <213〉人造序列 -618 ·
151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 456
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly -619- 151681·序列表.doc 201127956 165 170 175
Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 457 <211〉 232 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 457
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly He Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp -620- 151681-序列表.doc 201127956 之蛋白質純化技術進行分離， 上不含天然締合組分之過程。 使化學物質（諸如多狀）實質 有It:::用”生物活性」係指分子之任何-或多種固 ,,特性（如活體内可見之天然存在之特性，或由重組 s V、或賦^之特性）^生物特性包括（但不限於）社合受 體；誘導細胞增殖、抑制細射長 '料其他細胞激素、 誘導細胞〉周亡、月綠作，工k ' 及酶促活性。生物活性亦包括Ig分子之活 性0 如本文所用之關於抗體、蛋白質或肽與第二化學物質之 相互作用的術語「特異性結合」意謂該相互作用隨化學物 質上特定結構（例如抗原決定子或抗原決定基）之存在而 定；例如，抗體可以識別且結合特定蛋白質結構，而不與 蛋白質廣泛結合。若抗體對抗原決定基「A」具有特異 性，則在含經標記「A」及抗體之反應中，含抗原決定基 A(或游離、未經標記之A)之分子之存在將減少與該抗體結 合之經標記A的量。 如本文所用之術語「抗體」泛指包含四個多肽鏈（兩個 重（H)鏈及兩個輕（L)鏈）之任何免疫球蛋白分子或其保 留Ig分子之必需抗原決定基結合特徵的任何功能片段、突 變體、變異體或衍生物。該等突變體、變異體或衍生物抗 體形式為此項技術中所已知。下文論述其非限制性實施 例0 在全長抗體中，各重鏈包含重鏈可變區（本文中縮寫為 HCVR或VH)及重鏈恆定區。重鏈恆定區包含3個結構區域 15168l.doc •124- 201127956 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140
He Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230 -621 · 151681·序列表.doc 201127956 <210> 458 <211> 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 458
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu 130 135 140 •622- 151681-序列表.doc 201127956
Va.l Lys Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Ala Tyr Tyr lie His Trp Val Lys Gin Ala Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr 195 200 205
Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 459 〈211〉 232 <212〉PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 459
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30 -623- 151681-序列表.doc 201127956
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Val Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr He Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly lie Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Val Pro Trp Thr Phe Gly Gly •624·
151681·序列表.doc 201127956 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 460 <211〉 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 460
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr He His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe •625 · 151681-序列表.doc 201127956 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 461 <211> 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 461
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly •626·
15168卜序列表.doc 201127956 5 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 115 120 125
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin 130 135 140
Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala 145 150 155 160
Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro 165 170 175
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190 15168丨-序列表doc •627- 201127956
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser 195 200 205
Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 210 215 220
Arg 225 <210〉 462 <211〉 253 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 462
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -628
151681·序列表.doc 201127956
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu 130 135 140
Val Lys Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Ala Tyr Tyr lie His Trp Val Lys Gin Ala Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Gly Arg Val Thr Phe Thr Thr Asp Thr 195 200 205
Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 463 <211〉 225 〈212〉 PRT <213〉人造序列 -629- 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 463
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn 130 135 140
Tyr Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro 145 150 155 160
Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro -630-
151681-序列表,doc 201127956 CHI、CH2及CH3。各輕鏈包含輕鏈可變區（本文中縮寫為 LCVR或VL)及輕鏈恆定區。輕鏈恆定區包含一個結構區域 CL。可將VH及VL區進-步再分為冑變區（稱為互補決定區 (CDR))，其間散佈有較為保守之區（稱為構架區（fr))。各 VH及VL由三個CDR及四個FR構成，該等區域自胺基末端 至羧基末端按以下順序排列：FR1、cdr1、FR2、 CDR2、FR3、CDR3、FR4。免疫球蛋白分子可為任何類 φ 型（例如igG、IgE、_、砂、¥及IgY)、類別（例如
IgGl、IgG2、IgG3、IgG4、IgAl 及 IgA2)或子類。 術語「Fc區」用於定義免疫球蛋白重鏈之c末端區，其 可由完整抗體之木瓜蛋白酶消化產生。Fc區可為原生序列 Fc區或變異Fcg。免疫球蛋白之以區一般包含兩個恆定區 域（CH2區域及CH3區域）’且視情況包含CH4區域。置換Fc 部分中之胺基酸殘基以改變抗體效應功能在此項技術中已 知（Winter等人，美國專利第5,648,26〇號及第5,624,821 φ 號）。抗體之Fc部分介導若干重要效應功能，例如細胞激 素誘導、ADCC、吞噬作用、補體依賴性細胞毒性（CDC) 以及抗體及抗原-抗體複合物之半衰期/清除率。視治療目 才示而疋’在一些情形下’此等效應功能為治療性抗體所 需’但在其他情形下可能並非必要或甚至有害。某些人類 IgG同型（尤其1§G1及IgG3)分別經由結合於FcYR及補體ciq 來介導ADCC及CDC。新生兒fc受體（FcRn)為確定抗體循 裱半衰期的關鍵組分。在另一實施例中’置換抗體恆定區 (例如抗體之Fc區）中的至少一個胺基酸殘基，使得抗體之 151681.doc •125· 201127956 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 180 185 190
Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser 195 200 205
Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys 210 215 220
225 <210> 464 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 464
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr He His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Tlir Asp Thr Ser Thr Ser Thr Ala Tyr •631 · 151681·序列表 _doc 201127956 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie 165 170 175
Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp 210 215 220
Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 151681-序列表.doc -632- 201127956 <210〉 465 <211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 465
Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg 100 105 HO
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 151681-序列表.doc -633 - 201127956 lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu He Lys Arg 225 230 <210〉 466 <211〉 246 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 466
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -634·
151681-序列表.doc 201127956
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser 130 135 140
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr Tyr 145 150 155 160
lie His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Tyr lie Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met 195 200 205
Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly Thr -635- 151681-序列表.doc 201127956 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210> 467 <211〉 232 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 467
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Met Thr Gin Ser Pro -636· 151681·序列表.doc 201127956 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Asn Tyr Gly lie Ser Phe Met Lys Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala 195 200 205
Val Tyr Tyr Cys Gin Gin Ser Lys Glu Val Pro Trp Thr Phe Gly Gly 210 215 220
Gly Thr Lys Val Glu lie Lys Arg 225 230
<210> 468 <211> 244 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 468
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn - 637- 151681··序列表.doc 201127956 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr 165 170 175
Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205 -638· 151681·序列表.doc 201127956
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val 210 215 220
Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser
<210> 469 <211〉 222 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 469
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95 •639 151681·序列表.doc 201127956
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 130 135 140
Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu 145 150 155 160
Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr 195 200 205
Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 2i〇 215 220 <210〉 470 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 470
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly i 5 10 15 -640
151681·序列表.doc 201127956 效應功能得以改變。免疫球蛋白之兩個相同重鏈的二聚化 由CH3區域之二聚化介導，且由鉸鏈區内之二硫鍵穩定化 (Huber等人，Nature; 264: 415-20 ; Thies等人，1999 J Mol Biol; 293: 67-79.)。使鉸鏈區内之半胱胺酸殘基突變以防 止形成重鏈-重鏈二硫鍵，將使CH3區域之二聚化不穩定。 已鑑別出負責CH3二聚化之殘基（Dall’Acqua 1998 Biochemistry 37: 9266-73.)。因此，有可能產生單價半 Ig。有趣的是，已在自然界中發現IgG及IgA子類兩者之此 等單價半 Ig 分子（Seligman 1978 Ann Immunol 129: 855-70 ; Biewenga等人，1983 Clin Exp Immunol 51: 395-400) 0 已測得FcRn:Ig Fc區之化學計量為2:l(West等人，2000 Biochemistry 39: 9698-708)，且一半Fc足以介導FcRn結合 (Kim 等人，1994 Eur J Immunol; 24: 542-548.)。破壞 CH3 區 域二聚化之突變可能不會對其FcRn結合產生較大不利影 響，此係因為對於CH3二聚化重要之殘基位於CH3 b折片 結構之内界面上，而負責FcRn結合之區位於CH2-CH3區域 之外界面上。然而，半Ig分子可能由於其尺寸小於常規抗 體而在組織穿透方面具有一定優勢。在一實施例中，置換 本發明結合蛋白之恆定區（例如Fc區）中的至少一個胺基酸 殘基，以致破壞重鏈之二聚化，從而產生半DVD Ig分子。 IgG之消炎活性完全視IgG Fc片段之N連接聚糖的唾液酸化 而定。已確定消炎活性之確切聚糖要求，使得可產生適當 IgGl Fc片段，藉此產生效能極大增強之完全重組《i液酸 化 IgGl Fc(Anthony，R.M.等人，（2008) Science 320:373- 151681.doc -126- 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn Trp lie 145 150 155 160
Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Tyr 165 170 175 lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin •641 · 151681·序列表.doc 201127956 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 2l〇 215 220
Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser
<210> 471 <211〉 222 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 471
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro • 642- 151681-序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205
Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 472 <211> 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 472
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly • 643 - 151681··序列表.doc 201127956 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Ser Asp Tyr Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala 180 185 190 -644 - 151681·序列表.doc 201127956
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 473 〈211〉 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 473
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 645- 151681-序列表.doc 201127956
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys 130 135 140
Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225 〈210〉 474 <211〉 251 <212〉 PRT <213〉人造序列 646-
151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 474
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Thr Asp Asn Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys -647- 151681·序列表.doc 201127956 165 170 175
Gly Leu Glu Trp Val Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 475 〈211〉 229 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 475
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly •648· 151681·序列表doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225 649· 151681·序列表.doc 201127956 <210〉 476 <211〉 251 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 476
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140 151681-序列表.doc -650- 201127956 376)。 如本文所用之術語抗體之「抗原結合部分」（或簡稱為 「抗體部分」）係指保留特異性結合於抗原之能力的抗體 之一或多個片段。已顯示抗體之抗原結合功能可由全長抗 體之片段執行。該等抗體實施例亦可為雙特異性、雙重特 異性或多特異性形式；其特異性結合於兩個或兩個以上不 同抗原。術語抗體之「抗原結合部分」内所涵蓋之結合片 _ 段的實例包括：（i) Fab片段，即由VL、VH、CL及CH1區 域組成之單價片段；（ii) F(ab·)2片段，即包含在鉸鏈區中 經二硫橋鍵連接之兩個Fab片段的二價片段；（⑴）Fd片 段，其係由VH及CH1區域組成；（iv) Fv片段，其係由抗體 之單臂之VL及VH區域組成；（v) dAb片段（Ward等人，
(1989) 341:544-546，Winter 等人，PCT公開案 WO 90/05144 A1，其以引用的方式併入本文中），其包含單一 可變區域；及（vi)經分離互補決定區（CDR)。此外，儘管 φ ^片段之兩個區域（VL及VH)係由獨立基因編碼，但可使 用重組方法藉由合成連接子將其連接，使得能夠製備為 VL區與VH區配對形成單價分子之單一蛋白質鏈（稱為單鏈 fv(scFv);參看例如 Bird 等人，（1988) 242 423_ 426 ;及Huston等人，（1988)户⑽勤汄炎心.〜·㈣ 85.5879-5883)。该等單鏈抗體亦欲涵蓋於術語抗體之「抗 原結合部分」内。亦涵蓋單鏈抗體之其他形式，諸如微型 雙功能抗體。微型雙功能抗體為二價雙特異性抗體，其中 VH區域及VL區域表現於單個多肽鏈上，但使用過短以致 151681.doc -127- 201127956
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 477 <211〉 222 〈212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 477
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30 • 651 · 151681..序列表.doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 130 135 140
Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu 145 150 155 160
Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr 195 200 205
Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg •652· 151681·序列表.doc 201127956 210 215 220 <210〉 478 <211> 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 478
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Va.l Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu -653 - 151681-序列表.doc 201127956 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Thr Asp Asn Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Tyr He Ser Pro Asn Ser Gly Phe Thr Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 479 <211〉 222 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 479
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala •654-
151681-序列表.doc 201127956 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205 151681-序列表.doc • 655 - 201127956
Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 480 〈211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 480
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125 151681·序列表.doc -656- 201127956
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr 165 170 175
Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val 210 215 220
Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser <210〉 481 <211〉 229 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 481
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 •657 151681-序列表.doc 201127956
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 130 135 140
Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr -658- 15168N 序列表.doc 201127956 195 200 205
Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225
<210> 482 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 482
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin -659- 151681-序列表.doc 201127956 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn Trp He 145 150 155 160
Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Tyr 165 170 175
He Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser <210> 483 <211〉 229 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -660· 151681-序列表.doc 201127956 相同鏈上之兩個結構區域之間不能配對的連接子，藉此迫 使該等結構區域與另一鏈之互補區域配對且形成兩個抗原 結合位點（參看例如Holliger，P.等人，（1993)尸roc. iVai/. Acad. Sci. USA 90:6444-6448 ； Poljak, R.J.等人，（1994) iSVrwciwre 2:1121-1123)。該等抗體結合部分為此項技術中 戶斤已知（Kontermann 及 Dubel 編，Antibody Engineering (2001) Springer-Verlag. New York.第 790 頁（ISBN 3-540-41354-5))。此外，單鏈抗體亦包括「線抗體」，其包含與 互補輕鏈多肽一起形成一對抗原結合區的一對串聯Fv區段 (VH-CHl_VH-CHl)(Zapata 等人，？1^6111£1^.8(10):1057-1062 (1995);及美國專利第 5,641，870號）。 術語「多價結合蛋白」在本說明書全文中用於表示包含 兩個或兩個以上抗原結合位點之結合蛋白。在一實施例 中，多價結合蛋白經工程改造成具有三個或三個以上抗原 結合位點且一般不為天然存在之抗體。術語「多特異性結 合蛋白」係指能夠結合兩個或兩個以上相關或不相關目標 之結合蛋白。本發明之雙重可變區域（DVD)結合蛋白包含 兩個或兩個以上抗原結合位點且為四價或多價結合蛋白。 DVD可為單特異性的，亦即能夠結合一個抗原；或多特異 性的，亦即能夠結合兩個或兩個以上抗原。包含兩個重鏈 DVD多肽及兩個輕鏈DVD多肽之DVD結合蛋白稱為DVD-Ig。DVD-Ig之每一半包含重鏈DVD多肽及輕鏈DVD多肽， 及兩個抗原結合位點。各結合位點包含重鏈可變區域及輕 鏈可變區域，其中每一抗原結合位點總計有6個CDR參與 151681.doc •128· 201127956 <400> 483
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175 •661 151681 -序列表.doc 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225
<210> 484 <211> 245 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400> 484
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 662-
151681-序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp He His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr 165 170 175
Pro Tyr Ser Gly.Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly 210 215 220
His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 485 151681-序列表.doc -663 - 201127956 <211> 222 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 485
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 1 ⑻ 105 110
Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg 130 135 140
Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu -664- 151681-序列表.doc 201127956 145 150 155 160
Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser 195 200 205
Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 486 <211> 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 486
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 665 - 151681·序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser .130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn Trp 145 150 155 160 lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 165 170 175
Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190
Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 151681-序列表.doc -666- 201127956 <210> 487 <211〉 222 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 487
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140 -667- 151681-序列表.d〇c 201127956
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205
Thr Val Thr .Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 488 <211〉 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 488
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60 -668-
151681-序列表.doc 201127956
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser •669- 151681 -序列表.doc 201127956 245 250 <210> 489 <211> 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 489
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 l〇 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys -670-
151681·序列表.doc 201127956 抗原結合。 如本文所用之術語「雙特異性抗體」係指藉由以下技術 產生之全長抗體：四源雜交瘤技術（參看Milstein，c.及 A.C. Cuello, Nature，1983. 305(5934):第 537_4〇頁）；使兩 種不同單株抗體化學結合（參看Staerz，UD等人，Nature， 1985. 314(6012):第628-31頁）；或將突變引入以區中之杵
臼結構技術或類似方法（參看H〇Uiger，p，T Pr〇sper〇&G
Winter’ Proc Natl Acad Sci U S A，1993. 90(14):第 0444- 8_18頁），該等技術產生多種不同免疫球蛋白物質，其中僅 一者為功能性雙特異性抗體。根據分子功能，雙特異性抗 體在其兩個結合臂（一對HC/LC)之一個臂上結合一個抗原 (或抗原決定基），且在其第二臂（一對不同的hc/lc)上結 合不同抗原（或抗原決定基）。根據此定義，雙特異性抗體 具有兩個不同抗原結合臂（在特異性及CDR序列方面），且 對於其結合之各抗原而言為單價的。 如本文所用之術語「雙重特異性抗體」係指可在兩個結 合臂(-對HC/LC)中之每一臂中結合兩個不同抗原(或抗原 決疋基）的全長抗體（參看PCT公開案WO 〇2/〇2773)。因 此雙重特異性結合蛋白具有兩個具有相同特異性及相同 CDR序列之相同抗原結合臂且對於其結合之各抗原而言 為二價的。 結合蛋白之「功能性抗原結合位點」為能夠結合目標抗 原之結合位點。抗原結合位點之抗原Μ纟親和力不一定與 產生抗原結合位點之親本抗體一樣強，但結合抗原之能力 15168l.doc •129· 201127956 130 135 140
Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Glri Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225 <210〉 490 <211〉 252 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 490
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 671 · 151681·序列表.doc 201127956 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Thr Asp Asn Trp lie Ser Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr 180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr 195 200 205
Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220 •672· 151681-序列表.doc 201127956
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 491 <211> 229 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 491
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 no 151681-序列表.doc -673 - 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser .Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225 <210〉 492 〈211〉 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 492
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 •674
151681-序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn - 675 - 151681-序列表.doc 201127956 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 493 <211> 222 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 493
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr -676- 151681·序列表.doc 201127956 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp A.rg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg 130 135 140
Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu 145 150 155 160
Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser 195 200 205
Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 494 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 494
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -677- 151681-序列表.doc 201127956 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Thr Asp Asn Trp lie Ser Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr 180 185 190 -678 - 151681·序列表.doc 201127956
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr 195 200 205
Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 ⑩ <210> 495 <211〉 222 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 495
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
O
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 679 - 151681-序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205
Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 496 <211〉 245 〈212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 680-
151681-序列表.d〇c 201127956 必須可使用多種已知用於評估抗體與抗原結合之方法中之 任一者來量測。此外，本文之多價抗體之各抗原結合位點 的抗原結合親和力在數量上不必相同。 術語「細胞激素」為由一個細胞群體釋放且以細胞間介 體形式作用於另一細胞群體的蛋白質之通用術語。該等細 胞激素之貫例為淋巴介質、單核球激素及傳統多肽激素。 細胞激素包括生長激素，諸如人類生長激素、N_甲硫胺醯 基人類生長激素及牛生長激素；副曱狀腺激素；甲狀腺 素；騰島素；前胰島素；鬆弛素；前鬆弛素；醣蛋白激 素’諸如促印泡激素（FSH)、促曱狀腺激素（TSH)及促黃體 激素（LH)，肝生長因子；纖維母細胞生長因子；促乳素； 胎盤生乳素；腫瘤壞死因子_α及腫瘤壞死因子—β;苗勒氏 抑制物質（mullerian-inhibiting substance);小鼠促性腺激 素相關肽；抑制素；活化素；血管内皮生長因子；整合 素；血小板生成素（TPO);神經生長因子，諸如NGF_a ; 血小板生長因子；胎盤生長因子；轉化生長因子（TGF)， 諸如TGF-α及TGF-β ;胰島素樣生長因子及胰島素樣生 長因子-11 ;紅血球生成素（EP0);骨生成誘導因子；干擾 素’諸如干擾素-α、干擾素_0及干擾素;群落刺激因子 (CSF) ’諸如巨噬細胞-CSF(M-CSF);粒細胞巨噬細胞_ CSF(GM-CSF);及粒細胞-CSF(G-CSF);介白素（il)，諸 WIL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9 、 IL-10 、 IL-11 、 IL-12 、 IL-13 、 IL-15 、 IL-18 、 IL-21 、 IL-22、IL-23、IL-33 ;腫瘤壞死因子，諸如 TNF-α 或 TNF- 151681.doc -130· 201127956 <400> 496
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
❶
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr 165 170 175
Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe -681 - 151681-序列表doc 201127956 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly 210 215 220
His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 497 <211〉 229 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 497
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro -682- 15168丨-序列表.doc 201127956 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 130 135 140
Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190 ❶
Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225
<210〉 498 <2；L1> 245 <212> PRT 683 - 151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 498
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Va.1 Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser 130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn Trp 145 150 155 160 684· 151681·序列表.doc 201127956
He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 165 170 175
Tyr He Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190
Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu· 225 230 235 240
Val Thr Val Ser Ser 245 <210> 499 <211〉 229 <212> PRT <213〉人造序列 〇 <220〉 <223〉人造序列之描述：合成多肽 <400〉 499
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 • 685 · 151681·序列表.doc 201127956
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg •686· 151681·序列表.doc 201127956 225 <210> 500 <211> 254 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 500
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Va.1 Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
O
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin - 687 - 151681-序列表.doc 201127956 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe 145 150 155 160
Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala 180 185 190
Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr 225 230 235 240
Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 501 <211〉 229 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 501
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala -688- 151681-序列表.doc 201127956 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 130 135 140 o
Ser Ala Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Val Leu He Tyr Phe Thr Ser Ser Leu His 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205 •689- 15168丨-序列表.doc 201127956
Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225 <210〉 502 〈211〉 254 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 502
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 •690
151681-序列表.doc 201127956 β;及其他多肽因子，包括LIF及kit配位體（KL)。如本文所 用之術語細胞激素包括來自天然來源或重組細胞培養物之 蛋白質，及原生序列細胞激素之生物活性等效物。 術語「連接子」用於表示包含兩個或兩個以上經肽鍵連 接之胺基酸殘基且用於連接一或多個抗原結合部分之多 肽。該等連接子多肽為此項技術令所熟知（參看例如 Holliger, P.等人，（1993) /Voc. Λ^，/, Jcai 5W. 90:6444-6448 ； Poljak, H.J.等人，(1994) Structure 2:1121-1123)。例示性連接子包括（但不限於）AKTTPKLEEGEFSEAR (SEQ ID NO: 1) ； AKTTPKLEEGEFSEARV(SEQ ID NO: 2)； AKTTPKLGG(SEQ ID NO: 3) ； SAKTTPKLGG(SEQ ID NO: 4) ； SAKTTP(SEQ ID NO: 5) ； RADAAP(SEQ ID NO: 6)； RADAAPTVS(SEQ ID NO: 7) ； RADAAAAGGPGS(SEQ ID NO: 8) ； RADAAAA(G4S)4(SEQ ID NO: 9) ； SAKTTPKL EEGEFSEARV(SEQ ID NO: 10) ； ADAAP(SEQ ID NO: 11) ； ADAAPTVSIFPP(SEQ ID NO: 12) ； TVAAP(SEQ ID NO: 13) ； TVAAPSVFIFPP(SEQ ID NO: 14) ； QPKAAP (SEQ ID NO: 15) ； QPKAAPSVTLFPP(SEQ ID NO: 16)； AKTTPP(SEQ ID NO: 17) ； AKTTPPSVTPLAP(SEQ ID NO: 18) ； AKTTAP(SEQ ID NO: 19) ； AKTTAPSVYPLAP(SEQ ID NO: 20) ； ASTKGP(SEQ ID NO: 21) ； ASTKGPSVFPLAP (SEQ ID NO: 22) ； GGGGSGGGGSGGGGS(SEQ ID NO: 23)； GENKVEYAPALMALS(SEQ ID NO: 24) ； GPAKELTPLKEAKVS (SEQ ID NO: 25) ； GHEAAAVMQVQYPAS(SEQ ID NO: 151681.doc -131 - 201127956
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly 130 135 140
Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 145 150 155 160
Ser Gly Phe Thr Phe Thr Asp Asn Trp He Ser Trp Val Ai'g Gin Ala 165 170 175
Pro Gly Lys Gly Leu Glu Trp Val Gly Tyr lie Ser Pro Asn Ser Gly 180 185 190
Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala 195 200 205
Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 503 <211〉 229 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 691· 151681·.序列表,doc 201127956 <400> 503
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr -692-
151681-序列表.doc 201127956 180 185 190 Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225
<210〉 504 <2U> 254 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 504
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -693 - 151681-序列表.doc 201127956 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe 145 150 155 160
Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala 180 185 190
Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr 225 230 235 240
Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 505 <211〉 222 <212〉 PRT 694·
151681·序列表.doc 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 505
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly i 5 l〇 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser 13〇 135 140
Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val 145 150 155 160 695 - 151681 -序列表.doc 201127956
Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val 195 200 205
Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220
<210〉 506 <211〉 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 506
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 696-
151681-序列表 doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly 130 135 140
Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 145 150 155 160
Ser Gly Phe Thr Phe Thr Asp Asn Trp He Ser Trp Val Arg Gin Ala 165 170 175
Pro Gly Lys Gly Leu Glu Trp Val Gly Tyr He Ser Pro Asn Ser Gly 180 185 190
Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala 195 200 205
Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Asn Phe Gly Gly Tyr 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 507 -697- 151681..序列表.doc 201127956 <211〉 222 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 507
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu -698- 151681-序列表.doc 201127956 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205
Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 508 <211> 247 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 508
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr He Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gl)r Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr -699- 151681-序列表doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn 165 170 175
Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe 180 185 190
Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro 210 215 220
His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 •700· 151681-序列表.doc 201127956 26) 〇 免疫求蛋白f互疋區域」係指重鏈或輕鏈恆定區域。人 類邮重鏈及輕鏈怪定區域胺基酸序列為此項技術中所已 知。 如本文所用之術語「單株抗體」或「mAb」係指自-群 實質上均質之抗體獲得的抗體，亦即構成該群體之個別抗 體除可以較J量存在之可能天然存在之突變外皆相同。單 株抗體針對單-抗原具有高度特異性。此外，與通常包括 針對不同决疋子(抗原決定基）之不同抗體的多株抗體製劑 相對照，各mAb針對抗原上之單―決^子。修飾語「單 株」不應理解為需要藉由任何特定方法製備抗體。 如本文所用之術語「人類抗體」意欲包括具有來源於人 類生殖系免疫球蛋白序列之可變區及怪定區的抗體。本發 明人類抗體可例如在CDR且尤其CDR3中包括不由人類生 殖系免疫球蛋白序列編碼之胺基酸殘基（例如，藉由活體 h隨機或位點特異性突變誘發或藉由活體内體細胞突變引 入之突變）。然而’如本文所用之術語「人類抗體」並不 欲包括來源於另一哺乳動物物種(諸如小鼠)之生殖系的 CDR序列已移植至人類構架序列上之抗體。 如本文所用之術語「重組人類抗體」意欲包括藉由重組 方式製備表現、產生或分離之所有人類抗體，諸如使用 轉染至宿主細胞中之重組表現載體表現之抗體（在下文章 節II C中進一步描述）、自重組組合人類抗體文庫分離之抗 體（Hoogenboom H.R. (1997) TIB Tech. 15:62-70 ; Azzazy 151681.doc -132· 201127956 〈210〉 509 <211〉 229 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 509
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 130 135 140 •701 - 151681·序列表,doc 201127956
Ser Ala Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Tyr Ser .Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225 〈210〉 510 <211> 247 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 510
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -702-
151681·序列表.doc 201127956
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 145 150 155 160
Asn Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly -703- 151681·序列表.doc 201127956 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 511 <211〉 229 <212〉 PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 511
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro •704·
151681·序列表.doc 201127956 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Thr Tyr Tyr 195 200 205
Cys Gin Gin Ser Tyr Thr Gly Thr Val Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu He Lys Arg 225
<210〉 512 <211> 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 512
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr •705- 151681-序列表.doc 201127956 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu He Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175 lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 180 185 190
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205 •706· 151681·序列表.doc 201127956
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245
<210〉 513 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 513
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 15 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95 -707 151681 ·序列表.d〇c 201127956
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160
He Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 514 <211〉 249 <212〉 PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 514
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 151681-序列表.doc -708 - 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly • 115 120 125
Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly 130 135 140
Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser 145 150 155 160
Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp 165 170 175 lie Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys 180 185 190
Phe Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala -709- 151681-序列表.doc 201127956 195 200 205
Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr 210 215 220
Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Thr Leu Thr Val Ser Ser 245 <210> 515 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 515
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp T)rr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp •710·
151681-序列表.doc 201127956 Η.及 Highsmith W.E. (2002) Clin. Biochem. 35:425-445 ; Gavilondo J_V.及 Larrick J.W. (2002) BioTechniques 29:128-145，Hoogenboom H.及 Chames P. (2000) Immunology Today 21:3 71-378)、自人類免疫球蛋白基因之轉殖基因動 物（例如小鼠）分離之抗體（參看Taylor, L· D_等人，（1992) Nucl. Acids Res· 20:6287-6295 ; Kellermann S-A.及 Green L.L. (2002) Current Opinion in Biotechnology 13:593-597 ; Little M.等人（2000) Immunology Today 21:364-3 70)、或藉由涉及將人類免疫球蛋白基因序列剪接至其他 DNA序列的任何其他方式製備、表現、產生或分離之抗 體。該等重組人類抗體具有來源於人類生殖系免疫球蛋白 序列之可變區及怪定區。然而，在某些實施例中，使該等 重組人類抗體進行活體外突變誘發（或當使用人類Ig序列之 轉殖基因動物時’使其進行活體内體細胞突變誘發）且因 此，重組抗體之VH區及VL區胺基酸序列為雖然來源於人 類生殖系VH及VL序列且與人類生殖系VH及VL序列相 關，但可能並非活體内天然存在於人類抗體生殖系譜系内 的序列。 「親和力成熟」抗體為在一或多個CDR中具有一或多處 變化之抗體’該（等）變化使得抗體對抗原之親和力相較於 不具有彼（等）變化之親本抗體得以改良。例示性親和力成 熟抗體對目標抗原將具有奈莫耳或甚至皮莫耳（pic〇m〇lar) 之親和力。親和力成熟抗體係藉由此項技術中已知的程序 製備。Marks等人.BidlTechnology 10:779-783 (1992)描述 151681.doc -133- 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro 195 200 205
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 516 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 516
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala •711 · 151681·序列表.doc 201127956 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr 180 185 190 •712· 151681-序列表.doc 201127956
Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser 195 200 205
Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255
<210〉 517 <211> 228 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 517
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 15 10 15
Gly Arg Val Thr He Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80 713· 151681-序列表.doc 201127956
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Ser 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu He Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 518 <211〉 256 <212> PRT <213〉人造序列 -714- 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400〉 518
Giu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly 130 135 140
Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Thr Phe Thr Ser Tyr Val lie Asn Trp Val Lys Gin Lys -715· 151681-序列表.doc 201127956 165 170 175
Pro Gly Gin Gly Leu Glu Trp lie Gly Leu He Asn Pro Tyr Asn Asp 180 185 190
Gly Thr Lys Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser 195 200 205
Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser 210 215 220
Glu Asp Ser Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg 225 230 235 240
Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210> 519 <211> 228 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽
<400〉 519
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly -716- 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly krg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Asp His He Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro t\rg Leu Leu lie Ser Gly Ala Thr Ser Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 -717· 151681-序列表doc 201127956 <210> 520 <211〉 256 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 520
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140 -718- 151681·序列表.doc 201127956
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr 180 185 190
Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser 195 200 205
Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255
<210> 521 <211> 221 〈212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多狀 <400> 521
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15
Gly Arg Val Thr He Thr Cys Lys Ala Ser Asp His He Asn Asn Trp 20 25 30 -719- 151681-序列表.doc 201127956
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg -720- 151681·序列表.doc 201127956 藉由VH及VL區域洗牌進行親和力成熟。以下文獻描述了 CDR及/或構架殘基之隨機突變誘發：Barbas等人.Proc Nat. Acad. Sci，USA 91:3809-3813 (1994); Schier等人. Gene 169:147- 155 (1995) ; Yelton 等人.J. Immunol· 155:1994-2004 (1995) ; Jackson 等人，J. Immunol. 154(7):3310-9 (1995) ; Hawkins 等人，J. Mol. BioL 226:889-896 (1992)，且在美國專利 US 6914128B1 中描述 了在選擇性突變誘發位置、接觸或超突變位置處以活性增 強型胺基酸殘基進行選擇性突變。 術語「嵌合抗體」係指包含來自一物種之重鍵及輕鏈可 變區序列及來自另一物種之怪定區序列的抗體，諸如具有 鼠類重鏈及輕鏈可變區連接至人類恆定區之抗體。 術語「CDR移植抗體」係指包含來自一物種之重鏈及輕 鏈可變區序列但其中VH及/或VL之一或多個CDR區之序列 經另一物種之CDR序列置換的抗體，諸如具有一或多個鼠 類CDR(例如CDR3)已經人類CDR序列置換之鼠類重鏈及輕 鏈可變區之抗體。 術語「人類化抗體」係指包含來自非人類物種（例如小 鼠）之重鏈及輕鏈可變區序列，但其中VH及/或VL序列之 至少一部分已經改變而更「類人類」，亦即更類似於人類 生殖系可變序列的抗體》—種類型之人類化抗體為〇][)尺移 植抗體，其中將人類CDR序列引入非人類VH& VL序列中 以置換相應非人類CDR序列。「人類化抗體」亦為免疫特 異性結合於相關抗原且包含實質上具有人類抗體胺基酸序 151681.doc -134- 201127956 210 215 220 <210〉 522 <211> 256 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 522
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly -721 - 151681-序列表.doc 201127956 130 135 140
Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Thr Phe Thr Ser Tyr Val He Asn Trp Val Lys Gin Lys 165 170 175
Pro Gly Gin Gly Leu Glu Trp He Gly Leu lie Asn Pro Tyr Asn Asp 180 185 190
Gly Thr Lys Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser 195 200 205
Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser 210 215 220
Glu Asp Ser Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg 225 230 235 240
Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210〉 523 <211> 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 523
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr •722·
151681-序列表.doc 201127956 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Va.1 Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro 195 200 205 151681-序列表.doc -723- 201127956
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 524 <211〉 249 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 524
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125 -724-
151681-序列表.doc 201127956
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175 lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 180 185 190
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser <210〉 525 〈211〉 228 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 525
Asp He Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15 151681-序列表doc -725 - 201127956
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys -726- 151681-序列表 _doc 201127956 195 200 205
Gin Gin Tyr Ser Thr Va.1 Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210〉 526 <211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 526
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val -727 · 15168〗-序列表.doc 201127956 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly 130 135 140
Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser 145 150 155 160
Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp 165 170 175
He Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys 180 185 190
Phe Lys Val L}rs Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala 195 200 205
Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr 210 215 220
Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Thr Leu Thr Val Ser Ser 245 <210> 527 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •728· 151681-序列表.doc 201127956 <400〉 527
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Asp His lie Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Thr Ser Leu Glu Thr 165 170 175 -729 151681-序列表.doc 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225
<210> 528 <211〉 246 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 528
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 730- 151681-序列表.doc 201127956 列之構架（FR)區及實質上具有非人類抗體胺基酸序列之互 補決定區（CDR)的抗體或其變異體、衍生物、類似物或片 段。如本文所用之術語「實質上」在CDR之情形下係指具 有與非人類抗體CDR之胺基酸序列至少8〇%、至少85。/〇、 至少90%、至少95%、至少98%或至少99%—致之胺基酸序 列的CDR。人類化抗體包含實質上全部之至少一個且通常 兩個可變區域（Fab、Fab'、F(ab')2、FabC、Fv)之，其中全 部或貫質上全部CDR區對應於非人類免疫球蛋白（亦即供 體抗體）之CDR區且全部或實質上全部構架區為人類免疫 球蛋白共同序列之構架區。在一實施例中，人類化抗體亦 包含免疫球蛋白恆定區（Fc)(通常為人類免疫球蛋白恆定 區）之至少一部分。在一些實施例中，人類化抗體含有輕 鏈以及至少重鍵之可變區域。抗體亦可包括重鏈之Cin、 鉸鏈區、CH2 ' CH3及CH4區。在一些實施例中，人類化 抗體僅含有人類化輕鏈。在一些實施例中，人類化抗體僅 含有人類化重鏈。在特定實施例中，人類化抗體僅含有輕 鏈及/或人類化重鏈之人類化可變區域。 術語「Kabat編號」、r Kabat定義」及「Kabat標記」在 本文中可互換使用。此項技術中公認之此等術語係指相較 於抗體或其抗原結合部分之重鏈及輕鏈可變區中之其他胺 基酸殘基可變（亦即高變）之胺基酸殘基的編號系統（Kabat 等人·（1971)知190:382-391 及Kabat, E.A. 專尺，Sequences 〇f pr〇teins 〇j· Immun〇l〇gical 農5廣，美國衛生及公共服務部（U.S. Department 151681.doc -135- 201127956
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly 165 170 175 lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210〉 529 151681-序列表 _doc -731 - 201127956 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 529
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His He Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95 φ
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu • 732- 15168丨-序列表.doc 201127956 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 530 <211> 246 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 530
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr -733 - 151681-序列表doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val lie 145 150 155 160
Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie Gly Leu 165 170 175 lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Val 180 185 190
Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Ser 210 215 220
Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245 151681·序列表.doc ·734· 201127956 <210〉 531 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 531
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn 130 135 140 151681 -序列表.d〇c • 735 - 201127956
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro 195 200 205
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 532 <211〉 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 532
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val He Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 • 736·
151681·序列表.doc 201127956
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser - 737. 151681·序列表.doc 201127956 245 250 <210〉 533 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 533
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser He Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser He Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg -738· 151681-序列表.doc 201127956 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser ,\rg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 2'20
Glu lie Lys Arg 225 <210> 534 <211> 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 534
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 δ 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val • 739- .151681-序列表.doc 201127956 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 . 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Ser Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin 165 170 175
Gly Leu Glu Trp He Gly Leu He Asn Pro Tyr Asn Asp Gly Thr Lys 180 185 190
Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser 195 200 205
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser 210 215 220 -740- 151681·序列表.doc 201127956 of Health and Human Services)，NIH公開案第 91-3242號）。 對於重鏈可變區而言，高變區範圍為CDR1之胺基酸位置 31至35，CDR2之胺基酸位置50至65，及CDR3之胺基酸位 置95至102。對於輕鏈可變區而言，高變區範圍為CDR1之 胺基酸位置24至34，CDR2之胺基酸位置50至56，及CDR3 之胺基酸位置89至97。 如本文所用之術語「CDR」係指抗體可變序列内之互補 決定區。重鏈及輕鏈之可變區中各存在三個CDR，各可變 區之該三個CDR指定為CDR1、CDR2及CDR3。如本文所 用之術語「CDR組」係指存在於單一可變區中能夠結合抗 原之三個CDR之群。此等CDR之確切邊界已根據不同系統 不同地加以界定。Kabat所述之系統（Kabat等人， Sequences of Proteins of Immunological Interest (美國國家 衛生研究院（National Institutes of Health), Bethesda，Md. (1987)及（1991))不僅提供適用於抗體之任何可變區的明確 殘基編號系統，且亦提供界定三個CDR之確切殘基邊界。 此等CDR可稱為Kabat CDR。Chothia及其同事（Chothia及 Lesk，J. Mol. Biol· 196:901-917 (1987)及 Chothia 等人， Nature 342:877-883 (1989))發現Kabat CDR内之某些子部 分即使在胺基酸序列層面具有極大多樣性’亦使用幾乎相 同的肽主鏈構形。此等子部分指定為L1、L2及L3或H1、 H2及H3，其中「L」及「H」分別表示輕鏈區及重鍵區。 此等區可稱為Chothia CDR，其具有與Kabat CDR重疊之邊 界。界定與Kabat CDR重疊之CDR之其他邊界已由 151681.doc •136- 201127956
Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210〉 535 <211> 228 <212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 535
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110 •741 151681-序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Asp His He Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Thr Ser Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210〉 536 <211> 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 536
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15 742
151681·序列表.doc 201127956
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu GIu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser •743- 151681-序列表 doc 201127956 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Phe *Val Phe Phe Leu Pro Tyr Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 537 <211> 221 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 537
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His He Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser He Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser He Pro Leu •744-
151681·序列表d〇c 201127956 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 538 <211〉 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 538
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -745- 151681-序列表.doc 201127956 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Ser Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin 165 170 175
Gly Leu Glu Trp lie Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys 180 185 190 151681-序列表.doc 746* 201127956
Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser 195 200 205
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser 210 215 220
Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250
<210〉 539 <211> 221 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 539
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 747- 151681-序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro 195 200 205
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 〈210〉 540 <211> 246 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 748·
151681-序列表.doc 201127956 <400> 540
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu He Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly 165 170 175
He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly • 749 151681·序列表.doc 201127956 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210〉 541 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 541
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 1 5 10 15
Gly Arg Val Thr He Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr • 750·
151681·序列表.doc 201127956
Padlan(FASEB J. 9:133-139(1995))及 MacCallum(J Mol Biol 262(5):732-45(1996))描述。其他CDR邊界界定可能不嚴格 遵循本文中之一種系統，但仍會與Kabat CDR重疊，不過 根據特定殘基或殘基群或甚至整個CDR不顯著影響抗原結 合之預測或實驗研究結果，其可能會縮短或延長。本文中 所用之方法可利用根據此等系統中之任一者所界定之 CDR，但特定實施例使用Kabat或Chothia界定之CDR。 如本文所用之術語「構架」或「構架序列」係指可變區 減去CDR之剩餘序列。因為CDR序列之確切界定可由不同 系統確定，所以構架序列之含義遵循相應的不同解釋。六 個CDR(輕鏈之CDR-L1、CDR-L2及CDR-L3，以及重鏈之 CDR-H1、CDR-H2及CDR-H3)亦將輕鏈及重鏈上之構架區 在各鏈上分成四個子區（FR1、FR2、FR3及FR4)，其中 CDR1位於FR1與FR2之間，CDR2位於FR2與FR3之間，且 CDR3位於FR3與FR4之間。在不將特定子區指定為FR1、 FR2、FR3或FR4之情形下，構架區當以其他名稱提及時代 表天然存在之單一免疫球蛋白鏈之可變區中之組合FR。如 本文所用之一 FR代表四個子區中之一者，且FR代表構成 構架區之四個子區中之兩個或兩個以上子區。 如本文所用之術語「生殖系抗體基因」或「基因片段」 係指由未經歷產生遺傳重排及突變以表現特定免疫球蛋白 之成熟過程之非淋巴細胞編碼的免疫球蛋白序列（參看例 如 Shapiro 等人，Crit. Rev. Immunol. 22(3): 183-200 (2002) ; Marchalonis 等人，Adv Exp Med Biol. 484:13-30 151681.doc -137- 201127956 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210〉 542 <211〉 246 <212> PRT -751 - 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 542
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val lie 145 150 155 160 151681-序列表.doc •752· 201127956
Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie Gly Leu 165 170 175
He Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Val 180 185 190
Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Ser 210 215 220
Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245 <210〉 543 <211> 228 <212〉 PRT <213〉人造序列
〈223>人造序列之描述：合成多肽 <400〉 543
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45 151681-序列表.doc -753 - 201127956
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Asp His He Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu He Ser Gly Ala Thr Ser Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg -754- 151681·序列表.doc 201127956 225 <210〉 544 <211> 247 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 544
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Leu He Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 no
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu • 755 · 151681-序列表.doc 201127956 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser Trp He 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala 165 170 175
He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 545 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 545
Asp He Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly I 5 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His He Asn Asn Trp •756· 151681·序列表-doc 201127956 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205 151681-序列表.doc - 757 - 201127956
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 546 <211〉 247 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 546
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125 -758-
151681-序列表.doc 201127956
Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser 130 135 140
Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val 145 150 155 160 lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 180 185 190
Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Thr Leu Thr Val Ser Ser
<210〉 547 <211〉 221 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 547
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 •759 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro -760- 151681-序列表.doc 201127956 (2001))。本發明之多個實施例所提供之一個優勢基於如下 認知：生殖系抗體基因比成熟抗體基因更可能保留物種中 個體之必需胺基酸序列結構特徵，因此當用於治療彼物種 時，不太可能認為其來自外來來源。 如本文所用之術語「中和」係指當結合蛋白特異性結合 抗原時抵消抗原之生物活性。在一實施例中，中和結合蛋 白結合細胞激素且使其生物活性降低至少約2〇%、4〇%、 60%、80%、85°/。或 85%以上。 術語「活性」包括諸如DVD-Ig對兩個或兩個以上抗原 之結合特異性及親和力的活性。 術語「抗原決定基」包括能夠特異性結合於免疫球蛋白 或T細胞受體之任何多肽決定子。在某些實施例中，抗原 決定基決定子包括分子之化學活性表面基團（諸如胺基 酸、糖側鏈、磷醯基或磺醯基），且在某些實施例中，其 可具有特定三維結構特徵及/或特定電荷特徵。抗原決定 基為抗體所結合之抗原區。在某些實施例中，當抗體在蛋 白質及/或大分子之複雜混合物中識別其目標抗原時則 稱抗體特異性結合抗原。若抗體交叉競爭（一抗體阻止另 一抗體之結合或調節效應），則認為抗體「結合於同一抗 原決疋基」。此外，抗原決定基之結構定義（重疊、類似、 相同）提供很多資訊，但因為功能定義涵蓋結構（結合）及功 能（調節、競爭）參數，所以其通常更有意義。
本文所用之術語「表面電漿子共振」係指允許藉由（例 如）使用 BlAcore® 系統（BIAcore Intemati〇nal AB，a GE 15168Kdoc •138· 201127956 195 200 205
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 548 <211> 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 548
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val He Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val •761 151681-序列表.doc 201127956 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala 225 230 235 240
Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 549 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400> 549
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly -762-
15168卜序列表.doc 201127956 15 10
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser He Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val He Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190 -763- 151681·序列表.doc 201127956
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 550 <211> 254 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 550
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 •764
151681-序列表.doc 201127956
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu 130 135 140
Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Ser Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr 180 185 190
Lys Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210> 551 <211> 228 <212> PRT <213〉人造序列 - 765 - 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400〉 551
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Asp His He Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Thr Ser Leu Glu Thr •766·
151681-序列表.doc 201127956 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser He Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210> 552 <211> 254 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 552
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr - 767- 151681-序列表.doc 201127956 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala 225 230 235 240
Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 -768- 151681·序列表.doc 201127956 <210> 553 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 553
Asp He Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 15 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser AIel Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val lie Arg Arg 130 135 140 151681-序列表.d〇c • 769- 201127956
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 554 <211〉 254 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 554
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 •770_
151681·序列表 _doc 201127956
Healthcare company, Uppsala, Sweden and Piscataway, NJ) 偵測生物感測器基質内蛋白質濃度之改變來分析即時生物 特異性相互作用之光學現象。更多描述參看jgnss〇n，U.等 人，（1993) /4««.方ζ·ο/· C7/«. 51:19-26 ; J3nsson，U.等人 (1991) 11:620-627 ; Johnsson，B.等人， (1995) ·/· Mo/· 8:125-131 ;及 Johnnson，B.等人， (1991) Ana!. Biochem. 198:268-277 〇 如本文所用之術語「k〇n」意欲指如此項技術所已知，結 合蛋白（例如抗體）締合於抗原形成例如抗體/抗原複合物之 締合速率常數。「KQn」亦稱為術語「締合速率常數」或 「ka」’其在本文中可互換使用。此值指示抗體結合於其 目標抗原之速率或抗體與抗原之間的複合物形成速率，由 以下方程式展示： 抗體（「Ab」）+抗原（「Ag」）— Ab-Ag。 如本文所用之術語「Koff」意欲指如此項技術中已知， 結合蛋白（例如抗體）自例如抗體/抗原複合物解離之解離速 率常數。此值指示抗體與其目標抗原解離或Ab_Ag複合物 隨時間分離成游離抗體及抗原之解離速率，由以下方程式 展示：
Ab+Ag<—Ab-Ag 〇 如本文所使用之術語「KD」意欲指「平衡解離常數」， 且係指在滴定量測中在平衡時獲得之值或藉由用解離速率 常數（kQff)除以締合速率常數（尺“獲得之值。締合速率常 數、解離速率常數及平衡解離常數係用於表示抗體與抗原 151681 .doc •139- 201127956
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu 130 135 140
Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Ser Tyr Val lie Asn Trp Val Lys Gin Lys Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr 180 185 190
Lys Tyr Asn Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Ser Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser -771 - 151681-序列表.doc 201127956 245 250 <210> 55δ <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 555
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu 115 120 125
Gly Gly Arg Val Thr He Thr Cys Lys Ala Ser Asp His lie Asn Asn •772-
151681·序列表doc 201127956 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glii Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro 195 200 205
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 556 <211> 247 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 556
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe -773- 151681-序列表.doc 201127956 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala 165 170 175
lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 , 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly 225 230 235 240 774· 151681·序列表.doc 201127956
Thr Leu Val Thr Val Ser Ser 245 <210> 557 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 557
Asp He Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 15 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Lea Leu lie 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leii Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125 151681-序列表.doc •775 - 201127956
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr.Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 558 <211> 247 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽· <400> 558
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30 -776- 151681·序列表.doc 201127956
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp. Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser 130 135 140
Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val 145 150 155 160 lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp He Gly 165 170 175
Leu He Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 180 185 190
Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Glu. Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala • 777- 151681·序列表.doc 201127956 210 215 220
Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Thr Leu Thr Val Ser Ser 245 <210> 559 <211> 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 559
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala -778-
151681-序列表.doc 201127956 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Tyr Leu Ser Val Ser Leu Gly Gly Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Asp His lie Asn Asn Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu He Ser Gly Ala Thr Ser Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser lie Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210〉 560 〈211〉 249 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 560
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala -779- 151681-序列表.doc 201127956 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175
He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 180 185 190 -780- 151681-序列表.doc 201127956 之結合親和力。測定締合及解離速率常數之方 々法'為此項技 術中所熟知的》使用基於螢光之技術可提供高靈敏度及檢 查平衡狀態生理緩衝液中之樣品的能力。可使用其他實驗 方法及儀器，諸如BIAcore®(生物分子相互作用分析）檢定 (例如可自 BIAc〇re International AB，GE 取祕2 company，Uppsala，Sweden購得之儀器）。另外，亦可使用 可自 Sapidyne Instruments(Boise，Idah〇)購得之 ⑧ (動力學排除檢定）檢定。
「標記物」及「可偵測標記物」意謂連接於特定結合搭 配物（諸如抗體或分析物）例如以便使特異性結合對之成員 (諸如抗體及分析物）之間的反應變得可偵測的部分如此 經標記者稱為「經可偵測標記」。因此，如本文所用之術 語「經標記結合蛋白」係指已併有標記物以便提供對結合 蛋白之鑑別的蛋白質。在一實施例中，標記物為能產生可 用目測或儀器方式偵測出之信號之可债測標諸物，例如併 入經放射性標記之胺基酸或與連接於可由經標記抗生物素 蛋白（例如含有可以光學或比色法伯測之螢光標誌、物或酶 促活性之抗生蛋白鏈菌素）偵測之具有生物素基部分之多 肽。用於多肽之標記物之實例包括（但*限於）以下：放射 性同位素或放射性核種（例如3pj、“c、35g、90γ、99«pc、 lnIn、125I、131I、mT 166 153
Lu Ho或Sm);色素原；螢光標 記物（例如FITC、若丹明（rh〇daraine)、鑭系金屬磷光體广 酶標記物（例如辣根過氧化酶、螢光素酶、鹼性磷酸酶” 化學發光標誌'物；生物素基；由第二報導體識別之預定多 151681.doc • M0· 201127956
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245
<210〉 561 <211〉 224 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 561
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80 781 - 151681 -序列表.doc 201127956
Gin Thr Glu Asp Glu Ala He Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125
Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp 130 135 140 lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 180 185 190
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser 195 200 205
Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 562 <211〉 249 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 782· 151681-序列表.doc 201127956 <400〉 562
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly 130 135 140
Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly 145 150 155 160
Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp 165 170 175
He Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys 783- 15168卜序列表.doc 201127956 180 185 190
Phe Lys Gly Lys Ala Thr Leu Tlir Val Asp Lys Ser Ser Ser Thr Ala 195 200 205
Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Thr Leu Thr Val Ser Ser 245 <210> 563 <211〉 223 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 563
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro -784- 151681-序列表.doc 201127956 6δ 70 75 80
Glu Asp Phe Ala Thr T)rr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly 115 120 125
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro yVla Arg 165 170 175
Phe Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly 180 185 190
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gl3r Thr Lys Leu Thr Val Leu Gly 210 215 220 <210> 564 <211〉 256 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 785· 151681-序列表.doc 201127956 <400> 564
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175 -786 151681-序列表.doc 201127956
Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr 180 185 190
Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser 195 200 205
Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 565 <211〉 231 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 565
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu He Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60 • 787· 151681-序列表.doc 201127956
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr He Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin Met Thr 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He 130 135 140
Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser 165 170 175
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu lie Lys Arg 225 230 <210> 566 788·
151681·序列表.doc 201127956 <211〉 256 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 566
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 TO 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly 130 135 140
Pro Glu Leu Glu Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala -789· 151681-序列表.doc 201127956 145 150 155 160
Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser 165 170 175
Asn Gly Lys Ser Leu Glu Trp lie Gly Asn He Asp Pro Tyr Phe Gly 180 185 190
Gly Thr Asn Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val 195 200 205
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser 210 215 220
Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly 225 230 235 240
Gly Cys Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210〉 567 <211〉 230 <212> PRT <213〉人造序列
<220〉 〈223>人造序列之描述：合成多肽 <400〉 567 Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 151681-序列表.doc -790- 201127956 肽抗原決疋基（例如白胺酸拉鏈對序列、二次抗體之結合 位點、金屬結合區域、抗原決定基標籤）；及諸如釓螯合 物之磁性劑。通常用於免疫檢定之標記物的代表性實例包 括發光。卩为（例如吖啶鏽（acridinium)化合物）及發螢光之部 分（例如螢光素）。於本文中描述其他標記物。就此而言， 部分本身可能未經可偵測標記但在與另一部分反應後可變 得可偵測。使用「經可偵測標記」意欲涵蓋後一類型之可 偵測標記。 術S吾「結合物」係指化學連接於諸如治療劑或細胞毒性 劑之第二化學部分的結合蛋白（諸如抗體）。本文所用之術 浯「藥劑」表示化合物、化合物之混合物、生物大分子或 由生物材料製備之提取物。在一實施例中，治療劑或細胞 毋性劑包括（但不限於）百曰咳毒素（pertussis t〇xin)、紫杉 醇（taxol)、細胞鬆他素B(cytochalasin B)、短桿菌肽 D(gramicidin D)、演化乙鍵、吐根素（emetine)、絲裂黴素 (mitomycin)、依託泊苷（etoposide)、特諾波赛 (tenoposide)、長春新驗（vincr〖stine)、長春驗 (vinblastine)、秋水仙鹼（colchicin)、小紅莓 (doxorubicin)、道諾黴素（daunorubicin)、二羥基炭疽菌素 二酮（dihydroxy anthracin dione)、米托蒽醌 (mitoxantrone)、光神黴素（mithramycin)、放線菌素 D(actinomycin D)、1-去氫睪固酮、糖皮質激素、普魯卡 因（procaine)、四卡因（tetracaine)、利多卡因（lidocaine)、 普萘洛爾（propranolol)及嘌吟黴素（puromycin)以及其類似 151681.doc -141 - 201127956 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu 145 150 155 160
Lys Pro Asp His Leu Phe Thr Gly Leu He Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu lie Gly Asp Lys 180 185 190
Ala Ala Leu Thr lie Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr 210 215 220 -791 · 151681* 序列表.doc 201127956
Lys Leu Thr Val Leu Gly 225 230 <210> 568 <211> 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 568
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 15168〗-序列表.doc -792- 201127956
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr 180 185 190
Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser 195 200 205
Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 569 <211> 224 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 569
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15 -793 151681.·序列表.doc 201127956
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125
Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp 130 135 140
He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 180 185 190
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser •794-
151681·序列表.doc 201127956 195 200 205
Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 570 <211〉 256 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 570
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly - 795 - 151681·序列表.doc 201127956 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly 130 135 140
Pro Glu Leu Glu Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala 145 150 155 160
Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser 165 170 175
Asn Gly Lys Ser Leu Glu Trp He Gly Asn He Asp Pro Tyr Phe Gly 180 185 190
Gly Thr Asn Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val 195 200 205
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser 210 215 220
Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly 225 230 235 240
Gly Cys Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210> 571 <211〉 223 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 571
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly •796·
151681·序列表.doc 201127956 5 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly 115 120 125
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg 165 170 175
Phe Ser Gly Ser Leu He Gly Asp Lys Ala Ala Leu Thr He Thr Gly 180 185 190 151681·序列表.doc - 797 - 201127956
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220 <210〉 572 <211〉 249 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 572
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110 -798
151681-序列表.doc 201127956
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175
lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe? Lys Arg 180 185 190
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 573 <211〉 231 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 799- 151681·序列表.doc 201127956 <400> 573
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu He Gly Asp Lys Ala Ala Leu Thr He Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala He Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp He Gin Met Thr 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He 130 135 140
Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He Tyr Phe Thr Ser Ser 165 170 175
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr -800-
151681-序列表.doc 201127956 物或同系物。當結合抗體在免疫檢定之情形中使用時，其 為用作偵測抗體之經可偵測標記抗體。 如本文所用之術語「晶體」及「結晶」係指以晶體形式 存在之結合蛋白(例如抗體)或其抗原結合部分。晶體為物 質的一種固態形式，其不同於諸如非晶形固態或液晶態之 其他形式。晶體係由原子、離子、分子（例如蛋白質，諸 如抗體）或分子組裝體（例如抗原/抗體複合物）之規則的重 複三維陣列構成。此等三維陣列係根據此領域中充分瞭解 之特定數學關係排列。晶體中重複之基本單元或建構塊件 _ (building block)稱為不對稱單元。以符合既定之定義明確 的晶體學對稱性之排列重複不對稱單元提供晶體之「單位 晶胞」。在所有三個維度中藉由規則平移重複單位晶胞提 供日日體。參看 Giege, R.及 Ducruix，A. Barrett,
Crystallization of Nucleic Acids and Proteins，a Praetical Approach，第 2版，第 20 1-16 頁，〇xford University Press，
New York, New York，（1999)。 術s吾「聚核普酸」意謂兩個或兩個以上核普酸（核糖核 _ 苷酸或去氧核苷酸或任一類核苷酸的經修飾形式）之聚合 形式。該術語包括DNA之單股及雙股形式。 術語「經分離聚核苷酸」將意謂一種聚核苷酸（例如基 因組、cDNA或合成來源者，或其某種組合），鑒於其來 源’該「經分離聚核苷酸」不與在自然界中可發現「經分 離聚核苦酸」之整個聚核皆酸或其一部分締合；可操作地 連接至在自然界中不與其連接之聚核苦酸；或在自然界中 151681.doc -142- 201127956 180 185 190
Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu lie Lys Arg 225 230
<210> 574 <211> 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 574
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -801 - 151681-序列表.doc 201127956 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly 130 135 140
Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly 145 150 155 160
Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp 165 170 175 lie Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys 180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala 195 200 205
Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Thr Leu Thr Val Ser Ser 245
<210> 575 <211〉 230 <212〉 PRT -802-
151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 575
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu 145 150 155 160 803- 151681·序列表.doc 201127956
Lys Pro Asp His Leu Phe Thr Gly Leu He Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu lie Gly Asp Lys 180 185 190
Ala Ala Leu Thr lie Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr 210 215 220
Lys Leu Thr Val Leu Gly 225 230 <210> 576 <211> 246 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 576
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60 -804-
151681-序列表.doc 201127956
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly 165 170 175
lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala T}rr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser • 805 · 151681-序列表.doc 245 201127956 <210〉 577 <211〉 224 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 577
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala He Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125
Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp -806-
151681-序列表.doc 201127956 130 135 140
Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 180 185 190
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr 195 200 205
Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 578 <211〉 246 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 578
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val -807- 151681"序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met 145 150 155 160
Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie Gly Asn 165 170 175
lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240 808· 151681-序列表.doc 201127956
Thr Leu Thr Val Ser Ser 245 <210〉 579 <211〉 223 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 579
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly 115 120 125 -809- 151681-序列表.doc 201127956
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg 165 170 175
Phe Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly 180 185 190
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220 <210> 580 〈211〉 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 580
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45 •810·
151681·序列表.doc 201127956 不作為較大序列之一部分存在。 術語「載體」意欲指一種能夠轉運已連接之另一核酸的 核酸分子。一種類型之載體為「質體」，其係指内部可接 合其他舰區段之環狀雙股DNA環。另一類型之載體為病 毒載體’其中可將其他DNA區段接合至病毒基因組中。某 些載體能夠在引入該等載體之宿主細胞中自主複製(例如 具有細菌複製起點之細菌載體及游離型哺乳動物載體）。 其他載體（例如非游離型哺乳動物載體）可在引入宿主細胞 中之後整合至宿主細胞之基因組中’且藉此與宿主基因組
-起複製。此外’某些載體㈣指導與其可操作地連接之 基因的表現。該等載體在本文中稱為「重組表現載體」 (或簡稱為「表現載體」）一般而言，適用於重組舰技 術中之表現載體通常呈質體形式。因為f 用形式，所以在本說明書，，「質體」與「載體」可2 使用U ’本發明意欲包括表現載體之該等其他形式， 諸如病毒載體（例如複製缺陷型反轉錄病毒、腺病毒及腺 相關病毒）’其提供等效功能。 —術語「可操作地連接」係指所述組分處於允許其按其預 定方式起作用之關係、中的併接。使控制序列「可操作地連 接」至編碼序列係以使編竭序列之表現在與控制序列相容 之條件下實現的方式接合。「可操作地連接」之序列包括 與相關基因相鄰之表現控制序列以及反式作用或在一定距 離外作用以控制相關基因的表現控制序列。如本文所用之 術語「表現控制序列」係指實現所接合之編碼序列表現及 151681.doc •】43 · 201127956
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met £ 151681·序列表 _doc -811 - 201127956 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 581 <211〉 231 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 581
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala He Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin Met Thr -812-
151681·序列表.doc 201127956 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He 130 135 140
Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe 165 170 175
Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu He Lys Arg 225 230
<210> 582 <211〉 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 582
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr •813- 151681-序列表.doc 201127956 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu 130 135 140
Glu Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys 165 170 175
Ser Leu Glu Trp He Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn 180 185 190
Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser 195 200 205 -814- 151681·序列表.doc 201127956
Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250
<210> 583 <211〉 230 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 583
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95 -815 151681·序列表.doc 201127956
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu 145 150 155 160
Lys Pro Asp His Leu Phe Thr Gly Leu He Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu lie Gly Asp Lys 180 185 190
Ala Ala Leu Thr He Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205 220
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr 210 215
Lys Leu Thr Val Leu Gly 225 230 <210〉 584 <211〉 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 816- 151681·序列表.doc 201127956 <400> 584
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr •817- 151681·序列表.doc 201127956 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 585 <211〉 224 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 585
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu He Gly Asp Lys Ala Ala Leu Thr He Thr Gly Ala -818 - 151681·序列表.doc 201127956 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125
Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp 130 135 140
Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 180 185 190
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr 195 200 205
Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 586 <211〉 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 819- 15168卜序列表.doc 201127956 <400> 586
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu 130 135 140
Glu Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys 165 170 175 • 820 151681-序列表.doc 201127956 力工所必需之聚核苷酸序列。表現控制序列包括適當轉錄 | 、’’、、啟動子及強化子序列；有效RNA加工信號， 諸如剪接及聚腺*酸化信號；使細胞質mRNA穩定之序 】提阿轉澤效率之序列（亦即Kozak共同序列）；增強蛋 質疋丨生之序列；及必要時增加蛋白質分泌之序列。該 等控制序列之性質視宿主生物體而不同；在原核生物中， §等控制序列一般包括啟動子、核糖體結合位點及轉錄終 止序列，在真核生物中，該等控制序列一般包括啟動子及 轉錄、、止序列。術語「控制序列」意欲包括對於表現及加籲 工而s有必要存在的組分，且亦可包括適宜存在之其他組 分’例如前導序列及融合搭配物序列。 「轉型」係指使外源DNA進入宿主細胞中之任何過程。 可使用此項技術中熟知的多種方法在天然或人工條件下進 行轉型。轉型可憑藉將外來核酸序列插入至原核生物或真 核生物宿主細胞中之任何已知方法進行。該方法係基於所 轉型之宿主細胞選擇且可包括（但不限於）病毒感染、電穿 孔' 脂質體轉染及粒子絲。該等「轉型」細胞包括插人· 之DNA能夠以自主複製質體或宿主染色體之一部分的形式 複製的穩定轉型細胞。其亦包括在有限時段内短暫表現所 插入之DNA或RNA的細胞。 術語「重組宿主細胞」（或簡稱為「宿主細胞」）意欲指 已引入外源DNA之細胞。應瞭解，該等術語不僅欲指特定 個體細胞，而且亦指該細胞之子代。因為某些修飾可能因 突變或環境影響而在繼代中發生，所以該子代實際上可能 151681.doc •144- 201127956
Ser Leu Glu Trp lie Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn 180 185 190
Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210> 587 <211〉 223 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 587
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 -821 · 15168 序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly 115 120 125
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg 165 170 175
Phe Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly 180 185 190
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220 <210> 588 <211> 246 <212> PRT <213〉人造序列 • 822- 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 588
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp He 35 40 45
Gly Asn He Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp He 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly -823- 151681·序列表.doc 201127956 165 170 175 lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210> 589 <211〉 231 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 589
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu He Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe -824- 151681·序列表.doc 201127956 50 55 60
Ser Gly Ser Leu He Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin Met Thr 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie 130 135 140
Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe 165 170 175
Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu He Lys Arg 225 230 -825- 151681-序列表d〇c 201127956 <210> 590 <211> 246 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 590
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala Ser Val 130 135 140 -826 * 15168丨·序列表doc 201127956
Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met 145 150 155 160
Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie Gly Asn 165 170 175 lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245
<210> 591 <211〉 230 〈212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400> 591
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30 • 827 · 151681-序列表.doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu 145 150 155 160
Lys Pro Asp His Leu Phe Thr Gly Leu lie Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu lie Gly Asp Lys 180 185 190
Ala Ala Leu Thr lie Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr -828·
151681-序列表.doc 201127956 210 215 220
Lys Leu Thr Val Leu Gly 225 230 <210〉 592 <211> 247 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 592
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val -829- 151681-序列表.doc 201127956 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala 165 170 175 lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210> 593 <211〉 224 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 593
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu •830· 151681-序列表.doc 201127956 不與親本細胞相同’但其仍包括在如本文所用之術語「宿 主細胞」之範疇内。在一貫施例中，宿主細胞包括選自生 物界中之任一者的原核細胞及真核細胞。在另一實施例 中’真核細胞包括原生生物、真菌、植物及動物細胞。在 另一實施例中，宿主細胞包括（但不限於）原核細胞株大腸 才干卤，哺乳動物細胞株CHO、HEK 293、COS、NSO、SP2 及PER_C6 ;昆蟲細胞株Sf9 ;及真菌細胞釀酒酵母。 _ 重組DNA、寡核苷酸合成及組織培養及轉型可使用標準 技術進行（例如電穿孔、脂質體轉染）。酶促反應及純化技 術可根據製造商說明書或如此項技術中通常所實現或如本 文所述執行。上述技術及程序一般可根據此項技術中熟知 之習知方法及如本說明書全文所引用及論述之各種综合性 參考文獻及更具體之參考文獻令所述執行。參看例如
Sambrook 等人，Molecular Cloning: a Lab〇ratory Manual (第 2版，Cold Spring Harbor Laboratory Press, Cold Spring φ Harbor，N.Y. (1989))，其為任何目的以引用的方式併入本 文中。 如此項技術中已知之「轉殖基因生物體」係指具有含有 轉殖基因之細胞的生物體，其中引入生物體（或生物體之 祖先）中之轉殖基因表現該生物體中天然不表現之多肽。 「轉殖基因」為穩定且可操作地整合至發育成轉殖基因生 物體之細胞之基因組中，從而引導所編碼基因產物於轉殖 基因生物體之一或多種細胞類型或組織中表現的Dna構築 體。 15168 丨.doc -145- 201127956 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125
Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val 130 135 140 lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 180 185 190 •831 151681·序列表.doc 201127956
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 195 200 205
Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 〈210〉 594 <211〉 247 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 594
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110 - 832 ·
151681-序列表.doc 201127956
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala Ser 130 135 140
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn 145 150 155 160
Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie Gly 165 170 175
Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Thr Leu Thr Val Ser Ser 245 <210> 595 <211〉 223 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 - 833 - 151681-序列表.doc 201127956 <400> 595
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly 115 120 125
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg 165 170 175
Phe Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr He Thr Gly •834·
151681·序列表.doc 201127956 180 185 190
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220
<210> 596 <211> 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 596
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin - 835 - 151681·序列表.doc 201127956 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala 225 230 235 240
Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 597 <211〉 231 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -836- 151681-序列表.doc 201127956 <400> 597
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu He Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp He Gin Met Thr 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He 130 135 140
Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn 165 170 175 -837 15168〗-序列表.doc 201127956
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu lie Lys Arg 225 230
<210> 598 <211〉 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 598
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 838· 151681·序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly loo 105 no
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu 130 135 140
Leu Glu Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly 165 170 175
Lys Ser Leu Glu Trp lie Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210〉 599 • 839· 151681-序列表.doc 201127956 <211〉 230 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 599
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu •840-
151681·序列表doc 201127956 15。調控」與「調節」可互換使用，且如本文中所使 用其係指改變或變化相關分子之活性（例如細胞激素之 生物活性）。調節可為增加或降低相關分子之某一活性或 功能之晉伯 ν 里值。为子之例示性活性及功能包括（但不限於）結 合特徵、酶促活性、細胞受體活化及信號轉導。 相應地’術語「調節劑」為能夠使相關分子之活性或功 月b (例如細胞激素之生物活性）改變或變化的化合物。舉例 而。調節劑可引起分子的某一活性或功能之量值相較於 在無該調節劑存在下所觀察到之活性或功能之量值增加或 減小。在某些實施例中，調節劑為降低分子之至少一種活 性或功能之量值的抑制劑。例示性抑制劑包括（但不限於） 蛋白質、肽、抗體、肽體（peptib〇dy)、碳水化合物或小有 機分子。肽體於例如WO 01/83525中描述。 術語「促效劑」係指當與相關分子接觸時引起分子的某 /舌丨生或功此之量值相較於在無促效劑存在下所觀察到之 活性或功能之量值增加的調節劑。相關特定促效劑可包括 (但不限於）多肽、核酸、碳水化合物或結合於抗原之任何 其他分子。 術語「拮抗劑」或「抑制劑」係指當與相關分子接觸時 引起分子的某一活性或功能之量值相較於在無拮抗劑存在 下所觀察到之活性或功能之量值降低的調節劑。相關特定 拮抗劑包括阻斷或調節抗原之生物或免疫活性之拮抗劑。 抗原之括抗劑及抑制劑可包括（但不限於）蛋白質、核酸、 碳水化合物或結合於抗原之任何其他分子。 151681.doc -146- 201127956 145 150 155 160
Lys Pro Asp His Leu Phe Thr Gly Leu lie Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu He Gly Asp Lys 180 185 190
Ala Ala Leu Thr lie Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr 210 215 220
Lys Leu Thr Val Leu Gly 225 230 <210> 600 <211> 254 <2].2> PRT <21.3>人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 600
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe -841 - 151681·序列表.doc 201127956 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr lie Asn Ala Ser Trp He His Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 195 200 205
Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala 225 230 235 240 -842- 151681·序列表.doc 201127956
Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 〈210〉 601 <211〉 224 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 601
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr He Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 115 120 125 - 843 · 151681 -序列表.doc 201127956
Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val 130 135 140 lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 145 150 155 160
Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 180 185 190
Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 195 200 205
Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 602 <211〉 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 602
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -844·
151681·序列表.doc 201127956
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Gin Ser Gly Pro Glu 130 135 140
Leu Glu Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Ser Asn Gly 165 170 175
Lys Ser Leu Glu Trp lie Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys •845· 151681-序列表.doc 201127956 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210〉 603 <211〉 223 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 603
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly • 846- 151681·序列表.doc 201127956 115 120 125
Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr 130 135 140
Ser Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr 145 150 155 160
Gly Leu He Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg 165 170 175
Phe Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly 180 185 190
Ala Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser 195 200 205
Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220
<210> 604 <211> 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 604
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Asn Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie -847· 151681·序列表.doc 201127956 35 40 45
Gly Asn He Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala 165 170 175 lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220 • 848 · 151681-序列表,doc 201127956
Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 605 <211> 231 <212〉 PRT <213〉人造序列 <220>
<223〉人造序列之描述：合成多肽 <400> 605
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110 -849- 151681-序列表.doc 201127956
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin Met Thr 115 120 125
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie 130 135 140
Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser Leu Ala Trp Tyr Gin 145 150 155 160
Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn 165 170 175
Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly 210 215 220
Thr Lys Val Glu He Lys Arg 225 230 〈210〉 606 <211> 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 606
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -850
151681·序列表.doc 201127956 如本文所用之術語「有效量」係指足以降低或改善病症 或其一或多種症狀之嚴重程度及/或持續時間；預防病症 進展；引起病症消退；預防與病症相關之一或多種症狀復 發、發展、發作或進展；偵測病症，或增強或改良另一療 法（例如預防劑或治療劑）之預防或治療作用的療法之量。 「患者」與「個體」在本文中可互換使用，指動物，諸 如哺乳動物，包括靈長類動物（例如人類、猴及黑猩猩）、 參 非靈長類動物（例如母牛、豬、駱駝、美洲駝、馬、山 羊、兔、綿羊、倉鼠、天竺鼠 '猫、犬、A a、小鼠、 鯨）禽類（例如鴨或鵝）及鯊魚。較佳地，患者或個體為人 類，諸如正在針對疾病、病症或病狀進行治療或評定之人 類、具有罹患疾病、病症或病狀風險之人類、罹患疾病、 病症或病狀之人類，及/或正在針對疾病、病症或病狀進 行治療之人類。 如本文所用之術語「樣品」係以其最廣泛意義使用。如 鲁本文所用之「生物樣品」包括（但不限於）來自活物 thing)或先前為活物之任何量的物質。該等活物包括（但不 阳；）人類、小鼠、大鼠、猴、犬、兔及其他動物。該等 物質包括（但不限於）血液（例如全血）、血漿、血清、尿 液羊水、滑液、内皮細胞、白血球、單核細胞、其他細 胞、器宫、組織、骨髓 '淋巴結及脾臟。 、、''刀」及「至少一種組分」一般係指可包括於套組中 以根據本文所述之方法及此項技術中已知之其他方法檢定 測忒樣(諸如患者尿液、血清或血漿樣品）之捕捉抗體、 151681.doc -147- 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala Ser 130 135 140
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn 145 150 155 160
Met Asn Trp Val Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp lie Gly 165 170 175
Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met •851 151681-序列表 doc 201127956 195 200 205
Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Thr Leu Thr Val Ser Ser 245 <210> 607 <211〉 230 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 607
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu -852- 151681·序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin Ala Val Val Thr Gin Glu Ser 115 120 125
Ala Leu Thr Thr Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Glu 145 150 155 160
Lys Pro Asp His Leu Phe Thr Gly Leu He Gly Gly Thr Asn Asn Arg 165 170 175
Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu lie Gly Asp Lys 180 185 190
Ala Ala Leu Thr lie Thr Gly Ala Gin Thr Glu Asp Glu Ala lie Tyr 195 200 205
Phe Cys Ala Leu Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr 210 215 220
Lys Leu Thr Val Leu Gly 225 230 <210〉 608 <211> 250 <212> PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 • 853 - 151681-序列表.doc 201127956 <400> 608
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125
Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro 130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys 145 150 155 160
Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu 165 170 175 -854
151681-序列表.doc 201127956
Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp 180 185 190
Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr 195 200 205
Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 609 <211> 234 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 609
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 855- 151681-序列表.doc 201127956
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 HO
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie 115 120 125
Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 130 135 140
Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser 165 170 175
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp 195 200 205
Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 610 856-
151681·序列表.doc 201127956 <211> 250 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 610
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu 130 135 140
Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly -857· 151681·序列表.doc 201127956 145 150 155 160
Ser Phe Ser Gly Tyr Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys 165 170 175
Gly Leu Glu Trp lie Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr 180 185 190
Asn Pro Ser Leu Lys Ser Arg Val Thr He Ser Val Glu Thr Ser Lys 195 200 205
Asn Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp 225 230 235 240
Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 611 <211〉 234 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 611
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -858- 151681·序列表.doc 201127956 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Glu Met Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr lie Asn Cys Arg 130 135 140
Ser Ser Gin Ser Val Leu Tyr Ser Ser Ser Asn Arg Asn Tyr Leu Ala 145 150 155 160
Trp Tyr Gin Gin Asn Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Gin Gin Tyr Tyr Ser Thr Pro Arg Thr Phe 210 215 220 •859- 151681·序列表.doc 201127956
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 〈210〉 612 <211〉 250 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 612
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 860- 151681·序列表.doc 201127956 偵測或結合抗體、對照物、校正劑、一系列校正劑、靈敏 度組（sensitivity panel)、容器、緩衝液、稀釋劑、鹽、 酶、酶之辅因子、偵測試劑、預處理試劑/溶液、受質（例 如呈溶液形式）、停止溶液及其類似物。因此，在本發明 之上下文中，「至少一種組分」及「組分」可包括如上之 多狀或其他分析物，諸如包含分析物（諸如多肽）之組合 物，其視情況諸如藉由結合於抗分析物（例如抗多肽）抗體 而固定於固體支撐物上。一些組分可呈溶液形式或經凍乾 以在復原後用於檢定中。 對照物」係指已知不含分析物（「陰性對照物」）或含 有分析物（「陽性對照物」）之組合物。陽性對照物可包含 已知濃度之分析物。「對照物」、「陽性對照物」及「校正 劑」在本文中可互換使用，指包含已知濃度之分析物的組 合物。「陽性對照物」可用於確定檢定效能特徵且為試劑 (例如分析物）完整性的適用指示劑。 預疋截止」及「預定程度」一般係指用以藉由將檢定 結果相對於預定截止/㈣進行比較來評定診斷/預後/治療 功效結果的檢定截止值，其中預定截止/程度已與各種臨 床參數(例如疾病之嚴重程度、進展/無進展/改良等)相聯 繫或相關聯。儘管本發明可提供例示性敎程度，作眾所 周知截止值可視免疫檢定之性f(g㈣狀抗體等）而 變化。此外’針對其他免疫檢定來調適本發明以基於本發 明獲得用於彼等其他免疫檢定之免疫檢定特定截止值完全 在熟習此項技術者之普通技能範圍内。儘管預定截止/程 151681.doc -148· 201127956
Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro 130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys 145 150 155 160
Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu 165 170 175
Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp 180 185 190
Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr 195 200 205
Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 613 <211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 613
Asp He Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 -861 15168K 序列表.doc 201127956
Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala 130 135 140
Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin -862-
151681·序列表.doc 201127956 195 200 205
Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg 225
<210〉 614 <211> 250 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 614
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin - 863 - 151681·序列表.doc 201127956 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu 130 135 140 Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly 145 150 155 160
Ser Phe Ser Gly Tyr Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys 165 170 175
Gly Leu Glu Trp He Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr 180 185 190
Asn Pro Ser Leu Lys Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys 195 200 205
Asn Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp 225 230 235 240
Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 615 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 864- 151681·序列表.doc 201127956 <400〉 615
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val. Ala Ala 100 105 110
Pro Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly 145 150 155 160
Gin Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175 -865 151681 -序列表.doc 201127956
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220
He Lys Arg 225
<210〉 616 <211> 243 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 616
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr He Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80 866-
151681·序列表.doc 201127956
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg G.Ly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val 115 120 125
Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser 130 135 140
Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr lie His Trp Val 145 150 155 160
Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie Tyr Pro 165 170 175
Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190
lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser 195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly 210 215 220
Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240
Val Ser Ser <210〉 617 867- 151681-序列表.doc 201127956 <211〉 234 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 617
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp He 115 120 125
Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 130 135 140
Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala -868-
151681·序列表.doc 201127956 160 145 150 155
Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser 165 170 175
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp 195 200 205
Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 618 <211〉 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 618
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val •869· 151681-序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu 130 135 140
Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr Tyr Trp 145 . 150 155 160
Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Glu 165 170 175 lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg 180 185 190
Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu Lys Leu 195 200 205
Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr 225 230 235 240 -870- 151681-序列表.doc 201127956 之轉切值可隨檢定而變化，但如本文所述之相關性（若 存在）應普遍適用。 如本文所述之診斷檢定中所用之「預處理試劑」（例如 ’今解、沈澱及/或增溶試劑）為使存在於測試樣品中之任何 、、田胞/合解及/或使存在於測試樣品中之任何分析物增溶的 忒劑。如本文中進一步描述，並非所有樣品均必需預處 尤其，使分析物（例如相關多肽）增溶可能使分析物自 存在於樣品中之任何内源結合蛋白釋放。預處理試劑可為 均質的（無需分離步驟）或異質的（需要分離步驟）。藉由使 用異質預處理試劑，自測試樣品移除任何沈澱之分析物結 合蛋白’隨後進行檢定之下一步驟。 '«質控制試劑」在本文所述之免疫檢定及套組的情形 =包括（但不限於）校正劑、對照組及靈敏度組。通常使用 「校正劑」或「標準物」（例如一或多個，諸如複數個）來 建立内插分析物（諸如抗體或分析物）濃度之校正（標準）曲 線。或者，可使用接近預定陽性/陰性截止之單一校正 劑。可聯合使用多個校正劑（亦即一種以上校正劑或不同 量之校正劑），以便構成「靈敏度組」。 「風險」係指目前或在將來某個時間點發生特定事件之 u或機率。「風險分層」係指使得醫師可將患者分成 /、有發展特疋疾病、病症或病狀之低、中、高或最高風險 的一系列已知臨床風險因子。 特異）生」在特異性結合對之成員（例如抗原（或其片幻 與抗體（或其抗原反應性片段）)之間的相互作用之情形下係 15168】.doc •149- 201127956
Val Ser Ser <210> 619 <211〉 234 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 619
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Glu Met Thr Gin Ser Pro 115 120 125 •871 · 151681·序列表doc 201127956
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr He Asn Cys Arg 130 135 140
Ser Ser Gin Ser Val Leu Tyr Ser Ser Ser Asn Arg Asn Tyr Leu Ala 145 150 155 160
Trp Tyr Gin Gin Asn Pro Gly Gin Pro Pro Lys Leu Leu He Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Gin Gin Tyr Tyr Ser Thr Pro Arg Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 620 <211〉 243 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 620
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30 - 872-
151681-序列表.doc 201127956
Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val 115 120 125
Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser 130 135 140
Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His Trp Val 145 150 155 160
Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie Tyr Pro 165 170 175
Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190
He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser 195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly •873- 151681-序列表 _doc 201127956 210 215 220
Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240
Val Ser Ser <210〉 621 <211〉 227 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 621
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie • 874·
151681-序列表doc 201127956 100 105 no
Lys Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala 130 135 140
Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin 195 200 205
Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220
He Lys Arg 225 <210〉 622 <211〉 243 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 622
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly •875 - 151681-序列表,doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu Thr Leu 130 135 140
Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr Tyr Trp 145 150 155 160
Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Glu 165 170 175 lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg 180 185 190 •876· 151681·序列表.doc 201127956
Val Thr He Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu Lys Leu 195 200 205
Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr 225 230 235 240
Val Ser Ser
<210> 623 <211> 227 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 623
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 877- 151681·序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Ala Thr lie Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr 130 135 140
Ser Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin .Asn Pro Gly 145 150 155 160 Gin Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175 Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220
He Lys Arg 225 <210> 624 <211〉 252 <212〉 PRT <213〉人造序列 878· 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 624
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160 lie Lys Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly - 879- 151681-序列表.doc 201127956 165 170 175
Leu Glu Trp Val Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 625 <211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 625
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly -880·
151681-序列表.doc 201127956 指相互作用之選擇反應性。片語「特異性結合於」及其類 似片語係指抗體（或其抗原反應性片段）特異性結合於分析 物（或其片段）且不特異性結合至其他實體之能力。 特異性結合搭配物」為特異性結合對之成員。特異性 結合對包含兩個不同分子，其經由化學或物理方式彼此特 異性結合。因此，除常見免疫檢定之抗原與抗體特異性結 合對以外，其他特異性結合對可包括生物素與抗生物素^ 白（或抗生蛋白鏈菌素）；碳水化合物與凝集素；互補核苷 酸序列；效應分子與受體分子；輔因子與酶；酶抑制劑與 酶；及其類似物。此外’特異性結合對可包括為初始特異 性結合成員之類似物的成員，例如分析物類似物。免疫反 應性特異性結合成員包括經分離或以重組方式產生之抗 原、抗原片段及抗體（包括單株及多株抗體）、以及其複合 物、片段及變異體（包括變異體片段）。 如本文所用之「變異體」意謂因胺基酸之添加（例如插 入）、缺失或保守性取代而在胺基酸序列方面不同於既定 多肽（例如IL-18、BNP、NGAL或HIV多肽，或抗多肽抗 體），但保留既定多肽之生物活性（例如變異體比-丨8可與抗 IL-18抗體競爭結合IL-18)的多肽。此項技術中認為胺基酸 之保守性取代（亦即胺基酸經具有類似特性（例如親水性及 帶電區程度及分佈）之不同胺基酸置換）通常涉及微小變 化。如此項技術中所瞭解’可部分地藉由考慮胺基酸之親 水指數來鑑別此等微小變化（參看例如Kyte等人，j. Mol. Biol. 157: 105-132 (1982))。胺基酸之親水指數係基於對 151681.doc •150. 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr GLn Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 •881 - 151681·序列表.doc 201127956 <210> 626 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 626
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140 -882 - 151681-序列表 doc 201127956
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser lie Tyr Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Ser Ser Thr He Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala 195 200 205
Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp 225 230 235 240 lie Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210〉 627 <211〉 228 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 627
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30 -883- 151681·序列表.doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin 130 135 140
Ala Ser Gin Asp He Thr Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Phe Thr lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Asn Cys 195 200 205
Gin Gin Cys Glu Asn Phe Pro lie Thr Phe Gly Gin Gly Thr Arg Leu -884 -
151681·序列表.doc 201127956 210 215 220
Glu He Lys Arg 225 <210> 628 <211> 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 628
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe - 885 - 151681·序列表.doc 201127956 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160 lie Lys Asp Thr Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 629 <211〉 221 <212> PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400〉 629
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -886 - 15168卜序列表.doc 201127956 10 15
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190 -887· 15168卜序列表doc 201127956
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 630 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 630
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110 -888· 15168卜序列表doc 201127956
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser He Tyr Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala 195 200 205
Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp 225 230 235 240
He Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210〉 631 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 889- 151681-序列表.doc 201127956 <400> 631
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin -890-
151681·序列表.doc 201127956 其疏水性及電荷之考慮。在此項技術中已知具有類似親水 指數之胺基酸可經取代且仍保留蛋白質功能。在一態樣 中，親水指數為±2之胺基酸經取代。胺基酸之親水性亦可 用於揭示將會產生保留生物功能之蛋白質的取代。對胺基 酸親水性之考慮在肽之情形下允許計算彼肽之最大局部平 均親水性，其為一種已經報導與抗原性及免疫原性密切相 關之適用量度（參看例如美國專利第4,554,1〇1號，其以引 用的方式併入本文中）。如此項技術中所瞭解，具有類似 親水性值之胺基酸之取代作用可產生保留生物活性（例如 免疫原性）之肽。在一態樣中，用彼此親水性值在±2範圍 内之胺基酸進行取代。胺基酸之疏水性指數及親水性值皆 受彼胺基酸之特定側鍵的影響。與彼觀測結果一致，與生 物功能相容之胺基酸取代作用據瞭解係視胺基酸，且尤其 彼等胺基酸之側鏈之相對類似性（如由疏水性、親水性、 電荷、尺寸及其他特性所揭示）而定。「變異體」亦可用於 描述已經差異性處理（諸如藉由蛋白質水解、麟酸化或其 他轉譯後修飾）’但仍保留生物活性或抗原反應性（例如結 合IL-18之能力）的多肽或其片段。除非上下文另有相反說 明’否則本文中使用「變異體」意欲涵蓋變異體之片段。 I·產生DVD結合蛋白 本發明係關於能夠結合一或多個目標之雙重可變區域結 合蛋白及其製備方法。在一實施例中，結合蛋白包含多肽 鏈’其中該多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中 VD1為第一可變區域’ VD2為第二可變區域，c為恆定區 151681.doc -151 - 201127956 180 185 190
Pro Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205 lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg 210 215 220
<210〉 632 <211> 245 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 632
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ser Tyr He Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly -891- 151681-序列表doc 201127956 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210> 633 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •892-
151681-序列表.doc 201127956 <400> 633
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175 893 151681-序列表 _doc 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210〉 634 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 634
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 894·
151681·序列表d〇c 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser He Tyr Ser Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 165 170 175
He Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly Thr Met 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 635 151681-序列表.doc -895- 201127956 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 635
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 δ 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin 130 135 140
Ala Ser Gin Asp He Thr Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro -896-
151681·序列表.doc 201127956 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Glu Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Pile Thr 180 185 190
Phe Thr lie Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Asn Cys 195 200 205
Gin Gin Cys Glu Asn Phe Pro lie Thr Phe Gly Gin Gly Thr Arg Leu 210 215 220
Glu He Lys Arg 225 <210> 636 <211> 245 <212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 636
Glu Val Gin Leu Val Glu Ser 01}^ Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val • 897- 151681，序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 · 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240 •898 · 151681-序列表.doc 201127956
Val Thr Val Ser Ser 245 <210〉 637 <：211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 637
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125 •899· 151681·序列表.doc 201127956
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp .Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 638 <211〉 245 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 638
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 •900-
151681-序列表.doc 201127956 域’ XI表示胺基酸或多肽，χ2表示以區，且η為〇或i。本 發明結合蛋白可使用多種技術產生。本發明提供產生結合 蛋白之表現載體、宿主細胞及方法。 Α.產生親本單株抗體 DVD結合蛋白之可變區域可獲自親本抗體（包括能結合 相關抗原之多株及mAb)。此等抗體可天然存在或可藉由 重組技術產生。 MAb可使用此項技術中已知之多種技術製備，包括使用 融合瘤、重組及噬菌體呈現技術或其組合。舉例而言，可 使用融合瘤技術產生mAb，包括此項技術中已知且例如在 以下文獻中教示之融合瘤技術：Harlow等人，Antibodies· A Laboratory Manual, (Cold Spring Harbor Laboratory
Press，第 2 版· 1988) ; Hammerling 等人，M〇noci〇nal
Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N Y 1 981)(該等參考文獻以全文引用的方式併入本文中）。如本 文所用之術語「單株抗體」不限於經由融合瘤技術產生之 抗體。術語「單株抗體」係指來源於單一純系，包括任何 真核、原核或嗟菌體純系之抗體，而非產生其之方法。如 下文實例1論述’選擇融合瘤，選殖且針對包括強健融合 瘤生長、高抗體產量及之所需抗體特徵之所需特徵進一步 篩選。融合瘤可在同基因型動物、缺乏免疫系統之動物 (例如裸小鼠）中活體内培養及擴增或在細胞培養物中活體 外培養及擴增。選擇、選殖及擴增融合瘤之方法為熟 習此項技術者所熟知。在一特定實施例中，融合瘤為小鼠 151681.doc •152· 201127956
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
.Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr Ser Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 165 170 175 lie Ser Ser Ser Ser Ser Thr He Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Arg Gly Asp Phe Asp Ala Phe Asp lie Trp Gly Gin Gly Thr Met -901 - 151681·序列表.doc 201127956 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 639 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 639
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val -902-
151681·序列表.doc 201127956 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro 195 200 205 lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg 210 215 220
<210> 640 <211> 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 640
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -903· 151681·序列表.doc 201127956 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140
He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val He 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn 195 200 205
Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala Arg Ala Leu 210 215 220 •904- 151681-序列表 doc 201127956
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ala <210〉 641 <211> 226 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 641
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 1 5 10 - 15
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45
lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser He Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110 •905 - 151681·序列表.doc 201127956
Gin Pro Lys Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie 115 120 125
Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser 130 135 140
Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly 145 150 155 160
Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser 180 185 190 lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin 195 200 205
Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 210 215 220
Lys Arg 225 <210〉 642 <211> 244 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 642
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15 •906
151681·序列表.doc 201127956
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asa Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin.Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr Val Met Ala 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser lie 165 170 175
Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met -907- 151681·序列表.doc 201127956 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg Gly 210 215 220
Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser <210> 643 ^ <211> 225 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 643
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr -908- 151681·序列表.doc 201127956 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly 115 120 125
Gin Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser 130 135 140
彎
Tyr Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys 145 150 155 160
Leu He lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg 165 170 175
Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr He Ser Gly 180 185 190
Leu Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly 195 200 205
Ser Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu 210 215 220
Gly 225 <210〉 644 <211〉 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •909· 151681·序列表.doc 201127956 <400〉 644
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val 130 135 140
Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser 145 150 155 160
Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly 165 170 175 151681-序列表.doc .910- 201127956 融合瘤。在另一實施例中，融合瘤產生於非人類非小鼠 物種中，諸如大鼠、綿羊、豬、山羊、牛或馬。在另一實 施例中，融合瘤為人類融合瘤，其中將人類非分泌性骨髓 瘤與表現能夠結合特異性抗原之抗體的人類細胞融合。 如美國專利第5,627,〇52號、PCT公開案第W0 92/〇2551 號及BabC0ck，JS.等人，（1996) #加/· id. 93:7843-7848中所述，亦使用此項技術中稱為選擇淋巴細 φ 胞抗體法（slam)之程序由單一經分離淋巴細胞產生重組 mAb。在此方法中’鑑別分泌相關抗體之單個細胞（例如 來源於經免疫動物之淋巴細胞），且藉由反轉錄酶pCR自細 胞救援重鏈及輕鏈可變區cDNA，且隨後可在適當免疫球 蛋白恆定區（例如人類恆定區）之情形下，於諸如c〇s或 CHO細胞之哺乳動物宿主細胞中表現此等可變區。隨後經 源自活體内選擇之淋巴細胞之經擴增免疫球蛋白序列轉染 的宿主細胞可於活體外進行進一步分析及選擇，例如藉由 # 淘選該等經轉染細胞以分離出表現針對相關抗原之抗體的 細胞。經擴增免疫球蛋白序列可在活體外諸如藉由活體外 親和力成熟法（諸如PCT公開案WO 97/29131及PCT公開案 WO 00/5 6772中所述之方法）進一步操縱。 單株抗體亦藉由以相關抗原使包含一些或全部人類免疫 球蛋白基因座的非人類動物免疫產生。在一實施例中，非 人類動物為XENOMOUSE轉殖基因小鼠，其為包含人類免 疫球蛋白基因座之大片段且缺乏小鼠抗體產生之經工程改 k之小鼠品系。參看例如Green等人， 151681.doc -153- 201127956
Leu Glu Trp Leu Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn 180 185 190
Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser 195 200 205
Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie 210 215 220
Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 <210> 645 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 645
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 15 10 15
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 •911 · 151681·序列表.doc 201127956
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Leu 115 120 125
Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg Val 130 135 140
Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn He His Trp 145 150 155 160
Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala 165 170 175
Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie 195 200 205
Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly 210 215 220
Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 <210〉 646 -912-
151681·序列表 doc 201127956 <211〉 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 646
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr •913- 151681 -序列表.doc 201127956 145 150 155 160
Phe Ser His Tyr Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ser Ser He Ser Ser Ser Gly Gly Trp Thr Leu Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys 195 200 205
Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 647 <211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 647
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He •914·
151681·序列表.doc 201127956 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 .
Pro Ser Val Phe lie Phe Pro Pro Gin Ser Ala Leu Thr Gin Pro Ala 115 120 125
Ser Val Ser Gly Ser Pro Gly Gin Ser lie Thr lie Ser Cys Thr Gly 130 135 140
Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser Trp Tyr Gin Gin 145 150 155 160
His Pro Gly Lys Ala Pro Lys Leu lie lie Tyr Glu Val Ser Gin Arg 165 170 175
Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 180 185 190
Ala Ser Leu Thr lie Ser Gly Leu Gin Thr Glu Asp Glu Ala Asp Tyr 195 200 205
Tyr Cys Cys Ser Tyr Ala Gly Ser Ser lie Phe Val lie Phe Gly Gly 210 215 220 -915- 151681·序列表.doc 201127956
Gly Thr Lys Val Thr Val Leu Gly 225 230 <210〉 648 <211> 251 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 648
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 9
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr He Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 -916· 151681-序列表.doc 201127956
Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val 130 135 140
Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser 145 150 155 160
Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly 165 170 175
Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn 180 185 190
Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser * 195 200 205
Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie 210 215 220
Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala
<210〉 649 〈211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400> 649
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 1 5 10 15 •917 151681 -序列表.doc 201127956
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie 115 120 125
Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser 130 135 140
Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly 145 150 155 160
Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser 180 185 190 lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin •918- 151681·序列表doc 201127956 195 200 205
Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 210 215 220
Lys Arg 225 <210> 650 <211> 251 <212> PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 650
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly •919- 151681-序列表.doc 201127956 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser His Tyr Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ser Ser He Ser Ser Ser Gly Gly Trp Thr Leu Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys 195 200 205
Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 651 <211〉 225 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -920- 151681·序列表doc 201127956 21(1994)及美國專利第5,916,771號、第5,939,598號、第 5,985,615 號、第 5,998,209 號、第 6,075,181 號、第 6,091,001 號、第 6,1 14,598 號及第6，130,364 號。亦參看 1991年7月25日公開之WO 91/10741、1994年2月3日公開之 WO 94/02602、1996年 10 月 31 日公開之 WO 96/34096及 WO 96/33735、1998 年 4 月 23 日公開之 WO 98/16654、1998 年 6 月11日公開之WO 98/24893、1998年11月12日公開之WO 98/50433、1999年 9 月 10日公開之w〇 99/45031、1999 年10 月21日公開之WO 99/53049、2000年2月24日公開之WO 00 09560 及 2000 年 6 月 29 日公開之 WO 00/037504。 XENOMOUSE轉殖基因小鼠產生完全人類抗體之成年樣人 類譜系且產生抗原特異性人類單株抗體。XENOMOUSE轉 殖基因小鼠經由引入人類重鏈基因座及X輕鏈基因座之百 萬鹼基（megabase)規模的生殖系構型YAC片段而含有約 80%人類抗體譜系。參看Mendez等人，iVa/wre 15:146-156 (1997) ’ Green 及 Jakobovits «/.五jc/7. Mei/. 188:483-495 (1998)，其揭示内容以引用的方式併入本文 中〇
亦可使用活體外方法來製備親本抗體，其中篩選抗體文 庫以鑑別具有所需結合特異性之抗體。該篩選重組抗體文 庫之方法為此項技術中所熟知且包括例如以下文獻中所述 之方法：Ladner等人’美國專利第5,223,409號；Kang等 人，PCT公開案第W0 92/18619號；Dower等人，PCT公開 案第WO 91/17271號；Winter等人，PCT公開案第WO 151681.doc -154- 201127956 <400> 651
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly 115 120 125
Gin Ser lie Thr He Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser 130 135 140
Tyr Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys 145 150 155 160
Leu lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg 165 170 175 -921 151681·序列表.doc 201127956
Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly 180 185 190
Leu Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly 195 200 205
Ser Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu 210 215 220
Gly 225
<210〉 652 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 652
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 151681·序列表.doc -922- 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140
lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn 195 200 205
Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu 210 215 220
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ala <210〉 653 923 - 151681-序列表.doc 201127956 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 653
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 1 5 10 15
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val He Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Leu 115 120 125
Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg Val 130 135 140
Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn lie His Trp -924-
151681-序列表.doc 201127956 145 150 155 160
Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala 165 170 175
Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser Glu Asp lie 195 200 205
Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly 210 215 220
Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 <210> 654 <21.1〉244 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 654
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 lo
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr -925 - 151681·序列表.doc 201127956 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr Val Met Ala 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser lie 165 170 175
Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg Gly 210 215 220
Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240 -926- 151681-序列表.doc 201127956
Thr Val Ser Ser 〈210〉 655 <211〉 232 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 655
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin Ser Ala Leu Thr Gin Pro Ala 115 120 125 - 927 - 151681-序列表.doc 201127956
Ser Val Ser Gly Ser Pro Gly Gin Ser lie Thr lie Ser Cys Thr Gly 130 135 140
Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser Trp Tyr Gin Gin 145 150 155 160
His Pro Gly Lys Ala Pro Lys Leu lie lie Tyr Glu Val Ser Gin Arg 165 170 175
Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 180 185 190
Ala Ser Leu Thr He Ser Gly Leu Gin Thr Glu Asp Glu Ala Asp Tyr 195 200 205
Tyr Cys Cys Ser Tyr Ala Gly Ser Ser lie Phe Val lie Phe Gly Gly 210 215 220
Gly Thr Lys Val Thr Val Leu Gly 225 230
<210> 656 <211> 245 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400> 656
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 151681·序列表.doc •928· 201127956
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr He Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg He 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp -929- 15168卜序列表.doc 201127956 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 657 <211〉 226 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 657
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 15 10 15
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr He Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly -930- 151681_ 序列表.doc 201127956 92/20791 號；Markland等人，PCT公開案第 WO 92/15679 號；Breitling 等人，PCT 公開案第 WO 93/01288 號； McCafferty 等人，PCT 公開案第 WO 92/01047 號；Garrard 等人，PCT公開案第WO 92/09690號；Fuchs等人，（1991) Bio/Technology 9:1370-1372 ; Hay 等人，（1992) //wm //Wrzc/omas 3:81-85 ; Huse 等人，（1989) 246:1275-1281 ; McCafferty 等人，(1990) 348:552-554 ; Griffiths 等人，（1993) «/ 12:725-734 ; Hawkins 等人，（1992) *7 Mo/ β，·〇/ 226:889-896 ; Clackson等人， (1991) iVaiwre 352:624-628 ; Gram 等人，（1992) ΡΛΜ5* 89:3576-3580 ; Garrad等人，（1991) Ao/rec/mo/ogy 9:1373-1377 ; Hoogenboom 等人，（1991) JcW 及以 19:4133-4137 ;及 Barbas 等人，（1991) 88:7978-7982，美國專 利申請公開案20030186374及PCT公開案第WO 97/29131 號，其各自之内容以引用的方式併入本文中。 亦可使用此項技術中已知的多種噬菌體呈現法產生本發 明之親本抗體。在噬菌體呈現法中，功能性抗體區域呈現 於載有編碼其之聚核苷酸序列之噬菌體粒子表面上。詳言 之，可利用s玄嚨菌體呈現由譜系或組合抗體文庫（例如人 類或鼠類）表現之抗原結合區域。可用抗原，例如使用經 標記抗原或結合或捕捉於固體表面或珠粒上之抗原來選擇 或鐘別表現結合相關抗原之抗原結合區域的噬菌體。此等 方法中所用之噬菌體通常為絲狀噬菌體，該噬菌體包括自 Fab、Fv或二硫化物穩定之Fv抗體區域與噬菌體基因ιπ或 15168I.doc -155- 201127956 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225 <210>* 658 <211> 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 658
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -931· 151681-序列表.doc 201127956 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr Val Met 145 150 155 160
Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser 165 170 175 lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys Gly 180 185 190 •932· 151681-序列表.doc 201127956
Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg 210 215 220
Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin GLy Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245
<210〉 659 <211〉 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400〉 659
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 5〇 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 -933 · 151681 -序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly 115 120 125
Gin Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser 130 135 140
Tyr Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys 145 150 155 160
Leu lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg 165 170 175
Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr He Ser Gly 180 185 190
Leu Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly 195 200 205
Ser Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu 210 215 220
Gly 225 〈210〉 660 〈211〉 252 〈212〉 PRT <213〉人造序列 151681-序列表.doc -934- 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 660
Gl.u Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 δ 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160 lie Lys Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly -935· 151681·序列表.doc 201127956 165 170 175
Leu Glu Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 661 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 661
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 15 10 15
Ser lie Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45
He lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe •936_ 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 •937· 151681·序列表.doc 201127956 <210> 662 <211〉 252 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 662
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu 130 135 140 -938-
151681-序列表.doc 201127956
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser His Tyr Val Met Ala Trp Val Arg Gin Ala Fro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser 195 200 205
Lys Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 663 〈211〉 232 〈212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 663
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30 •939· 151681-序列表.doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Gin Ser Ala Leu Thr Gin Pro Ala 115 120 125
Ser Val Ser Gly Ser Pro Gly Gin Ser lie Thr lie Ser Cys Thr Gly 130 135 140
Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser Trp Tyr Gin Gin 145 150 155 160
His Pro Gly Lys Ala Pro Lys Leu He He Tyr Glu Val Ser Gin Arg 165 170 175
Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 180 185 190
Ala Ser Leu Thr He Ser Gly Leu Gin Thr Glu Asp Glu Ala Asp Tyr 195 200 205
Tyr Cys Cys Ser Tyr Ala Gly Ser Ser lie Phe Val lie Phe Gly Gly -940- 151681·序列表.doc 201127956 基因VIII蛋白質重組融合之噬菌體表現的fd及M13結合區 域。可用於製備本發明抗體之噬菌體呈現法之實例包括以 下文獻中揭示之方法：Brinkman等人，J. Immunol. Methods 182:41-50 (1995) ; Ames 等人，J. Immunol. Methods 184:177-186 (1995) ; Kettleborough等人，Eur· J. Immunol. 24:952-958 (1994) ; Persic等人，Gene 187 9-18 (1997) ; Burton等人，Advances in Immunology 57:191-280 (1994) ; PCT 申請案第 PCT/GB91/01134號；PCT 公開案 WO 90/02809 ； WO 91/10737 ； WO 92/01047 ； WO 92/18619 ； WO 93/11236 ; WO 95/15982 ; WO 95/20401 ;及美國專利 第 5,698,426 號；第 5,223,409 號；第 5,403,484 號；第 5,580,717 號；第 5,427,908 號；第 5,750,753 號；第 5,821，047 號；第 5,571，698 號；第 5,427,908 號；第 5,516,637 號；第 5,780,225 號；第 5,658,727 號；第 5,733,743號及第5,969，108號；其各自以全文引用的方式併 入本文中。
如本文參考文獻中所述，在噬菌體選擇後，可自噬菌體 分離抗體編碼區且將其用於產生包括人類抗體之完整抗體 或任何其他所要抗原結合片段，且例如下文詳細描述，使 其於包括哺乳動物細胞、昆蟲細胞、植物細胞、酵母及細 菌之任何所要宿主中表現。舉例而言’亦可使用此項技術 中已知之方法採用重組產生Fab、Fab’及F(ab')2片段之技 術，諸如PCT公開案WO 92/22324 ; Mullinax等人， BioTechniques 12(6):864-869 (1992)，及 Sawai 專人，AJRI 151681.doc -156- 201127956 210 215 220
Gly Thr Lys Val Thr Val Leu Gly 225 230 <210〉 664 <211〉 252 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 664
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe •941 - 151681·序列表.doc 201127956 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160 lie Lys Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 665 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 665
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin -942·
151681-序列表.doc 201127956 5 10 15
Ser He Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45
He lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 -943 · 151681·序列表.doc 201127956 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He 210 215 220
Lys Arg 225 <210〉 666 〈211〉 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 666
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -944
151681·序列表.doc 201127956
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser His Tyr Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser 195 200 205
Lys Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 667 <211〉 225 <212〉 PRT <213〉人造序列 -945- 151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 667
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly 115 120 125
Gin Ser He Thr He Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser 130 135 140
Tyr Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys 145 150 155 160
Leu lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg -946-
151681·序列表.doc 201127956 165 170 175
Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly 180 185 190
Leu Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly 195 200 205
Ser Ser He Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu 210 215 220
225 <210> 668 <211> 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 668
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr • 947- 151681·序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 •948· 151681-序列表.doc 201127956 <210〉 669 <211〉 233 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 669
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 15 10 15
Ser He Thr lie Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45 lie lie Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr He Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser He Phe Val He Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140 -949- 151681·序列表.doc 201127956
Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210> 670 <211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 670
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -950-
151681·序列表.doc 201127956 34:26-34 (1995);及 Better 等人，Science 240:104卜 1043 (1988)中揭示之方法（該等參考文獻以全文引用的方式併 入）。可用於產生單鏈Fv及抗體之技術的實例包括美國專 利 4,946,778 及 5,258,498 ; Huston 等人，Methods in Enzymology 203:46-88 (1991); Shu等人，PNAS 90:7995-7999 (1993);及 Skerra 等人，Science 240:1038-1040, (1988)中所述之技術。 φ 可應用此項技術中已知之篩選大型組合文庫之其他方法 替代用嗔菌體呈現篩選重組抗體文庫來鑑別親本抗體。一 種類型之替代表現系統為如以下文獻中所述將重組抗體文 庫表現為RNA-蛋白質融合物之表現系統：Sz〇stak及
Roberts之 PCT公開案第 w〇 98/31700號，及 Roberts，R.W.
及 Szostak，J.W. (1997) Proc. iVa". Jcad «SW. t/M 94:12297-123〇2。在此系統中’在mRNA與其藉由活體外 轉譯在3'端具有嘌呤黴素（一種肽基受體抗生素）之合成 # mRNA而編碼之肽或蛋白質之間形成共價融合物。因此， 可基於所編碼之肽或蛋白質（例如抗體或其部分）之特性（諸 如抗體或其部分結合於雙重特異性抗原），自mRNA之複雜 混合物（例如組合文庫）中富集特異性mRNA。可藉由如本 文所述之重組方式（例如在哺乳動物宿主細胞中）表現自該 等文庫篩選回收之編碼抗體或其部分之核酸序列，且此 外，可藉由再進行幾輪已在最初選擇之序列中引入突變之 mRNA·肽融合物的篩選或藉由如本文所述使重組抗體活體 外親和力成熟之其他方法使該等核酸序列進一步親和力成 151681.doc •157- 201127956
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr Val Met 145 150 155 160
Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser 165 170 175 lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg 210 215 220
Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly Thr Leu -951 · 151681-序列表doc 201127956 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 671 <211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 671
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Gin Ser Ala Leu Thr Gin Pro Ala -952-
151681-序列表 doc 201127956 115 120 125
Ser Val Ser Gly Ser Pro Gly Gin Ser lie Thr lie Ser Cys Thr Gly 130 135 140
Thr Ser Ser Asp Val Gly Ser Tyr Asn Val Val Ser Trp Tyr Gin Gin 145 150 155 160
His Pro Gly Lys Ala Pro Lys Leu lie He Tyr Glu Val Ser Gin Arg 165 170 175
Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 180 185 190
Ala Ser Leu Thr lie Ser Gly Leu Gin Thr Glu Asp Glu Ala Asp Tyr 195 200 205
Tyr Cys Cys Ser Tyr Ala Gly Ser Ser lie Phe Val He Phe Gly Gly 210 215 220
Gly Thr Lys Val Thr Val Leu Gly 225 230
<210> 672 <21.1> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 672
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr •953 - 151681-序列表.doc 201127956 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr 165 170 175
Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe *180 185 190
Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205 -954· 151681-序列表.doc 201127956
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr 210 215 220
Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245
<210〉 673 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 673
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95 -955 151681·序列表.doc 201127956
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160
He Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 674 <211> 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 674
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 •956 151681-序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser 130 135 140
Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr 145 150 155 160
Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp 165 170 175
Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe 180 185 190 lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe - 957- 151681·序列表.doc 201127956 195 200 205
Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys 2i〇 215 220
Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 675 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 675
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp •958· 151681-序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160
He Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 676 <211> 252 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 676
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin -959- 151681-序列表.doc 201127956 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn 145 150 155 160
Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp 180 185 190 ·%0· 15168卜序列表.doc 201127956 熟。 在另-方法中，亦可使用此項技術中已知的酵母呈現法 產生親本抗體。在酵母呈現法中，使用遺傳學方法將抗體 區域繫栓於酵母細胞壁且使其在酵母表面上呈現。詳一 之，可利用該酵母來呈現由譜系或組合抗體文庫（例如I 類或鼠類）表現之抗原結合區域。可用於製備親本抗體之 酵母呈現法的實例包括以引用的方式併入本文中的胸㈣ 等人之美國專利第6,699,658號中所揭示之方法。 本文所述之抗體可經進一步修飾產生CDR移植抗體及人 類化親本抗體。CDR移植親本抗體包含來自人類抗體之重 鏈及輕鏈可變區序列，其中％及/或乂的一或多個CDRg 經能夠結合相關抗原之鼠類抗體之（：]〇11序列置換。來自任 何人類抗體之構架序列可用作CDR移植之模板。然而，該 構架上之直鏈置換通常導致對抗原之結合親和力在一定程 度上損失。人類抗體與初始鼠類抗體之同源性愈高，組合 鼠類CDR與人類構架在CdR中引入可能降低親和力的變形 之可能性愈小。因此，在一實施例中，經選擇以置換除 CDR之外的鼠類可變構架之人類可變構架與鼠類抗體可變 區構架具有至少65%序列一致性。在一實施例中，人類與 鼠類可變區除CDR之外具有至少70%序列一致性。在一特 定實施例中，人類與鼠類可變區除CDR之外具有至少75% 序列一致性。在另一實施例中，人類與鼠類可變區除CDR 之外具有至少80%序列一致性。此項技術中已知產生該等 抗體之方法（參看EP 239,400 ; PCT公開案WO 91/09967 ; 151681.doc -158- 201127956
Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp 225 230 235 240
Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 677 <211> 228 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 677
Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80 961 - 151681-序列表.doc 201127956
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser 130 135 140
Ala Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu He Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210〉 678 <211〉 252 <212〉 PRT 〈213〉人造序列 -962- 151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 〈400> 678
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala. Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly 130 135 140
Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val 145 150 155 160
Ser Gly Phe Ser Leu Thr Thr Tyr Gly He His Trp Val Arg Gin Ser • 963- 151681 ·序列表.doc 201127956 165 170 175
Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp 180 185 190
Thr Asp Tyr Asp Ala Ala Phe lie Ser Arg Leu Ser lie Ser Lys Asp 195 200 205
Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn 210 215 220
Asp Thr Gly He Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Ser Va.l Thr Val Ser Ser 245 250 <210〉 679 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 679
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 lo
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly •964- 151681-序列表 _doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Glu Asp lie Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser He Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 965- 151681·序列表.doc 201127956 <210〉 680 <211〉 252 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 680
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140 •966-
151681-序列表.doc 201127956
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn 145 150 155 160
Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp 180 185 190
Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp 225 230 235 240
Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 681 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 681
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30 -967- 151681·序列表.doc 201127956
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp .85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160
He Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg •968·
151681·序列表.doc 201127956 210 215 220 <210> 682 <211> 252 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 682
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly 969· 151681·序列表 _doc 201127956 130 135 140
Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr Val 145 150 155 160
Ser Gly Phe Ser Leu Thr Thr Tyr Gly He His Trp Val Arg Gin Ser 165 170 175
Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp 180 185 190
Thr Asp Tyr Asp Ala Ala Phe He Ser Arg Leu Ser lie Ser Lys Asp 195 200 205
Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn 210 215 220
Asp Thr Gly He Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250 <210〉 683 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 683
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr •970- 151681-序列表.doc 201127956 美國專利第 5,225,539號；第 5,530，1()1號及第 5,585,089); 面飾或表面重塑（EP 592,106 ; EP 519,596 ; Padlan， Molecular Immunology 28(4/5):489-498 (1991) ; Studnicka 等人，Protein Engineering 7(6):805-814 (1994) ; Roguska等 人，PNAS 91:969-973 (1994));及鏈洗牌（美國專利第 5,565,3 52號）；及抗個體基因型抗體。
人類化抗體為來自結合所要抗原之非人類物種抗體的抗 體分子，其具有一或多個來自非人類物種之互補決定區 (CDR)及來自人類免疫球蛋白分子之構架區。已知人類Ig 序歹|J 揭示於伤，J 如 www.ncbi.nlm.nih.gov/entrez_/query.fcgi ; www.atcc.org/phage/hdb.html ; www.sciquest.com/ ； www. abcam.com/ ; www.antibodyresource.com/onlinecomp.html ； w w w. pub 1 i c. i ast ate. e du/. ab out. pedro/res earch_tools.html ; www.mgen.uni-heidelberg.de/SD/IT/IT.html ; www.whfreeman.com/ immunology/CH-05/kuby05.htm ; www.library.thinkquest.org/ 12429/Immune/Antibody.html ； www.hhmi.org/grants/lectures/ 1996/vlab/ ; www.path.cam.ac.uk/.about.mrc7/m-ikeimages.html ; www.antibodyresource.com/ ; mcb.harvard.edu/BioLinks/Immuno-logy.html.www.immunologylink.com/ ; pathbox.wustl.edu/. about.hcenter/index.-html ; www.biotech.ufl.edu八about.hcl/ ; www.pebio.com/pa/340913/340913.html- ; www.nal.usda.gov/ awic/pubs/antibody/ ; www.m.ehime-u.acjp/.about.yasuhito-/Elisa.html ; www.biodesign.com/table.asp ; www.icnet.uk/axp/facs/ davies/lin-ks.html ; www.biotech.ufl.edu/.about.fccl/protocol.html ; 151681.doc -159- 201127956 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp .85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205 •971 151681·序列表.doc 201127956
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210> 684 <211> 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 684
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15 9
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125 -972· 151681·序列表.doc 201127956
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp He Asn Thr Tyr 165 170 175
Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe 180 185 190
Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr 210 215 220
Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser
<210〉 685 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400> 685
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15 151681-序列表.doc -973· 201127956
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Ser 130 135 140
Ala Ser Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu He Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys •974·
151681-序列表.doc 201127956 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210> 686 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 686
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val •975 · 15168卜序列表doc 201127956 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser 130 135 140
Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr 145 150 155 160
Tyr Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp 165 170 175
Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe 180 185 190 lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe 195 200 205
Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys 210 215 220
Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser 225 230 235 240
Val Thr Val Ser Ser 245 <210> 687 <211> 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •976·
151681·序列表.doc 201127956 <400〉 687
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Lea Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp lie Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175 151681-序列表.doc -977- 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225
<210〉 688 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 688
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80 978-
15168卜序列表.doc 201127956
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala 165 170 175
Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe 210 215 220
Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210〉 689 151681-序列表.doc -979 · 201127956 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 689
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 δ 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu •980-
151681-序列表.doc 201127956 www.isac-net.org/sites_geo.html ; aximtl.imt.uni-marburg. de/.about.rek/AEP-Start.html ; baserv.uci.kun.nl/. about. jraats/1 inksl.html ; www.recab.uni-hd.de/immuno.bme.nwu. edu/ ; www.mrc-cpe.cam.ac.uk/imt-doc/pu-blic/INTRO.html *» www.ibt.unam.mx/vir/V_mice.html ; imgt.cnusc.fr:8104/ ; www.biochem.ucl.ac.uk/.about.martin/abs/index.html ; antibody. bath.ac.uk/ ; abgen.cvm.tamu.edu/lab/wwwabgen.html ； www. unizh.ch/.about.honegger/AHOsem-inar/SlideOl .html ;
www.cryst.bbk.ac.uk7.about.ubcg07s/ ; www.nimr.mrc.ac.uk/ CC/ccaewg/ccaewg.htm ; www.path.cam.ac.ukV.about.mrc7/h-umanisation/TAHHP.html ; www.ibt.unam.mx/vir/structure/ stat_aim.html ; www.biosci.missouri.edu/smithgp/index.html ;
www. cryst.bioc.c am. ac.uk/. abo-ut.fmolina/Web-pages/Pept/ spottech.html ; www.jerini.de/fr roducts.htm ； www.patents. ibm.com/ibm.html.Kabat 等人，Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983)中，各以 全文引用的方式併入本文中。該等輸入序列可用於降低免 疫原性或降低、增強或改變結合、親和力、締合速率、解 離速率、親合力、特異性、半衰期或如此項技術中已知之 任何其他適合特徵。 可用來自CDR供體抗體之相應殘基取代人類構架區中之 構架殘基以改變、例如改良抗原結合。此等構架取代係由 此項技術中熟知之方法鑑別，例如藉由建立CDR與構架殘 基相互作用模型以鑑別對抗原結合重要之構架殘基以及進 151681.doc •160- 201127956 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 690 <211〉 242 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 690
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr •981 · 151681-序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140
Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly lie 145 150 155 160
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175
Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie Ser Arg 180 185 190
Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala Arg Tyr 210 215 220
Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val 225 230 235 240
Ser Ser 982· 151681-序列表.doc 201127956 <210〉 691 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 691
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140 • 983 - 15168卜序列表.doc 201127956
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 692 <211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 692
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He 50 55 60 .984·
151681·序列表.doc 201127956
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Ty:r Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp 145 150 155 160
Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser - 985 - 151681-序列表.doc 245 201127956 <210> 693 <211> 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 693
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg -986- 151681-序列表.doc 201127956 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210> 694 <211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 694
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val - 987- 151681-序列表.doc 201127956 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu 130 135 140
Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe 145 150 155 160
Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr 180 185 190
Asp Ala Ala Phe lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly 210 215 220 • 988- 151681·序列表.doc 201127956
He Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Thr Val Ser Ser 245 <210〉 695 <211〉 228 <212〉 PRT 〈213>人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 695
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110 -989 151681-序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp lie Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 <210〉 696 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 696
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15 -990 151681·序列表.doc 201127956
行序列比較以鑑別特定位置之異常構架殘基。（參看例如 Queen等人，美國專利第5,585,089號；Riechmann等人， Nature 332:323 (1988)，其以全文引用的方式併入本文 中。）三維免疫球蛋白模塑為常用的且為熟習此項技術者 所熟悉。可利用說明及顯示所選候選免疫球蛋白序列之可 能三維構形結構的電腦程式。對此等顯示之檢驗准許分析 殘基在候選免疫球蛋白序列發揮功能過程中的可能作用’ 亦即，分析影響候選免疫球蛋白結合其抗原之能力的殘 基。以此方式，可自共同及輸入序列選擇FR殘基且將其組 合以便達成所要之抗體特徵’諸如對目標抗原之親和力增 加。一般而言，CDR殘基直接且最大程度上參與影響抗原 結合。可使用此項技術中已知之多種技術使抗體人類化， 諸如（但不限於）以下文獻中所述之技術：Jones等人， Nature 321:522 (1986) ; Verhoeyen等人，Science 239:1534 (1988))，Sims 等人，J. Immunol. 151: 2296 (1993);
Chothia及Lesk, J. Mol. Biol. 196:901 (1987) ’ Carter等人， Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992) ; Presta等人， J. Immunol. 151:2623 (1993), Padlan, Molecular
Immunology 28(4/5):489-498 (1991) ; Studnicka 等人，
Protein Engineering 7(6):805-814 (1994) ; Roguska.等人， PNAS 91:969-973 (1994) ; PCT 公開案 WO 91/09967、 PCT/: US 98/16280、US 96/18978、US 91/09630、US 91/05939、US 94/01234、GB 89/01334、GB 91/01134 ' GB 92/01755 ; WO 90/14443 、 WO 90/14424 、 WO 151681.doc -161 - 201127956
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp 145 150 155 160
Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala -991 - 151681-序列表.doc 201127956 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210> 697 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 697
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp -992·
151681-序列表.doc 201127956 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 698 <211〉 249 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述·.合成多肽 <400> 698
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -993 - 151681·序列表.doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu 130 135 140
Val Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe 145 150 155 160
Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr 180 185 190 -994· 151681·序列表.doc 201127956
Asp Ala Ala Phe lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn A；sp Thr Gly 210 215 220 lie Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Thr Val Ser Ser 245
<210〉 699 <211> 221 <212〉 PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 699
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 995 - 151681 -序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 〈210〉 700 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 • 996· 15168丨·序列表.doc 201127956 <400> 700
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala 165 170 175
Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 997- 151681-序列表.doc 201127956 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe 210 215 220
Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210> 701 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 701
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr -998- 151681·序列表.doc 201127956 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Va.l Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210> 702 <211> 242 <212> PRT 999- 151681-序列表.doc 201127956 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 702
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140
Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly He 145 150 155 160 • 1000 - 151681-序列表.doc 201127956 90/14430、EP 229246、EP 592，106 ; EP 519,596、ΕΡ 239,400、美國專利第 5,565,332 號、第 5,723,323 號、第 5,976,862號、第 5,824,514號、第 5,817,483號、第 5814476 號、第 5763192 號、第 5723323 號、第 5J66886 號、第 5,714,352 號、第 6,204,023 號、第 6，180,370 號、第 5,693,762 號、第 5,530，101 號、第 5,585,089 號、第 5,225,539號；第4,816,567號，其各以全文引用的方式併入 本文中（包括其中引用之參考文獻）。 B.選擇親本單株抗體之準則 籲 本發明之一實施例係關於選擇具有DVD-Ig分子所要之 至少一或多種特性的親本抗體。在一實施例中，所要特性 係選自一或多種抗體參數。在另一實施例中，抗體參數係 選自由以下組成之群：抗原特異性、對抗原之親和力、效 能、生物功能、抗原決定基識別性、穩定性、溶解度、生 產效率、免疫原性、藥物動力學、生物可用性、組織交又 反應性及直系同源抗原結合性。 B1.對抗原之親和力 籲 治療性mAb之所要親和力可視抗原性質及所要治療终點 而定。在一實施例中，當單株抗體阻斷細胞激素_細胞激 素受體相互作用時，其具有較高親和力（Kd=〇.〇l_〇i5〇 pM) ’因為該等相互作用通常為高親和力相互作用（例如 <ΡΜ·<ηΜ範圍）。在該等情形下，—對其目標之親和力 應等於或高於細胞激素（配位體）對其受體之親和力。另— 方面，親和力較小（>nM範圍）之mAb可在治療上有效用於 151681.doc •162· 201127956
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175
Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He Ser Arg 180 185 190
Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala Arg Tyr 210 215 220
Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val 225 230 235 240
Ser Ser <210〉 703 <211〉 228 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 703
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 -1001 - 151681-序列表.doc 201127956
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp lie Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 151681·序列表.doc - 1002- 201127956 225 <210〉 704 <211〉 243 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 704
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys • 1003 · 151681-序列表.doc 201127956 130 135 140
Ala Ala Ser Gly Phe Thr He Asn Ala Ser Trp He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr 165 170 175
Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser 210 215 220
Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240
Val Ser Ser <210> 705 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 705
Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 l〇 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg •1004-
151681·序列表.doc 201127956 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser He Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205 151681-序列表doc _ 1 ⑻5- 201127956
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 706 <211〉 243 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 706
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125 -1006- 15168丨-序列表.doc 201127956
Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser 130 135 140
Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly 145 150 155 160 lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly 165 170 175
Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie Ser 180 185 190
Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys 195 200 205
Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala Arg 210 215 220
Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 225 230 235 240
Val Ser Ser
<210> 707 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 707
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 -1007· 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp T)rr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro -1008· 151681·序列表.doc 201127956 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210> 708 <211〉 250 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽
<400〉 708
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 115
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala -1009- 151681-序列表.doc 201127956 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala 145 150 155 160
Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220 240
Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp 225 230 235
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 709 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 709
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1010-
151681·序列表.doc 201127956 例如 > 肖除循環之、、称— 八及、生咚δ :原性蛋白質，該mAb例如結合、螯 〇及α除Α-β類澱粉蛋 _ * 蛋白之循娘物質的單株抗體。在其他
〔藉由疋點突變誘發降低現有高親和力爪从之親和 ’使用對目標具有較低親和力之mAb可用於避免潛在副 作=，例如高親和力mAb可整合/中和其所有預期目標，從 而完全消耗/消除所靶向之蛋白質的功能。在此情形下， 低親和力mAb可螯合/中和目標中可能造成疾病症狀（病理 !·生或過度產生之含量）之部分而使目標之一部分可繼 、.’只執行其正*生理功能。因&，有可能降低以調整劑量 及或降低wj作用。親本mAb之親和力可能在適當乾向細胞 表面分子方面起作用以實現所要治療結果。舉例而言，若 目標以高密度表現於癌細胞上且以低密度表現於正常細胞 上，則較低親和力mAb將在腫瘤細胞上結合比在正常細胞 上數目多之目標，使得經由ADCC或CDC引起腫瘤細胞消 除，且因此可能產生所要治療效應。因此，選擇具有所要 親和力之mAb可能與可溶性目標與表面目標兩者均相關。 受體在與其配位體相互作用後引起之信號傳導可視受 體-配位體相互作用之親和力而定。類似地，可設想mAb 對表面受體之親和力可決定細胞内信號傳導之性質及mAb 可傳遞促效劑信號還是傳遞拮抗劑信號。mAb介導之信號 傳導的基於親和力之性質可影響其副作用概況。因此，需 要藉由活體外及活體内實驗仔細確定治療性單株抗體之所 要親和力及所要功能。 結合蛋白（例如抗體）之所要Kd可視所要治療結果以實驗 1516El.doc -163- 201127956 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr f5ro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190 1011 151681·序列表.doc 201127956
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210> 710 <211〉 250 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 710
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -1012 151681-序列表.doc 201127956
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Giy Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly 130 135 140
Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly 145 150 155 160
Phe Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly 165 170 175
Lys Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp 180 185 190
Tyr Asp Ala Ala Phe lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser 195 200 205
Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr 210 215 220
Gly lie Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250 <210〉 711 <211> 228 〈212〉 PRT <213〉人造序列 -1013· 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 711
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly · 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Ala He Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp He Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala -1014- 151681-序列表.doc 201127956 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225 <210> 712 <211〉 250 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 712
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe •1015- 151681·序列表.doc 201127956 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala 145 150 155 160
Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 1016· 151681-序列表.d〇c 201127956 <210> 713 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 713
Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg 130 135 140 -1017· 151681-序列表.doc 201127956
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 714 <211〉 250 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 714
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 -1018-
151681-序列表.doc 201127956
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly 130 135 140
Leu Val Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr Val Ser Gly 145 150 155 160
Phe Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly 165 170 175
Lys Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp 180 185 190
Tyr Asp Ala Ala Phe He Ser Arg Leu Ser lie Ser Lys Asp Asn Ser 195 200 205
Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr 210 215 220
Gly lie Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Ser Val Thr Val Ser Ser 1019- 151681-序列表,doc 201127956 245 250 <210〉 715 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 715
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp He Tyr Asn • 1020· 151681·序列表.doc 201127956 方式確定。在一實施例中，選擇對特定抗原之親和力（Kd) 等於或大於DVD-Ig對同一抗原之所要親和力的親本抗 體。藉由心⑽或另—類似技術評定抗原結合親和力及動 力子纟|施例中，各親本抗體對其抗原之解離常數 (Kd)選自由以下組成之群：至多約ι〇-7 μ;至多約ι〇·8 m; 至多約Η)·9 Μ;至多約1〇.】o M;至多約1(rll m;至多約i〇.l2 及至夕10 M。獲得VD1之第一親本抗體及獲得VD2 之第二親本抗體可對各別抗原具有類似或不同親和力 (KD)。如表面電漿子共振所量測，各親本抗體對抗原之締 合速率常數（Kon)選自由以下組成之群：至少約1〇2 Μ·νι ;至 少約1〇3 Μ'·丨；至少約1〇4 Μ丨s-,;至少約ι〇5 μ、·,;及 至^约10 M S 。獲得VD1之第一親本抗體及獲得VD2之 第二親本抗體可對各別抗原具有類似或不同之締合速率常 數（Kon卜在一實施例中，如表面電漿子共振所量測，各 親本抗體對抗原之解離速率常數（K〇ff)選自由以下組成之 群·至多約10-3 S_1 ;至多約1〇·4 s·1 ;至多約1〇_5 s·1 ;及至 夕約10 s »獲得VD1i第一親本抗體及獲得VD2之第二 親本抗體可對各別抗原具有類似或不同解離速率常數 (Koff) 〇 Β2·效能
親本單株抗體之所要親和力/效能將視所要治療結果而 疋°舉例而言’對於受體-配位體（R-L)相互作用，親和力 (kd)等於或大於R_L kd(pM範圍）。為簡單清除病理性循環 蛋白質’例如清除各種循環Α-β肽物質，kd可能處於低nM 151681.doc -164- 201127956 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gljr Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 716 <211> 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 716
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He • 1021 · 151681·序列表.doc 201127956 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr He Asn Ala Ser Trp He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr 165 170 175
Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser 210 215 220
Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240 - 1022- 15168卜序列表doc 201127956
Val Ser Ser <210〉 717
<211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 717
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125 151681·序列表 doc • 1023 - 201127956
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val He Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225
〈210〉 718 <211〉 243 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 718
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30 1024. 201127956
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser 130 135 140
Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly 145 150 155 160
lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly 165 170 175
Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie Ser 180 185 190
Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys 195 200 205
Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala Arg • 1025· 151681-序列表.doc 201127956 210 215 220
Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 225 230 235 240
Val Ser Ser <210〉 719 <211> 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 719
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala • 1026-
151681·序列表.doc 201127956 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp lie Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu lie Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225 <210〉 720 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 720
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin - 1027· 151681-序列表.doc 201127956 1 δ 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie Tyr Pro Thr 165 170 175
Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190 -1028· 151681·序列表.doc 201127956
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp 210 215 220
Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser
<210〉 721 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 721
Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp He Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80 151681-序列表.doc -1029· 201127956
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 722 <211> 242 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 1030-
151681·序列表.doc 201127956 範圍内。此外，Kd亦將視目標是否表現相同抗原決定基之 多個複本而定，例如mAb靶向Αβ寡聚物中之構形抗原決定 基。 若VDI與VD2結合相同抗原但結合不同抗原決定基，則 DVD-Ig將含有4個結合相同抗原之位點，因此增大親合力 且從而增大DVD-Ig之表觀kd。在一實施例中，選擇kd等 於或小於DVD-Ig之所要kd的親本抗體。親本mAb之親和力 φ 考慮因素亦可視DVD-Ig是否含有4個或4個以上相同抗原 結合位點（亦即來自單個mAb之DVD-Ig)而定。在此情形 下’表觀kd由於親合力而大於mAb。該等DVD_Ig可用於使 表面受體交聯、增大中和效能、增強對病理性蛋白質的清 除等。 在一實施例中，選擇對特異性抗原之中和效能等於或大 於DVD-Ig對相同抗原之所要中和潛力的親本抗體。可藉 由目標依賴性生物檢定評定中和效能，其中適當類型之細 • 胞回應於目標刺激而產生可量測信號（亦即增殖或細胞激 素產生），且由mAb對目標之中和可以劑量依賴性方 弱該信號。 B3.生物功能 單株抗體可潛在地執行若干功能。.一些此等功能列於表 1中。此等功能可由活體外檢定（例如基於細胞之檢定及生 物化學檢定）及活體内動物模型來評定。 151681.doc -165 - 201127956 <400> 722
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro GLn Val 115 120 125 • Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140
Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly lie 145 150 155 160
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175
Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie Ser Arg • 1031 · 151681.•序列表.doc 201127956 180 185 190
Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala Arg Tyr 210 215 220
Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val 225 230 235 240
Ser Ser <210〉 723 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 723
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 1032. 151681-序列表.doc 201127956 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg'Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 724 <211> 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 1033 - 151681-序列表.doc 201127956 <400> 724
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp 145 150 155 160
Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175 • 1034.
151681·序列表.doc 201127956
Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 725 <211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 725
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 1035 - 151681·序列表.doc 201127956
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 726 • 1036- 151681-序列表.doc 201127956 <211〉 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 726
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 9S
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu 130 135 140
Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe -1037· 151681·序列表.doc 201127956 145 150 155 160
Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr 180 185 190
Asp Ala Ala Phe He Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly 210 215 220 lie Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Tlir Val Ser Ser 245 <210〉 727 <211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 727
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -1038 -
151681-序列表.doc 201127956 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ala lie Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Glu Asp He Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Asn Ala Pro Arg Leu Leu He Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser He Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220 1039- 151681·序列表.doc 201127956
Glu He Lys Arg 225 <210〉 728 〈211〉 249 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 728
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 -1040·
151681-序列表.doc 201127956 表1 · 療性抗體的一些潛在應用 目標(類別） 可溶性(細胞激素、其他） --J用機制(目標） 甲和活性(例如細胞激素） 增強清除(例如Αβ募聚物） 增加半衰期(例如GLP1) 細脃表面(受體、其他） 促效劑(例如GLP1 R ; EPOR等） 拮抗劑(例如整合素等） 細胞毒素(CD 20等） 蛋白質沈積物 增強清除/降解(例如Αβ斑塊、澱粉樣蛋白沈葙物） 可選擇具有本文實例中於表1中所述之不同功能的MAb 以實現所要治療結果。接著可以DVD-Ig形式使用兩種或 兩種以上所選親本單株抗體以在單一 DVD-Ig分子中實現 兩種不同功能。舉例而言，可藉由選擇中和特定細胞激素 功能之親本mAb及選擇增強對病理性蛋白質之清除的親本 mAb來產生DVD-Ig。類似地，可選擇識別兩種不同細胞表 面受體之兩種親本單株抗體，一種mAb對一種受體具有促 效劑功能，且另一種mAb對另一受體具有拮抗劑功能。此 等兩種各具有不同功能之所選單株抗體可用於建構單一 DVD-Ig分子，在單一分子中具有所選單株抗體之兩種不 同功能（促效劑及拮抗劑）。類似地’兩種各阻斷各別受體 配位體（例如EGF及IGF)結合之針對細胞表面受體具有拮抗 性之單株抗體可以DVD-Ig形式使用。相反’可選擇拮抗 性抗受體mAb(例如抗EGFR)及中和抗可溶介體（例如抗 IGFl/2)mAb來製備 DVD-Ig。 B4·抗原決定基識別： 蛋白質之不同區可執行不同功能。舉例而言’細胞激素 之特定區與細胞激素受體相互作用以引起受體活化，而蛋 151681.doc -166 - 201127956
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp 145 150 155 160
Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser
<210〉 729 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 729
Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15 -1041 151681-序列表-doc 201127956
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 1042·
151681·序列表.doc 201127956 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 730 <211> 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 730
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 %
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val • 1043 · 151681-序列表.doc 201127956 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu 130 135 140
Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe 145 150 155 160
Ser Leu Thr Thr Tyr Gly lie His Trp Val Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp Leu Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr 180 185 190
Asp Ala Ala Phe lie Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly 210 215 220
He Tyr Tyr Cys Ala Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Thr Val Ser Ser 245 <210> 731 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 731
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly • 1044· 151681-序列表.doc 201127956 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 _ 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ala He Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn 130 135 140
Arg Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu 145 150 155 160 lie Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin 180 185 190 -1045- 151681·序列表.doc 201127956
Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro 195 200 205
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210〉 732 <211〉 242 <212> PRT <213〉人造序列 <220〉 <223>人造序列冬描述：合成多肽 <400〉 732
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Va.1 Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly lie His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser He Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110 • 1046·
151681·序列表.doc 201127956
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie Tyr Pro Thr 165 170 175
Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp 210 215 220
Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210〉 733 <211〉 228 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 1047- 151681-序列表.doc 201127956 <400〉 733
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser He Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He T)rr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr - 1048· 151681·序列表.doc 201127956 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210> 734 <2L1> 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 734
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys • 1049· 151681·序列表.doc 201127956 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140
Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr Gly lie 145 150 155 160
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175
Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe He Ser Arg 180 185 190
Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ala Asn Asp Thr Gly He Tyr Tyr Cys Ala Arg Tyr 210 215 220
Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val 225 230 235 240
Ser Ser
<210〉 735 <211〉 228 <212〉 PRT -1050-
151681·序列表.doc 201127956 白質之其他區可能為使細胞激素穩定所需。在此情形下， 可選擇特異性結合至細胞激素上之受體相互作用區之mAb 且因此阻斷細胞激素-受體相互作用。在一些情形下，例 如某些結合多個配位體之趨化因子受體情形下，可選擇結 合於僅與一種配位體相互作用之抗原決定基（趨化因子受 體上之區）的mAb。在其他情形下，雖然單株抗體可結合 於目標上不直接負責蛋白質生理功能之抗原決定基，但使 φ mAb結合於此等區會干擾蛋白質的生理功能（位阻）或改變 蛋白質構形’像知蛋白質不能起作用（mAb與具有多個配 位體之受體結合會改變受體構形，使得任何一個配位體皆 無法結合）。亦已鑑別出不阻斷細胞激素與其受體結合但 阻斷信號轉導之抗細胞激素單株抗體（例如125·2Η，一種 抗 IL-1 8 mAb) 〇 抗原決定基及mAb功能之實例包括（但不限於）阻斷受體_ 配位體（R-L)相互作用（中和結合尺_相互作用位點之瓜八匕）； φ 引起R_結合減少或無R_結合之位阻。雖然Ab可在除受體結 合位點以外之位點處結合目標，但仍因誘導構形變化且消 除功能（例如Xolair)、結合於尺但阻斷信號傳導（125_2H)來 干擾目標之受體結合及功能。 在一實施例中，親本mAb需要靶向適當抗原決定基以實 現最大功效。該抗原決定基在DVD_Ig中應為保守的。mAb 之結合抗原決定基可由若干方法來確定，包括共結晶術、 mAb-抗原複合物之限制性蛋白質水解加上質譜肽圖分析 (mass specuometric peptide mapping)(Legr〇s v 等人 2〇〇〇 151681.doc -167- 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 735
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Ala He Gin Met Thr Gin Ser Ser 115 120 125
Ser Ser Phe Ser Val Ser Leu Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asp He Tyr Asn Arg Phe Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160 1051 - 151681·序列表.doc 201127956
Gly Asn Ala Pro Arg Leu Leu He Ser Gly Ala Ala Ser Leu Glu Ala 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gin Asp Tyr Thr 180 185 190
Leu Ser lie Thr Ser Leu Gin Thr Glu Asp Val Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Trp Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 <210> 736 〈211〉 242 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 736
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60 1052· 151681·序列表doc 201127956
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly He Thr Pro Ala 165 170 175
Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe 210 215 220
Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser - 1053· 151681-序列表.doc 201127956 <210〉 737 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 737
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser •1054-
151681·序列表.doc 201127956 130 135 140
Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190
He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225 <210> 738 <211〉 242 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 738
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 1Γ)
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val • 1055- 151681·序列表.doc 201127956 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr He 145 150 155 160
Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He Gly Trp 165 170 175 lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val Arg 210 215 220 151681-序列表.doc - 1056- 201127956
Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val 225 230 235 240
Ser Ser <210〉 739 <211> 226 <212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 739
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Sei' Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110 • 1057. 151681-序列表 doc 201127956
Pro Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225 <210〉 740 <211〉 249 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 〈400> 740
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15 -1058 151681-序列表.doc 201127956
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr He Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp 145 150 155 160
Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala A:sp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 1059- 151681-序列表.doc 201127956 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 741 <211> 233 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 741
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin -1060-
151681·序列表.doc 201127956
Protein Sci. 9:1002-10)、噬菌體呈現肽文庫（O'Connor ΚΗ 等人，2005 J Immunol Methods. 299:21-35)以及突變誘發 (Wu C.等人，2003 J Immunol 170:5571-7)。 B5.物理化學及醫藥特性： 以抗體進行治療性處理通常需要投與高劑量，通常為每 公斤數毫克（歸因於因分子量通常較大而以質量計之效能 較低）。為了調節患者順應性且為了適當處理慢性疾病療 法及門診患者治療，需要皮下（s.c·)或肌肉内（i m )投與治 療性mAb ^舉例而言，皮下投與之所要最大體積為約1 .〇 mL，且因此，需要>100 mg/mL之濃度以限制每劑量之注 射次數《在一實施例中，以一次劑量投與治療性抗體。然 而，該等調配物之開發受限於蛋白質_蛋白質相互作用（例 如潛在地增大免疫原性風險之聚集）及在加工及傳遞期間 之限制因素（例如黏度）。因此，臨床功效所需之大量及相 關開發限制因素會限制抗體調配物之潛能之充分利用及以 尚劑量方案皮下投與。顯然蛋白質分子及蛋白質溶液之物 理化學及醫藥特性（例如穩定性、溶解度及黏度特徵）極為 重要。 β5·1·穩定性： 「穩定」抗體調配物為抗體在儲存後基本上保留其物理 穩定性及/或化學穩定性及/或生物活性的調配物。可量測 在所選溫度下，所選時段内之穩定性。在一實施例中，調 配物中之抗體在室溫（約3(rc )下或在4〇r下穩定至少i個月 及/或在約2至8。(：下穩定至少丨年、至少2年。此外，在一 151681.doc -168- 201127956 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu He Lys Arg 225 230 <210> 742 <211> 249 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -1061 · 151681-序列表.doc 201127956 〈400> 742
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asp Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin 165 170 175 -1062
151681-序列表.doc 201127956
Gly Leu Glu Trp He Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys 180 185 190
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr 210 215 220
Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Leu Thr Val Ser Ser 245 <210> 743 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽
<400〉 743
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 1063- 151681·序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu He Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210〉 744 - 1064- 151681·序列表.doc 201127956 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 744
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp • 1065- 151681·序列表.doc 201127956 145 150 155 160
Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245
<210> 745 <211〉 226 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 745
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin -1066- 151681·序列表.doc 201127956 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He 210 215 220 -1067- 151681-序列表doc 201127956
Lys Arg 225 <210〉 746 <211> 249 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 746
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 151681-序列表doc -1068 · 201127956
Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asp Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin 165 170 175
Gly Leu Glu Trp He Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys 180 185 190
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr 210 215 220
Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Leu Thr Val Ser Ser
<210〉 747 <211〉 226 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 747
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 •1069 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Pile Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Ίγτ Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys • 1070 · 151681·序列表.doc 201127956 實施例中，調配物在將調配物冷凍（至例如_7〇<t)及解凍 (下文稱作「凍/融循環」）後為穩定的。在另一實例中， 「穩定」調配物可為調配物中少於約10%及少於約5%之蛋 白質以聚集體形式存在之調配物。
在各種溫度下在活體外長時段穩定之DVD_Ig為合乎需 要的。可藉由快速4選在高溫下（例如在4 〇 〇C下）在活體外 穩疋2至4週之親本mAb來達成此目的，且接著評定穩定 性。在2至8 C下儲存期間，蛋白質在至少丨2個月，例如至 少24個月内展現穩寒性。穩定性（完整單體分子之百分比） 可使用各種技術（諸如陽離子交換層析 '尺寸排阻層析、 SDS-PAGE以及生物活性測試）來評定。關於可用於分析共 價及構形修飾之分析技術的更全面列舉，請參看J〇nes, A J. S. (1993) Analytical methods for the assessment of protein formulations and delivery systems ； Cleland, J. L.;
Langer, R.編 _ Formulation and delivery of peptides and proteins,第 1 版，Washington，ACS,第 22-45 頁；及 Pearlman, R.; Nguyen, T. H.(1990) Analysis of protein drugs ’ Lee，V. H_編，Peptide and protein drug delivery，第 1 版，New York, Marcel Dekker，Inc.，第 247-301 頁。 異質性及聚集體形成：抗體之穩定性可使調配物可顯示 低於約10% ’且在一實施例中’低於約5%，在另一實施例 中’低於約2% ’或在一實施例中，在0.5%至i 5%之範圍 内或更少之GMP抗體物質以聚集體形式存在。尺寸排阻層 析為一種靈敏 '可再現且極穩固之偵測蛋白質聚集體的方 151681.doc -169- 201127956 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225
<210> 748 <211> 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 748
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu • 1071 · 151681-序列表.doc 201127956 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala 165 170 175
Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe 210 215 220
Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser <210〉 749 <211〉 233 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -1072-
151681-序列表.doc 201127956 <400〉 749
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175 -1073- 151681·序列表.doc 201127956
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Val
Gin Gly Thr Lys 225
Glu lie Lys Arg 230 <210〉 750 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 750
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 1074· 151681-序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110 G'ly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr lie 145 150 155 160
Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly Trp 165 170 175 lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin 195 2⑻ 205
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val Arg 210 215 220
Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val 225 230 235 240
Ser Ser <210〉 751 1075- 151681-序列表.doc 201127956 <211> 233 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 751
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Pile Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala -1076-
151681-序列表.doc 201127956 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu He Lys Arg 225 230 <210> 752 〈211〉 243 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 752
Glri Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe -1077- 151681-序列表.doc 201127956 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala He Tyr Pro Tyr 165 170 175
Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser 210 215 220
Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240 -1078
151681·序列表.doc 201127956
Val Ser Ser <210〉 753 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400〉 753
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125 151681-序列表.doc -1079- 201127956
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190
lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin· Gin 195 200 205
Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu He 210 215 220
Lys Arg 225
<210〉 754 <211〉 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 754
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30 151681·序列表.doc -1080- 201127956 法。 除低聚集體含量之外，在一實施例中，抗體必需化學穩 定。化學穩定性可由離子交換層析（例如陽離子或陰離子 交換層析）、疏水性相互作用層析或諸如等電聚焦或毛細 官電泳之其他方法來測定。舉例而言，抗體之化學穩定性 可使得在2至8X：下儲存至少12個月後，相較於儲存測試前 之抗體溶液，陽離子交換層析中表示未經修飾之抗體的峰 值可能增加至多20%，在一實施例中，增加至多丨〇%，或 在另一實施例中，增加至多5%。 在一實施例中’親本抗體呈現結構完整性、正確二硫鍵 形成及正確摺疊：歸因於抗體二級或三級結構變化之化學 不穩疋性可影響抗體活性。舉例而言，如由抗體活性所指 示之穩定性可使得在2至8。(：下儲存至少12個月後，相較於 儲存測試前之抗體溶液，抗體活性可降低至多5〇%，在一 實施例中’降低至多30%或甚至至多1 〇%，或在一實施例 中’降低至多5 %或1 %。可使用適合抗原結合檢定來測定 抗體活性。 B5.2.溶解度： mAb之「溶解度」與正確摺疊之單體IgG的產生相關。 因此，可藉由HPLC評定IgG之溶解度。舉例而言，可溶性 (單體）IgG將在HPLC層析譜上產生單峰，而不溶（例如多聚 體及聚集體）IgG將產生複數個峰。因此熟習此項技術者將 能夠使用常規HPLC技術偵測IgG溶解度的增加或降低。關 於可用於分析溶解度之分析技術的更全面列舉（參看Jones， 151681.doc -170- 201127956
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser 130 135 140
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr 145 150 155 160 lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys 180 185 190
Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val -1081 - 151681-序列表.doc 201127956 210 215 220
Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr 225 230 235 240
Val Ser Ser <210> 755 <211> 226 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 755
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Va.1 Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala • 1082-
151681-序列表.doc 201127956 100 105 110
Pro Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu He 210 215 220
Lys Arg 225 <210> 756 <211> 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 756
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro G'ly Ala - 1083· 151681-序列表.doc 201127956 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala 145 150 155 160
Ser Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser 180 185 190 • 1084· 151681·序列表.doc 201127956
Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 757 <211〉 233 <212> PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 757
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 - 1085- 151681 ·序列表.doc 201127956
He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala 165 170 175
Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 758 <211〉 250 <212〉 PRT 〈213〉人造序列 1086-
151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 758
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu 130 135 140
Leu Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Asp Tyr Tyr He Asn Trp Val Lys Leu Ala Pro Gly -1087- 151681·序列表.doc 201127956 165 170 175
Gin Gly Leu Glu Trp lie Gly Trp He Tyr Pro Gly Ser Gly Asn Thr 180 185 190
Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr lie Asp Thr 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220
Thr Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Leu Thr Val Ser Ser 245 250 <210〉 759 <211〉 233 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 759
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly -108$ · 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu- Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu He Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu He Lys Arg 225 230 1089- 15168丨-序列表.doc 201127956 <210> 760 <211〉 250 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 760
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 δ 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
Tyr He Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140 1090-
151681·序列表.doc 201127956 A. G. Dep. Chem. Biochem. Eng.，Univ. Coll. London， London, UK.編者：Shamlou，P. Ayazi，Process. Solid-Liq. Suspensions (1993)，93-117.出版商：Butterworth-
Heinemann, Oxford, UK及 Pearlman，Rodney; Nguyen, Tue H，Advances in Parenteral Sciences (1990), 4 (pept· Protein Drug Delivery), 247-301)。治療性mAb之溶解度對於調配 成足量給樂通$所而之tfj濃度而言至關重要e如本文所概
述’可能需要大於100 mg/mL之溶解度以適應有效抗體給 藥。舉例而§ ’抗體溶解度在研究初期可能不低於約5 mg/mL ’在一實施例中’在過程科學後期不低於約25 mg/mL，或在一實施例中’不低於約1 〇〇 mg/mL，或在一 實施例中，不低於約150 mg/mL。熟習此項技術者顯而易 見，蛋白質分子之固有特性對於蛋白質溶液之物理化學特 性（例如穩定性、溶解度、黏度）而言為重要的。然而，熟 習此項技術者應瞭解存在多種可用作添加劑以有利影響最 終蛋白質調配物之特徵的賦形劑。此等賦形劑可包括··⑴ 液體溶劑、共溶劑（例如醇類，諸如乙醇）；（⑴緩衝劑（例 如碌酸鹽、6 S㈣、檸檬酸鹽、胺基酸緩衝液）；糖或 糖醇(例如蔬糖、海藻糖、果糖、棉子糖、甘露糖醇、山 梨糖醇、聚葡萄糖）；(iv)界面活性劑(例如聚山梨醇酷 2〇、聚山梨醇醋40、聚山梨醇醋6〇、以梨_、泊洛 沙姆(v)等張性調節劑（例如，諸如_之 鹽、糖、糖醇）；及（vi)其他賦形劑（例如防腐劑、餐合 劑、抗氧化劑、螯合物質(例如EDTA)、生物可降解聚合 151681.doc -171. 201127956
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala 145 150 155 160
Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 761 〈211〉 226 〈212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 761
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30 151681-序列表.doc -1091 - 201127956
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie • 1092·
15168卜序列表.doc 201127956 210 215 220
Lys Arg 225 <210〉 762 <211> 250 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 762
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser • 1093- 151681-序列表.doc 201127956 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu 130 135 140
Leu Val Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Asp Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr 180 185 190
Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr He Asp Thr 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220 240
Thr Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp 225 230 235
Gly Gin Gly Thr Leu Leu Thr Val Ser Ser 245 250 <210〉 763 <211> 226 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 763
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly •1094·
151681·序列表.doc 201127956 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 - 1095 · 151681-序列表doc 201127956
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225 <210> 764 <211〉 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 764
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 •1096 151681-序列表.doc 201127956
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr Pro Tyr 165 170 175
Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser 210 215 220
Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240
Val Ser Ser <210> 765 <211〉 233 〈212〉 PRT <213〉人造序列 151681·序列表.doc - 1097- 201127956 <220〉 〈223>人造序列之描述：合成多肽 <400> 765
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser Leu Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala • 1098·
151681·序列表-doc 201127956 165 170 175
Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230 <210〉 766 <211〉 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 766
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr • 1099- 151681-序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser 130 135 140
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr 145 150 155 160 lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys 180 185 190
Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val 210 215 220
Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr 225 230 235 240
Val Ser Ser • 1100- 151681·序列表.doc 201127956 物、載劑分子（例如HSA、PEG))。 黏度為與抗體製造及抗體加工（例如透濾/超濾）、填充_ 精整製程（泵送部分、過濾部分）及傳遞部分（可注射性、完 善裝置傳遞）有關之極重要參數。低黏度使抗體之液體溶 液能夠具有較高濃度。此使得可能以較小體積投與相同劑 量。小注射體積固有注射疼痛感覺較小之優勢，且溶液不 一定必需為等張的以減輕患者注射時之疼痛。抗體溶液之 黏度可使得在100 (Ι/s)之剪切速率下，抗體溶液黏度低於 200 mPa s ’在一實施例中，低於125 mPa s，在另一實施 例中’低於70 mPa s，且在另一實施例中，低於25 mPa s 或甚至低於10 mPa s。 Β 5·3·生產效率
在一實施例中’有效表現於哺乳動物細胞（諸如中國倉 鼠卵巢細胞（CHO))中之DVD-Ig的產生將需要兩種自身有 效表現於哺乳動物細胞中之親本單株抗體。來自穩定哺乳 動物細胞株（亦即CHO)之產率應高於約〇·5 g/L，在一實施 例中’高於約1 g/L ’且在另一實施例中，處於約2至5 g/L 或 5 g/L以上之範圍内（Kipriyanov SM，Little Μ. 1999 Mol Biotechnol. 12:173-201 ； Carroll S, Al-Rubeai M. 2004 Expert Opin Biol Ther. 4:1821-9)。 在哺乳動物細胞中抗體及I g融合蛋白之產生受若干因素 影響。經由併入強啟動子、強化子及選擇標誌物對表現載 體進行工程改造’可使相關基因自整合載體複本之轉錄最 大化。對允許南度基因轉錄之載體整合位點的鑑別可增加 151681.doc -172- 201127956 <210> 767 <211> 233 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 767
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140 151681·序列表.doc -1101 - 201127956
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210〉 768 <211〉 242 <212> PRT <213〉人造序列
<220> <223〉人造序列之描述：合成多肽 <400> 768
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45 151681-序列表.doc •1102· 201127956
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr He His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg He Tyr Pro Thr 165 170 175
Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp 210 215 220
Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val • 1103 · 151681-序列表.doc 201127956 225 230 235 240
Ser Ser <210> 769 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 769
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
He Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu He Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser •1104- 151681-序列表doc 201127956 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190
He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225 <210〉 770 <2：L1> 242 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 770
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr •1105- 151681·序列表.doc 201127956 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr lie 145 150 155 160
Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly Trp 165 170 175 lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205 • 1106- 151681·序列表.doc 201127956
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val Arg 210 215 220
Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val 225 230 235 240
Ser Ser
<210> 771 〈211〉 226 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 771
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95 •1107· 151681-序列表.doc 201127956
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu He 2i〇 215 220
Lys Arg 225 <210〉 772 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 -1108-
151681·序列表.doc 201127956 <400> 772
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp 145 150 155 160
Thr Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser -1109- 151681-序列表.doc 201127956 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 773 <211> 233 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 773
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr -1110- 151681-序列表.doc 201127956 蛋白質自載體表現（Wurm等人，2〇〇4，Nature Biotechnology，2004，第 22卷/第^ 期第（1393 1398)頁）。 此外，產生含量受抗體重鏈與輕鏈之比率及蛋白質組裝與 分泌過程中之各種步驟影響（Jiang等人，2〇〇6, Biotechnology Progress，2006年1 月至2月第 22卷第 1號， 第 313-8頁）。 B 6·免疫原性 $ 投與治療性mAb可能引起發生特定免疫反應（亦即形成 針對治療性mAb之内源抗體）。在選擇親本單株抗體期間 應分析可能誘導免疫原性之潛在要素，且可採取降低該風 險之步驟以在DVD-Ig建構前最佳化親本單株抗體。已發 現來源於小鼠之抗體在患者中具有高度免疫原性。包含小 鼠可變區及人類恆定區之嵌合抗體的產生為降低治療性抗 體免疫原性之下一合乎邏輯之步驟（M〇n*ison及Schlom， 1990)。或者，如由Riechmann等人，1988關於治療性抗體 φ 所述’可藉由將鼠類CDR序列轉移至人類抗體構架中（重 塑/CDR移植/人類化）來降低免疫原性。另一方法稱為「表 面重塑」或「面飾」’其以齧齒動物輕鏈區域及重鏈區域 起始，僅將表面可及之構架胺基酸變為人類之構架胺基 酸，同時CDR及内埋之胺基酸仍來自親本齧齒動物抗體 (Roguska等人，1996)。在另一類型人類化中，一種技術僅 移植「特異性決定區」（SDR)而非移植整個CDR，該等 SDR定義為抗體結合於其目標中所涉及之cdr殘基子集 (Kashmiri等人，2005)。此使得有必要經由分析抗體-目標 1516Sl.doc 173- 201127956 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp 145 150 155 160
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Gin Gly Thr Lys Val Glu lie Lys Arg 225 230
<210> 774 <211〉 249 <212〉 PRT -1111 - 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 774
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160 1112 151681-序列表.doc 201127956
Thr Phe Thr Asp Tyr Tyr He Asn Trp Val Lys Leu Ala Pro Gly Gin 165 170 175
Gly Leu Glu Trp lie Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys 180 185 190
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr He Asp Thr Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr 210 215 220
Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Leu Thr Val Ser Ser 245 <210〉 775 <211> 233 <212> PRT <213〉人造序列
<223〉人造序列之描述：合成多肽 <400〉 775
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 151681-序列表.doc -1113 - 201127956
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu lie Lys Arg 151681·序列表.doc 201127956 225 230 <210〉 776 <211〉 249 <212> PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 776
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 151681·序列表.doc 201127956 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp 145 150 155 160
Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210> 777 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 777
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 151681·序列表.doc 201127956 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Asp Yal Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205 151681·序列表.doc -1117- 201127956
His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225 <210〉 778 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 778
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110 151681·序列表.doc 201127956
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asp Tyr Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin 165 170 175
Gly Leu Glu Trp lie Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys 180 185 190
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr 210 215 220
Ala Val Tyr Phe Cys Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Leu Thr Val Ser Ser 245 <210〉 779 <211〉 226 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 1119· 151681-序列表.doc 201127956 <400> 779
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu 115 120 125
Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn 130 135 140
Ser Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu -1120- 151681-序列表.doc 201127956 複合物之可利用三維結構或對抗體CDR殘基進行突變分析 以確定與目標相互作用之殘基來鑑別SDR。或者，相較於 鼠類、嵌合或人類化抗體，完全人類抗體可具有降低之免 疫原性。 另一降低治療性抗體之免疫原性的方法為消除某些經預 測具有免疫原性之特異性序列。在一方法中，在人類中測 試第一代生物製劑且發現其具有不可接受之免疫原性後， 可對B細胞抗原決定基進行定位且接著進行改變以避免免 疫偵測。另一方法使用預測及移除潛在T細胞抗原決定基 之方法。已開發出計算方法來掃描且鑑別有可能結合於 MHC蛋白質之生物治療劑之肽序列（Desmet等人，2005)。 或者，可使用基於人類樹突狀細胞之方法鑑別潛在蛋白質 過敏原中之CD4+ T細胞抗原決定基（Stickler等人，2005 ; S.L. Morrison及 J. Schlom，yic/ν. (9加〇/· (1990)， 第 3-18 頁；Riechmann, L·，Clark，M.，Waldmann，Η.及 Winter, G. 「Reshaping human antibodies for therapy.」 Nature (1988) 332: 323-327 ； Roguska-M-A, Pedersen-J-T, Henry-A-H, Searle-S-M，Roja-C-M, Avery-B, Hoffee-M， Cook-S, Lambert-J-M, Blattler-W-A, Rees-A-R, Guild-B-C. A comparison of two murine mAbs humanized by CDR-grafting and variable domain resurfacing, Protein engineering, {Protein-Eng}, 1996,第 9卷，第 895-904 頁； Kashmiri-Syed-V-S, De-Pas cal is-Roberto, Gonzales-Noreen-R, Schlom-Jeffrey. SDR grafting--a new approach to 151681.doc -174- 201127956 180 185 190
Thr lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys 195 200 205
Gin Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie 210 215 220
Lys Arg 225
<210〉 780 <211〉 242 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 780
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
Tyr lie Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Trp lie Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys -1121 - 151681·序列表.doc 201127956 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys 130 135 140
Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His Trp Val Arg 145 150 155 160
Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie Tyr Pro Thr 165 170 175
Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie 180 185 190
Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu 195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp 210 215 220
Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser
<210〉 781 <211〉 233 <212> PRT 1122-
151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 781
Asp lie Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Plie Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu He Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin 115 120 125
Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 130 135 140
Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp 145 150 155 160 •1123- 15168】·序列表.doc 201127956
Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala 165 170 175
Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser 180 185 190
Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe 195 200 205
Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly 210 215 220
Val
Gin Gly Thr Lys 225
Glu He Lys Arg 230 <210〉 782 <211〉 242 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 782
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 -1124-
151681-序列表.doc 201127956
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys lie Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr lie 145 150 155 160
Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp lie Gly Trp 165 170 175
He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Val Arg 210 215 220
Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu Thr Val 225 230 235 240
Ser Ser •1125· 151681-序列表.doc 201127956 <210〉 783 <211〉 233 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 783
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Val Leu Thr Gin Ser Pro 115 120 125
Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys 1126- 151681·序列表.doc 201127956 130 135 140
Ser Ser Gin Ser Leu Leu Asn Ser Gly Met Arg Lys Ser Phe Leu Ala 145 150 155 160
Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Leu Leu lie Tyr Trp 165 170 175
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp 195 200 205
Val Ala Val Tyr Tyr Cys Lys Gin Ser Tyr His Leu Phe Thr Phe Gly 210 215 220
Ser Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210> 784 <211〉 255 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 784
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -1127. 151681-序列表.doc 201127956 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Phe Thr lie Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro 165 170 175
Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr 180 185 190
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp 195 200 205
Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220 -1128- 151681-序列表.doc 201127956
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr 225 230 235 240
Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 785 <211〉 228 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 785
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110 -1129 151681-序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 786 <211〉 255 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 786
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 • 1130· 151681·序列表.doc 201127956 antibody humanization. Methods (San Diego Calif.), {Methods}，2005 年 5 月，第 36卷，第 1 號，第 25-34 頁； Desmet-Johan, Meersseman-Geert, Boutonnet-Nathalie, Pletinckx-Jurgen, De-Clercq-Krista, Debulpaep-Maja, Braeckman-Tessa, Lasters-Ignace. Anchor profiles of HLA-specific peptides: analysis by a novel affinity scoring method and experimental validation. Proteins, 2005,第 58 卷，第 53-69 頁；Stickler-M-M，Estell-D-A，Harding-F-A. CD4+ T-cell epitope determination using unexposed human donor peripheral blood mononuclear cells. Journal of immunotherapy 2000,第 23 卷，第 654-60 頁）。 B7.活體内功效 為產生具有所要活體内功效之DVD-Ig分子，重要的是 產生且選擇在以組合形式給予時具有類似所要活體内功效 的mAb。然而，在一些情形下，DVD-Ig可能展現2種獨立 mAb之組合無法實現的活體内功效。舉例而言，DVD-Ig可 使2個目標緊密鄰近，從而產生由2個獨立mAb之組合無法 實現的活性。其他所要生物功能於本文B 3章節中描述。 具有DVD-Ig分子中所要之特徵的親本抗體可基於諸如藥 物動力學以；組織分佈；可溶性目標相對於細胞表面目 標；及目標濃度（可溶性V密度（表面）之因素來選擇。 B8.活體内組織分佈 為產生具有所要活體内組織分佈之DVD-Ig分子，在一 實施例中，必需選擇具有類似所要之活體内組織分佈概況 15168I.doc .175- 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser Asp Tyr Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala -1131 · 151681 -序列表.doc 201127956 195 200 205
Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val 225 230 235 240
Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 787 <211〉 228 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 787
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro -1132- 151681·序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Gly He Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210> 788 <211〉 255 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -1133- 151681-序列表.doc 201127956 <400〉 788
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Pile Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Phe Thr He Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro 165 170 175 1134· 151681-序列表 doc 201127956
Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr 180 185 190
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp 195 200 205
Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr 225 230 235 240
Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 789 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 789
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu He 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60 -1135- 151681·序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 790 <211〉 255 <212〉 PRT <213〉人造序列 1136· 151681 _序列表.doc 201127956 <220〉 <223>人造序列之描述：合成多肽 <400〉 790
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser Asp Tyr Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys •1137- 151681·序列表.doc 201127956 165 170 175
Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala 195 200 205
Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 2i〇 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val 225 230 235 240
Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 791 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 791
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly •1138. 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220
<210〉 792 <211> 248 <212〉 PRT 1139· 151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 792
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 145 150 155 160 1140-
151681-序列表.doc 201127956 之親本mAb。或者，基於雙重特異性靶向策略之機制，在 其他情形下可此不需要選擇在以組合形式給予時具有同樣 所要之活體内組織分佈的親本mAbe舉例而言，在一結合 組分使DVD-Ig靶向一特異性位點，從而將第二結合組分 引至同一目標位點之DVD-Ig的情況下即如此。舉例而 言’ DVD-Ig之一結合特異性可靶向胰臟（胰島細胞），且另 一特異性可將GLP1引至胰臟以誘導胰島素。 B9.同型：
在一實施例中，為了產生具有所要特性（包括（但不限於） 同型、效應功能及循環半衰期）之DVD-Ig分子’視治療效 用及所要治療終點而定選擇具有適當^效應功能之親本 mAb。存在5個主要重鏈類別或同型，其中一些具有若干 次型且此等類別或同型決定抗體分子之效應功能。此等效 應功能存在於抗體分子之鉸鏈區、CH2及CH3區域中。然 而，抗體分子之其他部分中之殘基亦可能對效應功能有影 響。鉸鏈區Fc效應功能包括：⑴抗體依賴性細胞毒性； (ii)補體（Clq)結合、活化及補體依賴性細胞毒性（CDC); (111)對抗原-抗體複合物之吞噬/清除；及（iv)在一些情形 下’細胞激素釋放。抗體分子之此等Fc效應功能係經由Fc 區與一組類別特異性細胞表面受體之相互作用來介導。 IgGl同型抗體最具活性，而IgG2&IgG4具有最小效應功能 或不具有效應功能^ IgG抗體之效應功能係經由與3種結構 上同源之細胞Fc受體類型（及次型）（FcgR1、FcgRII及 FcgRIII)相互作用來介導。可藉由使下游鉸鏈區中為FcgR 151681.doc •176· 201127956
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 793 <211〉 228 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 793
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45 -1141 - 151681·序列表.doc 201127956
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg -1142· 151681·序列表.doc 201127956 225 <210〉 794 <211〉 248 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 794
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu -1143· 151681-序列表.doc 201127956 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met 145 150 155 160
Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 165 170 175
He Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210> 795 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 795
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala -1144- 151681-序列表.doc 201127956 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Gly lie Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205 151681-序列表.doc -1145- 201127956
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 796 <211〉 248 <212> PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 796
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110 -1146-
151681-序列表.doc 201127956
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 145 150 155 160
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 〈210〉 797 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -1147- 151681-序列表.doc 201127956 <400〉 797
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu He 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro . 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ser Ala Ser Phe Leu T)rr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin -1148-
151681·序列表.doc 201127956 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 798 <211> 248 <212> PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 798
Glu Val Gin Leu Val Glu Ser Gly Gly.Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin -1149- 151681-序列表.doc 201127956 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met 145 150 155 160
Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 165 170 175 lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210> 799 〈211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -1150-
151681-序列表.doc 201127956 及Clq結合所要之特定胺基酸殘基（例如L234A、L235A)突 變來消除IgGl之此等效應功能。卜區（尤其CH2ch3區域） 中之胺基酸殘基亦決定抗體分子之循環半衰期。此Fc功能 係經由Fc區與新生兒Fc受體（FcRn)之結合來介導，該結合 負責使抗體分子自酸性溶酶體再循環回全身循環中。 mAb是否應具有活性或非活性同型將視抗體之所要治療 終點而定。同型之使用及所要治療結果之一些實例列於下 文： a) 若所要終點為功能性中和可溶性細胞激章，則可使用非 活性同型； b) 若所要結果為清除病理性蛋白，則可使用活性同型； c) 若所要結果為清除蛋白質聚集體，則可使用活性同型； d) 若所要結果為拮抗表面受體，則使用非活性同型（泰沙 比（Tysabri) ’ lgG4 ; OKT3，突變型 IgGl); e) 右所要結果為消除目標細胞，則使用活性同型（赫賽汀 (Herceptin) ’ igGl (且具有增強之效應功能））；及 f) 若所要結果為自循環清除蛋白質而不進入CNS中，則可 使用IgM同型（例如清除循環Ab肽物質）。 親本mAb之Fc效應功能可由此項技術中熟知之各種活體 外方法來測定。 如所為述，對同型之選擇，及從而對效應功能之選擇將 視所要治療終點而定。在需要簡單中和循環目標（例如阻 斷受體-配位體相互作用）之情形下，可能不需要效應功 月"*。在該等情形下，抗體之消除效應功能之同型或Fc區中 151681.doc •177· 201127956 <400> 799
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175 -1151 151681-序列表.doc 201127956
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 800 <211〉 256 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 800
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -1152
151681·序列表.doc 201127956
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Phe Thr lie Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro 165 170 175
Gly Lys Gly Leu Glu Trp Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr 180 185 190
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp 195 200 205
Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro 225 230 235 240
Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 801 〈211〉 228 <212〉 PRT <213〉人造序列 -1153- 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 801
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val He Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser -1154- 151681-序列表.doc 201127956 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210〉 802 <211〉 256 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 802
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr • U55- 151681.序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Ser Asp Tyr Tyr Met Ser Trp lie Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr He 180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn 195 200 205
Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr 225 230 235 240
Val Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 •1156- 151681-序列表.doc 201127956 <210〉 803 <211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 803
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140 151681·序列表.doc • 1157- 201127956
Ala Ser Gin Gly lie Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 804 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 804
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 • 1158-
151681-序列表.doc 201127956
Ser Tyr lie Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Phe Thr He Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro 165 170 175
Gly Lys Gly Leu Glu Trp Val Gly Ala He Tyr Pro Tyr Ser Gly Tyr 180 185 190
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp 195 200 205
Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro -1159- 151681-序列表.doc 201127956 225 230 235 240
Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 805 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 805
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Va.l Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val •1160·
151681-序列表.doc 201127956 之突變為合乎需要的。在消除目標細胞為治療終點（例如 消除腫瘤細胞）之其他情形下，增強效應功能之同型或F c 區中之突變或去海藻糖基化（de-fucosylation)為合乎需要的 (Presta GL, Adv. Drug Delivery Rev. 58:640-656, 2006 ; Satoh M., Iida S., Shitara K. Expert Opinion Biol. Ther. 6:1161-1173，2006)。類似地，視治療效用而定，抗體分子 之循環半衰期可藉由在Fc區中引入特定突變來調節抗體-FcRn相互作用而縮短/延長（Dall’Acqua WF，Kiener PA，Wu H. J. Biol. Chem. 281:23 514-23 524, 2006 ； Petkova SB., Akilesh S·，Sproule TJ.等人，11^61>1131:.11111111111〇1.18:1759-1769, 2006 ; Vaccaro C·，Bawdon R.，Wanjie S 等人，PNAS 103:18709-18714, 2007)。 關於DVD-Ig，可能需要確認關於影響正常治療性mAb之 不同效應功能之多種殘基的公開資訊。在DVD-Ig形式 中，除經鑑別用於調節單株抗體效應功能之Fc區殘基以外 之其他（不同）Fc區殘基有可能會很重要。 總之，關於最終DVD-Ig形式中關鍵之Fc效應功能（同型） 之決定將視疾病適應症、治療目標、所要治療終點及安全 考慮因素而定。下文列出例示性適當重鏈及輕鏈恆定區， 包括（但不限於）： 〇 IgGl-異型：Glmz o IgGl 突變體-A234，A235 〇 IgG2-異型：G2m(n-) o K-Km3 151681.doc -178- 201127956 115 120 125
Gly Asp Arg Val Thr lie Thr CysArg Ala Ser Gin Val lie Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 806 <211〉 256 <212> PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400〉 806
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -1161 - 151681·序列表.doc 201127956 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Ser Asp Tyr Tyr Met Ser Trp He Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie 180 185 190
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn 195 200 205
Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220 1162- 151681-序列表.doc 201127956
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr 225 230 235 240
Val Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 807 <211〉 221 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 807
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110 -1163· 151681·序列表.doc 201127956
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 808 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 808
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 -1164- 151681·序列表.doc 201127956
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 145 150 155 160
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys •1165· 151681·序列表.doc 201127956 2i〇 215 220
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210> 809 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 809
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu He 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala •1166· 151681·序列表.doc 201127956
100 105 HO
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 〈210〉 810 <211> 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 810
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly •1167- 151681·序列表 _doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr 145 150 155 160
Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 165 170 175
Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys 180 185 190 •1168- 151681·序列表.doc 201127956
Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245
<210〉 811 <211> 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 811
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 1169- 151681-序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Gly lie Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu He Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210> 812 <211〉 249 <212〉 PRT 〈213>人造序列 1170·
151681·序列表.doc 201127956 〇 λ
Fc受體及Clq研究：可藉由（例如L234A、L235A)鉸鏈區 突變來消除以下可能性：由抗體與細胞膜上任何過度表現 之目標複合引起的不合需要之抗體依賴性細胞介導之細胞 毒性（ADCC)及補體依賴性細胞毒性（CDC)。預期存在於 mAb之IgGl鉸鏈區中的此等經取代胺基酸會使mAb與人類 Fc受體（而非FcRn)之結合減少，因為認為FcgR結合發生於 IgG 1欽鍵區上之重疊位點内。mAb之此特徵可使其安全概 況比含有野生型IgG之抗體有所改良。mAb與人類Fc受體 之結合可藉由流動式細胞量測實驗使用細胞株（例如THP-1、K562)及表現FcgRIIb(或其他FcgR)之經工程改造之 CHO細胞株來測定。相較於IgGl對照單株抗體，mAb展示 與FcgRI及FcgRIIa之結合降低，而與FcgRIIb之結合不受影 響。由抗原/IgG免疫複合物結合及活化Clq引發典型補體 級聯，及後續發炎性及/或免疫調節反應。IgG上之Clq結 合位點已定位至IgG鉸鏈區内之殘基。藉由Clq ELIS A評定 C1 q與遞增濃度之mAb的結合。結果表明如所預期，當與 野生型對照IgGl之結合相比時，mAb不能結合C 1 q。總 之，L234A、L235A鉸鏈區突變消除mAb與FcgRI、 FcgRIIa及Clq之結合，但不影響mAb與FcgRIIb之相互作 用。此資料表明雖然具有突變型Fc之mAb通常將在活體内 與抑制性FcgRIIb相互作用，但可能無法與活化FcgRI及 FcgRIIa受體或Clq相互作用。 人類FcRn結合：新生兒受體（FcRn)負責轉運IgG穿過胎 151681.doc 179· 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 812
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 δ 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 145 150 155 160
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val •1171 151681-序列表.doc 201127956 165 170 175
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 813 <211〉 221 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 813
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu He 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly -1172- 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220
<210〉 814 <211〉 249 <212〉 PRT •1173- 151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 814
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala He Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser 130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr 145 150 155 160 1174- 151681-序列表.doc 201127956
Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 165 170 175
Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys 180 185 190
Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210> 815 <211> 221 <212> PRT <213〉人造序列
<220> <223〉人造序列之描述：合成多肽 <400〉 815
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 151681·序列表.doc -1175- 201127956
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 816 151681·序列表.doc -1176- 201127956 <211> 247 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 816
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu He Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr He Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin GLy Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp 151681·序列表.doc -1177· 201127956 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn 165 170 175
Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe 180 185 190
Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro 210 215 220
His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 817 <211〉 221 <212〉 PRT 〈213>人造序列 <220〉 <223〉冬造序列之描述：合成多肽 <400> 817
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie • 1178- 151681-序列表.doc 201127956 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Fhe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160
lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 -1179· 151681-序列表.doc 201127956 <210> 818 <211〉 247 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 818
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 130 135 140 -1180- 151681·序列表.doc 201127956 盤且控制IgG分子之分解代謝半衰期。可能需要增加抗體 之終末半衰期以改良功效’降低投藥之劑量或頻率，或改 良對目標之定位。或者，可能、益— 、且進行相反操作，亦即縮 短抗體之終料㈣㈣低^暴露或改良目標與非目標 結合比。調整igG與其救助受體卜以之間的相互作用可提 供增加或縮短1gG之終末半衰期的方式。循環中蛋白質（包 括柳在流體相中經由某些細胞（諸如血㈣^㈣^ 微胞飲作用被吸收。IgG在内體中在略微酸性之條件（pH 6.0-6.5)下可結合卜如且可再循環至細胞表面，在細胞表 面上其在近中性條件（ρΗ 7·〇_7.4)下釋放。對FcRn8〇、 16、17上Fc區結合位點之定位展示在物種之間呈保守性之 2個組胺酸殘基（His3丨〇及His43 5)造成此相互作用之pH值依 賴性。使用噬菌體呈現技術，鑑別出增加與FcRn之結合且 延長小鼠IgG之半衰期的小鼠Fc區突變（參看Vict〇r，g等 人；Nature Biotechnology (1997)，15(7)，637-640)。亦已鑑 別出可增加人類IgG在pH 6.0下而非在pH 7.4下對FcRn之結 合親和力的Fc區突變（參看Dall，Acqua william F等人，
Journal of Immunology (2002)，169(9)，5171-80)。此外， 在一種情形下’對於怪河猴FcRn亦觀測到類似之pH值依 賴性結合增加（高達27倍），且此使得恆河猴之血清半衰期 相較於親本IgG增加兩倍（參看Hinton，Paul R等人，J〇urnal of Biological Chemistry (2004)，279(8)，6213-6216)。此等 研究結果指示藉由調整FC區與FcRn之相互作用來延長抗體 治療劑之血漿半衰期為可行的。相反，減弱與FcRn之相互 151681.doc •180· 201127956
Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr 145 150 155 160
Tyr Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp 165 170 175
Met Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser 180 185 190
Phe Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala 195 200 205
Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr 210 215 220
Cys Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245
〈210〉 819 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 819
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30 1181 · 151681·序列表.doc 201127956
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
lie Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg -1182· 151681-序列表.doc 201127956 2i〇 215 220 <210〉 820 <211〉 254 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 820
Glu Val Gin Leu Va.1 Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15
Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser He Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin -1183- 151681-序列表 doc 201127956 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe 145 150 155 160
Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Trp lie Asn Tlir Tyr Thr Gly Glu Pro Thr Tyr Ala 180 185 190
Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr 225 230 235 240
Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 821 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 821
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly i 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr -1184-
151681-序列表.doc 201127956 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205 151681·序列表.doc -1185· 201127956
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 822 <211> 254 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 822
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 • 1186· 151681-序列表d〇c 201127956
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly 130 135 140
Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys lie Ser Cys Lys Gly 145 150 155 160
Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met 165 170 175
Pro Gly Lys Gly Leu Glu Trp Met Gly Glu lie Asn Pro Thr Asn Gly 180 185 190
His Thr Asn Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr lie Ser Ala 195 200 205
Asp Lys Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala 210 215 220
Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser lie 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 823 〈211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •1187- 151681-序列表.doc 201127956 <400> 823
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175
Gl)r Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr -1188-
151681·序列表.doc 201127956 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gl)r Thr Lys Leu 210 215 220
Glu lie Lys Arg 225
<210> 824 <211> 254 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 824
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys -1189- 151681-序列表.doc 201127956 8δ 90 95
Ala Arg Asn Tyr Val Gly Ser He Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe 145 150 155 160
Tlir Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Trp lie Asn Thr Tjrr Thr Gly Glu Pro Thr Tyr Ala 180 185 190
Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr 225 230 235 240
Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 825 <211〉 221 <212〉 PRT 1190- 151681-序列表.doc 201127956 作用的Fc區突變可縮短抗體半衰期。 B.10藥物動力學（PK): 在一實施例中，為產生具有所要藥物動力學概況之 DVD-Ig分子，選擇具有類似所要之藥物動力學概況之親 本mAb。一個考慮因素為對單株抗體之免疫原性反應（亦 即HAHA，人類抗人類抗體反應；HACA，人類抗嵌合抗 體反應）進一步使此等治療劑之藥物動力學複雜化。在一 實施例中，使用具有最低免疫原性或不具有免疫原性之單 株抗體建構DVD-Ig分子使得所得DVD_Ig亦將具有最低免 疫原性或不具有免疫原性。決定mAb之PK的一些因素包括 (但不限於）mAb之固有特性（VH胺基酸序列）、免疫原性、 FcRn結合及Fc功能。 所選親本單株抗體之PK概況可輕易地在齧齒動物體内 測定，此係因為齧齒動物之PK概況與在食蟹猴 (cynomolgus monkey)及人類中單株抗體之PK概況密切相 φ 關（或前者可精密預測後者）。PK概況係如實例1.2.2.3.A章 節中所述測定。 選擇具有所要PK特徵（及如本文所述之其他所要功能特 性）之親本單株抗體之後，建構DVD-Ig。因為DVD-Ig分子 含有兩個來自兩種親本單株抗體之抗原結合區域，所以亦 評定DVD-Ig之PK特性。因此，在測定DVD-Ig之PK特性 時，可使用基於來源於2種親本單株抗體之2個抗原結合區 域之功能性來測定PK概況的PK檢定。可如實例1.2.2.3.A 中所述測定DVD-Ig之PK概況。可影響DVD-Ig之PK概況的 151681.doc -181 - 201127956 <213〉人造序列 <220〉 <2之3>人造序列之描述：合成多肽 <400〉 825
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 151681·序列表.doc • 1191 201127956 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220
<210〉 826 <211> 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 826
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 1192·
151681·序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly 130 135 140
Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys lie Ser Cys Lys Gly 145 150 155 160
Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met 165 170 175
Pro Gly Lys Gly Leu Glu Trp Met Gly Glu lie Asn Pro Thr Asn Gly 180 185 190
His Thr Asn Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr lie Ser Ala 195 200 205
Asp Lys Ser He Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala 210 215 220
Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser lie 225 230 235 240
Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 827 151681.序列表.doc · 1193· 201127956 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 827
Asp lie Gin Met Thr Glri Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 δ 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu -1194-
15168卜序列表doc 201127956 145 150 155 160 lie Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210> 828 <211〉 247 <212〉 PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 828
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr -1195- 151681-序列表.doc 201127956 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn 165 170 175
Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe 180 185 190
Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro 210 215 220
His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 -1196- 151681·序列表.doc 201127956 <210> 829 <211> 228 〈212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 829
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asa Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Ser 130 135 140 1197. 151681·序列表.doc 201127956
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210〉 830 <211> 247 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 830
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -1198-
151681-序列表.doc 201127956
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 130 135 140
Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr 145 150 155 160
Tyr Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp 165 170 175
Met Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser 180 185 190
Phe Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala 195 200 205
Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr 210 215 220
Cys Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly 1199- 151681·序列表doc 201127956 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210> 831 〈211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 831
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro •1200·
151681·序列表.doc 201127956 其他因素包括抗原結合區域（CDR)定向、連接子尺寸及 Fc/FcRn相互作用。親本抗體之ρκ特徵可藉由評定以下參 數來評估：吸收、分佈、代謝及排泄。 吸收··迄今為止，治療性單株抗體係經由非經腸途徑 (例如靜脈内[iv]、皮下[sc]或肌肉内[ΙΜ])投與。在3(：或 ΙΜ投與後，mAb主要經由淋巴路徑自胞間隙吸收至體循環 中。可飽和之體循環前蛋白質水解降解可在也管外投與後 產生可變之絕對生物可用性。通常，由於在較高劑量下蛋 白質水解容量飽和，所以可觀測到絕對生物可用性隨單株· 抗體劑量增加而增加。因為淋巴流體緩慢排入血管系統 中，所以mAb之吸收過程通常相當緩慢，且吸收持續時間 可歷，’座數小時至數天。單株抗體在sc投與後之絕對生物可 用性一般處於50°/〇至1 〇〇%之範圍内。 分佈·在IV投與之後，單株抗體通常遵循以快速分佈相 ^ 、應之以緩慢消除相之兩相血清（或血漿）濃度-時間概 況。-般而t ’雙減藥物動力學模型最佳描述此種藥物 動:學概況。mAb於中央室（Vc)中之分佈體積通常等於或· 略Γ7於血毁體積（2公升·3公升卜其他非經腸投與途徑（諸 如ΙΜ或SC)的血清（金襞）濃度相對於時間之概況的獨特兩 才模式可敗《不明顯，因為血清（血漿）濃度-時間曲線之分佈 長吸收部分掩蓋。包括物理化學特性、位點特異性及 目標定向受體介導之吸收、組織結合能力及_劑量之多 種因素可衫響mAb之生物分佈。—些此等因素可造成mAb 生物分佈之非線性。 151681.doc -182- 201127956 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 <210〉 832 <211〉 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 832
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr • 1201 151681-序列表.doc 201127956 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr 165 170 175
Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205 151681-序列表.doc - 1202- 201127956
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val 210 215 220
Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser
<210> 833 <211〉 221 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 833
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95 .1203 151681-序列表.doc 201127956
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 834 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 834
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 151681·序列表.doc • 1204- 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu 130 135 140
Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Met 145 150 155 160
His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Glu 165 170 175 lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe Gin Gly 180 185 190
Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr Leu Gin • 1205- 151681-序列表 _doc 201127956 195 200 205
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 210 215 220
Asn Tyr Va.1 Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr Leu Va.1 225 230 235 240
Thr Val Ser Ser
<210> 835 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 835
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro - 1206- 151681-序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 836 <211〉 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 836
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu • 1207- 151681 -序列表.doc 201127956 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Fro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Va.l Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala 180 185 190 151681·序列表.doc -1208- 201127956
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 837 <211> 228 <212> PRT <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400> 837
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 1209- 151681·序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp T.yr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 838 <211〉 251 〈212〉 PRT <213〉人造序列 1210-
151681·序列表.doc 201127956 代謝及排液：完整單株抗體由於分子
臟排泄至尿中。其主要藉由代謝（例如分解代謝)而失Z 對於基於IgG之治療性單株抗體，半衰期通常在數小時或^ 至2天至20天以上之範圍内。mAb之消除可受多種因㈣ 響，包括（但不限於）料心受體之親和力、_之免疫原 性、mAb之糖基化程度、mAb對蛋白質水解之敏感性及受 體介導之消除。 φ B·11人類及毒理學物種之組織交又反應性模式： 相同染色模式表明可以毒理學物種評估潛在人類毒性。 毒理學物種為用於研究無關毒性之彼等動物。 選擇滿足2個準則之個別抗體。⑴組織染色適合於已知 抗體目標表現。（2)來自相同器官之人類組織與毒理學物種 組織之間的染色模式類似。 準則1 :免疫及/或抗體選擇通常使用重組或合成抗原（蛋 白質、碳水化合物或其他分子）。結合於天然對應物及針 • 對無關抗原之反篩選通常為用於治療性抗體之篩選漏斗的 一部分。然而’針對大量抗原進行筛選通常不切實際。因 使用來自所有主要器官之人類組織進行組織交又反應 性研究可用㈣免抗體與任何無關抗原之不纟需要之結 合。 ”準則2 .對人類及毒理學物種組織（食蟹猴、犬、可能為 齧齒動物及其他動物，如人類研究中般測試相同36或37個 、、且織）之比杈組織交叉反應性研究有助於驗證毒理學物種 之選擇。在對冷凍組織切片之典型組織交叉反應性研究 151681 .doc -183 - 201127956 <220〉 〈223>人造序列之描述：合成多肽 <400> 838
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val 130 135 140
Lys Lys Pro Gly Glu Ser Leu Lys lie Ser Cys Lys Gly Ser G'Ly Tyr 145 150 155 160
Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met Pro Gly Lys • 1211 · 151681-序列表.doc 201127956 165 170 175
Gly Leu Glu Trp Met Gly Glu He Asn Pro Thr Asn Gly His Thr Asn 180 185 190
Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser 195 200 205 lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr 210 215 220
Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser He Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 839 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 839
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly • 1212· 151681·序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225 -1213· 151681·序列表.doc 201127956 <210〉 840 <211> 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 840
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140 •1214-
151681-序列表.doc 201127956
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Ser Asp Tyr Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
〈210〉 841 <211> 221 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400> 841
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30 -1215- 151681-序列表.doc 201127956
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg -1216- 151681 ·序列表.doc 201127956 210 215 220 <210〉 842 <211〉 251 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 842
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 1Γ)
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val -1217- 151681•序列表.doc 201127956 130 135 140
Lys Lys Pro Gly Glu Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr 145 150 155 160
Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met Pro Gly Lys 165 170 175
Gly Leu Glu Trp Met Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn 180 185 190
Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser 195 200 205
He Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr 210 215 220
Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser He Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 843 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 843
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala -1218·
151681·序列表.doc 201127956 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Va.1 Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205 151681-序列表·doc -1219- 201127956
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 844 <211> 244 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述··合成多肽 <400〉 844
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr He Ser Ala Asp Lys Ser He Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125 • 1220- 151681·序列表.doc 201127956 中，治療性抗體可展現與已知抗原之預期結合及/或基於 低相互作用程度（非特異性結合、與類似抗原之低結合程 度、基於低電平電荷之相互作用等）與組織以較低程度結 合》在任何情形下，最具相關性之毒理學動物物種為與人 類及動物組織之結合重合度最高的動物物種。 組織父叉反應性研究遵循適當法規指南，包括EC cpMp 指南 IIU5271/94「Production and quality c〇ntr〇1 〇f mAbs」及 1997 US FDA/CBER「Points t〇 consider in the
Manufacture and Testing of Monoclonal Antibody Products for Human Use」。在物鏡上固定在屍體解剖或活組織檢查 時獲得之人類組織冷凍切片（5 pm)，且乾燥。使用抗生物 素蛋白·生物素系統對組織切片進行過氧化酶染色。Fda 為南「Points to Consider in the Manufacture and Testing of Monocional Antibody Products for Human Use」。相骑象考 文獻包括 Clarke J 2004，Boon L. 2002a，Boon L 2002b，
Ryan A 1999 ° 組織交叉反應性研究通常以兩個階段進行，其中第一階 段包括製成來自一個人類供者之32個組織（通常：腎上 腺、胃腸道、前列腺、膀胱、心臟、骨骼肌、血球、腎 臟、皮膚、骨髓、肝、脊髓、乳房、肺、脾臟、小腦、淋 巴結、睪丸、大腦皮質、卵巢、胸腺、結腸、胰臟、甲狀 腺、内皮、副甲狀腺、輸尿管、眼、垂體、子宮、輸卵管 及胎盤）的冷凍切片。在第二階段中，用來自3個無關成人 之多達38個組織（包括腎上腺、血液、血管、骨髓、小 151681.doc -184- 201127956
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly lie Thr 165 170 175
Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val 210 215 220
Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser <210〉 845 <211〉 228 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 845
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -1221 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Ser Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 1222· 151681-序列表.doc 201127956 195 200 205
Gin Gin Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 846 <211〉 244 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 846
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
Ala Gly lie Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin - 1223 · 151681·序列表.doc 201127956 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu 130 135 140
Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp Met 145 150 155 160
His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Glu 165 170 175
He Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe Gin Gly 180 185 190
Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr Leu Gin 195 200 205
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 210 215 220
Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ser <210〉 847 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -1224-
151681·序列表.doc 201127956 <400> 847
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175 151681-序列表.doc -1225- 201127956
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225 <210〉 848 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 848
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu He Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr 65 70 75 80 151681·序列表.doc -1226- 201127956
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp lie His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala lie Tyr 165 170 175
Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly 210 215 220
His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 849 151681-序列表.doc - 1227- 201127956 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 849
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr
Tlir Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu -1228- 151681·序列表.doc 201127956 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 850 <211〉 245 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 850
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr • 1229- 151681·序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 130 135 140
Leu Lys I]e Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp 145 150 155 160
Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 165 170 175
Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe Gin 180 185 190
Gly Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr Leu 195 200 205
Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220
Arg Asn Tyr Val Gly Ser He Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 - 1230· 151681-序列表.doc 201127956 腦、大腦、子宮頸、食道、目艮、心臟、腎臟、大腸、肝、 肺淋巴結、礼腺、卵巢、輸卵管、騰臟、副甲狀腺、周 邊神經、垂體、胎盤、前列腺、唾液腺、皮膚、小腸、脊 髓脾臟胃、橫紋肌、畢丸、胸腺、甲狀腺、爲桃體、 輸尿S、膀胱及子宮）進行完全交叉反應性研究。通常以 最少2個劑量進行研究。 ^療I·生抗體（亦即測試物品）及同型匹配對照抗體可經生
物素私n己以用於抗生物素蛋白_生物素複合物偵測； 其他制方法可包括肖經打代（或卩其他方式）標記之測試 物。σ進行一人抗體偵_，或冑未標記之測試物品與經標記 之抗人類IgG預複合。 簡<=»之，在物鏡上固定在屍體解剖或活組織檢查時獲: 之人類組織冷;東切片（約5㈣，且乾燥。使用抗生物素、 白-生物素系統對組織切片進行過氧化酶染色。首先⑷ 複合偵測系統之情形下），將測試物品與經生物素標記： 二次抗人類1gG"'起培育且形成免疫複合物。將測試物c 之最終濃度為2 _及10叫就之免疫複合物添加至4 鏡上的組織切片上，泛垃益 且接者使組織切片與抗生物素蛋白 生物素過氧化酶套組反應3〇分鐘。隨後，塗佈以叩,3 二胺基聯苯胺）(過氧化酶反應之受f)，歷時4分鐘以進 組織染色。抗原-瓊脂糖珠粒係用作陽性對照組織切片。 基於所討論之目標抗原的已知表現來判斷任何特显性汰 ^具有翻反應性（例如與抗原表現相符）或非預期反二 針對強度及頻率，對任何經判斷具特異性之染色進Γ J5168I.doc
S -185· 201127956 <210> 851 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 851
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140 • 1231 · 151681-序列表.doc 201127956
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 〈210〉 852 <211〉 252 <212> PRT 〈213>人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 852
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60 1232-
151681·序列表.doc 201127956
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He 145 150 155 160
Asn Ala Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Tbr Asn Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1233- 151681-序列表 *d〇c 201127956 245 250 <210> 853 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 853
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie. Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg -1234.
151681-序列表.doc 201127956 130 135 140
Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210〉 854 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 854
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Va.l Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 1235, 151681-序列表.doc 201127956 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu 130 135 140
Val Lys Lys Pro Gly Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly 145 150 155 160
Tyr Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met Pro Gly 165 170 175
Lys Gly Leu Glu Trp Met Gly Glu lie Asn Pro Thr Asn Gly His Thr 180 185 190
Asn Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr lie Ser Ala Asp Lys 195 200 205
Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp 210 215 220 • 1236· 15168卜序列表.doc 201127956
Thr Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser He Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 855 <211> 228 <212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400> 855
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110 151681·序列表.doc -1237 - 201127956
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 <210> 856 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 856
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 • 1238· 151681-序列表.doc 201127956
Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie 145 150 155 160
Asn Ala Ser Trp He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 165 170 175
Glu Trp Val Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn •1239· 151681-序列表.doc 201127956 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 857 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 857
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr • 1240· 151681·序列表.doc 201127956 評分。抗原或血清競爭或阻斷研究可進一步輔助確定所觀 測到的染色為特異性的或非特異性的。 若發現2種所選抗體滿足選擇準則（即組織染色適合、人 類與毒理學動物特定組織之間的染色匹配），則可選擇其 用於DVD-Ig產生。 必需用最終DVD-Ig構築體重複組織交叉反應性研究， 但當此等研究遵循如本文所概述之相同方案時，對其之評 估更複雜，因為任何結合均可由2種親本抗體中之任一者 所致，且需要用複雜抗原競爭研究確定任何無法解釋之結 合。 顯而易見，若選擇如下2種親本抗體，則可極大簡化對 多特異性分子（如DVD-Ig)之組織交叉反應性研究的複雜操 作：（1)缺乏非預期之組織交叉反應性研究結果及（2)相應 人類與毒理學動物物種組織之間的組織交叉反應性研究結 果存在適當類似性。 B.12特異性及選擇性： 為了產生具有所要特異性及選擇性之DVD-Ig分子，需 要產生且選擇具有類似所要特異性及選擇性概況之親本 mAb 0 對於DVD-Ig之特異性及選擇性的結合研究可因四個或 四個以上結合位點（每兩個針對一種抗原）而變得複雜。簡 言之，對DVD-Ig之使用ELISA、BIAcore、KinExA之結合 研究或其他相互作用研究需要監測1種、2種或2種以上抗 原與DVD-Ig分子之結合。BIAcore技術可分析多種抗體之 -186 - 151681.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val He Arg Arg 130 135 140
Ser Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro 195 200 205
Leu Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 858 <211〉 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 858
Glu Val Gin Leu Val Glu Ser Gly Gl}r Gly Leu Val Gin Pro Gly Gly -1241 - 151681-序列表.doc 201127956 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu 130 135 140
Val Lys Lys Pro Gly Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly 145 150 155 160
Tyr Ser Phe Thr Thr Tyr Trp Met His Trp Val Arg Gin Met Pro Gly 165 170 175
Lys Gly Leu Glu Trp Met Gly Glu lie Asn Pro Thr Asn Gly His Thr 180 185 190 • 1242· 151681-序列表.doc 201127956
Asn Tyr Asn Pro Ser Phe Gin Gly Gin Val Thr He Ser Ala Asp Lys 195 200 205
Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp 210 215 220
Thr Ala Met Tyr Tyr Cys Ala Arg Asn Tyr Val Gly Ser lie Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210〉 859 〈211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 859
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 151681·序列表.doc -1243 - 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser 130 135 140
Tyr Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210> 860 <211> 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 1244-
15168卜序列表.doc 201127956 <400〉 860
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15
Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Pile Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu He Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser Trp He His Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala ILe Tyr 165 170 175
Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe -1245- 151681·序列表.doc 201127956 180 185 190
Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly 210 215 220
His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 861 <211〉 228 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 861
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro -1246- 151681-序列表.doc 201127956 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Val lie Arg Arg Ser Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Ala Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ser Asn Thr Ser Pro Leu Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225
<210> 862 <211〉 245 <212> PRT 1247- 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 862
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr He Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 130 135 140
Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr Trp 145 150 155 160 -1248-
151681-序列表.doc 201127956
Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 165 170 175
Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe Gin 180 185 190
Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr Leu 195 200 205
Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220
Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr Leii 225 230 235 240
Val Thr Val Ser Ser 245 〈210〉 863 〈211〉 228 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 863
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val lie Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 151681·序列表.doc -1249- 201127956
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Glu Asn Val Val Ser Tyr Val Ser Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu He Tyr Gly Ala Ser Asn Arg Asn Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gly Gin Ser Tyr Asn Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 151681-序列表.doc - 1250- 201127956 連續獨立結合’而較傳統之方法（包括elisa)或較現代之 技術（如KinExA)卻不能。因此，對各親本抗體進行仔細表 徵至關重要。在已針對特異性對各個抗體進行表徵後，對 DVD-Ig分子中個別結合位點之特異性保留的確認將極大 簡化。 顯而易見，若針對特異性來選擇該2種親本抗體，之後 將其組合成DVD-Ig，則測定DVD_Ig特異性之複雜操作將 極大簡化。 抗原-抗體相互作用研究可採取多種形式，包括多種典 型蛋白質-蛋白質相互作用研究，包括ELISA(酶聯結免疫 吸附劑分析法）、質譜、化學交聯、使用光散射 之SEC、平 衡透析、凝膠滲透、超濾、凝膠層析、大區域分析型 SEC、微量製備級超速離心（沈降平衡）、光譜法、滴定微 里熱法、沈降平衡（在分析型超速離心機中）、沈降速度（在 分析型離心機中）、表面電漿子共振（包括BiAcore)。相關 參考文獻包括John Wiley & Sons Inc.出版之「Current
ProtocolsinProteinScience」，J〇hnE.Coligan，BenM.
Dunn, David W· Speicher，Paul T，Wingfield (編）第 3 卷，第 19及20早’及其中所包括之參考文獻，及j〇hn wiley &
Sons Inc出版之「Current Protocols in Immunology」，j〇hn E. Coligan, Barbara E. Bierer, David H. Margulies, Ethan M. Shevach，Warren Strober (編），及其中包括之相關參考 文獻。 全血中之細胞激素釋放：可藉由細胞激素釋放檢定研究 151681.doc -187· 201127956 225 <210> 864 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 864
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu -1251 - 15】681-序列表.doc 201127956 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr Thr Met 145 150 155 160
Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asp 165 170 175
Val Asn Pro Asn Ser Gly Gly Ser He Tyr Asn Gin Arg Phe Lys Gly 180 185 190
Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 865 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 865
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala • 1252- 151681·序列表.doc 201127956 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Asp Val Ser lie 130 135 140
Gly Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr lie Tyr Pro 195 200 205 151681-序列表.doc -1253 - 201127956
Tyr Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 866 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 866
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30
Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser lie Tyr Asn Gin Arg Phe 50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125 151681-序列表 _doc -1254- 201127956
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 867 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 867
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 - 1255 · 151681·序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Asp Val Ser lie Gly 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr lie Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro -1256-
151681·序列表.doc 201127956 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 868 <211> 252 <2I2> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 868
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 1257· 151681-序列表.doc 201127956 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Thr Asp Tyr Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser He 180 185 190
Tyr Asn Gin Arg Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser 195 200 205
Lys Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 869 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 869
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -1258- 151681-序列表.doc 201127956 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Lys 130 135 140
Ala Ser Gin Asp Val Ser lie Gly Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Tyr Arg Tyr Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190 151681·序列表.doc -1259- 201127956
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Tyr lie Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 870 <211〉 252 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 870
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30
Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser He Tyr Asn Gin Arg Phe 50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 • 1260·
151681·序列表.doc 201127956 mAb與人類血球的相互作用（Wing，M. G. Therapeutic Immunology (1995)，2(4)，183-190 ; John Wiley & Sons Inc 出版之「Current Protocols in Pharmacology」，S.J. Enna， Michael Williams, John W. Ferkany, Terry Kenakin, Paul Moser，（編）；Madhusudan，S. Clinical Cancer Research (2004)，10(19), 6528-6534 ； Cox, J. Methods (2006), 38(4), 274-282 ； Choi, I. European Journal of Immunology (2001), 31(1), 94-106)。簡言之，各種濃度之mAb與人類全血一起 培育24小時。所測試之濃度應涵蓋包括模擬患者體内典型 血液含量之最終漢度的寬範圍（包括（但不限於）100 ng/ml-100 pg/ml)。培育後，分析上清液及細胞溶解產物中仏-lRa、TNF-α、IL-lb、IL-6及 IL-8之存在。比較mAb產生之 細胞激素濃度概況與陰性人類IgG對照組及陽性LPS或PHA 對照組產生之概況。來自細胞上清液及細胞溶解產物之 mAb呈現之細胞激素概況與對照人類IgG之概況相當。在 一實施例中，單株抗體不與人類血球相互作用以自發釋放 發炎性細胞激素。 DVD-Ig之細胞激素釋放研究由於四個或四個以上結合 位點（每2個針對一種抗原）而變得複雜。簡言之，如本文所 述之細胞激素釋放研究量測整個DVD-Ig分子對全血或其 他細胞系統之效應，但可分析引起細胞激素釋放之分子部 分。一旦偵測到細胞激素釋放，則必需確定DVD-Ig製劑 的純度，因為一些共純化細胞組分可獨自引起細胞激素釋 放。若純度並非問題，則可能需要使用DVD-Ig之斷裂（包 151681.doc -188 - 201127956
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly 100 105 no
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gla Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160
lie Lys Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 871 <211〉 228 <212〉 PRT <213〉人造序列 • 1261 · 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 871
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Gin Asp Val Ser He Gly 20 25 30
Val Ala Trp Tyr Gin Gin Lys.Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr lie Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu T}rr Ser -1262-
151681·序列表.doc 201127956 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 872 <211> 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 872
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr • 1263. 15168卜序列表.doc 201127956 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 J05 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125
Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Thr Asp Tyr Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser lie 180 185 190
Tyr Asn Gin Arg Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser 195 200 205
Lys Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 -1264- 151681·序列表.doc 201127956 <210〉 873 <211〉 221 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 873
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Lys Ala Ser Gin Asp Val Ser lie 130 135 140 -1265- 151681-序列表.doc 201127956
Gly Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr He Tyr Pro 195 200 205
Tyr Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 〈210〉 874 <211> 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 874
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30
Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser He Tyr Asn Gin Arg Phe 50 55 60 -1266- 151681-序列表.doc 201127956
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn 145 150 155 160 lie Lys Asp Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser -1267- 151681·序列表.doc 201127956 245 250 <210〉 875 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 875
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Gin Asp Val Ser He Gly 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr He Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr -1268-
151681-序列表doc 201127956 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg F^e Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 876 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 876
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val • 1269. 151681-序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 Π0
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr Thr Met 145 150 155 160
Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Asp 165 170 175
Val Asn Pro Asn Ser Gly Gly Ser lie Tyr Asn Gin Arg Phe Lys Gly 180 185 190
Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240 151681·序列表.doc • 1270· 201127956 括（但不限於）移除Fc部分、分離結合位點等）、結合位點突 變誘發或其他方法來重疊合任何觀測結果。顯而易見，若 選擇缺乏細胞激素釋放之2種親本抗體，之後將其組合成 DVD-Ig，則可極大簡化此複雜操作。 B.13與用於毒物學研究之其他物種的交叉反應性： 在一實施例中，選擇與適當毒理學物種（例如食蟹猴）具 有充分交又反應性的個別抗體。親本抗體需要結合於直系 φ 同源物種目標（亦即食蟹猴）且引發適當反應（調節、中和、 活化）。在一實施例中，對直系同源物種目標之交又反應 性（親和力/效能）應在人類目標之10倍以内。實際上，針對 包括小鼠、大鼠、犬、猴（及其他非人類靈長類動物）之多 種物種以及疾病模型物種（亦即用於哮喘模型之綿羊）評估 親本抗體。親本單株抗體對毒理學物種之可接受交叉反應 性允s午將來以同一物種進行DVD-Ig-Ig的毒理學研究。出 於彼原因，2種親本單株抗體應對常見毒理學物種具有可 鲁接受之交叉反應性’從而允許以同一物種對DVD-Ig進行 毒理學研究。 親本mAb可選自能夠結合特異性目標且在此項技術中熟 知之各種mAb。此等包括（但不限於）抗TNF抗體（美國專利 第6,258,562號）、抗IL-12及/或抗IL-12p40抗體（美國專利 第 6,914，128 號）；抗 IL-18抗體（US 2005/0147610 A1)、抗 C5、抗 CBL、抗 CD147、抗 gpl20、抗 VLA-4、抗 CDlla、 抗CD18、抗VEGF、抗CD40L、抗CD-40(參看例如 WO2007124299)、抗 id、抗 ICAM-1、抗 CXCL13、抗 151681.doc •189· 201127956
Val Thr Val Ser Ser 245 <210〉 877 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多狀 <400〉 877
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Se:r Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125 • 1271 - 151681-序列表.doc 201127956
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Lys 130 135 140
Ala Ser Gin Asp Val Ser lie Gly Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Tyr Arg Tyr Thr 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Tyr lie Tyr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 878 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 878
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 • 1272·
151681-序列表.doc 201127956
Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser lie Tyr Asn Gin Arg Phe 50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 1273 - 151681-序列表.doc 201127956 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 879 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 879
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Gin Asp Val Ser He Gly 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr lie Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 1274·
151681·序列表.doc 201127956 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210〉 880 <211〉 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 880
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala -1275 - 151681-序列表.doc 201127956 15 10
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val 130 135 140
Ala Pro Ser Gin Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser 145 150 155 160
Leu Pro Asp Tyr Gly Val Ser Trp lie Arg Gin Pro Pro Arg Lys Gly 165 170 175
Leu Glu Trp Leu Gly Val lie Trp Gly Ser Glu Gly Thr Thr Tyr Tyr 180 185 190 15168卜序列表.doc 1276- 201127956
Asn Ser Ala Leu Lys Ser Arg Leu Thr lie lie Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Pro Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala 210 215 220 lie Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250
<210〉 881 〈211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400〉 881
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80 151681-序列表.doc -1277- 201127956
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Thr Thr Ser 115 120 125
Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr lie Ser Cys Arg Ala 130 135 140
Ser Gin Asp lie Ser Lys Thr Leu Asn Trp Tyr Gin Gin Lys Pro Asp 145 150 155 160
Gly Thr Val Lys Leu Leu lie Tyr His Thr Ser Arg Leu His Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 180 185 190
Thr lie Ser Asn Leu Glu Gin Glu Asp lie Ala Thr Tyr Phe Cys Gin 195 200 205
Gin Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220
He Thr Arg 225 <210> 882 <211> 253 <212〉 PRT <213〉人造序列 -1278- 151681·序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400> 882
Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin 15 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30
Gly Val Ser Trp lie Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu 50 55 60
Lys Ser Arg Leu Thr He lie Lys Asp Asn Ser Lys Ser Gin Val Pro 65 70 75 80
Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys 85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu 130 135 140
Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gin Arg Pro Gly -1279- 151681·序列表.doc 201127956 165 170 175
Gin Gly Leu Glu Trp lie Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210> 883 <211〉 227 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 883
Asp He Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 15 10 15
Asp Arg Val Thr He Ser Cys Arg Ala Ser Gin Asp He Ser Lys Thr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie 35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly • 1280· 151681·序列表.doc 201127956 CD2、抗 EGFR、抗 TGF-p2、抗 HGF、抗 cMet、抗 DLL-4、 抗NPR1、抗PLGF、抗ErbB3、抗E-選擇素、抗Fact VII、 抗 Her2/neu、抗 F gp、抗 CD11/18、抗 CD14、抗 ICAM-3、 抗 RON、抗 CD-19、抗 CD80(參看例如 W02003039486、抗 CD4、抗CD3、抗CD23、抗-β2_整合素、抗-α4β7、抗 CD52、抗HLA DR、抗CD22(參看例如美國專利第 5,789,554號）、抗 CD20、抗 MIF、抗 CD64(FcR)、抗 TCR α β、抗 CD2、抗 Hep Β、抗 CA 125、抗 EpCAM、抗 gpl20、 抗 CMV、抗 gpllbllla、抗 IgE、抗 CD25、抗 CD33、抗 HLA、抗 IGF1，2、抗 IGFR、抗 VNR整合素、抗 IL-la、抗 IL-Ιβ、抗IL-1受體、抗IL-2受體、抗IL-4、抗IL-4受體、 抗IL5、抗IL-5受體、抗IL-6、抗IL-8、抗IL-9、抗IL-13、 抗 IL-13 受體、抗 IL-17、及抗 IL-23(參看 Presta LG· 2005 Selection, design, and engineering of therapeutic antibodies J Allergy Clin Immunol. 116:73 1-6及 http://www.path.cam. ac.uk/〜mrc7/humanisation/antibodies.html)。 親本mAb亦可選自各種批准使用、正經臨床試驗、或正 經開發供臨床使用之治療性抗體。該等治療性抗體包括 (但不限於）利妥昔單抗（rituximab，Rituxan®，IDEC/ Genentech/Roche)(參看例如美國專利第5,736，137號），一 種批准用於治療非霍奇金淋巴瘤之嵌合抗CD20抗體； HuMax-CD20，一種當前正由Genmab開發之抗CD20 ;美 國專利第5,500,362號所述之抗CD20抗體，AME-133 (Applied Molecular Evolution) ; hA20(Immunomedics, 151681.doc -190- 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr lie Ser Asn Leu Glu Gin 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Thr Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Gin He Val Leu Thr Gin Ser Pro 115 120 125
Ala lie Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser 130 135 140
Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gin Gin Lys Ser Gly 145 150 155 160
Thr Ser Pro Lys Arg Trp He Tyr Asp Thr Ser Lys Leu Ala Ser Gly 165 170 175
Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu 180 185 190
Thr lie Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin 195 200 205
Gin Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu 210 215 220
He Asn Arg 225 •1281· 151681-序列表.doc 201127956 <210> 884 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 884
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Thr Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Leu lie Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Lys Leu Gin Glu Ser Gly Pro 130 135 140 1282-
151681·序列表.doc 201127956
Gly Leu Val Ala Pro Ser Gin Ser Leu Ser Val Thr Cys Thr Val Ser 145 150 155 160
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp lie Arg Gla Pro Pro 165 170 175
Arg Lys Gly Leu Glu Trp Leu Gly Val lie Trp Gly Ser Glu Gly Thr 180 185 190
Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr lie lie Lys Asp 195 200 205
Asn Ser Lys Ser Gin Val Pro Leu Lys Met Asn Ser Leu Gin Thr Asp 210 215 220
Asp Thr Ala lie Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser 225 230 235 240
Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250 255
<210〉 885 〈211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 885
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Arg Asn Tyr 20 25 30 -1283 - 151681-序列表.doc 201127956
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Thr Thr 115 120 125
Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr He Ser Cys Arg 130 135 140
Ala Ser Gin Asp lie Ser Lys Thr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Asp Gly Thr Val Lys Leu Leu lie Tyr His Thr Ser Arg Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser 180 185 190
Leu Thr He Ser Asn Leu Glu Gin Glu Asp lie Ala Thr Tyr Phe Cys 195 200 205
Gin Gin Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu -1284- 151681·序列表.doc 201127956 2i〇 215 220
Glu lie Thr Arg 225 <210〉 886 <211> 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 886
Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin 1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30
Gly Val Ser Trp He Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu
Lys Ser Arg Leu Thr lie lie Lys Asp Asn Ser Lys Ser Gin Val Pro 65 70 75 80
Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys 85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser -1285- 151681-序列表.doc 201127956 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ala Leu lie Asn Pro Tyr Lys Gly Val Ser 180 185 190
Thr Tyr Asn Gin Lys Phe Lys Asp Arg Phe Thr He Ser Val Asp Lys 195 200 205
Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 887 <211> 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 887
Asp lie Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly •1286- 151681·序列表.doc 201127956 10 15
Asp Arg Val Thr lie Ser Cys Arg Ala Ser Gin Asp lie Ser Lys Thr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie 35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr lie Ser Asn Leu Glu Gin 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Thr Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Asp lie Arg Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Tyr Thr Ser Arg Leu Glu Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 180 185 190 -1287- 151681·序列表.doc 201127956
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Gly Asn Thr Leu Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 〈210〉 888 <211〉 253 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 888
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 -1288 151681-序列表.doc 201127956
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Gin Glu Ser Gly Pro Glu Leu Val 130 135 140
Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala 145 150 155 160
Phe Ser Ser Ser Trp Met Asn Trp Val lie Gin Arg Pro Gly Gin Gly 165 170 175
Leu Glu Trp lie Gly Arg lie Tyr Pro Gly Asp Gly Asp Thr Asn Tyr 180 185 190
Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 195 200 205
Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Val Asp Ser Ala 210 215 220
Val Tyr Phe Cys Ala Arg Ser Gly Phe He Thr Thr Val Leu Asp Phe 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 <210〉 889 <211> 231 <212〉 PRT <213〉人造序列 -1289- 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400> 889
Gin He Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Tlir 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe He Phe Pro Pro Asp He Val Leu Thr Gin Ser Pro Thr 115 120 125
Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr He Ser Cys Arg Ala 130 135 140
Ser Glu Ser Val Asp Thr Phe Gly lie Ser Phe Met Asn Trp Phe Gin 145 150 155 160
Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie His Ala Ala Ser Asn • 1290-
151681·序列表.doc 201127956
Inc.) ； HumaLYM(Intracel)及 PR070769(PCT/US2003/ 040426，標題為「Immunoglobulin Variants and Uses Thereof」）；曲妥珠單抗（trastuzumab，Herceptin®， Genentech)(參看例如美國專利第5,677,171號），一種批准 用於治療乳癌之人類化抗Her2/neu抗體；當前正由 Genentech 開發之帕妥珠單抗（pertuzumab，rhuMab-2C4， Omnitarg®);美國專利第4,753,894中所述之抗Her2抗體； 西妥昔單抗（cetuximab，Erbitux®，Imclone)(美國專利第 4,943,533號；PCT WO 90/40210)，一種在臨床試驗中用於 多種癌症之嵌合抗EGFR抗體；當前正由Abgenix-Immunex-Amgen 開發之 ABX-EGF(美國專利第 6,235,883 號）；當前正由Genmab開發之HuMax-EGFr(美國第 10/172,317號）；425、EMD55900、EMD62000及 EMD72000 (Merck KGaA)(美國專利第 5,558,864 號；Murthy 等人， 1987，Arch Biochem Biophys. 252(2):549-60 ; Rodeck等人， 1987，J Cell Biochem. 35(4):315-20 ; Kettleborough 等人， 1991, Protein Eng. 4(7):773-83) ； ICR62(Institute of Cancer Research)(PCT WO 95/20045 ; Modjtahedi等人，1993，J. Cell Biophys. 1993, 22(1-3):129-46 ; Modjtahedi 等人， 1993，Br J Cancer. 1993，67(2):247-53 ; Modjtahedi 等人， 1996，Br J Cancer, 73(2):228-35 ; Modjtahedi 等人，2003, Int J Cancer, 105(2):273-80) ； TheraCIM hR3(YM
Biosciences, Canada and Centro de Immunologia Molecular, (：1^&)(美國專利第5,891，996號；美國專利第6,506,883號； 151681.doc -191 - 201127956 165 170 175
Gin Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Ser Leu Asn lie His Pro Met Glu Glu Asp Asp Ser Ala Met 195 200 205
Tyr Phe Cys Gin Gin Ser Lys Glu Val Pro Phe Thr Phe Gly Ser Gly 210 215 220
Thr Lys Leu Glu He Lys Arg 225 230 <210> 890 <211〉 253 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 890
Glu Val Gin Leu Gin Glu Ser Gly Pro Glu Leu Val Ljrs Pro Gly Ala
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30
Trp Met Asn Trp Val lie Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr -1291 - 151681-序列表.doc 201127956 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Ser Gly Phe He Thr Thr Val Leu Asp Phe Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu 130 135 140
Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly 145 150 155 160
Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gin Arg Pro Gly 165 170 175
Gin Gly Leu Glu Trp lie Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr 180 185 190
Asn Tyr Asn Gin Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys 195 200 205
Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp 210 215 220
Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu 225 230 235 240
Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 • 1292- 151681-序列表.doc 201127956 <210〉 891 <211〉 231 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 891
Asp lie Val Leu Thr Gin Ser Pro Thr Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr He Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Phe 20 25 30
Gly He Ser Phe Met Asn Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He His Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Ser 50 55 60
Arg Phe Ser Gly Ser.Gly Ser Gly Thr Asp Phe Ser Leu Asn He His 65 70 75 80
Pro Met Glu Glu Asp Asp Ser Ala Met Tyr Phe Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys Arg 100 105 no
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Gin lie Val Leu 115 120 125
Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly Glu Lys Val Thr 130 135 140 - 1293- 151681·序列表.doc 201127956
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gin 145 150 155 160
Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr Asp Thr Ser Lys 165 170 175
Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr 180 185 190
Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu Asp Ala Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly 210 215 220
Thr Lys Leu Glu He Asn Arg 225 230 〈210〉 892 <211〉 256 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 892
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Thr Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 151681-序列表doc -1294- 201127956
Ala Leu lie Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Glu Ser Gly Pro 130 135 140
Glu Leu Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys Lys Ala Ser 145 150 155 160
Gly Tyr Ala Phe Ser Ser Ser Trp Met Asn Trp Val lie Gin Arg Pro 165 170 175
Gly Gin Gly Leu Glu Trp He Gly Arg lie Tyr Pro Gly Asp Gly Asp 180 185 190
Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 195 200 205
Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Val 210 215 220
Asp Ser Ala Val Tyr Phe Cys Ala Arg Ser Gly Phe lie Thr Thr Val • 1295· 151681-序列表.doc 201127956 225 230 235 240
Leu Asp Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210> 893 <211〉 232 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 893
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp lie Arg Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Val Leu Thr Gin Ser Pro 1296- 151681-序列表.doc 201127956 115 120 125
Thr Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr lie Ser Cys Arg 130 135 140
Ala Ser Glu Ser Val Asp Thr Phe Gly He Ser Phe Met Asn Trp Phe 145 150 155 160
Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie His Ala Ala Ser 165 170 175
Asn Gin Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Phe Ser Leu Asn lie His Pro Met Glu Glu Asp Asp Ser Ala 195 200 205
Met Tyr Phe Cys Gin Gin Ser Lys Glu Val Pro Phe Thr Phe Gly Ser 210 215 220
Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210> 894 <211> 256 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 894
Glu Val Gin Leu Gin Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 1297- 151681·序列表.doc 201127956 20 25 30
Trp Met Asn Trp Val lie Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Ser Gly Phe lie Thr Thr Val Leu Asp Phe Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Tyr Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ala Leu lie Asn Pro Tyr Lys Gly Val Ser 180 185 190
Thr Tyr Asn Gin Lys Phe Lys Asp Arg Phe Thr He Ser Val Asp Lys 195 200 205 -1298- 151681·序列表.doc 201127956
Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255
<210〉 895 <211〉 232 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 895
Asp lie Val Leu Thr Gin Ser Pro Thr Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Phe 20 25 30
Gly lie Ser Phe Met Asn Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie His Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Ser 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn He His 65 70 75 80
Pro Met Glu Glu Asp Asp Ser Ala Met Tyr Phe Cys Gin Gin Ser Lys 85 90 95 1299- 151681-序列表.doc 201127956
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Arg Ala Ser Gin Asp He Arg Asn Tyr Leu Asn Trp Tyr 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Tyr Thr Ser 165 170 175
Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Tyr Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu He Lys Arg 225 230 <210> 896 〈211〉 256 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -1300-
151681-序列表.doc 201127956
Mateo 等人，1997，Immunotechnology，3(1):71-81) ;mAb-806(Ludwig Institue for Cancer Research, Memorial Sloan-Kettering)(Jungbluth等人，2003，Proc Natl Acad Sci USA. 100(2):639-44) ; KSB-102(KS Biomedix) ; MR1-1(IVAX，
National Cancer Institute)(PCT WO 0162931A2);及 SC100(Scancell)(PCT WO 01/88138);阿來組單抗 (alemtuzumab，Campath®，Millenium)，一 種當前批准用 於治療B細胞慢性淋巴細胞白血病之人類化mAb ;莫羅莫 那-CD3(muromonab-CD3，Orthoclone OKT3®)，一種由 Ortho Biotech/Johnson & Johnson開發之抗 CD3抗體；替伊
莫單抗（ibritumomab tiuxetan，Zevalin®)，一種由 IDEC/Schering AG開發之抗CD20抗體；吉妥單抗 (gemtuzumab ozogamicin ， Mylotarg®) ， 一種由 Celltech/Wyeth開發之抗CD33(p67蛋白）抗體；阿法赛特 (alefacept，Amevive®)，一種由Biogen開發之抗LFA-3 Fc 融合物；由Centocor/Lilly開發之阿昔單抗（abciximab，
ReoPro®);由 Novartis 開發之巴利昔單抗（basiliximab， Simulect®); 由Medimmune開發之帕利珠單抗 (palivizumab，Synagis®);英利昔單抗（infliximab， Remicade®)，一種由Centocor開發之抗TNFa抗體；阿達木 單抗（adalimumab，Humira®)，一種由 Abbott 開發之抗 TNFa抗體；Humicade®，一種由 Celltech開發之抗TNFa抗 體；戈利木單抗（golimumab，CNTO-148)，一種由 Centocor開發之完全人類TNF抗體；依那西普（etanercept， 151681.doc -192- 201127956 <400> 896
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly GLn Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Le;u Val 130 135 140
Arg Pro Gly Ser Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala 145 150 155 160
Phe Ser Ser Tyr Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly 165 170 175
Leu Glu Trp lie Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr • 1301 151681-序列表.doc 201127956 180 185 190
Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser 195 200 205
Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala 210 215 220
Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr 225 230 235 240
Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250 255 <210〉 897 <211〉 231 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 897
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu • 1302· 151681·序列表.doc 201127956 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe lie Phe Pro Pro Asp lie Leu Leu Thr Gin Thr Pro Ala 115 120 125
Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr lie Ser Cys Lys Ala 130 135 140
Ser Gin Ser Val Asp Tyr Asp Gly Asp Ser Tyr Leu Asn Trp Tyr Gin 145 150 155 160
Gin lie Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn 165 170 175
Leu Val Ser Gly He Pro Pro Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Phe Thr Leu Asn He His Pro Val Glu Lys Val Asp Ala Ala Thr 195 200 205
Tyr His Cys Gin Gin Ser Thr Glu Asp Pro Trp Thr Phe Gly Gly Gly 210 215 220
Thr Lys Leu Glu He Lys Arg 225 230
<210> 898 <211〉 256 <212> PRT 151681-序列表.doc - 1303 - 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多狀 <400> 898
Gin Va.1 Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin He Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser 130 135 140
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys 145 150 155 160 1304
151681-序列表.doc 201127956
Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gin 165 170 175
Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr lie Asn Pro Ser Arg 180 185 190
Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp Lys Ala Thr Leu Thr 195 200 205
Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr 210 215 220
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His 225 230 235 240
Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr Val Ser Ser 245 250 255 <210〉 899 <211〉 231 <212〉 PRT <213〉人造序列
<220> <223〉人造序列之描述：合成多肽 <400> 899
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45 -1305- 151681·序列表doc 201127956
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Gin lie Val Leu 115 120 125
Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly Glu Lys Val Thr 130 135 140
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gin 145 150 155 160
Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr Asp Thr Ser Lys 165 170 175
Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr 180 185 190
Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu Asp Ala Ala Thr 195 200 205
Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly 210 215 220
Thr Lys Leu Glu lie Asn Arg -1306·
151681·序列表.doc 201127956 225 230 <210> 900 <211〉 259 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 900
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Thr Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Leu lie Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin Ser Gly Ala 1307· 151681-序列表.doc 201127956 130 135 140
Glu Leu Val Arg Pro Gly Ser Ser Val Lys lie Ser Cys Lys Ala Ser 145 150 155 160
Gly Tyr Ala Phe Ser Ser Tyr Trp Met Asn Trp Val Lys Gin Arg Pro 165 170 175
Gly Gin Gly Leu Glu Trp He Gly Gin He Trp Pro Gly Asp Gly Asp 180 185 190
Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 195 200 205
Glu Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Ala Ser Glu 210 215 220
Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr Thr Val Gly 225 230 235 240
Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 245 250 255
Val Ser Ser <210〉 901 <211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 901
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala. Ser Va.l Gly -1308- 151681-序列表.doc 201127956 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Arg Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Leu Leu Thr Gin Thr Pro 115 120 125
Ala Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr He Ser Cys Lys 130 135 140
Ala Ser Gin Ser Val Asp Tyr Asp Gly Asp Ser Tyr Leu Asn Trp Tyr 145 150 155 160
Gin Gin He Pro Gly Gin Pro Pro Lys Leu Leu He Tyr Asp Ala Ser 165 170 175
Asn Leu Val Ser Gly He Pro Pro Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190 • 1309· 151681-序列表.doc 201127956
Thr Asp Phe Thr Leu Asn lie His Pro Val Glu Lys Val Asp Ala Ala 195 200 205
Thr Tyr His Cys Gin Gin Ser Thr Glu Asp Pro Trp Thr Phe Gly Gly 210 215 220
Gly Thr Lys Leu Glu lie Lys Arg 225 230 <210〉 902 <211> 259 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 902
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 1310·
151681·序列表.doc 201127956
Enbrel®) ’ 一種由 immunex/Amgen 開發之 p75 TNF 受體 Fc
融合物；來那西普（lenercept)，一種先前由Roche開發之 p55TNF受體Fc融合物；ABX-CBL，一種正由Abgenix開發 之抗€0147抗體；八8乂-11：8，一種正由八58611丨\開發之抗 IL8抗體；ABX-MA1，一種正由Abgenix開發之抗MUC18 抗體；帕姆替珠單抗（Pemtumomab，R1549，90Y-muHMFGl)，一 種由 Antisoma 開發之抗 MUCl ; Therex(R15 5 0)，一 種正由 Antisoma 開發之抗 MUC1 抗體； 正由 Anti soma 開發之 AngioMab( AS 1405);正由Antisoma 開 發之 HuBC-1 ;正由 Antisoma開發之 Thioplatin(AS 1407); Antegren®(那他珠單抗（natalizumab))，一 種正由 Biogen 開 發之抗 a-4-p-l(VLA-4)及 α-4-β-7 抗體；VLA-1 mAb，一種 正由Biogen開發之抗VLA-1整合素抗體；LTBR mAb，一 種正由Biogen開發之抗淋巴毒素β受體（LTBR)抗體；CAT-152 ， 一 種正由 Cambridge Antibody Technology 開 發之抗 TGF-P2抗體；ABT 874 (J695)，一種正由Abbott開發之抗 IL-12 p40抗體；CAT-192，一 種正由 Cambridge Antibody Technology及 Genzyme開發之抗TGFpi抗體；CAT-213，一 種正由Cambridge Antibody Technology開發之抗嗜酸性粒 細胞趨化因子 l(anti-Eotaxinl)抗體；LymphoStat-B®，一 種正由 Cambridge Antibody Technology 及 Human Genome Sciences Inc.開發之抗Blys抗體；TRAIL-R1 mAb，一種正 由 Cambridge Antibody Technology 及 Human Genome Sciences, Inc.開發之抗TRAIL-R1抗體；Avastin®貝伐單抗 151681.doc -193 - 201127956
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser 130 135 140
Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 145 150 155 160
Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met. Asn Trp Val Arg Gin 165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Leu He Asn Pro Tyr Lys 180 185 190
Gly Val Ser Thr Tyr Asn Gin Lys Phe Lys Asp Arg Phe Thr lie Ser 195 200 205
Val Asp Lys Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg 210 215 220
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly 225 230 235 240
Asp Ser Asp Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr 245 250 255
Val Ser Ser <210> 903 • 1311 · 151681·序列表.doc 201127956 <211〉 232 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽 <400> 903
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Gin Arg Ala Thr He Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn He His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met 115 120 125
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 130 135 140 lie Thr Cys Arg Ala Ser Gin Asp lie Arg Asn Tyr Leu Asn Trp Tyr •1312· 151681·序列表.doc 201127956 145 150 155 160
Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He Tyr Tyr Thr Ser 165 170 175
Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 180 185 190
Thr Asp Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala 195 200 205
Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp Thr Phe Gly Gin 210 215 220
Gly Thr Lys Val Glu He Lys Arg 225 230 <210〉 904 <211〉 259 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 904
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp -1313· 151681-序列表.doc 201127956 50 55 60
Ser Val Lys Asp Arg Phe Thr lie Ser Arg Asp Asp Ser Lys Asn Thr 65 70 . 75 80
Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110
Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Glu Val Lys Leu Gin Glu 130 135 140
Ser Gly Pro Gly Leu Val Ala Pro Ser Gin Ser Leu Ser Val Thr Cys 145 150 155 160
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp lie Arg 165 170 175
Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val lie Trp Gly Ser 180 185 190
Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr lie 195 200 205
He Lys Asp Asn Ser Lys Ser Gin Val Pro Leu Lys Met Asn Ser Leu 210 215 220
Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr 225 230 235 240 •1314·
151681·序列表.doc 201127956
Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 245 250 255
Val Ser Ser <210> 905 <211〉 231 <212〉 PRT <213〉人造序列 <220>
〈223>人造序列之描述：合成多肽 <400> 905
Glu Leu Val Val Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly 35 40 45
Leu lie Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 65 70 75 80
Gin Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn 85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110 -1315 151681-序列表.doc 201127956
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Gin Met Thr 115 120 125
Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr lie 130 135 140
Ser Cys Arg Ala Ser Gin Asp lie Ser Lys Thr Leu Asn Trp Tyr Gin 145 150 155 160
Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie Tyr His Thr Ser Arg 165 170 175
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 180 185 190
Asp Tyr Ser Leu Thr lie Ser Asn Leu Glu Gin Glu Asp lie Ala Thr 195 200 205
Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly 210 215 220
Thr Lys Leu Glu He Thr Arg 225 230 <210〉 906 <211〉 259 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 906
Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin 15 10 15 •1316
151681-序列表.doc 201127956
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30
Gly Val Ser Trp He Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu 50 55 60
Lys Ser Arg Leu Thr lie lie Lys Asp Asn Ser Lys Ser Gin Val Pro 65 70 75 80
Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys 85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ala Arg lie Arg Ser Lys Tyr Asn Asn T)rr 180 185 190
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr lie Ser Arg •1317- 151681·序列表.doc 201127956 195 200 205
Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn 225 230 235 240
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr 245 250 255
Val Ser Ser <210〉 907 <211〉 230 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 907
Asp He Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Ser Cys Arg Ala Ser Gin Asp He Ser Lys Thr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu He 35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr He Ser Asn Leu Glu Gin -1318- 151681-序列表.doc 201127956 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Thr Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Glu Leu Val Val Thr Gin Glu Pro 115 120 125
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Arg Ser 130 135 140
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Gin 145 150 155 160
Lys Pro Gly Gin Ala Pro Arg Gly Leu lie Gly Gly Thr Asn Lys Arg 165 170 175
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 180 185 190
Ala Ala Leu Thr Leu Ser Gly Val Gin Pro Glu Asp Glu Ala Gla Tyr 195 200 205
Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr 210 215 220
Lys Leu Thr Val Leu Gly 225 230
<210〉 908 <211〉 259 <212〉 PRT 151681-序列表 _doc - 1319- 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 908
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60
Ser Val Lys Asp Arg Phe Thr He Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80
Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110
Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Gin Glu 130 135 140
Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys lie Ser Cys 145 150 155 160 1320- 151681-序列表.doc 201127956 (Avastin® bevacizumab，rhuMAb-VEGF)，一 種正由 Genentech開發之抗VEGF抗體；正由Genentech開發之抗 HER受體家族抗體；抗組織因子（ATF)，一種正由 Genentech開發之抗組織因子抗體；Xolair®(奥馬珠單抗 (Omalizumab))，一 種正由 Genentech 開發之抗 IgE 抗體； Raptiva®(依法珠單抗（Efalizumab))，一 種正由 Genentech 及Xoma開發之抗CD1 la抗體；正由Genentech及Millenium
Pharmaceuticals 開發之 MLN-02 抗體（先前為 LDP-02); HuMax CD4，一種正由Genmab開發之抗CD4抗體； HuMax-IL 1 5，一種正由Genmab及Amgen開發之抗IL1 5抗 體；正由Genmab 及 Medarex 開發之 HuMax-Inflam; HuMax-Cancer’ 一 種正由 Genmab 及 Medarex 及 Oxford GcoSciences 開發之抗I型肝素酶抗體；正由Genmab及Amgen開發之 HuMax-Lymphoma ;正由 Genmab開發之 HuMax-TAC ;正由 IDEC Pharmaceuticals 開發之 IDEC-131 及抗 CD40L 抗體； IDEC-151(克立昔單抗（Clenoliximab))，一 種正由 IDEC Pharmaceuticals開發之抗 CD4抗體；IDEC-114，一 種正由 IDEC Pharmaceuticals 開發之抗 CD80 抗體；IDEC-152，一 種正由 IDEC Pharmaceuticals 開發之抗 CD23 ;正由 IDEC Pharmaceuticals開發之抗巨噬細胞遷移因子（MIF)抗體； BEC2，一種正由Imclone開發之抗個體基因型抗體；IMC-1C11，一種正由Imclone開發之抗KDR抗體；DC101，一種 正由Imclone開發之抗flk-Ι抗體；一種正由Imclone開發之 抗VE鈣黏素抗體；CEA-Cide®(拉貝珠單抗（labetuzumab))， 151681.doc -194- 201127956
Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser Trp Met Asn Trp Val lie 165 170 175
Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Arg lie Tyr Pro Gly 180 185 190
Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu 195 200 205
Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu 210 215 220
Thr Ser Val Asp Ser Ala Val Tyr Phe Cys Ala Arg Ser Gly Phe lie 225 230 235 240
Thr Thr Val Leu Asp Phe Asp Tyr Trp Gly Gin Gly Thr Thr Leu Thr 245 250 255
Val Ser Ser
<210> 909 <211〉 235 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 909
Glu Leu Val Val Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 -1321 - 151681-序列表.doc 201127956
Asn Ίγτ Ala Asn Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly 35 40 45
Leu lie Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 65 70 75 80
Gin Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn 85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Val Leu Thr 115 120 125
Gin Ser Pro Thr Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr lie 130 135 140
Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Phe Gly lie Ser Phe Met 145 150 155 160
Asn Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie His 165 170 175
Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 180 185 190
Gly Ser Gly Thr Asp Phe Ser Leu Asn He His Pro Met Glu Glu Asp 195 200 205
Asp Ser Ala Met Tyr Phe Cys Gin Gin Ser Lys Glu Val Pro Phe Thr - 1322 -
151681·序列表.doc 201127956 210 215 220
Phe Gly Ser Gly Thr Lys Leu Glu lie Lys Arg 225 230 235 <210> 910 <211> 259 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 910
Glu Val Gin Leu Gin Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30
Trp Met Asn Trp Val lie Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Ser Gly Phe lie Thr Thr Val Leu Asp Phe Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser -1323 - 15168卜序列表.doc 201127956 115 120 125
Val Phe Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly 130 135 140
Leu Val Gin Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly 145 150 155 160
Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gin Ala Pro Gly 165 170 175
Lys Gly Leu Glu Trp Val Ala Arg lie Arg Ser Lys Tyr Asn Asn Tyr 180 185 190
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr He Ser Arg 195 200 205
Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn 225 230 235 240
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr 245 250 255
Val Ser Ser <210〉 911 <211〉 234 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -1324- 151681-序列表.doc 201127956 <400> 911
Asp lie Val Leu Thr Gin Ser Pro Thr Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Phe 20 25 30
Gly lie Ser Phe Met Asn Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie His Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Ser 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn lie His 65 70 75 80
Pro Met Glu Glu Asp Asp Ser Ala Met Tyr Phe Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Glu Leu Val Val 115 120 125
Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 130 135 140
Thr Cys Arg Ser Ser Thr Gly Ala Val* Thr Thr Ser Asn Tyr Ala Asn 145 150 155 160
Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly Leu lie Gly Gly 165 170 175 151681-序列表.doc • 1325 - 201127956
Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu 180 185 190
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gin Pro Glu Asp 195 200 205
Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe 210 215 220
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 225 230
〈210〉 912 <211〉 262 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 912
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60
Ser Val Lys Asp Arg Phe Thr He Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 151681-序列表.doc • 1326- 201127956
Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 HO
Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Gin Gin 130 135 140
Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser Val Lys lie Ser Cys 145 150 155 160
Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr Trp Met Asn Trp Val Lys 165 170 175
Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Gin He Trp Pro Gly 180 185 190
Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu 195 200 205
Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu 210 215 220
Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr 225 230 235 240
Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 245 250 255
Ser Val Thr Val Ser Ser -1327- 151681-序列表.d〇c 260 201127956 <210> 913 <211〉 235 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 913
Glu Leu Val Val Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 15 10 15 丁hr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly 35 40 45
Leu lie Gly Gly Thr Asn Lys Arg Ala. Pro Gly Thr Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 65 70 75 80
Gin Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn 85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro 100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Leu Leu Thr 115 120 125
Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly Gin Arg Ala Thr lie -1328-
151681-序列表.doc 201127956 130 135 140
Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp Gly Asp Ser Tyr Leu 145 150 155 160
Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro Lys Leu Leu lie Tyr 165 170 175
Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro Arg Phe Ser Gly Ser 180 185 190
Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His Pro Val Glu Lys Val 195 200 205
Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr Glu Asp Pro Trp Thr 210 215 220
Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 225 230 235 <210〉 914 <211> 262 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 914
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie - 1329. 151681-序列表.doc 201127956 35 40 45
Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser 130 135 140
Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 145 150 155 160
Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gin 165 170 175
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg He Arg Ser Lys Tyr 180 185 190
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 195 200 205 lie Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gin Met Asn Asn 210 215 220 • 1330· 151681-序列表.doc 201127956
一種正由Immunomedics開發之抗癌胚抗原（CEA)抗體； LymphoCide®(依帕珠單抗（Epratuzumab))，一 種正由 Immunomedics開發之抗CD22抗體；正由 Immunomedics開 發之 AFP-Cide ;正由 Immunomedics 開發之 MyelomaCide ; 正由 Immunomedics 開發之 LkoCide ;正由 Immunomedics 開 發之ProstaCide ; MDX-010，一種正由Medarex開發之抗 CTLA4抗體；MDX-060，一種正由Medarex開發之抗CD30 抗體；正由Medarex開發之MDX-070 ;正由Medarex開發之 MDX-018 ;正由 Medarex及 Immuno-Designed Molecules 開 發之 Osidem®(IDM-l)及抗 Her2抗體；HuMax®_CD4，一種 正由 Medarex及 Genmab開發之抗CD4抗體；HuMax-IL15， 一種正由Medarex及Genmab開發之抗IL15抗體；CNTO 148，一 種正由 Medarex 及 Centocor/J&J 開發之抗 TNFa 抗 體；CNTO 1275，一種正由Centocor/J&J開發之抗細胞激 素抗體；MOR101及MOR102，正由MorphoSys開發之抗細 胞間黏附分子-1(ICAM-1)(CD54)抗體；MOR201，一種正 由MorphoSys開發之抗纖維母細胞生長因子受體3(FGFR-3) 抗體；Nuvion®(維西珠單抗（visilizumab))，一種正由 Protein Design Labs開發之抗 CD3抗體；HuZAF®，一種正 由Protein Design Labs開發之抗γ干擾素抗體；正由Protein Design Labs 開發之抗 α5β1 整合素；正由 Protein Design Labs開發之抗IL-12 ; ING-1，一種正由Xoma開發之抗Ep-CAM抗體；Xolair®(奥馬珠單抗（Omalizumab))，一種由 Genentech及Novartis開發之人類化抗IgE抗體；及 j 151681.doc -195- 201127956
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 225 230 235 240
Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gin Gly Thr 245 250 255
Leu Val Thr Val Ser Ser 260
<210> 915 <211> 234 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 915
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95 -1331 - 151681-序列表」〇c 201127956
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Glu Leu Val Val 115 120 125
Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 130 135 140
Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn 145 150 155 160
Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly Leu lie Gly Gly 165 170 175
Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu 180 185 190
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gin Pro Glu Asp 195 200 205
Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe 210 215 220
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 225 230 <210〉 916 <211> 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 - 1332-
15168丨·序列表.doc 201127956 <400> 916
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 1 5 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin He Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro 130 135 140
Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn 145 150 155 160
Thr Tyr Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu 165 170 175
Trp Val Ala Arg He Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr • 1333- 151681-序列表.doc 201127956 180 185 190
Ala Asp Ser Val Lys Asp Arg Phe Thr lie Ser Arg Asp Asp Ser Lys 195 200 205
Asn Thr Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser 225 230 235 240
Trp Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 917 <211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 917
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly
Gin Arg Ala Thr He Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His -1334- 151681-序列表.doc 201127956 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Glu Leu Val Val Thr Gin Glu Pro Ser Leu Thr 115 120 125
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly 130 135 140
Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gin Gin Lys Pro Gly 145 150 155 160
Gin Ala Pro Arg Gly Leu He Gly Gly Thr Asn Lys Arg Ala Pro Gly 165 170 175
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 180 185 190
Thr Leu Ser Gly Val Gin Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala 195 200 205
Leu Trp Ίγτ Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 210 215 220
Val Leu Gly 225
<210〉 918 <211.> 246 <212> PRT • 1335 · 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 918
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Lys 115 120 125
Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin Ser Leu Ser 130 135 140
Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser 145 150 155 160 151681·序列表.doc • 1336- 201127956
Trp He Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu Giy Val lie 165 170 175
Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg 180 185 190
Leu Thr lie lie Lys Asp Asn Ser Lys Ser Gin Val Pro Leu Lys Met 195 200 205
Asn Ser Leu Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys Ala Lys His 210 215 220
Tyr. Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Ser Val Thr Val Ser Ser 245 〈210〉 919 〈211〉 220 <212〉 PRT 〈213〉人造序列
<220〉 〈223>人造序列之描述：合成多肽 <400〉 919
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45 151681-序列表.doc - 1337- 201127956
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 115 120 125
Asp Arg Val Thr He Ser Cys Arg Ala Ser Gin Asp lie Ser Lys Thr 130 135 140
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie 145 150 155 160
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr He Ser Asn Leu Glu Gin 180 185 190
Glu Asp lie Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr 195 200 205
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Thr Arg 210 215 220 <210> 920 • 1338-
151681-序列表.doc 201127956 <211> 246 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 920
Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin 15 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30
Gly Val Ser Trp lie Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu 50 55 60
Lys Ser Arg Leu Thr lie lie Lys Asp Asn Ser Lys Ser Gin Val Pro 65 70 75 80
Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala lie Tyr Tyr Cys 85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser 130 135 140
Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr -1339- 151681-序列表.doc 201127956 145 150 155 160
Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245 <210> 921 <211〉 220 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 921
Asp lie Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15
Asp Arg Val Thr lie Ser Cys Arg Ala Ser Gin Asp He Ser Lys Thr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie • 1340-
151681·序列表.doc 201127956 MLN01，一種正由Xoma開發之抗β2整合素抗體，本段中 所有本文引用之參考文獻以引用的方式明確併入本文中。 在另一實施例中，治療劑包括KRN330(Kirin) ; huA33抗體 (A33，Ludwig Institute for Cancer Research) ; CNTO 95(aV 整合素，Centocor) ; ΜΕϋΙ-522(ανβ3 整合素， Medimmune);伏洛昔單抗（volociximab)(aVpl 整合素， Biogen/PDL);人類mAb 216(B細胞糖基化抗原決定基， NCI) ; BiTE MT103(雙特異性 CD19xCD3，Medimmune);
4G7xH22(雙特異性 B細胞 xFcyRl，Medarex/Merck KGa); rM28(雙特異性CD28xMAPG，美國專利第EP1444268號）； MDX447(EMD 82633)(雙特異性 CD64xEGFR，Medarex); 卡妥索單抗（Catumaxomab)(瑞莫瓦（removab))(雙特異性
EpCAMx 抗 CD3，Trion/Fres);厄妥索單抗（Ertumaxomab)
(雙特異性 HER2/CD3，Fresenius Biotech);奥戈伏單抗 (oregovomab ，OvaRex)(CA-125 ，ViRexx) ; Rencarex® (WX G250)(碳酸酐酶 IX，Wilex) ; CNTO 888(CCL2， Centocor) ; TRC105(CD105(安多林（endoglin))，Tracon); BMS-663513(CD137 促效劑 ’ Brystol Myers Squibb); MDX-1342(CD19，Medarex);西利珠單抗（Siplizumab， MEDI，507)(CD2，Medimmune);奥法木單抗（Ofatumumab， Humax-CD20)(CD20，Genmab);利妥昔單抗（Rituxan) (CD20，Genentech);維塔珠單抗（veitUZumab，hA20) (CD20，Immunomedics);依帕珠單抗（CD22，Amgen);魯 昔單抗（lumiliximab，IDEC 152)(CD23，Biogen);莫羅莫 151681.doc -196- 201127956 35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr lie Ser Asn Leu Glu Gin 65 70 75 80
Glu Asp He Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Thr Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He 145 150 155 160
Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe 195 200 205
Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 220 -1341 · 15168卜序列表doc 201127956 <210> 922 <211〉 238 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 922 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val 1 5 10 Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr 20 25 Gly Met His Trp Val Arg Gin Ala Pro Gly Arg Gly 35 40 Ala Tyr lie Thr Ser Ser Ser lie Asn He Lys Tyr 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys 65 70 75 Leu Gin Met Asn lie Leu Lys Ser Glu Asp Thr Ala 85 90 Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gin 100 105 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val 130 135 140
Pro Gly Lys 15
Ser Gly Tyr
Glu Ser Val
Asp Ala Val
Leu Leu Phe 80
Thr Met Val 110
Leu Gin Gin
Leu Ser Cys
151681·序列表.doc -1342- 201127956
Lys Val Ser Gly Asp Thr He Thr Phe Tyr Tyr Met His Phe Val Lys 145 150 155 160
Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Arg lie Asp Pro Glu 165 170 175
Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe Lys Asn Lys Ala Thr Leu 180 185 190
Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Lys Leu Ser Ser Leu 195 200 205
Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys He Tyr Gly Gly Tyr Tyr 210 215 220
Phe Asp Tyr Trp Gly Gin Gly Val Met Val Thr Val Ser Ser 225 230 235 <210> 923 <211> 221 <212> PRT <213〉人造序列
<220〉 <223>人造序列之描述：合成多肽 <400> 923
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 15 10 15
Asp Arg Val Thr He Asn Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 151681-序列表.doc •1343· 201127956
Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr lie Ser Ser Leu Glu Ser 65 70 75 80
Glu Asp lie Gly Ser Tyr Tyr Cys Gin Gin Tyr Tyr Asn Tyr Pro Trp 85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Thr Ser Leu 115 120 125
Gly Glu Thr Val Thr He Gin Cys Gin Ala Ser Glu Asp lie Tyr Ser 130 135 140
Gly Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ser Pro Gin Leu Leu 145 150 155 160
He Tyr Gly Ala Ser Asp Leu Gin Asp Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Gin Tyr Ser Leu Lys lie Thr Ser Met Gin 180 185 190
Thr Glu Asp Glu Gly Val Tyr Phe Cys Gin Gin Gly Leu Thr Tyr Pro 195 200 205
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210〉 924 • 1344-
151681 -序列表.doc 201127956 <211〉 238 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 924
Glu Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Thr 1 δ 10 15
Ser Val Lys Leu Ser Cys Lys Val Ser Gly Asp Thr He Thr Phe Tyr 20 25 30
Tyr Met His Phe Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Arg lie Asp Pro Glu Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe 50 55 60
Lys Asn Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80
Leu Lys Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95
He Tyr Gly Gly Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Val Met Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu 115 120 125
Ser Gly Gly Gly Leu Val Gin Pro Gly Lys Ser Leu Lys Leu Ser Cys 130 135 140
Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr Gly Met His Trp Val Arg - 1345. 151681 -序列表.doc 201127956 145 150 155 160
Gin Ala Pro Gly Arg Gly Leu Glu Ser Val Ala Tyr lie Thr Ser Ser 165 170 175
Ser lie Asn He Lys Tyr Ala. Asp Ala Va.l Lys Gly Arg Phe Thr Val 180 185 190
Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe Leu Gin Met Asn lie Leu 195 200 205
Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg Phe Asp Trp Asp 210 215 220
Lys Asn Tyr Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 225 230 235 <210〉 925 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 925
Asp He Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Thr Ser Leu Gly 1 5 10 15
Glu Thr Val Thr lie Gin Cys Gin Ala Ser Glu Asp lie Tyr Ser Gly 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ser Pro G]n Leu Leu He 35 40 45
Tyr Gly Ala Ser Asp Leu Gin Asp Gly Val Pro Ser Arg Phe Ser Gly 1346 - 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Gin Tyr Ser Leu Lys He Thr Ser Met Gin Thr 65 70 75 80
Glu Asp Glu Gly Val Tyr Phe Cys Gin Gin Gly Leu Thr Tyr Pro Arg 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Pro Ala Ser Leu 115 120 125
Gly Asp Arg Val Thr lie Asn Cys Gin Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr lie Ser Ser Leu Glu 180 185 190
Ser Glu Asp lie Gly Ser Tyr Tyr Cys Gin Gin Tyr Tyr Asn Tyr Pro 195 200 205
Trp Thr Phe Gly Pro Gly Thr Lys Leu Glu He Lys Arg 210 215 220
<210〉 926 <211〉 245 <212〉 PRT -1347- 15168N 序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 926
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Lys 15 10 15
Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30
Gly Met His Trp Val Arg Gin Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45
Ala Tyr He Thr Ser Ser Ser He Asn He Lys Tyr Ala Asp Ala Val 50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80
Leu Gin Met Asn lie Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gin Gly Thr Met Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly 130 135 140
Thr Ser Val Lys Leu Ser Cys Lys Val Ser Gly Asp Thr He Thr Phe 145 150 155 160 151681-序列表.doe 1348 · 201127956
Tyr Tyr Met His Phe Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp 165 170 175 lie Gly Arg lie Asp Pro Glu Asp Glu Ser Thr Lys Tyr Ser Glu Lys 180 185 190
Phe Lys Asn Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala 195 200 205
Tyr Leu Lys Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe 210 215 220
Cys He Tyr Gly Gly Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Val Met 225 230 235 240
Val Thr Val Ser Ser 245 <210> 927 <211〉 228 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 927
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Asn Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45 • 1349- 151681-序列表 doc 201127956
Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr lie Ser Ser Leu Glu Ser 65 70 75 80
Glu Asp lie Gly Ser Tyr Tyr Cys Gin Gin Tyr Tyr Asn Tyr Pro Trp 85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ala Ser Leu Ser Thr Ser Leu Gly Glu Thr Val Thr lie Gin Cys Gin 130 135 140
Ala Ser Glu Asp lie Tyr Ser Gly Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ser Pro Gin Leu Leu lie Tyr Gly Ala Ser Asp Leu Gin Asp 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gin Tyr Ser 180 185 190
Leu Lys lie Thr Ser Met Gin Thr Glu Asp Glu Gly Val Tyr Phe Cys 195 200 205
Gin Gin Gly Leu Thr Tyr Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg • 1350·
151681·序列表.doc 201127956
那-CD3(CD3，Ortho) ; HuM291(CD3 fc 受體，PDL Biopharma) ; HeFi-l(CD30，NCI) ; MDX-060(CD30， Medarex) ; MDX-1401(CD30，Medarex) ; SGN-30(CD30， Seattle Genentics) ; SGN-33(林妥珠單抗（Lintuzumab)) (CD33，Seattle Genentics);紮木單抗（Zanolimumab， HuMax-CD4)(CD4，Genmab) ; HCD122(CD40，Novartis); SGN-40(CD40，Seattle Genentics) ; Campathlh(阿來組單 抗）（CD52，Genzyme) ; MDX-1411(CD70，Medarex); hLLl(EPB-l)(CD74.38，Immunomedics);加利昔單抗 (Galiximab > IDEC-144)(CD80 > Biogen) ； MT293(TRC093/ D93)(裂解之膠原蛋白，Tracon) ; HuLuc63(CSl，PDL Pharma);伊普利單抗（ipilimumab，MDX-010)(CTLA4， Brystol Myers Squibb);川利木單抗（Tremelimumab，替西 單抗（Ticilimumab)，CP-675,2)(CTLA4，Pfizer) ; HGS-ETR1(馬帕木單抗（Mapatumumab))(DR4 TRAIL-R1 促效 劑，Human Genome Science/Glaxo Smith Kline) ; AMG-655(DR5，Amgen);阿普單抗（Apomab)(DR5，Genentech); CS-1008(DR5，Daiichi Sankyo) ; HGS-ETR2(來沙木單抗 (lexatumumab))(DR5 TRAIL-R2促效劑，HGS);西妥昔單 抗（Erbitux)(EGFR，Imclone) ; IMC-11F8(EGFR，Imclone); 尼妥珠單抗（Nimotuzumab)(EGFR，YM Bio);帕尼單抗 (Panitumumab，Vectabix)(EGFR，Amgen);紮魯木單抗 (Zalutumumab，HuMaxEGFr)(EGFR，Genmab) ； CDX-110(EGFRvIII，AVANT Immunotherapeutics);阿德木單抗 151681.doc -197- 201127956 225 <210〉 928 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 928
Glu Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15
Ser Val Lys Leu Ser Cys Lys Val Ser Gly Asp Thr lie Thr Phe Tyr 20 25 30
Tyr Met His Phe Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Asp Pro Glu Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe 50 55 60
Lys Asn Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80
Leu Lys Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 lie Tyr Gly Gly Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Val Met Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly -1351- 151681·序列表.doc 201127956 130 135 140
Lys Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly 145 150 155 160
Tyr Gly Met His Trp Val Arg Gin Ala Pro Gly Arg Gly Leu Glu Ser 165 170 175
Val Ala Tyr lie Thr Ser Ser Ser lie Asn lie Lys Tyr Ala Asp Ala 180 185 190
Va.l Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu 195 200 205
Phe Leu Gin Met Asn lie Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr 210 215 220
Cys Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gin Gly Thr Met 225 230 235 240
Val Thr Val Ser Ser 245 <210〉 929 <211〉 228 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 929
Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Thr Ser Leu Gly 15 10 15
Glu Thr Val Thr lie Gin Cys Gin Ala Ser Glu Asp lie Tyr Ser Gly - 1352-
151681-序列表.doc 201127956 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ser Pro Gin Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asp Leu Gin Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Gin Tyr Ser Leu Lys lie Thr Ser Met Gin Thr 65 70 75 80
Glu Asp Glu Gly Val Tyr Phe Cys Gin Gin Gly Leu Thr Tyr Pro Arg 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Pro Ala Ser Leu Gly Asp Arg Val Thr lie Asn Cys Gin 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Leu Leu lie Tyr Tyr Thr Asn Lys Leu Ala Asp 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Asp Ser Ser 180 185 190
Phe Thr lie Ser Ser Leu Glu Ser Glu Asp lie Gly Ser Tyr Tyr Cys 195 200 205 151681-序列表.doc -1353 · 201127956
Gin Gin Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Pro Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225 <210> 930 <211〉 7185 <212〉 DNA <213〉人造序列 <220〉 <223〉人造序列之描述：合成聚核苷酸 <400> 930 gcgtcgacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt. gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgcgaggag 720 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 •1354· 151681-序列表.doc 900 900
201127956 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa tgagcggccg ctcgaggccg gcaaggccgg atcccccgac ctcgacctct ggctaataaa ggaaatttat tttcattgca atagtgtgtt ggaatttttt gtgtctctca ctcggaagga catatgggag ggcaaatcat ttggtcgaga tccctcggag atctctagct agaggatcga tccccgcccc ggacgaacta aacctgacta cgacatctct gccccttctt cgcggggcag tgcatgtaat cccttcagtt ggttggtaca acttgccaac tgggccctgt tccacatgtg acacgggggg ggaccaaaca caaaggggtt ctctgactgt agttgacatc cttataaatg gatgtgcaca tttgccaaca ctgagtggct ttcatcctgg agcagacttt gcagtctgtg gactgcaaca caacattgcc tttatgtgta aotcttggct gaagctctta caccaatgct gggggacatg tacctcccag gggcccagga agactacggg aggctacacc aacgtcaatc agaggggcct gtgtagctac cgataagcgg accctcaaga gggcattagc aatagtgttt ataaggcccc cttgttaacc ctaaacgggt agcatatgct tcccgggtag tagtatatac tatccagact aaccctaatt caatagcata tgttacccaa cgggaagcat atgctatcga attagggtta gtaaaagggt cctaaggaac agcgatatct cccaccccat gagctgtcac ggttttattt acatggggtc aggattccac gagggtagtg aaccatttta gtcacaaggg cagtggctga agatcaagga gcgggcagtg aactctcctg aatcttcgcc tgcttcttca ttctccttcg tttagctaat agaataactg ctgagttgtg aacagtaagg tgtatgtgag gtgctcgaaa acaaggtttc aggtgacgcc cccagaataa aatttggacg gggggttcag tggtggcatt gtgctatgac accaatataa ccctcacaaa ccccttgggc aataaatact agtgtaggaa tgaaacattc tgaatatctt taacaataga aatccatggg gtggggacaa gccgtaaaga ctggatgtcc atctcacacg aatttatggc tatgggcaac acataatcct agtgcaatat gatactgggg ttattaagat 151681-序列表.doc -1355 - 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 201127956 gtgtcccagg cagggaccaa gacaggtgaa ccatgttgtt acactctatt tgtaacaagg 2280 ggaaagagag tggacgccga cagcagcgga ctccactggt tgtctctaac acccccgaaa 2340 attaaacggg gctccacgcc eiatggggccc ataaacaaag acaagtggcc actctttttt 2400 ttgaaattgt ggagtggggg cacgcgtcag cccccacacg ccgccctgcg gttttggact 2460 gtaaaataag ggtgtaataa cttggctgat tgtaaccccg ctaaccactg cggtcaaacc 2520 acttgcccac aaaaccacta atggcacccc ggggaatacc tgcataagta ggtgggcggg 2580 ccaagatagg ggcgcgattg ctgcgatctg gaggacaaat tacacacact tgcgcctgag 2640 cgccaagcac agggttgttg gtcctcatat tcacgaggtc gctgagagca cggtgggcta 2700 atgttgccat gggtagcata tactacccaa atatctggat agcatatgct atcctaatct 2760 atatctgggt agcataggct atcctaatct atatctgggt agcatatgct atcctaatct 2820 atatctgggt agtatatgct atcctaattt atatctgggt agcataggct atcctaatct 2880 atatctgggt agcatatgct atcctaatct atatctgggt agtatatgct atcctaatct 2940 gtatccgggt agcatatgct atcctaatag agattagggt agtatatgct atcctaattt 3000 atatctgggt agcatatact acccaaatat ctggatagca tatgctatcc taatctatat 3060 ctgggtagca tatgctatcc taatctatat ctgggtagca taggctatcc teiatctatat 3120 ctgggtagca tatgctatcc taatctatat ctgggtagta tatgctatcc taatttatat 3180 ctgggtagca taggctatcc taatctatat ctgggtagca tatgctatcc taatctatat 3240 ctgggtagta tatgctatcc taatctgtat ccgggtagca tatgctatcc tcatgataag 3300 ctgtcaaaca tgagaatttt cttgaagacg aaagggcctc gtgatacgcc tatttttata 3360 ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt 3420 gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 3480 acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattceiaca 3540 tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 3600 -1356-
15168卜序列表.doc 201127956
agaaacgctg cgaactggat aatgatgage gcaagagcaa agtcacagaa aaccatgagt gctaaccgct ggagctgaat aacaacgttg aatagactgg tggctggttt agcactgggg ggcaactatg ttggtaactg ttaatttaaa acgtgagttt agatcctttt ggtggtttgt cagagcgcag gaactctgta cagtggcgat gcagcggtcg gtgaaagtaa ctcaacagcg acttttaaag ctcggtcgcc aageatetta gataacactg tttttgcaca gaagccatac cgcaaactat atggaggegg attgetgata ccagatggta gatgaaegaa tcagaccaag aggatetagg tcgttccact tttctgcgcg ttgeeggate ataccaaata gcaccgccta aagtcgtgtc ggctgaacgg aagatgctga gtaagatcct ttctgctatg gcatacacta eggatggeat cggccaactt acatggggga caaacgacga taactggcga ataaagttgc aatctggagc agccctcccg atagacagat tttactcata tgaagatcct gagegteaga taatctgctg aagagctacc ctgttcttct catacctcgc ttaccgggtt ggggttcgtg agatcagttg tgagagtttt tggcgcggta ttctcagaat gacagtaaga acttctgaca tcatgtaact gcgtgacacc actacttact aggaccactt cggtgagcgt tategtagtt egetgagata tataetttag ttttgataat ccccgtagaa cttgcaaaca aactcttttt agtgtagccg tetgetaate ggactcaaga cacacagccc ggtgcacgag cgccccgaag ttatcccgtg gacttggttg gaattatgea aegateggag cgccttgatc acgatgcctg ctagcttccc ctgcgctcgg gggtctcgcg atctacacga ggtgcctcac attgatttaa ctcatgacca aagatcaaag aaaaaaccac ccgaaggtaa tagttaggee ctgttaccag cgatagttac agettggage tgggttacat aacgttttcc ttgaegeegg agtactcacc gtgctgccat gaccgaagga gttgggaacc oagcaatggc ggcaacaatt cccttccggc gtatcattgc cggggagtca tgattaagea aacttcattt aaatccctta gatettettg cgctaccagc ctggcttcag accacttcaa tggctgctgc c^gataaggc gaacgaccta caccgaactg agatacctac agegtgaget atgagaaage gccacgcttc ccgaagggag 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 -1357- 151681.·序列表.doc 201127956 aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct 5040 tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga 5100 gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc 5160 ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct ttcctgcgtt 5220 atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata ccgctcgccg 5280 cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc gcccaatacg 5340 caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg acaggtttcc 5400 cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca ctcattaggc 5460 accccaggct ttacacttta tgcttccggc tcgtatgttg tgtggaattg tgagcggata 5520 acaatttcac acaggaaaoa gctatgacca tgattacgcc aagctctagc tagaggtcga 5580 gtccctcccc agcaggcaga agtatgcaaa gcatgcatct caattagtca gcaaccatag 5640 tcccgcccct aactccgccc atcccgcccc taactccgcc cagttccgcc cattctccgc 5700 cccatggctg actaattttt tttatttatg cagaggccga ggccgcctcg gcctctgagc 5760 tattccagaa gtagtgagga ggcttttttg gaggcctagg cttttgcaaa aagctttgca 5820 aagatggata aagttttaaa cagagaggaa tctttgcagc taatggacct tctaggtctt 5880 gaaaggagtg ggaattggct ccggtgcccg tcagtgggca gagcgcacat cgcccacagt 5940 ccccgagaag ttggggggag gggtcggcaa ttgaaccggt gcctagagaa ggtggcgcgg 6000 ggtaaactgg gaaagtgatg tcgtgtactg gctccgcctt tttcccgagg gtgggggaga 6060 accgtatata agtgcagtag tcgccgtgaa cgttcttttt cgcaacgggt ttgccgccag 6120 aacacaggta agtgccgtgt gtggttcccg cgggcctggc ctctttacgg gttatggccc 6180 ttgcgtgcct tgaattactt ccacctggct gcagtacgtg attcttgatc ccgagcttcg 6240 ggttggaagt gggtgggaga gttcgaggcc ttgcgcttaa ggagcccctt cgcctcgtgc 6300 ttgagttgag gcctggcctg ggcgctgggg ccgccgcgtg cgaatctggt ggcaccttcg 6360 • 1358 ·
15168丨-序列表.doc 201127956
cgcctgtctc gctgctttcg ataagtctct agccatttaa aatttttgat gacctgctgc gacgcttttt ttctggcaag atagtcttgt aaatgcgggc caagatctgc acactggtat ttcggttttt ggggccgcgg gcggcgacgg ggcccgtgcg tcccagcgca catgttcggc gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg gggtagtctc aagctggccg gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc ccgccctggg cggcaaggct ggcccggtcg gcaccagttg cgtgagcgga aagatggccg cttcccggcc ctgctgcagg gagctcaaaa tggaggacgc ggcgctcggg agagcgggcg ggtgagtcac ccacacaaag gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac tccacggagt accgggcgcc gtccaggcac ctcgattagt tctcgagctt ttggagtacg tcgtctttag gttgggggga ggggttttat gcgatggagt ttccccacac tgagtgggtg gagactgaag ttaggccagc ttggcacttg atgtaattct ccttggaatt tgcccttttt gagtttggat cttggttcat tctcaagcct cagacagtgg ttcaaagttt ttttcttcca tttcaggtgt cgtgaggaat tctctagaga tccctcgacc tcgagatcca ttgtgcccgg gcgccaccat ggagtttggg ctgagctggc tttttcttgt cgcgatttta aaaggtgtcc agtgc 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7185
<210〉 931 <211> 6521 <212> DNA <213〉人造序列 <220〉 <223〉人造序列之描述：合成聚核苷酸 <400〉 931 acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaia agtacagtgg aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 60 120 151681-序列表.doc •】359· 180 201127956 aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240 cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300 ttcaacaggg gagagtgttg agcggccgct cgaggccggc aaggccggat cccccgacct 360 cgacctctgg ctciataaagg aaatttattt tcattgcaat agtgtgttgg aattttttgt 420 gtctctcact cggaaggaca tatgggaggg caaatcattt ggtcgagatc cctcggagat 480 ctctagctag aggatcgatc cccgccccgg acgaactaaa cctgactacg acatctctgc 540 cccttcttcg cggggcagtg catgtaatcc cttcagttgg ttggtacaac ttgccaactg 600 ggccctgttc cacatgtgac acgggggggg accaaacaca aaggggttct ctgactgtag 660 ttgacatcct tataaatgga tgtgcacatt tgccaacact gagtggcttt catcctggag 720 cagactttgc agtctgtgga ctgcaacaca acattgcctt tatgtgtaac tcttggctga 780 agctcttaca ccaatgctgg gggacatgta cctcccaggg gcccaggaag actacgggag 840 gctacaccaa cgtcaatcag aggggcctgt gtagctaccg ataagcggac cctcaagagg 900 gcattagcaa tagtgtttat aaggccccct tgttaaccct aaacgggtag catatgcttc 960 ccgggtagta gtatatacta tccagactaa ccctaattca atagcatatg ttacccaacg 1020 ggaagcatat gctatcgaat tagggttagt aaaagggtcc taaggaacag cgatatctcc 1080 caccccatga gctgtcacgg ttttatttac atggggtcag gattccacga gggtagtggLa 1140 ccattttagt cacaagggca gtggctgaag atcaaggagc gggcagtgaa ctctcctgaa 1200 tcttcgcctg cttcttcatt ctccttcgtt tagctaatag aataactgct gagttgtgaa 1260 cagtaaggtg tatgtgaggt gctcgaaaac aaggtttcag gtgacgcccc cagaataaaa 1320 tttggacggg gggttcagtg gtggcattgt gctatgacac caatataacc ctcacaaacc 1380 ccttgggcaa taaatactag tgtaggeiatg aaacattctg eiatatcttta acaatagaaa 1440 tccatggggt ggggacaagc cgtaaagact ggatgtccat ctcacacgaa tttatggcta 1500 tgggcaacac ataatcctag tgcaatatga tactggggtt attaagatgt gtcccaggca 1560 - 1360·
151681·序列表.doc 201127956
(adecatumumab，MT201)(Epcam，Merck);依決洛單抗 (edrecolomab，Panorex，17-lA)(Epcam，Glaxo/Centocor); MORAb-003(葉酸鹽受體a，Morphotech); KW-2871(神經 結餹月旨 GD3，Kyowa) ; MORAb-009(GP-9，Morphotech); CDX-1307(MDX-1307)(hCGb，Celldex);曲妥珠單抗（赫赛 汀（Herceptin))(HER2，Celldex);帕妥珠單抗（rhuMAb 2C4)(HER2(DI)，Genentech);阿泊珠單抗（apolizumab) (HLA-DRP 鏈，PDL Pharma) ； AMG-479(IGF-1R ，
Amgen);抗 IGF-1R R1507(IGF1-R，Roche) ; CP 751871 (IGF1-R，Pfizer) ; IMC-A12(IGF1-R，Imclone) ; BIIB022 (IGF-1R，Biogen) ; Mik-P-l(IL-2Rb(CD122)，Hoffman
LaRoche) ； CNTO 328(IL6，Centocor);抗 KIR( 1-7F9)(殺 手細胞 Ig 樣受體（KIR)，Novo) ; Hu3S193(Lewis (y)，
Wyeth, Ludwig Institute of Cancer Research) ； hCBE-
11(LTPR > Biogen) ； HuHMFGl(MUCl » Antisoma/NCI) i RAVI2(N連接碳水化合物抗原決定基，Raven) ; CAL(副甲 狀腺激素相關蛋白（PTH-rP)，University of California); CT-011(PD1 > CureTech) ； MDX-1106(ono-453 8)(PD 1 >
Medarex/Ono) ； MAb CT-011(PD1 ，Curetech) ; IMC-3G3(PDGFRa，Imclone);巴維昔單抗（bavituximab)(填脂 酿絲胺酸，Peregrine) ; huJ591(PSMA，Cornell Research
Foundation) ； muJ591(PSMA > Cornell Research Foundation) I GC1008(TGFb (pan)抑制劑（IgG4)，Genzyme);英利昔單 抗（Remicade)(TNFa，Centocor); Α27·15(運鐵蛋白受體， 151681.doc -198-
201127956 gggaccaaga caggtgaacc atgttgttac actctatttg taacaagggg aaagagagtg gacgccgaca gcagcggact ccactggttg tctctaacac ccccgaaaat taaacggggc tccacgccaa tggggcccat aaacaaagac aagtggccac tctttttttt gaaattgtgg agtgggggca cgcgtcagcc cccacacgcc gccctgcggt tttggactgt aaaataaggg tgtaataact tggctgattg taaccccgct aaccactgcg gtcaaaccac ttgcccacaa aaccactaat ggcaccccgg ggaatacctg cataagtagg tgggcgggcc aagatagggg cgcgattgct gcgatctgga ggacaaatta cacacacttg cgcctgagcg ccaagcacag ggttgttggt cctcatattc acgaggtcgc tgagagcacg gtgggctaat gttgccatgg gtagcatata ctacccaaat atctggatag catatgctat cctaatctat atctgggtag cataggctat cctaatctat atctgggtag catatgctat cctaatctat atctgggtag tatatgctat cctaatttat atctgggtag cataggctat cctaatctat atctgggtag catatgctat cctaatctat atctgggtag tatatgctat cctaatctgt atccgggtag catatgctat cctaatagag attagggtag tatatgctat cctaatttat atctgggtag catatactac ccaaatatct ggatagcata tgctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagcata ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata tgctatccta atttatatct gggtagcata ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata tgctatccta atctgtatcc gggtagcata tgctatcctc atgataagct gtcaaacatg agaattttct tgaagacgaa agggcctcgt gatacgccta tttttatagg ttaatgtcat gataataatg gtttcttaga cgtcaggtgg cacttttcgg ggeiaatgtgc gcggaacccc tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg atafiatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt 151681-序列表.doc -1361- 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 201127956 gaaagtaaaa gatgctgaag atcagttggg caacagcggt aagatccttg agagttttcg ttttaaagtt ctgctatgtg gcgcggtatt cggtcgccgc atacactatt ctcagaatga gcatcttacg gatggcatga cagtaagaga taacactgcg gccaacttac ttctgacaac tttgcacaac atgggggatc atgtaactcg agccatacca aacgacgagc gtgacaccac caaactatta actggcgaac tacttactct ggaggcggat aaagttgcag gaccacttct tgctgataaa tctggagccg gtgagcgtgg agatggtaag ccctcccgta tcgtagttat tgaacgaaat agacagatcg ctgagatagg agaccaagtt tactcatata tactttagat gatctaggtg aagatccttt ttgataatct gttccactga gcgtcagacc ccgtagaaaa tctgcgcgta atctgctgct tgcaaacaaa gccggatcaa gagctaccaa ctctttttcc accaaatact gttcttctag tgtagccgta accgcctaca tacctcgctc tgctaatcct gtcgtgtctt accgggttgg actcaagacg ctgaacgggg ggttcgtgca cacagcccag atacctacag cgtgagctat gagaaagcgc tgcacgagtg ggttacatcg aactggatct 3000 ccccgaageia cgttttccaa tgatgagcac 3060 atcccgtgtt gacgccgggc aagagcaact 3120 cttggttgag tactcaccag tcacagaaaa 3180 attatgcagt gctgccataa ccatgagtga 3240 gatcggagga ccgaaggagc taaccgcttt 3300 ccttgatcgt tgggaaccgg agctgaatga 3360 gatgcctgca gcaatggcaa caacgttgcg 3420 agcttcccgg caacaattaa tagactggat 3480 gcgctcggcc cttccggctg gctggtttat 3540 gtctcgcggt atcattgcag cactggggcc 3600 ctacacgacg gggagtcagg caactatgga 3660 tgcctcactg attaagcatt ggtaactgtc 3720 tgatttaaaa cttcattttt aatttaaaag 3780 catgaccaaa atcccttaac gtgagttttc 3840 gatcaaagga tcttcttgag atcctttttt 3900 aaaaccaccg ctaccagcgg tggtttgttt 3960 gaaggtaact ggcttxagca gagcgcagat 4020 gttaggccac cacttcaaga actctgtagc 4080 gttaccagtg gctgctgcca gtggcgataa 4140 atagttaccg gataaggcgc agcggtcggg 4200 cttggagcga acgacctaca ccgaactgag 4260 cacgcttccc gaagggagaa aggcggacag 4320 • 1362- 151681·序列表.doc
201127956 gtatccggta agcggcaggg tcggaacagg agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc cttttgctca catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg cctttgagtg agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga gcgaggaagc ggaagagcgc ccaatacgca aaccgcctct ccccgcgcgt tggccgattc attaatgcag ctggcacgac aggtttcccg actggaaagc gggcagtgag cgcaacgcaa ttaatgtgag ttagctcact cattaggcac cccaggcttt acactttatg cttccggctc gtatgttgtg tggaattgtg agcggataac aatttcacac aggaaacagc tatgaccatg attacgccaa gctctagcta gaggtcgagt ccctccccag caggcagaag tatgcaaagc atgcatctca attagtcagc aaccatagtc c-cgcccctaa ctccgcccat cccgccccta actccgccca gttccgccca ttctccgccc catggctgac taattttttt tatttatgca gaggccgagg ccgcctcggc ctctgagcta ttccagaagt agtgaggagg cttttttgga ggcctaggct tttgcaaaaa gctttgcaaa gatggataaa gttttaaaca gagaggaatc tttgcagcta atggaccttc taggtcttga aaggagtggg aattggctcc ggtgcccgtc agtgggcaga gcgcacatcg cccacagtcc ccgagaagtt ggggggaggg gtcggcaatt gaaccggtgc ctagagaagg tggcgcgggg taaactggga aagtgatgtc gtgtactggc tccgcctttt tcccgagggt gggggagaac cgtatataag tgcagtagtc gccgtgaacg ttctttttcg caacgggttt gccgccagaa cacaggtaag tgccgtgtgt ggttcccgcg ggcctggcct ctttacgggt tatggccctt gcgtgccttg aattacttcc acctggctgc agtacgtgat tcttgatccc gagcttcggg ttggaagtgg gtgggagagt tcgaggcctt gcgcttaagg agccccttcg cctcgtgctt gagttgaggc ctggcctggg cgctggggcc gccgcgtgcg aatctggtgg caccttcgcg cctgtctcgc 151681·序列表.doc -1363 - 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 201127956 tgctttcgat aagtctctag ccatttaaaa tttttgatga cctgctgcga cgcttttttt ctggcaagat agtcttgtaa atgcgggcca agatctgcac actggtattt cggtttttgg ggccgcgggc ggcgacgggg cccgtgcgtc ccagcgcaca tgttcggcga ggcggggcct gcgagcgcgg ccaccgagaa tcggacgggg gtagtctcaa gctggccggc ctgctctggt gcctggcctc gcgccgccgt gtatcgcccc gccctgggcg gcaaggctgg cccggtcggc accagttgcg tgagcggaaa gatggccgct tcccggccct gctgcaggga gctcaaaatg gaggacgcgg cgctcgggag agcgggcggg t.gagtcaccc acacaaagga aaagggcctt tccgtcctca gccgtcgctt catgtgactc cacggagtac cgggcgccgt ccaggcacct cgattagttc tcgagctttt ggagtacgtc gtctttaggt tggggggagg ggttttatgc gatggagttt ccccacactg agtgggtgga gactgfiagtt aggccagctt ggcacttgat gtaattctcc ttggaatttg ccctttttga gtttggatct tggttcattc tcaagcctca gacagtggtt caaagttttt ttcttccatt tcaggtgtcg tgaggaattc tctagagatc cctcgacctc gagatccatt gtgcccgggc gcaccatgga catgcgcgtg cccgcccagc tgctgggcct gctgctgctg tggttccccg gctcgcgatg c <210〉 932 〈211〉 6513 <212> DNA <213〉人造序列<220> <223〉人造序列之描述：合成聚核苷酸 <400〉 932 caacccaagg ctgccccctc ggtcactctg ttcccgccct cctctgagga gcttcaagcc aacaaggcca cactggtgtg tctcataagt gacttctacc cgggagccgt gacagtggcc tggaaggcag atagcagccc cgtcaaggcg ggagtggaga ccaccacacc ctccaaacaa agcaacaaca agtacgcggc cagcagctac ctgagcctga cgcctgagca gtggaagtcc 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6521 60120 180
】51681·序列表.doc •1364· 240 300 300
201127956 cacagaagct acagctgcca ggtcacgcat gaagggagca ccgtggagaa gacagtggcc cctacagaat gttcatgagc ggccgctcga ggccggcaag gccggatccc ccgacctcga cctctggcta ataaaggaaa tttattttca ttgcaatagt gtgttggaat tttttgtgtc tctcactcgg aaggacatat gggagggcaa atcatttggt cgagatccct cggagatctc tagctagagg atcgatcccc gccccggacg aactaaacct gactacgaca tctctgcccc ttcttcgcgg ggcagtgcat gtaatccctt cagttggttg gtacaacttg ccaactgggc cctgttccac atgtgacacg gggggggacc aaacacaaag gggttctctg actgtagttg acatccttat aaatggatgt gcacatttgc caacactgag tggctttcat cctggagcag actttgcagt ctgtggactg caacacaaca ttgcctttat gtgtaactct tggctgaagc tcttacacca. atgctggggg acatgtacct cccaggggcc caggaagact acgggaggct acaccaacgt caatcagagg ggcctgtgta gctaccgata agcggaccct caagagggca ttagcaatag tgtttataag gcccccttgt taaccctaaa cgggtagcat atgcttcccg ggtagtagta tatactatcc agactaaccc tsiattcaata gcatatgtta cccaacggga agcatatgct atcgaattag ggttagtaaa agggtccteia ggaacagcga tatctcccac cccatgagct gtcacggttt tatttacatg gggtcaggat tccacgaggg tagtgaacca ttttagtcac aagggcagtg gctgaagatc aaggagcggg cagtgaactc tcctgaatct tcgcctgctt cttcattctc cttcgtttag ctaatagaat aactgctgag ttgtgaacag taaggtgtat gtgaggtgct cgaaaacaag gtttcaggtg acgcccccag aataaaattt ggacgggggg ttcagtggtg gcattgtgct atgacaccaa tataaccctc acaaacccct tgggcaataa atactagtgt aggaatgaaa cattctgaat atctttaaca atagaaatcc atggggtggg gacaagccgt aaagactgga tgtccatctc acacgaattt atggctatgg gcaacacata atcctagtgc aatatgatac tggggttatt aagatgtgtc ccaggcaggg accaagacag gtgaaccatg ttgttacact ctatttgtaa caaggggaaa gagagtggac 151681·序列表.doc • 1365· 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 201127956 gccgacagca gcggactcca ctggttgtct ctaacacccc cgaaaattaa acggggctcc 1680 acgccaatgg ggcccataaa caaagacaag tggccactct tttttttgaa attgtggagt 1740 gggggcacgc gtcagccccc acacgccgcc ctgcggtttt ggactgtaaa ataagggtgt 1800 aataacttgg ctgattgtaa ccccgctaac cactgcggtc aaaccacttg cccacaaaac 1860 cactaatggc accccgggga atacctgcat aagtaggtgg gcgggccaag ataggggcgc 1920 gattgctgcg atctggagga caaattacac acacttgcgc ctgagcgcca agcacagggt 1980 tgttggtcct catattcacg aggtcgctga gagcacggtg ggctaatgtt gccatgggta 2040 gcatatacta cccaaatatc tggatagcat atgctatcct aatctatatc tgggtagcat 2100 aggctatcct aatctatatc tgggtagcat atgctatcct aatctatatc tgggtagtat 2160 atgctatcct aatttatatc tgggtagcat aggctatcct aatctatatc tgggtagcat 2220 atgctatcct aatctatatc tgggtagtat atgctatcct aatctgtatc cgggtagcat 2280 atgctatcct aatagagatt agggtagtat atgctatcct aatttatatc tgggtagcat 2340 atactaccca aatatctgga tagcatatgc tatcctaatc tatatctggg tagcatatgc 2400 tatcctaatc tatatctggg tagcataggc tatcctaatc tatatctggg tagcatatgc 2460 tatcctaatc tatatctggg tagtatatgc tatcctaatt tatatctggg tagcataggc 2520 tatcctaatc tatatctggg tagcatatgc tatcctaatc tatatctggg tagtatatgc 2580 tatcctaatc tgtatccggg tagcatatgc tatcctcatg ataagctgtc aeiacatgaga 2640 attttcttga agacgaaagg gcctcgtgat acgcctattt ttataggtta atgtcatgat 2700 aataatggtt tcttagacgt caggtggcac ttttcgggga aatgtgcgcg gaacccctat 2760 ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat aaccctgata 2820 aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc gtgtcgccct 2880 tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa cgctggtgaa 2940 agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac tggatctcaa 3000 151681·序列表.doc - 1366-
201127956 cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttcceiatga tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtgttgac gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgcagca atggcaacaa cgttgcgcaa actatteiact ggcgaactac ttactctagc ttcccggcaa caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac ttcaagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag ggggaaacgc 151681·序列表.doc - 1367· 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 201127956 ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc gatttttgtg 4440 atgctcgtca ggggggcgga gcctatggeia aaacgccagc aacgcggcct ttttacggtt 4500 cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc ctgattctgt 4560 ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc gaacgaccga 4620 gcgcagcgag tcagtgagcg aggaagcgga agagcgccca atacgcaaac cgcctctccc 4680 cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg tttcccgact ggaaagcggg 4740 cagtgagcgc aacgcaatta atgtgagtta gctcactcat taggcacccc aggctttaca 4800 ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc ggataacaat ttcacacagg 4860 aaacagctat gaccatgatt acgccaagct ctagctagag gtcgagtccc tccccagcag 4920 gcagaagtat gcaaagcatg catctcaatt agtcagcaac catagtcccg cccctaactc 4980 cgcccatccc gcccctaact ccgcccagtt ccgcccattc tccgccccat ggctgactaa 5040 ttttttttat ttatgcagag gccgaggccg cctcggcctc tgagctattc cagaagtagt 5100 gaggaggctt ttttggaggc ctaggctttt gcaaaaagct ttgcaaagat ggataaagtt 5160 ttaaacagag aggaatcttt gcagctaatg gaccttctag gtcttgaaag gagtgggaat 5220 tggctccggt gcccgtcagt gggcagagcg cacatcgccc acagtccccg agaagttggg 5280 gggaggggtc ggcaattgaa ccggtgccta gagaaggtgg cgcggggtaa actgggaaag 5340 tgatgtcgtg tactggctcc gcctttttcc cgagggtggg ggagaaccgt atataagtgc 5400 agtagtcgcc gtgaacgttc tttttcgcaa cgggtttgcc gccagaacac aggtaagtgc 5460 cgtgtgtggt tcccgcgggc ctggcctctt tacgggttat ggcccttgcg tgccttgaat 5520 tacttccacc tggctgcagt acgtgattct tgatcccgag cttcgggttg gaagtgggtg 5580 ggagagttcg aggccttgcg cttaaggagc cccttcgcct cgtgcttgag ttgaggcctg 5640 gcctgggcgc tggggccgcc gcgtgcgaat ctggtggcac cttcgcgcct gtctcgctgc 5700 tttcgataag tctctagcca tttaaaattt ttgatgacct gctgcgacgc tttttttctg 5760 - 1368·
151681-序列表.doc 201127956 gcaagatagt cttgtaaatg cgggccaaga tctgcacact ggtatttcgg tttttggggc 5820 cgcgggcggc gacggggccc gtgcgtccca gcgcacatgt tcggcgaggc ggggcctgcg 5880 agcgcggcca ccgagaatcg gacgggggta gtctcaagct ggccggcctg ctctggtgcc 5940 tggcctcgcg ccgccgtgta tcgccccgcc ctgggcggca aggctggccc ggtcggcacc 6000 agttgcgtga gcggaaagat ggccgcttcc cggccctgct gcagggagct; caaaatggag 6060 gacgcggcgc tcgggagagc gggcgggtga gtcacccaca caaaggaaaa gggcctttcc 6120 gtcctcagcc gtcgcttcat gtgactccac ggagtaccgg gcgccgtcca ggcacctcga 6180 ttagttctcg agcttttgga gtacgtcgtc tttaggttgg ggggaggggt tttatgcgat 6240 ggagtttccc cacactgagt gggtggagac tgaagttagg ccagcttggc acttgatgta 6300 attctccttg gaatttgccc tttttgagtt tggatcttgg ttcattctca agcctcagac 6360 agtggttcaa agtttttttc ttccatttca ggtgtcgtga ggaattctct agagatccct 6420 cgacctcgag atccattgtg cccgggcgcc accatgactt ggaccccact cctcttcctc 6480 6513 accctcctcc tccactgcac aggaagctta teg <210〉 933 〈211〉 6515 <212〉 DNA <213〉人造序列 <220> <223〉人造序列之描述：合成聚核苷酸 <400> 933 acggtggctg caccatctgt cttcatcttc ccgccatctg atgageagtt gaaatctgga 60 actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120 ^ggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180 aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga etaegagaaa 240 -1369- 151681-序列表.doc 201127956 cacaeiagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300 ttcaacaggg gagagtgttg agcggccgct cgaggccggc aaggccggat cccccgacct 360 cgacctctgg ctaataaagg aaatttattt tcattgcaat agtgtgttgg aattttttgt 420 gtctctcact cggaaggaca tatgggaggg caaatcattt ggtcgagatc cctcggagat 480 ctctagctag aggatcgatc cccgccccgg acgaactaaa cctgactacg acatctctgc 540 cccttcttcg cggggcagtg catgtaatcc cttcagttgg ttggtacaac ttgccaactg 600 ggccctgttc cacatgtgac acgggggggg accaaacaca aaggggttct ctgactgtag 660 ttgacatcct tataaatgga tgtgcacatt t.gccaacact gagtggcttt catcctggag 720 cagactttgc agtctgtgga ctgcaacaca acattgcctt tatgtgtaac tcttggctga 780 agctcttaca ccaatgctgg gggacatgta cctcccaggg gcccaggaag actacgggag 840 gctacaccaa cgtcaatcag aggggcctgt gtagctaccg ataagcggac cctceiagagg 900 gcattagcaa tagtgtttat aaggccccct t.gttaaccct aaacgggtag catatgcttc 960 ccgggtagta gtatatacta tccagactaa ccctaattca atagcatatg ttacccaacg 1020 ggaagcatat gctatcgaat tagggttagt aaaagggtcc taaggaacag cgatatctcc 1080 caccccatga gctgtcacgg ttttatttac atggggtcag gattccacga gggtagtgaa 1140 ccattttagt cacaagggca gtggctgaag atcaaggagc gggcagtgaa ctctcctgaa 1200 tcttcgcctg cttcttcatt ctccttcgtt tagctaatag aataactgct gagttgtgaa 1260 cagtaaggtg tatgtgaggt gctcgaaaac aaggtttcag gtgacgcccc cagaataaaa 1320 tttggacggg gggttcagtg gtggcattgt gctatgacac caatataacc ctcacaaacc 1380 ccttgggcaa taaatactag tgtaggaatg aaacattctg aatatcttta acaatagaaa 1440 tccatggggt ggggacaagc cgteiaagact ggatgtccat ctcacacgaa tttatggcta 1500 tgggcaacac ataatcctag tgcaatatga tactggggtt attaagatgt gtcccaggca 1560 gggaccaaga caggtgaacc atgttgttac actctatttg taacaagggg aaagagagtg 1620 151681·序列表.doc · 1370· 201127956
Salk Institute，INSERN WO 2005/111082) ·’ Ε2·3(運鐵蛋白 受體，Salk Institute);貝伐單抗（阿瓦斯汀（Avastin)) (VEGF，Genentech) ; HuMV833(VEG.F，Tsukuba Research Lab-WO/2000/03 433 7, University of Texas) ； IMC-18F1 (VEGFR1，Imclone) ; IMC-1121(VEGFR2, Imclone)。 B.建構DVD分子： 雙重可變區域免疫球蛋白（DVD-Ig)分子經設計以藉由重 組DNA技術使來自兩種不同親本單株抗體之兩個不同輕鏈 可變區域（VL)以串聯方式直接連接或經由短連接子連接， 接著為輕鏈恆定區域。類似地，重鏈包含兩個以串聯方式 連接之不同重鏈可變區域（VH)，接著為恆定區域CH1及Fc 區（圖1A)。 可使用重組DNA技術自由本文所述之任一種方法產生之 親本抗體獲得可變區域。在一實施例中，可變區域為鼠類 重鏈可變區域或輕鏈可變區域。在另一實施例中，可變區 域為CDR移植或人類化重鏈可變區域或輕鏈可變區域。在 一實施例中，可變區域為人類重鏈或輕鏈可變區域。 在一實施例中，使用重組DNA技術使第一及第二可變區 域彼此直接連接。在另一實施例中，可變區域係經由連接 子序列連接。在一實施例中，兩個可變區域連接。三個或 三個以上可變區域亦可直接連接或經由連接子序列連接。 可變區域可結合相同抗原或可結合不同抗原。本發明之 DVD分子可包括1個免疫球蛋白可變區域及1個非免疫球蛋 白可變區域（諸如受體之配位體結合區域、酶之活性區 151681.doc -199-
201127956 gacgccgaca gcagcggact ccactggttg tctctaacac ccccgaaaat taaacggggc tccacgccaa tggggcccat aaacaaagac aagtggccac tctttttttt gaaattgtgg agtgggggca cgcgtcagcc cccacacgcc gccctgcggt tttggactgt aaaataaggg tgtaataact tggctgattg taaccccgct aaccactgcg gtcaaaccac ttgcccacaa aaccactaat ggcaccccgg ggaatacctg cataagtagg tgggcgggcc aagatagggg cgcgattgct gcgatctgga, ggacaaatta cacacacttg cgcctgagcg ccaagcacag ggttgttggt cctcatattc acgaggtcgc tgagagcacg gtgggctaat gttgccatgg gtagcatata ctacccaaat atctggatag catatgctat ccteiatctat atctgggtag cataggctat cctaatctat atctgggtag catatgctat cctaatctat atctgggtag tatatgctat cctaatttat atctgggtag cataggctat cctaatctat atctgggtag catatgctat cctaatctat atctgggtag tatatgctat cctaatctgt atccgggtag catatgctat cctaatagag attagggtag tatatgctat cctaatttat atctgggtag catatactac ccaaatatct ggatagcata tgctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagcata ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata tgctatccta atttatatct gggtagcata ggctatccta atctatatct gggtagcata tgctatccta atctatatct gggtagtata tgctatccta atctgtatcc gggtagcata tgctatcctc atgataagct gtcaaacatg agaattttct tgaagacgaa agggcctcgt gatacgccta tttttatagg ttaatgtcat gataataatg gtttcttaga cgtcaggtgg cacttttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag atcagttggg tgcacgagtg ggttacatcg aactggatct 151681-序列表.doc -1371- 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 201127956 caacagcggt aagatccttg agagttttcg ccccgaagaa cgttttccaa tgatgagcac 3060 ttttaaagtt ctgctatgtg gcgcggtatt atcccgtgtt gacgccgggc aagagcaact 3120 cggtcgccgc atacactatt ctcagaatga cttggttgag tactcaccag tcacagaaaa 3180 gcatcttacg gatggcatga cagtaagaga attatgcagt gctgccataa ccatgagtga 3240 taacactgcg gccaacttac ttctgacaac gatcggagga ccgaaggagc taaccgcttt 3300 tttgcacaac atgggggatc atgtaactcg ccttgatcgt tgggaaccgg agctgaatga 3360 agccatacca aacgacgagc gtgacaccac gatgcctgca gcaatggcaa caacgttgcg 3420 caaactatta actggcgaac tacttactct agcttcccgg caacaattaa tagactggat 3480 ggaggcggat aaagttgcag gaccacttct gcgctcggcc cttccggctg gctggtttat 3540 tgctgataaa tctggagccg gtgagcgtgg gtctcgcggt atcattgcag cactggggcc 3600 agatggtaag ccctcccgta tcgtagttat ctacacgacg gggagtcagg caactatgga 3660 tgaacgaaat agacagatcg ctgagatagg tgcctcactg atteiagcatt ggtaactgtc 3720 agaccaagtt tactcatata tactttagat tgatttaaaa cttcattttt aatttaaaag 3780 gatctaggtg aagatccttt ttgataatct catgacceiaa atcccttaac gtgagttttc 3840 gttccactga gcgtcagacc ccgtagaaaa gatcaaagga tcttcttgag atcctttttt 3900 tctgcgcgta atctgctgct tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt 3960 gccggatcaa gagctaccaa ctctttttcc gaaggtaact ggcttcagca gagcgcagat 4020 accaaatact gttcttctag tgtagccgta gttaggccac cacttcaaga actctgtagc 4080 accgcctaca tacctcgctc tgctaatcct gttaccagtg gctgctgcca gtggcgataa 4140 gtcgtgtctt accgggttgg actcaagacg atagttaccg gataaggcgc agcggtcggg 4200 ctgaacgggg ggttcgtgca cacagcccag cttggagcga acgacctaca ccgaactgag 4260 atacctacag cgtgagctat gagaaagcgc cacgcttccc gaagggagaa aggcggacag 4320 gtatccggta agcggcaggg tcggaacagg agagcgcacg agggagcttc cagggggaaa 4380 - 1372·
151681-序列表.doc
201127956 cgcctggtat ctttatagtc ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc cttttgctca catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg cctttgagtg agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga gcgaggaagc ggaagagcgc ccaatacgca aaccgcctct ccccgcgcgt tggccgattc attaatgcag ctggcacgac aggtttcccg actggaaagc gggcagtgag cgcaacgcaa ttaatgtgag ttagctcact cattaggcac cccaggcttt acactttatg cttccggctc gtatgttgtg tggaattgtg agcggataac aatttcacac aggaaacagc tatgaccatg attacgccaa gctctagcta gaggtcgagt ccctccccag caggcagaag tatgcaaagc atgcatctca attagtcagc aaccatagtc ccgcccctaa ctccgcccat cccgccccta actccgccca gttccgccca ttctccgccc catggctgac taattttttt tatttatgca gaggccgagg ccgcctcggc ctctgagcta ttccagaagt agtgaggagg cttttttgga ggcctaggct tttgcaaaaa gctttgcaaa gatggataaa gttttaaaca gagaggaatc tttgcagcta atggaccttc taggtcttga fiaggagtggg aattggctcc ggtgcccgtc agtgggcaga gcgcacatcg cccacagtcc ccgagaagtt ggggggaggg gtcggcaatt gaaccggtgc ctagagaagg tggcgcgggg taaactggga aagtgatgtc gtgtactggc tccgcctttt tcccgagggt gggggagaac cgtatataag tgcagtagtc gccgtgaacg ttctttttcg caacgggttt gccgccagaa cacaggtaag tgccgtgtgt ggttcccgcg ggcctggcct ctttacgggt tatggccctt gcgtgccttg aattacttcc acctggctgc agtacgtgat tcttgatccc gagcttcggg ttggaagtgg gtgggagagt tcgaggcctt gcgcttaagg agccccttcg cctcgtgctt gagttgaggc ctggcctggg cgctggggcc gccgcgtgcg aatctggtgg caccttcgcg cctgtctcgc tgctttcgat aagtctctag ccatttaiaaa tttttgatga cctgctgcga cgcttttttt 151681-序列表.doc - 1373 · 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 201127956 ctggcaagat agtcttgtaa atgcgggcca agatctgcac actggtattt cggtttttgg 5820 ggccgcgggc ggcgacgggg cccgtgcgtc ccagcgcaca tgttcggcga ggcggggcct 5880 gcgagcgcgg ccaccgagaa tcggacgggg gtagtctcaa gctggccggc ctgctctggt 5940 gcctggcctc gcgccgccgt gtatcgcccc gccctgggcg gcaaggctgg cccggtcggc 6000 accagttgcg tgagcggaaa gatggccgct tcccggccct gctgcaggga gctcaaaatg 6060 gaggacgcgg cgctcgggag agcgggcggg tgagtcaccc acacaaagga aaagggcctt 6120 tccgtcctca gccgtcgctt catgtgactc cacggagtac cgggcgccgt ccaggcacct 6180 cgattagttc tcgagctttt ggagtacgtc gtctttaggt tggggggagg ggttttatgc 6240 gatggagttt ccccacactg agtgggtgga gactgaagtt aggccagctt ggcacttgat 6300 gtaattctcc ttggaatttg ccctttttga gtttggatct tggttcattc tcaagcctca 6360 gacagtggtt caaagttttt ttcttccatt tcaggtgtcg tgaggaattc tctagagatc 6420 cctcgacctc gagatccatt gtgcccgggc gcaccatgac ttggacccca ctcctcttcc 6480 tcaccctcct cctccactgc acaggaagct tatcg 6515 <210> 934 <211〉 6519 <212> DNA <213〉人造序列 <220〉 <223〉人造序列之描述：合成聚核苷酸 <400〉 934 caacccaagg ctgccccctc ggtcactctg ttcccgccct cctctgagga gcttcaagcc 60 aacaaggcca cactggtgtg tctcataagt gacttctacc cgggagccgt gacagtggcc 120 tggaaggcag atagcagccc cgtcaaggcg ggagtggaga ccaccacacc ctccaaacaa 180 agcaacaaca agtacgcggc cagcagctac ctgagcctga cgcctgagca gtggaagtcc 240 cacagaagct acagctgcca ggtcacgcat gaagggagca ccgtggagaa gacagtggcc 300 -1374- 151681-序列表.doc 360 360
201127956 cctacagaat gttcatgagc ggccgctcga ggccggcaag gccggatccc ccgacctcga cctctggcta ataaaggaaa tttattttca ttgceiatagt gtgttggaat tttttgtgtc tctcactcgg aaggacatat gggagggcaa atcatttggt cgagatccct cggagatctc tagctagagg atcgatcccc gccccggacg aactaaacct gactacgaca tctctgcccc ttcttcgcgg ggcagtgcat gtaatccctt cagttggttg gtacaacttg ccaactgggc cctgttccac atgtgacacg gggggggacc aaacacaeiag gggttctctg actgtagttg acatccttat aaatggatgt gcacatttgc caacactgag tggctttcat cctggagcag actttgcagt ctgtggactg caacacaaca ttgcctttat gtgtaactct tggctgaagc tcttacacca atgctggggg acatgtacct cccaggggcc caggaagact acgggaggct acaccaacgt caatcagagg ggcctgtgta gctaccgata agcggaccct caagagggca ttagcaatag tgtttataag gcccccttgt taaccctaaa cgggtagcat atgcttcccg ggtagtagta tatactatcc agactaaccc taattcaata gcatatgtta cccaacggga agcatatgct atcgaattag ggttagtaaa agggtcctaa ggaacagcga tatctcccac cccatgagct gtcacggttt tatttacatg gggtcaggat tccacgaggg tagtgaacca ttttagtcac aagggcagtg gctgaagatc aaggagcggg cagtgaactc tcctgaatct tcgcctgctt cttcattctc cttcgtttag ctaatagaat aactgctgag ttgtgaacag taaggtgtat gtgaggtgct cgaaaacaag gtttcaggtg acgcccccag aataaaattt ggacgggggg ttcagtggtg gcattgtgct atgacaccaa tataaccctc acaaacccct tgggcaataa atactagtgt aggaatgaaa cattctgaat atctttaaca atagaaatcc atggggtggg gacaagccgt aaagactgga tgtccatctc acacgaattt atggctatgg gcaacacata atcctagtgc aatatgatac tggggttatt aagatgtgtc ccaggcaggg accaagacag gtgaaccatg ttgttacact ctatttgtaa caaggggaaa gagagtggac gccgacagca gcggactcca ctggttgtct ctaacacccc cgaaaattaa acggggctcc 151681-序列表.doc -1375 - 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 201127956 acgccaatgg ggcccataaa caaagacaag gggggcacgc gtcagccccc acacgccgcc aataacttgg ctgattgtaa ccccgctaac cactaatggc accccgggga atacctgcat gattgctgcg atctggagga caaattacac tgttggtcct catattcacg aggtcgctga gcatatacta cccaaatatc tggatagcat aggctatcct aatctatatc tgggtagcat atgctatcct aatttatatc tgggtagcat atgctatcct aatctatatc tgggtagtat atgctatcct aatagagatt agggtagtat atactaccca aatatctgga tagcatatgc tatcctaatc tatatctggg tagcataggc tatcctaatc tatatctggg tagtatatgc tatcctaatc tatatctggg tagcatatgc tatcctaatc tgtatccggg tagcatatgc attttcttga. agacgaaagg gcctcgtgat aataatggtt tcttagacgt caggtggcac ttgtttattt ttctaaatac attcaaatat aatgcttcaa taatattgaa aaaggaagag tattcccttt tttgcggcat tttgccttcc agtaaaagat gctgaagatc agttgggtgc cagcggtaag atccttgaga gttttcgccc tggccactct tttttttgaa attgtggagt 1740 ctgcggtttt ggactgtaaa ataagggtgt 1800 cactgcggtc aaaccacttg cccacaaaac 1860 aagtaggtgg gcgggccaag ataggggcgc 1920 acacttgcgc ctgagcgcca agcacagggt 1980 gagcacggtg ggctaatgtt gccatgggta 2040 atgctatcct aatctatatc tgggtagcat 2100 atgctatcct aatctatatc tgggtagtat 2160 aggctatcct aatctatatc tgggtagcat 2220 atgctatcct aatctgtatc cgggtagcat 2280 atgctatcct aatttatatc tgggtagcat 2340 tatcctaatc tatatctggg tagcatatgc 2400 tatcctaatc tatatctggg tagcatatgc 2460 tatcctaatt tatatctggg tagcataggc 2520 tatcctaatc tatatctggg tagtatatgc 2580 tatcctcatg ataagctgtc aaacatgaga 2640 acgcctat.tt ttataggtt.a. at.gtcatgat 2700 ttttcgggga aatgtgcgcg gaacccctat 2760 gtatccgctc atgagacaat aaccctgata 2820 tatgagtatt caacatttcc gtgtcgccct 2880 tgtttttgct cacccagaaa cgctggtgaa 2940 acgagtgggt tacatcgaac tggatctcaa . 3000 cgaageiacgt tttccaatga tgagcacttt 3060 • 1376- 151681-序列表.doc
201127956 taaagttctg ctatgtggcg cggtattatc ccgtgttgac gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgcagca atggcaacaa ogttgcgcaa a.ctattaact ggcgaactac ttactctagc ttcccggcaa caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt aactgtca.ga ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat ttsiaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcEiagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac ttceiagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc ggtcgggctg sLacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc gatttttgtg 151681·序列表.doc • 1377· 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 201127956 atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct ttttacggtt 4500 cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc ctgattctgt 4560 ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc gaacgaccga 4620 gcgcagcgag tcagtgagcg aggaagcgga agagcgccca atacgcaaac cgcctctccc 4680 cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg tttcccgact ggaaagcggg 4740 cagtgagcgc aacgcaatta atgtgagtta gctcactcat taggcacccc aggctttaca 4800 ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc ggataacaat ttcacacagg 4860 aaacagctat gaccatgatt acgccaagct ctagctagag gtcgagtccc tccccagcag 4920 gcagaagtat gcaaagcatg catctcsiatt agtcagcaac catagtcccg cccctaactc 4980 cgcccatccc gcccctaact ccgcccagtt ccgcccattc tccgccccat ggctgactaa 5040 ttttttttat ttatgcagag gccgaggccg cctcggcctc tgagctattc cagaagtagt 5100 gaggaggctt ttttggaggc ctaggctttt gcaaaaagct ttgcaaagat ggataaagtt 5160 ttaaacagag aggaatcttt gcagctaatg gaccttctag gtcttgaaag gagtgggaat 5220 tggctccggt gcccgtcagt gggcagagcg cacatcgccc acagtccccg agaagttggg 5280 gggaggggtc ggcaattgaa ccggtgccta gagaaggtgg cgcggggtaa actgggaaag 5340 tgatgtcgtg tactggctcc gcctttttcc cgagggtggg ggagaaccgt atataagtgc 5400 agtagtcgcc gtgaacgttc tttttcgcaa cgggtttgcc gccagaacac aggtaagtgc 5460 cgtgtgtggt tcccgcgggc ctggcctctt tacgggttat ggcccttgcg tgccttgaat 5520 tacttccacc tggctgcagt acgtgattct tgatcccgag cttcgggttg gaagtgggtg 5580 ggagagttcg aggccttgcg cttaaggagc cccttcgcct cgtgcttgag ttgaggcctg 5640 gcctgggcgc tggggccgcc gcgtgcgaat ctggtggcac cttcgcgcct gtctcgctgc 5700 tttcgataag tctctagcca tttaaaattt ttgatgacct gctgcgacgc tttttttctg 5760 gcaagatagt cttgtaaatg cgggccaaga tctgcacact ggtatttcgg tttttggggc 5820 -1378-
151681-序列表.doc 201127956
cgcgggcggc gacggggccc gtgcgtccca gcgcacatgt tcggcgaggc ggggcctgcg 5880 agcgcggcca ccgagaatcg gacgggggta gtctcaagct ggccggcctg ctctggtgcc 5940 tggcctcgcg ccgccgtgta tcgccccgcc ctgggcggca aggctggccc ggtcggcacc 6000 agttgcgtga gcggaaagat ggccgcttcc cggccctgct gcagggagct caaaatggag 6060 gacgcggcgc tcgggagagc gggcgggtga gtcacccaca caaaggaaaa gggcctttcc 6120 gtcctcagcc gtcgcttcat gtgactccac ggagtaccgg gcgccgtcca ggcacctcga 6180 ttagttctcg agcttttgga gtacgtcgtc tttaggttgg ggggaggggt tttatgcgat 6240 ggagtttccc cacactgagt gggtggagac tgaagttagg ccagcttggc acttgatgta 6300 attctccttg gaatttgccc tttttgagtt tggatcttgg ttcattctca agcctcagac 6360 agtggttcaa agtttttttc ttccatttca ggtgtcgtga ggaattctct agagatccct 6420 cgacctcgag atccattgtg cccgggcgcc accatggaca tgcgcgtgcc cgcccagctg 6480 ctgggcctgc tgctgctgtg gttccccggc tcgcgatgc 6519 <210〉 935 <211> 7185 <212〉 DNA <213〉人造序列 <220> <223〉人造序列之描述：合成聚核苷酸 <400〉 935 gcgtcgacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 -1379· 151681-序列表.doc 201127956 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgcgaggag 720 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc tccgggtaaa tgagcggccg ctcgaggccg gcaaggccgg 1020 atcccccgac ctcgacctct ggctaataaa ggaaatttat tttcattgca atagtgtgtt 1080 ggaatttttt gtgtctctca ctcggaagga catatgggag ggcaeiatcat ttggtcgaga 1140 tccctcggag atctctagct agaggatcga tccccgcccc ggacgaacta aacctgacta 1200 cgacatctct gccccttctt cgcggggcag tgcatgtaat cccttcagtt ggttggtaca 1260 acttgccaac tgggccctgt tccacatgtg acacgggggg ggaccaaaca caaaggggtt 1320 ctctgactgt agttgacatc cttataaatg gatgtgcaca tttgccaaca ctgagtggct 1380 ttcatcctgg agcagacttt gcagtctgtg ga.ctgcaa,ca caacattgcc tttatgtgta 1440 actcttggct gaagctctta caccaatgct gggggacatg tacctcccag gggcccagga 1500 agactacggg aggctacacc aacgtcaatc agaggggcct gtgtagctac cgataagcgg 1560 accctcaaga gggcattagc aatagtgttt ataaggcccc cttgttaacc ctaaacgggt 1620 agcatatgct tcccgggtag tagtatatac tatccagact aaccctaatt caatagcata 1680 - 1380. 151681·序列表.doc 201127956 域）。DVD分子亦可包含2個或2個以上非Ig區域。 連接子序列可為單個胺基酸或多肽序列。在一實施例 中，連接子序列係選自由以下組成之群： AKTTPKLEEGEFSEAR(SEQ ID NO: 1) ； AKTTPKLEEGEF SEARV(SEQ ID NO: 2) ； AKTTPKLGG(SEQ ID NO: 3)； SAKTTPKLGG(SEQ ID NO: 4) ； SAKTTP(SEQ ID NO: 5)； RADAAP(SEQ ID NO: 6) ； RADAAPTVS(SEQ ID NO: 7)； RADAAAAGGPGS(SEQ ID NO: 8) ; RADAAAA(G4S)4(SEQ ID NO: 9) ； SAKTTPKLEEGEFSEARV(SEQ ID NO: 10)； ADAAP(SEQ ID NO: 11) ； ADAAPTVSIFPP(SEQ ID NO: 12) ； TVAAP(SEQ ID NO: 13) ； TVAAPSVFIFPP(SEQ ID NO: 14) ； QPKAAP(SEQ ID NO: 15) ； QPKAAPSVTLFPP (SEQ ID NO: 16) ； AKTTPP(SEQ ID NO: 17) ； AKTTPPSVTPLAP (SEQ ID NO: 18) ； AKTTAP(SEQ ID NO: 19) ； AKTTAPSVYPLAP (SEQ ID NO: 20) ； ASTKGP(SEQ ID NO: 21) ； ASTKGPSVFPLAP (SEQ ID NO: 22) ； GGGGSGGGGSGGGGS(SEQ ID NO: 23) ； GENKVEYAPALMALS(SEQ ID NO: 24) ； GPAKELTP LKEAKVS(SEQ ID NO: 25) ； GHEAAAVMQVQYPAS(SEQ ID NO: 26)。基於對若干Fab分子之晶體結構分析選擇連接 子序列。在Fab或抗體分子結構中，可變區域與CH1/CL恆 定區域之間存在天然可撓性鍵聯。此天然鍵聯包含約10至 12個胺基酸殘基，由來自V區域之C末端的4至6個殘基及 來自CL/CH1區域之N末端的4至6個殘基提供。本發明之 DVD Ig係分別使用CL或CH1之N末端5至6個胺基酸殘基或 151681.doc -200-
201127956 tgttacccaa cgggaagcat atgctatcga attagggtta gtaaaagggt cctaaggaac agcgatatct cccaccccat gagctgtcac ggttttattt acatggggtc aggattccac gagggtagtg aaccatttta gtcacaaggg cagtggctga agatcaagga gcgggcagtg aactctcctg aatcttcgcc tgcttcttca ttctccttcg tttagctaat agaataactg ctgagttgtg aacagtaagg tgtatgtgag gtgctcgaaa acaaggtttc aggtgacgcc cccagaataa aatttggacg gggggttcag tggtggcatt gtgctatgac accaatataa ccctcacaaa ccccttgggc aataaatact agtgtaggaa tgaaacattc tgaatatctt taacaataga aatccatggg gtggggacaa gccgtaaaga ctggatgtcc atctcacacg aatttatggc tatgggcaac acataatcct agtgcaatat gatactgggg ttattaagat gtgtcccagg cagggaccaa gacaggtgaa ccatgttgtt acactctatt tgtaacaagg ggaaagagag tggacgccga cagcagcgga ctccactggt tgtctctaac acccccgaaa attaaacggg gctccacgcc aatggggccc ataaacaaag acaagtggcc actctttttt ttgaaattgt ggagtggggg cacgcgtcag cccccacacg ccgccctgcg gttttggact gtaaaataag ggtgtaataa cttggctgat tgtaaccccg ctaaccactg cggtcaaacc acttgcccac aaaaccacta atggcacccc ggggaatacc tgcataagta ggtgggcggg ccaagatagg ggcgcgattg ctgcgatctg gaggacaaat tacacacact tgcgcctgag cgccaagcac agggttgttg gtcctcatat tcacgaggtc gctgagagca cggtgggcta atgttgccat gggtagcata tactacccaa atatctggat agcatatgct atcctaatct atatctgggt agcataggct atcctaatct atatctgggt agcatatgct atcctaatct atatctgggt agtatatgct atcctaattt atatctgggt agcataggct atcctaatct atatctgggt agcatatgct atcctaatct atatctgggt agtatatgct atcctaatct gtatccgggt agcatatgct atcctaatag agattagggt agtatatgct atcctaattt atatctgggt agcatatact acccaaatat ctggatagca tatgctatcc taatctatat 151681序列表.doc 1381 · 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 201127956 ctgggtagca tatgctatcc taatctatat ctgggtagca taggctatcc taatctatat 3120 ctgggtagca tatgctatcc taatctatat ctgggtagta tatgctatcc taatttatat 3180 ctgggtagca taggctatcc taatctatat ctgggtagca tatgctatcc taatctatat 3240 ctgggtagta tatgctatcc taatctgtat ccgggtagca tatgctatcc tcatgataag 3300 ctgtcaaaca tgagaatttt cttgaagacg aaagggcctc gtgatacgcc tatttttata 3360 ggtt-aatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt 3420 gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 3480 acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 3540 tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 3600 agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 3660 cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 3720 aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg ttgacgccgg 3780 gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 3840 agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 3900 aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 3960 gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 4020 ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg cagcaatggc 4080 Eiacaacgttg cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt 4140 aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc 4200 tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc 4260 agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca 4320 ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca 4380 ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa aacttcattt 4440 -1382-
151681·序列表.doc
201127956 ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa eiagatcaaag gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag ciigagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc cagtggcgat eLagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc gcccaatacg caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca ctcattaggc accccaggct ttacacttta tgcttccggc tcgtatgttg tgtggaattg tgagcggata acaatttcac acaggaaaca gctatgacca tgattacgcc aagctctagc tagaggtcga gtccctcccc agcaggcaga agtatgcaaa gcatgcatct caattagtca gcaaccatag tcccgcccct aactccgccc atcccgcccc taactccgcc cagttccgcc cattctccgc cccatggctg actaattttt tttatttatg cagaggccga ggccgcctcg gcctctgagc tattccagaa gtagtgagga ggcttttttg gaggcctagg cttttgcaaa aagctttgca 151681-序列表.doc • 1383· 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 201127956 aagatggata aagttttaaa cagagaggaa tctttgcagc taatggacct tctaggtctt 5880 gaaaggagtg ggaattggct ccggtgcccg tcagtgggca gagcgcacat cgcccacagt 5940 ccccgagaag ttggggggag gggtcggcaa ttgaaccggt gcctagagaa ggtggcgcgg 6000 ggtaaactgg gaaagtgatg tcgtgtactg gctccgcctt tttcccgagg gtgggggaga 6060 accgtatata agtgcagtag tcgccgtgaa cgttcttttt cgcaacgggt ttgccgccag 6120 aacacaggta agtgccgtgt gtggttcccg cgggcctggc ctctttacgg gttatggccc 6180 ttgcgtgcct tgaattactt ccacctggct gcagtacgtg attcttgatc ccgagcttcg 6240 ggttggaagt gggtgggaga gttcgaggcc ttgcgcttaa ggagcccctt cgcctcgtgc 6300 ttgagttgag gcctggcctg ggcgctgggg ccgccgcgtg cgaatctggt ggcaccttcg 6360 cgcctgtctc gctgctttcg ataagtctct agccatttaa aatttttgat gacctgctgc 6420 gacgcttttt ttctggcaag atagtcttgt aaatgcgggc caagatctgc acactggtat 6480 ttcggttttt ggggccgcgg gcggcgacgg ggcccgtgcg tcccagcgca catgttcggc 6540 gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg gggtagtctc aagctggccg 6600 gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc ccgccctggg cggcaaggct 6660 ggcccggtcg gcaccagttg cgtgagcgga aagatggccg cttcccggcc ctgctgcagg 6720 gagctcaaaa tggaggacgc ggcgctcggg agagcgggcg ggtgagtcac ccacacaaag 6780 gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac tccacggagt accgggcgcc 6840 gtccaggcac ctcgattagt tctcgagctt ttggagtacg tcgtctttag gttgggggga 6900 ggggttttat gcgatggagt ttccccacac tgagtgggtg gagactgaag ttaggccagc 6960 ttggcacttg atgtaattct ccttggaatt tgcccttttt gagtttggat cttggttcat 7020 tctcaagcct cagacagtgg ttcaaagttt ttttcttcca tttcaggtgt cgtgaggaat 7080 tctctagaga tccctcgacc tcgagatcca ttgtgcccgg gcgccaccat ggagtttggg 7140 ctgagctggc tttttcttgt cgcgatttta aaaggtgtcc agtgc 7185 - 1384· 151681·序列表.doc 201127956 11至12個胺基酸殘基作如叩七之輕鏈及重鏈中之連接子 產生。CL或CH1區域之]^末端殘基（尤其前5至6個胺基酸殘 基）抓用環構形而無穩固二級結構，因此可用作2個可變區 域之間的可撓性連接子。CL4CH1區域之N末端殘基由於 其為Ig序列之一部分而為可變區域之天然延長，因此在很 大程度上使任何可能由連接子及接點引起之免疫原性降至 最低。 其他連接子序列可包括CL/CH1區域之任何長度之任何 序列，而非CL/CH1區域之所有殘基，例如CL/CH1區域的 則5至12個胺基酸殘基；輕鏈連接子可來自Ck或;且重 鏈連接子可來源於任何同型之CH1，包括Cyl、C/y2、 ' (：γ4' Cal ' Ca2'以、以及〇。連接子序列亦可來 源於其他蛋白質，諸如Ig樣蛋白（例如TCR、FcR、KIR); 基於G/S之序列（例如G4S重複序列）（SEQ ID n〇:27);來源 於鉸鏈區之序列；及來自其他蛋白質之其他天然序列。 在一貫施例中，使用重組DNA技術使恆定區域連接至2 個連接之可變區域上。在一實施例中，包含連接之重鏈可 變區域的序列係連接至重鏈恆定區域而包含連接之輕鏈可 變區域的序列係連接至輕鏈恆定區域。在一實施例中，恆 疋區域分別為人類重鏈但定區域及人類輕鏈怪定區域。在 一實施例中，DVD重鏈係進一步連捿至Fc區。卜區可為原 生序列Fc區或變異Fc區。在另一實施例中，Fc區為人類Fc 區。在另一實施例中，Fc區包括來自IgGl、IgG2、igG3、 IgG4、IgA、IgM、IgE 或 IgD之 Fc 區。 151681.doc 201 · 201127956 在另一實施例中，兩個重鏈DVD多肽及兩個輕鏈DVD多 肽經組合形成DVD-Ig分子。表2列出適用於治療疾病（例如 治療癌症）之目標的例示性抗體之VH及VL區的胺基酸序 列。在一實施例中，本發明提供包含任何定向之表2中所 列VH及/或VL區中至少兩者的DVD。 表2:用於產生DVD-Ig之抗體的VH及VL區之胺基酸序列 清單
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 ^ 28 AB001VH VH CD20 QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQT PGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAY MQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS A 29 AB001VL VL CD20 QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWFQQKPG SSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAE DAATYYCQQWTSNPPTFGGGTKLEIKR 30 AB002VH VH CD3 (序列1) QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQR PGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAY MQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 31 AB002VL VL CD3 (序列1) QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWYQQKSG TSPKRWIYDTSKVASGVPYRFSGSGSGTSYSLTISSMEAE DAATYYCQQWSSNPLTFGSGTKLEINR 32 AB003VH VH EGFR (序列1) QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIR QSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQF SLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS j 33 AB003VL VL EGFR (序列1) DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKP GKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQP EDIATYFCQHFDHLPLAFGGGTKVEIKR 34 AB004VH VH HER2 (序列1) EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQA PGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 35 AB004VL VL HER2 (序列1) DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKP GKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQP EDFATYYCQQHYTTPPTFGQGTKVEIKR 36 AB005VH VH RON (序列1) EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMHWVRQA PGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARFSGWPNNYYYYGMDVWGQGTTV TVSS 37 AB005VL VL RON (序列1) DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGFNYVDW YLQKPGQSPHLLIYFGSYRASGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQALQTPPWTFGQGTKVEIRR •202· I51681.doc 201127956
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 38 AB006VH VH CD-19 (序列1) QVQLQQSGAELVRPGSSVK工SCKASGYAFSSYWMNWVKQR PGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAY MQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTSV TVSS 39 AB006VL VL CD-19 (序列1) DILLTQTPASLAVSLGQRATISCKASQSVDYDGDSYLNWY QQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIH PVEKVDAATYHCQQSTEDPWTFGGGTKLEIKR 40 AB007VH VH CD-80 QVQLQESGPGLVKPSETLSLTCAVSGGSISGGYGWGWIRQ PPGKGLEWIGSFYSSSGNTYYNPSLKSQVTISTDTSKNQF SLKLNSMTAADTAVYYCVRDRLFSVVGMVYNNWFDVWGPG VLVTVSS 41 AB007VL VL CD-80 ESALTQPPSVSGAPGQKVTISCTGSTSNIGGYDLHWYQQL PGTAPKLLIYDINKRPSGISDRFSGSKSGTAASLAITGLQ TEDEADYYCQSYDSSLNAQVFGGGTRLTVLG 42 AB008VH VH CD-22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWLHWVRQA PGQGLEWIGYINPRNDYTEYNQNFKDKATITADESTNTAY MELSSLRSEDTAFYFCARRDITTFYWGQGTTVTVSS 43 AB008VL VL CD-22 DIQLTQSPSSLSASVGDRVTMSCKSSQSVLYSANHKNYLA WYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCHQYLSSWTFGGGTKLEIKR 44 AB009VH VH CD-40 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQA PGKGLEWVAVISYEESNRYHADSVKGRFTISRDNSKITLY LQMNSLRTEDTAVYYCARDGGIAAPGPDYWGQGTLVTVSS 45 AB009VL VL CD-40 DIVMTQSPLSLTVTPGEPASISCRSSQSLLYSNGYNYLDW YLQKPGQSPQVLISLGSNRASGVPDRFSGSGSGTDFTLKI SRVEAEDVGVYYCMQARQTPFTFGPGTKVDIRR 46 AB010VH VH IGF1, 2 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQA TGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAY MELSSLRSEDTAVYYCARDPYYYYYGMDVWGQGTTVTVSS 47 AB010VL VL IGF1, 2 QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVSWYQQL PGTAPKLLIYD關KRPSGIPDRFSGSKSGTSATLGITGLQ TGDEADYYCETWDTSLSAGRVFGGGTKLTVLG 48 AB011VH VH IGF1R (序列1) EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMNWVRQA PGKGLEWVSAISGSGGTTFYADSVKGRFTISRDNSRTTLY LQMNSLRAEDTAVYYCAKDLGWSDSYYYYYGMDVWGQGTT VTVSS 49 AB011VL VL 工GF1R (序列1) DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGWYQQKP GKAPKRLIYAASRLHRGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCLQHNSYPCSFGQGTKLEIKR 50 AB012VH VH HGF (序列1) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQA PGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVTV ss 51 AB012VL VL HGF (序列1) DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKP GKAPNLLIYEASSLQSGVPSRFGGSGSGTDFTLTISSLQP EDFATYYCQQANGFPWTFGQGTKVEIKR 151681.doc -203 - 201127956
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 52 AB013VH VH c-MET QVQLQQSGPELVRPGASVKWSCPASGYTFTSYWLHWVKKQ RPGQGLEWIGMIDPSNSDTRFNPPNFKDKATLNVDRSSNT AYNLLSSLTSADSAVYYCATYGSYVSPLDYWGQGTSVYVS S 53 AB013VL VL c-MET DIMMSQSPSSLTVSVGEKVTVSCKSSQSLLVTSSQKNYLA WYQQKPQQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLT ITSVKADDLAVYYCQQYYAYPWTFGDGTKLEIKR 54 AB014VH VH VEGF (序列1) EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 55 AB014VL VL VEGF (序列1) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYSTVPWTFGQGTKVEIKR 56 AB015VH VH DLL-4 (序列1) EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWISWVRQA i PGKGLEWVGYISPNSGFTYYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCARDNFGGYFDYWGQGTLVTVSS 57 AB015VL VL DLL-4 (序列1) DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKP GKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQP EDFATTYYCQQSYTGTVTFGQGTKVEIKR 58 AB016VH VH NRP1 (序列1) EVQLVESGGGLVQPGGSLRLSCAASGFSFSSEPISWVRQA PGKGLEWVSSITGKNGYTYYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCARWGKKVYGMDVWGQGTLVTVSS 59 AB016VL VL NRP1 (序列1) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKP GKAPKLLIYGASSRASGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYMSVPITFGQGTKVEIKR 60 AB033VH VH EGFR (序列2) QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQS PGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 61 AB033VL VL EGFR (序列2) DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRT NGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVES EDIADYYCQQNNNWPTTFGAGTKLELKR i 62 AB034VH VH RON (序列2) QVQLQESGPGLVKPSEILSLTCTVSGGSISSHYWSWVRQP PGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSL NLSSVTAADTAVYYCARIPNYYDRSGYYPGYWYFDLWGRG TLVTVSS 63 AB034VL VL RON (序列 2) QAVLTQPSSLSAPPGASASLTCTLRSGFNVDSYRISWYQQ KPGSPPQYLLRYKSDSDKQQGSGVPSRFSGSKDASANAGI LLISGLQSEDEADYYCMIWHSSAWVFGGGTKLTVLR 64 AB035VH VH NRP1 (序列2) EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQA PGKGLEWVSQISPAGGYTNYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCARELPYYRMSKVMDVQGQGTLVTV SS 65 AB035VL VL NRP1 (序列2) DIQMTQSPSSLSASVGDRVTITCRASQYFSSYLAWYQQKP GKAPKLLIYGASSRASGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYLGSPPTFGQGTKVEIKR -204- 151681.doc 201127956
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 66 AB039VH VH CD3 (序列2) QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQR PGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAY MQLS SLT SEDSAVYYCARYY DDHYCLDYWGQGTTLTVS S 67 AB039VL VL CD3 (序列2) QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSG TSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAE DAATYYCQQWSSNPFTFGSGTKLEINR 68 AB047VH VH PLGF (序列1) QVQLQQSGAELVKPGASVKISCKASGYTFTDYYINWVKLA PGQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSSSTAY MQLSSLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 69 AB047VL VL PLGF (序列1) DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMRKSFLA WYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLT ISSVQAEDVAVYYCKQSYHLFTFGSGTKLEIKR 70 AB062VH VH ErbB3 (序列1) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQP PGKGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSL KLSSVTAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 71 AB062VL VL ErbB3 (序列1) DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLA WYQQNPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLT ISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIKR 72 AB063VH VH ErbB3 (序列2) EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQA PGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLY LQMNSLRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 73 AB063VL VL ErbB3 (序列2) DIQMTQSPSSLSASVGDRVTITCQASQDITNYLtWYQQKP GKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQP EDIATYNCQQCENFPITFGQGTRLEIKR 74 AB067VH VH ErbB3 (序列3) EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMAWVRQA PGKGLEWVSSISSSGGWTLYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCTRGLKMATIFDYWGQGTLVTVSS 75 AB067VL VL ErbB3 (序列3) QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVVSWYQQ HPGKAPKLIIYEVSQRPSGVSNRFSGSKSGNTASLTISGL QTEDEADYYCCSYAGSSIFVIFGGGTKVTVLG 76 AB069VH VH DLL4 (序列2) QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIHWVKQA PGQGLEWIGYISSYNGATNYNQKFKGRVTFTTDTSTSTAY MELRSLRSDDTAVYYCARDYDYDVGMDYWGQGTLVTVSS 77 AB069VL VL DLL4 (序列2) DIVMTQSPDSLAVSLGERATISCRASESVDNYGISFMKWF QQKPGQPPKLLIYAASNQGSGVPDRFSGSGSGTDFTLTIS SLQAEDVAVYYCQQSKEVPWTFGGGTKVEIKR 78 AB070VH VH VEGF (序列2) EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQA PGKGLEWVAGITPAGGYTYYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 79 AB070VL VL VEGF (序列2) DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKP GKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQSYTTPPTFGQGTKVEIKR 80 AB071VH VH VEGF (序列3) EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQA PGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVS S 81 AB071VL VL VEGF (序列3) DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKP GKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQSNTSPLTFGQGTKVEIKR 151681.doc -205 - 201127956
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 82 AB072VH VH DLL4 (序列3) EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVINWVKQK PGQGLEWIGLINPYNDGTKYNEKFKVKATLTSDKSSSTAY MELSSLTSEDSAVYYCASYYYGSRYYFDYWGQGTTLTVSS 83 AB072VL VL DLL4 (序列3) DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAWYQQKP GNAPRLLISGATSLETGVPSRFSGSGSGKDYTLSITSLQT EDVATYYCQQYWSIPLTFGAGTKLELKR 84 AB073VH VH DLL4 (序列4) EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMNWVKQS NGKSLEWIGNIDPYFGGTNYNQKFKGKATLTVDKSSSTAY MQLKSLTSEDSAVYYCARNYDYDGGCFDYWGQGTTLTVSS 85 AB073VL VL DLL4 (序列4) QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQE KPDHLFTGLIGGTNNRAPGVPARFSGSLIGDKAALTITGA QTEDEAIYFCALWYSNHWVFGGGTKLTVLG 86 AB074VH VH PLGF (序列2) QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQS PGKGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKSQVFF KMNSLQANDTGIYYCARYRFYGMDYWGQGTSVTVSS έ 87 AB074VL VL PLGF (序列2) AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAWYQQKP 1 GNAPRLLISGAASLEAGVPSRFSGSGSGQDYTLSITSLQT EDVATYYCQQYWSTPWTFGGGTKLEIKR 88 AB075VH VH IGF1R (序列2) EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQA PGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAY MELSSLRSEDTAVYYCARAPLRFLEWSTQDHYYYYYMDVW GKGTTVTVSS 89 AB075VL VL IGF1R (序列2) SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWYQQKPG QAPILVIYGENKRPSGIPDRFSGSSSGNTASLTITGAQAE DEADYYCKSRDGSGQHLVFGGGTKLTVLG 90 AB077VH VH IGF1R (序列3) EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMHWVRQA PGKGLEWISVIDTRGATYYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTAVYYCARLGNFYYGMDVWGQGTTVTVSS 91 AB077VL VL 工GF1R (序列3) EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHWYQQKP GQAPRLLIKYASQSLSGIPDRFSGSGSGTDFTLTISRLEP EDFAVYYCHQSSRLPHTFGQGTKVEIKR 92 AB079VH VH HGF (序列2) EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMHWVRQM ( PGKGLEWMGEINPTNGHTNYNPSFQGQVTISADKSISTAY LQWSSLKASDTAMYYCARNYVGSIFDYWGQGTLVTVSS 93 AB079VL VL HGF (序列2) DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSWYQQKP GKAPKLLIYGASNRNTGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCGQSYNYPYTFGQGTKLEIKR 94 AB080VH VH HER2 (序列2> EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQA PGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLY LQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS 95 AB080VL VL HER2 (序列2) DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKP GKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYYIYPYTFGQGTKVEIKR 96 AB107VH VH CD3 (序列3) EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQA PGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAY LQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTV SS •206- 151681.doc 201127956
SEQ ID No. ABT 唯一 ID 蛋白質區 序列 1234567890123456789012345678901234567890 97 AB107VL VL CD3 (序列3) DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKP GKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQP EDFATYYCQQGNTLPWTFGQGTKVEIKR 98 AB108VH VH CD3 (序列4) EVQLLESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQA PGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNT AYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTL VTVSS 99 AB108VL VL CD3 (序列4) ELVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQ KPGQAPRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGV QPEDEAEYYCALWYSNLWVFGGGTKLTVLG 100 AB110VH VH mCD3 EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQA PGRGLESVAYITSSSINIKYADAVKGRFTVSRDNAKNLLF LQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS 101 AB110VL VL mCD3 DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKP GKAPKLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLES EDIGSYYCQQYYNYPViTFGPGTKLEIKR 102 AB111VH VH CD19 (序列2) EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQP PRKGLEWLGVIWGSEGTTYYNSALKSRLTIIKDNSKSQVP LKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVS S 103 AB111VL VL CD19 (序列2) DIQMTQTTSSLSASLGDRVTISCRASQDISKTLNWYQQKP DGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQ EDIATYFCQQGNTLPYTFGGGTKLEITR 104 AB112VH VH CD19 (序列3) EVQLQESGPELVKPGASVKISCKASGYAFSSSWMNWVIQR PGQGLEWIGRIYPGDGDTNYNGKFKGKATLTADKSSSTAY MQLSSLTSVDSAVYFCARSGFITTVLDFDYWGQGTTLTVS S 105 AB112VL VL CD19 (序列3) DIVLTQSPTSLAVSLGQRATISCRASESVDTFGISFiyiNWF QQKPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFSLNIH PMEEDDSAMYFCQQSKEVPFTFGSGTKLEIKR 106 AB114VH VH mCD19 EVQLQQSGAELVRPGTSVKLSCKVSGDTITFYYMHFVKQR PGQGLEWIGRIDPEDESTKYSEKFKNKATLTADTSSNTAY LKLSSLTSEDTATYFCIYGGYYFDYWGQGVMVTVSS 107 AB114VL VL mCD19 DIQMTQSPASLSTSLGETVTIQCQASEDIYSGLAWYQQKP GKSPQLLIYGASDLQDGVPSRFSGSGSGTQYSLKITSMQT EDEGVYFCQQGLTYPRTFGGGTKLELKR 下文實例章節中提供能夠結合特異性目標之特異性 DVD-Ig分子及其製備方法的詳細描述。 C.產生DVD蛋白 可藉由此項技術中已知之多種技術中之任一者製造本發 明結合蛋白。舉例而言，自宿主細胞表現，其中藉由標準 技術將編碼DVD重鏈及DVD輕鏈之表現載體轉染至宿主細 -207- 151681.doc 201127956 胞中。術語「轉染」之各種形式意欲涵蓋通常用於將外源 DNA引入原核生物或真核生物宿主細胞中之多種技術，例 如電穿孔、磷酸鈣沈澱、DEAE-聚葡萄糖轉染及其類似技 術。儘管可能於原核生物或真核生物宿主細胞中表現本發 明之DVD蛋白，但DVD蛋白應表現於真核細胞（例如哺乳 動物宿主細胞）中，因為該等真核細胞（且尤其哺乳動物細 胞）比原核細胞更有可能組裝及分泌適當摺疊且具免疫活 性之DVD蛋白。 表現本發明重組抗體之例示性哺乳動物宿主細胞包括中 國倉鼠卵巢（CHO)細胞（包括dhfr-CHO細胞，其係描述於 Urlaub 及 Chasin，（ 1980) Proc. TVai/. USA 77: 4216-4220 中，例如如 R.J. Kaufman 及 P. A. Sharp (1982) Mo/.价〇/. 159: 601-621中所述，其係與DHFR可選標誌物 一起使用）、NS0骨髓瘤細胞、COS細胞、SP2及PER.C6細 胞。當將編碼DVD蛋白之重組表現載體引入哺乳動物宿主 細胞中時，藉由培養宿主細胞歷時足以使DVD蛋白在宿主 細胞中表現或足以將DVD蛋白分泌至使宿主細胞生長之培 養基中的時段來產生DVD蛋白。可使用標準蛋白質純化方 法自培養基回收DVD蛋白。 在用於重組表現本發明之DVD蛋白的例示性系統中，藉 由磷酸鈣介導之轉染將編碼DVD重鏈及DVD輕鏈兩者之重 組表現載體引入dhfr-CHO細胞中。在重組表現載體中， DVD重鏈與輕鏈基因各自可操作地連接於CMV強化子/ AdMLP啟動子調控元件以驅動基因之高水準轉錄。重組表 151681.doc -208· 201127956 現載體亦運載DHFR基因，其允許使用甲胺4呤選擇/擴增 來選擇已經該載體轉染之CHO細胞。培養所選擇之轉型體 宿主細胞以允許表現DVD重鏈及輕鏈且自培養基回收完整 DVD蛋白。使用標準分子生物學技術來製備重組表現載 體、轉染宿主細胞、選擇轉型體、培養宿主細胞及自培養 基回收DVD蛋白。本發明進—步提供合成本發明dvd蛋白 之方法，該方法藉由在適合培養基巾培養本發明之宿主細
胞直至合成本發明之DVD蛋白來進行。該方法可進一步包 含自培養基分離DVD蛋白。 精-Ig之重要特徵在於其可以與習知抗體類似之方式 產生及純化。DVD-Ig之產生形成具有所要雙重特里性活 性之均質單-主要產物’而無對恆定區之任何序列修飾或 任何種類之化學修飾。其他先前所述之產生「雙特異 性」、「多特異性」及「多特異性多價」全長結合蛋白之方 法不產生單-主產物，而是引起細胞内產生或分泌產生經 組裝之非活性、單特異性、多特異性、多價全長結合蛋白 及具有不同結合位點組合之多價全長结合蛋白的混合物。 舉例而言，基於Miller及Presta(pcT公開案w〇 2刪/ 〇77342(A1))所述之設計，存在重鏈與輕鏈之_可能组 合。因此，僅6.25%蛋白質可能里所要之活性形式，心 其他15種可能組合相比，並非為單—主要產物或單—主產 物。使用通常用於大規模製造之標準層析技術分離蛋白質
之所要完全活㈣式與蛋白質之非活性及部分活 有待證實》 A 151681.doc -209- 201127956 令人驚訝的是，本發明之「雙重特異性多價全長結合蛋 白」之计產生主要組裝成所要「雙重特異性多價全長結 合蛋白」的雙重可變區域輕鏈及雙重可變區域重鏈。 至）50/。、至少75%及至少90%之經組裝及經表現之雙 重可變區域免疫球蛋白分子為所要雙重特異性四價蛋白 質。本發明之此態樣尤其增進本發明之商業效用。因此， 本發明包括使雙重可變區域輕鏈及雙重可變區域重鏈在單 細胞中表現以產生「雙重特異性四價全長結合蛋白」作為 單一主產物的方法。 本發明提供使雙重可變區域輕鏈及雙重可變區域重鏈在 皁細胞中表現以產生「雙重特異性四價全長結合蛋白」作 為「主產物」的方法’其中該「主產物」佔所有包含雙重 可變區域輕鏈及雙重可變區域重鏈之經組裝蛋白質之5〇% 以上。 本發明提供使雙重可變區域輕鏈及雙重可變區域重鏈在 單細胞中表現以產生「雙重特異性四價全長結合蛋白」作 為單-「主產物」的方法，其中該「主產物」佔所有包含 雙重可變區域輕鏈及雙重可變區域重鏈之經組裝蛋白質之 7 5 %以上。 本發明提供使雙重可變區域輕鏈及雙重可變區域重鏈在 單細胞中表現以產生「雙重特異性四價全長結合蛋白」作 為單-「主產物」的方法’其中該「主產物」佔所有包含 雙重可變區域輕鏈及雙重可變區域重鏈之經組裝蛋白質之 9 0 %以上。 151681.doc •210· 201127956 Π·衍生之DVD結合蛋白： -實施例提供本發明之結合蛋白經衍生化或連接於另一 功能分子(例如另一肽或蛋白質)的經標記結合蛋白。舉例 而言，可藉由將本發明之結合蛋白功能性連接於一或多個 其他分子實體（例如藉由化學偶合、基因融合、非共價締 合或其他方式）來衍生本發明之經標記結合蛋白，該一或 夕個其他分子實體諸如另一抗體（例如雙特異性抗體或微 籲型雙功能抗體)、可偵測劑、細胞毒性劑、醫藥劑及/或可 介導結合蛋白與另_ yV v / 兴为刀子（诸如杬生蛋白鏈菌素核心區或 t组胺酸標籤）締合之蛋白質或肽。 可用來衍生本發明之結合蛋白之適用可该測劑包括營光 化合:。例示性螢光可谓測劑包括營光素、異硫氰酸營光 素右丹明、5-—甲胺小蔡續氣、藻紅素及其類似物。 亦可用諸如驗性磷酸酶、辣根過氧化酶、葡萄糖氧化酶及 f類似酶之可偵測酶衍生結合蛋白。當用可偵測酶衍生結 籲 α蛋白0寺’藉由添加其他試劑（酶使用該等試劑來產生可 偵測反應產物）對其加以偵測。舉例而言，當存在可憤測 %辣根過氧化酶時’添加過氧化氫及二胺基聯苯胺會產生 可债測之有色反應產物。亦可以生物素衍生結合蛋白且 ，’！由間接$測抗生物素蛋白或抗生蛋白鏈菌素結合來須 測。 本發明之另-實施例提供—種結晶結合蛋白及包含該等 日日體之〇周配物及組合物。在一實施例中，結晶結合蛋白具 有匕、蛋白之可溶對應物高之活體内半衰期。在另一實 151681.doc •211 · 201127956 施例中，結合蛋白在結晶後保留生物活性β 本發明之結晶結合蛋白可按照此項技術中已知及如以引 用的方法併入本文中的WO 02072636中所揭示之方法產 生。 本發明之另一實施例提供一種糖基化結合蛋白，其中抗 體或其抗原結合部分包含一或多個碳水化合物殘基。初期 活體内蛋白質產生可經歷稱為轉譯後修飾之進一步加工。 詳言之，可酶促添加糖（糖基）殘基，此過程稱為糖基化。 所得具有共價連接之募醣側鏈之蛋白質稱為糖基化蛋白質 或醣蛋白。抗體為在Fc區域以及可變區域中具有一或多個 碳水化合物殘基之醣蛋白。Fc區域中之碳水化合物殘基對 Fc區域之效應功能具有重要影響，而對抗體之抗原結合或 半衣期影響極小（R· Jefferis，/Vog·. 21 (2005) 第11-16頁）。相對而言，可變區域之糖基化可對抗體之抗 原結合活性產生影響。可變區域中之糖基化可能由於位阻 作用而可能對抗體結合親和力具有不利影響（C〇，m.S.等 人，Mol_ Immunol. (1993) 30:1361-1367)或導致對抗原之親 和力增加（Wallick，S.C.等人，丑父卩.1^〇1.(1988) 168:1099-1109 ; Wright，A.等人，EMBO J. (1991) 10:2717 2723)。 本發明之一態樣係關於產生結合蛋白之0連接或N連接 糖基化位點已突變之糖基化位點突變體。熟習此項技術者 可使用標準熟知技術產生該等突變體。保留生物活性但具 有增加或減小之結合活性的糖基化位點突變體為本發明之 另一目標。 151681.doc -212- 201127956 在另一實施例中，本發明之抗體或抗原結合部分之糖基 化經改質。舉例而言，可製備去糖基化之抗體（亦即缺乏 糖基化之抗體）。糖基化可經改變以例如增加抗體對抗原 之親和力。該等碳水化合物修飾可藉由例如改變抗體序列 中之一或多個糖基化位點貫現。舉例而言，可進行一或多 個胺基酸取代，其導致消除一或多個可變區糖基化位點從 而消除彼位點處之糖基化。該去糖基化可增加抗體對抗原 之親和力。該種方法在PCT公開案wo 2003016466A2及美 國專利第5,714,350號及第6,350,861號中進一步詳細描述， 其以全文引用的方式併入本文中。 或者或另外，可製備具有改變之糖基化類型的本發明之 經修飾結合蛋白，諸如海藻糖基殘基之量減少的低海藻糖 基化抗體（參看Kanda，Yutaka等人，journai 〇f
Biotechnology (2007)，130(3)，300-3 10)或平分型 GicNAc結 構增加之抗體。已證明該等經改變之糖基化模式增強抗體 之ADCC能力。該專碳水化合物修飾可藉由例如使抗體在 糖基化機構改變之宿主細胞中表現來實現。此項技術中已 描述糖基化機構改變之細胞且其可用作表現本發明之重組 抗體’由此產生糖基化改變之抗體之宿主細胞。參看例如
Shields，R. L.等人，（2002) J. Biol. Chem· 277:26733-26740; Umana等人，（1999) Nat. Biotech. 17:176-1以及歐 洲專利第 EP 1，176，195號；PCT公開案 WO 03/035835 ; WO 99/54342 80，其各自以全文引用的方式併入本文中。 蛋白質糖基化視相關蛋白質之胺基酸序列以及表現該蛋 151681.doc -213- 201127956 白質之宿主細胞而定。不同生物體可產生不同糖基化酶 (例如糖基轉移酶及酿皆酶）且具有不同的可利用受質（核苦 酸糖）。由於該等因素，蛋白質糖基化模式及糖基殘基之 成可視表現特足蛋白質之宿主系統而不同。適用於本發 明之糖基殘基可包括（但不限於）葡萄糖、半乳糖、甘露 糖、海藻糖、η·乙醯基葡糖胺及唾液酸。在一實施例中， 糖基化結合蛋白包含糖基殘基以使得糖基化模式為人類糖 基化模式。 熟習此項技術者已知不同}白質糖基化可產生不同蛋白 質特徵。舉例而言，在諸如酵母之微生物宿主中產生，且 利用酵母内源途徑糖基化之治療性蛋白f的功效可能比諸 如CHO細胞株之哺乳動物細胞中表現之相同蛋白質的功效 低。該等醣蛋白亦可能在人類中具有免疫原性且在投與後 展示降低之活體内半衰期。人類及其他動物中之特定受體 可識別特定糖基殘基且促進自血流中快速清除蛋白質。其 他不利仙可包括蛋白質摺#、溶解度、對蛋白酶之敏感 X運輸轉運、區室化、分泌、由其他蛋白質或因子識 別、抗原性或過敏原性較變。因此，醫師可能選擇具有 特定糖基化組成及模式（例如與人類細胞或預定個體動物 之物種特異性細胞中所產生者相同或至少類似的糖基化組 成及模式）之治療性蛋白質。 表現不同於宿主細胞之糖基化蛋白質的糖基化蛋白質可 藉由基因修飾宿主細胞以表現異源糖基化酶來實現。使用 此項技術中已知之技術，醫師可產生展現人類蛋白質糖基 151681.doc •214- 201127956 化之抗體或其抗原結合部分。舉例而言，已對酵母菌株進 行基因修飾以表現非天然存在之糖基化酶，以使得此等酵 母菌株中所產生之糖基化蛋白質（醣蛋白）展現與動物細胞 (尤其人類細胞）之蛋白質糖基化相同的蛋白質糖基化（美國 專利申請案2004001 8590及20020137134及PCT公開案w〇 2005100584 A2)。 除結合蛋白外’本發明亦係關於對本發明之該等結合蛋 白具有特異性之抗個體基因型（抗Id)抗體。抗1(1抗體為識 別一般與另一抗體之抗原結合區締合之獨特決定子的抗 體。可藉由以結合蛋白或其含CDR之區域使動物免疫來製 備抗Id。經免疫動物將識別且回應免疫抗體之遺傳型決定 子且產生抗Id抗體。顯而易見，可能較易於產生併入 DVD-Ig分子中之兩種或兩種以上親本抗體的抗個體基因 型抗體，且藉由此項技術中充分瞭解之方法（例如 BIAcore ' ELISA)確認結合研究以驗證針對各親本抗體之 個體基因型具有特異性之抗個體基因型抗體在DVD_Ig之 情形下亦識別個體基因型（例如抗原結合位點）。針對dvd_ Ig之兩個或兩個以上抗原結合位點中各者具有特異性之抗 個體基因型抗體提供量測患者血清中人類DVD-Ig之DVD-Ig濃度的理想試劑；DVD-Ig濃度檢定可使用「夾心檢定 ELIS A形式」建立，其中將針對第一抗原結合區之抗體塗 覆於固相（例如BIAcore晶片、ELISA板等）上，用沖洗緩衝 液沖洗，與血清樣品一起培育，再次沖洗，且最後與針對 另一抗原結合位點之另一抗個體基因型抗體一起培育，該 151681.doc •215- 201127956 另一抗個體基因型抗體本身經酶標記以定量結合反應。在 一實施例中，對於具有2個以上不同結合位點之DVD_Ig， 針對2個最外側（位於恆定區之最遠端及最近端）結合位點的 抗個體基因型抗體將不僅有助於測定人類血清中之DVD_ Ig濃度’且亦有助於證明分子在活體内之完整性。各抗Id 抗體亦可用作在另一動物中誘發免疫反應之「免疫原」， 從而產生所謂抗抗Id抗體。 此外’熟習此項技術者應瞭解可使用經基因工程改造以 表現各種糖基化酶之宿主細胞文庫來表現相關蛋白質，以 使得該文庫之成員宿主細胞產生具有變異糖基化模式之相 關蛋白質。醫師隨後可選擇及分離具有特定新穎糖基化模 式之相關蛋白質。在一實施例中，具有經特定選擇之新穎 糖基化模式之蛋白質展現改良或改變之生物特性。 III· DVD-Ig之用途 鑒於本發明之結合蛋白結合於兩個或兩個以上抗原之能 力，可使用該等結合蛋白以使用諸如酶聯結免疫吸附劑分 析法（ELISA)、放射免疫檢定（RIA)或組織免疫組織化學之 習知免疫檢定偵測抗原（例如諸如血清或血漿之生物樣品 中DVD-Ig經可偵測物質直接或間接標記以便於偵測結 合或未結合抗體。適合可偵測物質包括各種酶、輔基、螢 光物質、發光物質及放射性物質。適合酶之實例包括辣根 過氧化酶、鹼性磷酸酶、P-半乳糖苷酶或乙醯膽鹼酯酶； 適合輔基複合物之實例包括抗生蛋白鏈菌素/生物素及抗 生物素蛋白/生物素；適合螢光物質之實例包括傘酮 151681.doc •216- 201127956 (umbemferone)、螢光素、異硫氰酸螢光素、若丹明、二 氯三嗪基胺螢光素 '丹醯氣或藻紅素；發光物質之實例包 括魯米諾（luminol);且適合放射性物質之實例包括3H、 I、mLU、66Ho 或 14C、35S、90Y、”Tc、丨丨^、丨25l 153Sm 〇 在一實施例中’本發明之結合蛋白能夠活體外及活體内 中和抗原活性。因此，該等DVD-Ig可用於在例如含有抗 φ 原之細胞培養物中’在具有與本發明結合蛋白交叉反應之 抗原的人類個體或其他哺乳動物個體中抑制抗原活性。在 另一貫施例中，本發明提供一種降低罹患抗原活性有害之 疾病或病症的個體之抗原活性之方法。可出於治療目的向 人類個體投與本發明之結合蛋白。 如本文所用之術語「抗原活性有害之病症」意欲包括以 下疾病及其他病症，其中已展示或懷疑罹患該病症之個體 中存在抗原為造成該病症之病理生理的原因，或為促使該 • 病症惡化之因素。因此，抗原活性有害之病症為預期降低 抗原活性會緩解病症之症狀及/或進展的病症。該等病症 可藉由例如罹患該病症之個體之生物流體中抗原濃度增加 (例如個體之血清、血漿、滑液等中抗原濃度增加）來證 實。可用本發明結合蛋白治療之病症的非限制性實例包括 下文及關於本發明抗體之醫藥組合物之章節中所論述的彼 等病症。 本發明之DVD-Ig可結合一個抗原或多個抗原。該等抗 原包括（但不限於）以下資料庫令所列之目標，該等資料庫 151681.doc -217- 201127956 以引用的方式併入本文中。此等目標資料庫包括下文所列 之彼等： 治療性目標（http://xin.cz3.nus.edu.sg/group/cjttd/ttd.asp); 細胞激素及細胞激素受體（http://www.cytokinewebfacts.com/， http://www. cop ewithcytokines.de/cope.cgi，及 http://cmbi.bjmu.edu.cn/cmbidata/cgf/CGF_Database/cytokine. medic.kumamoto-u.ac.jp/CFC/indexR.html)；
趨化因子（http://cytokine.medic.kumamoto-u.ac.jp/CFC/CK/ Chemokine.html); 趨化因子受體及 GPCR(http://csp.medic.kumamoto-u.ac.jp/ CSP/Receptor.html, http://www.gpcr.org/7tm/)； 嗅覺受體（Olfactory Receptor)(http://senselab.med.yale.edu/ senselab/ORDB/default.asp)； 受體（http://www.iuphar_db.org/iuphar-rd/list/inciex.htm); 癌症目標（http://cged.hgc.jp/cgi-bin/input.cgi);
作為潛在抗體目標之分泌蛋白（http://spd.cbi.pku. edu.cn/); 蛋白激酶（http://spd.cbi.pku.edu.cn/)及
人類 CD 標誌、物（http://content.labvelocity.com/tools/ 6/1226/CD_table_final_locked.pdf)及（Zola Η, 2005 CD molecules 2005: human cell differentiation molecules Blood, 106:3123-6) 〇 DVD-Ig適用作治療劑以同時阻斷兩種不同目標，從而 增強功效/安全性及/或增加患者覆蓋範圍。該等目標可包 151681.doc -218- 201127956 括可溶目標（TNF)及細胞表面受體目標（VEGFR及EGFR)。 其亦可用於誘導腫瘤細胞與T細胞（Her2及CD3)之間（對於 癌症療法而言）、或自身反應性細胞與效應細胞之間（對於 自體免疫疾病或移植而言）、或任何目標細胞與效應細胞 之間的重導向細胞毒性以消除任何既定疾病中引起疾病之 細胞。 此外，當DVD-Ig經設計以靶向同一受體上兩個不同抗 φ 原決定基時’其可用於引發受體叢集及活化。此有益於製 備促效性及结抗性抗GPCR治療劑。在此情形下，DVD-Ig 可用於把向一個細胞上的兩個不同抗原決定基（包括環區 及胞外區域兩者上之抗原決定基）以實現叢集/信號傳導（兩 個細胞表面分子）或信號傳導（一個分子上）。類似地， DVD-Ig分子可經設計以藉由乾向CTLA-4胞外區域之兩個 不同抗原決定基（或同一抗原決定基之2個複本）引發ctla-4接合及負信號，導致免疫反應下調。CTLA-4為用於治療 性處理多種免疫學病症的經臨床驗證之目標。CTLA-4/B7 相互作用藉由削弱細胞週期進展、IL-2產生及T細胞在活 化後的增殖負調控T細胞活化，且CTLA-4(CD152)唾合可 下調T細胞活化及促進誘導免疫对受。然而，藉由ctlA-4 之促效性抗體鳴合削弱T細胞活化之策略已失敗，因為 CTLA-4活化需要接合。如晶體結構分析戶斤證實，ctlA-4/B7之分子相互作用為「斜拉鏈」陣列形式（Stamper 2〇〇1
Nature 410:608)。然而，當前可獲得之CTLA-4結合試劑 (包括抗CTLA-4 mAb)均不具有接合特性。已進行多種嘗 151681 doc -219· 201127956 試來解決此問題。在一種情形下，產生細胞成員結合之單 鏈抗體，且其顯著抑制小鼠之同種異體排斥（Hwang 2〇〇2 JI 169:633)。在另一種情形下，產生針對cTLA_4之人工 APC表面連接型單鏈抗體，且證明其削弱τ細胞反應 (Griffin 2000 JI 164:4433)。在兩種情形下，藉由在人工系 統中緊密定位成員結合之抗體實現CTLA_4接合。儘管此 等實驗提供藉由引發CTLA-4負信號傳導使免疫下調之概 念驗證，但此等報導中所使用之試劑不適於治療性用途。 為此，可藉由使用無向CTLA-4胞外區域之兩個不同抗原 決定基（或同一抗原決定基之2個複本）的DVD_Ig分子實現 CTLA-4接合。基本原理為跨越igG之兩個結合位點的距離 (約i5〇-i7〇A)過大以致無法活性接合CTLA_4(2個CTLA 4 均二聚體之間30-50 A)。然而，DVD-Ig( —個臂）上兩個結 合位點之間的距離短得多（亦在30-50 A範圍内），從而允許 適當接合CTLA-4。 類似地，DVD-Ig可靶向細胞表面受體複合物之兩個不 同成員（例如IL-12R α及β)。此外，DVD-Ig可乾向cri及可 溶蛋白質/病原體，從而驅使快速清除目標可溶性蛋白質/ 病原體。 此外，本發明之DVD-Ig可用於組織特異性傳遞（乾向組 織標§志物及疾病介體以提南局部P K ’從而具有較高功效及/ 或較低毒性），包括胞内傳遞（靶向内化受體及胞内分子）、 傳遞至腦内（靶向運鐵蛋白受體及CNS疾病介體以跨越血腦 屏障）。DVD-Ig亦可用作載體蛋白以經由結合於抗原之非 151681.doc -220- 201127956
中和抗原決定基將彼抗原傳遞至特定位置及亦提高抗原半 衰期。此外，DVD-Ig可經設計以物理連接於植入患者體 内之醫學裝置或靶向此等醫學裝置（參看Burke，Sandra E.; Kuntz, Richard E.; Schwartz, Lewis B., Zotarolimus eluting stents. Advanced Drug Delivery Reviews (2006), 58(3), 43 7-446 ， Surface coatings for biological activation and functionalization of medical devices, Hildebrand, H. F.; Blanchemain, N.; Mayer, G.; Chai, F.; Lefebvre, M.; Boschin，F.，Surface and Coatings Technology (2006)， 200(22-23), 6318-6324 i Drug/device combinations for local drug therapies and infection prophylaxis, Wu, Peng; Grainger, David W., Biomaterials (2006), 27(11), 2450-2467 ； Mediation of the cytokine network in the implantation of orthopedic devices., Marques, A. P.; Hunt, J. A.; Reis, Rui L., Biodegradable Systems in Tissue
Engineering and Regenerative Medicine (2005)，377-397) 〇 簡言之，將適當類型之細胞引導至醫藥植入部位可促進癒 合且修復正常組織功能。或者，亦提供對在裝置植入後藉 由偶合於裝置上或靶向裝置之DVD釋放之介體（包括（但不 限於）細胞激素）的抑制作用。舉例而言，介入心臟病學多 年來使用支架疏通阻塞之動脈及改善血液至心肌之流動。 然而，已知傳統裸金屬支架在一些患者體内會引起再狹窄 (所治療區域中之動脈再變狹窄）且可產生血液凝塊。最 近，已描述塗有抗CD34抗體之支架，其藉由捕捉在整個 151681.doc -221 - 201127956 血液中循環之内皮祖細胞（EPC)來減輕再狹窄且防止出現 血液凝塊。内皮細胞為内襯於血管内使血液順暢流動之細 胞。EPC黏附於支架之硬質表面上，形成光滑層，該光滑 層不僅促進癒合而且亦防止再狹窄及血液凝塊，與使用支 架相關之先前併發症（Aoji等人· 2005 J Am Coll Cardiol 45(10):1574-9)。除改善需要支架之患者的結果以外，對 需要心血管繞道手術之患者亦有涉及。舉例而言，塗有抗 EPC抗體之修復血管管道（人工動脈）將消除使用來自患者 腿部或手臂之動脈用於繞道手術移植的需要。此將減少手 術及麻醉次數，繼而將減少冠狀動脈手術死亡。以一定方 式設計DVD-Ig，該方式使得其結合於細胞表面標誌物（諸 如CD34)以及已塗於植入之裝置上以促進細胞募集之蛋白 質（或任何種類之抗原決定基，包括（但不限於）蛋白質、脂 質及多醣）。該等方法一般亦可用於其他醫學植入物。或 者’可將DVD_Ig塗於醫學裝置上且在裝置植入且自該裝 置釋放所有DVD後（或可能需要額外新鮮DVD-Ig之任何其 他需求，包括已裝載之DVD-Ig老化及變性），可藉由向患 者全身性投與新鮮DVD-Ig再裝載該裝置，其中DVD-Ig經 3又计以一組結合位點結合於相關目標（細胞激素、細胞表 面標誌、物（諸如CD34)等）且以另一組結合位點結合於裝置 上塗有之目標（包括蛋白質，任何種類之抗原決定基，包 括（但不限於）脂質、多醣及聚合物）。此技術具有擴展經塗 覆植入物之適用性的優勢。 A. DVD-Ig在各種疾病中之用途 151681.doc -222· 201127956 本發明之DVD-Ig分子亦適用作治療各種疾病之治療性 分子。該等DVD分子可結合特定疾病中所涉及之一或多種 目標。各種疾病中之該等目標之實例描述如下。 1.人類自體免疫及發炎反應 一般自體免疫及發炎反應中涉及許多蛋白質，包括C5、 CCL 1(1-3 09)、CCL11(嗜酸性粒細胞趨化因子）、 CCL13(mcp-4)、CCL15(MIP-ld)、CCL16(HCC-4)、CCL17 (TARC)、CCL18(PARC)、CCL19、CCL2(mcp-l)、CCL20 (MIP-3a)、CCL21(MIP-2)、CCL23(MPIF-1)、CCL24(MPIF-2/ 嗜酸性粒細胞趨化因子-2)、CCL25(TECK)、CCL26、 CCL3(MIP-la)、CCL4(MIP-lb)、CCL5(RANTES)、CCL7 (mcp-3)、CCL8(mcp-2)、CXCL1、CXCLIO(IP-IO)、CXCL11 (I-TAC/IP-9)、CXCL12(SDF1)、CXCL13、CXCL14、 CXCL2、CXCL3、CXCL5(ENA-78/LIX)、CXCL6(GCP-2)、CXCL9、IL13、IL8、CCL13(mcp-4)、CCR1、 CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、 CCR9、CX3CR1、IL8RA、XCRl(CCXCRl)、IFNA2、 IL10、IL13、IL17C、ILIA、IL1B、IL1F10、IL1F5、 IL1F6 、 IL1F7 、 IL1F8 、 IL1F9 、 IL22 、 IL5 、 IL8 、 IL9 、 LTA、LTB、MIF、SCYE1(内皮單核細胞活化細胞激素）、 SPP1、TNF、TNFSF5、IFNA2、IL10RA、IL10RB、 IL13、IL13RA1、IL5RA、IL9、IL9R、ABCF1、BCL6、 C3、C4A、CEBPB、CRP、ICEBERG、IL1R1、IL1RN、 IL8RB、LTB4R、TOLLIP、FADD、IRAKI 、IRAK2、 151681.doc -223 - 201127956 MYD88、NCK2、TNFAIP3、TRADD、TRAFl、TRAF2、 TRAF3、TRAF4、TRAF5、TRAF6、ACVR1、ACVR1B、 ACVR2、ACVR2B、ACVRL1、CD28、CD3E、CD3G、 CD3Z 、 CD69 、 CD80 、 CD86 、 CNR1 、 CTLA4 、 CYSLTR1 、 FCER1A 、 FCER2 、 FCGR3A 、 GPR44 、 HAVCR2 、OPRD1 、P2RX7、TLR2 、TLR3 、TLR4 、 TLR5 、 TLR6 、 TLR7 、 TLR8 、 TLR9 、 TLR10 、 BLR1 、 CCL1 、 CCL2 、 CCL3 、 CCL4 、 CCL5 、 CCL7 、 CCL8 、
CCL11 、 CCL13 、 CCL15 、 CCL16 、 CCL17 、 CCL18 、 CCL19 、 CCL20 、 CCL21 、 CCL22 、 CCL23 、 CCL24 、
CCL25、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、 CCR7 、 CCR8 、 CCR9 、 CX3CL1 、 CX3CR1 、 CXCL1 、 CXCL2、CXCL3、CXCL5、CXCL6、CXCL10、CXCL11、 CXCL12、CXCL13、CXCR4、GPR2、SCYE1、SDF2、 XCL1、XCL2、XCR1、AMH、AMHR2、BMPR1A、 BMPR1B、BMPR2、C19orflO(IL27w)、CER1、CSF1、 CSF2、CSF3、DKFZp451J0118、FGF2、GFI1、IFNA1、 IFNB1、IFNG、IGF1、ILIA、IL1B、IL1R1、IL1R2、 IL2、IL2RA、IL2RB、IL2RG、IL3、IL4、IL4R、IL5、 IL5RA ' IL6、IL6R、IL6ST、IL7、IL8、IL8RA、 IL8RB、IL9、IL9R、IL10、IL10RA、IL10RB、IL11、 IL11RA、IL12A、IL12B、IL12RB1、IL12RB2、IL13、 IL13RA1、IL13RA2、IL15、IL15RA、IL16、IL17、 IL17R、IL18、IL18R1、IL19、IL20、KITLG、LEP、 151681.doc -224- 201127956 LTA、LTB、LTB4R、LTB4R2、LTBR、MIF、NPPB、 PDGFB、TBX21、TDGF1、TGFA、TGFB1、TGFB1I1、 TGFB2 、 TGFB3 、 TGFBI 、 TGFBR1 、 TGFBR2 、 TGFBR3、TH1L、TNF、TNFRSF1A、TNFRSF1B、 TNFRSF7 、 TNFRSF8 、 TNFRSF9 、 TNFRSF11A 、 TNFRSF21、TNFSF4、TNFSF5、TNFSF6、TNFSF11、 VEGF、ZFPM2及RNF110(ZNF144)。在一態樣中，提供能 I 夠結合一或多個本文所列目標之DVD-Ig。 2.哮喘 過敏性哮喘特徵在於存在嗜伊紅血球增多、杯狀細胞化 生、上皮細胞改變、氣管過度反應（AHR)以及Th2及Thl細 胞激素表現以及血清IgE含量升高。目前廣泛認可氣管炎 症為哮喘發病機制之關鍵因素，涉及諸如T細胞、B細胞、 嗜伊紅血球、肥大細胞及巨噬細胞之發炎性細胞及其分泌 之介體（包括細胞激素及趨化因子）的複雜相互作用。皮質 φ 類固醇為當今用於哮喘之最重要的消炎治療劑，然而其作 用機制不具特異性，且存在安全性問題，尤其在青少年患 者群體中更是如此。因此有必要開發更具特異性及靶向性 之治療。愈來愈多跡象表明小鼠中之IL-13模擬許多哮喘 特徵，包括AHR、黏液分泌過多及氣管纖維化，而與嗜伊 紅血球發炎無關（Finotto 等人，International Immunology (2005), 17(8), 993-1007 ; Padilla 等人，Journal of
Immunology (2005), 174(12)，8097-8105) 〇 已暗示IL-13在引起與哮喘相關之病理學反應中起關鍵 151681.doc •225· 201127956 作用。降低IL-13在肺中之效應的抗IL-13 mAb療法之發展 為激勵人心的新方法，其作為哮喘之新穎治療具有相當大 的前景。然而，哮喘發病機制中亦涉及具有差異免疫球蛋 白路徑之其他介體，且除IL-13之外亦阻斷此等介體可提 供額外治療益處。該等目標對包括（但不限於）IL-13及促炎 性細胞激素，諸如腫瘤壞死因子-a(TNF-a)。TNF-α可增強 哮喘之發炎反應，且可能與疾病嚴重程度相關聯 (McDonnell等人，Progress in Respiratory Research (2001)， 31(New Drugs for Asthma, Allergy and COPD)，247-250.) 〇 此表明阻斷IL-13及TNF-α兩者可能具有有益作用，尤其在 嚴重氣管疾病中更是如此。在另一實施例中，本發明之 DVD-Ig結合目標IL-13及TNFa，且用於治療哮喘。 可評定炎症及AHR之動物模型（諸如OVA誘導哮喘之小 鼠模型）在此項技術中已知，且可用於測定各種DVD-Ig分 子治療哮喘之能力。用於研究哮喘之動物模型於Coffman 等人，Journal of Experimental Medicine (2005)，201(12)， 1875-1879 ; Lloyd 等人，Advances in Immunology (2001), 77，263-295 ; Boyce等人，Journal of Experimental Medicine (2005)，201(12)，1869-1873 ;及 Snibson等人，Journal of the British Society for Allergy and Clinical Immunology (2005)，3 5(2)，146-52中揭示。除對此等目標對之常規安全 性評定以外，可能有必要針對免疫抑制度進行特定測試且 其有助於選擇最佳目標對（參看Luster等人，Toxicology (1994)，92(1-3), 229-43 ; Descotes 等人，Developments in 151681.doc -226- 201127956 biological standardization (1992)，77 99-102 ; Hart 等人，
Journal of Allergy and Clinical Immunology (2001), 108(2), 250-257)。 基於本文所揭示之基本原理且使用功效及安全性之相同 評估模型，可測定DVD-Ig分子可結合且適用於治療哮喘 之其他目標對。在一實施例中，該等目標包括（但不限 於）IL-13與IL-Ιβ，因為IL-Ιβ亦涉及於哮喘之發炎反應 中；IL-13與炎症中涉及之細胞激素及趨化因子，諸如IL-13 與 IL-9 ; IL-13 與 IL-4 ; IL-13 與 IL-5 ; IL-13 與 IL-25 ; IL-13 與 TARC ; IL-13 與 MDC ; IL-13 與 MIF ; IL-13 與 TGF-β ; IL-13 與 LHR 促效劑；IL-13 與 CL25 ; IL-13 與 SPRR2a ; IL-13 與SPRR2b ; 及 IL-13與ADAM8 。 本發明亦 提供能夠結合 哮喘中涉及之一或多個目標的DVD-Ig，該（等）目標選自由 以下組成之群：CSFl(MCSF) 、CSF2(GM-CSF)、 CSF3(GCSF)、FGF2、IFNA1、IFNB1、IFNG、組織胺及 組織胺受體、ILIA、IL1B、IL2、IL3、IL4、IL5、IL6、 IL7、IL8、IL9、IL10、IL11、IL12A、IL12B、IL13、 IL14、IL15、IL16、IL17、IL18、IL19、KITLG、 PDGFB 、 IL2RA 、 IL4R 、 IL5RA 、 IL8RA 、 IL8RB 、 IL12RB1、IL12RB2、IL13RA1、IL13RA2、IL18R1、 TSLP 、 CCL1 、 CCL2 、 CCL3 、 CCL4 、 CCL5 、 CCL7 、 CCL8 、 CCL13 、 CCL17 、 CCL18 、 CCL19 、 CCL20 、 CCL22、CCL24、CX3CL1、CXCL1、CXCL2、CXCL3、 XCL1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、 151681.doc •227- 201127956 CCR8、CX3CR1、GPR2、XCRl、FOS、GATA3、JAKl、 JAK3、STAT6、TBX21、TGFB1、TNF、TNFSF6、YY1、 CYSLTR1、FCER1A、FCER2、LTB4R、TB4R2、LTBR及 殼質酶。 3.類風濕性關節炎 類風濕性關節炎（RA)為一種全身性疾病，其特徵在於關 節滑膜中之慢性發炎反應，且與軟骨退化及近關節骨侵蝕 有關。患病關節中表現包括TNF、趨化因子及生長因子之 許多促炎性細胞激素。向RA小鼠模型全身性投與抗TNF抗 體或sTNFR融合蛋白顯示消炎及關節保護。藉由靜脈内投 與英利昔單抗（Harriman G，Harper LK，Schaible TF. 1999 Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFalpha treatment. Ann Rheum Dis 58 增刊1:161-4)(—種嵌合抗TNF mAb)阻斷RA患者之TNF活 性的臨床研究已提供證據表明TNF調控IL-6、IL-8、MCP-1及VEGF產生、免疫及發炎性細胞募集至關節中、血管生 成及降低基質金屬蛋白酶1及3血液含量。類風濕性關節炎 之發炎路徑的較佳理解導致鑑別類風濕性關節炎中涉及的 其他治療目標。過去幾年中，已在隨機對照試驗中測試有 前景之治療劑，諸如介白素-6拮抗劑（由Chugai，Roche開 發之IL-6受體抗體MRA)(參看Nishimoto，Norihiro等人， Arthritis & Rheumatism (2004)， 50(6), 1761-1769)、 CTLA4Ig(阿巴西普（abatacept)，Genovese Me 等人，2005 Abatacept for rheumatoid arthritis refractory to tumor 151681.doc -228 - 201127956 necrosis factor alpha inhibition. N Engl J Med. 353:11 14-23.)及抗B細胞療法（利妥昔單抗，Okamoto H，Kamatani N. 2004 Rituximab for rheumatoid arthritis. N Engl J Med. 351:1909)。已鑑別出其他細胞激素，且已顯示其在動物模 型中具有益處，包括介白素-15(治療性抗體仙]^\-IL—15、AMG 714 ’ 參看 Baslund, Bo 等人，Arthritis & Rheumatism (2005)，52(9)，2686-2692)、介白素-17及介白 素-18’且目前正在進行此等試劑之臨床試驗。雙重特異 性抗體療法組合抗TNF及另一介體在提高臨床功效及/或患 者覆蓋範圍方面具有極大潛力。舉例而言，阻斷TNF及 VEGF可能根除炎症及血管生成，其皆涉及於ra病理生理 學中。亦涵蓋以特異性DVD Ig阻斷RA中涉及之其他目標 對，包括（但不限於）TNF與IL-18 ; TNF與IL-12 ; TNF與IL-23 ; TNF 與 IL-Ιβ ; TNF 與 MIF ; TNF 與 IL-17 ; TNF 與 IL- 1 5。除對此等目標對之常規安全性評定以外，可能有必要 針對免疫抑制度進行特定測試且其有助於選擇最佳目標對 (參看Luster 等人，Toxicology (1994)，92(1-3)，229-43 ; Descotes專人，Developments in biological standardization (1992)，77 99-102 ; Hart 等人，Journal of Allergy and Clinical Immunology (2001)，108(2)，250-257)。可使用臨 床前動物RA模型（諸如膠原蛋白誘導關節炎之小鼠模型）評 定DVD Ig分子是否將適用於治療類風濕性關節炎。其他適 用模型亦為此項技術中所熟知（參看Brand DD.，Comp Med. (2005) 55(2):114-22)。基於人類親本抗體與小鼠直系同源 151681.doc -229· 201127956 物之交又反應性（例如人類與小鼠TNF、人類與小鼠IL- 1 5 等之反應性），可以「匹配之替代抗體」產生之DVD-Ig分 子進行小鼠CIA模型中之驗證研究；簡言之’基於兩個（或 兩個以上）小鼠目標特異性抗體之0¥1)_1§可在可能的程度 上匹配用於人類DVD-Ig建構之親本人類抗體或人類化抗 體之特徵（類似親和力、類似中和效能、類似半农期等）。
4. SLE SLE之免疫病原性特點為多株B細胞活化’此導致高球 蛋白血症、產生自體抗體及形成免疫複合物。基本異常似 乎為T細胞由於全身性T細胞功能障礙而無法抑制禁忌B細 胞純系。此外，若干細胞激素（諸如IL-10)以及起始第二信 號之協同刺激分子（諸如CD40及CD40L、Β7及CD28及 CTLA-4)促進B細胞與T細胞相互作用。此等相互作用以及 免疫複合物及細胞凋亡物質的吞嗤細胞清除受損使免疫反 應及由此導致之組織損傷持續。以下目標可涉及於SLE中 且可潛在地用於供治療性干預的DVD-Ig方法中：B細胞把 向療法：CD-20、CD-22、CD-19、CD28、CD4、CD80、 HLA-DRA、IL10、IL2、IL4、TNFRSF5、TNFRSF6、 TNFSF5 、 TNFSF6 、 BLR1 、 HDAC4 、 HDAC5 、 HDAC7A、HDAC9、ICOSL、IGBP1、MS4A1、RGS1、 SLA2、CD81 、IFNB1 、IL10、TNFRSF5 、TNFRSF7、 TNFSF5、AICDA、BLNK、GALNAC4S-6ST、HDAC4、 HDAC5、HDAC7A、HDAC9、IL10、IL11、IL4、INHA、 INHBA、KLF6、TNFRSF7、CD28 、CD38 、CD69 、 151681.doc •230· 201127956 CD80、CD83 、 CD86、DPP4、FCER2、IL2RA、 TNFRSF8、TNFSF7、CD24、CD37、CD40、CD72、 CD74、CD79A、CD79B、CR2、IL1R2、ITGA2、ITGA3、 MS4A1 、 ST6GAL1 、 CD1C 、 CHST10 、 HLA-A 、 HLA-DRA及NT5E.;協同刺激信號：CTLA4或B7.1/B7.2 ;抑制 B細胞存活：BlyS、BAFF ;補體失活：C5 ;細胞激素調 節：關鍵原理在於任何組織中之淨生物反應均係促炎性細 | 胞激素或消炎細胞激素局部含量之間的平衡結果（參看 Sfikakis PP等人 2005 Curr Opin Rheumatol 17:550-7)。 SLE視作Th-2驅動之疾病，已證實其血清IL-4、IL-6、IL-10升高。亦涵蓋能夠結合一或多種選自由以下組成之群之 目標的 DVD-Ig : IL-4、IL-6、IL-10、IFN-α及 TNF-α。本 文所述之目標組合將增強針對SLE之治療功效，其可在多 種狼瘡臨床前模型中得以測試（參看Peng SL (2004) Methods Mol Med.; 102:227-72) 〇基於人類親本抗體與小鼠 φ 直系同源物之交又反應性（例如人類與小鼠CD20、人類與 小鼠干擾素a等之反應性），可以「匹配之替代抗體」產生 之DVD-Ig分子進行小鼠狼瘡模型中之驗證研究；簡言 之，基於兩個（或兩個以上）小鼠目標特異性抗體之DVD-Ig 可在可能之程度上匹配用於人類DVD-Ig建構之親本人類 抗體或人類化抗體之特徵（類似親和力、類似中和效能、 類似半衰期等）。 5.多發性硬化症 多發性硬化症（MS)為病因基本上未知之一種複雜的人類 151681.doc -231 - 201127956 自體免疫型疾病。在整個神經系統中髓鞘鹼性蛋白（mbp) 的免疫破壞為多發性硬化症之主要病理。MS為具有涉及 CD4+及CD8+ T細胞浸潤之複雜病理及中樞神經系統内之 反應之疾病。細胞激素、反應性氮物質及協同刺激分子在 CNS中之表現皆已關於MS有所描述。主要考慮因素為促進 產生自體免疫的免疫機制。詳言之，抗原表現、細胞激素 與白血球相互作用及有助於平衡/調節其他T細胞（諸如丁匕1 及Th2細胞）之調控性T細胞為治療目標鑑別之重要方面。 IL-12為由APC產生且促進Th 1效應細胞分化之促炎性細 胞激素。IL-12在罹患MS之患者正形成之病變中以及在罹 患EAE之動物體内產生。先前已展示干擾化_12路徑有效防 止齧齒動物之EAE，且使用抗il-12 mAb活體内中和IL_ 12p40對普通狨猿之髓勒誘發性eae模型中具有有益作 用。 TWEAK為TNF家族之成員，其組成性表現於中柩神經系 統（CNS)中，視細胞類型而定具有促炎性、增殖性或細胞 凋亡效應。其受體Fnl4係由内皮細胞、反應性星形膠質細 胞及神經元表現於CNS中。在實驗性自體免疫腦脊髓炎 (EAE)期間，脊髓中之tWEAK及Fnl4 mRNA表現增加。對 C57BL/6小鼠之髓鞘寡樹突神經膠質細胞醣蛋白（m〇g)誘 發之EAE進行抗TWEAK抗體治療在預致敏階段後治療小 鼠時會引起疾病嚴重程度及白血球浸潤降低。 本發明之一態樣係關於能夠結合一或多種（例如兩個）選 自由以下組成之群之目標的DVD Ig分子：、 15168I.doc •232- 201127956 TWEAK ' IL-23、CXCL13、CD40、CD40L、IL-18、 VEGF、VLA-4、TNF、CD45RB、CD200、IFNy、GM-CSF、FGF、C5、CD52及CCR2。一實施例包括雙重特異 性抗IL-12/TWEAK DVD Ig作為有益於治療MS之治療劑。 若干用於評定DVD分子治療MS之適用性的動物模型為 此項技術所已知（參看Steinman L等人，（2005) Trends Immunol. 26(11):565-71 ; Lublin FD.等人，（1985) Springer Semin Immunopathol.8(3):197-208 ; Genain CP等人，（1997) ^ J Mol Med. 75(3):187-97 ; Tuohy VK 等人，（1999) J Exp Med. 189(7):1033-42 ; Owens T 等人，（1995) Neurol Clin.13(1):51-73 ;及’t Hart BA 等人，（2005) J Immunol 175(7：):4761-8)。基於人類親本抗體與動物物種直系同源 物之交叉反應性（例如人類與小鼠1L_12、人類與小鼠 TWEAK等之反應性）’可以「匹配之替代抗體」產生之 DVD-Ig分子進行小鼠EAE模型中之驗證研究；簡言之，基 ^ 於兩個（或兩個以上）小鼠目標特異性抗體之DVD-Ig可在可 能的程度上匹配用於人類DVD-Ig建構之親本人類抗體或 人類化抗體之特徵（類似親和力、類似中和效能、類似半 衰期等）。相同概念適用於其他非齧齒動物物種之動物模 型，其中將選擇「匹配之替代抗體」產生之DVD-Ig用於 預期藥理學及可能的安全性研究°除對此等目標對之常規 安全性評定以外’有必要針對免疫抑制度進行特定測試且 其有助於選擇最佳目標對（參看Luster等人，T〇xic〇i〇gy (1994)，92(1-3)，229-43 ; Descotes 等人，Developments in 151681.doc •233- 201127956 biological standardization (1992)，77 99-102 ; J0nes r. 2000 Rovelizumab (ICOS Corp). IDrugs.3(4):442-6)。 6.敗血症 敗血症之病理生理係由革蘭氏陰性生物體（脂多醣 [LPS]、知質A、内毒素）及革蘭氏陽性生物體（脂填壁酸 (lipoteichoic acid)、肽聚糖）之外膜組分起始❶此等外膜組 分能夠結合於單核細胞表面上之CD 14受體。根據最近描 述之toll樣受體，接著將信號傳遞至細胞，導致最終產生 促炎性細胞激素腫瘤壞死因子_a(TNF_a)及介白素_1(IL_ 1)。嚴重發炎及免疫反應為敗血性休克之基本特徵，且在 由敗血症誘導之組織損傷、多器宫衰竭及死亡之發病機制 中起重要作用。細胞激素（尤其腫瘤壞死因子（TNF)及介白 素（IL-1))已經展示為敗血性休克之關鍵介體。此等細胞激 素對組織具有直接毒性作用；其亦活化磷脂酶A2。此等及 其他效應導致血小板活化因子濃度增加、促進氧化氮合成 酶活性、促進嗜中性白血球之組織浸潤及促進嗜中性白血 球活性》 對敗血症及敗血性休克之治療仍為臨床難題，且以針對 發炎反應之生物反應調節劑（亦即抗TNF、抗MIF)進行之 新近前瞻性試驗僅展示中等臨床益處。最近，關注轉向目 的在於逆轉免疫抑制伴發期之治療。對實驗動物及危重患 者之研究已表明淋巴器官及一些實質組織之細胞瑪亡增加 促成此免疫抑制、無反應性及器官系統功能障礙。在敗血 症症侯群期間，淋巴細胞細胞鴻亡可由缺乏或由釋放 151681.doc 201127956 糖皮質激素、顆粒酶或所謂之「死亡」細胞激素（即腫瘤 壞死因子α或Fas配位體）引發。細胞凋亡經由胞内及/或粒 線體卡斯蛋白酶之自體活化繼續進行，該自體活化可受 Bcl-2家族之促細胞凋亡及抗細胞凋亡成員影響。在實驗 動物中，用細胞凋亡抑制劑治療不僅可防止淋巴細胞之細 胞凋亡；其亦可改善結果。儘管對抗細胞凋亡劑之臨床試 驗在很大程度上歸因於與其投與及組織靶向相關之技術困 難而難以進行’但抑制淋巴細胞細胞凋亡代表用於敗血症 患者之有吸引力的治療目標。同樣，靶向發炎性介體及細 胞凋亡介體之雙重特異性藥劑可具有額外益處。本發明之 一態樣係關於能夠結合一或多種選自由以下組成之群的涉 及於敗血症中之目標（在一實施例，兩種目標）的DVD-Ig : TNF、IL-1、MIF、IL-6、IL-8、IL-18、IL-12、IL-23、 FasL、LPS、Toll 樣受體、TLR-4、組織因子、MIP-2、 ADORA2A、CASP1、CASP4、IL-10、IL-1B、NFKB1、 PROC、TNFRSF1A、CSF3、CCR3、IL1RN、MIF、 NFKB1、PTAFR、TLR2、TLR4、GPR44、HMOX1、中期 因子（midkine)、IRAKI、NFKB2、SERPINA1、SERPINE1 及TREM1。該等DVD Ig對於敗血症之功效可在此項技術 中已知之臨床前動物模型中評定（參看Buras JA等人， (2005) Nat Rev Drug Discov. 4(10):854-65及 Calandra T等 人，（2000) Nat Med. 6(2):164-70)。 7.神經病症 7 · 1 ·神經退化性疾病 151681.doc -235 - 201127956 慢性神經退化性__般料齡_性疾病， 於神經元功能進行性喪失（神經元細胞死亡、脫 =喪失及㈣喪失1於慢性神經退化性疾 纽海默氏病）之基礎之機制的新興知識展示複雜 : 已認可多制素造成其產生及進展，例如年齡、血糖狀 況類歲粉蛋白產生及多聚化、晚期糖基化終點產物 (AGE)(其結合其受mage(age之受體))積聚、腦氧化廣 激增加、腦血流量減少、包括發炎性細胞激素及趨化因; 之釋放的神經炎症、神經元功能障礙及微神經膠質細胞活 化。因此，此等慢性神經退化性疾病代表多種細胞類型與 介體之間的複雜相互作用。針對該等疾病之治療策略有限 且主要為用非特異性消炎劑（例如皮質類固醇、cox抑制 ⑴阻斷發炎過程或使用防止神經元喪失及/或突觸功能之 藥劑。此等治療不能終止疾病進展。新近研究表明更具乾 向性之療法（諸如針對可溶性A_b肽（包括A_b寡聚形式）之抗 體）不僅可有助於終止疾病進展且亦可有助於維持記憶 力。此等初步觀測結果表明靶向一種以上疾病介體（例如 A-b及促炎性細胞激素（諸如TNF))之特異性療法對慢性神 經退化性疾病所提供的治療功效甚至比靶向單一疾病機制 (例如單獨可溶性A-b)所觀測到之治療功效更好（參看CE.
Shepherd等人，Neurobiol Aging. 2005年 10月 24 日；Nelson RB.，Curr Pharm Des. 2005;1 1:3335 ; William L. Klein.; Neurochem Int. 2002 ;41:345 ; Michelle C Janelsins等人，j
Neuroinflammation. 2005 ；2:23 ； Soloman B., Curr 151681.doc -236- 201127956
Alzheimer Res. 2004;1:149 ; Igor Klyubin等人，Nat Med. 2005;11:556-61 ; Arancio O 等人，EMBO Journal (2004) 1-10 ; Bornemann KD 等人，Am J Pathol. 2001;158:63 ; Deane R 等人，Nat Med. 2003;9:907-13 ;及 Eliezer Masliah 等人， Neuron. 2005;46:857) ° 本發明之DVD-Ig分子可結合一或多種涉及於諸如阿茲 海默氏病之慢性神經退化性疾病中的目標。該等目標包括 (但不限於）涉及於AD發病機制中之任何可溶性或細胞表面 介體，例如AGE(S 1 00 A、兩性黴素）、促炎性細胞激素（例 如IL-1)、趨化因子（例如MCP 1)、抑制神經再生之分子（例 如Nogo、RGM A)、增強神經突生長之分子（神經營養素 (neurotrophin))。DVD-Ig分子之功效可在諸如過度表現類 澱粉前驅蛋白或RAGE且形成阿茲海默氏病樣症狀之轉殖 基因小鼠的臨床前動物模型中得以驗證。此外，可建構 DVD-Ig分子且測試其在動物模型中之功效，且可選擇最 佳治療性DVD-Ig在人類患者中進行測試。DVD-Ig分子亦 可用於治療其他神經退化性疾病，諸如帕金森氏病。α-突 觸核蛋白（Alpha-Synuclein)涉及於帕金森氏病的病理中。 能夠靶向α-突觸核蛋白及發炎性介體（諸如TNF、IL-1、 MCP-1)之DVD-Ig可證明為帕金森氏病之有效療法且涵蓋 於本發明中。 7.2神經元再生及脊髓損傷 儘管對病理機制的認識增加，但脊髓損傷（SCI)仍為一 種破壞性病狀且代表特徵在於高醫藥需求之醫學適應症。 151681.doc -237- 201127956 大多數脊髓損傷為挫傷或壓傷且原發性損傷後通常為使初 始損傷惡化且引起病變區域顯著擴大（有時ίο倍以上）之繼 發性損傷機制（發炎性介體，例如細胞激素及趨化因子）。 SCI中之此等原發性及繼發性機制與由其他方式（例如中 風）引起之腦損傷中之原發性及繼發性機制極相似β無令 人滿意之治療且高劑量快速注射曱潑尼龍 (methylprednisolone)(MP)為在損傷後8小時之窄時間窗内 使用之唯一治療。然而，此治療僅意欲預防繼發性損傷而 不引起任何顯著功能恢復。其由於缺乏明確功效且不利作 用嚴重（如免疫抑制伴有後續感染及嚴重組織病理學肌肉 改變）而受到嚴厲批評。無其他刺激内源再生潛能之藥 物、生物劑或小分子獲批准，但近年來有前景之治療原理 及藥物候選物已在SCI動物模型中展示功效。在很大程度 上’人類SCI功能恢復之缺乏係由抑制病變部位處、症痕 組織中、髓鞘中以及損傷相關細胞上之神經突生長之因子 所引起。該等因子為髓鞘相關蛋白N〇g〇A、〇Mgp及 MAG、RGM A、疤痕相關CSPG(硫酸軟骨素蛋白聚糖）及 反應性星形膠質細胞上之抑制因子（一些信號蛋白及蝶 素）。然而，在病變部位處不僅發現生長抑制性分子且亦 發現神經突生長刺激因子（如神經營養素、層黏連蛋白、 L1及其他因子）。神經突生長抑制性分子及生長促進分子 之此集合可解釋阻斷如NogoA或RGM A之單一因子會在齧 齒動物SCI模型中引起顯著功能恢復，因為減小抑制性影 響可使平衡自生長抑制作用轉向生長促進作用。然而，在 151681.doc •238- 201127956 阻斷單一神經突外生長抑制分子下觀測到之恢復不完全。 為實現更快且更顯著之恢復，可能需要阻斷兩種神經突外 生長抑制分子（例如Nogo及RGM A)，或阻斷神經突外生長 抑制分子且增強神經突外生長增強分子（例如Nogo與神經 營養素）之功能，或阻斷神經突外生長抑制分子（例如 Nogo)及促炎性分子（例如TNF)(參看McGee AW等人， Trends Neurosci. 2003;26:193 ； Marco Domeniconi 等人，J Neurol Sci. 2005;233:43 ; Milan Makwanal 等人，FEBS J. 2005;272:2628 ; Barry J. Dickson, Science. 2002; 298:1959 ; Felicia Yu Hsuan Teng 等人，J Neurosci Res. 2005;79:273 ; Tara Karnezis 等人，Nature Neuroscience 2004; 7，736 ; Gang Xu 等人，J. Neurochem.2004; 91; 1018)〇 在一態樣中，DVD-Ig能夠結合以下目標對：諸如NgR與 RGM A ; NogoA與 RGM A : MAG與 RGM A ; OMGp與 RGM A ; RGM A與RGM B ; CSPG與RGM A ;聚集蛋白聚糖 (aggrecan)、中期因子、神經蛋白聚糖（neurocan)、多功能 蛋白聚糖（versican)、填酸蛋白聚糖（phosphacan) ' Te38與 TNF-α ;提供與促進樹突及軸突萌芽之抗體組合之Αβ球聚 體特異性抗體。樹突病變為AD的極早期徵兆，且已知 NOGO a限制樹突生長。可將該類型之ab與SCI-候選物（髓 鞘-蛋白質）Ab中之任一者組合。其他DVD-Ig目標可包括
NgR-p75、NgR-Troy、NgR-Nogo66(Nog〇)、NgR-Lingo、 Lingo-Troy、Lingo-p75、MAG 或 Omgp 之任何組合。此 151681.doc • 239- 201127956 外，目標亦可包括涉及抑制神經突之任何可溶性或細胞表 面之介體’例如Nogo、Ompg、MAG、RGM A、信號蛋 白、蝶素、可溶A-b、促炎性細胞激素（例如IL-1)、趨化因 子（例如MIP 1 a)、抑制神經再生之分子。抗n〇g〇/抗RGM A 或類似DVD-Ig分子之功效可在脊髓損傷之臨床前動物模 型中得以驗證。此外，可建構此等DVD-Ig分子且測試其 在動物模型中之功效’且可選擇最佳治療性DVD-Ig在人 類患者中進行測試。此外’可建構靶向單一受體（例如結 合三種配位體Nogo、Ompg及MAG之Nogo受體以及結合A-b及 S100 A 之 RAGE)上之 兩個不 同配位 體結合位點的 DVD-Ig分子。此外，在如多發性硬化症之免疫疾病中’例如 nogo及nogo受體之神經突外生長抑制劑亦在防止神經再生 中起作用。對nogo-nogo受體相互作用之抑制已在多發性 硬化症之動物模型中展示增強之恢復。因此，可阻斷一種 免疫介體（例如細胞激素，如IL-12)及神經突外生長抑制分 子（例如nogo或RGM)功能的DVD-Ig分子可提供比單獨阻斷 免疫或神經突外生長抑制分子之功效更快且更大之功效。 8.腫瘤病症 單株抗體療法已顯現為癌症之重要治療模式（von Mehren Μ 等人，2003 Monoclonal antibody therapy for cancer. Annu. Rev. Med. 54: 343-69)。抗體可藉由誘導細 胞凋亡、重導向細胞毒性、干擾配位體-受體相互作用或 阻止對贅生性表型關鍵之蛋白質表現來發揮抗腫瘤作用。 此外，抗體可靶向腫瘤微環境之組分，擾亂重要結構，諸 151681.doc -240- 201127956
如腫瘤相關血管結構形成。抗體亦可靶向配位體為生長因 子之受體，諸如表皮生長因子受體。抗體因此抑制刺激細 胞生長之天然配位體結合於靶向之腫瘤細胞。或者，抗體 可誘導抗個體基因型網狀物、補體介導之細胞毒性或抗體 依賴性細胞毒性（ADCC)。使用靶向兩種各別腫瘤介體之 雙重特異性抗體相較於單特異性療法將可能提供額外益 處。亦涵蓋能夠結合以下目標對來治療腫瘤疾病之DVD Ig : IGF1 與 IGF2 ; IGF1/2 與 HER-2 ; VEGFR 與 EGFR ; CD20 與 CD3 ; CD138 與 CD20 ; CD38 與 CD20 ; CD38 與 CD138 ; CD40 與 CD20 ; CD138 與 CD40 ; CD38 與 CD40 ; CD-20 與 CD-19 ; CD-20 與 EGFR ; CD-20 與 CD-80 ; CD-20 與 CD-22 ; CD-3 與 HER-2 ; CD-3 與 CD-19 ; EGFR 與 HER-2 ; EGFR與 CD-3 ; EGFR與 IGF1，2 ; EGFR與 IGF1R ; EGFR 與 RON ; EGFR 與 HGF ； EGFR 與 c-MET ; HER-2 與 IGF1，2 ; HER-2 與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ; VEGF 與 HER-2 ; VEGF 與 CD-20 ; VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD20 與 CD3 ; VEGF 與 PLGF ; DLL4 與 PLGF ; ErbB3 與 EGFR ; HGF 與 ErbB3，HER-2 與 ErbB3 ; c-Met 與 ErbB3 ; HER-2與 PLGF ;及 HER-2與 HER-2。 在另一實施例中，本發明之DVD能夠結合VEGF及磷脂 醯絲胺酸；VEGF 與 ErbB3 ; VEGF 與 PLGF ; VEGF 與 R0B04 ； VEGF 與 BSG2 ; VEGF 與 CDCP1 ； VEGF 與 ANPEP ； VEGF 與 c-MET ; HER-2 與 ERB3 ； HER-2 與 151681.doc -241 - 201127956
BSG2 ; HER-2 與 CDCP1 ; HER-2 與 ANPEP ; EGFR 與 CD64 ; EGFR與 BSG2 ; EGFR與 CDCP1 ; EGFR與 ANPEP ; IGF1R與 PDGFR ; IGF1R與 VEGF ; IGF1R與 CD20 ; CD20 與 CD74 ; CD20與 CD30 ; CD20與 DR4 ; CD20與 VEGFR2 ; CD20 與 CD52 ; CD20 與 CD4 ; HGF 與 c-MET ; HGF 與 NRP1 ; HGF與磷脂醯絲胺酸；ErbB3與IGF1R ; ErbB3與 IGF1，2 ; c-Met與 Her-2 ; c-Met與 NRP1 ; c-Met 與 IGF1R ; IGF1，2與 PDGFR ; IGF1，2與 CD20 ; IGF1，2與 IGF1R ; IGF2 與 EGFR ; IGF2 與 HER2 ; IGF2 與 CD20 ; IGF2 與 VEGF ; IGF2 與 IGF1R ; IGF1 與 IGF2 ； PDGFRa 與 VEGFR2 ； PDGFRa 與 PLGF ; PDGFRa 與 VEGF ; PDGFRa 與 c-Met ; PDGFRa與 EGFR ; PDGFRb與 VEGFR2 ; PDGFRb與 c-Met ; PDGFRb 與 EGFR ; RON 與 c-Met ; RON 與 MTSP1 ; RON 與 MSP ; RON 與 CDCP1 ; VGFR1 與 PLGF ; VGFR1 與 RON ; VGFR1 與 EGFR ; VEGFR2 與 PLGF ; VEGFR2 與 NRP1 ; VEGFR2 與 RON ; VEGFR2 與 DLL4 ; VEGFR2 與 EGFR ; VEGFR2與 R0B04 ; VEGFR2與 CD55 ; LPA與 SIP ; EPHB2 與 RON ; CTLA4 與 VEGF ; CD3 與 EPCAM ; CD40 與 IL6 ; CD40 與 IGF ; CD40 與 CD56 ; CD40 與 CD70 ; CD40 與 VEGFR1 ; CD40 與 DR5 ; CD40 與 DR4 ; CD40 與 APRIL ; CD40與 BCMA ; CD40與 RANKL ; CD28與 MAPG ; CD80與 CD40 ; CD80 與 CD30 ; CD80 與 CD33 ; CD80 與 CD74 ; CD80與 CD2 ; CD80與 CD3 ; CD80與 CD19 ; CD80與 CD4 ; CD80 與 CD52 ; CD80 與 VEGF ; CD80 與 DR5 ; CD80 與 151681.doc • 242· 201127956
VEGFR2 ; CD22 與 CD20 ; CD22 與 CD80 ; CD22 與 CD40 ; CD22 與 CD23 ; CD22 與 CD33 ; CD22 與 CD74 ; CD22 與 CD19 ; CD22 與 DR5 ; CD22 與 DR4 ; CD22 與 VEGF ; CD22 與 CD52 ; CD30 與 CD20 ; CD30 與 CD22 ; CD30 與 CD23 ; CD30 與 CD40 ; CD30 與 VEGF ; CD30 與 CD74 ; CD30 與 CD19 ; CD30 與 DR5 ; CD30 與 DR4 ; CD30 與 VEGFR2 ; CD30 與 CD52 ; CD30 與 CD4 ; CD138 與 RANKL ; CD33 與 FTL3 ; CD33 與 VEGF ; CD33 與 VEGFR2 ; CD33 與 CD44 ; CD33 與 DR4 ; CD33 與 DR5 ; DR4 與 CD137 ; DR4 與 IGF1，2 ; DR4與 IGF1R ; DR4與 DR5 ; DR5 與 CD40 ; DR5 與 CD137 ; DR5 與 CD20 ; DR5 與 EGFR ; DR5 與 IGF1，2 ; DR5 與IGFR ; DR5與HER-2 ; EGFR與DLL4。其他目標組合包 括EGF/erb-2/erb-3家族中之一或多個成員。腫瘤疾病中所 涉及的DVD Ig可結合之其他目標（一或多種）包括（但不限 於）選自由以下組成之群之目標：CD52、CD20、CD19、 CD3、CD4、CD8、BMP6、IL12A、ILIA、IL1B、IL2、 IL24、INHA、TNF、TNFSF10、BMP6、EGF、FGF1、 FGF10 、 FGF11 、 FGF12 、 FGF13 、 FGF14 、 FGF16 、 FGF17、FGF18、FGF19、FGF2、FGF20、FGF21、 FGF22、FGF23、FGF3、FGF4、FGF5、FGF6、FGF7、 FGF8、FGF9、GRP、IGF1、IGF2、IL12A、ILIA、 IL1B、IL2、INHA、TGFA、TGFB1、TGFB2、TGFB3、 VEGF、CDK2、FGF10、FGF18、FGF2、FGF4、FGF7、 IGF1R、IL2、BCL2、CD164、CDKN1A、CDKN1B、 5 151681.doc •243 · 201127956 CDKN1C 、 CDKN2A 、 CDKN2B 、 CDKN2C 、 CDKN3 、 GNRH1、IGFBP6、ILIA、IL1B、ODZ1、PAWR、PLG、 TGFB1I1、AR、BRCA1、CDK3、CDK4、CDK5、CDK6、 CDK7、CDK9、E2F1、EGFR、ENOl、ERBB2、ESR1、 ESR2、IGFBP3、IGFBP6、IL2、INSL4、MYC、NOX5、 NR6A1、PAP、PCNA、PRKCQ、PRKD1、PRL、TP53、 FGF22、FGF23、FGF9、IGFBP3、IL2、INHA、KLK6、 TP53、CHGB、GNRH1、IGF1、IGF2、INHA、INSL3、 INSL4、PRL、KLK6、SHBG、NR1D1、NR1H3、NR1I3、 NR2F6 、 NR4A3 、 ESR1 、 ESR2 、 NR0B1 、NR0B2 、 NR1D2、NR1H2、NR1H4、NR1I2、NR2C1 、NR2C2、 NR2E1 、 NR2E3 、 NR2F1 、 NR2F2 、 NR3C1 、 NR3C2 、 NR4A1 、 NR4A2 、NR5A1 、NR5A2 、NR6A1 、PGR、 RARB、FGF1、FGF2、FGF6、KLK3、KRT1、APOC1、 BRCA1 ' CHGA、CHGB、CLU、COL1A1 ' COL6A1、
EGF、ERBB2、ERK8、FGF1、FGF10、FGF11、FGF13、 FGF14 、 FGF16 、 FGF17 、 FGF18 、 FGF2 、 FGF20 、 FGF21、FGF22、FGF23、FGF3、FGF4、FGF5、FGF6、 FGF7、FGF8、FGF9、GNRH1、IGF1、IGF2、IGFBP3、 IGFBP6 ' IL12A、ILIA、IL1B、IL2、IL24、INHA、 INSL3 、 INSL4 、 KLK10 、 KLK12 、 KLK13 、 KLK14 、 KLK15、KLK3、KLK4、KLK5、KLK6、KLK9、MMP2、 MMP9、MSMB、NTN4、ODZ1 、PAP、PLAU、PRL、 PSAP 、SERPINA3 、SHBG、TGFA、TIMP3 、CD44、 151681.doc -244- 201127956 CDHl、CDH10、CDH19、CDH20、CDH7、CDH9、 CDH1、CDH10、CDH13、CDH18、CDH19、CDH20、 CDH7、CDH8、CDH9、R0B02、CD44、ILK、ITGA1、 APC、CD164、C0L6A1 、MTSS1 、PAP、TGFB1I1 、 AGR2 、 AIG1 、 AKAP1 、 AKAP2 、 CANT1 、 CAV1 、 CDH12、CLDN3、CLN3、CYB5、CYC1、DAB2IP、 DES 、 DNCL1 、 ELAC2 、 EN02 、 EN03 、 FASN 、
FLJ12584 、FLJ25530 、GAGEB1 、GAGEC1 、GGT1 、 GSTP1 、HIP1 、HUMCYT2A、IL29 、K6HF、KAI1 、 KRT2A、MIB1 、PARTI 、PATE、PC A3、PIAS2、 PIK3CG、PPID、PR1 、PSCA、SLC2A2、SLC33A1 、 SLC43A1、STEAP、STEAP2、TPM] 、TPM2、TRPC6、 ANGPT1、ANGPT2、ANPEP、ECGF1、EREG、FGF1、 FGF2、FIGF、FLT1 、JAG1 、KDR、LAMA5、NRP1、 NRP2、PGF、PLXDC1、STAB1、VEGF、VEGFC、 ANGPTL3、BAI1、COL4A3、IL8、LAMA5、NRP1、 NRP2、STAB1、ANGPTL4、PECAM1、PF4、PROK2、 SERPINF1 、TNFAIP2 、CCL11 、CCL2 、CXCL1 、 CXCL10、CXCL3、CXCL5、CXCL6、CXCL9、IFNA1、 IFNB1、IFNG、IL1B、IL6、MDK、EDG1、EFNA1、 EFNA3、EFNB2、EGF、EPHB4、FGFR3、HGF、IGF1、 ITGB3、PDGFA、TEK、TGFA、TGFB1、TGFB2、 TGFBR1 、CCL2、CDH5、C0L18A1 、EDG1 、ENG、 ITGAV 、 ITGB3 、 THBS1 、 THBS2 、 BAD 、 BAG1 、 151681.doc - 245 - 201127956
BCL2、CCNAl、CCNA2、CCNDl、CCNEl、CCNE2、 CDH1(E-鈣黏素）、CDKNlB(p27Kipl) 、 CDKN2A (pl6INK4a)、COL6A1、CTNNBl(b-索烴素）、CTSB(組織 蛋白酶 B)、ERBB2(Her-2)、ESR1、ESR2、F3(TF)、 FOSLl(FRA-l)、GATA3、GSN(膠溶素）、IGFBP2、 IL2RA、IL6、IL6R、IL6ST(醣蛋白 130)、ITGA6(a6整合 素）、JUN、KLK5、KRT19、MAP2K7(c-Jun)、MKI67(Ki-67)、NGFB(NGF)、NGFR、NME1(NM23A)、PGR、 PLAU(uPA)、PTEN、SERPINB5(乳腺絲抑蛋白）、 SERPINEl(PAI-l)、TGFA、THBS1(血小板反應蛋白-1)、 TIE(Tie-l)、TNFRSF6(Fas)、TNFSF6(FasL)、TOP2A(拓撲 異構酶Iia)、TP53、AZGP1(鋅-a-醣蛋白）、BPAG1(網蛋白 (plectin))、CDKNlA(p21Wapl/Cipl)、CLDN7(緊密連接蛋 白-7(claudin-7))、CLU(凝聚素（。11!3161^11))、£11632(1161·-2)、FGF1、FLRT1(纖維結合蛋白）、GABRP(GABAa)、 GNAS1、ID2、ITGA6(a6 整合素）、ITGB4(b 4 整合素）、 KLF5(GC Box BP)、KRT19(角蛋白 19)、KRTHB6(毛髮特 異性II型角蛋白）、MACMARCKS、MT3(金屬硫蛋白-Ill(metallothionectin-III))、MUC1(黏蛋白）、卩丁082((：0乂-2) 、RAC2(p21Rac2) 、 S100A2 、 SCGB1D2(親脂素 B (lipophilin B))、SCGB2A1(乳腺珠蛋白 2(mammaglobin 2))、SCGB2A2(乳腺珠蛋白 1)、SPRRlB(Sprl)、THBS1、 THBS2、THBS4、及 TNFAIP2(B94)、RON、c-Met、 CD64、DLL4、PLGF、CTLA4、磷脂醯絲胺酸、R0B04、 151681.doc -246- 201127956 CD80、CD22、CD40、CD23、CD28、CD80、CD55、 CD38、CD70、CD74、CD30、CD138、CD56、CD33、 CD2、CD137、DR4、DR5、RANKL、VEGFR2、PDGFR、 VEGFR1、MTSP1、MSP、EPHB2、EPHA1、EPHA2、 EpCAM、PGE2、NKG2D、LPA、SIP、APRIL、BCMA、 MAPG、FLT3、PDGFRa、PDGFRp、ROR1、PSMA、 PSCA、SCD1 及 CD59。 IV.醫藥組合物 本發明亦提供包含本發明結合蛋白及醫藥學上可接受之 載劑的醫藥組合物。包含本發明結合蛋白之醫藥組合物係 用於（但不限於）診斷、偵測或監測病症；預防、治療、處 理或改善病症或其一或多種症狀；及/或研究。在一特定 實施例中，組合物包含一或多種本發明結合蛋白。在另一 實施例中，醫藥組合物包含一或多種本發明結合蛋白及除 本發明結合蛋白以外的一或多種用於治療病症的預防劑或 治療劑。在一實施例中，已知預防劑或治療劑適用於或已 用於或目前正用於預防、治療、處理或改善病症或其一或 多種症狀。根據此等實施例，組合物可進一步包含載劑、 稀釋劑或賦形劑。 本發明之結合蛋白可併入適於向個體投與之醫藥組合物 中。通常，醫藥組合物包含本發明之結合蛋白及醫藥學上 可接受之載劑。如本文所用之「醫藥學上可接受之載劑」 包括在生理學上相容之任何及所有溶劑、分散介質、包 衣、抗細菌劑及抗真菌劑、等張及吸收延遲劑及其類似 151681.doc -247- 201127956 物醫藥學上可接受之載劑的實例包括 —臨^ _貫例包括水、鹽水、磷酸鹽 '孤 右旋糖、甘油、乙醇及其類似物中之一或多者 以及其組合。在一些實施例中’組合物中包括等張劑，例 :糖；諸如甘露糖醇、山梨糖醇之多元醇；或氣化鈉。醫 樂學上可接受之載劑可進-步包含微量輔助物質，諸如濕 潤劑或乳化劑、防㈣或緩衝液，其增強抗體或抗體部分 之存放期或有效性。 各種傳遞系統為已知的且可用於投與一或多種本發明抗 體或一或多種本發明抗體與適用於預防、處理、治療或改 善病症或其一或多種症狀之預防劑或治療劑的組合，例如 囊封於脂質體、微粒、微膠囊中；可表現抗體或抗體片段 之重組細胞；受體介導之内飲作用（參看例如Wu及Wu，J.
Biol. Chem. 262:4429-4432 (1987));建構作為反轉錄病毒 或其他載體之一部分之核酸等。投與本發明之預防劑或治 療劑的方法包括（但不限於）非經腸投與（例如皮内、肌肉 内、腹膜内、靜脈内及皮下）、硬膜外投與、腫瘤内投與 及黏膜投與（例如鼻内及經口途徑）。此外，可例如藉由使 用吸入器或喷霧器及具有氣霧劑之調配物使用肺部投與。 參看例如美國專利第6,019,968號；第5,985,320號；第 5,985,309 號；第 5,934,272 號；第 5,874,064 號；第 5,855,913號；第 5,290,540號及第 4,880,078號；及卩(：丁公開 案第 WO 92/19244號；第 WO 97/32572號；第 WO 97/44013 號；第WO 98/3 1346號；及第WO 99/66903號，其各自以 全文引用的方式併入本文中。在一實施例中’使用 151681.doc • 248· 201127956
Alkemes AIR®肺部藥物傳遞技術（Alkermes，⑻， Cambridge，Mass.)投與本發明之結合蛋白、組合療法或本 發明之組合物。在一特定實施例中，肌肉内、靜脈内、腫 瘤内、經口、鼻内、肺部或皮下投與本發明之預防劑或治 療劑。預防劑或治療劑可藉由任何適宜途徑，例如藉由輸 注或快速注射、藉由經上皮或皮膚黏膜内層（例如口腔點 膜、直腸及腸黏膜等）吸收投與且其可與其他生物活性劑 φ 一起投與。投與可為全身性或局部投與。 在一實施例中，可使用如下方法靶向腫瘤細胞：使偶合 抗體之碳奈米管（CNT)在活體外特異性結合於腫瘤細胞， 隨後用近紅外（NIR)光對其進行高特異性切除術。舉例而 言，可使用經生物素標記之極性脂質來製備穩定、生物相 容性、無細胞毒性之CNT分散液，接著使其連接於一或兩 種針對一或多種腫瘤抗原（例如CD22)之不同neutrame抗生 物素蛋白衍生之DVD-Ig上（Chakravarty，P·等人，（2〇〇8) # Proc· Nat1· Acad. Sci. USA 105:8697-8702)。 在一特定實施例中，可能需要向需要治療之區域局部投 與本發明之預防劑或治療劑；此可藉由例如（但不限於）局 邙輸庄、注射或藉助於植入物（該植入物為多孔或非多孔 材料，包括膜及基質，諸如矽橡膠膜（siaUstic membrane)、聚合物、纖維基質（例如Tissuel®)或膠原蛋白 基質)實ί見纟-實施例中，向個體之患病區域局部投與 有效量之一或多種本發明抗體拮抗劑以預防、治療、處理 及/或改善病症或其症狀。在另一實施例十，向個體之患 151681.doc -249- 201127956 病區域局部投與有效量之一或多種本發明抗體與有效量之 一或多種除本發明結合蛋白以外的療法（例如一或多種預 防劑或治療劑）的組合以預防、治療、處理及/或改善病症 或其一或多種症狀。
在另一貫施例中，預防劑或治療劑可以控制釋放或持續 釋放系統傳遞。在一實施例中，可使用泵來實現控制釋放 或持續釋放（參看Langer ’同上文；Sefton, 1987，CRC
Crit· Ref. Biomed. Eng. 14:20 ; Buchwald 等人，1980, Surgery 88:507 ; Saudek等人，1989，Ν· Engl. J. Med· 321:574) »在另一實施例中’可使用聚合材料來實現本發 明療法之控制釋放或持續釋放（參看例如Medical
Applications of Controlled Release, Langer 及 Wise (編）， CRC Pres.，Boca Raton，Fla. (1974) ; Controlled Drug
Bioavailability, Drug Product Design and Performance, Smolen及 Ball (編），Wiley, New York (1984) ; Ranger及 Peppas，1983，J.，Macromol. Sci. Rev. Macromol. Chem. 23:61 ;亦參看 Levy 等人，1985, Science 228:190 ; During 等 人，1989, Ann. Neurol. 25:351 ; Howard 等人，1989，】· Neurosurg. 7 1:105 ;美國專利第5,679,3 77號；美國專利第 5,916,597號；美國專利第5,912,015號；美國專利第 5,989,463號；美國專利第5，128,326號；PCT公開案第WO 99/15154號；及PCT公開案第WO 99/20253號）。持續釋放 調配物中使用之聚合物的實例包括（但不限於）聚（甲基丙烯 酸2-羥乙酯）、聚（甲基丙烯酸曱酯）、聚（丙烯酸）、聚（乙 •250- 151681.doc 201127956
烯-共-乙酸乙烯酯）、聚（甲基丙烯酸）、聚乙交酯（PLG)、 聚酸酐、聚（N-乙烯基吡咯啶酮）、聚（乙烯醇）、聚丙烯醯 胺、聚（乙二醇）、聚丙交酯（PLA)、聚（丙交酯-共-乙交 酯）(PLGA)及聚原酸酯。在一實施例中，持續釋放調配物 中使用之聚合物為惰性的、不含可浸出雜質、儲存穩定、 無菌且生物可降解。在另一實施例中，控制釋放或持續釋 放系統可鄰近預防或治療目標置放，因此僅需要全身劑量 之一部分（參看例如 Goodson, Medical Applications of Controlled Release,同上文，第 2 卷，第 115-138 頁 (1984))。 控制釋放系統於Langer之評述（1990，Science 249:1527-1 533)中論述。可使用熟習此項技術者已知之任何技術製 備包含一或多種本發明治療劑之持續釋放調配物。參看例 如美國專利第4,526,938號；PCT公開案WO 91/05548 ; PCT公開案 W0 96/20698 ; Ning等人，1996， 「Intratumoral
Radioimmunotheraphy of a Human Colon Cancer Xenograft Using a Sustained-Release Gel,」Radiotherapy & Oncology 39:179-189 ; Song等人，1995, 「Antibody Mediated Lung Targeting of Long-Circulating Emulsions,」PDA Journal of Pharmaceutical Science & Technology 50:372-39 ; Cleek等 人，1997，「Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular Application，」 Pro. Int'l. Symp. Control. Rel. Bioact. Mater· 24:853-854 ;及 Lam 等 人， 1997， 「 Microencapsulation of Recombinant 151681.doc -251 - 201127956
Humanized Monoclonal Antibody for Local Delivery,」 Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760， 其各自以全文引用的方式併入本文中。 在本發明組合物為編碼預防劑或治療劑之核酸的特定實 施例中，可藉由將核酸建構為適當核酸表現載體之一部 分’且例如藉由使用反轉錄病毒載體（參看美國專利第 4,980,2 86號）或藉由直接注射或藉由使用微粒轟擊（例如基 因搶；Biolistic，Dupont)或以脂質或細胞表面受體或轉染
劑包覆，或藉由將其與已知進入核之同源盒樣肽鍵聯投與 (參看例如 Joliot等人’ 1991, Pr〇c NaU Acad. Sci uSA 88.1864-1868)將其投與以使其變為在細胞内，來活體内投 與核酸以促進其所編碼之預防劑或治療劑表現。或者，可 將核S文引入胞内且藉由同源重組使其併入宿主細胞中 以供表現。 〜配本發明之醫藥組合物使其與其預定投與途徑相容。 投與途徑之實例包括(但不限於)非經腸，例如靜脈内、皮 内、皮下、經口、鼻内（例如吸入）、經皮（例如局部）、經 黏膜，及直腸投盘。尤—4* . ι_ 一 在特疋貫施例中，組合物係根據常 規程序調配為適於靜脈内、皮下、肌肉内、經Π、鼻内或 局部投與人類之醫藥組合物。通常，用於靜脈内投與之組 =物為於無菌等張水性緩衝液中之溶液。需要時，组合物 ’、可包括增㈣及局部麻醉劑（諸如㈣相⑴g騰a—) 以減輕注射部位之疼痛。 若欲局部投與本發明組合物，則組合物可調配為軟膏、 151681.doc 201127956 乳膏、經皮貼片、洗劑、凝膠、洗髮精、噴霧劑、氣霧 劑、溶液、乳液之形式或熟習此項技術者熟知之其他形 式。參看例如 Remingtonis Pharmaceutical Sciences and
Introduction to Pharmaceutical D0sage Forms，第 19 版，
Mack Pub. Co.，Easton，Pa· (1995)。在一實施例中，對於 不可喷霧之局部劑型而言，使用包含與局部施用相容之載 劑或一或多種賦形劑且動力黏度大於水之黏稠形式至半固
體或固體形式。適合調配物包括（但不限於）溶液、懸浮 液、乳液、乳膏、軟膏、散劑、擦劑、油膏及其類似物， 必要時將其減菌或與影響諸如滲透壓之各種特性之助劑 (例如防腐劑、穩定劑、濕潤劑、緩衝液或鹽）混合。其他 適合局部_包括可喷霧之氣霧劑製劑，纟中在—實施例 中’活性成分與固體或液體惰性載劑組合以與加壓揮發性 物質(例如氣體推進劑，諸如氟利昂之混合物形式 封裝或封裝於擠壓報（squeeze⑽叫中。必要時，亦可向 醫藥組合物及劑型中添加增濕劑或保濕劑。該等其他成分 之實例為此項技術中所熟知。 刀 =發明方法包含鼻内投與組合物，則組合物可調配成 乳霧劑形式、喷霧劑、薄霧或滴劑形式。詳言《， 發：使用之預防劑或治療劑可使用適合推進劑(例如二氣 二曱烷-乳氟曱烷、二氣四氟乙烷、二氧化碳戈1他 適合氣體㈣丨喷^現形式自加壓包裝或 二遞。在加壓氣霧劑之情形下，可藉由提供閱門二 疋Ο卓位以傳遞計量之量。可調配含有化合物與諸如乳 1516Sl.doc -253 - 201127956 糖或澱粉之適合粉末基劑之粉末混合物的膠囊及藥筒(由 例如明膠構成）用於吸入器或吹入器。 若本發明方法包含經口投與，則組合物可調配為經口之 旋劑、膠囊、扁膠劑、膠囊錠（gelcap)、溶液、懸浮液及 其類似物之形式。錠劑或膠囊可藉由習知方式用醫藥學上 可接又之賦形劑製備，該等賊形劑諸如黏合劑（例如預勝 凝化玉米殿粉、聚乙稀対唆酮或㈣基甲基纖維素）； 填充劑（例如礼糖、微晶纖維素或鱗酸氯辦）；潤滑劑（例如 硬脂酸鎂、滑石或石夕石）；崩解劑（例如馬鈴薯殿粉或乙醇 酉文羸粕鈉）’或濕潤劑（例如十二烷基硫酸鈉）。錠劑可藉由 此項技術中熟知之方法包覆。用於經口投與之液體製劑可 採=(但不限於）溶液 '糖漿或懸浮液形式，或其可以在使 用引乂尺或其他適合媒劑復原之乾燥產品形式提供。該等 液體製劑可藉由習知方式用醫藥學上可接受之添加劑來製 備，該等添加劑諸如懸浮劑(例如山梨糖醇糖漿 '纖維素 衍生物或氫化可食用脂肪）；乳化劑（例如卵磷脂或阿拉伯 膠）；非水性媒劑（例如杏u、油性醋、乙醇或經分德之 植物油）；及防腐劑（例如對羥基苯甲酸甲酯或對羥基苯甲 酸丙醋或山梨酸卜適當時’製劑亦可含有緩衝鹽、調味 劑、者色劑及甜味劑。經口投與之製劑可經適當調配以供 緩慢釋放、控制釋放或持續釋放預防劑或治療劑。 本發明方法可包含例如藉由使用吸人器或喷霧器肺部投 與與氣霧劑一起調配之組合物。參看例如美國專利第 6’019’968 號’帛 5’985,320 號；第 5,985,309 號；第 151681.doc •254- 201127956 5,934,272 號；第 5,874,064 號；第 5,855,913 號；第 5,290,540號及第4,880,078號；及PCT公開案第WO 92/19244號；第 WO 97/32572號；第 WO 97/44013 號；第
WO 98/3 1346號；及第WO 99/66903號，其各自以全文引 用的方式併入本文中。在一特定實施例中，使用Alkermes AIR® 肺部藥物傳遞技術（Aikermes，Inc.，Cambridge, Mass.)投與本發明結合蛋白、組合療法及/或本發明組合 物。 本發明方法可包含藉由注射（例如藉由快速注射或連續 輪1注）投與經調配用於非經腸投與之組合物。用於注射之 調配物可以添加有防腐劑之單位劑型（例如於安瓿中或於 多劑量容器中）提供。組合物可採取諸如於油性或水性媒 劑中之懸淨液、溶液或乳液之形式且可含有諸如懸浮劑、 穩定劑及/或分㈣之調配劑。或者，活性成分可為在使 用前以適合媒劑(例如無菌無熱原質水)復原之粉末形式。 本發明方法可另外包含投與調配為儲槽式製劑之組合 物。該等長效調配物可藉由植入(例如皮下或肌肉内)或藉 由肌肉内注射來投與。因此，例如組合物可與適合聚合或 二"生物質(例如調配為可接受之油中之乳液)或與離子交 換樹脂一起調配；或調配成 鹽）。 合订生物（例如調配為微溶 本發明方法涵蓋投與調配為中性或鹽 藥學上可接為+BSA 孤乂式之，’且σ物。醫 樂予上了接受之鹽包括與陰離子 趟 # 酸、磷酸、乙酸、草酸 S ’诸如衍生自鹽 屑石馱專之鹽；及與陽離子 151681.doc •255- 201127956 衍生自氫氧化納、氫氧化卸、氫氧化 二氫氧化鐵、異丙胺、“胺、2·乙基胺基乙醇: 胺1、’日魯卡因等之鹽。 ° 一般而言，組合物之成分單獨 .,,,本 卞謂4 M成合在一起之單位劑 型（例如以乾燥凍乾粉末或 ^ 夕旦… 物末或無水濃縮物形式)於指示活性劑 里之密封容器（諸如安瓶哎藥壸、由坦/ Μ昧“人 女瓶切囊）中提供。當投與模式為 月’w時，，且&物可以含有無菌 ^ . 樂趿水或鹽水之輸液瓶分 配° S才又與模式為注射時， 〜 提仏注射用無菌水或鹽水之 女瓿以便可在投與之前混合成分。 詳言之，本發明亦提供一式客 制—、Μ 一 、次種本發明之預防劑或治療 劑或4樂組合物封裝於指藥 、 里之密封容器（諸如安 訊或樂囊）中。在_眘丨+ ' ，—或多種本發明之預防劑 或>D療劑或醫藥組合物係乾 ^ 東乾粉末或無水濃縮 W 7t/八义在封谷裔中提 再了设原（例如用水或鹽水）成 適“度以向個體投與。在-實施例中，-或多種本發明 t預防劑或治療劑或醫藥組合物係以乾燥無菌綠粉末形 式，以至少5 mg、至少10 m 6 王夕15 mg、至少25 mg、 至少hmg、至少45mg、至少5〇叫、至少75叫或至少 100 mg之單位劑量於密封容器中提供。本發明之束乾預防 劑或治療劑或醫藥組合物應在其初始容器中在代至代下 儲存，且本發明之預_或治療劑或醫藥組合物應在復原 後1週内’例如5天内、72小時内、48小時内、Μ小時内、 12小時内、6小時内、5小時内、3小時内❹小時内投與。 在替代!生實施例中，一或多種本發明之預防劑或治療劑 151681.doc •256· 201127956 或醫藥組合物係以液體形式龙^ _ 一 飞於心不樂劑之量及濃度的密封 谷益中提供。在一實施例中，Λ k 所投與組合物之液體形式係 以至少0.25mg/ml、至少“ g 主^ 〇.5 mg/m卜至少1 mg/m卜至少 2·5 mg/ml、至少 5 mg/ml、至少 8 mg/m卜至少 10 mg/mI、 至少15 mg/kg、至少25 mg/ml、至少5〇叫㈤、至少μ 叫編或至少議mg/ml於密封容器中提供。液體形式應在 其初始容器中在2。(：至8°C下儲存。
本發明：合蛋白可併入適於非經腸投與之醫藥組合物 中。在-實施例中’抗體或抗體部分將製備為含有〇1至 250 mg/ml結合蛋白之可注射溶液。可注射溶液可由燒石 或琥珀色小瓶、安瓿或預填充注射器中之液體或凍乾劑型 構成。緩衝液可為L-組胺酸（1至5〇 mM)，最佳5至1〇 mM，pH值為5.0至7·〇(最佳為pH 6 〇)。其他適合緩衝液包 括（但不限於）丁二酸鈉、擰檬酸鈉、磷酸鈉或磷酸鉀。可 使用濃度為0至300 mM(對於液體劑型而言最佳為15〇 mM) 之氯化鈉來調節溶液毒性。對於凍乾劑型而言可包括低溫 保護劑，主要為0至10%蔗糖（最佳為〇 5%至】〇%)。其他適 合低溫保護劑包括海藻糖及乳糖。對於凍乾劑型而言可包 括增積劑，主要為1%至10%甘露糖醇（最佳為2%至4%)。 液體與凍乾劑型中均可使用穩定劑，主要為1至5〇mML_ 曱硫胺酸（最佳為5至10 mM)。其他適合增積劑包括甘胺 酸、精胺酸（可包括0至0.05%)、聚山梨醇酯8〇(最佳為 0.005%至0.01%)。其他界面活性劑包括（但不限於）聚山梨 醇酯20及BRIJ界面活性劑。製備成用於非經腸投與之可注 151681.doc -257· 201127956 射溶液的包含本發明之結合蛋白的醫藥組合物可進一步包 含適用作佐劑之藥劑’諸如用於增加治療性蛋白質（例如 抗體）之吸收或分散的藥劑。尤其適用之佐劑為玻尿酸 轉’諸如Hylenex⑧（重組人類玻尿酸酶）。在可注射溶液中 添加玻尿酸酶在非經腸投與後’尤其皮下投與後改良人類 生物可用性。其亦允許較大注射部位體積（亦即大於1 ml) 以及使疼痛及不適較少，及注射部位反應發生率最低。 (參看以引用的方式併入本文中之W〇 2〇〇4〇7814〇及us 2006104968)。 本發明組合物可呈多種形式。此等形式包括例如液體、 半固體及固體劑型，諸如液體溶液（例如可注射溶液及可 輸/主/谷液）刀散液或懸浮液、鍵劑、丸劑、散劑、脂質 體及栓劑。所選形式視投與及治療應用之預定模式而定。 典型組合物為可注射或可輸注溶液形式，諸如類似於彼等 以其他杬體使人類被動免疫所用之組合物的組合物。所選 投與模式為非經腸（例如靜脈内、皮下、腹膜内、肌肉内） 模式。在一實施例中，藉由靜脈内輸注或注射來投與抗 在另實施例中，抗體係藉由肌肉内或皮下注射投 與。 A療、、且13物在製造及儲存條件下通常須無菌且穩定。組 ° :可調配為溶液、微乳液、分散液、脂質體或適於高藥 物艰度之其他有序結構。可藉由將所要量之活性化合物 (:即抗體或抗體部分）連同本文列舉之一種成分或該等成 刀之、’且0併入適當溶劑中，接著根據需要過濾滅菌來製備 151681.doc 201127956
無菌可注射溶液。-般而言，藉由將活性化合物併入含有 基本分散介質及來自本文所列舉之成分之所要其他成分的 無菌媒劑中來製備分散液。在用於製備無菌可注射溶液之 無菌珠乾粉末之情形下，製備方法為真空㈣及喷霧乾 燥，、產生活[生成分加來自其先前無菌過濾之溶液的任何 其他所要成分之粉纟。可例如藉由使用諸如卵磷脂之衣 料，藉由維持所要粒度（在分散液情形下），及藉由使用界 面活性劑來維持溶液之適當流動性。可注射組合物之延長 吸收可藉由在組合物中包括延緩吸收之藥劑（例如單硬脂 酸鹽及明膠）來達成。 可藉由此項技術中已知之多種方法投與本發明之結合蛋 白，但在一實施例中，對於許多治療應用而言，投與途徑/ 模式為皮下注射、靜脈内注射或輸注。如熟習此項技術者 所應瞭解，投與途徑及/或模式將視所要結果而變化。在 某些實施例中，活性化合物可與防止化合物快速釋放之載 劑一起製備，諸如控制釋放調配物，包括植入物、經皮貼 片及微囊封傳遞系統。可使用生物可降解、生物相容性聚 合物，諸如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、膠原蛋 白、^^原酸酿及聚乳酸。製備該等調配物之許多方法均已 取得專利權或通常為熟習技術者所已知。參看例如 Sustained and Controlled Release Drug Delivery Systems J.R. Robinson編，Marcel Dekker, Inc·, New York, 1978。 在某些實施例十，本發明之結合蛋白可例如與惰性稀釋 劑或可吸收之可食用載劑一同經口投與。化合物（必要時 lS1681.doc -259- 201127956 連同其他成分）亦可封閉於硬殼或軟殼明膠膠囊中，壓製 為錠劑或直接併入至個體飲食中，對於經口治療性投與而 言，化合物可併有賦形劑且以如下形式使用：可攝入錠 劑、經頰錠劑、糖衣鍵、膠囊、酿劑、懸浮液、糖漿、粉 片（wafer)及其類似形式。為了藉由非經腸投與之外的方式 投與本發明化合物，可能需要將化合物以防止其失活之材 料包覆或將化合物與防止其失活之材料共同投與。 補充活性化合物亦可併入組合物中。在某些實施例中， 將本發明之結合蛋自與—或多種適用於與本發明結合蛋白 -起治療病症的其他治療劑共調配及/或共投與。舉例而 言，可將本發明之結合蛋白與一或多種結合其他目標之其 他抗體（例如結合其他細胞激素或結合細胞表面分子之抗 體）共調配及/或共投與。此外，—或多種本發明抗體可與 兩種或兩種以上上述治療劑組合使用。該等組合療法可適 宜地利用較低劑量之所投與治療劑，從而避免與各種單一 療法相關之可能毒性或併發症。 在某些實施例中，將結合蛋白連接於此項技術中已知的 延長半衰期之媒劑。該等媒劑包括(但不限於W區域、聚 乙二醇及聚葡萄糖。該等媒介於例如美國申請案第 0⑽M82號及公開之PCT申請案第w〇 99/25〇44號令描 述，其為任何目的以弓丨用的方式併入本文中。 在-特定實施例中，投與料本發明結合蛋白或本發明 之另-預防劑或治療劑的核酸序列以藉助於基因… 療、預防、處理或改善病症或其-或多種症狀。基因療^ J51681.doc -260- 201127956 係指藉由向個體投與已表現或可表現之核酸執行之療法。 在本發明之此實施例中，核酸產生介導預防或治療作用之 其所編碼之本發明之抗體或預防劑或治療劑。 可根據本發明使用此項技術中可利用之用於基因療法的 任何方法。關於基因療法之方法的综述參看Goldspiel等 人，1993，Clinical Pharmacy 12:488-505 ; Wu及 Wu，1991,
Biotherapy 3:87-95 ； Tolstoshev, 1993, Ann. Rev.
Pharmacol. Toxicol. 32:573-596 ； Mulligan, Science 260:926- 932 (1993);以及Morgan&Anderson，1993，Ann. Rev. Biochem. 62:191-217 ; 1993 年 5 月，TIBTECH 11(5):15 5-215。可使用之重組DNA技術之領域中通常已知 的方法於 Ausubel 等人（編），Current Protocols in Molecular Biology，John Wiley & Sons, NY (1993);及 Kriegler，Gene
Transfer and Expression, A Laboratory Manual, Stockton
Press，NY (1990)中描述。基因療法之各種方法的詳細描述 於以引用的方式併入本文中的us 2〇〇5〇〇42664 Ai中揭 示。 本發明之結合蛋白適用於治療該等結合蛋白所識別之目 :有°的各種疾病。該等疾病包括（但不限於）類風濕性關 郎炎、骨關節炎、青少年慢性關節炎、敗A性關節炎、萊 姆關郎久、牛皮癬性關節炎、反應性關節炎、脊椎關節 病,、全身性紅斑狼瘡症、克羅恩氏病、潰癌性結腸炎、發 炎i·生腸病、胰島素依賴性糖尿病、甲狀腺炎、哮喘、過敏 ^疾病4皮癬、皮膚炎硬皮病' 移植物抗宿主疾病、器 151681.doc -261 - 201127956 官移植排斥反應、與器官移植有關之急性或慢性免疫疾 病、肉狀瘤病、動脈粥樣硬化、散播性血管内凝血、川崎 氏病、格雷氏病、腎病症候群、慢性疲勞症候群、韋格納 氏肉芽腫病、亨偌-絲奇恩賴紫癜、腎顯微性血管炎、慢 性活動型肝炎、葡萄膜炎、敗血性休克、中毒性休克徵^ 群、敗血症症候群、惡病質、感染性疾病、寄生蟲病、後 天免疫缺乏症候群、急性橫貫性脊髓炎、亨廷頓氏舞蹈 病、帕金森氏病、阿兹海默氏病、中風、原發性膽汁性= 硬化、溶血性貧血、惡性病、心臟衰竭、心肌梗塞、艾迪 森氏病、偶發性I型多腺體分泌不足症及„型多腺體分泌不 足症、施密特氏症候群、成人（急性）呼吸窘迫症候群、脫 髮、斑形脫髮、血清陰性關節病、關節病、萊特爾氏病、 牛皮癬性關節病、潰瘍性結腸炎關節病、腸病性滑膜炎、 披衣菌、耶氏桿菌及沙門氏菌相關之關節病、脊椎關節 病、動脈粥樣瘤病/動脈硬化、異位性過敏、自體免疫大 跑病、尋常天癌瘡、葉狀天疱瘡、類天疱瘡、線狀igA 病、自體免疫溶血性貧血、庫姆氏陽性溶血性貧血、後天 惡性貧血、青少年惡性貧血、肌痛腦炎/皇家自由病、慢 性皮膚黏膜念珠菌病、巨細胞動脈炎、原發性硬化性肝 炎、原因不明性自體免疫肝炎、後天免疫缺乏疾病症候 群、後天免疫缺乏相關疾病、8型肝炎、C型肝炎、常見 變異性免疫缺之（常見變異性似球蛋白血症）、擴張性心肌 病、雌性不孕症1巢功能衰竭、卵巢早衰、纖維變性肺 病、原因不明性纖維性肺泡炎、發炎後間質性肺病、間質 I51681.doc 201127956 性肺炎、結締組織病相關之間質性肺病、混合結締组織病 相關之肺$、全身性硬化症相關之間質性肺冑、類風濕性 關節炎相關之間質性肺病、全身性紅斑狼瘡症相關:肺 病、皮肌炎/多發性肌炎相關之肺病、休格連氏病相關之 肺病、僵直性脊椎炎相關之肺病、血.管炎擴散性肺病、含 鐵血黃素沈積症相關之肺病、藥物誘發之間質性肺病、纖 維化、放射性纖維化、閉塞性細支氣管炎、慢性嗜伊红血 籲㈣肺炎、淋巴球浸潤性肺病、感染後間質性肺二、痛風 性關節炎、自體免疫性肝炎、i型自體免疫性肝炎（經典自 體免疫或類狼瘡性肝炎）、2型自體免疫性肝炎（抗lkm抗 體肝炎）' 自體免疫介導之低企糖症、B型騰島素抗性伴發 黑色棘皮病、副曱狀腺低能症、與器官移植有關之急性免 疫疾病、與器官移植有關之慢性免疫疾病、骨性關節病、 原發性硬化性膽管炎、i型牛皮癖、2型牛皮癬、特發性白 血球減少病、自體免疫性嗜中性球減少症、N〇s型腎病、 镛血管球性腎炎、賢顯微性血管炎、萊姆病、盤狀紅斑狼 瘡、特發性或NOS型雄性不育症、精子自體免疫、多發性 硬化症（所有次型）、交感性眼炎、結締組織病繼發之肺循 環血壓過高、古巴士德氏症候群、結節性多動脈炎之肺表 現形式、急性風濕熱、類風濕性脊椎炎、史提爾氏病、全 身性硬化症、休格連氏症候群、高安氏病/動脈炎、自體 免疫性血小板減少症、特發性血小板減少症、自體免疫性 曱狀腺病、甲狀腺機能充進症、甲狀腺腫性自體免疫性甲 狀腺低能症（橋本氏病）、萎縮性自體免疫性甲狀腺低能 151681.doc 263· 201127956 症、原發性黏液水腫、晶狀體源性葡萄膜炎、原發性血管 炎、白斑病急性肝病、慢性肝病、酒精性肝硬化、酒精誘 發之肝損傷、膽汁鬱滞、特f性肝病、藥物誘發之肝炎、 非酒精性脂肪變性肝炎、過敏症及哮$、Β群鍵球菌（gbs) 感染、精神障礙（例如抑鬱症及精神分裂症）、Th2型及m 型介導之疾病、急性及慢性疼痛（不同形式之疼痛）、及諸 如肺癌、乳癌、胃癌、膀胱癌、結腸癌、胰腺癌、印巢 癌、則列腺癌及直腸癌之癌症及造血性惡性病（白血病及 淋巴瘤）、無β脂蛋白血症、手足發紺、急性及慢性寄生或 感染過程、急性白血病、急性淋巴母細胞白血病（ALL)、 急性骨髓白血病（AML)、急性或慢性細菌感染、急性胰腺 炎、急性腎衰竭、腺癌、心房異位搏動、AIDS癡呆複合 症、酒精誘發之肝炎、過敏性結膜炎、過敏性接觸性皮膚 炎、過敏性鼻炎、同種異體移植排斥反應、心^抗胰蛋白 酶缺乏、肌肉萎縮性側索硬化、貧血、心絞痛、前角細胞 退化、抗cd3療法、抗磷脂症候群、抗受體過敏反應、主 動脈及周邊動脈瘤、主動脈剝離、動脈性高血壓、動脈硬 化、動靜脈瘺、共濟失調、心房纖維性顫動（持續性或陣 發性）、心房撲動 '房室傳導阻滯、B細胞淋巴瘤、骨移植 物排斥反應、骨髓移植（BMT)排斥反應、束枝傳導阻滯、 伯基特淋巴瘤、燒傷、心律不整 '心臟頓抑症候群、心臟 腫瘤、心肌病、心肺繞道發炎反應、軟骨移植排斥反應、 小腦皮質退化、小腦病症、紊亂性或多灶性房性心動過 速、與化學療法有關之病症、慢性髓細胞白血病（CML)、 151681.doc -264· 201127956 慢性酒精中毒、慢性發炎性病變、慢性淋巴細胞性白血病 (CLL)、慢性阻塞性肺病（c〇pD)、慢性水揚酸中毒、結腸 直腸癌、充血性心臟衰竭、結膜炎、接觸性皮膚炎、肺原 性心臟病、冠狀動脈疾病、庫賈氏病、培養物陰性敗血 症、囊腫性纖維化、細胞激素療法相關之病症、拳擊員癡 呆、脫髓鞘疾病、出血性登革熱、皮膚炎、皮膚病病狀、 糖尿病（diabetes ’ diabetes mellitus)、糖尿病性動脈硬化 φ 病、泛發性路易體疾病、擴張型充血性心肌病、基底神經 即病症、中年唐氏症候群、由阻斷CNS多巴胺受體之藥物 誘發的藥物誘發之運動障礙、藥物敏感、濕疹、腦脊髓 炎、心内膜炎、内分泌病、會厭炎、£]5病毒感染、肢端紅 痛症、錐體外及小腦病症、家族性噬血性淋巴組織細胞瘤 病、胚胎胸腺移植排斥反應、弗里德賴希氏共濟失調、功 能性周圍動脈病症、真菌性敗血症、氣性壞疽、胃潰瘍、 腎小球腎炎、任何器官或組織的移植物排斥反應、革蘭氏 # 陰性敗血症、革蘭氏陽性敗血症、胞内生物體引起之肉芽 腫、毛細胞白血病、哈洛弗登_史巴茲氏蒼白球色素退化 症、橋本氏曱狀腺炎、枯草熱、心臟移植排斥反應、血色 素沈著症 '血液透析、溶血性尿毒癥候群/溶栓性血小板 減少（·生1癜、出血、A型肝炎、希氏束心律不整、感 木/HIV神經病、隹奇金病、過動性運動病症、過敏反應、 過敏性肺炎、高血壓、運動不足運動病症、下丘腦.垂體-腎上腺軸。乎估、特發性艾迪森氏病、特發性肺纖維化、抗 體；I導之細胞毒性、衰弱、嬰兒脊髓性肌萎縮症、主動脈 151681.doc -265 - 201127956 發炎、a型流感、電離輻射曝露、虹膜睫狀體炎/葡萄膜炎/ 視神經炎、缺血再灌注損傷、缺血性中風、青少年類風满 性關節炎、青少年脊髓性肌萎縮症、卡波西氏肉瘤、腎臟 移植排斥反應、退伍軍人病、利什曼體病、麻風病、皮質 脊髓系統病變、脂性水腫、肝移植排斥反應、淋巴水腫、 癍疾、惡性淋巴瘤、惡性組織細胞增多病、惡性黑素瘤、 腦膜炎、腦膜炎球菌血症、代謝性/特發性疾病、偏頭 痛、粒線體多系統病症、混合結締組織病、單株球蛋白 症、多發性骨髓瘤、多系統退化(曼切、代哲因_托馬斯、 史德爾格及馬查多·約瑟夫）、重症肌無力、禽細胞内分枝 桿菌、結核分枝桿菌、骨髓發育不良症候群、心肌梗塞、 心肌缺血病症、鼻咽癌、新生兒慢性肺病、腎炎、腎病、 神經退化性疾#、;[型神經原性肌肉萎縮、嗜中性白血球 減少性發熱、非霍奇金淋巴瘤、腹主動脈及其分支閉塞、 閉塞性動脈病纟、okt3療法、睪丸炎/副睪丸炎、睪丸炎/ 輸精管復通術、ϋ官腫大、骨f疏鬆症 '騰腺移植排斥反 應、膜腺癌、副腫瘤症候群/惡性高血弼症、副甲狀腺移 植排斥反應、骨盆腔炎疾病、常年性鼻炎、心包疾病、周 邊動脈粥樣硬化疾病、周圍血管疾病、腹膜炎、惡性貧 血、卡氏肺囊蟲肺炎、肺炎、P〇EMs症候群（多發性神經 病 '器官腫大、内分泌病、單株球蛋白症及皮膚變化症候 群）、灌注後症候群、菜後症候群、⑽心切開術後症候 群、子癇前症、進行性核上性麻癖、原發性肺高血壓、放 射療法、雷諾現象及疾病、雷諾病、冑弗素姆氏病、規則 I5I681.doc -266- 201127956 性QRS波狹窄型心動過速、腎血管性高血壓、再灌注損 傷、限制型心肌病、肉瘤、硬皮病、老年性舞蹈病、路易 體型老年癡呆、血清陰性關節病、休克、鐮形細胞性貧 血、皮膚同種異體移植排斥反應、皮膚變化症候群、小腸 移植排斥反應、實體腫瘤、特異性心律不整、脊椎共濟失 調、脊髓小腦退化、鏈球菌肌炎、小腦結構病變、亞急性 硬化全腦炎、昏厥、心血管系統梅毒、全身性過敏、全身 性發炎反應症候群、全身發作型青少年類風濕性關節炎、 T細胞或FAB ALL、毛細管擴張、血栓閉塞性血管炎、血 小板減少症、中毒、移植、外傷/出血、ΠΙ型過敏反應、 IV型過敏、不穩定型心絞痛、尿毒癥、尿膿毒病、蓴麻 疹、心臟瓣膜病、靜脈曲張、血管炎、靜脈疾病、靜脈血 栓形成、心室纖維性顫動、病毒及真菌感染、病毒性腦炎/ 無菌性腦膜炎、病毒相關之嗜血細胞症候群、韋尼克-科 爾薩科夫症候群、威爾遜氏病、任何器官或組織的異種移 植物排斥反應。（參看Peritt等人，PCT公開案第w〇 2002097048A2號；Leonard等人，PCT公開案第 WO 9524918 A1號；及 Salfeld 等人，PCT 公開案第 WO 00/56772A1號）。 本發明之結合蛋白可用於治療罹患自體免疫疾病之人 類’該等自體免疫疾病尤其與炎症有關，包括類風濕性關 節炎、脊椎炎、過敏症、自體免疫性糖尿病、自體免疫性 葡萄膜炎。在一實施例中’本發明之結合蛋白或其抗原結 合部分係用於治療類風濕性關節炎、克羅恩氏病、多發性 硬化症、胰島素依賴性糖尿病及牛皮癖。 151681.doc •267- 201127956 在一貫施例中，可以本發明之組合物及方法治療或診斷 之疾病包括（但不限於）原發性及轉移性癌症，包括乳癌、 結腸癌、直腸癌、肺癌、口咽癌、下嚥癌、食道癌、胃 癌、胰腺癌、肝癌、膽囊癌及膽管癌、小腸癌、尿道癌 (包括腎癌、膀胱癌及尿道上皮癌）、雌性生殖道癌（包括子 宮頸癌、子宮癌及卵巢癌、以及絨膜癌及妊娠滋養細胞疾 病）、雄性生殖道癌（包括前列腺癌、精囊癌、睪丸癌及生 殖細胞腫瘤）、内分泌腺癌（包括甲狀腺癌、腎上腺癌及垂 體腺癌）及皮膚癌，以及血管瘤、黑素瘤、肉瘤（包括骨骼 及軟組織產生之肉瘤以及卡波西氏肉瘤）、腦腫瘤、神經 腫瘤、眼腫瘤及腦膜腫瘤（包括星形細胞瘤、神經膠質 瘤、膠質母細胞瘤、視網膜胚細胞瘤、神經瘤、神經母細 胞瘤、神經鞘瘤及腦膜瘤）、由諸如白血病及淋巴瘤（霍奇 金淋巴瘤及非霍奇金淋巴瘤）之造血性惡性病引起的實體 腫瘤。 在-實施例巾，本發明之抗體或其抗原結合部分在單獨 使用或與放射療法及/或其他化學治療劑組合使用時可用 於治療癌症或用於預防自本文所述之腫瘤轉移。 本發明之抗體或其抗原結合部分可與包括(但不限於)以 下之藥劑組合：抗贅生劑；放射療法；化學療法，諸如 腦院基化劑、職、卡箱、抗微管蛋白劑、太平洋紫和 醇、多婦紫杉醇、紫杉醇、小紅每、吉西他濱、健擇 環黴素、阿德力黴素、拓撲異構酶:抑制劑、拓撲異構酶； 抑制劑、5-氟尿㈣（5_FU)、曱酿四氫葉酸、伊立替康、 15I681.doc •268- 201127956 受體酷胺酸激酶抑制劑（例如埃羅替尼、吉非替尼）、cox 2抑制劑（例如塞内昔布）、激酶抑制劑及siRNA。）C〇X· 本發明之結合Iώ 之其他治療劑-起投與一或多種適用於治療各種疾病 本發明之結合卷ώ 1丄、 可早獨或組合使用以治療該等。 ::Γ结白可單獨使用或與其他藥劑(例如治療劑)組 治療由本發明抗n 、射為此項技術認為適用於 α /σ療之疾病或病狀之治療劑。該另一藥 劑亦可為賦予治療組合物 .、 物黏度之藥劑。 有-屬杜的樂劑’例如影響組合 應進一步瞭解，欲包括於本發㈣之組 目的之彼等組合。下女陆，今—* 艰疋 下文陳述之樂劑係出於說明性目的且不 机具有限制性。作為本發 體及至少一種選自以下、 ρ 合可為本發明抗 士…人選自以下清早之額外藥劑。若組合使得所形 成之ι物可執行其預定功能，則組合亦可包括一種以上 額外藥劑，例如兩種或三種額外藥劑。 治療自體免疫及發炎疾狀組合為非類 稱作NSAID)，其包括如布洛芬之藥物。其他組合為皮ί 類固醇，包括潑尼…藉由在與本發明之DvDig組合治 療患者時逐漸減少所要之類固醇劑量來降低或甚至消除類 =酵使用之熟知副作用。可與本發明之抗體或抗體部分組 5之用於類風濕性關節炎之治療劑的非限制性實例包括以 下：細胞激素抑制性消炎藥（CSAID);針對其他人類細胞 151681.doc •269- 201127956 激素或生長因子之抗體或拮抗劑，該等其他人類細胞激素 或生長因子為例如 TNF、LT、IL-l、IL-2、IL-3、IL-4、 IL-5、IL-6、IL-7、IL-8、IL-15、IL-16、IL-18、IL-21、 IL-23、干擾素、EMAP-II、GM-CSF、FGF 及 PDGF。本發 明之結合蛋白或其抗原結合部分可與針對細胞表面分子之 抗體組合，該等分子諸如CD2、CD3、CD4、CD8、 CD25 、 CD28 、CD30 、 CD40 、CD45 、 CD69 、 CD80(B7.1)、CD86(B7.2)、CD90、CTLA或其配位體，包 括 CD154(gp39或 CD40L)。 治療劑之組合可在不同點干擾自體免疫及後續發炎性級 聯；實例包括TNF拮抗劑（如嵌合、人類化或人類TNF抗 體）、阿達木單抗（PCT公開案第WO 97/29131號）、 CA2(RemicadeTM)、CDP 571 及可溶性 p55 或 p75 TNF受體、 其衍生物（p75TNFRlgG(EnbrelTM)或 p55TNFRlgG(來那西 普）；以及TNFa轉化酶（TACE)抑制劑；類似地，IL-1抑制 劑（介白素-1轉化酶抑制劑、IL-1RA等）可能由於相同原因 而為有效的。其他組合包括介白素11。另一組合包括可與 IL-12功能平行起作用、依賴於IL-12功能起作用或與IL-12 功能協同起作用的自體免疫反應關鍵作用者；尤其為IL-18拮抗劑，包括IL-18抗體或可溶性IL-18受體，或IL-18結 合蛋白。已顯示IL-12及IL-18具有重疊但不同之功能，且 兩者之括抗劑的組合可能最有效。另一組合為非消耗性抗 CD4抑制劑。其他組合包括協同刺激路徑CD80 (B7.1)或 CD86 (B7.2)之拮抗劑，包括抗體、可溶性受體或拮抗性 151681.doc -270· 201127956 配位體。
本發明之結合蛋白亦可與以下藥劑組合：諸如甲胺嗓 呤、6-MP、硫唑嘌呤、柳氮磺胺吡啶、美沙拉嗓 (mesalazine)、奥沙拉嗪、氯喹/羥基氯喹、青黴胺 (pencillamine)、硫代蘋果酸鹽（aurothiomalate)(肌肉内及 經口）、硫唑嘌呤、秋水仙鹼 '皮質類固醇（經口、吸入及 局部注射）、β-2腎上腺素受體促效劑（沙丁胺醇 (salbutamol)、特布他林（terbutaline)、沙美特羅 (salmeteral))、黃嘌呤（茶鹼（theophylline)、胺茶鹼 (aminophylline))、色甘酸鹽（cromoglycate)、奈多羅米 (nedocromil)、酮替酚（ketotifen)、異丙托銨（ipratropium) 及氧托敍（oxitropium)、環孢靈、FK506、雷帕黴素、黴盼 酸嗎淋乙酯、來氟米特、NS AID(例如布洛芬）、皮質類固 醇（諸如潑尼龍）、填酸二酯酶抑制劑、腺苷促效劑、抗血 栓劑、補體抑制劑、腎上腺素激導劑、干擾促炎性細胞激 素（諸如TNF-α或IL-1)信號傳導之藥劑（例如IRAK、NIK、 IKK、p38或MAP激酶抑制劑）、IL-Ιβ轉化酶抑制劑、 TNFa轉化酶（TACE)抑制劑、T細胞信號傳導抑制劑（諸如 激酶抑制劑）、金屬蛋白酶抑制劑、柳氮磺胺吡啶、硫唑 °票呤、6-酼基嗓吟、血管收縮素轉化酶抑制劑、可溶性細 胞激素受體及其衍生物（例如可溶性p55或p75 TNF受體及 衍生物p75TNFRIgG(EnbrelTM及p55TNFRIgG(來那西普））、 sIL-lRI、sIL-lRII、SIL-6R)、消炎性細胞激素（例如 IL-4 ' IL-10、IL-11、IL-13及TGFP)、塞内昔布、葉酸、硫酸羥 151681.doc -271 - 201127956
基氣喹、羅非考昔（rofecoxib)、依那西普、英利昔單抗、 萘普生（naproxen)、伐地考昔（valdecoxib)、柳氮續胺0比 啶、曱潑尼龍、美儂西康（meloxicam)、乙酸甲潑尼龍、硫 代蘋果酸金鈉、阿司匹靈（aspirin)、曲安奈德 (triamcinolone acetonide)、萘續酸丙氧芬（propoxyphene napsylate)/apap、葉酸鹽、萘 丁美酮（nabumetone)、雙氯芬 酸（diclofenac)、°比羅昔康（piroxicam)、依託度酸 (etodolac)、雙氯芬酸納（diclofenac sodium)、奥沙普唤 (oxaprozin)、鹽酸經考_ (oxycodone hcl)、氫可酮酒石酸 氫鹽（hydrocodone bitartrate)/apap、雙氣芬酸鈉/米索前列 醇（misoprostol)、芬太尼（fentanyl)、人類重組阿那白滯素 (anakinra, human recombinant)、鹽酸曲馬多（tramadol hcl)、雙水楊醋（salsalate)、舒林酸（sulindac)、氰钻胺素 (cyanocobalamin)/fa/ °比。多醇（pyridoxine)、乙酿胺苯紛 (acetaminophen)、阿侖膦酸鈉（alendronate sodium)、潑尼 龍、硫酸嗎啡（morphine sulfate)、鹽酸利多卡因、°弓卜朵美 辛（indomethacin)、硫酸葡糖胺（glucosamine sulf)/軟骨素 (chondroitin)、鹽酸阿米替林（amitriptyline hcl)、石黃胺 °密 咬（sulfadiazine)、鹽酸經考鲷/乙醢胺苯盼、鹽酸奥洛他定 (olopatadine hcl)、米索前列醇、萘普生納、奥美拉吐 (omeprazole)、環填醯胺（cyclophosphamide)、利妥昔單 抗、IL-1 TRAP、MRA、CTLA4-IG、IL-18 BP、抗 IL-18、 抗 IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、羅氟司特（Roflumilast)、IC-485、CDC-801 及美索潘 151681.doc -272- 201127956 (Mesopram)。組合包括甲胺喋呤或來氟米特，且在中度或 重度類風濕性關節炎情形下，包括環孢靈。 亦可與結合蛋白組合用於治療類風濕性關節炎之非限制 性其他藥劑包括（但不限於）以下：非類固醇消炎藥 (NSAID);細胞激素抑制性消炎藥（CSAID) ; CDP-571/BAY-10-3356(人類化抗 TNFa抗體；Celltech/Bayer); cA2/英利昔單抗（嵌合抗TNFa抗體；centocor) ; 75 kdTNFR-IgG/依那西普（75 kD TNF受體-igG融合蛋白； Immunex ；參看例如 Arthritis & Rheumatism (1994)第 37卷， S295 ; ·/. iwve". Med. (1996)第 44 卷，235A); 55 kdTNF-IgG(55 kD TNF 受體-IgG 融合蛋白；Hoffmann-LaRoche); 1〇£(：-€£9_1/88 2103 96(非消耗性靈長類動物化抗〇〇4抗 體；IDEC/SmithKline ;參看例如 Jri/zWiz.i ά Λ/zewwai^w (1995)第 38卷，S185); DAB 486-IL-2及 / 或 DAB 389-IL-2(IL-2融合蛋白；Seragen ;參看例如dri/ir/心ά Rheumatism (1993)第 36 卷，1223);抗 Tac(人類化抗仏-2Rct ; Protein Design Labs/Roche) ; IL-4(消炎性細胞激 素）；DNAX/Schering) ; IL-10(SCH 52000 ;重組IL-10消炎 性細胞激素；DNAX/Schering) ; IL-4 ; IL-10及 / 或 IL-4 促 效劑（例如促效劑抗體）；IL-1RA(IL-1受體拮抗劑； Synergen/Amgen)；阿那白滯素（Kineret®/Amgen) ; TNF-bp/s-TNF(可溶性TNF結合蛋白；參看例如Arthritis & (1996)第 39卷，第 9期（增刊），S284 ; Jwer «/· Physiol.-Heart and Circulatory Physiology (\995~)第 268 151681.doc -273 - 201127956 卷’第37-42頁）；R973401(IV型磷酸二酯酶抑制劑；參看 例如ά（1996)第39卷，第9期（增刊）， S282) ; MK-966(C〇X-2抑制劑；參看例如没 則…所（1996)第39卷，第9期（增刊），S81);伊洛前列 素（Iloprost)(參看例如j—W山*舢⑼咖沿所〇996)第39 卷’第9期（增刊），S82);甲胺喋呤；沙立度胺 (thalidomide)(參看例如ά _ (1996)第39 卷，第9期（增刊），S282)及沙立度胺相關藥物（例如西爾金 (Celgen));來氟米特（消炎藥及細胞激素抑制劑；參看例 如 (1996)第 39卷，第 9期（增刊）， S131，及e5earc；j (1996)第45卷 第 頁）；胺甲環酸（tranexamic acid)(纖維蛋白溶酶原活化抑制 劑，參看例如jriWib ά仙⑽讲加/⑽（1996)第39卷，第9 期（增刊），S284) ; Τ-614(細胞激素抑制劑；參看例如 沿所（1996)第39卷第 9期（增刊）， S282)，則列腺素E1(參看例如々仏”·…没及心· (1996)第39卷，第9期（增刊），S282);替尼達普（Tenidap) (非類固醇消炎藥’參看例如&及心謂αίζ·請 (1996)第39卷，第9期（增刊），S28〇);萘普生（非類固醇消 炎藥，參看例如#ewr〇 (1996)第7卷第12〇91213 頁），美儂西康（非類固醇消炎藥）；布洛芬（非類固醇消炎 樂）；°比羅昔康（非類固醇消炎藥）；雙氣芬酸（非類固醇消 炎藥）’吲哚美辛（非類固醇消炎藥）；柳氮磺胺η比啶（參看 例如沿所（1996)第39卷，第9期（增刊）， 151681.doc •274· 201127956 S281)’硫唑嘌呤（參看例如设仙⑽漏沿w (1996) 第39卷，第9期（增刊），S281) ; ice抑制劑（酶介白素·^轉 化酶之抑制劑），zap_7〇及/或lck抑制劑（酪胺酸激酶 或lck之抑制劑）；乂£〇1?抑制劑及/或vEGF_r抑制劑（血管 内皮細胞生長因子或血管内皮細胞生長因子受體之抑制 劑’血管生成抑制劑）；皮質類固醇消炎藥（例如 SB203580) ; TNF轉化酶抑制劑；抗IL_12抗體；抗虬_18抗 體’介白素-ιι(參看例如」以；^山ά沢心謂如⑽（1996)第 卷第9期（增刊），S296)，介白素-13(參看例如Jri/zr/iz··? c& (1996)第39卷’第9期（增刊），S308);介白 素-17抑制劑（參看例如 (1996)第39 卷’第9期（增刊），s 120);金；青黴胺；氯喹；苯丁酸氮芥 (chlorambucil);羥基氯喹；環孢素；環磷醯胺；全身淋巴 組織照射；抗胸腺細胞球蛋白；抗CD4抗體；CD5毒素； 系二口投與之肽及膠原蛋白；氣苯紮利二納（l〇benZarit disodium)；細胞激素調控劑（CRA)HP228 及 HP466 (Houghten Pharmaceuticals，Inc.); ICAM-1反義硫代磷酸 酉曰养去氧核 4 酸（ISIS 2302 ; Isis Pharmaceuticals, Inc.); 可溶性補體受體1(TP10 ; T Cell Sciences, Inc.);潑尼松 (prednisone);肝蛋白（orgotein);葡糖胺聚糖多硫酸酯 (glycosaminoglycan polysulphate)；二曱胺四環素 (minocycline);抗IL2R抗體；海洋生物及植物脂質（魚及植 物種子脂肪酸；參看例如DeLuca等人，（1995) Db. TVori/i Jw. 21:759-777);金諾芬（auranofin);苯基丁 1516Sl.doc •275 - 201127956 氮酮（phenylbutazone);甲氯芬那酸（meclofenamic acid); 氟芬那酸（flufenamic acid);靜脈内免疫球蛋白；齊留通 (zileuton);阿紮立平（azaribine);黴酚酸（mycophenolic acid)(RS-61443);他克莫司（tacrolimus)(FK-506);西羅莫 司（sirolimus)(雷帕黴素）；胺普立糖（amiprii〇se)(鹽酸胺普 立糖（therafectin));克拉曲濱（Cladribine)(2-氣去氧腺苷）； 曱胺蝶bcl-2抑制劑（參看Bruncko，Milan等人，Journal of Medicinal Chemistry (2007)，50(4)，641-662);抗病毒劑 及免疫調節劑。 在一貫施例中，結合蛋白或其抗原結合部分與一種以下 藥劑組合投與以治療類風濕性關節炎：KDR之小分子抑制 劑；Tie-2之小分子抑制劑；曱胺喋呤；潑尼松；塞内昔 布；葉酸；硫酸經基氣唾；、羅非考#;依那西普；英利昔 單抗；來氟米特；蔡普生；伐地考昔；柳氮續胺^比咬；甲 潑尼龍’冑洛芬，美傻西康；乙酸甲潑尼龍；硫代顏果酸 金鈉，阿司匹靈，硫„坐嗓呤；曲安奈德；萘項酸丙氧芬/
apap ;葉酸鹽；萘丁基雔惫艾 丁、J吳酮，又鼠分酸；吡羅昔康；依託 酸；雙氣芬酸鈉；奥沙普唤；鹽酸經考酮；氫可嗣酒石, 氫鹽—am芬酸納/米索前列醇；芬太尼；人類重; 阿那白素，鹽酸曲$客.雜永搭花匕
典馬夕，雙水杨酯；舒林酸；氰鈷胺J f a/ »比°多醇，乙酿胺笨胁.阿合酿缺a 本酚，叮"9膦酸鈉；潑尼龍；硫酸， 啡；鹽酸利多卡因；坤丨皞盖妄. 弓丨木美辛’硫酸葡糖胺/軟骨素；. 孢靈；鹽酸阿米曲巷姓. 林’ κ胺喷。定；鹽酸羥考酮/乙醯 苯紛；鹽酸奥洛他定.佘前 疋，米索刖歹丨醇；萘普生鈉；奥美 151681.doc -276- 201127956 唑；黴酚酸嗎啉乙醋；環磷酿胺；利妥昔單抗；IL_1 TRAP ; MRA ; CTLA4-IG ; IL-18 BP ; IL-12/23 ;抗 IL 18 ;抗 IL 15 ； BIRB-796 ； SCIO-469 ； VX-702 ； AMG-548 ; VX-740 ;羅氟司特；IC-485 ; CDC-801 ;及美索 潘。 可與本發明之結合蛋白組合用於發炎性腸病之治療劑的 非限制性實例包括以下：布地奈德；表皮生長因子；皮質 類固醇；環孢靈；柳氮磺胺吡啶；胺基水揚酸鹽；6-酼基 嘌呤；硫唑嘌呤；曱硝噠唑；脂質加氧酶抑制劑；美沙拉 嗪；奥沙拉唤；巴柳氮；抗氧化劑；凝血脂素抑制劑； IL-1受體拮抗劑；抗IL-Ιβ mAb ;抗IL-6 mAb ;生長因 子；彈性蛋白酶抑制劑；°比啶基-咪唑化合物；針對其他 人類細胞激素或生長因子(^WTNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-15、IL-16、IL-17、IL-18、EMAP-II、 GM-CSF、FGF及PDGF)之抗體或拮抗劑。本發明之抗體或 其抗原結合部分可與針對細胞表面分子（諸如CD2、CD3、 CD4、CD8、CD25、CD28、CD30、CD40、CD45、 CD69、CD90)或其配位體之抗體組合。本發明之抗體或其 抗原結合部分亦可與以下之藥劑組合：諸如甲胺喋呤；環 孢靈；FK506 ;雷帕黴素；黴酚酸嗎啉乙酯；來氟米特； NSAID，例如布洛芬；皮質類固醇，諸如潑尼龍；磷酸二 酯酶抑制劑；腺苷促效劑；抗金栓劑；補體抑制劑；腎上 腺素激導劑；干擾促炎性細胞激素（諸如TNFa或IL-1)信號 傳導之藥劑（例如IRAK、NIK、IKK、p38或MAP激酶抑制 151681.doc -277- 201127956 劑）；IL-Ιβ轉化酶抑制劑；TNFtx轉化酶抑制劑；T細胞信 號傳導抑制劑，諸如激酶抑制劑；金屬蛋白酶抑制劑；柳 氮續胺。比》定；硫嗤D票呤；6 -疏基°票吟；jk管收縮素轉化酶 抑制劑；可溶性細胞激素受體及其衍生物（例如可溶性p55 或 p75 TNF受體、sIL-lRI、sIL-lRII、SIL-6R);及消炎性 細胞激素（例如 IL-4、IL-10、IL-11、IL-13 及 TGFP);及 bcl-2抑制劑。 可與結合蛋白組合之用於克羅恩氏病之治療劑的實例包 括以下：TNF拮抗劑（例如抗TNF抗體）、阿達木單抗（PCT 公 開 案第 WO 97/29131 號；HUMIRA)、 CA2(REMICADE) 、 CDP 571 、 TNFR-Ig 構築體 (p75TNFRIgG(ENBREL)及 p55TNFRIgG(來那西普））抑制劑 及PDE4抑制劑。本發明之抗體或其抗原結合部分可與皮 質類固醇（例如布地奈德及地塞米松）組合。本發明之結合 蛋白或其抗原結合部分亦可與以下藥劑組合：諸如柳氮磺 胺吡啶、5-胺基水揚酸及奥沙拉嗪，以及干擾諸如IL-1之 促炎性細胞激素合成或作用的藥劑（例如IL-Ιβ轉化酶抑制 劑及IL-lra)。本發明之抗體或其抗原結合部分亦可與T細 胞信號傳導抑制劑（例如酪胺酸激酶抑制劑6-巯基嘌呤）一 起使用。本發明之結合蛋白或其抗原結合部分可與IL-11 組合。本發明之結合蛋白或其抗原結合部分可與以下組 合：美沙拉。秦、潑尼松、硫。坐嘌吟、疏基嘌呤、英利昔單 抗、曱潑尼龍琥珀酸納、地芬諾酯（diphenoxylate)/硫酸阿 托品（atrop sulfate)、鹽酸洛 π底丁胺（loperamide 151681.doc -278 - 201127956
hydrochloride)、甲胺喋呤、奥美拉唑、葉酸鹽、環丙沙星 (ciprofloxacin)/右旋糖-水、氫可酮酒石酸氫鹽/apap、鹽酸 四環素（tetracycline hydrochloride)、醋酸氟輕鬆 (fluocinonide)、甲硝嗓唑、硫柳汞（thimerosal)/硼酸、消 膽胺（cholestyramine)/蔗糖、鹽酸環丙沙星、硫酸莨菪鹼 (hyoscyamine sulfate)、鹽酸哌替啶（meperidine hydrochloride)、鹽酸咪達唑侖（midazolam hydrochloride)、鹽酸羥考酮/乙醯胺苯酚、鹽酸普敏太定 (promethazine hydrochloride) ' 填酸鈉、場胺甲0惡 〇坐 (sulfamethoxazole)/ 甲氧苄胺嘧咬（trimethoprim)、赛利克 西、聚卡波非（polycarbophil)、萘磺酸丙氧芬、氫化可的 松（hydrocortisone)、多種維生素劑（multivitamin)、巴柳氮 二納、填酸可待因（codeine phosphate)/apap、鹽酸考來維 侖（colesevelam hcl)、氰鈷胺素、葉酸、左氧氟沙星 (levofloxacin)、曱潑尼龍、那他珠單抗及干擾素_γ。 可與本發明之結合蛋白組合用於多發性硬化症之治療劑 的非限制性實例包括以下：皮質類固醇；潑尼龍；甲潑尼 龍；硫唑嘌呤；環磷醯胺；環孢靈；曱胺喋呤；4-胺基吡 啶；替紮尼定（tizanidine);干擾素-pla(AVONEX ; Biogen);干擾素-plb(BETASERON ; Chiron/Berlex);干 擾素 a-n3(Interferon Sciences/Fujimoto);干擾素-a(Alfa Wassermann/J&J);干擾素 β 1 A-IF(Serono/Inhale Therapeutics);聚乙二醇化干擾素 α 2b(Enzon/Schering-Plough);共聚物 l(Cop-l ;克帕松（COPAXONE) ; Teva 151681.doc -279· 201127956
Pharmaceutical Industries，Inc.);高壓氧；靜脈内免疫球 蛋白；克拉曲濱（clabribine);針對其他人類細胞激素或生 長因子及其受體 H?，jWTNF、LT、IL-l、IL-2、IL-6、IL-7、IL-8、IL-23、IL-15、IL-16、IL-18、EMAP-II、GM-CSF、FGF及PDGF)之抗體或拮抗劑。本發明之結合蛋白 可與針對細胞表面分子（諸如CD2、CD3、CD4、CD8、 CD19 、 CD20 、 CD25 、 CD28 、 CD30 、 CD40 、 CD45 、 CD69、CD80、CD86、CD90)或其配位體之抗體組合。本 發明之結合蛋白亦可與以下藥劑組合：諸如甲胺喋呤、環 孢靈、FK506、雷帕黴素、黴酚酸嗎啉乙酯、來氟米特、 NSAID(例如布洛芬）、皮質類固醇（諸如潑尼龍）、磷酸二 酯酶抑制劑、腺苷促效劑、抗血栓劑、補體抑制劑、腎上 腺素激導劑、干擾促炎性細胞激素（諸如TNFa或IL-1)信號 傳導之藥劑（例如IRAK、NIK、IKK、p38或MAP激酶抑制 劑）、IL-1 β轉化酶抑制劑、TACE抑制劑、T細胞信號傳導 抑制劑（諸如激酶抑制劑）、金屬蛋白酶抑制劑、柳氮磺胺 °比。定、硫°坐17票呤、6-酼基嗓吟、血管收縮素轉化酶抑制 劑、可溶性細胞激素受體及其衍生物（例如可溶性ρ55或 p75 TNF受體、sIL-lRI、sIL-lRII、SIL-6R)、消炎性細胞 激素（例如 IL-4、IL-10、IL-13及 TGFp)及 bcl-2抑制劑。 可與本發明結合蛋白組合用於多發性硬化症之治療劑的 實例包括干擾素-β(例如IFNPla& IFNPlb);克帕松、皮質 類固醇、卡斯蛋白酶抑制劑（例如卡斯蛋白酶-1抑制劑）、 IL-1抑制劑、TNF抑制劑及針對CD4〇配位體及CD80之抗 151681.doc -280- 201127956 體。
本發明之結合蛋白亦可與以下藥劑組合：諸如阿來組單 抗、屈大麻盼（dronabinol)、尤利美（Unimed)、達利珠單 抗、米托蒽醒、鹽酸紮利羅登（xaliproden hydrochloride)、 胺0比。定（fampridine)、乙酸格拉替美（glatiramer acetate)、 那他珠單抗、西納°比°^(3丨!11131)丨(1〇1)、a-伊木諾金NNS03(a-immunokine NNS03)、ABR-215062、AnergiX.MS、趨化因 子受體抬抗劑、BBR-2778、卡拉脈素（calagualine)、CPI-1189、LEM(脂質體囊封之米托蒽醌）、THC.CBD(類大麻酚 (cannabinoid)促效劑）、MBP-8298、美索潘（PDE4 抑制 劑）、MNA-71 5、抗IL-6受體抗體、萘羅瓦西（neurovax)、 0比非尼酮（pirfenidone)、阿羅曲普 1258(allotrap 1258) (RDP-1258)、sTNF-Rl、他侖帕奈（talampanel)、特立氟胺 (teriflunomide)、TGF-P2、替利莫肽（tiplimotide)、VLA-4 拮抗劑（例如 TR-14035、VLA4 Ultrahaler、Antegran-ELAN/Biogen)、干擾素γ结抗劑、IL-4促效劑。 可與本發明之結合蛋白組合用於心絞痛之治療劑的非限 制性實例包括以下：阿司匹靈、确化甘油（nitroglycerin)、 單硝酸異山梨醇酯、丁二酸美托洛爾（metoprolol succinate)、阿替洛爾（atenolol)、酒石酸美托洛爾、苯續 酸胺氯地平（amlodipine besylate)、鹽酸地爾硫卓 (diltiazem hydrochloride)、二石肖酸異山梨醇S旨、氣D比格雷 硫酸氫鹽（clopidogrel bisulfate)、琐苯地平（nifedipine)、 阿托伐他、;丁約（atorvastatin calcium)、氣化斜、吱嗔苯胺酸 151681.doc -281 - 201127956 (furosemide)、辛伐他、汀（simvastatin)、鹽酸維拉帕米 (verapamil hcl)、地高辛（digoxin)、鹽酸普萘洛爾、卡維 地洛（carvedilol)、賴諾普利（lisinopril)、螺内酯 (spironolactone)、氫氣苯n塞噠嗪（hydrochlorothiazide)、順 丁稀一酸依拉普利（enalapril maleate)、納多洛爾 (nadolol)、雷米普利（ramiprii)、依諾肝素鈉（en〇xaparin sodium)、肝素鈉、纈沙坦（vaisartan)、鹽酸索他洛爾 (sotalol hydrochloride)、非諾貝特（fen〇nbrate)、依澤替米 貝（ezetimibe)、布美他尼（bumetanide)、氣沙坦鉀（losartan potassium)、賴諾普利/氫氣苯噻噠嗪、非洛地平 (felodipine)、卡托普利（capt〇pril)、反丁烯二酸比索洛爾 (bisoprolol fumarate)。 可與本發明之結合蛋白組合用於僵直性脊椎炎之治療劑 的非限制性實例包括以下：布洛芬、雙氯芬酸及米索前列 醇、萘普生、美儂西康、吲哚美辛、雙氯芬酸、塞内昔 布、羅非考昔、柳氮磺胺吡啶、曱胺嗓呤、硫唑嘌呤、二 甲胺四環素、潑尼松、依那西普、英利昔單抗。 可與本發明之結合蛋白組合用於哮喘之治療劑的非限制 性貫例包括以下.沙丁胺醇（albuterol)、沙美特羅 (salmeterol)/氟替卡松（fluticas〇ne)、孟魯司特鈉 (montelukast sodium)、丙酸氟替卡松、布地奈德 (budesonide)、潑尼松、羥萘甲酸沙美特羅、鹽酸左旋沙 丁胺醇（levalbuterol hcl)、硫酸沙丁胺醇/異丙托銨、潑尼 龍填Ssl納、曲女奈德、一丙酸倍氣米松（beclomethasone 151681.doc -282· 201127956 dipropionate)、溴化異丙托铵、阿奇黴素（azithromycin)、 乙酸吡布特羅（pirbuterol acetate)、潑尼龍、無水茶鹼、甲 潑尼龍丁二酸納、克拉黴素（clarithromycin)、紮魯司特 (zafirlukast)、反丁烯二酸福莫特羅（form〇ter〇1 fumarate)、流感病毒疫苗、甲潑尼龍、三水合阿莫西林 (amoxicillin trihydrate)、氟尼縮松（fiunis〇iide)、過敏注射 液、色甘酸鈉、鹽酸非索非那定（fexofenadine hydrochloride)、氟尼縮松/薄荷腦、阿莫西林/棒酸鹽 (clavulanate)、左氧氟沙星、吸入器輔助裝置、愈創甘油 醚（guaifenesin)、地塞米松磷酸鈉、鹽酸莫西沙星 (moxifloxacin hcl)、鹽酸多西環素（doxycycline hyClate)、 愈創甘油醚/d-美沙芬（d-methorphan)、對麻黃素/c〇d/氣芬 那敏（chlorphenir)、加替沙星（gatifloxacin)、鹽酸西替利 唤（cetirizine hydrochloride)、糠酸莫美他松（mometas〇ne furoate)、經蔡甲酸沙美特羅、苯佐那醋（benz〇natate)、頭 孢胺苄（cephalexin)、pe/氫可酮/氯芬那敏、鹽酸西替利嗪/ 假麻黃素（pseudoephed)、苯腎上腺素/c〇d/普敏太定、可待 因/普敏太疋、頭孢丙烯（Cefpr〇zil)、地塞米松、愈創甘油 驗/假麻貫素、氣芬尼拉明（chl〇rphenjramine)/氫可酮、奈 多羅米鈉、硫酸特布他林、腎上腺素、甲潑尼龍、硫酸間 輕·異丙腎上腺素（metapr〇teren〇i suifate)。 可與本發明之結合蛋白組合用於COPD之治療劑的非限 制性實例包括以下：硫酸沙丁胺醇/異丙托銨、溴化異丙 托鉍、沙美特羅/氟替卡松、沙丁胺醇、羥萘甲酸沙美特 151681.doc 201127956 羅、丙酸氟替卡松、潑尼松、無水茶鹼、f潑尼龍丁二酸 鈉、孟魯司特鈉、布地奈德、反丁烯二酸福莫特羅、曲安 奈德、左氧氟沙星、愈創甘油醚、阿奇黴素、二丙酸倍氣 米松、鹽酸左旋沙丁胺醇、氟尼縮松、頭孢曲松鈉 (ceftriaxone s〇dium)、三水合阿莫西林、加替沙星、紮魯 司特、阿莫西林/棒酸鹽、氟尼縮松/薄荷腦、氣芬尼拉明/ 氫可酮、硫酸間羥異丙腎上腺素、曱潑尼龍、糠酸莫美他 松、p-麻黃素/cod/氣芬那敏、乙酸吡布特羅、麻黃素/洛 拉他定（loratadine)、硫酸特布他林、噻托溴銨（ti〇tr〇pium bromide)、（R，R)_福莫特羅、TgAAT、西洛司特 (Cilomilast)、羅氟司特。 可與本發明之結合蛋白組合用於HCV之治療劑的非限制 性實例包括以下：干擾素a_2a、干擾素a_2b、干擾素α c〇nl、干擾素α_η1、聚乙二醇化干擾素α·2&、聚乙二醇化 干擾素ct-2b、病毒唑（ribavirin)、聚乙二醇化干擾素a_2b+ 病毒唑、熊去氧膽酸（Ursodeoxycholic Acid)、甘草酸 (Glycyrrhizic Acid)、胸腺法新（Thymaifasin)、二鹽酸組胺 (Maxamine)、VX_497及藉由干預以下目標用以治療Hcv之 任何化合物：HCV聚合酶、HCV蛋白酶、HCV解螺旋酶、 HCV IRES(内部核糖體入口位點）。 可與本發明之結合蛋白組合用於特發性肺纖維化之治療 劑的非限制性實例包括以下：潑尼松、硫唑嘌呤、沙丁胺 醇、秋水仙鹼、硫酸沙丁胺醇、地高辛、γ干擾素、甲潑 尼龍丁二酸鈉、勞拉西泮（l〇razepam)、呋喃苯胺酸、賴諾 I5168I.doc -284- 201127956 普利、硝化甘油、螺内酯、環磷醯胺、溴化異丙托銨、放 線菌素d、阿替普酶（alteplase)、丙酸氟替卡松、左氧氟沙 星、硫酸間經異丙腎上腺素、硫酸嗎《•非、鹽酸經考酮、氯 化鉀、曲安奈德、無水他克莫司、鈣、干擾素α '曱胺嗓 吟、黴紛酸嗎乙酯、干擾素γ_ 1 β。
可與本發明之結合蛋白組合用於心肌梗塞之治療劑的非 限制性實例包括以下：阿司匹靈、硝化甘油、酒石酸美托 洛爾、依諾肝素鈉、肝素鈉、氯吡格雷硫酸氫鹽、卡維地 洛、阿替洛爾、硫酸嗎啡、丁二酸美托洛爾、華法林鈉 (warfarin sodium)、賴諾普利、單硝酸異山梨醇酯、地高 辛、咬喃苯胺酸、辛伐他汀、雷米普利、替奈普酶 (tenecteplase)、順丁烯二酸依拉普利、托西邁 (torsemide)、瑞替普酶（retavase)、氣沙坦鉀、鹽酸喹那普 利（quinapril hcl)/mag carb、布美他尼、阿替普酶、依那普 利拉（enalaprilat)、 鹽酸乙胺碘呋酮（aini〇darone hydrochloride)、m-水合鹽酸替羅非班（tirofiban hcl m- hydrate)、鹽酸地爾硫卓、卡托普利、厄貝沙坦 (irbesartan)、纈沙坦、鹽酸普萘洛爾、福辛普利鈉 (fosinopril sodium)、鹽酸利多卡因、埃替菲巴肽 (eptifibatide)、頭孢唑林鈉（cefazolin sodium)、硫酸阿托 品（atropine sulfate)、胺基己酸、螺内酯、干擾素、鹽酸 索他洛爾、乳化斜、多庫S旨納（docusate sodium)、鹽酸多 巴盼丁胺（dobutamine hcl)、阿普 η坐命·（aipraz〇iam)、普伐 他汀鈉（pravastatin sodium)、阿托伐他汀鈣、鹽酸咪達唑 151681.doc - 285 - 201127956 侖、鹽酸哌替啶、二硝酸異山梨醇酯、腎上腺素、鹽酸多 巴胺、比伐盧定（bivalirudin)、羅素他汀（rosuvastatin)、依 澤替米貝/辛伐他汀、阿伐麥布（avasimibe)、卡立泊來德 (cariporide) ° 可與本發明之結合蛋白組合用於牛皮癣之治療劑的非限 制性實例包括以下：KDR之小分子抑制劑、Tie-2之小分子 抑制劑、轉泊三醇（calcipotriene)、丙酸氯倍他索 (clobetasol propionate)、曲安奈德、丙酸鹵貝他索 (halobetasol propionate)、他紮羅汀（tazarotene)、曱胺喋 呤、醋酸氟輕鬆、強化二丙酸倍他米松（betamethas〇ne diprop augmented)、丙酮化氟新龍（fluocinol〇ne acetonide)、阿曲汀（acitretin)、植物性洗髮精（tar shampoo)、戊酸倍他米松、糠酸莫美他松、_康。坐 (ketoconazole)、普莫卡因（pramoxine)/氟輕鬆、戊酸氫化 可的松、氟氫縮松（flurandrenolide)、尿素、倍他米松、丙 酸氣倍他索/潤膚劑、丙酸氟替卡松、阿奇黴素、氫化可 的松、增濕配方（moisturizing formula)、葉酸、地奈棟 (desonide)、吡美莫司（pimecr〇limus)、煤焦油（c〇ai tar)、 二乙酸二氟拉松（diflorasone diacetate)、葉酸依那西普、 乳酸、曱氧沙林（methoxsalen)、he/鹼式沒食子酸叙 (bismuth subgal)/znox/resor、乙酸甲潑尼龍、潑尼松、防 曬劑、哈西奈德（halcinonide)、水揚酸、蒽三紛 (anthralin)、特戊酸氯可托龍（cl〇c〇rtol〇ne pivalate)、煤提 取物、煤焦油/水楊酸、煤焦油/水揚酸/硫、去經米松 151681.doc -286- 201127956 (desoximetasone)、安定（diazepam)、潤膚劑、醋酸氟輕鬆/ 潤膚劑、礦物油/蓖麻油/na lact、礦物油/花生油、石油/十 四烧酸異丙酯、補骨脂素（pSoralen)、水楊酸、皂類/三溴 沙侖（tribromsalan)、硫柳汞/硼酸、塞内昔布、英利昔單 抗、環孢靈、阿法赛特、依法利珠單抗、他克莫司、。比美 莫司、PUVA、UVB、柳氮讀胺吡啶。 可與本發明之結合蛋白組合用於牛皮癬性關節炎之治療 劑的非限制性實例包括以下：曱胺喋呤、依那西普、羅非 考昔、塞内昔布、葉酸、柳氮磺胺〇比啶、萘普生、來氟米 特、乙酸甲潑尼龍、吲哚美辛、硫酸羥基氣喹、潑尼松、 舒林酸、強化二丙酸倍他米松、英利昔單抗、曱胺喋呤、 葉酸鹽、曲安奈德、雙氯芬酸、二曱亞颯、吡羅昔康、雙 氣芬酸鈉、酮洛芬、美儂西康、甲潑尼龍、萘丁美酮、托 美丁鈉、鈣泊三醇、環孢靈、雙氯芬酸鈉/米索前列醇、 醋酸氟輕鬆、硫酸葡糖胺、硫代蘋果酸金鈉、氫可_酒石 酸氫鹽/apap、布洛芬 '利塞膦酸鈉、磺胺嘧啶、硫鳥嘌 呤、伐地考昔、阿法赛特、依法利珠單抗及心丨一抑制劑。 可與本發明之結合蛋白組合用於再狹窄之治療劑的非限 制性實例包括以下：西羅莫司、太平洋紫杉醇、依維莫司 (ever〇llmus)、他克莫司、唑他莫司乙醯胺 苯酚。 可與本發明之結合蛋白組合用於坐骨神經痛之治療劑的 非限制性實例包括以下：氫可酮酒石酸氫鹽/apap、羅非考 曰風酉夂環笨紮林（cyclobenzaprine hcl)、甲潑尼龍、萘普 151681.doc -287- 201127956 生、布洛芬、鹽酸羥考酮/乙醯胺苯酚、塞内昔布、伐地 考昔、乙酸甲潑尼龍、潑尼松、填酸可待因/apap、鹽酸曲 馬多/乙醯胺苯酌、美他沙嗣（metaxalone)、美儂西康、美 索巴莫（methocarbamol)、鹽酸利多卡因、雙氣芬酸鈉、加 巴喷丁（gabapentin)、地塞米松、肌安寧（carisoprodol)、_ 洛酸胺丁三醇（ketorolac tromethamine)、0引。朵美辛、乙離 胺苯盼、安定、萘丁美酮、鹽酸經考酮、鹽酸替紮尼定、 雙氣芬酸鈉/米索前列醇、萘磺酸丙氧芬/apap、 asa/oxycod/羥考酮ter、布洛芬/氫可酮酒石酸氫鹽、鹽酸 曲馬多、依託度酸、鹽酸丙氧芬、鹽酸阿米替林、肌安寧/ 磷酸可待因/asa、硫酸嗎啡、多維生素、萘普生鈉、擰檬 酸奥务那君（orphenadrine citrate)、 替馬西淨 (temazepam)。 可與本發明之結合蛋白組合用於SLE(狼瘡）之治療劑的 實例包括以下：NSAID，例如雙氣芬酸、萘普生、布洛 芬、吼羅昔康、吲哚美辛；COX2抑制劑，例如塞内昔 布、羅非考昔、伐地考昔；抗瘧劑，例如羥基氣喹；類固 醇，例如潑尼松、潑尼龍、布地奈德、地塞米松；細胞毒 性劑’例如硫唾嘌呤、環磷醯胺、黴酚酸嗎啉乙酯、曱胺 。巣吟；PDE4抑制劑或嘌呤合成抑制劑，例如驍悉 (Cellcept)。本發明之結合蛋白亦可與以下之藥劑組合：諸 如柳氮磺胺吡啶、5-胺基水楊酸、奥沙拉嗪、依木蘭 (ImUran)及干擾促炎性細胞激素（諸如IL-1)合成、產生或作 用之藥齊丨例如卡斯蛋白酶抑制劑，如IL-1 β轉化酶抑制 151681.doc 201127956 劑及IL-Ira。本發明之結合蛋白亦可與T細胞信號傳導抑制 劑（例如酪胺酸激酶抑制劑）；或靶向Τ細胞活化分子之分 子（例如CTLA-4-IgG或抗Β7家族抗體、抗PD-1家族抗體）一 起使用。本發明之結合蛋白可與IL-11或抗細胞激素抗體 (例如芳妥珠單抗（fonotolizumab)(抗IFNg抗體））或抗受體之 受體抗體（例如抗IL-6受體抗體）及針對B細胞表面分子之抗 體組合。本發明之抗體或其抗原結合部分亦可與以下一起 使用：LJP 394(阿貝莫司（abetimus));消耗B細胞或使B細 胞失活之藥劑，例如利妥昔單抗（抗CD20抗體）、貝利單抗 (lymphostat-B)(抗BlyS抗體）；TNF拮抗劑，例如抗TNF抗 體、阿達木單抗（PCT公開案第WO 97/29131號； HUMIRA)、CA2(REMICADE)、CDP 571、TNFR-Ig構築體 (p75TNFRIgG(ENBREL)及 p55TNFRIgG(來那西普））；及 bcl-2抑制劑，由於已證實bcl-2在轉殖基因小鼠體内之過 度表現產生狼瘡像表型（參看Marquina, Regina等人， Journal of Immunology (2004), 172(11), 7177-7185) » 因此 預期抑制具有治療作用。 本發明之醫藥組合物可包括「治療有效量」或「預防有 效量」之本發明結合蛋白。「治療有效量」係指在必需劑 量下且歷時必需時段有效達成所要治療效果之量。結合蛋 白之治療有效量可由熟習此項技術者確定且可根據諸如疾 病病況、個體之年齡、性別及體重以及結合蛋白在個體中 引起所要反應之能力的因素而變化。治療有效量亦為抗體 或抗體部分之治療有益作用超過任何毒性或有害作用的 I5168l.doc -289- 201127956 係指在必㈣量下時必需時段有 達成所要預防結果之量。通常，因為在疾病早期階段之 則或在疾病早期階段時對個體使用預防劑量 效量將小於治療有效量。 頂万秀 可調整給樂方案以提供最佳所要反應(例如治 反應）。舉例而言，可投與單次劑量，可隨時間投與若干 分開劑量，或依治療情況之緊急性指示，可按比例減少或 增加劑量。出於易於投與且劑量均一之目的，將非經腸組 合物調配為單位劑型尤其適宜。如本文所用之單位劑型係 “適σ作為整體劑量用於欲治療哺乳動物個體的物理個別 單元；各單元含有經計算以產生所要治療作用之預定量的 活性化合物以及所要醫藥載劑。本發明之單位劑型的規格 由以下因素衫且直接視以下因素⑷活性化合物之 獨特特徵及欲達成之特定治療或預防作用；及⑻混配該活 陡化&物以達成個體之治療靈敏度之技術中所固有之限 制。 本發明結合蛋白之治療或預防有效量之例示性非限制範 圍為0.1至20 mg/kg，例如丨至⑺mg/kg。應注意劑量值可 月b隨欲緩解之病狀的類型及嚴重程度而變化。應進一步瞭 解，對於任何特定個體而言，特定劑量方案應根據個體需 要及投與或監督組合物投與之個人的專業判斷隨時間而加 以調整，且本文所述之劑量範圍僅供例示，而並非意欲限 制所主張之組合物的範疇或實施。 對於熟習此項技術者而言將顯而易見，本文所述之本發 151681.doc •290· 201127956 明方法的其他適合修改及改推Ss二只s ，_ 文進顯而易見且可使用適合等效 物進行，而不悖離本發明$ a本文所揭不之實施例之範疇。 現已詳細描述本發明，i去 〜 參考以下貫例將更清楚理解本發 明，該等實例僅出於說明 <目的包括在内且不欲限制本發 明。 V.診斷
本文之揭示内容亦提供診斷應用。下文將對此進行進一 步闡述。 I.檢定方法 本發明亦提供使用至少一種如本文所述之DVIMg測定 測試樣品中分析物（或其片段）之存在、量或濃度的方法。 該方法中可使用此項技術中已知之任何適合檢^。實例包 括（但不限於）免疫檢定，諸如夾心免疫檢定（例如單株多 株及/或DVD-Ig夾心免疫檢定或其任何變化形式（例如單株/ DVD-Ig、DVD_Ig/多株等），包括放射性同位素偵測（放射 免疫檢定（RIA))及酶偵測（酶免疫檢定（EIA)或酶聯結免疫 吸附劑分析法（ELISA)(例如Quantikine ELISA檢定R 〇
Systems，Minneapolis，MN))、競爭抑制免疫檢定（例如正 向及反向）、螢光偏振免疫檢定（FPIA)、酶倍增免疫檢定技 術（EMIT)、生物發光共振能量傳遞（BRET)及均質化學發 光檢定等。在基於SELDI之免疫檢定中，將特異性結合相 關分析物（或其片段）之捕捉試劑連接於質譜探針（諸如預活 化之蛋白質晶片陣列）表面。接著將分析物（或其片段）特異 性捕捉於生物晶片上，且藉由質譜法偵測所捕捉之分析物 151681.doc -291 - 201127956 (或其片段）。或者，可自捕捉試劑溶離分析物（或其片段） 且藉由傳統MALDI(基質輔助雷射脫附/離子化）或藉由 SELDI加以偵測。化學發光微粒免疫檢定（尤其採用 ARCHITECT® 自動分析儀（Abbott Laboratories，Abbott
Park，IL)之化學發光微粒免疫檢定）為較佳免疫檢定之實 例0 舉例而言，在如本文所述之DVD_Ig用作免疫診斷試劑 及/或用於分析物免疫檢定套組中時，使用此項技術中熟 知之收集、處理及加工尿液、血液、血清及血漿及其他體 液之方法來實踐本發明。測試樣品除相關分析物以外亦可 包含其他部分，諸如抗體、抗原、半抗原、激素、藥物、 酶、受體、蛋白質、肽、多肽、寡核苷酸及/或聚核苷 酸。舉例而言，樣品可為自個體獲得之全血樣品。在如本 文所述之免疫檢定前可能必需或需要例如用預處理試劑處 理測試樣品（尤其全血）。即使在預處理並非必需之情形（例 如大多數尿液樣品）下，仍可視情況進行預處理（例如，作 為基於商業平台之方案的一部分）。 預處理試劑可為任何適於與本發明之免疫檢定及套組一 起使用之試劑。預處理視情況包含：（a)一或多種溶劑（例 如甲醇及乙二醇）及視情況選用之鹽，（b)一或多種溶劑及 鹽及視情況選用之清潔劑，（c)清潔劑，或（幻清潔劑及 鹽。預處理試劑為此項技術中所已知，且可（例如）如 Abbott TDx，AxSYM® 及 ARCHITECT⑧分析器（Abb〇u
Laboratories，Abbott Park，IL)上之檢定所用 '如文獻（參見 \5l6Sl.doc -292- 201127956 例如 Yatscoff 等人 Abbott TDx Monoclonal Antibody Assay
Evaluated for Measuring Cyclosporine in Whole Blood, Clin. Chem. 36: 1969-1973 (1990)及 Wallemacq 等人
Evaluation of the New AxSYM Cyclosporine Assay: Comparison with TDx Monoclonal Whole Blood and EMIT
Cyclosporine Assays, Clin. Chem. 45: 432-435 (1999))中描 述及/或如可購得來運用該預處理。此外，可如Abbott的美 φ 國專利第5，135,875號、歐洲專利公開案第0 471 293號、 2006年12月29日申請之美國臨時專利申請案6〇/878,〇17以 及美國專利申請公開案第2008/0020401號（針對其關於預處 理之教示以全文引用的方式併入）中所述進行預處理。預 處理試劑可為異質試劑或均質試劑。 在使用異質預處理試劑下，預處理試劑使樣品中存在之 分析物結合蛋白（例如可結合至分析物或其片段之蛋白質） 沈澱。該預處理步驟包含藉由將沈澱之分析物結合蛋白與 • 藉由將預處理劑添加至樣品中所形成之混合物的上.音液八 離來移除任何分析物結合蛋白。在該檢定中，將不存在任 何結合蛋白之混合物上清液用於檢定，直接進行至抗體捕 捉步驟。 在使用均質預處理試劑下’不存在該分離步驟。使測試 樣品與預處理試劑之整個混合物與分析物（或其片段）之經 標記特異性結合搭配物(諸如經標記之抗分析物抗體(或其 抗原反^性片段）)接觸。通常在由第一特異性結合搭配物 捕捉之别或期間，將用於該檢定之預處理試劑於經預處理 151681.doc •293- 201127956 之測試樣品混合物中稀釋。儘管存在該稀釋，但在捕捉期 間測試樣品混合物中仍存在（或殘留）_定量預處理試劑。 根據本發明，經標記特異性結合搭配物可為(或其 片段、變異體或變異體之片段 在異質形式中，在自個體獲得測試樣品後，製備第一混 合物。混合物含有對分析物（或其片段）進行評定之測試樣 。。及第-特異性結合搭配物，其中該第一特異性結合搭配 物與測試樣品中所含之任何分析物形成第一特異性結合搭 配物-分析物複合物。第一特異性結合搭配物較佳為抗分籲 析物抗體或其片段。第一特異性結合搭配物可為如本文所 述之DVD-Ig(或其片段、變異體或變異體之片段）。添加測 試樣品及第一特異性結合搭配物以形成混合物之順序並非 關鍵所在。較佳將第一特異性結合搭配物固定於固相上。 用於免疫檢定（用於第一特異性結合搭配物及視情況用於 第一特異性結合搭配物）之固相可為此項技術中已知之任 何固相，諸如（但不限於）磁性粒子、珠粒、試管、微量滴 定板、光析管、膜、骨架分子、薄模、遽紙、圓盤及晶籲 片。 形成3有第特異性結合搭配物-分析物複合物之混合 物後’使用此項技術中已知之任何技術自複合物移除任何 未結合之分析物。舉例而言’可藉由洗滌移除未結合之分 析物。然而，理想的是存在之第一特異性結合搭配物之量 超過測試樣品中存在之任何分析物，以使測試樣品中存在 之所有分析物皆與第一特異性結合搭配物結合。 151681.doc •294· 201127956 移除任何未結合之分析物後，將第二特異性結合搭配物 添加至屍合物中以形成第一特異性結合搭配物-分析物-第 二特異性結合搭配物複合物。第二特異性結合搭配物較佳 為結合至分析物上不同於第一特異性結合搭配物在分析物 上所結合之抗原決定基之抗原決定基的抗分析物抗體。此 外’第二特異性結合搭配物亦較佳經如上文所述之可偵測 標記物來標記或含有如上文所述之可偵測標記物。第二特 異性結合搭配物可為如本文所述之DVD-Ig(或其片段、變 異體或變異體之片段）。 可使用此項技術中已知之任何適合之可偵測標記物。舉 例而言’可偵測標記物可為放射性標記物（諸如3H、i2h、 35S、14c、32p及33p)、酶標記物（諸如辣根過氧化酶、鹼性 過氧化酶、葡萄糖6-磷酸脫氫酶及其類似物）、化學發光標 記物（諸如吖啶鏽酯、硫酯、或磺醯胺；魯米諾、異魯米 諾（isoluminc^)、啡咬鏽醋（phenanthridinium ester)及其 類似物）、螢光標記物（諸如螢光素（例如5-螢光素、6-羧基 螢光素、3’6-羧基螢光素、5(6)-羧基螢光素、6-六氯-螢光 素、6-四氯螢光素、異硫氰酸螢光素及其類似者））、若丹 明、藻膽蛋白（phycobiliprotein)、R-藻紅素、量子點（例 如硫化辞封端之硒化鎘）、測溫標記物或免疫聚合酶鏈反 應標記物。標記物之引入、標記程序及對標記物之偵測可 見 於 Polak 及 Van Noorden, Introduction to Immunocytochemistry,第 2版，Springer Verlag，Ν·Y. (1997) 及 Haugland，Handbook of Fluorescent Probes and Research 151681.doc -295- 201127956
Chemicals (1996)(其為由 Molecular Probes，Inc.，Eugene， Oregon出版之組合手冊及目錄）中。螢光標記物可用於 FPIA中（參看例如美國專利第5,593,896號、第5,573,904 號、第 5,496,925號、第 5,359,093號及第 5,352,803號，其 以全文引用的方式併入本文中）。吖啶鏽化合物可在均質 或異質化學發光檢定中用作可偵測標記物（參看例如 Adamczyk 等人，Bioorg. Med. Chem. Lett. 16: 1324-1328 (2006) ; Adamczyk等人，Bioorg· Med. Chem· Lett. 4: 2313-2317 (2004) ; Adamczyk等人，Biorg. Med. Chem. Lett. 14: 3917-3921 (2004);及 Adamczyk 等人，Org. Lett. 5: 3779-3782 (2003)) 〇 較佳吖啶鏽化合物為吖啶鏽-9-甲醯胺。製備吖啶鏽9-甲 醯胺之方法係描述於Mattingly，J. Biolumin. Chemilumin. 6: 107-114 (1991) ; Adamczyk 等人，J. Org. Chem. 63: 5636-5639 (1998) ; Adamczyk等人，Tetrahedron 55: 10899-10914 (1999) ; Adamczyk 等人，〇rg. Lett. 1: 779-781 (1999) ; Adamczyk等人，Bioconjugate Chem· 11: 714-724 (2000) ; Mattingly 等人，Luminescence Biotechnology: Instruments and Applications ; Dyke，K. V.編；CRC Press: Boca Raton,第 77-105 頁（2002) ; Adamczyk 等人，0犷吕· Lett. 5: 3779-3782 (2003);及美國專利第 5,468,646號、第 5,543,524號及第5,783,699號中（其各自關於相同目的之教 示以全文引用的方式併入本文中）。另一較佳吖啶鑌化合 物為吖啶鏽-9-曱酸芳酯。吖啶鏽-9-曱酸芳酯之實例為10- 151681.doc •296· 201127956 甲基-9-(苯氧幾基）。丫咬錯氣績酸鹽（可自Cayman Chemical， Ann Arbor，MI獲得）。製備吖啶鏽9-曱酸芳酯之方法係描 述於 McCapra 等人，Photochem. Photobiol. 4: 1111-21 (1965); Razavi等人，Luminescence 15: 245-249 (2000); Razavi等人，Luminescence 15: 239-244 (2000);及美國專 利第5,241，070號中（其各自關於相同目的之教示以全文引 用的方式併入本文中）。關於吖啶鑌_9_甲酸芳酯及其用途 之其他細節於US 2〇08-0248493中闡述。 可根據 Adamczyk 等人，Anal. Chim. Acta 579(1): 61-67 (2006)中所述之方法進行化學發光檢定（例如，使用如上文 所述之。丫啶鏽或其他化學發光劑）。儘管可使用任何適合 之檢定形式，但微板化學發光計（Mithras LB-940, Berthold Technologies u.s.A.，LLC，〇ak Ridge，TN)使得能夠快速檢 定多個小體積樣品。 添加測試樣品及特異性結合搭配物以形成用於化學發光 檢定之混合物之順序並非關鍵所在。若第一特異性結合搭 配物經諸如。丫啶鏽化合物之化學發光劑可偵測標記，則形 成經可偵測標記之第一特異性結合搭配物-分析物複合 物或者，右使用第二特異性結合搭配物且第二特異性結 合搭配物經諸如吖啶鏽化合物之化學發光劑可偵測標記， 則形成經可偵測標記之第一特異性結合搭配物-分析物-第 一特異性結合搭配物複合物。可使用此項技術中已知之任 何技術（諸如洗滌）自混合物移除任何經標記或未經標記的 未結合之特異性結合搭配物。 151681.doc •297· 201127956 在添加上述。丫啶鏽化合物之前、同時或之後，可在混合 物中就地產生過氧化氫或可向混合物中提供或供應過氧化 氫（例如，過氧化氫之來源為一或多種已知含有過氧化氫 之緩衝液或其他溶液過氧化氫可以多種方式（諸如為熟 習此項技術者所顯而易見之方式）就地產生。 在同時或隨後向樣品中添加至少一種鹼性溶液後，產生 指示分析物存在之可偵測信號，即化學發光信號。鹼性溶 液含有至少一種鹼且具有大於或等於1〇，較佳大於或等於 12之pH值。鹼性溶液之實例包括（但不限於）氫氧化鈉、氫 氧化鉀、氫氧化鈣、氫氧化銨、氫氧化鎂、碳酸鈉、碳酸 氫鈉、氫氧化鈣、碳酸鈣及碳酸氫鈣。添加至樣品中之鹼 性溶液之量視鹼性溶液之濃度而定。基於所用鹼性溶液之 濃度’熟習此項技術者可輕易地確定添加至樣品中之鹼性 溶液之量。 可使用熟習此項技術者所已知之常規技術偵測所產生之 化學發光信號。基於所產生之信號強度，可定量樣品中分 析物之量。特定言之’樣品中分析物之量與所產生之信號 強度成比例。可藉由將所產生光之量與分析物之標準曲線 相比較或藉由與參考標準物相比較來定量存在之分析物之 S。可藉由質譜分析、重量分析法及此項技術中已知之其 他技術使用已知濃度之分析物的連續稀釋液或溶液產生標 準曲線。儘管上文著重描述使用吖啶鑌化合物作為化學發 光劑’但一般熟習此項技術者可輕易地改變此描述以使用 其他化學發光劑。 151681.doc -298- 201127956
分析物免疫檢定一般可使用此項技術中已知之任何形式 (諸如（但不限於）夾心形式）來進行。特定言之，在一種免 疫檢疋形式中，採用至少2種抗體來分離及定量樣品中之 分析物，諸如人類分析物或其片段。更特定言之，至少2 種抗體結合於分析物（或其片段）上之不同抗原決定基以形 成免疫複合物，其稱作「灸心广一般而言，在免疫檢^ 中’可使用—或多帛抗體來捕捉測試樣品中之分析物（或 其片段）（此等抗體通常稱作「捕捉」抗體），且可使用—或 多種抗體以使可偵測(即可定量)標記物結合於夾心(此等抗 體常稱作「债測抗體」、「結合物」}。因此，在夾心免疫 檢定形式之情形中，如本文所述之则_1§(或其片段、變 異體或變異體之片段)可用作捕捉抗體、债測抗體或兩 者。舉例而言，一種具有可結合分析物(或其片段)上之第 扩原決疋基之、.，α構區域的DVD_Ig可用作捕捉抗體及/或 另一具有可結合分析物（或其片段）上之第二抗原決定基之 結構區域的則_Ig可用作们則抗體。就此而t，具有可 結合分析物(或其片段)上之第一抗原決定基之第一結構區 析物（或其片段）上之第二抗原決定基之第二 構區域的DVD-Ig可用作捕捉抗體及/或偵測抗體。或 者種具有可結合第—分析物（或其片段）上之抗原決定 土，=、·、。構區域及可結合第二分析物(或其片段)上之抗 '、、疋基之第_!。構區域的DVD_ig可用作捕捉抗體及/或 偵測抗體來偵測且視情況定量兩種或兩種以上分析物。若 斤物可此卩種以上形式（諸如單體形式及二聚/多聚形 151681.doc •299- 201127956 式’其可為均聚（homomeric)或雜聚（heteromeric))存在於 樣品中’則一種具有可結合僅暴露於單體形式上之抗原決 定基之結構區域的DVD_Ig及另一種具有可結合二聚/多聚 形式之不同部分上之抗原決定基之結構區域的DVD-Ig可 用作捕捉抗體及/或偵測抗體，從而使得能夠偵測及視情 況疋量不同形式之既定分析物。此外，使用單個DVD-Ig 中及/或DVD-Ig之間親和力有所不同之j)VD-Ig可提供親合 力優勢。在如本文所述之免疫檢定之上下文中，將一或多 個連接子併入DVD-Ig之結構中一般可能為有幫助或合乎 需要的。若存在連接子，則最佳連接子應具有足夠長度及 結構可撓性以使内部結構區域能夠結合抗原決定基以及外 部結構區域能夠結合另一抗原決定基。就此而言，若 DVD-Ig可結合兩種不同分析物且一種分析物大於另一種 時，則合乎需要的是，由外部結構區域結合較大分析物。 一般而言，測試（例如懷疑含有）分析物（或其片段）之樣 品可同時或依序及按任何順序與至少一種捕捉抗體及至少 一種偵測抗體（例如在捕捉及/或偵測抗體包含多種抗體之 情形下’其可為第二偵測抗體或第三_抗體或甚至連續 編號之抗體）接觸。舉例而言，可使測試樣品首先與至少 一種捕捉抗體接觸且接著（依序）與至少—種偵測;體接 觸:^ ’可使測試樣品首先與至少，測抗體接觸且 接著（依序）與至少一種捕捉抗體接觸。在另一替代方案 中，可使測試樣品同時與捕捉抗體及债測抗體接觸。 在夾心檢定形式中，使懷疑含有分析物（或其片段）之樣 151681.doc -300· 201127956 品首先與至少一種第一捕捉抗體在使得形成第一抗體/分 析物複合物之條件下接觸。若使用一種以上捕捉抗體，則 形成包含兩種或兩種以上捕捉抗體之第一捕捉抗體/分析 物複合物。在夾心檢定中，以比測試樣品中預期之分析物 (或其片#又）之最大篁莫耳過量之量使用抗體（亦即較佳至少 一種捕捉抗體）。舉例而言，可使用每毫升緩衝液（例如微 粒塗覆緩衝液）約5微克至約1毫克抗體。 φ 由於品要僅由一種抗體結合而常用於量測小分析物之競 爭抑制免疫檢定包含依序及經典形式。在依序競爭抑制免 疫檢定中，將相關分析物之捕捉抗體塗覆於微量滴定板之 孔或其他固體支樓物上。當將含有相關分析物之樣品添加 至孔中時，相關分析物結合於捕捉抗體。洗$條後，將已知 里之經軚s己（例如生物素或辣根過氧化酶分析物添 加至孔中。酶標記物之受質為產生信號所必需。之適 Q又質之實例為3’3’，5,5’·四甲基聯苯胺（TMB)。洗條後， 镛 s測由經^ s己之分析物產生之信號且該信號與樣品中分析 θ成反比在經典競爭抑制免疫檢定中，將相關分析 物之抗體塗覆於固體支撐物（例如微量滴定板之孔）上。然 而、不同於依序競爭抑制免疫檢定，同時將樣品及經標記 析物添加至孔中。樣品中之任何分析物與經標記之分 析物競爭結合於捕捉抗體。洗務後，量測由經標記之分析 物產生之仏號且該信號與樣品中分析物之量成反此。 視障况在使測試樣品與至少—種捕捉抗體（例如第一捕 捉抗體）接觸之前，可使至少-種捕捉抗體結合於固體支 151681.doc -301 · 201127956 撐物上，此便利於使第一抗艚/八姑札“ ^體/刀析物（或其片段）複合物與 測試樣品分離。捕捉抗體所έ士入 听、σ σ之雙質可為便利於捕捉抗 體析物複合物自樣品分離之杯彳^、电人 刀離之任何適合固體支撐物或固 相。 實例包括培養板（諸如微量滴定板）之孔、試管、多孔凝 膠（例如石夕膠、禮脂糖、聚葡萄糖或明膠）、聚合薄膜（例如 聚丙稀醯胺）、林（例如聚苯乙稀珠粒或磁性珠粒）、滤紙/ 膜（例如硝化纖維素或耐綸）之條帶、微粒（例如乳膠粒子、 可磁化微粒（例如具有氧化鐵或氧化鉻核心及均聚或雜聚 塗層及半徑為約1至10微米之微粒）。受質可包含適合多孔 材料，其具有適於結合抗原之表面親和力及足以使偵測抗 體出入之孔隙率。儘管可使用呈水合狀態之凝膠狀材料， 但微孔材料一般為較佳的。該等多孔受質較佳為厚度為約 0.01 mm至約0.5 mm，較佳約〇. 1 mm之薄片形式。雖然微 孔尺寸可大不相同，但較佳微孔尺寸為約0.025至約1 5 μηι ’更佳為約0.15至約15 μιη。該等受質之表面可藉由使 抗體與受質共價鍵聯之化學製程活化。引起抗原或抗體一 般藉由經疏水力吸附而不可逆結合於受質；或者，可使用 化學偶合劑或其他方式使抗體共價結合於受質，其限制條 件為該結合不干擾抗體結合分析物之能力。或者，抗體可 與微粒結合，該等微粒先前塗有抗生蛋白鏈菌素（例如 DYNAL®磁性珠粒，invitrogen, Carlsbad，CA)或生物素（例 如使用Power-BindTM-SA-MP抗生蛋白鏈菌素塗覆之微粒 (Seradyn，Indianapolis，IN))或抗物種特異性單株抗體。必 151681.doc • 302- 201127956 要時’受質可經衍生化以對抗體上之各種官能基具有反應 隹 玄讨生化需要使用某些偶合劑，其實例包括（但不限 於）順丁烯二酸酐、N_羥基丁二醯亞胺及丨_乙基_3_(3_二曱 基胺基丙基）碳化二亞胺。需要時，可使一或多種捕捉試 劑（諸如抗體（或其片段），其各對分析物具有特異性）連接 於固相之不同物理或可定址位置上（例如呈生物晶片組 態）（參看例如美國專利第6,225,047號；國際專利申請公開 案第墀〇 99/51773號；美國專利第6,329,209號；國際專利 申請公開案第WO 00/56934號；及美國專利第5,242,828 號）。若使捕捉試劑連接於作為固體支撐物之質譜探針 上’則可藉由雷射脫附離子化質譜偵測結合於探針之分析 物之置。或者，可用經一或多種捕捉試劑衍生化之不同珠 粒填充單個管柱，從而在單一位置上捕捉分析物（參見， 基於丄抗體衍生化之珠粒的技術，例如Luminex(Aushn， TX)之χΜΑΡ技術）。 在使檢定分析物（或其片段）之測試樣品與至少一種捕捉 抗體（例如第一捕捉抗體）接觸後，培育混合物以使形成第 一抗體（或多種抗體）-分析物（或其片段）複合物。培育可在 約4.5至約10.0之pH值下，在約2。〇至約45t之溫度下進行 且歷經至少約i分鐘至約18小時，較佳約1分鐘至約24分 鐘，最佳約4分鐘至約丨8分鐘之時段。本文所述之免疫檢 定可以一個步驟進行（意謂依序或同時將測試樣品、至少 一種捕捉抗體及至少一種偵測抗體全部添加至反應容器 中）或以一個以上步驟，諸如兩個步驟、三個步驟等進 151681.doc 303 · 201127956 行。 、在（第—或第若干）捕捉抗體/分析物（或其片段）複合物形 成後，接著使複合物與至少一種偵測抗體在允許形成（第 I或第若干）捕捉抗體/分析物（或其片段v第二伯測抗體複 «物之條件下接觸。儘管為清楚起見而冠以「第二」抗體 (例如第—偵測抗體）之名稱，但實際上若使用第若干抗體 2仃捕捉及/或偵測’至少_種偵測抗體可為用於免疫檢 =之第-抗體、第三抗體、第四抗體等。若使捕捉抗體/ 分析物（或其片段）複合物與一種以上偵測抗體接觸，則形 成（第—或第若干）捕捉抗體/分析物（或其片段）/(第若干）偵 測抗體複合物。如同捕捉抗體（例如第一捕捉抗體），當使 —種（例如第二及任何後續編號）偵測抗體與捕捉抗體/ 为析物（或其片段）複合物接觸時，需要在與上文所述之條 件類似的條件下培育一段時間，以形成（第一或第若干）捕 捉抗體/分析物（或其片段）/(第二或第若干）偵測抗體複合 物。至少一種偵測抗體較佳含有可偵測標記物。可偵測標 °己物可在（第—或第若干）捕捉抗體/分析物（或其片段）/(第 二或第若干）偵測抗體複合物形成之前、同時或之後結合 於至j 一種偵測抗體（例如第二偵測抗體）。可使用此項技 術中已知之任何可偵測標記物（參看上文論述，包括P〇lak 及 Van N〇orden (1997)及 Haugiand (1996)參考文獻）。 可偵測標記物可直接或經由偶合劑結合至抗體。可使用 之偶合劑之實例為EDAC(1•乙基_3_(3_二甲基胺基丙基）碳 化二亞胺鹽酸鹽），其可自Sigma-Aldrich，St. Louis，MO購 15168I.doc •304· 201127956 知·。可使用之其他偶合劑為此項技術所已知。使可彳貞測標 δ己物結合至抗體之方法為此項技術所已知。此外，多種已 含有促成可偵測標記物偶合於抗體之端基的可偵測標記物 可購得或合成，諸如CPSP-吖啶鑌酯（亦即9-[Ν-曱笨磺醯 基-Ν-(3-叛基丙基）]_ι〇_(3-磺丙基）吖啶鏽甲醯胺）或SPSp_ 丫 °定錄Sa (亦即Nl〇-(3-續丙基）-N-(3-確丙基）-〇>丫咬鐵_9_甲 酿胺）。 在定量標記物之前’可（但並非必需）將（第一或第若干） 捕捉抗體/分析物/(第二或第若干）偵測抗體複合物與測試 樣品之其餘部分分離。舉例而言，若至少一種捕捉抗體 (例如第一捕捉抗體）與固體支撐物（諸如孔或珠粒）結合， 則可藉由移除流體（測試樣本之流體）’不再與固體支樓物 接觸來達成分離。或者，若至少第一捕捉抗體結合於固體 支撑物’則其可同時與含有分析物之樣品及至少一種第二 偵測抗體接觸，以形成第一（第若干）抗體/分析物/第二（第 若干）抗體複合物，繼而移除流體（測試樣品），不再與固體 支撐物接觸。若至少一種第一捕捉抗體未結合於固體支撐 物，則無需自測試樣品移除（第一或第若干）捕捉抗體/分析 物/(第二或第若干）偵測抗體複合物即可定量標記物之量。 在經標s己之捕捉抗體/分析物/偵測抗體複合物（例如第一 捕捉抗體/分析物/第二偵測抗體複合物）形成後，使用此項 技術中已知之技術定量複合物中之標記物之量。舉例而 5，若使用酶標記物，則使經標記之複合物與標記物之受 質反應，產生可定量反應，諸如顯色。若標記物為放射性 151681.doc • 305· 201127956 標記物’則使用適合方式（諸如閃爍計數隊量標記物。 若標記物為螢光標記物，則藉由用單色光（其稱作「激發 波長」）刺激標記物且偵測由標記物回應刺激所發射之另 顏色（八稱作發射波長」）來定量標記物。若標記物為 化干發光私。己物’則藉由目測或使用光度計、X射線膠 片、高速攝影膠片、CCD攝像機等價測所發射之光來定量 標記物。在定量出複合物中標記物之量之後，則藉由適合 方式’諸如藉由使用已使用已知濃度之分析物或其片段之 連續稀釋液產生之標準曲線來測定測試樣品中分析物或其 片段之漠度。除使时析物或以段之㈣稀釋液以外， 可以重量分析方式、藉由質错分析及藉由此項技術中已知 之其他技術產生標準曲線。 在採用ARCHITECT®*析儀之化學發光微粒檢定中，結 合物稀釋劑pH值應為約6·0+/·0.2，微粒塗覆緩衝液應維持 於約室溫下（亦即在約17t至約27。〇下），微粒塗覆緩衝液 pH值應為約6.5+/_〇.2，且微粒稀釋劑pH值應為約7 8+/_ 〇.2。固體較佳少於約〇.2%，諸如少於約〇 15%、少於約 0.14%、少於約〇,13%、少於約〇 12%或少於約〇 ιι%，諸如 約 0.10%。 FPIA係基於競爭性結合免疫檢定原理。經螢光標記之化 合物在由線性偏振光激發時將發射偏振度與其旋轉速率成 反比之螢光。當藉由線性偏振光激發經螢光標記之示蹤 劑-抗體複合物時，所發射之光仍保持高度偏振，因為螢 光團在吸收光之時間與發射光之時間之間旋轉受限》當藉 151681.doc •306· 201127956 由線ϋ偏振光激發「游離」示縱劑化合物（亦即未結合至 抗體之化合物）時’其旋轉比競爭性結合免疫檢定中所產 生之相應示縱劑★體結合物快得多。fpia由於不存在需 要特殊處理及處置之放射性物質而優於ria ^此外，阳A 為可輕易且快速進行之均質檢定。 蓉於上文’提供測定分析物（或其片段）於測試樣品中之 存在、量或濃度的方法。該方法包含藉由如下檢定來檢定 式樣Q口之/刀析物（或其片段），該檢定⑴採用可結合於 分析物之抗體、抗體片m合於分析物之抗體之變異 體，可結合於分析物之抗體變異體之片&;及可結合於分 :物之DVD-Ig(或其片段、變異體或變異體之片段）中之至 者及（11 )至少一種可偵測標記物；且（ii)包含將由可 貞、。己物產生作為分析物(或其片段)於測試樣品中之存 在里或浪度的直接或間接指示的信號與產生作為分析物 (或其片段）於對照物或校正劑中之存在、量或濃度之直接 广信號相比較。校正劑視情況為一系列校正劑 部分，其中各校正劑與其他校正劑之分析物濃度不 ^法可包含⑴使測試才策品與至少一種選自由以下 之群的分析物（或其片段）之第一 帮 一 订f王、·、°合搭配物接觸以 結人特異性結合搭配物/分析物（或其片段）複合物：可 IS析物之抗體、抗體片段；可結合至分析物之抗體 合至、a，可結合至分析物之抗體變異體之片段；及可结 〇分析物之DVD-〗g(或其片段、變異體或變異體之片° 15168l,d〇( -307- 201127956 段）；（ii)使第一特異性結合搭配物/分析物（或其片段）複合 物與至少一種選自由以下組成之群的分析物（或其片段）之 第二特異性結合搭配物接觸以形成第一特異性結合搭配物/ 分析物（或其片段）/第二特異性結合搭配物複合物：可結合 至分析物的經可偵測標記之抗分析物抗體、經可偵測標記 之抗分析物抗體片段；可結合至分析物的經可偵測標記之 抗分析物抗體變異體；可結合至分析物的經可偵測標記之 抗分析物抗體變異體片段；及經可偵測標記之DvD_Ig(或 其片丰又良異體或變異體之片段）；及（iii)藉由偵測或量測 由（ii)中所形成之第一特異性結合搭配物/分析物（或其片 •k )/第一特異性結合搭配物複合物中之可偵測標記物產生 之信號來測定分析物於測試樣品中之存在、量或濃度。至 少一種針對分析物（或其片段）之第—特異性結合搭配物及/ 或至少—種針對分析物（或其片段）之第二特異性結合搭配 物為如本文所述之DVD_Ig(或其片&、變# 片段）的方法可為較佳的。 '體之 或者’該方法可包含使測試樣品與至少_種選自由以下 物接* #的針對刀析物（或其片段）之第—特異性結合搭配 結合至分析物之抗體、抗體之片段；可結合至 f.及d:體隻異體可結合至分析物之抗體變異體之片 丰又’及 DVD-Ig(或 Ml h eη . 時或r总 變異體或變異體之片段)；且同 “ 以任—順序使測試樣品與至少-種第1里性 結合搭配物接觸，該 種第-特異性 分析物(或其片段)競泰 異性結合搭配物可與 (戈其片μ競♦結合至至少一種第—特異性結合搭 151681.doc 201127956 配物且係選自由以下組成之群：可結合至第一特異性結合 搭配物的經可偵測標記之分析物、經可偵測標記之分析物 片段；可結合至第一特異性結合搭配物的經可偵測標記之 分析物變異體’及可結合至第一特異性結合搭配物的經可 偵測標記之分析物變異體片段。測試樣品中存在之任何分 析物（或其月段）與至少一種第二特異性結合搭配物彼此競 爭以分別形成第一特異性結合搭配物/分析物（或其片段）複 Φ 合物及第一特異性結合搭配物/第二特異性結合搭配物複 合物。該方法進一步包含藉由偵測或量測由（丨丨）中所形成 之第一特異性結合搭配物/第二特異性結合搭配物複合物 中之可偵測標記物所產生之信號來測定分析物於測試樣品 中之存在、量或濃度’其中由第一特異性結合搭配物/第 二特異性結合搭配物複合物中之可偵測標記物產生之信號 與測試樣品中分析物之量或濃度成反比。 上述方法可進一步包含對獲得測試樣品之患者之治療性 φ /預防性處理的功效進行診斷、預後或評定。若該方法進 一步包含评定對獲得測試樣品之患者之治療性/預防性處 理的功效，則该方法視情況進一步包含根據需要改變患者 的治療性/預防性處理以改良功效。該方法可經改進用於 自動化系統或半自動化系統中。 關於檢定方法（及其套組），可能使用可購得之抗分析物 抗體或如文獻中所述製造抗分析物之方法。各種抗體之供 應商包括（但不限於）Santa Cruz Biotechn〇1〇gy Inc (Santa
Cruz，CA)、GenWay Biotech，Inc· (San Diego, CA)及 R&D 151681.doc •309· 201127956
Systems (RDS; Minneapolis, MN)。 一般而言，可❹預定含量作為評定檢定測試樣品之分 析物或其片段（例如用於债測疾病或疾病風險）所獲得社果 之基準。-般而言，在進行該種比較中，藉由在適合條件 下進行特定檢定足夠多次數來獲得預定含量，使得可建立 分析物存在、量或濃度與疾病、病症或病狀之特定階段或 終點或與特定臨床指標之關聯或聯繫。通常，藉由檢定參 考個體（或個體之群體）獲得預定含量。所量測:分析物可 包括其片段、其降解產物及/或其酶裂解產物。 特定言之’關於用於監測疾病進展及/或治療之預定含 量，分析物或其片段之量或濃度可「不變」、「有利」（或 「有利地改變」）或「不利」（「不利地改變」「升高 或「增加」係指測試樣品中之量或濃度高於典型或正常二 量或範圍(例如預定含量)，或高於另-參考含量或範圍(例 如初期或基線樣品）。術語「降低」或「減少」係指測試 2中之量或濃度低於典型或正常含量或範圍（例如預定 含篁），或低於另-參考含量或範圍（例如初期或基線樣 品）。術語「改變 係样0 士 係扣樣。σ中之量或濃度改變（增加或降 低）超出典型或正常含量或範圍（例如預定含量）或超出另一 參考含量或範圍(例如初期或基線樣品卜 刀析物之典型或正常含量或範圍係根據標準操作來定 由於分析物含量在-些情形下極低，所以當與典型或 申3里或範圍’或參考含量或範圍相比出現不能由實驗 s、或樣印差異解釋之任何淨變化時，可認為已發生所謂 151681.doc •310· 201127956 改變之含量或改變。因此，將在特定樣品中所量測之含量 與在來自所謂正常個體之類似樣品甲所測定之含量或含量 範圍相比較。在此情形令，「正常個體」為例如盔可 疾病之個體，且例如「正常」（有時稱作「對照」）患者或 群體分別為不展現可偵測疾病之患者或群體。此外，假定 在絕大部分人類群體中通常未發現高含量之分析物，又：
「正常個體」可視作分析物之量或濃度無實質可憤測增加 或升高之個體，且「正常」（有時稱作「對照」）患者或群 體為展現分析物之量或濃度無實質可偵測增加或升高的串 者或群體。「表觀正常個體」為尚未評定分析物或當前： 坪定分析&之μ。當分析物通常為不可摘測（例如正常 含量為零’或處於正常群體之約25%至約75%之範圍内）， =在測試樣品中倘測到分析物時，以及當分析物以高於正 :含量之量存在於測試樣品中時，認為分析物之含量「升 =」。因此，本發明尤其提供筛選罹患特定疾病、病症或 、狀或有罹患特定疾病、病症或病狀之風險之個體的方 > °檢定方法亦可涉及檢定其他料物及其類似物。 ^此’本文所述之方法亦可用於確定個體是否罹患既定 浃病、病症或病狀或有產生既定 疋展届病症或病狀之風 特叱吕之，該方法可包含以下步驟： 來自個體之測試樣品中分析物（或其片段）之濃 二例如使用本文所述之方法或此項技術中已知之方 /去），及 將步驟⑷中測定之分析物（或其片段）之濃度或量與預 151681.doc -311. 201127956 定含量相比較，其中若步驟⑷中所測定之分析物之濃度或 量相對於預定含量而言為有利的，則確定個體未罹患既定 疾病、病症或病狀或無罹患既定疾病、病症或病狀之風 險。然而’若步驟⑷中測定之分析物之濃度或量相對於預 定含量而言為不利的，則確定個體羅患既定疾病、病症或 病狀或有罹患既定疾病、病症或病狀之風險。 此外，本文提供監測個體疾病進展的方法。該方法最佳 包含以下步驟： ⑷測定來自個體之測試樣品中分析物之濃度或量. 旦⑼測定來自個體之隨後測試樣品中分析物之濃度或 ®，及 ⑷將如步驟（b)中所心之分析物之濃度或量與步驟 中^則定之分析物之濃度或量相比較，其中若步驟（b)中所 測疋之濃度或量在與步驟⑷中測定之分析物之濃度或量相 比較時無變化或為不利的’則確定該個體之疾病持續、進 展或惡化。藉由比較，若步驟㈦中所測定之分析物之濃产 或量在與步驟（a)中所測定之分析 又 <，辰度或量相比較時為 有利的’則確定該個體之疾病已中止、消退或改善。 〇亥方法視情況進一步包含將牛聰/1 之:Μ （）中所測定之分析物 例如預定含量相比較。此外，該方法視情況 :::=r(b)中所測定之分析物之濃度或量例如 1ΓΓ 不利改變，則用-或多種醫藥組合物 治療個體一段時間。 口卿 此外，可使用該等方法來監測接受對使用一或多種醫藥 15I681.doc -312· 201127956 組合物治療之個體之治療。特定言之，該等方法涉及提供 來自個體之第一測試樣品，隨後向個體投與一或多種醫藥 組合物。隨後，測定來自個體之第一測試樣品中分析物之 濃度或量（例如使用本文所述或如此項技術中已知之方 法）。在測疋分析物之濃度或量後，接著視情況將分析物 之濃度或量與預定含量相比較。若在第一測試樣品中所測 定之分析物之濃度或量低於預定含量，則不用一或多種醫 Φ 藥組合物治療個體。然而，若在第一測試樣品中所測定之 分析物之濃度或量高於預定含量，則用一或多種醫藥組合 物治療個體一段時間。以一或多種醫藥組合物治療個體之 時段叮由熟習此項技術者來確定（例如該時段可為約7天至 約2年’較佳為約14天至約1年）。 在以一或多種醫藥組合物治療過程期間，接著自個體獲 知第一及後續之測試樣品。測試樣品之數目及自個體獲得 s亥專測§式樣品之時間並非關鍵所在。舉例而言，可在第一 φ 次向個體投與一或多種醫藥組合物後7天獲得第二測試樣 品，可在第一次向個體投與一或多種醫藥組合物後2週獲 知第二測試樣品’可在第一次向個體投與一或多種醫藥組 合物後3週獲仔第四測試樣品’可在第一次向個體投與一 或多種醫藥組合物後4週獲得第五測試樣品等。 在自個體獲得各第二或後續之測試樣品後，測定第二或 後續之測試樣品中分析物之濃度或量（例如使用本文所述 或如此項技術中已知之方法）。接著將在各第二及後續測 試樣品中所測定之分析物之濃度或量與在第一測試樣品 151681.doc -313· 201127956 (例如最初視情況與預定含量相比較 平乂則喊樣品）中所測定 之分析物之濃度或量相比較。若击娜山 右步驟（C)中所測定之分析物 之濃度或量在與步驟（a)中所測定之分 <刀斫物之濃度或量相比 較時為有利的，則確定個體之疾病已中止、消退或改善， 且應繼續向該個體投與步驟（b)之—或多種醫藥組合物。然 而’若步驟（C)中所測定之濃度或|扃 X兄里在與步驟（a)中所測定 之分析物之濃度或量相比較時無變化或為不利的，則確定 個體之疾病持續、進展或惡化，且應以較高濃度之一或多 種在步驟（b)中向個體投盥之鑿蘊έΒ人，，+ 彳τ丨』uj姐仅，、I晉樂組合物治療該個體或應以 一或多種不同於步驟（b)中向個體投與之一或多種醫藥組合 物的醫藥組合物治療該個體。特定言之，可用一或多種不 同於該個體先前所接受之-或多種醫藥組合物的醫藥組合 物來治療個體以減少或降低該個體之分析物含量。 一般而言，對於可能進行重複測試之檢定（例如監測疾 病進展及/或對治療之反應）’在已自個體獲得第—測試樣 品後一段時間内獲得第二或後續測試樣品。特定言之，可 在已自個體獲得第一測試樣品後數分鐘 '數小時、數天、 數週或數年自個體獲得第二測試樣品。舉例而言，可在自 個體獲彳于第一測試樣品後約丨分鐘、約5分鐘、約^ 〇分鐘、 約15分鐘、約3〇分鐘、約45分鐘、約6〇分鐘約2小時、 約3小時、約4小時、約5小時 '約6小時、約7小時、約8小 時、約9小時、約丨〇小時、約丨丨小時、約丨2小時、約丨3小 時、約14小時、約15小時、約16小時、約17小時、約18小 時、約19小時、約2〇小時、約21小時、約22小時、約23小 151681.doc •314· 201127956 時、約24小時、約2天、約3天、約4天、約5天、約6天、 約7天、約2週、約3週、約4週、約5週、約6週、約7週、 約8週、約9週、約10週、約11週、約12週、約13週、約14 週、約1 5週、約1 6週、約1 7週、約1 8週、約1 9週、約2 0 週、約21週、約22週、約23週、約24週、約25週、約26 週、約27週、約28週、約29週、約;ί〇週、約31週、約32 週、約3 3週、約3 4週、約3 5週、約3 6週、約3 7週、約3 8 週、約3 9週、約4 0週、約41週、約4 2週、約4 3週、約4 4 週、約45週、約46週、約47週、約48週、約49週、約50 週、約51週、約52週、約1.5年、約2年、約2.5年、約3.0 年、約3.5年、約4.0年、約4.5年、約5.0年、約5.5年、約 6.0年、約6.5年、約7.0年、約7.5年、約8.0年、約8.5年、 約9.0年、約9.5年或約ι〇·〇年之時段自個體獲得第二測試 樣品。 當上述檢定用於監測疾病進展時，可使用上述檢定來監 測罹患急性病狀之個體之疾病進展。急性病狀亦稱作危急 護理病狀，其係指危及生命之急性疾病或其他危急醫學病 狀’涉及例如心企管系統或排泄系統。危急護理病狀通常 係指需要在醫院機構（包括（但不限於）急救室、加護病房、 外傷中心或其他急救護理機構）中進行急性醫藥介入或由 濩理人員或其他領域之醫務人員進行投藥的病狀。對於危 急護理病狀，一般在較短時間範圍内重複監測，即數分 鈿、數小時或數天（例如約2分鐘、約5分鐘、約丨〇分鐘、 約15分鐘、約30分鐘、約45分鐘、約6〇分鐘、約2小時、 151681.doc 315. 201127956 約3小時、約4小時、約5小時 ^ '，勺6小時、約7小時、約8小 時、約9小時、約1〇小時、約 子、，勺11小時、約12小時、約13小 時、約1 4小時、約〗5小時、 @ & 矸約16小時、約17小時、約18小 時、約19小時、約2〇小時、的,。士 f約21小時、約22小時、約23小 時、約24小時、約2天、約3天 ,, '^六·、約5天、約ό天戎 ··、勺7天），且初始檢定同樣一般在 一 牡屎病或病狀發作之較短時 間紅圍内’例如約數分鐘、數小時或數天内進行。 該等檢定亦可歸監„患慢性或㈣㈣狀之個體之 疾病進展m護理或㈣性㈣健除危及生命之夸 性疾病及其他危急醫學病狀(涉及例如心血管系統及,或： 泄系統）以外的病狀。非急性病狀通常包括具有較長期或 慢性持續時間之病狀。對於非急性病狀，—般在較長時間 範圍内進行重複監測，例如數小時、數天、數週、數月或 數年(例如約!小時、約2小時、約3小時、約4小時、約5: 時、約6小日夺、約7小日夺、約8小時、約9小日夺、約1〇小時、 約u小時、約12小時、約13小時、約14小時、約15小時、 約16小時、約17小時、約18小時、約19小時約2()小時、 約21小時、約22小時、約23小時、約24小時、約之天、約3 天、約4天、約5天、約6天、約7天、約2週、約㈣、約4 週、約5週 '約6週、約7週、約8週、約9週、約⑺週、約 11週、約12週、約13週、約14週、約15週、約“週、約17 週、約18週、約19週、約20週、約21週、約22週、約23 週、約24週、約25週、約26週、約27週、約28週、約29 週、約30週、約31週、約32週、約33週、約“週、約35 151681.doc •316- 201127956 週、約36週、約37週 '約38週、約39週、約40週、約41 週、約42週、約43週、約44週、約45週、約46週、約47 週、約48週、約49週、約50週、約51週、約52週、約1.5 年、約2年、約2.5年、約3_〇年、約3.5年、約4.0年、約4.5 年、約5.0年、約5.5年、約6.0年、約6.5年、約7.0年、約 7_5年、約8.0年、約8 5年、約9 〇年、約9 5年或約1〇 〇 年）’且初始檢定同樣一般在疾病或病狀發作之較長時間 範圍内，例如約數小時、數天、數月或數年内進行。 此外’可使用自個體獲得之第一測試樣品進行上述檢 定，其中該第一測試樣品係獲自一種來源，諸如尿液、血 清或血漿。接著可視情況使用自個體獲得之第二測試樣品 重複上述檢定，其中該第二測試樣品係獲自另一來源。舉 例而言，若第一測試樣品係自尿液獲得，則第二測試樣品 可自血β或血漿獲得。可比較使用第一測試樣品與第二測 試樣品之檢定獲得之結果。該比較可用於評定個體之疾病 或病狀之狀態。 此外，本發明亦關於確定易患或罹患既定疾病、病症或 病狀之個體是否將得益於治療之方法。特定言之，本發明 係關於分析物相伴診斷方法及產物。因此，如本文所述之 「監測對個體之疾病治療」之方法最佳另外亦可涵蓋選擇 或鑑別治療之候選者。 因此，在特定實施例中，本發明亦提供確定罹患既定疾 病、病症或病狀或具有罹患既定疾病、病症或病狀之風險 的個體是否為治療之候選者的方法。一般而言，個體為經 151681.doc •317· 201127956 =既2疾病、病症或病狀之—些症㈣實際上已經診斷羅 心=疾病、病症或病狀或有罹患既定疾病、病症或病狀 :二固體；及’或如本文所述表現不利濃度或量之分 析物或其片段的個體。 該方法視情況包含如本文所述之檢定，其中在用一或多 種醫樂組合物(例如尤其用與涉及分析物之作用機制相關 之樂：)、用免疫抑制治療或藉由免疫吸附治療來治療個 體之前及之後評定分析物，或其中在該治療後評；t分析物 且將分析物之濃度或量與職含量相比較。在治療後所觀 制分析物之不利濃度或量確定該個體不會得益於接受進 -步或繼續治療，而在治療後觀測到分析物之有利濃度或 量確定該個體會得益於接受進m續治療。此確定有 助於管理臨床研究且提供改良之患者護理。 不5而喻，雖然本文之某些實施例在用於評定如本文所 述之既m病症或病狀時為適宜的，但可使用檢定及 套組來β平疋其他疾病、病症及病狀中之分析物。檢定方法 亦可涉及檢定其他標誌物及其類似物。 入檢定方法亦可用於鑑別改善既定疾病、病症或病狀之化 口物°舉例而t ’可使表ί見分析物之細胞與候選化合物接 觸。可使用本文所述之檢定方法將與化合物接觸之細胞令 刀析物之表現含量與對照細胞中之分析物表現含量相比 較。 n·套組 亦提供針對測試樣品中分析物（或其片段）之存在、量或 151681.doc -318- 201127956 /農度對測試樣品進行檢定之套組。該套組包含至少一種檢 疋測試樣品之分析物（或其片段）之組分及檢定測試樣品之 分析物（或其片段）的說明書。至少一種檢定測試樣品之分 析物（或其片段）的組分可包括包含視情況固定於固相上之 抗分析物DVD-Ig(或其片段、變異體或變異體之片段）的組 合物。 套組可包含至少一種藉由免疫檢定（例如化學發光 免疫檢疋）檢定測試樣品之分析物的組分及藉由免疫檢定 (例如化學發光微粒免疫檢定）檢定測試樣品之分析物的說 明書。舉例而言，套組可包含分析物之至少一種特異性結 合搭配物，諸如抗分析物單株/多株抗體（或其可結合至分 析物之片& ’其可結合至分析物之變異體，或可結合至分 析物之變異體片段)、或抗分析物DVI)-Ig(或其片段、變異 體或欠異體片段）’其任一者均可經可福測標記。或者或 1外’套組可包含經可偵測標記之分析物（或其可結合至 抗分析物單株/多株抗體、或抗分析物刪七（或其片段、 變異體或變異體片段）之片段），其可與測試樣品中之任何 ^斤物競爭結合於抗分析物單株/多株抗體（或其可結合至
:析物之片攸’其可結合至分析物之變異體，或可結合至 &析物之變異體片段）、或抗分析物D 異體或變異體片段) m又變 -任者可固定於固體支撐物上。 、，可L 3校正劑或對照組 物。套組可包含至…田一.分離或純化之分析 将旦、态—& ^種用於進行檢定之容器（例如管、 微里滴疋板或條帶，其可 如匕塗有第一特異性結合搭 151681.doc -319· 201127956 配物）；及/或緩衝液，諸如檢定 任一者可^縮溶液之形式提供；可❹衝液’其 標記物）之受質溶液；或停止溶液。套組較=^== 定所必需之所有組分，亦即試劑、標準物二== 劑等。鳍昍查~Γ * , 緩衝液、稀釋 °曰可為·Λ張形式或電腦可讀之形1 碟、⑶、DVD或其類似物。 …式，诸如磁 (諸如抗分析物抗體)、或抗分析物_々、戍
:㈣可併有如本文所述之可谓測標記物，諸如勞光V :射性部分、酶、生物素/抗生物素蛋白標記物:色 團、化學發光標記物或其類似物 發色 可偵測標記之試劑。抗體m, /'、·且可包括用於進行 冬…“ 劑及/或對照物可提供於 '中或預先分配於適合之檢定形式中，例如預先分 配於微量滴定板中。 】如預无刀 及2視情況包括品質控制組分（例如靈敏度组、校正劑 ，照物）。品質控制試劑之製備為此項技術 =於多種免疫診斷產品之插頁上描述。靈敏度組成員视 於建立檢定效能特徵’且進一步視情況為免疫檢定 i忒劑之完整性及檢定標準化的適用指標。 套組亦可視情況包括進行診斷檢定或有助於品質控制評 /斤需之其他試劑’諸如緩衝液、鹽、酶、酶辅因子、酶 广質、偵測試劑及其類似物4財亦可包括其他組分， =如緩衝液及用於分離及/或處理測試樣品之溶液（例如預 ^試劑）。套組可另外包括一或多種其他對照物。套兔 之-或多個組分可經;東乾’在該情形下，套組可進一步包 15168l.doc 201127956 含適於復原：東乾紐_分之試劑。 套組之各種組分根據需要視情況提供於適合容器，例如 微量滴定板中。套組可進一步包括容納或儲存樣品之容器 (例如尿液樣品之容器或筒）„適當時，套組視情況亦可含 有反應容器、混合容器及有助於製備試劑或測試樣品之其 他組分。套組亦可包括一或多種幫助獲得測試樣品之儀 器諸如，主射器、吸液管、钳子、量匙（measured sp〇〇n) 或其類似物。 若可偵測標記物為至少一種吖啶鏽化合物，則套組可包 含至少一種吖啶鏽_9_曱醯胺、至少一種吖啶鏽_9_曱酸芳 酯或其任何組合。若可偵測標記物為至少一種吖啶鏽化合 物，則套組亦可包含過氧化氫之來源，諸如緩衝液、溶液 及/或至少一種鹼性溶液。必要時，套組可含有固相諸 如磁性粒子 '珠粒、試管、微量滴定板、光析管、膜 '骨 架分子、薄膜、濾紙、圓盤或晶片。 III·套組及方法之改進 藉由如本文所述之檢定（諸如免疫檢定）測定分析物於測 «式樣αο中之存在、量或濃度的套組（或其組分）以及方法可 經改進以用於例如美國專利第5，G89,424號及第5，嶋，3〇9號 中所述且例如由 Abbott Laboratories(Abbott Park, IL)以 ARCHITECT®出售之多種自動及半自動系統（包括固相包 含微粒之系統）中。 自動或半自動系統相較於非自動系統（例如ELISA)的一 些差異包括連接有第一特異性結合搭配物（例如抗分析物 151681.doc •321 · 201127956 單株/多株抗體（或其片段、其變異體或其變異體片段）、或 抗分析物DVD-Ig(或其片段、其變異體或其變異體片段）， 任一方式皆可影響夾心形成及分析物反應性）之受質；以 及捕捉、偵測及/或任何視情況存在之洗滌步驟的時間長 短及時序。非自動形式（諸如ELISA)可能需要與樣品與捕 捉試劑一起培育相對較長時間（例如約2小時），而自動或半 自動形式（例如 ARCHITECT®, Abbott Laboratories)可能具 有相對較短之培育時間（例如對於ARCHITECT®，為約18 分鐘）。類似地，非自動形式（諸如ELISA)可培育偵測抗體 (諸如結合物試劑）歷時相對較長之培育時間（例如約2小 時），但自動或半自動形式（例如ARCHITECT®)可能具有相 對較短之培育時間（例如對於ARCHITECT®，為約4分 鐘）。 可自Abbott Laboratories獲得之其他平台包括（但不限 於）AxSYM®、IMx®(參看例如美國專利第5,294,404號，其 以全文引用的方式併入本文中）、PRISM®、EIA(珠粒）及 Quantum™ II以及其他平台。另外，檢定、套組及套組組 分可以其他形式使用，例如在電化學或其他手持或即時 (point-of-care)檢定系統上。本發明例如適用於執行夾心免 疫檢定之商業 Abbott Point of Care(i-STAT®，Abbott Laboratories)電化學免疫檢定系統。免疫感測器及其製造 方法及在一次性使用測試裝置中操作之方法描述於例如美 國專利第5,063,081號、美國專利申請公開案第2003/ 0170881號、美國專利申請公開案第2004/0018577號、美 151681.doc .322 - 201127956 國專利申請公開案第2005/0054078號及美國專利申請公開 案第2006/01 601 64號中，其關於相同目的之教示以全文引 用的方式併入本文中。 詳言之，關於將分析物檢定針對丨^丁八丁⑧系統進行調適 而言，以下組態較佳》製造具有一對金電流測定操作電極 及銀-氯化銀參考電極的微加工之矽晶片。在—個操作電 極上，將具有固定化抗分析物單株/多株抗體（或其片段、 其變異體或其變異體片段）、或抗分析物DVD_ig(或其片 段、其變異體或其變異體片段）之聚苯乙稀珠粒（〇2 _直 徑）黏附於電極上經圖案化之聚乙烯醇之聚合物塗層上。 將此晶片組裝至具有適用於免疫檢定之流體形式之】_ STAT®筒中。在該筒容納樣品之腔室壁的一部分上，存在 包含對分析物具特異性之結合搭配物（諸如抗分析物單株/ 多株抗體(或其可結合分析物之片段、其變異體或其變異 體片段）、或抗分析物DVD_Ig(或其可結合分析物之片段、 其變異體或其變異體gj/L、 +1.. Ή呉體片|又）’其任一者皆可經可偵測標記） 之層。在該筒之流體囊内為包括對胺基苯盼她旨之水性 試劑。 在操作中’將懷疑含有分析物之樣品添加至測試筒之容 納腔室中，且將筒插入咖⑧讀取器中。在對分析物具 特異性之結合搭配物溶解於樣品中之後，該筒内之栗元件 适使樣印進入含有晶片之管道中。此時，將其振盈以促進 =成夾心。在檢定之倒數第二個步驟中，迫使流體自囊中 桃出且進入管道中以將樣品自晶片洗去且進入廢料腔室 151681.doc •323· 201127956 中。在檢定之最後步驟中，鹼性磷酸酶標記物與對胺基苯 酚磷酸酯反應以裂解磷酸酯基且使所釋放之對胺基苯酚在 工作電極處被電化學氧化。基於所量測之電流，讀取器能 夠藉助於嵌入演算法及工廠確定之校正曲線來計算樣品中 分析物之量。 更不言而喻的是，如本文所述之方法及套組必然涵蓋進 行免疫檢定之其他試劑及方法。舉例而言，涵蓋各種緩衝 液，諸如此項技術中已知及/或可輕易地製備或最佳化以 例如用於洗滌、用作結合物稀釋劑、微粒稀釋劑及/或用 作校正劑稀釋劑的緩衝液。例示性結合物稀釋劑為某些套 組（Abbott Laboratories, Abbott Park，IL)中所用且含有 2-(N-嗎啉基）乙烷磺酸（MES)、鹽、蛋白質阻斷劑、抗微生 物劑及清潔劑之ARCHITECT®結合物稀釋劑。例示性校正 劑稀釋劑為某些套組（Abbott Laboratories, Abbott Park, IL) 中所用之ARCHITECT®人類校正劑稀釋劑，其包含含有 MES、其他鹽、蛋白質阻斷劑及抗微生物劑之缓衝液。另 外，如2008年12月31曰申請之美國專利申請案第61/ 142,048號中所述，可例如在I-Stat筒形式中，使用連接於 信號抗體之核酸序列作為信號放大器獲得改良之信號產 生。 實例 實例1 : DVD-Ig之設計、建構及分析 實例1.1:用於鑑別及表徵親本抗體及DVD-Ig之檢定 除非另外說明，否則實例全文中使用以下檢定鑑別及表 151681.doc -324- 201127956 徵親本抗體及DVD-Ig。
實例1.1.1 :用於測定親本抗體及DVD-Ig針對其目標抗原 之結合及親和力之檢定 實例1.1.1A:直接結合ELISA
篩選結合所要目標抗原之抗體的酶聯結免疫吸附劑分析 法係如下進行。在4°C下，以每孔100 μί含1〇 pg/ml所要目 標抗原（R&D Systems, Minneapolis，MN)或所要目標抗原胞 外區域/FC融合蛋白（R&D Systems, Minneapolis, MN)或單 株小鼠抗聚組胺酸抗體（R&D Systems # MAB050,
Minneapolis，MN)之填酸鹽緩衝鹽水（10X PBS, Abbott Bioresearch Center, Media Prep# MPS-073, Worcester, MA) 塗覆高度結合 ELISA板（Corning Costar # 3369，Acton, MA) 隔夜。以含有0.02% Tween 20之PBS洗滌板四次。在室溫 下，藉由添加每孔300 μί阻斷溶液（在PBS中稀釋至2%的 脫脂奶粉（non-fat dry milk powder)，多個零售供應商）阻斷 板歷時1/2小時。在阻斷後，以含有0.02% Tween 20之PBS 洗滌板四次。 或者，向如上文所述塗覆有單株小鼠抗聚組胺酸抗體之 ELISA板中添加每孔1〇〇 μΐ^ 10 pg/ml組胺酸（His)標記之所 要目標抗原（R&D Systems, Minneapolis, MN) ’且在室溫下 培育1小時。以含有0.02% Tween 20之PBS洗滌各孔四次。 向如上文所述製備之所要目標抗原板或所要目標抗原/ FC融合板或抗聚組胺酸抗體/His標記之所要目標抗原板中 添加100 μΐ^在如上文所述之阻斷溶液中稀釋之抗體或 151681.doc -325 - 201127956 DVD-Ig製劑，且在室溫下培育1小時。以含有〇.〇2°/。Tween 20之PBS洗滌各孔四次。 · 向所要目標抗原板或抗聚組胺酸抗體/組胺酸標記之所 要目標抗原板的各孔中添加100 μΐ^ 10 ng/mL山羊抗人類 IgG -FC 特異性 HRP 結合抗體（Southern Biotech # 2040-05, Birmingham，AL)。或者，向所要目標抗原/FC融合板之各 孔中添加100 pL 10 ng/mL山羊抗人類IgG -κ輕鏈特異性 HRP結合抗體（Southern Biotech # 2060-05 Birmingham， AL)，且在室溫下培育1小時。以含有0.02% Tween 20之 PBS洗務板4次。 向各孔中添加100 pL增強之TMB溶液^6〇呂611(：(^?· #308177，K Blue，Lexington，KY)，且在室溫下培育 10 分 鐘。藉由添加50 pL 1 N硫酸停止反應。在450 nm之波長下 以分光光度法對板讀數。 表3含有直接結合檢定中所用之抗原清單。 表4含有直接結合ELISA檢定中所測試之彼等抗體及 DVD-Ig構築體之以EC50表示（nM)的結合資料。 有時在直接結合ELISA中觀測不到結合，此可能因為在 塗覆於塑膠表面時，目標抗原上之抗體結合位點「被遮 蔽」或抗原「變形」。DVD-Ig不能結合其目標亦可能由於 直接結合ELISA形式對DVD-Ig施加之空間限制。在直接結 合ELISA形式中不結合之親本抗體及DVD-Ig在其他ELISA 形式（諸如FACS、Biacore或生物檢定）中結合至目標抗 原。如上文所述，亦藉由調整DVD-Ig之兩個可變區域之 151681.doc •326· 201127956 間的連接子長度來修復DVD-Ig之不結合。 表3:直接結合ELISA中所用之抗原 檢定 抗原 供應商命名 供應商 目錄號 CD-22 CD22/FC Siglec-2 ECD/FC嵌合體 R&D 1968-SL-050 CD-40 CD40/FC CD40 ECD/FC嵌合體-His標籤 R&D 1493-CD-050 CD-80 CD80/FC B7-1 ECD/FC 嵌合體 R&D 140-B1-100 DLL4 DLL4 DLL4 ECD/His標籤 R&D 1506-D4-050 EGFR EGFR/FC EGFR ECD/FC嵌合體 R&D 344-ER-050 HER-2 HER-2/FC ErbB2 ECD/FC嵌合體-His標籤 R&D 1129-ER-050 HGF HGF HGF-His 標籤 R&D 294-HG-025 IGF1 IGF1 IGF-I R&D 291-G1-050 IGF2 IGF2 IGF-2 R&D 292-G2-050 IGF1R IGF1R IGF1R ECD R&D 391-GR-050 NRP1 NRP1 神經纖毛蛋白-1 Npn-1 -His標籤 R&D 3870-N1-025 P1GF P1GF 胎盤GF R&D 264-PG-050 RON RON MSP受體ECD-His標籤 R&D 1947-MS-050 VEGF VEGF VEGF 1-165 aa R&D 293-VE-010 ErbB3 ErbB3 ErbB3 ECD/FC嵌合體-His標籤 R&D 348-RB-050
ECD:胞外區域
/FC嵌合體=抗原/IgG FC區域融合蛋白 表4:親本抗艘及DVD-Ig構築體之直接結合ELISA 親本抗體或 DVD-IgID N末端可變 區域(VD) c末端可變 區域(VD) 直接結合ELISA N-末端VD EC50(nM^ 直接結合ELISA C末端VD EC50fnM) AB006 UD-19 _ 0.( )4 AB001 CD -20 DVD001 CD-20 CD-19 12.93 DVD002 CD-19 CD-20 0.07 AB007 CD-80 0.77 AB001 CD -20 DVD005 CD-20 CD-80 9.77 DVD006 CD-80 CD-20 1.09 AB008 CD-22 3.^ 14 AB001 CD-20 DVD007 CD-20 CD-22 --- 30.54 DVD008 CD-22 CD-20 4.79 AB009 CD-40 ~~-0« AB001 CD -20 DVD009 CD-20 CD-40 3.55 DVD010 CD-40 CD-20 0.82 •327- 151681.doc 201127956 親本抗體或 DVD-Ig ID N末端可變 區域(VD) c末端可變 區域(VD) 直接結合ELISA N-末端VD EC50(nM) 直接結合ELISA C末端VD EC50(nM) AB002 CD-3 AB004 HE R-2 0. 15 DVD011 CD-3 HER-2 6.63 DVD012 HER-2 CD-3 1.24 AB002 CD-3 AB006 CD-19 0. 14 DVD013 CD-3 CD-19 7.29 DVD014 CD-19 CD-3 0.12 AB033 EGFR 0.66 AB004 HE R-2 1.9 DVD015 EGFR HER-2 0.41 148.48 DVD016 HER-2 EGFR 1.25 5.23 AB002 CD-3 AB033 EGFR 0.28 DVD017 EGFR CD-3 0.3 DVD018 CD-3 EGFR 1.93 AB033 EGFR 0.27 ABO 11 IGF1R 0.28 DVD021 EGFR IGF1R 0.33 134.95 DVD022 IGF1R EGFR 0.26 0.74 AB005 RON 0.26 AB033 EGFR 0.28 DVD023 EGFR RON 0.23 40.18 DVD024 RON EGFR 0.54 1.87 AB033 EGFR 0.27 ABO 12 HGF 0.22 DVD025 EGFR HGF 0.31 251.45 DVD026 HGF EGFR 0.33 7.89 AB004 HE] R.-2 0.44 ABO 10 IGF 1,2 4.77/ 10.02 DVD029 HER-2 IGF1/IGF2 1226.04 229.33/206.12 DVD030 IGF1/IGF2 HER-2 1.75/5.49 10.65 AB004 HE] R-2 0. 15 ABO 11 IGF1R 0.28 DVD031 HER-2 IGF1R 0.28 171.04 DVD032 IGF1R HER-2 0.16 11.03 AB005 RON 0.21 ABO 12 HGF 0. 19 DVD033 RON HGF 0.22 11.95 DVD034 HGF RON 0.27 116.46 ABO 14 VEGF 0.87 AB033 EGFR 0.28 DVD035 VEGF EGFR 0.74 1.24 DVD036 EGFR VEGF 0.18 336.13 ABO 14 VEGF 2.71 AB004 HER-2 0.15 151681.doc -328· 201127956
親本抗體或 DVD-Ig ID N末端可變 區域(VD) C末端可變 區域(VD) 直接結合ELISA N-末端VD EC50(nM) 直接結合ELISA C末端VD EC50(nM) DVD037 VEGF HER-2 1.86 1.44 DVD038 HER-2 VEGF 0.66 106.77 AB001 CD-20 ABO 14 VEGF 2.71 DVD039 VEGF CD-20 1.27 DVD040 CD-20 VEGF 71.18 AB014 VEGF 0·{ 57 ABO 10 IGF 1,2 4.77/1 18.13 DVD041 VEGF IGF1/IGF2 0.68 381.18/7335.24 DVD042 IGF1/IGF2 VEGF 2.54/17.62 42.3 ABO 15 DL L-4 0.31 ABO 14 VEGF 2.71 DVD043 VEGF DLL4 28.25 2.12 DVD044 DLL4 VEGF 0.53 10.88 ABO 14 VEGF 2.95 AB012 HGF 0. 19 DVD045 「VEGF HGF 2.87 184.53 DVD046 HGF VEGF 0.5 46.3 AB005 RON 0.26 ABO 14 VEGF 2.95 DVD047 VEGF RON 19.2 94.82 DVD048 RON VEGF 0.46 42.95 AB014 VEGF 2.95 ABO 16 NRP1 0.58 DVD049 VEGF NRP1 1.71 0.5 DVD050 NRP1 VEGF 0.46 219.02 ABO 15 DL L-4 0.31 AB047 P1GF 0.2 DVD257 DLL4 P1GF 0.28 2 DVD258 P1GF DLL4 0.08 2.3 AB014 VEGF 1.( )9 AB047 P1GF 0.2 DVD259 VEGF P1GF 0.79 1.3 DVD260 P1GF VEGF 0.12 19.06 AB062 ErbB3 1.93 AB033 EGFR 0.68 DVD299 ErbB3 EGFR 1.96 17.38 DVD300 EGFR ErbB3 0.49 7633.3 AB063 ErbB3 0.28 AB033 EGFR 0.68 DVD305 ErbB3 EGFR 0.44 24.39 DVD306 EGFR ErbB3 0.36 150.92 所有DVD-Ig構築體之結合均得以維持且與親本抗體相 當。所有N末端可變區域以與親本抗體以及DVD-Ig構築體 151681.doc •329· 201127956 DVD009、DVD016、DVD018、DVD022、DVD024、 DVD035 、DVD37 、DVD043 、DVD044 、DVD49 、 DVD257、DVD25 8及DVD259之C末端可變區域類似的高親 和力結合。 表5及表6含有C末端（C-term.)或N末端（N-term.)可變區域 源自親本VEGF參考抗體（Ref. Ab.)AB014-VEGF(序列1)、 AB071-VEGF(序列2)及AB070-VEGF(序列3)之可變區域的 三種VEGF親本抗體及96種DVD-Ig構築體的VEGF直接結 合ELISA資料。此等可變區域與源自4個DLL-4 Ref. Ab. (AB015-DLL-4(序列 1)、AB069-DLL-4(序歹，J 2)、AB073-DLL-4(序列3)及AB072-DLL-4(序列4)之4個DLL-4可變區 域配對。DVD-Ig可變區域經2種長度之連接子（重鏈（HC連 接子）及/或輕鏈（LC連接子）中之短連接子及長連接子）連 接，產生4種可能連接子組合：短-短、長-長、短-長及長-短。此等5種因素（3種VEGF序列X 2種定向X 2種HC連接子 X 2種LC速接子X 4種DLL-4序列）組合產生96種DVD之全因 子實驗。
表5 :具有各種VEGF序列、定向及連接子長度組合的96種 DVD構築體與VEGF之直接結合ELIS A DVD ID 序列ID 位置 HC 連接子 LC 連接子 其他DVD 區域 DVD VEGF EC50 (nM) Ref. Ab. ID RefAb VEGF EC50 (nM) DVD043 VEGFi序列 1) N-term. 短 短 DLL4(序列 1) 1.25 AB014 2.36 DVD044 VEGF(序列 I) C-term. 短 短 DLL4(序列 1) 407.52 AB014 2.36 DVD469 VEGF(序列 1) C-term. 長 長 DLL4(序列 1) 1262.59 AB014 2.36 DVD470 VEGFi 序列 1) N-term. 長 長 DLL4(序列 1) 1.87 AB014 2.36 DVD475 VEGFi 序列 1) C-term. 長 短 DLL4(序列 1)H 19.17 AB014 1.51 DVD476 VEGF(序列 1) N-term. 長 短 DLL4(序列 1) 0.55 ABO 14 1.51 151681.doc •330. 201127956
DVD ID 序列ID 位置 HC 連接子 LC 連接子 其他】)VD 區域 DVD VEGF EC50 (nM) Ref. Ab. ID RefAb VEGF EC50 (nM) DVD481 VEGF(序列 1) C-term. 短 長 DLL4(序列 1) 150.24 ABO 14 1.51 DVD482 VEGF(序列 1) N-term. 短 長 DLL4(序列 1) 1.30 AB014 1.51 DVD467 VEGF(序列 2) C-term. 短 短 DLL4(序列 1) 1805.23 AB071 60.82 DVD468 VEGF(序列 2) N-term. 短 短 DLL4(序列 1) 25.55 AB071 60.82 DVD473 VEGF(序列 2) C-term. 長 長 DLL4(序列 1) 388.01 AB071 60.82 DVD474 VEGF(序列 2) N-term. 長 長 DLL4(序列 1) 17.93 AB071 60.82 DVD479 VEGF(序列 2) C-term. 長 短 DLL4(序列 1) 455.50 AB071 68.55 DVD480 VEGF(序列 2) N-term. 長 短 DLL4(序列 1) 22.98 AB071 68.55 DVD485 VEGF(序列 2) C-term. 短 長 DLL4(序列 1) 121.21 AB071 68.55 DVD486 VEGF(序列 2) N-term. 短 長 DLL4(序列 1) 27.96 AB071 68.55 DVD465 VEGF(序列 3) C-term. 短 短 DLL4(序列 1) 396.45 AB070 1.82 DVD466 VEGF(序列 3) N-term. 短 短 DLL4(序列 1) 2.61 AB070 1.82 DVD471 VEGF(序列 3) C-term. 長 長 DLL4(序列 1) 30.05 AB070 1.82 DVD472 VEGF(序列 3) N-term. 長 長 DLL4(序列 1) 9.22 AB070 1.82 DVD477 VEGF(序列 3) C-term. 長 短 DLL4(序列 1) 41.66 AB070 3.59 DVD478 VEGF(序列 3) N-term. 長 短 DLL4(序列 1) 2.72 AB070 3.59 DVD483 VEGF(序列 3) C-term. 短 長 DLL4(序列 1) 46.09 AB070 3.59 DVD484 VEGF(序列 3) N-term. 短 長 DLL4(序列 1) 4.84 AB070 3.59 DVD441 VEGF(序列 1) C-term. 短 短 DLL4(序列 2) 247.99 ABO 14 1.52 DVD442 VEGF(序列 1) N-term. 短 短 DLL4(序列 2) 0.59 ABO 14 1.52 DVD447 VEGF(序列 1) C-term. 長 長 DLL4(序列 2) 5.05 AB014 1.52 DVD448 VEGF(序列 1) N-term. 長 長 DLL4(序列 2) 1.59 AB014 1.52 DVD453 VEGF(序列 1) C-term. 長 短 DLL4(序列 2) 35.28 ABO 14 1.50 DVD454 VEGF(序列 1) N-term. 長 短 DLL4(序列 2) 1.43 AB014 1.50 DVD459 VEGF(序列 1) C-term. 短 長 DLL4(序列 2) 6.17 AB014 1.50 DVD460 VEGF(序列 1) N-term. 短 長 DLL4(序列 2) 0.94 ABO 14 1.50 DVD445 VEGF(序列 2) C-term. 短 短 DLL4(序列 2) 14482.02 AB071 48.07 DVD446 VEGF(序列 2) N-term. 短 短 DLL4(序列 2) 14.38 AB071 48.07 DVD451 VEGF(序列 2) C-term. 長 長 DLL4(序列 2) 2404.95 AB071 48.07 DVD452 VEGF(序列 2) N-term. 長 長 DLL4(序列 2) 17.75 AB071 48.07 DVD457 VEGF(序列 2) C-term. 長 短 DLL4(序列 2) 1475.74 AB071 40.24 DVD458 VEGF(序列 2) N-term. 長 短 DLL4(序列 2) 21.51 AB071 40.24 DVD463 VEGF(序列 2) C-term. 短 長 DLL4(序列 2) 1730.97 AB071 40.24 DVD464 VEGF(序列 2) N-term. 短 長 DLL4(序列 2) 19.31 AB071 40.24 DVD443 VEGF(序列 3) C-term. 短 短 DLL4(序列 2) 610.53 AB070 1.05 DVD444 VEGF(序列 3) N-term. 短 短 DLL4(序列 2) 2.44 AB070 1.05 DVD449 VEGF(序列 3) C-term. 長 長 DLL4(序列 2) 15.61 AB070 1.05 DVD450 VEGF(序列 3) N-term. 長 長 DLL4(序列 2) 12.06 AB070 1.05 DVD455 VEGF(序列 3) C-term. 長 短 DLL4(序列 2) 26.71 AB070 1.11 DVD456 VEGF(序列 3) N-term. 長 短 DLL4(序列 2) 1.63 AB070 1.11 DVD461 VEGF(序列 3) C-term. 短 長 DLL4(序列 2) 10.44 AB070 1.11 DVD462 VEGF(序列 3) N-term. 短 長 DLL4(序列 2) 8.00 AB070 1.11 DVD511 VEGF(序列 1) C-term. 短 短 DLL4(序列 3) 35.11 AB014 0.75 DVD512 VEGF(序列 1) N-term. 短 短 DLL4(序列 3) 0.71 ABO 14 0.75 DVD517 VEGF(序列 1) C-term. 長 長 DLL4(序列 3) 9.78 AB014 0.75 DVD518 VEGF(序列 1) N-term. 長 長 DLL4(序列 3) 162.44 ABO 14 0.75 DVD523 VEGF(序列 1) C-term. 長 短 DLL4(序列 3) 9.67 AB014 0.49 DVD524 VEGF(序列 1) N-term. 長 短 DLL4(序列 3) 0.30 ABO 14 0.49 DVD529 VEGF(序列 1) C-term. 短 長 DLL4(序列 3) 2.64 ABO 14 0.49 151681.doc •331 - 201127956 DVD ID 序列ID 位置 HC 連接子 LC 連接子 其他DVD 區域 DVD VEGF EC50 (nM) Ref. Ab.ID RefAb VEGF EC50 (nM) DVD530 VEGF(序列 1) N-term. 短 長 DLL4(序列 3) 0.79 AB014 0.49 DVD515 VEGF(序列 2) C-term. 短 短 DLL4(序列 3) 3015.10 AB071 35.19 DVD516 VEGF(序列 2) Ν-term. 短 短 DLL4(序列 3) 24.65 AB071 35.19 DVD521 VEGF(序列 2) C-term. 長 長 DLL4(序列 3) 654.85 AB071 35.19 DVD522 VEGF(序列 2) N-term. 長 長 DLL4(序列 3) 23.53 AB071 35.19 DVD527 VEGF(序列 2) C-term. 長 短 DLL4(序列 3) 2380.25 AB071 52.97 DVD528 VEGF(序列 2) N-term. 長 短 DLL4(序列 3) 27.69 AB071 52.97 DVD533 VEGF(序列 2) C-term. 短 長 DLL4(序列 3) 1260.61 AB071 52.97 DVD534 VEGF(序列 2) N-term. 短 長 DLL4(序列 3) 23.61 AB071 52.97 DVD513 VEGF(序列 3) C-term. 短 短 DLL4(序列 3) 58.54 AB070 0.97 DVD514 VEGF(序列 3) N-term. 短 短 DLL4(序列 3) 67.41 AB070 0.97 DVD519 VEGF(序列 3) C-term. 長 長 DLL4(序列 3) 77.17 AB070 0.97 DVD520 VEGF(序列 3) N-term. 長 長 DLL4(序列 3) 247.74 AB070 0.97 DVD525 VEGF(序列 3) C-term. 長 短 DLL4(序列 3) 21.79 AB070 1.42 DVD526 VEGF(序列 3) N-term. 長 短 DLL4(序列 3) 96.22 AB070 1.42 DVD531 VEGF(序列 3) C-term. 短 長 DLL4(序列 3) 60.39 AB070 1.42 DVD532 VEGF(序列 3) N-term. 短 長 DLL4(序列 3) 28.91 AB070 1.42 DVD487 VEGF(序列 1) C-term. 短 短 DLL4(序列 4) 39.78 AB014 1.61 DVD488 VEGF(序列 1) N-term. 短 短 DLL4(序列 4) 4.98 AB014 1.61 DVD493 VEGF(序列 1) C-term. 長 長 DLL4(序列 4) 2.26 AB014 1.61 DVD494 VEGF(序列 1) N-term. 長 長 DLL4(序列 4) 712.21 AB014 1.61 DVD499 VEGF(序列 1) C-term. 長 短 DLL4(序列 4) 5.07 AB014 1.41 DVD500 VEGF(序列 1) N-term. 長 短 DLL4(序列 4) 5.28 AB014 1.41 DVD505 VEGF(序列 1) C-term. 短 長 DLL4(序列 4) 1.27 ABO 14 1.41 DVD506 VEGF(序列 1) N-term. 短 長 DLL4(序列 4) 1.84 AB014 1.41 DVD491 VEGF(序列 2) C-term. 短 短 DLL4(序列 4) 1249.97 AB071 45.67 DVD492 VEGF(序列 2) N-term. 短 短 DLL4(序列 4) 8.42 AB071 45.67 DVD497 VEGF(序列 2) C-term. 長 長 DLL4(序列 4) 858.21 AB071 45.67 DVD498 VEGF(序列 2) N-term. 長 長 DLL4(序列 4) 30.61 AB071 45.67 DVD503 VEGF(序列 2) C-term. 長 短 DLL4(序列 4) 429.96 AB071 37.84 DVD504 VEGF(序列 2) N-term. 長 短 DLL4(序列 4) 16.74 AB071 37.84 DVD509 VEGF(序列 2) C-term. 短 長 DLL4(序列 4) 121.28 AB071 37.84 DVD510 VEGF(序列 2) N-term. 短 長 DLL4(序列 4) 23.89 AB071 37.84 DVD489 VEGF(序列 3) C-term. 短 短 DLL4(序列 4) 180.95 AB070 2.80 DVD490 VEGF(序列 3) N-term. 短 短 DLL4(序列 4) 6.70 AB070 2.80 DVD495 VEGF(序列 3) C-term. 長 長 DLL4(序列 4) 69.95 AB070 2.80 DVD496 VEGF(序列 3) N-term. 長 長 DLL4(序列 4) 107.87 AB070 2.80 DVD501 VEGF(序列 3) C-term. 長 短 DLL4(序列 4) 45.16 AB070 2.44 DVD502 VEGF(序列 3) N-term. 長 短 DLL4(序列 4) 3.25 AB070 2.44 DVD507 VEGF(序列 3) C-term. 短 長 DLL4(序列 4) 34.85 AB070 2.44 DVD508 VEGF(序列 3) N-term. 短 長 DLL4(序列 4) 7.88 AB070 2.44
所有DVD-Ig構築體與VEGF之結合均得以維持且與親本 抗體相當。所有N末端可變區域以與親本抗體類似之高親 和力結合。重鏈及輕鏈中連接子長度的一些特定組合使C •332 · 151681.doc 201127956 末端區域之結合親和力改良至與親本抗體相當。特定言 之，使用輕鏈中之長連接子而非短連接子之c末端區域之 親和力存在統計顯著（p = 0.01 9)改良。
表6 :具有各種DLL4序列、定向及連接子長度組合的96種 DVD-Ig構築體與DLL之直接結合ELISA
DVD-Ig ID 序列ID 定向 HC 連接子 LC 連接子 其他DVD-Ig 可變區域 DVD-Ig DLL4 EC50 (nM) Ref· Ab.ID Ref.Ab DLL4 EC50 (nM) DVD043 DLL4(序列 1) C-term. 短 短 VEGF(序列 1) 0.67 AB015 1.39 DVD044 DLL4(序列 1) N-term. 短 短 VEGF(序列 1) 0.25 ABO 15 1.39 DVD469 DLL4(序列 1) N-term. 長 長 VEGF(序列 1) 2.78 ABO 15 1.39 DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 0.19 ABO 15 1.39 DVD475 DLL4(序列 1) N-term. 長 短 VEGF(序列 1) 0.23 ABO 15 1.23 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 0.30 ABO 15 1.23 DVD481 DLL4(序列 1) N-term. 短 長 VEGF(序列 1) 3.30 ABO 15 1.23 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 0.36 ABO 15 1.23 DVD441 DLL4(序列 4) N-term. 短 短 VEGF(序列 1) 0.04 AB069 0.10 DVD442 DLL4(序列 4) C-term. 短 短 VEGF(序列 1) 10.55 AB069 0.10 DVD447 DLL4(序列 4) N-term. 長 長 VEGF(序列 1) 0.12 AB069 0.10 DVD448 DLL4(序列 4) C-term. 長 長 VEGF(序列 1) 0.41 AB069 0.10 DVD453 DLL4(序列 4) N-term. 長 短 VEGF(序列 1) 0.09 AB069 0.04 DVD454 DLL4(序列 4) C-term. 長 短 VEGF(序列 1) 1.01 AB069 0.04 DVD459 DLL4(序列 4) N-term. 短 長 VEGF(序列 1) 0.26 AB069 0.04 DVD460 DLL4(序列 4) C-term. 短 長 VEGF(序列 1) 0.64 AB069 0.04 DVD511 DLL4(序列 2) N-term. 短 短 VEGF(序列 1) 0.10 AB073 0.08 DVD512 DLL4(序列 2) C-term. 短 短 VEGF(序列 1) 1.71 AB073 0.08 DVD517 DLL4(序列 2) N-term. 長 長 VEGF(序列 1) 0.10 AB073 0.08 DVD518 DLL4(序列 2) C-term. 長 長 VEGF(序列 1) 5.90 AB073 0.08 DVD523 DLL4(序列 2) N-term. 長 短 VEGF(序列 1) 0.09 AB073 0.03 DVD524 DLL4(序列 2) C-term. 長 短 VEGF(序列 1) 0.22 AB073 0.03 DVD529 DLL4(序列 2) N-term. 短 長 VEGF(序列 1) 0.10 AB073 0.03 DVD530 DLL4(序列 2) C-term. 短 長 VEGF(序列 1) 0.22 AB073 0.03 DVD487 DLL4(序列 3) N-term. 短 短 VEGF(序列 1) 0.14 AB072 1.29 DVD488 DLL4(序列 3) C-term. 短 短 VEGF(序列 1) 1.84 AB072 1.29 DVD493 DLL4(序列 3) N-term. 長 長 VEGF(序列 1) 0.06 AB072 1.29 DVD494 DLL4(序列 3) C-term. 長 長 VEGF(序列 1) 39.48 AB072 1.29 DVD499 DLL4(序列 3) N-term. 長 短 VEGF(序列 1) 0.09 AB072 0.70 DVD500 DLL4(序列 3) C-term. 長 短 VEGF(序列 1) 0.57 AB072 0.70 DVD505 DLL4(序列 3) N-term. 短 長 VEGF(序列 1) 0.09 AB072 0.70 DVD506 DLL4(序列 3) C-term. 短 長 VEGF(序列 1) 0.32 AB072 0.70 DVD467 DLL4(序列 1) N-term. 短 短 VEGF(序列 2) 0.54 ABO 15 0.30 DVD468 DLL4(序列 1) C-term. 短 短 VEGF(序列 2) 2.28 ABO 15 0.30 DVD473 DLL4(序列 1) N-term. 長 長 VEGF(序列 2) 1.80 ABO 15 0.30 DVD474 DLL4(序列 1) C-term. 長 長 VEGF(序列 2) 0.57 ABO 15 0.30 151681.doc - 333 · 201127956 DVD-Ig ID 序列ID 定向 HC 連接子 LC 連接子 其他DVD-Ig 可變區域 DVD-Ig DLL4 EC50 (nM) Ref. Ab. ID Ref.Ab DLL4 EC50 (nM) DVD479 DLL4(序列 1) N-term. 長 短 VEGF(序列 2) 1.69 ABO 15 0.28 DVD480 DLL4(序列 1) C-term. 長 短 VEGF(序列 2) 0.60 ABO 15 0.28 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 1.41 ABO 15 0.28 DVD486 DLL4(序列 1) C-term. 短 長 VEGF(序列 2) 0.59 ABO 15 0.28 DVD445 DLL4(序列 4) N-term. 短 短 VEGF(序列 2) 0.17 AB069 0.20 DVD446 DLL4(序列 4) C-term. 短 短 VEGF(序列 2) 13.92 AB069 0.20 DVD451 DLL4(序列 4) N-term. 長 長 VEGF(序列 2) 0.40 AB069 0.20 DVD452 DLL4(序列 4) C-term. 長 長 VEGF(序列 2) 0.34 AB069 0.20 DVD457 DLL4(序列 4) N-term. 長 短 VEGF(序列 2) 0.13 AB069 0.21 DVD458 DLL4(序列 4) C-term. 長 短 VEGF(序列 2) 1.54 AB069 0.21 DVD463 DLL4(序列 4) N-term. 短 長 VEGF(序列 2) 0.50 AB069 0.21 DVD464 DLL4(序列 4) C-term. 短 長 VEGF(序列 2) 0.80 AB069 0.21 DVD515 DLL4(序列 2) N-term. 短 短 VEGF(序列 2) 0.20 AB073 0.11 DVD516 DLL4(序列 2) C-term. 短 短 VEGF(序列 2) 4.33 AB073 0.11 DVD521 DLL4(序列 2) N-term. 長 長 VEGF(序列 2) 0.26 AB073 0.11 DVD522 DLL4(序列 2) C-term. 長 長 VEGF(序列 2) 0.48 AB073 0.11 DVD527 DLL4(序列 2) N-term. 長 短 VEGF(序列 2) 0.20 AB073 0.11 DVD528 DLL4(序列 2) C-term. 長 短 VEGF(序列 2) 0.81 AB073 0.11 DVD533 DLL4(序列 2) N-term. 短 長 VEGF(序列 2) 0.25 AB073 0.11 DVD534 DLL4(序列 2) C-term. 短 長 VEGF(序列 2) 0.47 AB073 0.11 DVD491 DLL4(序列 3) N-term. 短 短 VEGF(序列 2) 0.39 AB072 1.99 DVD492 DLL4(序列 3) C-term. 短 短 VEGF(序列 2) 1.77 AB072 1.99 DVD497 DLL4(序列 3) N-term. 長 長 VEGF(序列 2) 0.53 AB072 1.99 DVD498 DLL4(序列 3) C-term. 長 長 VEGF(序列 2) 0.45 AB072 1.99 DVD503 DLL4(序列 3) N-term. 長 短 VEGF(序列 2) 0.33 AB072 1.85 DVD504 DLL4(序列 3) C-term. 長 短 VEGF(序列 2) 0.53 AB072 1.85 DVD509 DLL4(序列 3) N-term. 短 長 VEGF(序列 2) 0.21 AB072 1.85 DVD510 DLL4(序列 3) C-term. 短 長 VEGF(序列 2) 0.42 AB072 1.85 DVD465 DLL4(序列 1) N-term. 短 短 VEGF(序列 3) 0.57 ABO 15 0.60 DVD466 DLL4(序列 1) C-term. 短 短 VEGF(序列 3) 19.84 ABO 15 0.60 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 0.89 AB015 0.60 DVD472 DLL4(序列 1) C-term. 長 長 VEGF(序列 3) 2.78 ABO 15 0.60 DVD477 DLL4(序列 1) N-term. 長 短 VEGF(序列 3) 0.69 AB015 0.58 DVD478 DLL4(序列 1) C-term. 長 短 VEGF(序列 3) 2.53 AB015 0.58 DVD483 DLL4(序列 1) N-term. 短 長 VEGF(序列 3) 0.63 ABO 15 0.58 DVD484 DLL4(序列 1) C-term. 短 長 VEGF(序列 3) 1.75 ABO 15 0.58 DVD443 DLL4(序列 4) N-term. 短 短 VEGF(序列 3) 0.20 AB069 0.23 DVD444 DLL4(序列 4) C-term. 短 短 VEGF(序列 3) 30.54 AB069 0.23 DVD449 DLL4(序列 4) N-term. 長 長 VEGF(序列 3) 0.36 AB069 0.23 DVD450 DLL4(序列 4) C-term. 長 長 VEGF(序列 3) 1.99 AB069 0.23 DVD455 DLL4(序列 4) N-term. 長 短 VEGF(序列 3) 0.24 AB069 0.24 DVD456 DLL4(序列 4) C-term. 長 短 VEGF(序列 3) 2.48 AB069 0.24 DVD461 DLL4(序列 4) N-term. 短 長 VEGF(序列 3) 0.52 AB069 0.24 DVD462 DLL4(序列 4) C-term. 短 長 VEGF(序列 3) 7.99 AB069 0.24 DVD513 DLL4(序列 2) N-term. 短 短 VEGF(序列 3) 0.66 AB073 0.22 DVD514 DLL4(序列 2) C-term. 短 短 VEGF(序列 3) 21.05 AB073 0.22 DVD519 DLL4(序列 2) N-term. 長 長 VEGF(序列 3) 1.53 AB073 0.22 -334· 151681.doc 201127956 DVD-Ig ID 序列ID 定向 HC 連接子 LC 連接子 其他DVD-Ig 可變區域 DVD-Ig DLL4 EC50 (nM) Ref. Ab. ID Ref.Ab DLL4 EC50 (nM) DVD520 DLL4(序列 2) C-term. 長 長 VEGF(序列 3) 17.34 AB073 0.22 DVD525 DLL4(序列 2) N-term. 長 短 VEGF(序列 3) 1.00 AB073 0.21 DVD526 DLL4(序列 2) C-term. 長 短 VEGF(序列 3) 1.57 AB073 0.21 DVD531 DLL4(序列 2) N-term· 短 長 VEGF(序列 3) 0.57 AB073 0.21 DVD532 DLL4(序列 2) C-term. 短 長 VEGF(序列 3) 1.43 AB073 0.21 DVD489 DLL4(序列 3) N-term. 短 短 VEGF(序列 3) 0.62 AB072 63.43 DVD490 DLL4(序列 3) C-term. 短 短 VEGF(序列 3) 9.27 AB072 63.43 DVD495 DLL4(序列 3) N-term. 長 長 VEGF(序列 3) 0.33 AB072 63.43 DVD496 DLL4(序列 3) C-term. 長 長 VEGF(序列 3) 5.59 AB072 63.43 DVD501 DLL4(序列 3) N-term. 長 短 VEGF(序列 3) 0.18 AB072 63.24 DVD502 DLL4(序列 3) C-term. 長 短 VEGF(序列 3) 3.17 AB072 63.24 DVD507 DLL4(序列 3) N-term. 短 長 VEGF(序列 3) 0.71 AB072 63.24 DVD508 DLL4(序列 3) C-term. 短 長 VEGF(序列 3) 0.61 AB072 63.24
所有DVD-Ig構築體與DLL4之結合均得以維持且與親本 抗體相當。所有N末端可變區域以與親本抗體類似之高親 和力結合。重鏈及輕鏈中連接子長度的一些特定組合使C 末端區域之結合親和力改良至與親本抗體相當。特定言 之，相較於輕鏈及重鏈中之短連接子，使用輕鏈及/或重 鏈中之長連接子的C末端區域之親和力傾向於改良。
表7:具有各種定向及連接子長度組合之8種DVD構築體的 RON及EGFR直接結合ELIS A DVD-Ig ID N-Term* VD序列 ID N-Term. VD EC50 (nM) N- Term. Ref. Ab. ID N-Term. Ref. Ab.EC50 inM) HC 連 接 子 LC 連 接 子 OTerm. VD序列 ID C- Term. VD EC50 (nM) C- Term. Ref. Ab. ID C-Term. Ref. Ab. EC50(nM) DVD023 EGFR 0.23 AB033 0.66 短 短 RON 40.18 AB005 0.26 DVD024 RON 0.54 AB005 0.26 短 短 EGFR 1.87 AB033 0.66 DVD535 RON 0.43 AB005 0.69 長 長 EGFR 1.7 AB033 1.17 DVD536 EGFR 1 AB033 1.17 長 長 RON 10.57 AB005 0.69 DVD537 RON 0.32 AB005 0.69 長 短 EGFR 0.94 AB033 1.17 DVD538 EGFR 1.17 AB033 1.17 長 短 RON 31.11 AB005 0.69 DVD539 RON 0.4 AB005 0.69 短 長 EGFR 1.38 AB033 1.17 DVD540 EGFR 1.1 AB033 1.17 短 長 RON 12.99 AB005 0.69 335 - 151681.doc 201127956 表8:具有各種序列、定向及連接子長度組合之44種DVD 構築體的£0『11.11£112(£1^62)及£1^83直接結合£1^18人
DVD-Ig ID
N- Term. VD序 列ID N-Term. VD EC50 (nM)
N- Term. Ref. Ab. ID N-Term. Ref. Ab· EC50 (nM) DVD385 ErbB3 1.72 AB062 0.75 DVD386 EGFR 0.56 AB033 0.46 DVD387 ErbB3 1.18 AB062 0.75 DVD388 HER-2 1.65 AB004 2.37 DVD389 ErbB3 1.25 AB062 0.75 DVD390 EGFR 0.36 AB033 0.46 DVD391 ErbB3 4.06 AB062 0.97 DVD392 HER-2 1.85 AB004 2.37 DVD393 ErbB3 1.39 AB062 0.97 DVD394 EGFR 0.56 AB033 0.46 DVD395 ErbB3 1.58 AB062 0.97 DVD396 HER-2 2.87 AB004 2.37 DVD397 ErbB3 1.05 AB063 0.87 DVD398 EGFR 0.43 AB033 0.49 DVD399 ErbB3 599.0 AB063 0.87 DVD400 HER-2 3.57 AB004 2.67 DVD401 ErbB3 0.79 AB063 0.87 DVD402 EGFR 0.65 AB033 0.49 DVD403 ErbB3 1.03 AB063 0.92 DVD404 HER-2 1.25 AB004 2.67 DVD405 ErbB3 1.08 AB063 0.92 DVD406 EGFR 0.60 AB033 0.49 DVD407 ErbB3 2.98 AB063 0.92 DVD408 HER-2 2.61 AB004 2.67 DVD409 ErbB3 3.60 AB067 1.78 DVD410 EGFR 0.36 AB033 0.59 DVD411 ErbB3 4.92 AB067 1.78 DVD412 HER-2 4.24 AB004 1.52 DVD413 ErbB3 4.77 AB067 1.12 DVD414 EGFR 0.49 AB033 0.59 DVD415 ErbB3 12.96 AB067 2.20 DVD416 HER-2 3.58 AB004 1.52 DVD417 ErbB3 6.56 AB067 1.12 DVD418 EGFR 0.46 AB033 0.59 DVD419 ErbB3 32.37 AB067 2.20 DVD420 HER-2 3.58 AB004 1.52 DVD421 ErbB3 5.10 AB067 1.12 DVD422 EGFR 0.48 AB033 0.59 DVD423 ErbB3 4.69 AB067 1.12 DVD424 HER-2 4.47 AB004 1.52 DVD683 ErbB3 0.58 AB062 1.60 DVD684 HER-2 0.93 AB004 2.22 DVD685 ErbB3 0.48 AB063 1.10 DVD686 HER-2 1.25 AB004 2.22 HC 連 接 子 LC 連 接 子
C- Term. VD序列 ID C- Term. VD EC50 (nM)
C- Term. Ref. Ab. ID C- Term. Ref. Ab. EC50 (nM) 長長長長長長長長短短短短長長 長長長長長長短短短短短短短短長長長長長長長長短短短短短短短短 長 EGFR 2.79 AB033 0.46 長 ErbB3 4.01 AB062 0.75 長 HER-2 4.23 AB004 2.37 長 ErbB3 3.40 AB062 0.75 短 EGFR 2.3 AB033 0.46 短 ErbB3 11.21 AB062 0.75 短 HER-2 25.26 AB004 2.37 短 ErbB3 16.26 AB062 0.97 長 EGFR 1.75 AB033 0.46 長 ErbB3 21.75 AB062 0.97 長 HER-2 5.98 AB004 2.37 長 ErbB3 24.75 AB062 0.97 長 EGFR 1.41 AB033 0.49 長 ErbB3 1.39 1102.5 AB063 0.87 長 HER-2 4 AB004 2.67 長 ErbB3 7.74 AB063 0.87 短 EGFR 1.65 AB033 0.49 短 ErbB3 0.13 AB063 0.87 短 HER-2 13.82 AB004 2.67 短 ErbB3 4.34 AB063 0.92 長 EGFR 1.68 AB033 0.49 長 ErbB3 1.11 AB063 0.92 長 HER-2 28.51 AB004 2.67 長 ErbB3 4.37 AB063 0.92 短 EGFR 1.75 AB033 0.48 短 ErbB3 55.38 AB067 2.20 短 HER-2 15.4 AB004 1.19 短 ErbB3 205.98 AB067 2.20 長 EGFR 1.1 AB033 0.48 長 ErbB3 21.27 AB067 2.20 長 HER-2 1.56 AB004 1.19 長 ErbB3 64.36 AB067 2.20 短 EGFR 1.62 AB033 0.48 短 ErbB3 18.20 AB067 2,20 短 HER-2 4.78 AB004 1.19 短 ErbB3 143.66 AB067 1.78 長 EGFR 1.1 AB033 0.45 長 ErbB3 17.97 AB067 1.78 長 HER-2 1.29 AB004 1.19 長 ErbB3 40.69 AB067 1.78 短 HER-2 35.64 AB004 2.22 短 ErbB3 215.63 AB062 1.60 短 HER-2 29.02 AB004 2.22 短 ErbB3 97.39 AB063 1.10 -336- 151681.doc 201127956
表9 :具有各種序列、定向及連接子長度組合之62種DVD 構築體的PLGF、HER-2及VEGF直接結合ELISA DVD-Ig ID N- Term. VD序 列ID N-Term. VD EC50(nM) N- Term. Ref. Ab. ID N-Term. Ref. Ab.ECSO(nM) HC 連 接 子 LC 連 接 子 C- Term. VD序 列ID C- Term. VD EC50 (nM) C- Term. Ref. Ab. ID C- Term. Ref. Ab. EC50 (nM) DVD541 P1GF 0.08 AB074 0.49 短 短 VEGF 64.44 ABO 14 1,40 DVD542 VEGF 0.80 ABO 14 1.40 短 短 P1GF 13.04 AB074 0.49 DVD543 P1GF 0.14 AB074 0.49 短 短 VEGF 1120.78 AB070 2.35 DVD544 VEGF 2.35 AB070 2.35 短 短 P1GF 13.76 AB074 0.49 DVD545 P1GF 98.78 AB074 0.49 短 短 VEGF >1000 AB071 35.38 DVD546 VEGF 25.8 AB071 35.38 短 短 P1GF 7.03 AB074 0.49 DVD547 P1GF 0.14 AB074 0.49 短 短 HER-2 167.82 AB004 1.3 DVD548 HER-2 1.26 AB004 1.3 短 短 P1GF 7.42 AB074 0.49 DVD549 P1GF 265.03 AB074 0.49 長 長 VEGF >1000 AB014 1.40 DVD550 VEGF >1000 AB014 1.40 長 長 PIGF 145.70 AB074 0.49 DVD551 P1GF 96.98 AB074 0.49 長 長 VEGF 1589.29 AB070 2.35 DVD552 VEGF 313.54 AB070 2.35 長 長 PIGF 8.54 AB074 0.49 DVD553 P1GF 66317.52 AB074 0.49 長 長 VEGF >1000 AB071 35.38 DVD554 VEGF 15.22 AB071 35.38 長 長 PIGF 0.45 AB074 0.49 DVD555 P1GF N/B AB074 0.49 長 長 HER-2 963.06 AB004 1.3 DVD556 HER-2 1.03 AB004 1.3 長 長 PIGF 0.24 AB074 0.49 DVD557 P1GF 0.17 AB074 0.49 長 短 VEGF 24.98 AB014 1.40 DVD558 VEGF 1.96 ABO 14 1.40 長 短 PIGF 3.37 AB074 0.49 DVD559 P1GF 0.13 AB074 0.49 長 短 VEGF 39.2 AB070 2.35 DVD560 VEGF 3.12 AB070 2.35 長 短 PIGF 2.53 AB074 0.49 DVD561 P1GF 1.04 AB074 0.49 長 短 VEGF 241.04 AB071 35.38 DVD562 VEGF 17.69 AB071 35.38 長 短 PIGF 1.12 AB074 0.49 DVD563 P1GF 0.21 AB074 0.49 長 短 HER-2 16.8 AB004 1.3 DVD564 HER-2 0.57 AB004 1.3 長 短 PIGF 1.37 AB074 0.49 DVD565 P1GF 3.24 AB074 0.49 短 長 VEGF 498.31 AB014 1.40 DVD566 VEGF 1.49 AB014 1.40 短 長 PIGF 1.42 AB074 0.49 DVD567 P1GF 340.25 AB074 0.49 短 長 VEGF >1000 AB070 1.68 DVD568 VEGF 3.14 AB070 1.68 短 長 PIGF 2.84 AB074 0.49 DVD569 P1GF 88.47 AB074 0.49 短 長 VEGF >1000 AB071 26.56 DVD570 VEGF 17.59 AB071 26.56 短 長 PIGF 1.44 AB074 0.49 DVD571 P1GF 33.1 AB074 0.49 短 長 HER-2 209.28 AB004 1.89 DVD572 HER-2 1.34 AB004 1.89 短 長 PIGF 2.34 AB074 0.49 DVD573 P1GF 0.14 AB047 0.14 短 短 VEGF >1000 AB070 1.68 DVD574 VEGF 11.72 AB070 1.68 短 短 PIGF 7.04 AB047 0.14 DVD575 P1GF 0.14 AB047 0.14 短 短 VEGF >1000 AB071 26.56 DVD576 VEGF 16.22 AB071 26.56 短 短 PIGF 1.82 AB047 0.14 DVD577 P1GF 0.15 AB047 0.14 短 短 HER-2 335.83 AB004 1.89 DVD578 HER-2 1.28 AB004 1.89 短 短 PIGF 1.21 AB047 0.14 DVD579 P1GF 1.18 AB047 0.17 長 長 VEGF 47.94 AB014 1.40 DVD580 VEGF >1000 ABO 14 1.40 長 長 PIGF 34.14 AB047 0.17 DVD581 P1GF 0.39 AB047 0.17 長 長 VEGF 35.9 AB070 1.68 DVD582 VEGF 4.36 AB070 1.68 長 長 PIGF 0.37 AB047 0.17 DVD583 P1GF 0.32 AB047 0.17 長 長 VEGF 559.56 AB071 26.56 •337· 151681.doc 201127956 DVD584 VEGF 18.36 AB071 26.56 DVD585 P1GF 0.26 AB047 0.13 DVD586 HER-2 1.04 AB004 1.89 DVD587 P1GF 0.13 AB047 0.13 DVD588 VEGF 4.1 AB014 1.40 DVD589 P1GF 0.12 AB047 0.13 DVD590 VEGF 21.09 AB070 1.9 DVD591 P1GF 0.13 AB047 0.14 DVD592 VEGF 19.21 AB071 20.92 DVD593 P1GF 0.09 AB047 0.14 DVD594 HER-2 1.03 AB004 1.78 DVD595 P1GF 0.21 AB047 0.14 DVD596 VEGF 12.73 AB014 1.40 DVD597 P1GF 0.17 AB047 0.13 DVD598 VEGF 6.66 AB070 1.9 DVD599 P1GF 0.23 AB047 0.13 DVD600 VEGF 17.04 AB071 20:92 DVD601 P1GF 0.24 AB047 0.13 DVD602 HER-2 1.12 AB004 1.78 長長長長長長長長長長長短短短短短短短短 長 P1GF 0.32 AB047 0.17 長 HER-2 5.44 AB004 1.89 長 P1GF 0.18 AB047 0.13 短 VEGF 12.71 ABO 14 1.40 短 P1GF 1.84 AB047 0.13 短 VEGF 1356.24 AB070 1.9 短 P1GF 2.78 AB047 0.13 短 VEGF 1166.31 AB071 20.92 短 P1GF 0.31 AB047 0.14 短 HER-2 17.53 AB004 1.78 短 P1GF 0.38 AB047 0.14 長 VEGF 4.63 ABO 14 1.40 長 P1GF 14.59 AB047 0.14 長 VEGF 31.08 AB070 1.9 長 P1GF 0.66 AB047 0.13 長 VEGF 664.22 AB071 20.92 長 P1GF 0.4 AB047 0.13 長 HER-2 10.03 AB004 1.78 長 P1GF 0.31 AB047 0.13
表ίο :具有各種序列、定向及連接子長度組合之46種DVD 構築體的HGF及VEGF直接結合ELISA DVD-Ig ID N- Term. VD序 列ID N-Term. VD EC50 (nM) N- Term. Ref. Ab. ID N-Term. Ref. Ab. EC50 (nM) HC 連 接 子 LC 連 接 子 C- Term. VD序 列ID C-Term. VDEC50 (nM) C- Term. Ref. Ab. ID C-Term· Ref· Ab. EC50 (nM) DVD641 HGF 0.47 ABO 12 0.15 長 長 VEGF 41.55 AB014 1.40 DVD642 VEGF 6.35 AB014 1.40 長 長 HGF 0.87 ABO 12 0.15 DVD643 HGF 0.26 AB012 0.15 長 長 VEGF 175.3 AB070 5.22 DVD644 VEGF 5.31 AB070 5.22 長 長 HGF 0.29 ABO 12 0.15 DVD645 HGF 0.17 AB012 0.15 長 長 VEGF >10000 AB071 40.35 DVD646 VEGF 30.74 AB071 40.35 長 長 HGF 0.49 ABO 12 0.15 DVD647 HGF 0.15 AB012 0.17 長 短 VEGF 25.45 ABO 14 1.40 DVD648 VEGF 1.72 AB014 1.40 長 短 HGF 4.17 ABO 12 0.17 DVD649 HGF 0.15 AB012 0.17 長 短 VEGF 185.88 AB070 5.22 DVD650 VEGF 2.67 AB070 5.22 長 短 HGF 4.63 AB012 0.17 DVD651 HGF 0.11 ABO 12 0.17 長 短 VEGF 340.64 AB071 40.35 DVD652 VEGF 13.83 AB071 40.35 長 短 HGF 4.71 AB012 0.17 DVD653 HGF 0.24 ABO 12 0.17 短 長 VEGF 16.77 AB014 1.40 DVD654 VEGF 3.71 ABO 14 1.40 短 長 HGF 0.91 ABO 12 0.17 DVD655 HGF 0.19 ABO 12 0.17 短 長 VEGF 92.93 AB070 5.22 DVD656 VEGF 7.87 AB070 5.22 短 長 HGF 1.27 ABO 12 0.17 DVD657 HGF 0.31 ABO 12 0.17 短 長 VEGF 357.93 AB071 40.35 DVD658 VEGF 28.66 AB071 40.35 短 長 HGF 0.94 ABO 12 0.17 DVD659 HGF 0.4 AB079 0.48 短 短 VEGF 161.03 AB014 1.40 DVD660 VEGF 1.51 AB014 1.40 短 短 HGF 449.24 AB079 0.48 DVD661 HGF 0.7 AB079 0.48 短 短 VEGF 566.36 AB070 4.64 DVD662 VEGF 70.17 AB070 4.64 短 短 HGF 213.76 AB079 0.48 DVD663 HGF 0.26 AB079 0.48 短 短 VEGF >10000 AB071 80.43 DVD664 VEGF 40.91 AB071 80.43 短 短 HGF 80.87 AB079 0.48 DVD665 HGF 0.23 AB079 0.39 長 長 VEGF 8.09 AB014 1.40 DVD666 VEGF 133.6 ABO 14 1.40 長 長 HGF 14/7 AB079 0.39 -338 - 151681.doc 201127956 DVD667 DVD668 DVD669 DVD670 DVD671 DVD672 DVD673 DVD674 DVD675 DVD676 DVD677 DVD678 DVD679 DVD680 DVD681 DVD682 DVD709 DVD710 DVD711 DVD712 HGF 0.33 VEGF 135.82 HGF 0.29 VEGF 48.28 HGF 0.35 VEGF 16.1 HGF 0.4 VEGF 10.57 HGF 0.48 VEGF 130.31 HGF 0.33 VEGF 0.65 HGF 0.32 VEGF 12.62 HGF 0.27 VEGF 53.09 HGF 0.14 VEGF 2.43 HGF 1.32 VEGF 64.2 AB079 AB070 AB079 AB071 AB079 AB014 AB079 AB070 AB079 AB071 AB079 AB014 AB079 AB070 AB079 AB071 AB012 AB070 AB012 AB071 0.39 4.64 0.39 80.43 0.4 1.40 0.4 4.64 0.4 80.43 0.41 1.40 0.41 5.62 0.41 79.48 0.16 5.62 0.16 79.48 長長長長長長長長長長短短短短短短短短短短 長 長 長 長 短 短 短 短 短 短 長 長 長 長 長 長 短 短 短 短 VEGF 51.29 HGF 20.23 VEGF 1663.25 HGF 3.1 VEGF 28.75 HGF 22.95 VEGF 65.28 HGF 17.6 VEGF 5767.36 HGF 35.83 VEGF 1.02 HGF 4.69 VEGF 92.36 HGF 5.17 VEGF 2161.65 HGF 6.55 VEGF 1366.2 HGF 17.76 VEGF 165.93 HGF 37.18 AB070 AB079 AB071 AB079 AB014 AB079 AB070 AB079 AB071 AB079 AB014 AB079 AB070 AB079 AB071 AB079 AB070 ABO 12 AB071 AB012 4.64 0.39 80.43 0.39 1.40 0.4 4.64 0.4 80.43 0.4 1.40 0.41 5.62 0.41 79.48 0.41 5.62 0.16 79.48 0.16 使用靶向HER2之2個不同抗原決定基（結構區域η及結構 區域IV)之兩種mAb製備具有不同mAb區域定向及連接子長 度的DVD-Ig。在直接ELISA及3丨扣0代檢定中測試此等 DVD-Ig之目標結合功能。 定向及連接子長度組合的 表11 :具有HER-2(erbB2)序列
8種DVD構築體與HER-2之直接結合ELISA 親本抗體或 DVD-Ig ID N末端 可變區域 (VD) C末端 可變區域 (VD) 直接結合 ELISA EC50(nM) AB004 HER-2(結; 虜區域IV) 0.68 AB080 HER-2(結構區域II) 3.84 DVD687 HER-2(結構區域IV) HER-2(結構區域Π) 1.71 DVD688 HER-2(結構區域II) HER-2(結構區域IV) 3.59 DVD689 HER-2(結構區域IV) HER-2(結構區域id 0.60 DVD690 HER-2(結構區域II) HER-2(結構區域IV) 0.48 DVD691 HER-2(結構區域IV) HER-2(結構區域Π) 0.19 DVD692 HER-2(結構區域II) HER-2(結構區域iv) 5.96 DVD693 HER-2(結構區域IV) HER-2(結構區域π) 0.16 DVD694 HER-2(結構區域II) HER-2(結構區域iv) 0.53 所有DVD-Ig構築體與HER-2之結合均得以維持且與親本 •339 - 151681.doc 201127956 抗體相當。N末端可變區域處之所有HER-2結構區域 與親本抗體類似之高親和力或改良之親和力結入。4 ° 重鏈及 輕鏈中連接子長度的一些特定組合使結合親和力改 又良至優 於親本抗體。 實例1.1.1.B:重導向細胞毒性（rCTL)檢定 重導向細胞毒性（rCTL)檢定測定DVD-Ig使τ細胞與腫瘤 細胞緊密接近使得T細胞可殺死腫瘤細胞的能力。 基於FACS之檢定（1):藉由負選擇增濃管柱（R&D目錄號 HTCC-525)自先前經冷凍分離之PBMC分離人類cD3+ 丁細 胞。在塗覆有含 10 pg/mL 抗 CD3(OKT-3，BD)及 2 CD28(CD28.2，Abeam)之完全RPMI培養基（L-麵醯胺酸， 55 mM β-ΜΕ，Pen/Strep，10% FCS)的燒瓶中刺激τ細胞 4 天。T細胞在用於檢定中之前，在30 U/mL IL-2(Peprotech) 中靜置隔夜。根據製造商說明書將DoHH2或Raji目標細胞 以PKH26(Sigma)標記。整個rCTL檢定中使用含有L·麩醯 胺酸及10% FBS(Hyclone)之RPMI 1640培養基（無苯酚， Invitrogen) ° 效應T細胞（E)及目標（T)分別以每孔105個細胞及每孔1〇4 個細胞接種於96孔板（Costar #3799)中，產生10:1之E:T 比。DVD-Ig分子經大致稀釋獲得濃度依賴性滴定曲線。 培育隔夜之後，使細胞集結成球且以PBS洗滌一次，隨後 再懸浮於含有0.1% BSA(Invitrogen)及0.5 pg/mL块化丙錠 (BD)之PBS中。在FACSCanto機（BD)上收集FACS資料且在 Flowjo(Treestar)中分析。 151681.doc •340· 201127956 計算DVD-Ig處理之樣品中的活目標百分比除以總目標 百分比（對照組，未處理）以測定特定溶解百分比。將資料 繪圖且在Prism(Graphpad)中計算IC50。 基於阻抗（2):如上製備T細胞。使表現EGFR之目標細 胞黏附於 ACEA RT-CES 96 孔板（ACEA Bio，San Diego)隔 夜。接著將效應T細胞（E)及目標（T)以每孔2x1 〇5個細胞及 每孔2χ104個細胞接種，產生10:1之Ε:Τ比。DVD-Ig分子經 大致稀釋獲得濃度依賴性滴定曲線。DVD-Ig處理之樣品 中的目標細胞指數除以對照目標（未處理）之細胞指數，計 算特定溶解百分比。將資料繪圖且在priSm(Graphpad)中計 算 IC50。（Dreier，T. (2002) Int J Cancer 100:690-697 ; Zhu， J. (2006) J· immun〇 Methods 309:25-33)。此 CD3/CD20 DVD_Ig之序歹於美國專利申請案第20070071675號中揭 示0 表U . DVD-Ig之重導向細胞毒性（rCTL) DVD-Ig ID ΤΛΛ ΤΤ\Ο^Π rw末端可 變區域 μ__1Υ〇) c末端可 變區域 (VD) 腫瘤目標細胞 rCTL IC50 (pM) 檢定 UVUoj / DVD003 DVD855 DVD856 DVD859 CD3 ~〇ΤΝ ------ CD19 DoHH2(DSMZACC47) 4 FACS ρτγ^**~·-- CD3 DoHH2 (DSMZ ACC47) 283 FACS ^Ui ~〇τΓ〇7ϊ---- CD-20 DoHH2(DSMZACC47) 472 FACS CD3 CD3 DoHH2 (DSMZ ACC47) 5053 FACS EGFR A431(ATCC CRL-1555) 0.4 阻抗 U V L/oOU DVD018 DVD012 Τ^ΛΤΊΛΟ^/Ι tGFR CD3^^- -- CD3 A431(ATCC CRL-1555) 31 阻抗 EGFR A431(ATCC CRL-1555) 15 阻抗 1 CD3 BT-474(ATCC HTB-20) 155 阻抗 JJ VJJo〇4 DVD865 HER*2^^· 'nfyT —— CD3 BT-474(ATCC HTB-20) 49 阻抗 IGF1R A431(ATCC CRL-1555) 58 阻抗 在DoHH-2 B細胞淋巴瘤早期側腹腫瘤模型中證明DVD_ 151681.doc •341 201127956
Ig ID 857之功效。在8(^(1小鼠側腹注射單獨之D〇HH2腫瘤 細胞或10:1比率之DoHH2腫瘤細胞加自周邊血液純化之 CD3 T細胞。第1天，在無τ細胞存在下，靜脈内給予8〇 pg Rituxan。在第1天至第5天，向僅給予Β〇ΗΗ^_胞或給 予DoHH2細胞+T細胞兩者之小鼠每天靜脈内給予8〇畔 DVD-Ig ID 857。在第32天，接受丁細胞或僅DVD_Ig 857之 DoHH-2組對D〇HH-2生長具有顯著影響，TGI%分別為63及 55 »以利妥昔單抗處理之D〇HH-2(TGI°/〇=94)與DOHH2對照 組比較時顯示有顯著功效（ρ$〇 〇〇〇1)β [T細胞+DVD-Ig ID 857]在與〇〇11112對照組比較時顯示與利妥昔單抗組（1>(31〇/〇 分別為95。/。及98%)相等的功效（p$〇 〇〇〇1)。第52天，利妥 昔單抗與[DVD-Ig ID 857+T細胞]組彼此無顯著不同。 Kaplan-Meier 存活曲線（lcc.端點）。對數秩（Logrank， Mantel-Cox)統計顯示以利妥昔單抗及[DVD-Ig ID 857+T細 胞]處理之組與DoHH-2對照組比較時存活顯著增加 (PS0.0001)。利妥昔單抗與[DVD,Ig ID 857+T細胞]組彼此 無顯著不同。 分別使用來自Ab002及AB006之可變區域產生CD3及 CD19 DVD-Ig 。使用對 Jurkat 細胞之 OKT3-PE (eBioscience，目錄號 12-0037)競爭 FACS 分析測定 DVD-Ig 對人類CD3之IC50。將EC90之OKT3-PE與不同濃度之 DVD-Ig混合在一起，且在冰上在96孑L圓底板（corning #3365)中與每孔0.5xl0e6個Jurkat細胞一起培育1小時。使 用 Flo J〇(Becton Dickinson)分析之 FACS Calibur(Becton 151681.doc -342· 201127956
Dickinson)獲得樣品。使用Meso Scale Discovery使用以人 類CD19穩定轉染之293細胞上經磺基標記之AB006測定 DVD-Ig對人類CD19之IC50 〇將EC90之經磺基標記之 AB006與各種濃度之DVD-Ig混合且添加至96孔高度結合板 (Meso Scale Discovery #LllXB-3)中每孔25,000個細胞的 293 hCD19 細胞中。在 Sector Image 6000(Meso Scale
Discovery)上對樣品讀數。
表13 : DVD-Ig與經標記參考Ab之競爭 N末端可變區 域(VD) C末端可變區 域(VD) HC連 接子 LC連 接子 競爭Jurkat細胞 (OKT3) IC50 nM 競爭 293-hCD19 (AB006)IC50 nM CD3 CD19 長 長 1,0.16 73, 180 CD3 CD19 短 短 1.9, 2.9 504, >1〇〇〇 CD3 CD19 短 長 1.1,3.4 70, 200 CD3 CD19 長 短 1.7, 1.3 124,490 CD19 CD3 長 長 >1000 29
實例 1.1.1.C:捕捉 ELISA-VEGF ELISA板（Nunc，MaxiSorp，Rochester，NY)與抗人類 Fc抗 體（PBS 中 5 pg/ml，Jackson Immunoresearch，West Grove, PA) —起在4°C下培育隔夜。在洗滌緩衝液（含有0·05% Tween 20之PBS)中洗滌板3次，且在25°C下在阻斷緩衝液 (含有1% BS A之PBS)中阻斷1小時。洗滌各孔3次’且向各 孔中添加各抗體或DVD-Ig於含有0.1% BS A之PBS中的連續 稀釋液，且在25°C下培育1小時。洗滌各孔3次，立向板中 添加經生物素標記之VEGF(2 nM)，且在25°C下培育1小 時。洗滌各孔3次，且接著在25r下與抗生蛋白鏈菌素-HRP(KPL #474-3000, Gaithersburg, MD)— 起培育 1小時。 151681.doc -343 - 201127956 洗滌各孔3次，且每孔添加100 μΐ ULTRA-TMB ELISA (Pierce, Rockford, IL)。顯色後，以1 N HCL停止反應且量 測450 nM下之吸光度。VEGF捕捉ELISA資料顯示於表14 中。
實例 l.l.l.D: IgG_Fc捕捉ELISA-RON 以含有2 pg/mL山羊抗人類IgG Fc特異性抗體（Jackson Immunoresearch # 109-055-098，West Grove，PA,每孔 50 pL)之 PBS(Gibco #10010-023，來自 Invitrogen，Grand Island，NY)塗覆96孔Nunc-Immuno板，且在4°C下培育隔 夜。以洗滌緩衝液（PBS，〇·〇5% Tween 20)洗滌板3次’且 隨後在室溫下以每孔1〇〇 阻斷緩衝液（PBS，2% BSA)阻 斷1小時。洗滌板3次，且在室溫下與每孔50 μι 1 pg/mL適 當抗體或DVD-Ig之溶液一起培育1小時。培育1小時後， 洗滌板3次，且在室溫下與每孔50 mL his標記之重組RON 蛋白（R&D Systems # 1947-MS，Minneapolis，MN，1000 nM 至0 nM最終劑量範圍）起培育1小時。洗條板3次’且添 加每孔50 μί兔抗His標籤-HRP抗體（Abeam abll87, Cambridge，MA，以 1:10,000稀釋於 BSA/PBS溶液中）’ 且板在室溫下培育1小時。最終洗滌後’添加每孔50 μ1 ΤΜΒ 受質（Pierce #34028, Rockford，IL)，且在 5 分鐘後使用 每孔50 μΐ 2 N H2S04終止反應。在450 nm下讀取吸光度 (Spectra Max Plus板讀取器，Molecular Devices，Sunnyvale， CA) » 在 GraphPad Prism 4.03 中計算 EC50。RON 捕捉 ELISA資料顯示於表14中。 151681.doc • 344- 201127956 實例 1.1.1.E:捕捉ELISA-IGF1，2 將96孔Nunc-Immuno板以含有5 pg/ml針對人類IgG之抗 體（Fey片段特異性，Jackson ImmunoResearch，West Grove, PA, #109-005-098,每孔 100 μΐ)之 D-PBS(Gibco # 14190, San Diego，CA)塗覆且在4°C下培育隔夜6在洗滌緩衝液 (PBS，0.05% Tween 20)中洗滌ELISA板 3次，接著在25°C 下以每孔200 μΐ阻斷緩衝液（D-PBS，1% BSA)阻斷1小時。 ^ 接著洗滌板，且在37°C下與每孔1〇〇 μΐ抗體或DVD-Ig(阻斷 緩衝液中〇·〇1 pg/mL -100 pg/mL)—起培育1小時。接著洗 務板3次，且與生物素標記之人類IGF 1或IGF2(阻斷緩衝液 中0.02 nM -100 nM劑量範圍，每孔100 μΐ)—起在37°C下培 育1小時。洗滌板3次，且與HRP結合之抗生蛋白鏈菌素 (KPL #474-3000, Gaithersburg, MD，在阻斷緩衝液中 1:10,000稀釋，每孔100 μΐ)—起在25°C下培育1小時。最終 洗滌後，板與每孔1〇〇 μΐ ELISA受質（1-Step Ultra TMB-• ELISA, Pierce #340280, Rockford, IL)-起培育。在 25〇C 下 5分鐘後，以每孔100 μΐ 2 N H2S04停止反應且在450 nm下 讀取吸光度。IGF1，2捕捉ELISA資料顯示於表14中。 實例 1.1.1.F:捕捉ELISA-DLL4 將 96孔Nunc-Immuno板（#439454，.Rochester，NY)以含有 5 pg/ml針對人類IgG之抗體（Fey片段特異性，Jackson ImmunoResearch，West Grove, PA #109-005-098，每孔 100 μΐ)之 D-PBS(Gibco #14190，Grand Island，NY)塗覆且在4〇C 下培育隔夜。以洗滌緩衝液（PBS，0.05% Tween 20)洗滌 151681.doc -345- 201127956 ELISA板3次，接著在25°C下以每孔200 μΐ阻斷緩衝液（0-PBS、1% BSA、1 mM CaC12、0.05% Tween 20)阻斷 1小 時。洗滌板3次，且在25°C下與每孔1〇〇 μΐ DLL4抗體 (0.000卜100 ηΜ，在阻斷緩衝液中10倍連續稀釋）一起培育 1小時，接著再洗滌3次。在25°C下將含有經捕捉DLL4 Ab 之板與生物素標記之人類DLL4胞外區域（阻斷緩衝液中10 nM，每孔100 μΐ)—起培育1小時，洗滌3次，且與HRP結合 之抗生蛋白鏈菌素（KPL #474-3000C) —起培育，洗滌3 次，且在25°C下與HRP結合之抗生蛋白鏈菌素（KPL #474-3000，Gaithersburg，MD，在阻斷緩衝液中 1:10,000稀釋， 每孔100 μΐ)—起培育1小時。最終洗滌後，板與每孔100 μΐ ELISA 受質（1-Step Ultra TMB-ELISA，Pierce #340280, Rockford，IL)一起培育。在25°C下2分鐘後，以每孔100 μΐ 2 N H2S04停止反應且在450 nm下讀取吸光度。DLL4捕捉 ELISA資料於表14中顯示。 實例1.1.1.0:捕捉£[18八-£|^63或£0罗11 96孔ELISA板以濃度為33 nM之山羊抗人類IgG Fc (Jackson Immunoresearch，PA)塗覆，且在 4°C 下培育隔夜。 以含有0.05% Tween 20之PBS洗滌各板3次，且在室溫下以 每孔200 μΐ 1% BSA/PBS阻斷1小時。向各孔中添加50 μΐ 5 nM DVD-Ig或抗體且在室溫下培育1小時。洗滌各板，接 著在室溫下與每孔50 μΐ各種濃度之生物素標記ErbB3或生 物素標記之EGFR—起培育1小時。再次洗滌各板，接著與 每孔50 μΐ抗生蛋白鏈菌素結合之HRP(KPL #474-3000, 151681-doc -346- 201127956
Protein Research Products，MD)—起培育，且在室溫下培 育1小時。洗滌各孔3次，且每孔添加100 μΐ ULTRA-TMB ELISA(Pierce，Rockford, IL)。顯色後，以1 N HCL停止反 應且在450 nM下量測吸光度。 表14含有親本抗體及DVD-Ig構築體VEGF、RON、 EGFR、IGFR、IGF-1，2、HER-2、DLL4 及 ErbB3 之親和 力，表示為EC50(nM)。
表14 :親本抗體及DVD-Ig構築體之VEGF、RON、 EGFR、ErbB3、IGFR、IGF-1，2、DLL4及 HER-2抗原捕 捉 ELISA 親本抗體或 DVD-Ig ID N末端可 變區域 C末端可 變區域 捕捉ELISA中之N末端 Ag結合(EC50，nM) 捕捉ELISA中之C末端 Ag結合(EC50，nM) AB004 HE R-2 0.4 ABO 10 IGF1，2 4.8.10 DVD029 HER-2 IGF1,2 229, 206 DVD030 IGF 1,2 HER-2 1.8, 5.5 10.7 AB033 EGFR 0.3 AB011 IGF1R 0.3 DVD021 EGFR IGF1R 0.3 135 DVD022 IGF1R EGFR 0.3 0.7 AB005 RON 1.6 DVD024 RON EGFR 1.96 DVD023 EGFR RON >100 AB004 HER-2 0.2 AB011 IGF1R 0.3 DVD031 HER-2 IGF1R 0.3 171 DVD032 IGF1R HER-2 0.2 11 AB005 RON 0.7 AB012 HGF DVD033 RON HGF 2.5 DVD034 HGF RON AB014 VEGF 0.24 DVD035 VEGF EGFR 0.24 AB014 VEGF 0.24 DVD038 HER-2 VEGF 2.00 ABO 14 VEGF 0.9 151681.doc •347- 201127956 親本抗體或 DVD-Ig ID N末端可 變區域 C末端可 變區域 捕捉EUSA中之N末端 Ag結合(EC50，nM) 捕捉ELISA中之C末端 Ag結合(EC50，nM) AB010 IGF 1,2 4.8. 18.1 DVD041 VEGF IGF 1,2 _______ 0.7 381,7335 DVD042 IGF1，2 VEGF 2.5,17.6 42.3 AB015 DLL-4 0. 03 ABO 14 VEGF 0.24 DVD044 DLL4 VEGF 0.06 4.20 DVD043 VEGF DLL4 0.20 0.50 AB014 VEGF 0. 24 AB012 H( 3F DVD045 VEGF HGF 0.29 >100 AB005 RON 1 3 AB014 VEGF 0.24 DVD048 RON VEGF 2.7 3.60 DVD047 VEGF RON 0.36 >100 AB014 VEGF 0.24 DVD049 VEGF NRP1 4.80 DVD050 NRP1 VEGF 2.30 ABO 14 VEGF 0.53 DVD260 P1GF VEGF 1.70 AB062 ErbB3 0.26 DVD299 ErbB3 EGFR 0.25 >10.0 AB063 ErbB3 0.67 AB033 EGFR DVD305 ErbB3 EGFR 0.92 >10.0 DVD306 EGFR ErbB3 0.48 >10.0 DVD385 ErbB3 EGFR 0.36 1.1 DVD409 ErbB3 EGFR 0.54 2.5 DVD410 EGFR ErbB3 >10 0.77 DVD413 ErbB3 EGFR 0.59 0.71 所有DVD-Ig構築體與可溶性抗原之結合均得以維持且 與親本抗體相當。所有N末端可變區域均以與親本抗體以 及 DVD022、DVD038、DVD043、DVD048、DVD50 及 DVD260之C末端可變區域類似之高親和力結合。 151681.doc •348- 201127956
表15: 7種DLL4/VEGF DVD-Ig構築體及親本抗體之DLL4 抗原捕捉ELISA DVD-Ig ID 序列ID 定向 HC 連接子 LC 連接子 其他DVD-Ig VD DVD-Ig DLL·!捕捉 ELISA EC50(nM) Ref. Ab. ID Ref.Ab. DLL4捕捉 ELISA EC50(nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 0.16 ABO 15 0.15 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 0.21 AB015 0.18 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 0.17 AB015 0.18 DVD474 DLL4(序列 1)1 C-term. 長 長 VEGF(序列 2) 0,14 ABO 15 0.15 DVD486 DLL4(序列 1) C-term. 短 長 VEGF(序列 2) 0.16 ABO 15 0.14 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 5.45 AB015 0.14 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 0.17 AB015 0.15
所有DVD-Ig構築體與DLL4抗原之結合均得以維持且與 親本抗體相當。所有N末端可變區域均以與親本抗體以及 DVD470、DVD476、DVD482、DVD474 及 DVD486 之 C 末 端可變區域類似之高親和力結合。
表16 : 7種DLL4/VEGF DVD-Ig構築體及親本抗體之VEGF 抗原捕捉ELISA DVD-Ig ID 序列ID 定向 HC 連接子 LC 連接子 其他 DVD-Ig VD DVD-Ig VEGF 捕 捉 ELISA EC50fnM) Ref. Ab. ID Ref.Ab. VEGF捕捉 ELISA EC50(nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF (序列1) 0.27 ABO 14 0.21 DVD476 DLL4(序列 1) C-term. 長 短 VEGF (序列1) 0.22 ABO 14 0.21 DVD482 DLL4(序列 1) C-term. 短 長 VEGF (序列1) 0.22 AB014 0.21 DVD474 DLL4(序列 1) C-term. 長 長 VEGF (序列2) 1.65 AB071 0.38 DVD486 DLL4(序列 1) C-term. 短 長 VEGF (序列2) 0.53 AB071 0.38 DVD485 DLL4(序列 1) N-term. 短 長 VEGF (序列2) 2.5 AB071 0.38 DVD471 DLL4(序列 1) N-term. 長 長 VEGF (序列3) 0.56 AB070 0.35 所有DVD-Ig構築體與VEGF抗原之結合均得以維持且與 親本抗體相當。所有N末端可變區域均以與親本抗體以及
J 151681.doc •349· 201127956 DVD470、DVD476、DVD482、DVD474 及 DVD486 之 C 末 端可變區域類似之高親和力結合。 實例1.1.1.H :藉由親本ErbB3抗體、EGFR抗體及DVD-Ig 構築體活體外抑制與配位體無關之ErbB3及EGFR磷酸化 使A431細胞以每孔40,000個細胞於96孔板中生長，且在 37。(：、5% C02下培育18至24小時。培育後，細胞以IX D-PBS洗滌2次，且在無血清培養基中饑餓隔夜。第二天’在 37°C下將細胞與50 μΐ含有60 μΜ單株抗體或DVD-Ig之無血 清培養基一起培育4小時。在培育抗體後，接著將細胞以 冰冷D-PBS洗滌2次，且採集於110 μΐ含有10 μΐ HALT®磷 酸酶抑制劑混合液（Thermo Scientific，Rockford，IL)、一份 Complete®無EDTA之蛋白酶抑制劑錠劑（每10毫升1粒錠劑， Roche Diagnostic，Mannheim, Germany)及 PMSF之細胞提 取緩衝液（Biosource International, Carlsbad, CA)中。在間 歇渦旋下將細胞溶解產物在冰上培育30分鐘，藉由離心 (10分鐘，14,000 RPM，4°C)預澄清，且處理以供ELISA分 析。藉由根據製造商方案使用人類Phospho-ErbB3偵測套 組（R&D Systems #DYC1769, Minneapolis，MN)偵測磷光 體-ErbB3。根據製造商方案使用人類Phospho-EGF R DuoSet套組（R&D Systems #DYC1095，Minneapolis，MN)偵 測磷光體-EGFR。 151681.doc •350· 201127956 表16A : ErbB3親本抗體及DVD-Ig構築體對ErbB3及EGFR 於A431細胞中之磷酸化的抑制 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) 對ErbB3磷酸化之抑 制(60nMAb/DVD 下 之抑制％) 對EGFR磷酸化之抑 制(在 60nMAb/DVD 下之抑制％) AB062 ErbB3 72% 0% AB033 EGFR 28% 54% DVD385 ErbB3 EGFR 77% 61% DVD409 ErbB3 EGFR 82% 63% DVD413 ErbB3 EGFR 83% 62% DVD299 ErbB3 EGFR 77% 55% AB008 CD22 0% 4%
實例l.l.l.I : ErbB3或EGFR單株抗體或DVD-Ig在活體外 之生長抑制作用 將稀釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏磷酸 鹽緩衝—鹽水（Dulbecco's phosphate buffered saline))中之 ErbB3、EGFR 單株抗體或 DVD-Ig 以 180 μί 中 2.4 nM及 21.6 nM的最終濃度添加至96孔板中之A431細胞中。板在37°C 下在含濕氣5% C02氛圍中培育3天。藉由根據製造商說明 使用 ATPlite套組（Perkin Elmer, Waltham，MA)評定 ATP含量 來直接量測細胞存活/增殖。無抗體處理之孔用作〇%抑制 之對照組，而無細胞之孔視為顯示100%抑制。 表16B :藉由ErbB3親本抗艎及DVD-Ig構築體抑制A431增殖 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) c末端可 變區域 (VD) 對A431增殖之抑制 (2.4 nMAb/DVDT 之抑制％) 對A431增殖之抑制 (21.6 nM Ab/DVD下 之抑制°/〇) AB062 ErbB3 14% 27% ~ AB033 EGFR 14% 49% DVD385 ErbB3 EGFR 57% 78% DVD409 ErbB3 EGFR 65% 78% DVD413 ErbB3 EGFR 52% 76% DVD299 ErbB3 EGFR 52% 70% ~ AB008 CD22 ND 6% 151681.doc -351 · 201127956 實例1.1.1.J:使用BIACORE技術之親和力測定 表17 : Biacore分析中所用之試劑
檢定 抗原 供應商命名 供應商 目錄號 DLL4 DLL4 DLLECDHis 標籤 R&D 1506-D4-050 EGFR EGFR EGFR ECD R&D 1095-ER HER-2 HER-2/FC ErbB2/FC嵌合體-His標籤 R&D 1129-ER-050 HGF HGF HGF R&D 294-HG-025 IGF1 IGF1 IGF-I R&D 291-G1-050 IGF2 IGF2 IGF-2 R&D 292-G2-050 IGF1R IGF1R IGF 1R ECD R&D 391-GR-050 NRP1 NRP1 神經纖毛蛋白-1 Npn-l-His標籤 R&D 3870-N1-025 P1GF P1GF 胎盤GF R&D 264-PG-050 RON RON MSP受體ECD-His標籤 R&D 1947-MS-050 VEGF VEGF VEGF R&D 293-VE-010 ErbB3 ErbB3 ErbB3/FC嵌合體-His標籤 R&D 348-RB ECD=胞外區域 /FC =抗原/IgG FC區域融合蛋白 BIACORE方法： BIACORE 檢定（Biacore，Inc，Piscataway，NJ)藉由動力學 量測締合速率及解離速率常數來測定抗體或DVD-Ig之親 和力。在25°C下，藉由基於表面電漿子共振之量測以
Biacore® 1000或 3000儀器（Biacore® AB，Uppsala，Sweden) 使用流動 HBS-EP(10 mM HEPES [pH 7.4]、150 mM NaCl、3mMEDTA及 0.005%界面活性劑P20)測定抗體或 DVD-Ig與目標抗原（例如純化重組目標抗原）之結合。所有 化學品係獲自Biacore® AB(Uppsala，Sweden)或獲自本文所 述之不同來源。舉例而言，根據製造商說明書及程序使用 標準胺偶合套組將25 pg/ml於10 mM乙酸鈉（pH 4.5)中稀釋 之約5000 RU山羊抗小鼠IgG(FcY)片段特異性多株抗體 (Pierce Biotechnology Inc, Rockford，IL)直接固定於CM5研 151681.doc 352· 201127956 究級生物感測器晶片上。生物感測器表面上之未反應部分 以乙醇胺阻斷。流槽2及4中之經修飾羧甲基聚葡萄糖表面 用作反應表面。流槽1及3中無山羊抗小鼠IgG之未經修飾 之羧曱基聚葡萄糖用作參考表面。為進行動力學分析，使 用Biaevaluation 4.0.1軟體將自1:1朗缪爾結合模型（1:1 Langmuir binding model)導出之速率方程式同時擬合至所 有8次注射之缔合相及解離相（使用整體擬合分析）。將經純 化抗體或DVD-Ig稀釋於HEPES緩衝鹽水中以於整個山羊抗 小鼠IgG特異性反應表面上捕捉。將欲捕捉作為配位體之 抗體或DVD-Ig(25 pg/ml)以5 μΐ/min之流動速率注射於反應 基質上。在25 μΐ/min之連續流動速率下測定締合及解離速 率常數koJM·、·1)及kofKs-1)。藉由在10至200 nM範圍内之 不同抗原濃度下進行動力學結合量測得出速率常數。接著 藉由下式由動力學速率常數計算抗體或DVD-Ig與目標抗 原之間反應之平衡解離常數（M) : Kfkoff/ku。記錄結合與 時間之函數關係，且計算動力學速率常數。在此檢定中， 可量測到快達10ό Μ·、—1之締合速率及慢至10_6 s — 1之解離速 率。 表18:親本抗體及DVD構築體之BIACORE分析 親本抗體或 DVD-Ig ID N末端可變 區域 (VD) C末端可變 區域 (VD) k〇n (M-ls-1) k〇fr (s-1) KD (M) AB011 IG1 71R 7.32E+04 6.21E-05 8.48E-10 DVD021 EGFR 1.22E+06 1.80E-03 1.47E-9 DVD021 IGF1R DVD022 IGF1R 1.06E+05 8.25E-05 7.78E-10 DVD022 EGFR 8.03E+04 2.26E-04 2.81E-9 AB004 HER-2 3.22E+05 1.28E-05 3.97E-11 151681.doc - 353 - 201127956 ABO 11 IG] :1R 7.32E+04 6.21E-05 8.48E-10 DVD031 HER-2 3.30E+05 7.02E-06 2.12E-11 DVD031 IGF1R DVD032 IGF1R 5.10E+04 4.23E-05 8.29E-10 DVD032 HER-2 1.84E+04 9.31E-06 5.05E-10 AB004 HER-2 3.22E+05 1.28E-05 3.97E-11 AB010 IGF1 3.17E+06 1.23E-03 3.88E-10 AB010 IGF2 6.47E+06 2.74E-06 4.23E-13 DVD029 HER-2 2.42E+05 9.64E-06 3.98E-11 DVD029 IGF1 6.65E+04 4.23E-04 6.36E-9 DVD029 IGF2 1.04E+05 3.15E-05 3.02E-10 DVD030 IGF1 3.96E+06 1.16E-03 2.92E-10 DVD030 IGF2 8.46E+06 1.98E-05 2.34E-12 DVD030 HER-2 1.54E+05 7.36E-04 4.77E-9 AB033 EGFR 7.93E+04 1.39E-03 1.75E-8 AB004 HER-2 3.22E+05 1.28E-05 3.97E-11 DVD015 EGFR 1.79E+06 1.96E-03 1.09E-9 DVD015 HER-2 DVD016 HER-2 2.44E+05 4.36E-06 1.78E-11 DVD016 EGFR 2.36E+04 4.53E-04 1.92E-8 ABO 14 VEGF 1.47E+05 3.03E-05 2.07E-10 ABO 10 IGF1 AB010 IGF2 3.35E+06 <1.00E-06 〈2.99E-13 DVD041 VEGF 5.26E+05 2.39E-06 4.55E-12 DVD041 IGF1 DVD041 IGF2 8.09E+04 〈1.00E-06 <1.24E-11 DVD042 IGF1 DVD042 IGF2 5.20E+06 5.18E-06 9.98E-13 DVD042 VEGF 3.45E+04 1.46E-05 4.21E-10 AB005 RON 3.66E+04 7.39E-04 2.02E-8 AB033 EGFR 7.93E+04 1.39E-03 1.75E-8 DVD024 RON 4.56E+04 8.52E-04 1.86E-8 DVD024 EGFR DVD023 EGFR 2.08E+06 2.22E-03 1.06E-9 DVD023 RON AB005 RON 3.66E+04 7.39E-04 2.02E-8 ABO 12 HGF >1.00E+7 2.84E-04 <2.84E-11 DVD033 RON 1.56E+05 1.18E-03 7.60E-09 DVD033 HGF 2.97E+05 9.20E-05 3.10E-10 DVD034 HGF 3.05E+06 6.55E-05 2.15E-11 DVD034 RON AB005 RON 3.66E+04 7.39E-04 2.01E-8 ABO 14 VEGF 3.06E+05 3.99E-06 1.30E-11 DVD048 RON DVD048 VEGF 3.85E+04 4.50E-05 1.17E-9 DVD047 VEGF 3.46E+05 2.79E-05 8.06E-11 DVD047 RON ABO 15 DLL-4 4.00E+05 1.66E-04 4.14E-10 AB014 VEGF 1.47E+05 3.03E-05 2.07E-10 151681.doc -354- 201127956
DVD044 DLL4 5.90E+05 2.05E-04 3.47E-10 DVD044 VEGF 3.67E+04 1.13E-05 3.08E-10 DVD043 VEGF 4.94E+05 8.26E-06 1.67E-11 DVD043 DLL4 9.37E+04 2.17E-04 2.32E-09 ABO 15 DLL-4 AB047 P1GF 3.80E+06 1.08E-04 2.84E-11 DVD257 DLL4 8.35E+05 1.96E-04 2.34E-10 DVD257 P1GF 3.02E+05 1.11E-04 3.67E-10 DVD258 P1GF >1.00E+07 2.54E-03 〈2.54E-10 DVD258 DLL4 AB014 VEGF 1.47E+05 3.03E-05 2.07E-10 AB033 EGFR 8.85E+05 1.23E-03 1.39E-09 DVD035 VEGF 2.25E+05 1.73E-05 8.23E-11 DVD035 EGFR DVD036 EGFR 1.21E+06 1.57E-03 1.30E-09 DVD036 VEGF 4.80E+04 3.19E-04 6.65E-09 AB014 VEGF 3.07E+05 3.39E-05 1.06E-11 AB004 HER-2 3.02E+05 1.03E-05 3.40E-11 DVD037 VEGF 4.45E+05 <1.00E-06 〈2.25E-12 DVD037 HER-2 7.61E+03 2.83E-06 3.72E-10 DVD038 HER-2 1.95E+05 4.81E-06 2.47E-11 DVD038 VEGF 3.67E+04 <1.00E-06 <2.27E-11 ABO 14 VEGF 1.47E+05 3.03E-05 2.07E-10 ABO 12 HGF >1.00E+7 2.84E-04 〈2.84E-11 DVD045 VEGF 2.01E+05 3.05E-06 1.52E-11 DVD045 HGF 1.84E+05 1.66E-04 9.01E-10 DVD046 HGF >1.00E+7 2.36E-04 <2.36E-11 DVD046 VEGF ABO 14 VEGF 3.06E+05 3.99E-06 1.30E-11 ABO 16 NRP1 1.47E+05 3.90E-04 2.67E-9 DVD049 VEGF DVD049 NRP1 1.42E+05 1.81E-04 1.28E-9 DVD050 NRP1 1.82E+05 2.61E-04 1.440E-9 DVD050 VEGF 1.82E+05 2.61E-04 1.440E-9 ABO 14 VEGF 3.07E+05 3.39E-05 1.06E-10 AB047 P1GF 3.80E+06 1.08E-04 2.85E-11 DVD259 VEGF 5.02E+05 2.06E-05 4.12E-11 DVD259 P1GF 2.99E+05 9.87E-05 3.30E-10 DVD260 P1GF 4.27E+06 5.14E-05 1.20E-11 DVD260 VEGF 4.99E+04 2.05E-05 4.11E-10 AB033 EGFR 8.85E+05 1.23E-03 1.39E-09 ABO 12 HGF >1.00E+7 2.84E-04 <2.84E-11 DVD025 EGFR 7.31E+05 1.44E-03 1.98E-09 DVD025 HGF 3.05E+05 2.28E-04 7.46E-10 DVD026 HGF 4.19E+06 6.67E-05 1.59E-11 DVD026 EGFR AB062 ErbB3 8.66E+04 1.17E-04 1.360E-9 AB033 EGFR 7.93E+04 1.39E-03 1.75E-8 DVD299 ErbB3 1.95E+05 1.60E-04 8.20E-10 151681.doc • 355 - 201127956 DVD299 EGFR 3.26E+04 4.48E-04 1.37E-8 DVD300 EGFR 1.52E+06 1.69E-03 1.11E-9 DVD300 ErbB3 AB063 ErbB3 1.17E+06 1.75E-04 1.50 E-10 AB033 EGFR 7.93E+04 1.39E-03 1.75 E-8 DVD305 ErbB3 2.27E+06 1.37E-04 6.03E-11 DVD305 EGFR 3.99E+04 3.17E-04 7.940 E-9 DVD306 EGFR 1.82E+06 1.86E-03 1.020 E-9 DVD306 ErbB3 藉由Biacore技術表徵之所有DVD-Ig構築體的結合均得 以維持且與親本抗體相當。所有N末端可變區域以與親本 抗體以及 DVD-Ig構築體 DVD022、DVD016、DVD042、 DVD044、DVD043、DVD038、DVD049、DVD260、 DVD299及DVD305之C末端可變區域類似的高親和力結 合。 表19:親本抗鱧及DVD構築體之BIACORE分析
Ref Ab 或 DVD-Ig ID N-Term. VD C-Term- VD ^on (Mls-1) ^off (s-1) K„ CM) AB004 HER-2(結構區域IV) 1.09E+05 2.01E-04 1.84E-09 AB080 HER-2(結構區域II) 7.03E+04 4.21E-04 5.99E-09 DVD687 HER-2(結構區域IV) HER-2(結構區域II) 1.03E+05 7.80E-05 7.57E-10 DVD688 HER-2(結構區域II) HER-2(結構區域IV) 4.85E+04 2.66E-04 5.48E-09 DVD689 HER-2(結構區域IV) HER-2(結構區域II) N/A N/A N/A DVD690 HER-2(結構區域II) HER-2(結構區域IV) N/A N/A N/A DVD691 HER-2(結構區域IV) HER-2(結構區域II) 1.18E+05 6.10E-05 5.17E-10 DVD692 HER-2(結構區域U) HER-2(結構區域IV) 4.66E+04 1.35E-04 2.90E-09 DVD693 HER-2(結構區域IV) HER-2(結構區域11) 1.26E+05 1.86E-05 1.48E-10 DVD694 HER-2(結構區域II) HER-2(結構區域IV) 7.89E+04 1.46E-04 1.85E-09 藉由Biacore技術表徵之6種DVD-Ig構築體的結合與親本 抗體相當或優於親本抗體。N末端可變區域處之所有HER-2結構區域IV以親本抗體1〇至40倍的親和力結合，且DVD-Ig構築體之C末端可變區域處之所有HER-2結構區域IV展 -356· 151681.doc 201127956 現與親本抗體相當之親和力。 表20 : VEGF/DLL4 DVD構築艎中之VEGF區域的 BIACORE 分析
DVD-Ig ID VEGF 序列ID DLL4 序列ID C- Term. VD N- Term. VD HC連 接子 LC連 接子 DLL4 ka DLL4 kd DLL4KD DVD044 VEGF (序列1) DLL4 (序列1) VEGF DLL4 S s 6.69E+05 1.45E-04 2.16E-10 DVD469 VEGF (序列1) DLL4 (序列1) VEGF DLL4 L L 1.41E+05 7.27E-05 5.15E-10 DVD475 VEGF (序列1) DLL4 (序列1) VEGF DLL4 L S 4.52E+05 1.95E-04 4.31E-10 DVD481 VEGF (序列υ DLL4 (序列1) VEGF DLL4 S L 1.87E+05 2.41E-04 1.29E-09 DVD441 VEGF (序列1) DLL4 (序列2) VEGF DLL4 s S 1.25E+05 5.71E-04 4.59E-09 DVD447 VEGF (序列1) DLL4 (序列2) VEGF DLL4 L L 9.92E+04 5.13E-04 5.17E-09 DVD453 VEGF (序列1) DLL4 (序列2) VEGF DLL4 L S 1.19E+05 5.97E-04 5.03E-09 DVD459 VEGF (序列1) DLL4 (序列2) VEGF DLL4 S L 1.22E+05 5.44E-04 4.48E-09 DVD511 VEGF (序列1) DLL4 (序列3) VEGF DLL4 S S 1.21E+06 1.73E-03 1.43E-09 DVD517 VEGF (序列1) DLL4 (序列3) VEGF DLL4 L L 1.19E+06 1.76E-03 1.48E-09 DVD523 VEGF (序列1) DLL4 (序列3) VEGF DLL4 L S 1.08E+06 2.09E-03 1.93E-09 DVD529 VEGF (序列1) DLL4 (序列3) VEGF DLL4 S L 8.40E+05 1.51E-03 1.80E-09 DVD487 VEGF (序列1) DLL4 (序列4) VEGF DLL4 S S 2.84E+05 8.19E-05 2.88E-10 DVD493 VEGF (序列1) DLL4 (序列4) VEGF DLL4 L L 2.92E+05 4.00E-05 1.37E-10 DVD499 VEGF (序列1) DLL4 (序列4) VEGF DLL4 L S 2.71E+05 8.01E-05 2.95E-10 DVD505 VEGF (序列1) DLL4 (序列4) VEGF DLL4 S L 2.62E+05 4.02E-05 1.53E-10 DVD043 VEGF (序列1) DLL4 (序列1) DLL4 VEGF S S 3.34E+04 2.81E-04 8.40E-09 DVD470 VEGF (序列υ DLL4 (序列1) DLL4 VEGF L L 6.84E+04 7.02E-05 1.03E-09 DVD476 VEGF (序列1) DLL4 (序列1) DLL4 VEGF L S 5.63E+04 1.67E-04 2.96E-09 DVD482 VEGF (序列1) DLL4 (序列1) DLL4 VEGF S L 1.11E+05 2.32E-04 2.08E-09 DVD442 VEGF (序列1) DLL4 (序列2) DLL4 VEGF s S 1.33E+05 2.18E-04 1.65E-09 DVD448 VEGF (序列1) DLL4 (序列2) DLL4 VEGF L L 1.92E+04 1.93E-04 1.01E-08 DVD454 VEGF (序列1) DLL4 (序列2) DLL4 VEGF L S 3.25E+03 2.37E-04 7.29E-08 151681.doc • 357· 201127956 DVD460 VEGF (序列1) DLL4 (序列2) DLL4 VEGF S L 1.54E+04 2.60E-04 1.69E-08 DVD512 VEGF( 序列1) DLL4 (序列3) DLL4 VEGF S S 2.58E+05 7.57E-04 2.94E-09 DVD518 VEGF (序列1) DLL4 (序列3) DLL4 VEGF L L 1.22E+05 4.54E-04 3.72E-09 DVD524 VEGF (序列1) DLL4(序 列3) DLL4 VEGF L S 9.28E+04 8.77E-04 9.45E-09 DVD530 VEGF (序列1) DLL4 (序列3) DLL4 VEGF S L 4.07E+05 2.19E-03 5.38E-09 DVD488 VEGF (序列1) DLL4 (序列4) DLL4 VEGF S S 1.59E+05 6.62E-05 4.18E-10 DVD494 VEGF (序列1) DLL4 (序列4) DLL4 VEGF L L 1.32E+05 1.83E-04 1.39E-09 DVD500 VEGF (序列1) DLL4 (序列4) DLL4 VEGF L S 1.05E+05 5.72E-05 5.48E-10 DVD506 VEGF (序列1) DLL4 (序列4) DLL4 VEGF S L 7.07E+04 1.04E-04 1.47E-09 DVD467 VEGF (序列2) DLL4 (序列1) VEGF DLL4 S S 5.85E+05 1.77E-04 3.02E-10 DVD473 VEGF (序列2) DLL4 (序列1) VEGF DLL4 L L 2.26E+05 1.61E-04 7.16E-10 DVD479 VEGF (序列2) DLL4 (序列1) VEGF DLL4 L S 3.95E+05 1.74E-04 4.41E-10 DVD485 VEGF (序列2) DLL4 (序列1) VEGF DLL4 S L 1.48E+05 1.71E-04 1.16E-09 DVD445 VEGF (序列2) DLL4 (序列2) VEGF DLL4 S S 1.29E+05 6.46E-04 5.01E-09 DVD451 VEGF (序列2) DLL4 (序列2) VEGF DLL4 L L 7.17E+04 1.00E-03 1.40E-08 DVD457 VEGF (序列2) DLL4 (序列2) VEGF DLL4 L S 1.20E+05 5.78E-04 4.82E-09 DVD463 VEGF (序列2) DLL4 (序列2) VEGF DLL4 S L 1.23E+05 4.72E-04 3.82E-09 DVD515 VEGF (序列2) DLL4 (序列3) VEGF DLL4 S S 1.06E+06 1.60E-03 1.51E-09 DVD521 VEGF (序列2) DLL4 (序列3) VEGF DLL4 L L 9.47E+05 1.68E-03 1.77E-09 DVD527 VEGF (序列2) DLL4 (序列3) VEGF DLL4 L S 5.74E+05 1.09E-03 1.90E-09 DVD533 VEGF (序列2) DLL4 (序列3) VEGF DLL4 S L 5.98E+05 1.33E-03 2.22E-09 DVD491 VEGF (序列2) DLL4 (序列4) VEGF DLL4 s S 2.67E+05 6.35E-05 2.37E-10 DVD497 VEGF( 序列2) DLL4 (序列4) VEGF DLL4 L L 2.68E+05 7.12E-05 2.66E-10 DVD503 VEGF (序列2) DLL4 (序列4) VEGF DLL4 L S 2.46E+05 4.72E-05 1.92E-10 DVD509 VEGF (序列2) DLL4 (序列4) VEGF DLL4 S L 2.30E+05 3.52E-05 1.53E-10 DVD468 VEGF (序列2) DLL4 (序列1) DLL4 VEGF s S 5.82E+04 2.19E-04 3.76E-09 DVD474 VEGF (序列2) DLL4 (序列1) DLL4 VEGF L L 6.31E+04 6.55E-05 1.04E-09 DVD480 VEGF (序列2) DLL4 (序列1) DLL4 VEGF L S 5.30E+04 1.79E-04 3.38E-09 •358- 151681.doc 201127956
DVD486 VEGF (序列2) DLL4 (序列1) DLL4 VEGF S L 6.27E+04 1.33E-04 2.13E-09 DVD446 VEGF (序列2) DLL4 (序列2) DLL4 VEGF S S 2.91E+04 1.69E-04 5.81E-09 DVD452 VEGF (序列2) DLL4 (序列2) DLL4 VEGF L L 2.37E+04 2.20E-04 9.30E-09 DVD458 VEGF (序列2) DLL4 (序列2) DLL4 VEGF L S 1.61E+04 2.61E-04 1.62E-08 DVD464 VEGF (序列2) DLL4 (序列2) DLL4 VEGF S L 3.28E+04 1.82E-04 5.53E-09 DVD516 VEGF (序列2) DLL4 (序列3) DLL4 VEGF S S 1.17E+05 5.83E-04 4.99E-09 DVD522 VEGF (序列2) DLL4 (序列3) DLL4 VEGF L L 1.15E+05 1.21E-03 1.05E-08 DVD528 VEGF (序列2) DLL4 (序列3) DLL4 VEGF L S 3.16E+05 1.52E-03 4.81E-09 DVD534 VEGF (序列2) DLL4 (序列3) DLL4 VEGF S L 3.46E+05 2.00E-03 5.78E-09 DVD492 VEGF (序列2) DLL4 (序列4) DLL4 VEGF s S 7.82E+04 8.35E-05 1.07E-09 DVD498 VEGF (序列2) DLL4 (序列4) DLL4 VEGF L L 6.46E+04 9.36E-05 1.45E-09 DVD504 VEGF (序列2) DLL4 (序列4) DLL4 VEGF L S 5.81E+04 7.32E-05 1.26E-09 DVD510 VEGF (序列2) DLL4 (序列4) DLL4 VEGF S L 5.69E+04 8.84E-05 1.55E-09 DVD465 VEGF (序列3) DLL4 (序列1) VEGF DLL4 s S 7.97E+05 1.64E-04 2.05E-10 DVD471 VEGF (序列3) DLL4 (序列υ VEGF DLL4 L L 3.76E+05 2.52E-04 6.72E-10 DVD477 VEGF (序列3) DLL4 (序列1) VEGF DLL4 L S 5.40E+05 1.65E-04 3.06E-10 DVD483 VEGF (序列3) DLL4 (序列1) VEGF DLL4 S L 4.16E+05 1.39E-04 3.34E-10 DVD443 VEGF (序列3) DLL4 (序列2) VEGF DLL4 s S 1.45E+05 5.96E-04 4.11E-09 DVD449 VEGF (序列3) DLL4 (序列2) VEGF DLL4 L L 1.21E+05 5.84E-04 4.81E-09 DVD455 VEGF (序列3) DLL4 (序列2) VEGF DLL4 L S 1.29E+05 6.04E-04 4.70E-09 DVD461 VEGF (序列3) DLL4 (序列2) VEGF DLL4 S L 1.15E+05 5.38E-04 4.69E-09 DVD513 VEGF (序列3) DLL4 (序列3) VEGF DLL4 s S 2.71E+05 6.77E-04 2.50E-09 DVD519 VEGF (序列3) DLL4 (序列3) VEGF DLL4 L L 1.67E+05 4.72E-04 2.83E-09 DVD525 VEGF (序列3) DLL4 (序列3) VEGF DLL4 L S 4.75E+05 1.22E-03 2.57E-09 DVD531 VEGF (序列3) DLL4 (序列3) VEGF DLL4 S L 2.48E+05 8.58E-04 3.47E-09 DVD489 VEGF (序列3) DLL4 (序列4) VEGF DLL4 S S 2.96E+05 8.38E-05 2.83E-10 DVD495 VEGF (序列3) DLL4 (序列4) VEGF DLL4 L L 3.01E+05 7.91E-05 2.63E-10 DVD501 VEGF (序列3) DLL4 (序列4) VEGF DLL4 L S 2.70E+05 8.14E-05 3.02E-10 151681.doc -359- 201127956 DVD507 VEGF (序列3) DLL4 (序列4) VEGF DLL4 S L 2.70E+05 7.16E-05 2.65E-10 DVD466 VEGF (序列3) DLL4 (序列1) DLL4 VEGF S S l.UE+05 1.39E-04 1.25E-09 DVD472 VEGF (序列3) DLL4 (序列1) DLL4 VEGF L L 9.80E+04 8.64E-05 8.81E-10 DVD478 VEGF (序列3) DLL4 (序列1) DLL4 VEGF L S 7.52E+04 1.67E-04 2.22E-09 DVD484 VEGF (序列3) DLL4 (序列1) DLL4 VEGF S L 9.97E+04 2.95E-04 2.96E-09 DVD444 VEGF (序列3) DLL4 (序列2) DLL4 VEGF S S 1.43E+05 3.40E-04 2.37E-09 DVD450 VEGF (序列3) DLL4 (序列2) DLL4 VEGF L L 3.38E+04 2.51E-04 7.41E-09 DVD456 VEGF (序列3) DLL4 (序列2) DLL4 VEGF L S 1.04E+05 1.74E-04 1.66E-09 DVD462 VEGF (序列3) DLL4 (序列2) DLL4 VEGF S L 8.39E+04 2.50E-04 2.98E-09 DVD514 VEGF (序列3) DLL4 (序列3) DLL4 VEGF S S 1.24E+05 4.32E-04 3.48E-09 DVD520 VEGF (序列3) DLL4 (序列3) DLL4 VEGF L L 1.24E+05 4.08E-04 3.30E-09 DVD526 VEGF (序列3) DLL4 (序列3) DLL4 VEGF L S 1.13E+05 6.29E-04 5.55E-09 DVD532 VEGF (序列3) DLL4 (序列3) DLL4 VEGF S L 1.18E+05 8.10E-04 6.85E-09 DVD490 VEGF (序列3) DLL4 (序列4) DLL4 VEGF s S 1.46E+05 7.70E-05 5.28E-10 DVD496 VEGF (序列3) DLL4 (序列4) DLL4 VEGF L L 1.20E+05 1.72E-04 1.44E-09 DVD502 VEGF (序列3) DLL4 (序列4) DLL4 VEGF L S 9.21E+04 7.43E-05 8.07E-10 DVD508 VEGF (序列3) DLL4 (序列4) DLL4 VEGF S L 9.84E+04 1.67E-04 1.70E-09 如Biacore技術所表徵之VEGF/DLL4 DVD-Ig構築體與 DLL4的結合與親本抗體相當。所有N末端或C末端可變區 _ 域以與親本抗體相當之親和力結合DLL4。 表21 : VEGF/DLL4 DVD構築體中之VEGF區域的 BIACORE 分析 DVD-Ig ID VEGF 序列ID DLL4 序列ID C- Term. VD N- Term. VD HC連 接子 LC連 接子 VEGFka VEGFkd VEGFKD DVD044 VEGF (序列1) DLL4 (序列1) VEGF DLL4 S s 3.67E+05 2.41E-04 6.57E-10 DVD469 VEGF (序列1) DLL4 (序列1) VEGF DLL4 L L 3.31E+07 1.51E-02 4.55E-10 DVD475 VEGF (序列1) DLL4 (序列1) VEGF DLL4 L S 2.86E+05 2.40E-04 8.38E-10 -360- 151681.doc 201127956
DVD481 VEGF (序列1) DLL4 (序列1) VEGF DLL4 S L 4.76E+05 5.73E-04 1.20E-09 DVD441 VEGF (序列1) DLL4 (序列2) VEGF DLL4 S S 1.33E+05 7.43E-05 5.58E-10 DVD447 VEGF (序列1) DLL4 (序列2) VEGF DLL4 L L 2.99E+05 4.76E-05 1.59E-10 DVD453 VEGF (序列1) DLL4 (序列2) VEGF DLL4 L S 1.58E+05 2.62E-07 1.66E-12 DVD459 VEGF (序列1) DLL4 (序列2) VEGF DLL4 S L 3.60E+05 5.66E-07 1.57E-12 DVD511 VEGF (序列l) DLL4 (序列3) VEGF DLL4 S S 3.66E+05 3.70E-04 1.01E-09 DVD517 VEGF (序列1) DLL4 (序列3) VEGF DLL4 L L 5.33E+05 3.03E-04 5.69E-10 DVD523 VEGF (序列1) DLL4 (序列3) VEGF DLL4 L S 5.73E+05 1.75E-04 3.05E-10 DVD529 VEGF (序列1) DLL4 (序列3) VEGF DLL4 S L 5.61E+05 1.86E-04 3.32E-10 DVD487 VEGF (序列1) DLL4 (序列4) VEGF DLL4 S S 3.15E+05 1.04E-04 3.30E-10 DVD493 VEGF (序列1) DLL4 (序列4) VEGF DLL4 L L 7.54E+05 2.09E-05 2.77E-11 DVD499 VEGF (序列1) DLL4 (序列4) VEGF DLL4 L S 3.40E+05 3.95E-05 1.16E-10 DVD505 VEGF (序列1) DLL4 (序列4) VEGF DLL4 S L 7.00E+05 6.05E-08 8.64E-14 DVD043 VEGF (序列1) DLL4 (序列1) DLL4 VEGF S S 1.68E+06 1.25E-04 7.46E-11 DVD470 VEGF (序列1) DLL4 (序列1) DLL4 VEGF L L 1.20E+06 2.40E-04 2.01E-10 DVD476 VEGF (序列1) DLL4 (序列1) DLL4 VEGF L S 1.69E+06 4.74E-05 2.81E-11 DVD482 VEGF (序列1) DLL4 (序列1) DLL4 VEGF S L 6.87E+05 1.38E-04 2.00E-10 DVD442 VEGF (序列υ DLL4 (序列2) DLL4 VEGF S S 1.93E+06 1.70E-04 8.80Ε-Π DVD448 VEGF (序列1) DLL4 (序列2) DLL4 VEGF L L 5.04E+05 1.36E-04 2.71E-10 DVD454 VEGF (序列1) DLL4 (序列2) DLL4 VEGF L S 1.59E+06 1.26E-04 7.90E-11 DVD460 VEGF (序列1) DLL4 (序列2) DLL4 VEGF S L 1.32E+06 2.28E-04 1.74E-10 DVD512 VEGF (序列1) DLL4 (序列3) DLL4 VEGF S S 9.39E+05 1.43E-04 1.53E-10 DVD518 VEGF (序列1) DLL4 (序列3) DLL4 VEGF L L 2.88E+08 1.25E-01 4.34E-10 DVD524 VEGF (序列1) DLL4 (序列3) DLL4 VEGF L S 1.67E+06 1.88E-04 1.13E-10 DVD530 VEGF (序列1) DLL4 (序列3) DLL4 VEGF S L 1.26E+06 1.71E-04 1.36E-10 DVD488 VEGF (序列1) DLL4 (序列4) DLL4 VEGF S S 6.99E+05 3.74E-04 5.36E-10 DVD494 VEGF (序列1) DLL4 (序列4) DLL4 VEGF L L 3.11E+07 1.76E-02 5.66E-10 DVD500 VEGF (序列1) DLL4 (序列4) DLL4 VEGF L S 4.92E+05 2.48E-04 5.04E-10 151681.doc -361 - 201127956 DVD506 VEGF (序列1) DLL4 (序列4) DLL4 VEGF S L 6.06E+05 1.71E-04 2.81E-10 DVD467 VEGF (序列2) DLL4 (序列υ VEGF DLL4 s S 1.77E+05 2.36E-04 1.33E-09 DVD473 VEGF (序列2) DLL4 (序列1) VEGF DLL4 L L 2.09E+05 2.65E-04 1.27E-09 DVD479 VEGF (序列2) DLL4 (序列υ VEGF DLL4 L S 2.99E+05 2.57E-04 8.60E-10 DVD485 VEGF (序列2) DLL4 (序列1) VEGF DLL4 S L 1.22E+05 4.54E-05 3.72E-10 DVD445 VEGF (序列2) DLL4 (序列2) VEGF DLL4 S S 6.64E+09 1.80E+00 2.72E-10 DVD451 VEGF (序列2) DLL4 (序列2) VEGF DLL4 L L 9.22E+04 1.06E-06 1.15E-11 DVD457 VEGF (序列2) DLL4 (序列2) VEGF DLL4 L S 1.77E+05 5.43E-05 3.07E-10 DVD463 VEGF (序列2) DLL4 (序列2) VEGF DLL4 S L 6.21E+05 4.79E-04 7.71E-10 DVD515 VEGF (序列2) DLL4 (序列3) VEGF DLL4 S S 4.05E+05 5.85E-04 1.45E-09 DVD521 VEGF (序列2) DLL4 (序列3) VEGF DLL4 L L 6.66E+05 5.88E-04 8.82E-10 DVD527 VEGF (序列2) DLL4 (序列3) VEGF DLL4 L S 5.29E+05 4.46E-04 8.42E-10 DVD533 VEGF (序列2) DLL4 (序列3) VEGF DLL4 S L 6.08E+05 5.01E-04 8.25E-10 DVD491 VEGF (序列2) DLL4 (序列4) VEGF DLL4 s S 3.40E+05 2.45E-04 7.20E-10 DVD497 VEGF (序列2) DLL4 (序列4) VEGF DLL4 L L 1.25E+05 8.37E-05 6.68E-10 DVD503 VEGF (序列2) DLL4 (序列4) VEGF DLL4 L S 2.26E+05 1.05E-04 4.66E-10 DVD509 VEGF (序列2) DLL4 (序列4) VEGF DLL4 S L 1.28E+05 7.83E-06 6.13E-11 DVD468 VEGF (序列2) DLL4 (序列1) DLL4 VEGF s S 1.18E+05 l‘74E-07 1.48E-12 DVD474 VEGF (序列2) DLL4 (序列1) DLL4 VEGF L L 1.36E+05 1.96E-07 1.44E-12 DVD4S0 VEGF (序列2) DLL4 (序列1) DLL4 VEGF L S 1.62E+05 4.91E-05 3.02E-10 DVD486 VEGF (序列2) DLL4 (序列1) DLL4 VEGF S L 1.54E+05 5.72E-05 3.71E-10 DVD446 VEGF (序列2) DLL4 (序列2) DLL4 VEGF s S 1.22E+05 3.62E-08 2.97E-13 DVD452 VEGF (序列2) DLL4 (序列2) DLL4 VEGF L L 1.04E+05 1.61E-08 1.55E-13 DVD458 VEGF (序列2) DLL4 (序列2) DLL4 VEGF L S 1.21E+05 3.39E-08 2.81E-13 DVD464 VEGF (序列2) DLL4 (序列2) DLL4 VEGF S L 9.37E+04 7.22E-08 7.70E-13 DVD516 VEGF (序列2) DLL4 (序列3) DLL4 VEGF S S 3.58E+05 2.80E-04 7.81E-10 DVD522 VEGF (序列2) DLL4 (序列3) DLL4 VEGF L L 4.89E+05 2.20E-04 4.50E-10 DVD528 VEGF (序列2) DLL4 (序列3) DLL4 VEGF L S 3.88E+05 1.60E-04 4.13E-10 -362- 151681.doc 201127956
DVD534 VEGF (序列2) DLL4 (序列3) DLL4 VEGF S L 3.74E+05 1.68E-04 4.49E-10 DVD492 VEGF (序列2) DLL4 (序列4) DLL4 VEGF S S 1.52E+05 7.60E-06 4.99E-11 DVD498 VEGF (序列2) DLL4 (序列4) DLL4 VEGF L L 1.62E+05 2.85E-05 1.76E-10 DVD504 VEGF (序列2) DLL4 (序列4) DLL4 VEGF L S 1.62E+05 1.52E-07 9.41E-13 DVD510 VEGF (序列2) DLL4 (序列4) DLL4 VEGF S L 1.64E+05 1.20E-05 7.33E-11 DVD465 VEGF (序列3) DLL4 (序列1) VEGF DLL4 S S 3.48E+05 4.14E-04 1.19E-09 DVD471 VEGF (序列3) DLL4 (序列1) VEGF DLL4 L L 2.53E+05 2.32E-04 9.17E-10 DVD477 VEGF (序列3) DLL4 (序列1) VEGF DLL4 L S 2.49E+05 2.54E-04 1.02E-09 DVD483 VEGF (序列3) DLL4 (序列1) VEGF DLL4 S L 9.05E+05 8.72E-04 9.63E-10 DVD443 VEGF (序列3) DLL4 (序列2) VEGF DLL4 S S 1.57E+05 2.67E-04 1.71E-09 DVD449 VEGF (序列3) DLL4 (序列2) VEGF DLL4 L L 2.30E+05 2.08E-04 9.03E-10 DVD455 VEGF (序列3) DLL4 (序列2) VEGF DLL4 L S 1.77E+05 8.15E-05 4.60E-10 DVD461 VEGF (序列3) DLL4 (序列2) VEGF DLL4 S L 2.69E+05 2.02E-04 7.50E-10 DVD513 VEGF (序列3) DLL4 (序列3) VEGF DLL4 s S 4.00E+05 4.97E-04 1.24E-09 DVD519 VEGF (序列3) DLL4 (序列3) VEGF DLL4 L L 2.35E+07 5.22E-03 2.23E-10 DVD525 VEGF (序列3) DLL4 (序列3) VEGF DLL4 L S 1.08E+06 4.83E-04 4.47E-10 DVD531 VEGF (序列3) DLL4 (序列3) VEGF DLL4 S L 7.56E+05 4.42E-04 5.84E-10 DVD489 VEGF (序列3) DLL4 (序列4) VEGF DLL4 S S 2.07E+05 3.65E-04 1.76E-09 DVD495 VEGF (序列3) DLL4 (序列4) VEGF DLL4 L L 3.16E+05 2.04E-04 6.45E-10 DVD501 VEGF (序列3) DLL4 (序列4) VEGF DLL4 L S 2.13E+05 1.75E-04 8.21E-10 DVD507 VEGF (序列3) DLL4 (序列4) VEGF DLL4 S L 2.38E+05 2.01E-04 8.47E-10 DVD466 VEGF (序列3) DLL4 (序列1) DLL4 VEGF S S 5.53E+05 3.93E-04 7.10E-10 DVD472 VEGF (序列3) DLL4 (序列1) DLL4 VEGF L L 1.20E+06 2.40E-04 2.01E-10 DVD478 VEGF (序列3) DLL4 (序列1) DLL4 VEGF L S 5.52E+05 1.95E-04 3.54E-10 DVD484 VEGF (序列3) DLL4 (序列1) DLL4 VEGF S L 1.61E+07 4.10E-03 2.55E-10 DVD444 VEGF (序列3) DLL4 (序列2) DLL4 VEGF S S 2.35E+07 3.80E-03 1.62E-10 DVD450 VEGF (序列3) DLL4 (序列2) DLL4 VEGF L L 1.69E+07 4.31E-03 2.55E-10 DVD456 VEGF (序列3) DLL4 (序列2) DLL4 VEGF L S 1.60E+07 4.48E-03 2.81E-10 151681.doc .363 · 5 201127956 DVD462 VEGF (序列3) DLL4 (序列2) DLL4 VEGF S L 9.93E+05 8.58E-04 8.64E-10 DVD514 VEGF (序列3) DLL4 (序列3) DLL4 VEGF S S 5.41E+05 5.49E-04 1.01E-09 DVD520 VEGF (序列3) DLL4 (序列3) DLL4 VEGF L L 1.18E+06 9.61E-04 8.17E-10 DVD526 VEGF (序列3) DLL4 (序列3) DLL4 VEGF L S 1.19E+06 8.01E-04 6.75E-10 DVD532 VEGF (序列3) DLL4 (序列3) DLL4 VEGF S L 4.47E+07 1.23E-02 2.76E-10 DVD490 VEGF (序列3) DLL4 (序列4) DLL4 VEGF S S 8.94E+05 1.69E-04 1.89E-10 DVD496 VEGF (序列3) DLL4 (序列4) DLL4 VEGF L L 2.12E+07 6.58E-03 3.11E-10 DVD502 VEGF (序列3) DLL4 (序列4) DLL4 VEGF L S 8.71E+05 2.31E-04 2.65E-10 DVD508 VEGF (序列3) DLL4 (序列4) DLL4 VEGF S L 1.31E+06 2.13E-04 1.62E-10 如Biacore技術所表徵之VEGF/DLL4 DVD-Ig構築體與 VEGF的結合與親本抗體相當。所有N末端或C末端可變區 域以與親本抗體相當之親和力結合VEGF。 實例1.1.2 :用於測定親本抗體及DVD-Ig之功能活性的檢 定 實例1.1.2.A:細胞激素生物檢定 藉由測定抗體或DVD-Ig之抑制潛力來分析抗細胞激素 或抗生長因子親本抗體或含有抗細胞激素或抗生長因子序 列之DVD-Ig抑制或中和目標細胞激素或生長因子生物活 性的能力。舉例而言，可使用抗IL-4抗體抑制IL-4介導之 IgE產生的能力。舉例而言，藉由Ficoll-paque密度離心， 隨後使用對人類slgD FITC標記之山羊F(ab)2抗體具特異性 的 MACS 珠粒（Miltenyi Biotec, Bergisch Gladbach， Germany)繼之以抗FITC MACS珠粒進行磁性分離自外周血 液（各別為白血球層）分離未經處理之人類B細胞。在37°C 下在5% C02存在下培養10天期間，磁力分選之未經處理之 151681.doc -364· 201127956 B細胞在XV15中調整至每毫升3χ105個細胞，且以96孔板 中每孔1 00 μΐ接種於板中心的6X6陣列中，周圍環繞以pBs 填充的孔。每種欲測試抗體各製備一個板，各板由未經誘 導對照組及經誘導對照組各3個孔及抗體滴定液之一式五 份重複組成’該等抗體滴定液自7 pg/ml起始且以3倍稀釋 降至29 ng/ml最終濃度’添加於50 μΐ四倍濃縮之預稀釋液 中。為了誘導IgE產生’向各孔中添加20 ng/ml之rhIL-4加 鲁 0·5 pg/ml最終濃度之抗CD40皁株抗體（Novartis，Basel
Switzerland)(各50 μΐ)，且在培養期結束時藉由標準夾心 ELISA法測定IgE濃度。 實例1·1.2.B:細胞激素釋放檢定 分析親本抗體或DVD-Ig引起細胞激素釋放之能力。藉 由靜脈穿刺自三名健康供者抽取周邊血液，並置於肝素化 真空採血管（vacutainertube)中。以rPMI_164〇培養基1:5稀 釋全血，且以每孔〇·5 mL置於24孔組織培養板中。將抗細 • 胞激素抗體（例如抗IL-4)稀釋於rPMI_164〇中，且以每孔 0.5 mL置於板中，獲得200、1〇〇、5〇、]〇及1心虹之最 終濃度。培養板中全血之最終稀釋度為1:1〇。將LPs及 PHA以2 pg/mL及5 pg/mL最終濃度添加至各別孔中作為細 胞激素釋放之陽性對照。多株人類IgG用作陰性對照抗 體。實驗一式兩份進行。將板在37t下在5% c〇2下培育。 24小時後，將各孔之内容物轉移至試管中，且在12⑻卬爪 下旋轉5分鐘。收集不合έ田晌夕、主、Λ Α + 卞个3、、，田肥之上清液’且冷凍用於細胞 激素檢定。留在板上及營中ιΙμ1、， 上及&干之細胞以0.5 mL溶胞溶液溶 151681.doc •365- 201127956 解，且置於-20°C下並解凍。添加0.5 mL培養基（使體積達 到與無細胞之上清液樣品相同之量），且收集細胞製劑， 且冷束用於細胞激素檢定。藉由ELISA檢定不含細胞之上 清液及細胞溶解產物的細胞激素含量，例如IL-8、IL-6、 IL-Ιβ、IL-1RA 或 TNF-α 之含量。 實例1.1.2.C:細胞激素交叉反應性研究 分析針對相關細胞激素之抗細胞激素親本抗體或DVD-Ig與其他細胞激素交叉反應的能力。將親本抗體或DVD-Ig 固定於Biacore生物感測器基質上。藉由首先以1〇〇 mM N-經基丁二醯亞胺（NHS)及400 mM N-乙基-N'-(3-二甲基胺基 丙基）-碳化二亞胺鹽酸鹽（EDC)活化基質上之叛基，使抗 人類Fc mAb經游離胺基共價連接至聚葡萄糖基質。約5〇 μL濃度為25μg/mL、稀釋於乙酸鈉中（pH4.5)的各抗體或 DVD-Ig製劑注射至經活化生物感測器上，且蛋白質上之 游離胺直接結合於經活化缓基。通常，固定5〇〇〇共振單位 (RU)。未反應之基質EDC酯藉由注射1 Μ乙醇胺失活。藉 由使用標準胺偶合套組固定人類IgGl/K製備第二流槽作為 參考標準。使用CM生物感測器晶片進行SPR量測。將所有 欲在生物感測器表面上分析之抗原於含有〇·〇丨％ P2〇之 HBS-EP操作緩衝液中稀釋。 為了檢驗細胞激素結合特異性，將過量相關細胞激素 (100 nM，例如可溶性重組人類細胞激素）注射至固定抗細 胞激素親本抗體或DVD-Ig之整個生物感測器表面上（5分鐘 接觸時間）。在注射相關細胞激素之前及之後立即使HB S - 151681.doc -366· 201127956 EP緩衝液單獨流過各流槽。獲取基線值與對應於細胞激素 注射完成後約3 0秒之點之間的信號淨差表示最終結合值。 此外，反應以共振單位為量度。在觀測到結合作用時在 注射下一樣品之前，使用1〇 mM HC丨使生物感測器基質再 生，或在基質上注射操作緩衝液。人類細胞激素（例如比· Ια、IL-Ιβ、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、 IL-9、IL-10、IL-11、il-12、il-13、IL-15、IL-16、IL- φ I7、IL-18、IL·19、IL-20、IL-22、IL-23、IL-27、TNF- α、TNF-β及IFN-γ)亦同時注射至經固定小鼠IgGl/K參考表 面上以記錄任何非特異性結合背景。藉由製備參考及反應 表面，Biacore可自動從反應表面資料減去參考表面資料， 以消除絕大部分折射率變化及注射雜訊。因此，有可能確 定歸因於抗細胞激素抗體或DVD_Ig結合反應的真結合反 應。 當相關細胞激素注射至整個經固定抗細胞激素抗體上 • 時，觀測到顯著結合。1〇 mM HC1再生完全移除所有非共 價締合之蛋白質。感測器圖譜檢驗顯示經固定抗細胞激素 抗體或DVD-Ig與可溶性細胞激素之結合有力且穩固。在 用相關細胞激素確認預期結果後，分別針對各抗體或 DVD-Ig測試剩餘重組人類細胞激素組。記錄各注射週期 結合或未結合細胞激素的抗細胞激素抗體或DVD_Ig之 量。使用三個獨立實驗之結果測定各抗體或Dvo-Ig之特 異性概況。選擇與相關細胞激素預期結合且未結合任何其 他細胞激素之抗體或DVD-Ig。 151681.doc -367· 201127956 實例1·1·2.Ι):組織交又反應性 組織交叉反應性研究分三個階段進行，第一階段包括32 種組織的冷凍切片，第二階段包括多達38種組織，且第三 階段包括如下文所述之來自三個不相關成體之額外組織。 研究通常以2個劑量進行。 階段1 :在物鏡上固定人類組織（在屍體解剖或活組織檢 查時獲得之來自一個人類供者之32種組織（通常：腎上 腺 骨骼肌、血細胞、腎 胃腸道、前列腺、膀胱、心臟 臟、皮膚、骨髓、肝、脊髓、乳房、肺、脾臟、小腦、淋 巴結、睪丸、大腦皮質、印巢、胸腺、結腸、胰腺、甲狀 腺 '内皮、副甲狀腺、輸尿管、眼、垂體、子宮、輸印管 及胎盤））的冷;東切片（約5 μιη)且乾燥。使用抗生物素蛋白_ 生物素系統對組織切片進行過氧化酶染色。 階段2 :在物鏡上固定人類組織（在屍體解剖或活組織檢 查時獲得之來自3個不相關成人之38種組織（包括腎上腺、 血液、▲管、骨髓、小腦、大腦、子宮頸、食道、眼、心 臟、腎臟、大腸、肝、肺、淋巴結、乳腺、#巢、輸卵 管、胰腺、副曱狀腺、周邊神經、垂體、胎盤、前列腺、 液腺、皮膚、小腸、脊髓、脾臟、胃、橫紋肌、畢丸、 胸腺、甲狀腺、扁桃體、輸尿管、膀胱及子宮））的冷凍切 片（約5 pm)且乾燥。使用抗生物素蛋白_生物素系統對組織 切片進行過氧化酶染色。 階段3 :在物鏡上固定食蟹猴組織(在屍體解剖或活組織 檢查時獲得之來自3個不相關成年猴之38種組織（包括腎上 151681.doc -368- 201127956 腺、血液、血管、骨髓、小腦、大腦、子宮頸、食道、 眼、心臟、腎臟、大腸、肝、肺、淋巴結、乳腺、卵巢、 輸卵管、胰腺、副甲狀腺、周邊神經、垂體、胎盤、前列 腺'唾液腺、皮膚、小腸、脊髓、脾臟、胃、橫紋肌、睪 丸、胸腺、曱狀腺、扁桃體、輸尿管、膀胱及子宮））的冷 /東切片（約5 μηι)且乾燥。使用抗生物素蛋白·生物素系統對 組織切片進行過氧化酶染色。 φ 將抗體或DVDdg與經生物素標記之二次抗人類IgG—起 月且形成免疫複合物。將抗體或DVD-ig之最終濃度為2 pg/mL及10 pg/mL之免疫複合物添加至物鏡上的組織切片 上，且接著使組織切片與抗生物素蛋白·生物素-過氧化酶 套組反應30分鐘。隨後，塗佈DAB(3 3，_二胺基聯苯胺）（一 種過氧化酶反應之受質）歷時4分鐘以進行組織染色。抗原_ 瓊脂糖珠粒用作陽性對照組織切片。目標抗原及人類血清 阻斷研究用作額外對照物。將抗體或DVD_Ig之最終濃度 # 為2 Mg/mL&10盹/mL之免疫複合物與目標抗原（最終濃度 為100 pg/ml)或人類血清（最終濃度1〇%)一起預培育3〇分 鐘，且接著添加至物鏡上之組織切片上，且接著使組織切 片與抗生物素蛋白·生物素_過氧化酶套組反應3〇分鐘。隨 後塗佈DAB(3,3 -二胺基聯苯胺）（一種過氧化酶反應之受 質）歷時4分鐘以進行組織染色。 基於所4論之目標抗原的已知表現來判斷任何特異性染 色具有預期反應性（例如與抗原表現相符）或非預期反應 生。針對強度及頻率’對任何經判斷具特異性之染色進行 151681.doc
• 369 - S 201127956 評分。階段2(人類組織）與階段3(食蟹猴組織）之間的組織 染色經判斷為類似或不同。 實例1.1.2.E :藉由VEGf親本抗體及DVD-Ig構築體抑制 HUVEC增殖/存活 在接種以供檢定之前，將正常人類臍帶血管内皮細胞或 HUVEC(第2至6繼代）維持於補充有EGM-2 SingleQuots (Lonza-Clonetics, Walkersville，MD，#CC-4176) 2EBM-2(Lonza-Clonetics，Walkersville，MD)中。將 HUVEC細胞以 每孔10,000個細胞接種於膠原蛋白塗覆之黑色96孔板上無 生長因子存在具有0.1% FBS之（100 μ1)ΕΜΒ-2中。第二 天，將培養基置換為無生長因子存在之0.1% FBS。第二 天’將培養基置換為100 μΐ ΕΜΒ-2(無生長因子或血清）， 且培育4小時，隨後添加VEGF及抗體/DVD-Ig。在具有 0.1% BSA之EMB-2中稀釋抗VEGF單株抗體或DVD-Ig(最 終濃度為67 nM、6.7 nM及0.67 nM)，且在25°C下以50 μΐ 與重組人類VEGF!65(50 ng/ml) —起預培育1小時。接著將 抗體/DVD-Ig及VEGF混合物添加至細胞（50 μΐ)中，且在 37°C下在含濕氣5% C02氛圍中培育板72小時。藉由根據製 造商說明書使用 ATPlite 套組（Perkin Elmer, Waltham，MA) 評定ATP含量來直接量測細胞存活/增殖。表22提供顯示對 HUVEC增殖/存活之抑制的資料。 151681.doc •370· 201127956 表22 :藉由VEGF親本抗體及DVD-Ig構築髏抑制HUVEC 增殖/存活
親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) hijvec增殖之N末端 VD抑制(67、6.7及 0.67 nM Ab/D VD-Ig 下 之抑制。/〇) HUVEC增殖之C末 端VD抑制(67、6.7及 0.67 nM Ab/D VD-Ig 下之抑制。/〇) AB014 VEGF 67 nM=98% ' 6.7 ηΜ=91°/〇 ' 0.67 ηΜ=12% DVD038 HER-2 VEGF 67 nM=45% ' 6.7 ηΜ=-18% ' 0.67 ηΜ=-22% AB014 VEGF 67 ηΜ=98°/〇 ' 6.7 ηΜ=91% ' 0.67 ηΜ=12% DVD044 DLL4 VEGF 67 ηΜ=99%、 6·7ηΜ=19%、 0.67 ηΜ=6% DVD043 VEGF DLL4 67 ηΜ=:89% ' 6.7 ηΜ=51%、 0.67 ηΜ=-22% AB014 VEGF 67 ηΜ=97°/〇 ' 6.7 ηΜ=91% ' 0.67 ηΜ=62°/〇 DVD048 RON VEGF 67ηΜ=91%、 6.7 ηΜ=88% ' 0.67 ηΜ=62% DVD047 VEGF RON 67 ηΜ=65%、 6.7ηΜ=31% ' 0.67 ηΜ=-5% AB014 VEGF 67 ηΜ=97% > 6.7 ηΜ=91% > 0.67 ηΜ=62% DVD049 VEGF NRP1 67ηΜ=108%、 6.7 ηΜ=86%、 0.67 ηΜ=43% DVD050 NRP1 VEGF 67ηΜ=103%、 6.7 ηΜ=74% ' 0.67 ηΜ=15°/〇 ABO 14 VEGF 67 ηΜ=98°/〇 ' 6.7 ηΜ=91% ' 0.67 ηΜ=12% DVD260 P1GF VEGF 67 ηΜ=51% ' 6.7 ηΜ=7%、 0.67 ηΜ=-16% 含有來自AB014之VD的所有DVD-Ig均抑制由VEGF引起 的 HUVEC 細胞增殖。DVD044、DVD048、DVD040、 DVD050在67 nM之DVD-Ig濃度下使HUVEC細胞增殖抑制 >90% ° 151681.doc •371 - 201127956 表23 :藉由7種DLL4/VEGF DVD-Ig構築體及親本抗體抑 制HUVEC增殖/存活 DVD-Ig ID 序列ID 定向 HC 連 接 子 LC 連 接 子 其他DVD-Ig VD HUVEC 增殖之 DVD-Ig 抑制 (IC50， nM) Ref· Ab.ID HUVEC 增殖之 Ref.Ab. 抑制 (ICSO · nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 0.45 AB0I4 0.19 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 0.24 AB014 0.19 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 0.32 AB014 0.19 DVD474 DLL4(序列 1) C-term. 長 長 VEGF(序列 2) 0.42 AB071 2.5 DVD486 DLL4(序列 1) C-term. 短 長 VEGF(序列 2) 0.88 AB071 2.5 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 59.5 AB071 2.5 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 6.8 AB070 7,0 含有來自AB014、AB071及AB071之VD的所有DVD-Ig抑 制由VEGF引起的HUVEC細胞增殖。DVD470、DVD476、 DVD482、DVD474、486、485 及 471 以與親本 mAb相當之 IC50抑制HUVEC細胞增殖。 實例1.1.2.F : IGF1，2單株抗體或DVD-Ig在活體外之腫瘤 細胞生長抑制作用。 將20 pL稀釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏 磷酸鹽緩衝鹽水）中之IGF 1,2單株抗體或DVD_Ig以200 μι 中0.01 pg/mL至100 Rg/mL的最終濃度添加至人類腫瘤細胞 中。將板在3 7°C下在含濕氣5% C02氛圍中培育3天。根據 製造商說明書使用MTS試劑（Promega，Madison，WI)定量各 孔中之活細胞數目，以測定腫瘤生長抑制百分比。無抗體 處理之孔用作0%抑制之對照組，而將無細胞之孔視為顯 示100%抑制。 • 372· 151681.doc 201127956 表24 :使用IGF1R及IGF1，2親本抗體及DVD-Ig構築體之 H929、IGFR細胞株增殖抑制檢定 親本抗體或 DVD-Ig ID N末端可變 區域 (VD) C末端可變區域 (VD) N末端VD增殖抑 制細胞檢定IC50 nM (H929 * IGF1R細胞株） C末端VD增殖抑 制細胞檢定IC50 nM (H929 » IGF1R細胞株） AB033 EGFR >67 (5% max) AB004 HER-2 >67 (10 % max) DVD015 EGFR IHER-2 >50 (20% max) DVD016 HER-2 IeGFR >50 (15% max) AB033 EGFR >67 (5% max) ABO 11 IGF1R 0.1 (65% max) DVD021 EGFR IGF1R >50 (10% max) DVD022 IGF1R EGFR 0.05 (70% max) AB004 HER-2 >67(10 % max) AB010 IGF1,2 1.6 (70% max) DVD029 HER-2 IGF 1,2 6.8 (40% max) DVD030 IGF 1,2 HER-2 0.8 (70% max) AB004 HER-2 >67 (10%) ABO 11 IGF1R 0.1 (65% max) DVD031 HER-2 IGF1R >50 (10% max) DVD032 IGF1R HER-2 0.1 (60% max)
在N末端或C末端位置任一處含有來自AB033、AB004、 AB011或AB010之VD的所有DVD-Ig在A431細胞增殖檢定 中顯示抑制作用。 實例1.1.2.G : EGFR單株抗體或DVD-Ig在活體外之生長抑 制作用 將20 pL稀釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏 磷酸鹽緩衝鹽水）中之EGFR單株抗體或DVD-Ig以180 μί中 之0.01 pg/mL至100 pg/mL的最終濃度添加至人類腫瘤細胞 中。將板在37°C下在含濕氣5°/。C02氛圍中培育3天。根據 製造商說明書使用MTS試劑（Promega, Madison，WI)定量各 孔中之活細胞數目，以測定腫瘤生長抑制百分比。無抗體 151681.doc - 373 - 201127956 處理之孔用作〇%抑制之對照組，而無細胞之孔視為顯示 1 00%抑制。 表25 :使用EGFR親本抗體及DVD-Ig構築體之A431、 EGFR細胞株增殖抑制檢定 N末端VD增殖抑制細胞 C末端VD增殖抑制細胞 親本抗體或 N末端可變 c末端可變 檢定IC50 nM (A431， 檢定IC50 nM (A431 DVD-Ig ID 區域(VD) 區域(VD) EGFR細胞株） EGFR細胞株） AB033 EGFR 1.0 (65% max) AB004 HER-2 >67 (10% max) DVD015 EGFR HER-2 1.7 (65% max) DVD016 HER-2 EGFR 5.4 (80% max) AB033 EGFR 1.0 (65% max) ABO 11 IGF1R >67 (5% max) DVD021 EGFR IGF1R 1.5 (50% max) DVD022 IGF1R EGFR 3.4 (65% max) AB004 HER-2 >67 (10% max) ABO 10 IGF 1,2 >67 (10% max) DVD029 HER-2 IGF 1,2 >50 (10% max) DVD030 IGF 1,2 HER-2 >50 (10% max) AB004 HER-2 >67 (10% max) ABO 11 IGF1R >67(5% max) DVD031 HER-2 IGF1R >50 (10% max) DVD032 IGF1R HER-2 >50 (10% max) ABO 14 VEGF >67 (0%) AB010 IGF1,2 >67 (10% max) DVD041 VEGF IGF 1,2 >50 (0%) 在N末端或C末端位置任一處含有來自AB033、AB004、 AB011、AB010、AB014之 VD的所有 DVD-Ig在 A431細胞增 殖檢定中顯示抑制作用。 151681.doc •374- 201127956 表26 :使用EGFR、IGF1R及IGF1，2親本抗體及DVD-Ig構 築體之GEO、EGFR/IGF1R細胞株增殖抑制檢定 親本抗體或 DVD-Ig ID N末端可 變區域 fVD) C末端可 變區域 (VD) N末端增殖抑制細胞 檢定IC50 nM (GEO ' EGFR/ IGF1R細胞株） c末端增殖抑制細胞 檢定IC50 nM (GEO ' EGFR/ IGF1R細胞株） AB033 EGFR 0.2 (60% max) AB004 HE R-2 >67(15' Vo max) DVD015 EGFR HER-2 13 (60% max) DVD016 HER-2 EGFR 10 (40% max) AB033 EGFR 0.2 (60% max) ABO 11 IGF1R >67(15« V〇 max) DVD021 EGFR 1GF1R 0.32 (60% max) 0.32 (60% max) DVD022 IGF1R EGFR 3.0 (40% max) 3.0 (40% max) AB004 HE R-2 >67 (15% max) AB010 IGF 1,2 在67 nM下 20% DVD029 HER-2 IGF1,2 >50 (10% max) >50 (10% max) DVD030 IGF 1,2 HER-2 >50 (10% max) >50 (10% max) AB004 HE R-2 >67 (15% max) AB011 IGF1R >67 (15% max) DVD031 HER-2 IGF1R >50 (10% max) >50 (10% max) DVD032 IGF1R HER-2 >50 (10% max) >50 (10% max)
在N末端或C末端位置任一處含有來自AB033、AB004、 AB011、AB010、AB014之 VD 的所有 I)VD-Ig在 CEO細胞増 殖檢定中顯示抑制作用° 實例1.1.2.H HER2親本抗體或DVD-Ig構築體在活體外之 腫瘤細胞生長抑制作用 將20 μι稀釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏 磷酸鹽緩衝鹽水）中之HER2單株抗體或DVD-Ig以0.01 pg/mL至100 pg/mL(180 μΙ〇的最終濃度添加至表現HER2之 人類腫瘤細胞（ΒΤ474)中。將板在37°C下在含濕氣5% C〇2 氛圍中培育3天。根據製造商說明書使用MTS試劑 (Promega，Madison，WI)定量各孔中之活細胞數目，以測定 151681.doc -375- 201127956 腫瘤生長抑制百为比。無抗體處理之孔用作0〇/〇抑制之對 照組，而無細胞之孔視為顯示1〇〇%抑制。 表27 .使用抗Her-2親本抗體及構築體2Βτ474、 Erb2(Her·2)細胞株增逭抑制檢定 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) 變區域t (VD) Ν末端VD增殖抑 制細胞檢定IC50 nM (BT474， ErbB2細胞株） C末端VD增殖抑 制細胞檢定IC50 nM (BT474， ErbB2細胞株） AB004 Ρ\Λ7Τ\Λ1 C HE! EGFR Χ.ΧΤγ^ 0 •9 U V LIU1 j >50 DVD016 HER-2 EGFR^ 17 AB004 HE] 0 .9 DVD029 HbK-z IGFQ 2.7 DVD030 IGF 1,2 her.? >50 AB004 HE] ϊ-2~— 0 .9 DVD031 HER-2 IgfTr 2.2 DVD032 IGF1R >50 在N末端或C末端位置任—處含有來自AB004之VD的所 有DVD-Ig在BT474細胞増殖檢定中顯示抑制作用。 實例1.1.2.I :藉由DLL4親本抗體及DVD-Ig構築體抑制
Eahy.926細胞中Svegfrl(Sfltl)之重組DLL4依賴性增加 96孔組織培養板以每孔1〇〇 μι含有5 pg/ml人類DLL4胞 外區域之D-PBS(Gibco #14190, Grand Island，NY)塗覆且在 4°C下培育隔夜。以D-PBS洗滌板一次且在無或有抗體或 DVD-Ig存在下接種4000個EA.hy926細胞。4天後，使用 CyQUANT 細胞增殖檢定套組（Invitrogen，#C35007,
Eugene, OR)量測細胞增殖。根據製造商推薦藉由ELISA套 組（R&D Systems #DVR100B, Minneapolis, MN)偵測條件培 養基中之sVEGFRl表現。根據CyQUANT檢定測定之RFU 校正sVEGFRl之含量，以解釋細胞增殖中之差異。 151681.doc -376- 201127956 表28 :藉由DLL4親本抗體或DVD-Ig構築體抑制Eahy.926 細胞中Svegfrl(Sfltl)之DLL4依賴性增加 親本抗體或 DVD-Ig ID N末端可 雙區域 (VD) C末端可 變區域 (VD) N末端VD可溶性 Fltl檢定(各nMAb 下之中和％) C末端VD可溶性 Fltl檢定(各nMAb 下之中和％) AB015 DLL-4 9·2 nM下75.2%、27.7 nM下78.7%、 83.3 nM下86.6% DVD044 DLL4 VEGF 9.2 nM下39.8%、 27.7 nM下76.2%、 83.3 nM下79.9% DVD043 VEGF DLL4 9.2nM下 1.1%、 27.7 nM下50.3%、 83.3 nM下57.9%
在N末端或C末端位置任一處含有來自ABO 1 5之VD的 DVD-Ig顯示對來自Eahy.926細胞之DLL4誘導之sFLT釋放 的劑量依賴性抑制。 表29:藉由7種DLL4/VEGF DVD-Ig構築體及親本抗體抑 制 EA.hy926細胞中之sVEGFRl(sFltl)的 DLL4(2 pg/ml)依 賴性增加 DVD-Ig ID 序列Π) 定向 HC連 接子 LC連 接子 其他DVD-Ig VD sFItl 之 DVD-Ig 抑制 (IC50 · nM) Ref. Ab.ID sFltl 之 Ref.Ab 抑制 (IC50， nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 1.02 AB015 0.34 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 1.68 ABO 15 0.34 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 1.11 ABO 15 0.34 DVD474 DLL4(序列 1) C-term. 長 長 VEGF(序列 2) 0.93 AB015 0.34 DVD486 DLL4(序列 1^1 C-term. 短 長 VEGF(序列 2) 0.70 ABO 15 0.34 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 6.67 ABO 15 0.34 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 1.92 ABO 15 0.34 在N末端或C末端位置任一處含有來自AB015之VD的 DVD-Ig顯示對來自Eahy.926細胞之DLL4誘導之sFLTl釋放 的劑量依賴性抑制。 151681.doc -377- 201127956 實例1.1.2.J :親本抗體或DVD-Ig抗體的活體外殺腫瘤作用 可分析結合於腫瘤細胞上之目標抗原的親本抗體或 DVD-Ig之殺腫瘤活性。簡言之’將親本抗體或DVD·1^稀 釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏磷酸鹽緩衝 鹽水）中且以0.01 pg/mL至100 pg/mL(200 μΙ〇之最終濃度添 加至人類腫瘤細胞中。在37°C下在含濕氣5% c〇2氛圍中培 育板3天。根據製造商說明書使用MTS試劑（Promega， Madison，WI)定量各孔中之活細胞數目，以測定腫瘤生長 抑制百分比。無抗體處理之孔用作〇°/◦抑制之對照組，而 無細胞之孔視為顯示100%抑制。 為了評定細胞凋亡，藉由以下方案測定卡斯蛋白酶-3活 化：在室溫下在振盪下，將96孔板中經抗體處理之細胞溶 解於 120 μΐ lx 溶解緩衝液（1·67 mM Hepes ’ pH 7.4、7 mM Κα、0.83 mM MgCl2、0.11 mM EDTA、0·11 mM EGTA、 0.5 7% CHAPS、1 mM DTT、lx蛋白酶抑制劑混合錠劑； 無 EDTA ; Roche Pharmaceuticals, Nutley，NJ)中歷時 20分 鐘。在細胞溶解後，添加80 μΐ卡斯蛋白酶-3反應緩衝液 (48 mM Hepes，pH 7.5、252 mM蔗糖、0.1% CHAPS、4 mM DTT及 20 μΜ Ac_DEVD-AMC 受質；Biomol Research Labs，Inc.，Plymouth Meeting，PA) ’ 且將板在37°C下培育 2 小時。在 1420 VICTOR 多標計數器（Perkin Elmer Life Sciences, Downers Grove，IL)上使用以下設定對板讀數： 激發=360/40，發射=460/40。抗體處理之細胞之螢光單位 相對於同型抗體對照組處理之細胞增加指示細胞凋亡。 151681.doc •378· 201127956 實例1.1.2·κ :藉由HGF親本抗醴及DVD-Ig構築體抑制 U87-MG腫瘤細胞增殖 將U87-MG人類神經膠質瘤細胞以每孔2,〇〇〇個細胞以 100 μΐ接種於96孔培養皿中補充有5°/。胳牛血清之rpmI培 養基中’且在37C ’ 5% C〇2下培育隔夜。第二天，細胞以 抗體或DVD-Ig之連續稀釋液（0.013 nM至133 nM劑量範圍） 處理，且在37°C下在含濕氣5% C〇2氛圍中培育5天。藉由 鲁 根據製造商說明書使用ATPlite套組（Perkin Eimer， Waltham, ΜΑ)評定ATP含量來間接量測細胞存活/增瘦。 表30 :藉由抗HGF親本抗趙及DVD-Ig構築艘之U87_mg腫 瘤增殖抑制 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) U87MG増殖之 N末端VD抑制 (EC50) U87MG增殖之 C末端VD抑制 (EC50) ABO 12 HGF 12 DVD025 EGFR HGF >200 ABO 12 HGF 12 DVD033 RON HGF >200 DVD034 HGF RON 136 ABO 12 HGF 12 DVD045 VEGF HGF >200 AB008 CD22 >200 在C末端位置或N末端位置含有來自ΑΒ012之VD的DVD-Ig抑制U87-MG腫瘤細胞增殖。 實例1.1.2.L :藉由RON親本抗體及DVD-Ig構築體活體外 抑制RON與MSP1的相互作用 以每孔 50 μΐ 抗 MSPa鏈抗體（R&D Systems #MAB352, Minneapolis, MN，2 pg/mL)塗覆96孔板’且在4 C下培月板 隔夜。在洗滌緩衝液（含有0.05% Tween 20之PBS)中洗務板 151681.doc -379· 201127956 3次，且隨後在25°C下以每孔100 μΐ阻斷緩衝液（含有2% BSA之PBS)阻斷1小時。接著洗滌板3次，且在25°C下與每 孔 50 μΐ 10 nM 重組人類 MSP1 溶液（R&D Systems #352-MS， Minneapolis，MN) —起培育1小時。在培育板期間’在25C 下將欲測試之抗體的連續1 〇倍稀釋液（〇 nM至1000 nM劑量 範圍）與 10 nM 重組 His-RON部分 ECD(R&D Systems ^1947-MS, Minneapolis, MN)—起 預培育 1 小時。 將與重 組人類 MSP 1 —起培育之板洗滌3次’接著一式三份添加每孔50 μΐ 抗體/His-RON複合物。在25°C下培育1小時後，接著洗滌 板，且添加每孔 50 μΐ TMB 受質（Pierce #34028，Rockford, IL)，且在25°C下培育5分鐘。5分鐘後，使用每孔50 μΐ 2 N H2SO4終止反應。在45〇 nm下讀取吸光度（Spectra Max Plus 板讀取器，Molecular Devices，Sunnyvale, CA)。在 GraphPad Prism 4.03 中計算 EC50。 實例1.1.2.M : VEGF親本抗體及DVD-Ig構築體預防 VEGF16S與VEGFR1之相互作用 在 4°C 下將 ELISA板（Nunc, MaxiSorp, Rochester, NY)與 100 μΐ含有重組VEGFR1胞外區域-Fc融合蛋白之PBS(5 pg/ml，R&D systems, Minneapolis, MN)—起培育隔夜。在 洗滌緩衝液（含有0.05% Tween 20之PBS)中洗滌板3次，且 在25°C下在阻斷緩衝液（含有1% BSA之PBS)中阻斷1小 時。在25°C下將各抗體/DVD-Ig於含有0.1% BSA之PBS中 之連續稀釋液與50 μΐ 2 nM生物素標記VEGF —起培育1小 時。接著將抗體/DVD-Ig-生物素標記VEGF混合物（100 μΐ) 151681.doc -380- 201127956 添加至VEGFRl-Fc塗覆之孔中，且在25°C下培育l〇分鐘。 洗滌各孔3次，且接著在25°C下與100 μΐ抗生蛋白鏈菌素-HRP(KPL #474-3000，Gaithersburg, ,MD)— 起培育 1小時。 洗滌各孔3次，且每孔添加1〇〇 μΐ ULTRA-TMB ELISA(Pierce，Rockford，IL)。顯色後，以 1 N HCL停止反 應且在450 nM下量測吸光度。結果於下表31中提供。 表31 : 7種DLL4/VEGF DVD-Ig構築體及親本抗體對VEGF 與VEGFR1之間的配位體-受體相互作用的抑制 DVD-Ig ID 序列ID 定向 HC 連接 子 LC連 接子 其他 DVD-Ig VD DVD-Ig VEGF 配 位體-受艏 結合抑制 (IC50， nM) Ref. Ab. ID Ref.Ab. VEGF配位 體_受體結 合抑制 (IC50， nM) DVD470 DLL4 (序列1) C-term. 長 長 VEGF (序列1) 2.7 AB014 2.2 DVD476 DLL4 (序列1) C-term. 長 短 VEGF (序列1) 2.4 ABO 14 2.2 DVD482 DLL4 (序列1) C-term. 短 長 VEGF (序列1) 1.7 AB014 2.2 DVD474 DLL4 (序列1) C-term. 長 長 VEGF (序列2) 1.89 AB071 7.3 DVD486 DLL4 (序列1) C-term. 短 長 VEGF (序列2) 1.98 AB071 7.3 DVD485 DLL4 (序列1) N-term. 短 長 VEGF (序列2) 8.63 AB071 7.3 DVD471 DLU (序列1) N-term. 長 長 VEGF (序列3) 5.46 AB070 2.8 在N末端或c末端位置任一處含有來自14及AB 071及 AB071之VD的所有DVD-Ig顯示抑制配位體（VEGF)與其受 體（VEGFR1)結合。DVD-Ig之N末端區域對配位體-受體相 互作用之阻斷與親本抗體一樣好。 實例1.1.2.N :藉由DLL4親本抗體及DVD-Ig構築體活體外 抑制DLL4與Notch-Ι之相互作用 以 16 nM 人類 Notch-l(R&D Systems #3647-TK, -381- 151681.doc 201127956
Minneapolis，MN，D-PBS 中每孔 100 μΐ)塗覆 96 孔 Nunc-Immuno板（Nunc，#439454，Rochester, NY)且在 4°C 下培育 隔夜。接著以洗滌緩衝液（PBS，0.05% Tween 20)洗滌板1 次，且在25°C下以每孔200 μΐ阻斷緩衝液（D-PBS、1% BSA、1 mM CaCl2、0.05% Tween 20)阻斷 1小時。在阻斷 時，在25°C下將300 μΐ生物素標記之人類DLL4胞外區域 (14 ηΜ)與抗體或DVD-Ig(3.4 ρΜ至66 ηΜ，於阻斷緩衝液 中之3倍連續稀釋液）混合1小時。在阻斷後洗滌檢定板， 且與DLL4抗體或DVD-Ig混合物（每孔100 μΐ，在25°C下1小 時）一起培育。再次洗滌板，且在25°C下添加每孔100 μΐ抗 生蛋白鏈菌素與HRP之結合物（KPL #474-3000, Gaithersburg，MD，在阻斷緩衝液中1:10,000稀釋）持續1小 時。最終洗滌後，板使用每孔100 μΐ受質（1-Step Ultra TMB-ELISA，Pierce #340280，Rockford, IL)顯色，且在 25°C下培育10至20分鐘後使用每孔100 μΐ 2 N H2S04停止反 應，且在450 nm下讀取吸光度。結果於下表32中提供。 表32: 7種DLL4/VEGF DVD-Ig構築體及親本抗體對DLL4 與Notchl之間配位體-受體相互作用的抑制 DVD-Ig ID 序列ID 定向 HC連 接子 LC連 接子 其他 DVD-Ig VD DVD-Ig DLL4配位 體-受體結 合抑制 (IC50， ηΜ) Ref.Ab. ID Ref.Ab. DLL4配位 體-受體結 合抑制 (IC50， ηΜ) DVD470 DLL4 (序列υ C-term. 長 長 VEGF (序列1) 2.82 AB015 2.47 DVD476 DLL4 (序列1) C-term. 長 短 VEGF (序列1) 4.90 AB015 2.69 DVD482 DLL4 (序列1) C-term. 短 長 VEGF (序列υ 2.65 AB015 2.53 151681.doc -382- 201127956 DVD474 DLL4 (序列1) C-term. 長 長 VEGF (序列2) 2.30 AB015 2.69 DVD486 DLL4 (序列1) C-term. 短 長 VEGF (序列2) 2.91 AB015 2.74 DVD485 DLL4 (序列1) N-term. 短 長 VEGF (序列2) 3.44 AB015 2.74 DVD471 DLL4 (序列1) N-term. 長 長 VEGF (序列3) 2.66 AB015 2.47 在N末端或C末端位置任一處含有來自AB015之VD的所 有DVD-Ig均顯示抑制配位體（DLL4)與其受體（Notchl)結 合。DVD-Ig之N末端區域對配位體-受體相互作用之阻斷 與親本抗體一樣好。 表33:藉由FACS測定之7種DLL4/VEGF DVD-Ig構築體及 親本抗體對293G-人類DLL4細胞與Notchl之間的配位體-受體相互作用之抑制 DVD-Ig ID 序列ID 定向 HC 連 接 子 LC 連 接 子 其他DVD-Ig VD 對 Notchl 結合至 DLL4細胞 之 DVD-Ig 抑制 FACS (IC50， nM) Ref. Ab. ID 對 Notchl 結合至 DLL4細胞 之 Ref.Ab· 抑制 FACS(IC5 0，nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 38.3 ABO 15 2.3 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 15.1 ABO 15 2.3 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 16.3 ABO 15 2.3 DVD474 DLL4(序列 1) C-term. 長 長 VEGF(序列 2) 27.5 ABO 15 2.3 DVD486 DLL4(序列 1) C-term. 短 長 VEGF(序列 2) 10.2 ABO 15 2.3 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 6.3 ABO 15 2.3 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 4.1 ABO 15 2.3
實例1.1.2.0 :藉由HGF親本抗體及DVD-Ig構築體抑制 HGF與c-Met的相互作用 在4°C下以每孔100 μΐ重組人類HGF(含2 pg/ml HGF之 PBS，R&D systems)塗覆 ELISA板（Nunc，MaxiSorp)隔夜。 共培育各抗體/DVD-Ig之連續稀釋液與2 nM可溶性c-Met Fc融合物（R&D systems)(50 μΐ)且添加至HGF塗覆之孔中。 -383 - 151681.doc 201127956 以生物素標記抗c-Met(BAF358，R&D Systems)及 100 μΐ抗 生蛋白鏈菌素-HRP(KPL)偵測c-Met結合。在PBST(含有 0.05% Tween 20之PBS)中洗滌各孔3次，且每孔添加1〇〇 μΐ ULTRA-TMB ELISA(Pierce)。顯色後，以1 N HCL停止反 應且量測450 nM下之吸光度。藉由計算相較於最大信號 (對照抗體或未添加抗體）之抑制百分比評估資料，且計算 IC50 值。 下表含有親本抗體及DVD-Ig構築體在如上文所述之 RON、VEGF、DLL4及HGF之配位體-受體結合競爭ELISA 檢定中的親和力資料，表示為IC50(nM)。 表34 :以RON、VEGF、DLL4、及HGF親本抗體及DVD· Ig構築體活體外抑制配位體-受體相互作用 親本抗體或DVD-IglD N末端可變 區域(VD) C末端可變 區域(VD) N末端VD配位 想-受體結合競 爭檢定(IC50， nM) C末端VD配位 體-受體結合競 爭檢定(IC50， nM) AB005 RON 8.1 DVD024 RON EGFR 9.6 DVD023 EGFR RON AB005 RON 0.2 \2 DVD033 RON HGF **0.0000097 DVD034 HGF RON AB014 V EGF 21.40 DVD035 VEGF EGFR 23.90 ABO 14 V EGF 21.40 DVD038 HER-2 VEGF 73.00 ABO 15 D1 X-4 0.37 ABO 14 V] EGF 21.4 DVD044 DLL4 VEGF 0.50 143 DVD043 VEGF DLL4 24.1 13.10 AB005 RON 0.1 AB014 V] EGF 2L4 DVD048 RON VEGF 0.1127 114 DVD047 VEGF RON 30.5 21.28 AB014 VEGF 21.40 151681.doc -384- 201127956 DVD050 NRP1 VEGF 79.00 AB015 D] 丄-4 0.4 DVD257 DLL4 P1GF 0.38 DVD258 P1GF DLL4 17.47 AB014 V EGF 21.40 DVD260 P1GF VEGF 13.00 AB012 Η GF 0.1 8 DVD025 EGFR HGF >100 AB012 Η GF 0.1 8 DVD045 VEGF HGF >100 AB012 Η GF 0.1 8 DVD033 RON HGF 8.7 DVD034 HGF RON 0.34 在N末端或C末端位置任一處含有來自AB005、AB015、
ABO 1 5、ABO 12之VD的所有DVD-Ig均顯示抑制配位體與 其各別受體結合。DVD-Ig之N末端區域對配位體-受體相 互作用之阻斷與親本抗體一樣好。 表35 :親本抗體及DVD-Ig構築體活體外抑制配位體-受體 相互作用 親本抗體或 DVD-Ig ID N末端可變 區域(YD) c末端可變 區域(YD) N末端VD配位體-受體結合競爭檢 定(IC:50，nM) C末端VD配位體-受體結合競爭檢 定(IC50，nM) AB047 P1GF 3.( )7 DVD573 P1GF VEGF 2.59 DVD574 VEGF P1GF 23.68 AB047 P1GF 3.( 〕7 DVD575 P1GF VEGF 2.9 DVD576 VEGF P1GF 19.28 AB047 P1GF 3.( )7 DVD577 P1GF HER2 2.74 DVD578 HER2 P1GF 21.36 AB047 P1GF 3.( 〕7 DVD579 P1GF VEGF 5.84 AB047 P1GF 3.( 〕7 DVD581 P1GF VEGF 3.5 DVD582 VEGF P1GF 5.71 AB047 P1GF 3.07 DVD583 P1GF VEGF 3.25 DVD584 VEGF P1GF 3.71 AB047 P1GF 3. 37 DVD585 P1GF HER2 3.4 DVD586 HER2 P1GF 3.87 151681.doc •385 · 201127956 ΑΒ047 P1GF 3.( 〕7 DVD587 P1GF VEGF 3.65 ΑΒ047 P1GF 3.( 〕7 DVD589 P1GF VEGF 2.87 ΑΒ047 P1GF 3.( 37 DVD591 P1GF VEGF 3.23 DVD592 VEGF P1GF 3.93 ΑΒ047 P1GF 3.( )7 DVD593 P1GF HER2 2.76 DVD594 HER2 P1GF 4.01 ΑΒ047 P1GF 3.( )7 DVD595 P1GF VEGF 3.65 ΑΒ047 P1GF 3.( 37 DVD597 P1GF VEGF 2.94 DVD598 VEGF P1GF 4.64 ΑΒ047 P1GF 3.( 37 DVD599 P1GF VEGF 3.19 DVD600 VEGF P1GF 4.02 ΑΒ047 P1GF 3.( )7 DVD601 P1GF HER2 2.98 DVD602 HER2 P1GF 3.75 在N末端或C末端位置任一處含有來自AB047之VD的所 有DVD-Ig均顯示抑制配位體與其受體（VEGFR1)結合。 DVD-Ig之N末端區域對配位體-受體相互作用之阻斷與親 本抗體一樣好。 實例1.1.2.P :藉由親本抗體或DVD-Ig構築體活體外抑制 IGF誘導之IGFR磷酸化 將人類癌細胞以每孔40,000個細胞接種於96孔板中的 180 μΐ無血清培養基（DMEM+ 0.1% BSA)中，且在37°C， 5% C02下培育隔夜。以每孔100 μΐ IGFR捕捉Ab(R&D Systems 目錄號 MAB391，Minneapolis, MN，最終濃度 4 pg/ml)塗覆Costar El A板（Lowell, ΜΑ)，且在室溫下在振盈 下培育隔夜。第二天，洗滌IGFR抗體塗覆之ELISA板（以 PBST=含 0.05% Tween 20 之 PBS，pH 7.2-7.4 洗滌 3次），且 在室溫下在振盪器上添加200 μΐ阻斷溶液（含1% BSA， 151681.doc -386- 201127956
0.05% NaN3之PBS，pH 7.2-7_4)阻斷2小時。將人類腫瘤細 胞與抗體或DVD-Ig及IGF配位體一起共培育。將於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏磷酸鹽緩衝鹽水）中稀釋 之 IGF1，2 單株抗體或 DVD-Ig 以 0.01 .ug/mL 至 100 gg/mL 之 最終濃度添加至人類癌細胞中。同時以1至1〇〇 ng/mL(200 μί)之濃度向細胞中添加生長因子（IGF 1及IGF2)，且在 37°C下在含濕氣5% C02氛圍中培育細胞1小時。將細胞溶 解於每孔120 μΐ冷細胞提取緩衝液（10 mM Tris，pH 7.4、 100 mM NaC卜 1 mM EDTA、1 mM EGTA、1 mM NaF、1 mM原鈒酿鈉、1% Triton X-100、10。/。甘油、0.1% SDS及 蛋白酶抑制劑混合液）中，且在4°C下在振盪下培育20分 鐘。將細胞溶胞物（100 μΐ)添加至ELISA板中，且在4°C下 在輕緩振盪下培育隔夜。第二天，洗滌ELISA板，且添加 每孔 100 μΐ pTyr-HRP偵測 Ab(p-IGF1R ELISA套組，R&D System # DYC1770, Minneapolis, MN)，且在 25 °C 下在暗處 培育板2小時。根據製造商說明書使板顯色以測定 phospho-IGFIR。結果於表36及表37中顯示0 表36 :使用抗IGF1，2親本抗體或DVB>-Ig構築體抑制IGF1 引起之IGF1R磷酸化 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) c末端计 變區域 (VD) N末端 VD pIGFIR 細胞檢定(hIGFl中 和 IC50 nM) C末端VD pIGFIR 細胞檢定(hIGFl中 和 IC50 nM) AB010 IGF 1.2 1.7 DVD029 HER^2 ~~ IGF 1,2 14.22(40% 最大） DVD030 Igfu HER-2 1.9 ABO 10 IGF1,2 1.7 DVD041 VEGF IGF 1,2 16.8(40% 最大） DVD042 Igfu VEGF 1.8 151681.doc -387 - 201127956 在N末端或C末端位置任一處含有來自AB010之VD的 DVD-Ig顯示抑制IGF1誘導之IGF1R受體磷酸化。DVD-Ig 之N末端位置中ABO 10之VD對受體磷酸化之阻斷與親本抗 體AB010 —樣好。 表37 :使用抗IGF1，2親本抗體或DVD-Ig構築體抑制IGF2 引起之IGF1R磷酸化
親本抗體或 DVD-Ig ID N末端可變 區域(VD) C末端可 變區域 (VD) N末端 VD pIGFRl 細胞檢定(IGF2誘導 之IC50 nM) C末端 VD pIGFRl 細胞檢定(IGF2誘導 之IC50 nM) ABO 10 IGF 1.2 0.3 DVD029 HER-2 IGF1,2 ND 1.9 DVD030 IGF1，2 HER-2 0.4 ND AB010 IGF1,2 0.3 DVD041 VEGF IGF1,2 ND 1.5 DVD042 IGF 1,2 VEGF 0.3 ND 在N末端或C末端位置任一處含有來自AB010之VD的 DVD-Ig顯示抑制IGF2誘導之IGF 1R受體璃酸化。DVD-Ig 之N末端位置中ABO 10之VD對受體磷酸化之阻斷與親本抗 體AB010 —樣好。 實例1.1.2.Q :藉由HGF親本抗體及DVD-Ig構築體抑制 HGF介導之Akt磷酸化 將H1299非小細胞肺腫瘤細胞以每孔20,000個細胞（100 μΐ總體積）接種於96孔板中，且在37°C，5% C02下血清饑 餓18小時。將抗HGF單株抗體或DVD-Ig(最終濃度為67 nM、6.7 nM及0.67 nM)於含有0.1% BSA之杜爾貝科氏最小 必需培養基中稀釋，且在25°C下與50 μΐ重組人類HGF(50 ng/ml) —起預培育1小時。接著向細胞中添加此等抗體 /DVD-Ig及HGF混合物（50 μΐ)，且在37°C下在含濕氣5% 151681.doc • 388 - 201127956
C〇2氛圍中培育板約15分鐘。接著藉由向各孔中添加等體 積之7.6%甲路固定細胞，且在25°C下培育板15分鐘。固定 後’在含有0.1% Triton X-1〇〇之PBS中洗滌細胞5次。接著 以每孔 150 μΐ LI-COR Odyssey阻斷緩衝液(Li-Cor Biosciences， Lincoln, NE)處理細胞，且在室溫下在適度振盪下培育90 分鐘。移除阻斷緩衝液，且在4°C下將細胞與稀釋於阻斷 緩衝液中之一次抗體（1:3 00稀釋之卩11〇3?11〇861473-八1^, Cell Signaling Technology #4060，Boston, MA)—起培育隔 夜。接著以含有0·1 % Tween 2〇之PBS洗滌各孔5次，接華 在 25°C下與二次抗體（抗兔IRDye™ 680CW LI-COR(Li-Cor Biosciences，Lincoln，NE)於具有 0.2% Tween 20之 1XPBS 中 的1:400稀釋液）一起培育1小時。以含有0.1% Tween 20之 PBS洗滌細胞5次’且使用Odyssey紅外顯影系統顯影。 表38:藉由HGF親本抗體及DVD-Ig構築體抑制HGF介導 之Akt磷酸化 親本抗體 或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) Akt填酸化之N末端VD 抑制(67、6.7及0.67 nM Ab/DVD下之抑制。/〇) Akt磷酸化之C末端VD 抑制(67、6.7及0.67 nm Ab/DVD下之抑制％) ABO 12 HGF 67 nM=106%、6.7 nM=110%、0.67 nM=790/〇 DVD033 RON HGF 67 nM=95% ' 6.7 ηΜ=91°/〇 ' 0.67 ηΜ=24% DVD034 HGF RON 67nM=lll%、 6.7nM=105% ' 0.67 nM=99% AB012 HGF 67 nM=106%、6.7 nM=110o/〇、0.67 nM=79% DVD045 VEGF HGF 67 ηΜ=64%、 6.7 ηΜ=-2% ' 0.67ηΜ=-15% AB008 CD22 67 nM=8% ' 6.7 nM=-13% 151681.doc - 389- 201127956 在N末端或C末端位置任一處含有來自AB012之VD的 DVD-Ig顯示良好抑制HGF謗導之Akt磷酸化。DVD-Ig之N 末端位置中AB012之VD對Akt磷酸化之阻斷與親本抗體 AB012 — 樣好。 實例1.1.2.R :藉由VEGF親本抗體及DVD-Ig構築體抑制 VEGFR2(KDR)磷酸化 將表現人類VEGFR2(KDR)之NIH3T3細胞以每孔20,000 個細胞（100 μΐ)接種於96孔板中補充有10% FBS之DMEM 中。第二天，以DMEM洗滌細胞2次，且在無FBS之DMEM 中血清饑餓3小時。在25°C下將稀釋於具有0.1% BSA之 DMEM中的抗VEGF親本抗體或DVD-Ig(最終濃度為67
nM、6.7 nM及 0.67 nM)與重組人類 VEGF丨65(50 ng/ml)—起 預培育1小時。接著向細胞中添加此等抗體/DVD-Ig及 VEGF混合物，且在37°C下在含濕氣5% C02氛圍中培育板 10分鐘。以冰冷之PBS洗滌細胞2次，且藉由添加每孔100 μΐ補充有0·1°/〇 NP40之細胞溶解緩衝液（Cell Signaling， Boston，ΜΑ)溶解。彙聚副份樣品（duplicate sample)，且向 先前以抗 VEGFR2抗體（R&D systems, AF357，Minneapolis， 河>〇塗覆之£1^13八板的各孔中添加170卜1’且在25°〇下在輕 緩振盪下培育2小時。以洗蘇緩衝液（含有〇·〇5% Tween 20 之PBS)洗滌各孔5次，且在25°C下與50 μΐ生物素標記抗磷 酸赂胺酸抗體（4G10; Millipore，Billerica，ΜΑ)之 1:2000 稀 釋液一起培育1小時。以含有0·05% Tween 20之PBS洗務各 孔5次，接著在25°C下與抗生蛋白鏈菌素-HRP(KPL #474- 151681.doc •390- 201127956 3000，Gaithersburg, MD)—起培育1小時°以抗生蛋白鏈菌 素-HRP(KPL #474-3000, Gaithersburg, MD)洗務各孔 3次。 以含有0.05% Tween 20之PBS洗滌各孔3次，且每孔添加 100 μΐ ULTRA-TMB ELISA(Pierce，Rockford，IL)。顯色 後，以1 N HCL停止反應且在450 nM下量測吸光度。結果 於表39中顯示。
表39 :藉由VEGF親本抗體或DVD-Ig構築體抑制VEGFR2 (KDR)磷酸化 親本抗體或 DVD-Ig ID C末端可變 區域(VD) N末端可變 區域(VD) Pkdr之N末端 VD抑制 (EC50) Pkdr之C末端 VD抑制 (EC50) ABO 14 VEGF 0.45 DVD044 DLL4 VEGF 10.40 DVD043 VEGF DLL4 0.54 AB014 VEGF 0.45 DVD048 RON VEGF 31.80 DVD047 VEGF RON 0.47 在N末端或C末端位置任一處含有來自AB014之VD的 DVD-Ig顯示良好抑制VEGF誘導之KDR填酸化。DVD-Ig之 N末端位置中AB014之VD對KDR磷酸化之阻斷與親本抗體 AB014 —樣好。 實例1.1.2.S : EGFR親本抗體或DVD-Ig構築體活體外抑制 EGF誘導之EGFR磷酸化 將稀釋於D-PBS-BSA(具有0.1% BSA之杜爾貝科氏磷酸 鹽緩衝鹽水）中之EGFR單株抗體或DVD-Ig以0.01 pg/mL至 100 gg/mL(180 gL)之最終濃度添加至人類癌細胞中。在 37°C下在含濕氣5% C02氛圍中培育板1小時。將最終濃度 為1至100 ng/mL(20 pL)之生長因子（EGF)添加至細胞中持 151681.doc •391 · 201127956 續5至15分鐘以刺激受體（EGFR)自體磷酸化。無抗體處理 之孔用作0%抑制之對照組，而無生長因子刺激之孔視為 顯示100%抑制。藉由與細胞提取緩衝液（10 mM Tris，pH 7.4、100 mM NaCl、1 mM EDTA、1 mM EGTA、1 mM NaF、1 mM原釩酸鈉、1% Triton X-100、10%甘油、0.1% SDS及蛋白酶抑制劑混合物）一起培育製得細胞溶解產物。 根據製造商說明書使用來自R&D System之p-EGFR ELISA 套組（#DYC 1095，Minneapolis, MN)測定此等細胞溶解產物 中之Phospho-EGFR。結果於表40及表41中顯示。 表40 :抗EGFR親本抗體及DVD-Ig構築體對EGF誘導之 EGFR磷酸化的抑制 親本抗體或 DVD-Ig ID N末端可變 區域(VD) C末端可變 區域(VD) N末端 VD pEGFR 細胞檢定(EGF誘 導之IC50 nM) C 末端 VD pEGFR 細胞檢定(EGF誘 導之 IC50 nM) AB033 EGFR 7.3 DVD015 EGFR HER-2 7.9 DVD016 HER-2 EGFR >50(10% max) AB033 EGFR 7.3 DVD021 EGFR IGF1R 7.7 DVD022 IGF1R EGFR >50(20% max) 在N末端或C末端位置任一處含有來自AB033之VD的 DVD-Ig顯示良好抑制EGF誘導之EGFR磷酸化。〇乂0-Ig(DVD015、DVD021)之 N末端位置中 AB033 之 VD對 EGFR 磷酸化之阻斷與親本抗體AB033—樣好。 151681.doc -392- 201127956 表41 ··抗EGFR親本抗體及DVD-Ig構築逋對EGF誘導之 EGFR磷酸化的抑制
親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) N末端細胞檢定，對 EGF誘導之phEGFR 的抑制(IC50，nM) c末端細胞檢定，對 EGF誘導之phEGFR 的抑制(IC50，nM) AB033 EG FR 0.35 DVD024 RON EGFR ND 7.143 DVD023 EGFR RON 0.54 ND 在N末端或C末端位置任一處含有來自AB033之VD的 DVD-Ig顯示良好抑制EGF誘導之EGFR破酸化。DVD-Ig(DVD023)之N末端位置中AB033之VD對EGFR磷酸化之 阻斷與親本抗體AB033—樣好。 實例1.1.2.T :藉由親本RON抗體及DVD-Ig構築體活髏外 抑制MSP1誘導之ERK1/2及AKT磷酸化
將於10% FBS/最小必需培養基中生長之近匯合DU145結 腸腫瘤細胞經胰蛋白酶化，且接種至6孔組織培養板（每2 毫升最終體積0.25 X 106個細胞）中，且在37°C，5% C02下 培育18至24小時。培育後，以IX D-PBS洗滌細胞2次，且 在無血清培養基中饑饿隔夜。第二天，在37°C下將細胞與 900 μΐ含有1 μΜ單株抗體或DVD-Ig之無血清培養基一起培 育1小時。在抗體培育後，接著以13 nM MSP1處理細胞 (3 7°C，30分鐘）。將細胞以冰冷D-PBS洗滌2次，且採集於 150 μΐ含有100 μΐ HALT®磷酸酶抑制劑混合液（Thermo Scientific, Rockford，IL)、一份 Complete®無 EDTA之蛋白 酶抑制劑錠劑（每10毫升1粒錠劑，Roche Diagnostic，
Mannheim，Germany)及 PMSF 之細胞提取緩衝液（Biosource 151681.doc •393· 201127956
International, Carlsbad，CA)中。在間歇满旋下將細胞溶解 產物在冰上培育30分鐘，藉由離心（10分鐘，14,000 RPM，4°C)預澄清，且處理以供西方墨點分析。藉由SDS-PAGE 使用 IX MOPS 操作緩衝液（Invitrogen，Carlsbad, CA) 在4至12% NuPage Bis-Tris凝膠上解析總共15 pg細胞溶解 產物。將蛋白質轉移至頌基纖維素膜（Invitrogen，Carlsbad， CA)上，且在室溫下在含有5°/❶脫脂奶之TBS-T(1X TBS/0.1% Tween 20)中阻斷1小時。阻斷後，在4°C下將膜 與兔多株 phospho-p44/42 MAPK(Thr202/Tyr204)抗體（Cell Signaling，Danvers, ΜΑ)或兔單株 phospho-AKT(Ser473)抗 體（Cell Signaling, Danvers, ΜΑ)之 1:1000 稀釋液一起培育 隔夜。洗滌墨點3次（IX TBS-T，15分鐘），且在室溫下與 抗兔IgG、HRP結合之二次山羊抗體（Jackson Immunoresearch，West Grove, PA)之 1:5000稀釋液一起在 5%脫脂奶/TBS-T溶液中培育1小時。洗滌墨點3次（IX TBS-T，15 分鐘），且藉由與 SuperSignal West Dura Luminol/Enhancer Solution®(Millipore，Temecula，CA)—起 培育5分鐘來活化過氧化酶結合之二次抗體，且偵測化學 發光，且以Luminescent Image分析器 LAS-3000(FUJIFilm， Tokyo，Japan)定量。使用 MultiGauge 軟體（FUJIFilm， Tokyo, Japan)測定頻帶密度，且定量各頻帶之總化學發光 信號。為了測定總ERK1/2及AKT含量，以IX Reblot Plus Strong Solution®(Thermo Scientific, Rockford, IL)剝離膜持 續 15分鐘，以兔多株p44/42 MAPK抗體（Cell Signaling， 151681.doc -394- 201127956
Danvers，ΜΑ)或兔單株 AKT抗體（Ce】l Signaling，Danvers， MA)之1:1000稀釋液再探測，且如上文針對PhosPh〇-抗體 所述處理。Ph-ERK及ph-Akt含量分別根據總ERK或總Akt 標準化。 表42 :藉由RON親本抗體或DVD-Ig構築體抑制MSP1誘導 之ERK1/2磷酸化 親本抗體 或 DVD-Ig ID N末端可 變區域 (VD) C末端可 變區域 (VD) N末端VD細胞檢定， 對RON誘導之 phERKl/2的抑制(各 11]\1入1>下之中和％) C末端VD細胞檢定， 對RON誘導之 phERKl/2的抑制(各 1|]\1入1)下之中和％) AB005 RON 1000 nM 下 80% DVD024 RON EGFR 1000 nM 下 97% AB005 RON 1000 nM 下 80% DVD033 RON HGF 1000 nM 下 60% 在N末端位置含有來自AB005之VD的DVD-Ig顯示極佳抑 制MSP1誘導之ERK1/2碟酸化。DVD024及DVD033之抑制 概況類似於親本抗體AB005之抑制概況。
實例1.1.2.U : DVD-Ig對人類癌皮下側腹異種移植物生長 的功效 使A-43 1人類表皮樣癌細胞在組織培養燒瓶中活體外生 長至99°/〇活力、85%匯合。在研究第〇天，向19至25 g之 SCID雌性小鼠（Charles Rivers Labs，Wilmington, MA)右側 腹皮下注射lxl〇6個人類腫瘤細胞（與基質膠（matrigel)成 1:1)。在將平均腫瘤體積為約200至320 mm3之小鼠按尺寸 匹配分組之後起始投與（IP，QD，每週3次）人類IgG對照組 或DVD-Ig。在腫瘤細胞注射後約第1〇天開始每週兩次量 測腫瘤。 151681.doc -395 - 201127956 可見在投與EGFR+IGFl/2 DVD Ig之動物中的腫瘤體積 相對於僅接受對照IgG之動物中的腫瘤減小。對於兩種不 同EGFR+IGF1/2 DVD Ig構築體，如在3週給藥期結束後4 天所量測’ TGI%為69及64。 實例1.1.2.V:如流動式細胞測量術所評定之單株抗體與人 類腫瘤細胞株表面的結合
自組織培養燒瓶採集過度表現相關細胞表面抗原之穩定 細胞株或人類腫瘤細胞株，且再懸浮於含有5%胎牛血清 之磷酸鹽緩衝鹽水（PBS)(PBS/FBS)中。在染色之前，將人 類腫瘤細胞在冰上與（100 μΐ)含5 pg/ml人類IgG之PBS/FCS 一起培育。在冰上，將1至5χ105個細胞與含抗體或DVD-Ig(2 pg/mL)之PBS/FBS —起培育30至60分鐘。洗滌細胞2 次，且添加100 μΐ F(ab')2山羊抗人類IgG、Fey-藻紅素 (1:200 稀釋於 PBS 中）（Jackson ImmunoResearch, West Grove，PA，目錄號109-116-170)。在冰上培育30分鐘後， 將細胞洗滌2次且再懸浮於PBS/FBS中。使用Becton Dickinson FACSCalibur(Becton Dickinson, San Jose，CA)量 測螢光》 表43顯示DVD-Ig構築體之FACS資料。幾何平均值為n個 螢光信號之乘積（al X a2 X a3….an)的η次根。採用對數轉 換之數據，使用幾何平均值來校正數據分佈之加權。下表 含有親本抗體及DVD-Ig構築體之FACS幾何平均值。 151681.doc •396- 201127956 表43 : DVD-Ig構築體之螢光活化細胞分選
親本抗體或 DVD-Ig ID N末端可變 區域 (VD) c末端可變 區域 (VD) FACS幾何平 均N末端 FACS幾何平 均C末端 AB006 CD-19 979 AB001 CD-20 DVD001 CD-20 CD-19 161 DVD002 CD-19 CD-20 1102 AB001 CD-20 95.8 AB002 CD-3 461 DVD003 CD-20 CD-3 45.9 5.7 DVD004 CD-3 CD-20 673 3.59 AB007 CD-80 25.4 AB001 CD-20 DVD005 CD-20 CD-80 6 DVD006 CD-80 CD-20 70.7 AB002 CD-3 897 AB004 HER-2 27.7 DVD011 CD-3 HER-2 1096 3.39 DVD012 HER-2 CD-3 7.14 41.6 AB002 CD-3 461/897 AB006 CD-19 661/989 DVD013 CD-3 CD-19 417 103 DVD014 CD-19 CD-3 1090 23.3 AB033 EGFR 955.4 AB004 HER-2 24.77 DVD015 EGFR HER-2 1006.4 200.07 DVD016 HER-2 EGFR 75.67 384.4 AB033 EGFR 955.4 ABO 11 IGF1R 1684.5 DVD021 EGFR IGF1R 888.4 733.5 DVD022 IGF1R EGFR 2016.5 411.4 AB005 RON 54.46 AB033 EG] FR 955.4 DVD024 RON EGFR 0.38 309.4 DVD023 EGFR RON 1001.4 164.96 AB033 EGFR 955.4 ABO 12 HGF DVD025 EGFR HGF 1045.4 DVD026 HGF EGFR 143.4 AB004 HER-2 24.77 ABO 10 IGF 1,2 DVD029 HER-2 IGF 1,2 22.37 DVD030 IGF 1,2 HER-2 0.23 AB004 HER-2 24.77 151681.doc -397- 201127956 親本抗體或 DVD-Ig ID N末端可變 區域 (VD) c末端可變 區域 (VD) FACS幾何平 均N末端 FACS幾何平 均C末端 ABO 11 IGF1R 168 4.5 DVD031 HER-2 IGF1R 4.99 24.7 DVD032 IGF1R HER-2 34.6 4.9 AB005 RON 54.46 ABO 12 HGF DVD033 RON HGF 6.46 DVD034 HGF RON 0.39 ABO 14 VEGF AB033 EG] FR 955.4 DVD035 VEGF EGFR 162.4 DVD036 EGFR VEGF 1081.4 ABO 14 VEGF AB004 HER-2 24.77 DVD037 VEGF HER-2 1.03 DVD038 HER-2 VEGF 7.47 ABO 15 DLL-4 308.27 ABO 14 VEGF DVD044 DLL4 VEGF 297.27 DVD043 VEGF DLL4 68.37 ABO 14 VEGF ABO 12 HGF DVD045 VEGF HGF DVD046 HGF VEGF AB005 RON 54.46 ABO 14 VEGF DVD048 RON VEGF 29.86 DVD047 VEGF RON 0.51 ABO 14 VEGF ABO 16 NR PI 33 8.4 DVD049 VEGF NRP1 352.4 DVD050 NRP1 VEGF 336.4 ABO 15 DLL-4 308.27 AB047 P1GF DVD257 DLL4 P1GF 274.27 DVD258 P1GF DLL4 5.57 所有DVD均顯示結合於其細胞表面目標。DVD之N末端 區域與細胞表面上其目標的結合與親本抗體一樣好或更 佳。結合可藉由調整連接子長度來修復或改良。 實例1.1.2.W :如流動式細胞測量術所評定之親本EGFR抗 151681.doc •398- 201127956 體及DVD-Ig構築體與人類腫瘤細胞株表面的結合
自組織培養燒瓶採集過度表現細胞表面EGFR之穩定細 胞株或人類腫瘤細胞株，且再懸浮於含有1%胎牛血清之 杜爾貝科氏磷酸鹽緩衝鹽水（DPBS)(DPBS/FCS)中。在冰 上，將1至5xl05個細胞與100 μ!^含抗體或DVD-Ig(10 pg/mL)之DPBS/FBS—起培育30至60分鐘。將細胞洗滌2 次，且添加50 μΐ山羊抗人類IgG-藻紅素（於DPBS/BSA中之 _ 1:50稀釋液）（Southern Biotech Associates，Birmingham, AL 目錄號2040-09)。在冰上培育30至45分鐘後，將細胞洗滌 兩次且再懸浮於每孔125 pL含1%甲醛之DPBS/FCS中。使 用 Becton Dickinson LSRII(Becton Dickinson, San Jose, CA)量測螢光。 表44 :藉由FACS測定之抗EGFR親本抗體及DVD-Ig構築 體對A431、EGFR細胞株之結合親和力
親本抗體或 DVD-Ig ID N末端可變 區域 c末端可變 區域 (VD) N末端VDAg結 合 A431 FACS (EC50 » nM) C末端VDAg結 合 A431 FACS (EC50，nM) AB005 —__ RON AB033 __EGFR 4.2 DVD024 ΚϋΝ EGFR ND 25.43 DVD023 ~egf^ RON 5.38 ND 所有DVD均結合於其細胞表面目標。dvd之N末端區城 與細胞表面上其目標的結合與親本抗體一樣好。 151681.doc •399· 201127956 表45 :藉由FACS測定之抗EGFR親本抗體及DVD-Ig構築 趙對BAFvar3細胞株之結合親和力
親本抗體或 DVD-Ig ID N末端可變 區域 (VD) C末端可變 區域 (VD) N末端VDAg結合 BAFvar3 FACS(EC50， nM) C末端VDAg結合 BAFvar3 FACS(EC50，_ AB005 RON AB033 EGFR 0.5 DVD024 RON EGFR ND 17.8 DVD023 EGFR RON 0.6 ND 所有DVD均結合於其細胞表面目標。DVD之N末端區域 與細胞表面上其目標的結合與親本抗體一樣好。 表46:藉由FACS測定之7種DLL4/VEGF DVD-Ig構築體及 親本抗體對293G人類DLL4細胞株的結合親和力 DVD-Ig ID 序列ID 定向 HC 連 接 子 LC 連 接 子 其他 DVD-Ig VD DVD-Ig DLL4細胞 結合FACS (EC50， nM) Ref. Ab.ID Rcf,Ab. DLL4細胞 結合FACS (EC50， nM) DVD470 DLL4(序列 1) C-term. 長 長 VEGF(序列 1) 1.72 AB015 0.50 DVD476 DLL4(序列 1) C-term. 長 短 VEGF(序列 1) 11.72 AB015 0.50 DVD482 DLL4(序列 1) C-term. 短 長 VEGF(序列 1) 3.25 AB015 0.50 DVD474 DLL4(序列 1) C-term. 長 長 VEGF(序列 2) 2.19 ABO 15 0.50 DVD486 DLL4(序列 1) C-term. 短 長 VEGF(序列 2) 2.09 ABO 15 0.50 DVD485 DLL4(序列 1) N-term. 短 長 VEGF(序列 2) 0.89 ABO 15 0.50 DVD471 DLL4(序列 1) N-term. 長 長 VEGF(序列 3) 1.13 ABO 15 0,50 所有DVD均結合於其細胞表面目標（DLL4)。DVD之N末 端及C末端DLL4結合區域與細胞表面上其目標的結合與親 本抗體一樣好。 實例1.2:產生針對相關人類抗原之親本單株抗體 如下獲得能夠結合及中和相關人類抗原及其突變體之親 本小鼠mAb : 實例1.2.A:以相關人類抗原使小鼠免疫 151681.doc •400- 201127956 在第1天，在5隻6至8週大Balb/C小鼠、5隻C57B/6小鼠 及5隻AJ小鼠中皮下注射2〇吨重組經純化人類抗原（例如 IGF1、2)與完全弗氏佐劑（Freund's adjuvant)或 Immunoeasy 佐劑（Qiagen，Valencia，CA)之混合物。在第24天、第38天 及第49天’向相同小鼠皮下注射2〇叩重組經純化人類抗 原變異體與不完全弗氏佐劑或ImrnunoeaSy佐劑之混合物。 在第84天或第112天或第144天，向小鼠靜脈内注射1 相 φ 關重組經純化人類抗原。 實例1.2.Β :產生融合瘤 根據 Kohler，G.及 Milstein (1975) Nature, 256: 495所述之 確定方法使自實例i.2.A中所述之經免疫小鼠獲得之脾細 胞與SP2/〇-Ag-14細胞以5:1比率融合以產生融合瘤。以每 孔2.5XI〇6個脾細胞的密度將融合產物接種於％孔板中含有 偶氣絲胺酸及次黃嘌呤之選擇培養基中。融合後7至1〇 天，觀測到肉眼可見之融合瘤群落。藉由ELISA測試來自 • 含有融合瘤群落之各孔的上清液中針對相關抗原之抗體的 存在（如實例丨.丨.丨.A所述）。接著測試呈現抗原特異性活性 之上清液的活性（如實例112之檢定所述），例如在生物檢 定中中和相關抗原之能力（諸如實例1.1.2.1所述）。 實例1.2.C :針對相關人類目標抗原之親本單株抗鱧的鑑 別及表徵 實例1.2.C.1 ··分析親本單株抗體中和活性 檢定融合瘤上清液中親本抗體之存在，該等抗體結合根 據實例1.2.A及1.2.B產生之相關抗原，且亦能夠結合相關 151681.doc -401 · 201127956 抗原之變異體（「抗原變異體」）。接著在例如實例Μ 2ι 之細胞激素生物檢定中測試在兩個檢定中呈抗體陽性之上 清液的抗原中和效能。在生物檢定中，由產生抗體之扣 值低於1000 PM，在一實施例中低於1〇〇 pM之融合瘤進行 擴增且藉由限制稀釋法選殖。將融合瘤細胞在含有丨低 IgG胎牛血清（Hyclone #SH30151，L〇gan，UT)之培養基中擴 增。平均每一融合瘤收集250 mL上清液（來源於純系群 體）’將其濃縮且藉由如Harlow, E.及Lane，D. 1988 「Antibodies: A Laboratory Manual」中所述之蛋白質 a親 _ 和力層析純化。例如使用如實例i.〗.2.1所述之細胞激素生 物檢定測定經純化mAb抑制其目標抗原活性之能力。 實例1.2.C.2 :分析親本單株抗體對相關食蟹猴目標抗原之 交叉反應性 為了測定本文所述之所選mAb是否識別相關食蟹猴抗 原’使用重組食蟹猴目標抗原如本文所述（實例丨丨丨G)進 行BIACORE分析。此外，亦可在細胞激素生物檢定（實例 1.1.2.1)中量測mAb針對相關重組食蟹猴抗原之中和效能。 · 選擇具有良好食蟹猴交叉反應性（在一實施例中，在人類 抗原之反應性的5倍以内）之MAb用於將來表徵。 實例1.2.D :測定各鼠類抗人類單株抗體之可變區胺基酸 序列 如下進行重組抗人類小鼠mAb之cDNA分離、表現及表 徵。對於各胺基酸序列測定，藉由離心分離約1 X 1 〇6個融 合瘤細胞，且根據製造商說明書使用Trizol(Gibco 151681.doc -402- 201127956 BRL/Invitrogen，Carlsbad，CA.)處理以分離全部 rnA。根 據製造商說明書使用Superscript First-Strand合成系統 (Invitrogen，Carlsbad, CA)對全部 RNA進行第一股DNA合 成。使用寡聚去氧胸苷酸（oligo(dT))引發第一股合成以選 擇聚（A)+ RNA。第一股cDNA產物接著藉由PCR，使用經 設計用於擴增鼠類免疫球蛋白可變區之引子（Ig-Primer Sets，Novagen，Madison，WI)來擴增。PCR產物經瓊脂糖凝 膠解析、切除、純化且接著以TOPO Cloning套組次選殖至 pCR2.1-TOPO載體（Invitrogen，Carlsbad, CA)中，且轉型至 TOP 10化學感受態大腸桿菌（Invitrogen, Carlsbad，CA)中。 針對轉型體進行群落PCR以鑑別含有插入物之純系。使用 QIAprep Miniprep 套組（Qiagen，Valencia，CA)自含有插入 物之純系分離質體DNA。使用M13正向引子及M13反向引 子（Fermentas Life Sciences, Hanover MD)對質體中之插入 物之兩股進行定序以確定可變重鏈DNA序列或可變輕鏈 DNA序列。鑑別mAb之可變重鏈序列及可變輕鏈序列。在 一實施例中，用於下一步開發（人類化）之前導mAb組的選 擇準則包括以下： 除CH2中之標準NXS外，抗體不含任何N連接之糖基化 位點（NXS) 除每一抗體中之正常半胱胺酸外，抗體不含任何額外半 胱胺酸 比對抗體序列與最接近之人類生殖系序列之VH及VL， 且應檢驗其他天然人類抗體中任何異常胺基酸之存在 151681.doc •403- 201127956 右不衫響抗體活性，則N太嫂姑# 則Ν禾知麵醯胺酸（Q)換為麩胺酸 (Ε)。此將減少由Q環化引起之異質性 藉由質譜分析確認有效信號序列裂解。此可使用cos細 胞或293細胞物質進行 檢驗蛋白質序列可能導致活性喪失之Asn脫㈣之風險 抗體具有低聚集程度 抗體/合解度大於5至1〇 mg/ml(在研究階段）；大於25 mg/ml 根據動態光散射（DLS)測得抗體具有正常尺寸（5至611111) 抗體具有低電荷異質性 抗體缺乏細胞激素釋放（參看實例M 2 b) 抗體對預定細胞激素具有特異性（參看實例1丨.2工） 抗體缺乏非預期組織交叉反應性（參看實例丨1.2 D) 抗體之人類與食蟹猴組織交又反應性之間具有類似性 (參看實例1.1.2.D) 實例1.2.2:重組人類化親本抗體 實例1.2.2.1 :建構及表現重組嵌合抗人類親本抗體 藉由在細菌中同源重組將編碼鼠類抗人類親本mAb之重 鏈恆定區的DNA置換為編碼含有2個鉸鏈區胺基酸突變之 人類IgGl恆定區的cDNA片段。此等突變為位置234(EU編 號）處之白胺酸改變為丙胺酸及位置23 5處之白胺酸改變為 丙胺酸（Lund等人，1991，J. Immunol·，147: 2657)。此等抗 體中之每一者的輕鏈恆定區置換為人類κ恆定區。藉由共 轉染接合至pBOS表現質體中之嵌合重鏈及輕鏈cDNA在 151681.doc •404- 201127956 COS細胞中短暫表現全長嵌合抗體（Mizushima及Nagata， Nucleic Acids Research 1990，第 18卷，第 5322頁）。藉由 蛋白質A瓊脂糖凝膠層析法純化含有重組嵌合抗體之細胞 上清液，且藉由添加酸緩衝液溶離已結合抗體。中和抗體 且透析至PBS中。 編碼欲合mAb之重鏈cDNA與其嵌合輕鏈CDNA(皆接合 至pBOS載體中）共轉染至COS細胞中。藉由蛋白質a瓊脂 糖凝膠層析法純化含有重組嵌合抗體之細胞上清液且藉由 添加酸緩衝液溶離已結合抗體。中和抗體且透析至PBS 中。 接著如實例1.1.1.G及1.1.2.B所述測試純化嵌合抗人類親 本mAb的結合能力（藉由Biacore)及例如抑制細胞激素誘導 之IgE產生的功能活性。選擇維持親本融合瘤mAb活性之 敌合mAb用於將來開發。 實例1.2.2.2:建構及表現人類化抗人類親本抗體 實例1.2·2.2·Α:選擇人類抗體構架 使用Vector ΝΤΙ軟體單獨比對各鼠類可變重鏈及可變輕 鏈基因序列與44個人類免疫球蛋白生殖系可變重鏈或粍個 生殖系可變輕鏈序列（來源於NCbi Ig Blast網站 http."www.ncbi.nlm.nih.gov/igblast/retrieveig.html.)。 基於胺基酸序列同源性、（：1)11叢集分析、所表現人類抗 體之使用頻率及可獲得之關於人類抗體之晶體結構之資訊 進行人類化。考慮到對抗體結合、VH-VL配對及其他因素 的可能影響，在鼠類與人類構架殘基不同之處，使鼠類殘 151681.doc -405 - 201127956 基突變成人類殘基’但有少數例夕卜基於對與鼠類抗體可 變區的實際胺基酸序列具有高度同源性（㈣序列類似性） ^類生㈣抗體序列或其子群之分析來設計其他人類化 朿略。 使用同源性模型化來鑑別預計對抗體組合位點c⑽結構 至關重要的鼠類抗體序列特有之殘基。同源模型化為產生 蛋白質之近似三維座標的計算方法。初始座標來源及其進 -步改進之指南為第二蛋白質(即參考蛋白質），其三維座 標已知且序列與第一蛋白質之序列相關。使用兩種蛋白質 之序列之間的關係產生參考蛋白質與需要座標之蛋白質 (目標蛋白質）之間的對應性。比對參考蛋白質與目標蛋白 質之-級序列’其中兩種蛋白質之―致部分的座標自參考 蛋白質直接轉移至目標蛋白質。自㈣結構模板建構例如 由殘基突變、插入或缺失產生之兩種蛋白質之錯配部分的 座標且改進能量以確保與已轉移模型座標的—致性。此計 异蛋白質結構可經進一步改進或直接用於模型化研究。模 型結構之品質由參考蛋白質與目標蛋白質相關之論點的準 確性及建構序列比對之精確性決定。 對於鼠類mAb，使用BLAST搜尋與目測之組合鑑別適合 參考結構。參考胺基酸序列與目標胺基酸序列之間25。/。的 序列一致性被視作嘗試執行同源性模型化之最低限度。人 工建構序列比對且以程式Jaekal產生模型座標（參看petrey, D.等人，（2003) Proteins 53 (增刊 6): 430-435)。 所選抗體之鼠類及人類構架區之一級序列共有顯著一致 15I681.doc -406- 201127956 性。不同之殘基位置為在人類化序列中包括鼠類殘基以保 留鼠類抗體的所觀測到的結合效能之候選位置。人工建構 人類序列與鼠類序列之間不同之構架殘基的清單。表47顯 示針對此研究選擇之構架序列。 表47:人類IgG重鏈恆定區域及輕鏈恆定區域之序列
蛋白質 SEQ ID NO 序列 12345678901234567890123456789012345678901 野生型hlgGl 恨定區 108 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 突變hlgGl怪 定區 109 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKiiwYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK IgK怪定區 110 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLS S PVTKS FNRGEC IgX怪定區 111 QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW KADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR SYSCQVTHEGSTVEKTVAPTECS 既定構架殘基影響抗體之結合特性的可能性視其與CDR 殘基之鄰近性而定。因此，使用模型結構，根據距CDR中 之任何原子的距離排列鼠類序列與人類序列之間的不同殘 基。在任何CDR原子4.5 A範圍内的彼等殘基經鑑別為最重 要的殘基且推薦其作為人類化抗體中保留鼠類殘基（亦即 回復突變）之候選殘基。 •407· 151681.doc 201127956 使用春核苦酸建構經電腦（/w 建構之人類化抗 體。對於各可變區cDNA而言，設計6個各自具有60至80個 核苷酸之寡核苷酸以在各寡核苷酸之5,及/或3,末端彼此重 疊20個核苷酸。在黏接反應中，組合所有6種寡核苷酸， 煮沸且在dNTP存在下使其黏接。添加DNA聚合酶1(大 (Klenow)片段（New England Biolabs #M0210，Beverley, MA.))以填充重疊寡核苷酸之間的約4〇 bp間隙。使用兩個 含有與經修飾pBOS載體中之多選殖位點互補之懸垂序列 的最外側引子進行PCR以擴增整個可變區基因（Mizushima， S·及Nagata，S· (1990) Nucleic Acids Res· 18: 17)。在璦脂 糖凝膠上分離自各cDNA總成獲得之PCR產物且切出對應 於經預測可變區cDNA尺寸之條帶且將其純化。在細菌中 藉由同源重組將可變重鏈區同框插入至編碼含有2個錢鏈 區胺基酸突變之人類IgGl恆定區的cDNA片段上。此等突 變為位置234(EU編號）處之白胺酸改變為丙胺酸及位置235 處之白胺酸改變為丙胺酸（Lund等人.（1991) J. Immunol. 147: 265 7)。藉由同源重組將可變輕鏈區與人類 <恆定區同 框插入。分離細菌群落，且提取質體DNA。對整個cDNA 插入物定序。將對應於各抗體之正確人類化重鏈及輕鏈共 轉染至COS細胞中以短暫產生全長人類化抗人類抗體。藉 由蛋白質A瓊脂糖凝膠層析法純化含有重組嵌合抗體之細 胞上清液’且藉由添加酸緩衝液溶離已結合抗體。中和抗 體且透析至PBS中。 實例1.2.2.3:人類化抗體之表徵 131681.doc •408· 201127956 例如使用如實例所述之細胞激素生物檢定來測定 經純化人類化抗體抑制功能活性之能力。冑用如實例 1.1.1 ·Β中所述之表面電漿子共振⑺丨&⑶κ⑧）量測來測定人 類化抗體對重組人類抗原之結合親和力。排列生物檢定之 ICw值及人類化抗體之親和力。選擇完全保留親本融合瘤 mAb活性之人類化mAb作為用於進一步開發之候選物。對 最適宜的2至3個人類化爪八匕進行進一步表徵。 實例1.2.2.3.A :人類化抗體之藥物動力學分析 在史泊格多利（Sprague-Dawley)大鼠及食蟹餱中進行藥 物動力學研究。對雄性及雌性大鼠及食蟹猴靜脈内或皮下 給予4 mg/kg mAb之單一劑量，且使用抗原捕捉eusa* 析樣品，且藉由非房室模型分析測定藥物動力學參數。簡 言之’用山羊抗生物素抗體（5 mg/mi ’ 4°C，隔夜）塗覆 ELISA板，用Superblock(Pierce)阻斷，且在室溫下與含5〇 ng/ml之經生物素標§己之人類抗原的1 〇% Superblock TTBS 一起培月2小時。血清樣品經連續稀釋（0.5%血清，ttbS 中之10¾ Superblock)’且在室溫下在板上培育3〇分鐘。以 HRP標記之山羊抗人類抗體進行彳貞測，且藉助於標準曲線 使用四參數邏輯擬合測定濃度。藉由非房室模型使用
WinNonlin軟體（Pharsight Corporation, Mountain View, CA) 測定藥物動力學參數值。選擇具有良好藥物動力學概況 (T1/2為8至13天或更佳’具有低清除率及50-1〇0%的極佳 生物可用性）之人類化mAb。 實例1·2·2.3.B :人類化單株抗體之物理化學及活體外穩定 151681.doc -409- 201127956 性分析 尺寸排阻層析 用水稀釋抗體至2.5 mg/mL，且取20 mL在Shimadzu HPLC系統上使用TSK凝膠G3000 SWXL管柱（Tosoh Bioscience，目錄號k5539-05k)分析。使用211 mM硫酸 鈉、92 mM填酸納（pH 7.0)以0.3 mL/min之流動速率自管柱 溶離樣品。HPLC系統操作條件如下：
移動相： 211 mM Na2S〇4 ' 92 mM
Na2HP04*7H20，pH 7.0 梯度： 等度 流動速率： 0.3 mL/min 偵測器波長： 280 nm 自動取樣器冷卻器溫度：4°C 管柱烘箱溫度： 環境溫度 運作時間： 50分鐘 表48含有如上述方案所測定以單體百分比（具有預期分 子量之未聚集蛋白質）表示之親本抗體及DVD-Ig構築體的 純度資料。 表48:藉由尺寸排阻層析測定之親本抗鱧及DVD-Ig構築 體之純度 親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可變 區域 (VD) 單體％(純度） AB033 EGFR 99.75 AB004 HER-2 95.6 DVD015 EGFR HER-2 96.98 DVD016 HER-2 EGFR 93.41 151681.doc -410- 201127956
親本抗體或 DVD-Ig ID N末端可 變區域 (VD) C末端可變 區域 (VD) 單體％(純度） AB033 EGFR 99.75 AB011 IG FIR 98.23 DVD021 EGFR IGF1R 99.25 DVD022 IGF1R EGFR 99.53 AB005 RON 79.34 AB033 EGFR 99.75 DVD024 RON EGFR 96.86 DVD023 EGFR RON 97.27 AB033 EGFR 99.75 ABO 12 HGF 98.97 DVD025 EGFR HGF 99.21 DVD026 HGF EGFR 99.48 AB004 HER-2 95.6 AB010 IG] FI,2 93.2 DVD029 HER-2 IGF 1,2 88.2 DVD030 IGF 1,2 HER-2 96.9 AB004 HER-2 95.6 ABO 11 IG FIR 98.23 DVD031 HER-2 IGF1R 94.53 DVD032 IGF1R HER-2 98.1 AB005 RON 79.34 ABO 12 HGF 98.97 DVD033 RON HGF 100 DVD034 HGF RON 100 ABO 14 VEGF 97.81 AB033 EGFR 99.75 DVD035 VEGF EGFR 97.7 DVD036 EGFR VEGF 99.36 ABO 14 VEGF 97.81 AB004 HER-2 95.6 DVD037 VEGF HER-2 45.4 DVD038 HER-2 VEGF 96.9 ABO 14 VEGF 97.81 ABO 10 IG FI,2 93.2 DVD041 VEGF IGF 1,2 94.7 DVD042 IGF 1,2 VEGF 92.4 ABO 15 DLL-4 97.52 AB014 VEGF 97.81 DVD044 DLL4 VEGF 48.66 DVD043 VEGF DLL4 96.72 ABO 14 VEGF 97.81 ABO 12 HGF 98.97 DVD045 VEGF HGF 97.88 DVD046 HGF VEGF 98.14 AB005 RON 79.34 ABO 14 VEGF 97.81 151681.doc • 411 - 201127956 親本抗體或 DVD-Ig ID N末端可 變區域 iVD) c末端可變 區域 (VD) 單體％(純度） DVD048 RON VEGF 100 DVD047 VEGF RON 100 AB014 ' VEGF 97.81 ABO 16 N1 93.54 DVD049 VEGF NRP1 97.74 DVD050 NRP1 VEGF 98.59 AB015 DLL-4 97.52 AB047 PI GF 99.47 DVD257 DLL4 P1GF 83.8 DVD258 P1GF DLL4 100 AB014 VEGF 97.81 AB047 PI GF 99.47 DVD259 VEGF P1GF 90.61 DVD260 P1GF VEGF 98.57 AB062 Er bB3 100 AB033 EGFR 99.75 DVD299 ErbB3 EGFR 98.8 DVD300 EGFR ErbB3 100 AB063 Erl bB3 96 AB033 EGFR 99.75 DVD305 ErbB3 EGFR 83.8 DVD306 EGFR ErbB3 100 DVD-Ig顯示極佳的SEC概況，其中多數DVD-Ig顯示 >90%單體。此DVD-Ig概況與關於親本抗體觀測到之概況 類似。 表49 :藉由尺寸排阻層析測定之VEGF/DLL4 DVD-Ig構築 體之純度 DVD ID 序列ID 位置 HC連接+ LC連接子 其他DVD區域 DVD043 VEGF(序列 1) N-term. 短 短 DLL4(序列 1) 96.8— DVD044 VEGF(序列 1) C-term. 短 短 DLL4(序列 1) 51.4 DVD469 VEGF(序列 1) C-term. 長 長 DLL4(序列 1) 44J~ DVD470 VEGF(序列 1) N-term. 長 DLL4(序列 1) 96ΪΓ DVD475 VEGF(序列 1) C-term. 長 短 DLL4(序列 1) 47.3 DVD476 VEGF(序列 1) N-term. 長 短 DLL4(序列 1) 97.6 DVD481 VEGF(序列 1) C-tenn. 短 長 DLL4(序列 1) DVD482 VEGF(序列 1) N-term. 短 長 DLL4(序列 1) 95.9 DVD467 VEGF(序列 2) C-term. 短 短 DLL4(序列 1) 70.1 DVD468 VEGF(序列 2) N-term. 短 短 DLL4(序列 1) 90.5 DVD473 VEGF(序列 2) C-term. 長 長 DLL4(序列 1) 96.8 DVD474 VEGF(序列 2) N-term. 長 長 DLL4(序列 1) 95.3 DVD479 VEGF(序列 2) C-term. 長 短 DLL4i序列 1) 151681.doc •412· 201127956 DVD ID 序列ID 位置 HC連接子 LC連接子 其他DVD區域 單體％ DVD480 VEGF(序列 2) N-term. 長 短 DLL4(序列 1) 94.1 DVD485 VEGF(序列 2) C-term. 短 長 DLL4(序列 1) 96.5 DVD486 VEGF(序列η N-term. 短 長 DLL4(序列 1) 95.5 DVD465 VEGF(序 C-term. 短 短 DLL4(序列 1) 80.6 DVD466 VEGF(序列 3) N-term. 短 短 DLL4(序列 1) 91.5 DVD471 VEGF(序列 3) C-term. 長 長 DLL4(序列 1) 78.8 DVD472 VEGF(序列 3) N-term. 長 長 DLL4(序列 1) 85.4 DVD477 VEGF(序列 3) C-term. 長 短 DLL4(序列 1) 79.2 DVD478 VEGF(序列 3) N-term. 長 短 DLL4(序列 1) 91.0 DVD483 VEGF(序列 3) C-term. 短 長 DLL4(序列 1) 76.9 DVD484 VEGF(序列 3) N-term. 短 長 DLL4(序列 1) 90.1 DVD-Ig顯示極佳的SEC概況，其中多數DVD-Ig顯示 >90%單體。此DVD-Ig概況與關於親本抗體觀測到之概況 類似。
SDS-PAGE 在還原性條件及非還原性條件下藉由十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳（SDS-PAGE)分析抗體。使用阿達木 單抗（批號AFP04C)作為對照組。對於還原性條件，1:卜混 合樣品與具有100 mM DTT之2X Tris甘胺酸SDS-PAGE樣品 緩衝液（Invitrogen，目錄號LC2676 ’批號1323208) ’且在 60°C下加熱3 0分鐘。對於非還原性條件，1:1混合樣品與樣 品緩衝液且在1 〇〇°C下加熱5分鐘。將經還原樣品（每泳道 10 mg)裝載於12%預製Tris甘胺酸凝膠（Invitrogen，目錄號 丑060051)〇\，批號6111021)上，且將未經還原之樣品（每泳 道10 mg)裝載至8%至16%預製Tris甘胺酸凝膠 (Invitrogen，目錄號EC6045box ’ 批號6111021)上。使用 SeeBlue Plus 2(Invitrogen，目錄號LC5925，批號 1351542) 作為分子量標諸物。在XCell SureLock小單元凝膠盒 (Invitrogen，目錄號EI0001)中運作凝膠’且藉由首先施加 151681.doc -413- 201127956 電壓75使樣品堆疊於凝膠中，隨後施加恆定電壓125直至 染料前沿到達凝膠底部來分離蛋白質。所用之電泳緩衝液 為自 10X Tris 甘胺酸 SDS 緩衝液（ABC, MPS-79-080106)製 備的IX Tris甘胺酸SDS緩衝液。用膠體藍染色劑（colloidal blue stain)(Invitrogen 目錄號 46-7015，46-7016)對凝膠染色 隔夜，且用Milli-Q水脫色直至背景透明。接著使用Epson Expression掃描儀（型號 1680，S/N DASX003641)掃描經染 色凝膠。 沈降速度分析 將抗體裝載至三個標準雙區碳環氧樹脂（epon)中心件中 之每一者的樣品室中。此等中心件具有1.2 cm之光徑長度 且經建造有藍寶石窗。使用PBS作為參考緩衝液且各腔室 含有 140 pL PBS。在Beckman ProteomeLab XL-Ι分析型超 離心機（序號PL106C01)中使用4孔（AN-60Ti)轉子同時檢查 所有樣品。 運作條件經程式化，且使用ProteomeLab(v5.6)執行離心 對照。在分析之前，使樣品及轉子熱平衡1小時 (20.0±0.1°C)。在3000 rpm下執行適當室負荷之確認，且記 錄各室之單一掃描。沈降速度條件如下：
樣品室體積.420 mL 參考室體積：420 mL 溫度：20°C 轉子速度：35,000 rpm 時間：8:00小時 151681.doc -414- 201127956 UV波長：280 nm 徑向步長：0.003 cm 資料收集：每步一個資料點，無信號平均。 總掃描數：100 完整抗體之LC-MS分子量量測 藉由LC-MS分析完整抗體之分子量。以水稀釋各抗體至 約1 mg/mL。使用具有蛋白質微捕集器（Michrom ^ Bioresources, Inc,目錄號 004/25109/03)之 1100 HPLC(Agilent)系統脫鹽，且將5 mg樣品引入至API Qstar pulsar i質譜儀（Applied Biosystems)中。使用短梯度溶離樣 品。用移動相A(HPLC水中0.08% FA、0.02% TFA)及移動 相B(乙腈中0.08% FA及0.02% TFA)以50 mL/min之流動速 率運作梯度。質譜儀在4.5千伏喷霧電壓下操作，掃描範 圍為2000至3500質荷比。 抗體輕鏈及重鏈之LC-MS分子量量測 φ 藉由LC-MS分析抗體輕鏈（LC)、重鏈（HC)及去糖基化
HC之分子量量測。以水稀釋抗體至1 mg/mL，且在37°C下 以最終濃度為10 mM之DTT使樣品還原為LC及HC歷時30分 鐘"為了使抗體去糖基化，將100 mg抗體與2 mL PNGase F、5 mL 10°/。N-辛基糖苷以100 mL之總體積在37°C下一起 培育隔夜。在去糖基化之後，在37°C下以最終濃度為1〇 mM之DTT使樣品還原30分鐘。使用具有C4管柱之Agilent 1100 HPLC 系統（Vydac，目錄號 214TP5115 ，S/N 060206537204069)脫鹽，且將樣品（5 mg)引入至 API Qstar 151681.doc -415- 201127956 pulsar i質譜儀（Applied Biosystems)中。使用短梯度溶離樣 品。用移動相A(HPLC水中0.08% FA、0.02% TFA)及移動 相B(乙腈中0.08% FA及0.02% TFA)以50 mL/min之流動速 率運作梯度。質譜儀在4.5千伏喷霧電壓下操作，掃描範 圍為800至3500質荷比。 肽圖譜 在室溫下在75 mM碳酸氫銨中用最終濃度為6 Μ之鹽酸 胍使抗體變性15分鐘。在37°C下以最終濃度為10 mM之 DTT使變性樣品還原60分鐘，隨後在37°C下在黑暗中以50 mM磁乙酸（IAA)使其炫基化30分鐘。在院基化之後’在 4。〇下針對4 L 1 〇 mM碳酸氫敍透析樣品隔夜。以10 mM碳 酸氫敍（？117.8)歸釋經透析樣品至1111§/1111^’且在37°(：下用 肤蛋白酶（Promega’目錄號V5111)或Lys-C(Roche’目錄 號11 047 825 〇〇1)以1:20(w/w)胰蛋白酶/Lys-C:抗體比率消 化100 mg抗體達4小時。以1 mL 1 N HC1淬滅消化物。對 於使用質譜儀傾測法之肽圖譜’使用Agilent 11 〇〇 HPLC系 統在 C18 管枉（vydac ’ 目錄號 218TP51 ’ S/N ΝΕ9606 10.3.5)上藉由逆相高效液相層析（尺1>1^[匚）分離4〇1111消化 物。以使用移動相八(《^1^級水中0.02%丁？八及0.08%卩入) 及移動相Β(乙腈中0_02% TFA及0.08% FA)之梯度以50 mL/min之流動速率下進行肽分離。API QSTAR Pulsar巧 譜儀在4.5千伏喷霧電壓下及800至25 〇〇質荷比之掃描範圍 内以正離子模式操作。 二硫鍵定位 151681.doc -416- 201127956 為了使抗體變性，將100 mL抗體與300 mL含8 Μ鹽酸胍 之100 mM碳酸氫銨混合。檢驗pH值以確保其在7與8之 間，且使樣品在室溫下在最終濃度為6 Μ之鹽酸脈中變性 15分鐘。用Milli-Q水稀釋一部分變性樣品（100 mL)至600 mL，獲得1 Μ之最終鹽酸胍濃度。在37°C下用胰蛋白酶 (Promega，目錄號 V5111 ，批號 22265901)或 Lys- C(Roche，目錄號 11047825001，批號 12808000)以 1:50胰蛋 白酶或1:50 Lys-C:抗體（w/w)比率（4.4 mg酶：220 mg樣品）消 化樣品（220 mg)約1 6小時。向樣品中再添加5 mg胰蛋白酶 或Lys-C，且於37°C下再消化2小時。藉由向各樣品中添加 1 mL TFA來停止消化。在Agilent HPLC系統上使用C18管 柱（Vydac，目錄號 218TP51 S/N NE020630-4-1A)藉由 R.PHPLC分離經消化之樣品。以與用於肽圖譜之梯度相同 之梯度，使用移動相A(HPLC級水中0.02% TFA及0.08°/〇 FA)及移動相 B(乙腈中 0.02% TFA及 0.08% FA)以 50 mL/min 之流動速率進行分離。HPLC操作條件與肽圖譜所用之操 作條件相同。API QSTAR Pulsar i質譜儀在4.5千伏喷霧電 壓及800至2500質荷比之掃描範圍内以正離子模式操作。 藉由匹配所觀測之肽MW與經二硫鍵連接之胰蛋白酶肽或 Lys-C肽的預測MW來指定二硫鍵。 游離硫氫基之測定 用於定量抗體中之游離半胱胺酸的方法係基於愛耳門試 劑（Ellman's reagent)(5,5|i-二硫基-雙（2-硝基苯曱 酸）(DTNB))與硫氫基（SH)之反應，該反應產生特徵性發色 151681.doc -417· 201127956 產物5-硫基-(2-硝基苯曱酸）（ΤΝΒ)。反應以下式說明： DTNB+RSH ® RS-TNB+TNB-+H+ 使用Cary 50分光光度計量測ΤΝΒ-在412 nm下之吸光 度。使用2-巯基乙醇（b-ME)稀釋液作為游離SH標準物繪製 吸光度曲線，且自樣品於412 nm下之吸光度測定蛋白質中 之游離疏氫基的濃度。 藉由以HPLC級水連續稀釋14.2 M b-ME直至0.142 mM的 最終濃度來製備b-ME標準儲備液。接著，一式三份製備 各濃度之標準物。使用amicon ultra 10,000 MWCO離心過 濾器（Millipore，目錄號UFC801096，批號L3KN5251)將抗 體濃縮至10 mg/mL，且將缓衝液換為用於阿達木單抗之調 配缓衝液（5.57 mM填酸二氫納、8.69 mM填酸氫二鈉、 106.69 mM NaCl、1.07 mM檸檬酸鈉、6.45 mM檸檬酸、 66.68 mM 甘露糖醇，pH 5.2、0.1 % (w/v) Twee η) ° 在室溫下 在振盪器上混合樣品20分鐘。接著，向各樣品及標準物中 添加1 80 mL 1 00 mM Tris緩衝液（pH 8.1)，隨後添加300 mL含2 mM DTNB之10 mM磷酸鹽緩衝液（pH 8.1)。在充分 混合之後，在Cary 50分光光度計上在412 nm下量測樣品 及標準物之吸光度。藉由繪製游離SH之量與b-ME標準物 之OD412 nm之曲線獲得標準曲線。在減去空白後，基於此 曲線計算樣品之游離SH含量。 弱陽離子交換層析 以10 mM磷酸鈉（pH 6.0)稀釋抗體至1 mg/mL。使用 Shimadzu HPLC系統用WCX-10 ProPac分析型管柱 151681.doc -418- 201127956 (Dionex，目錄號05 4993，S/N 02722)分析電荷異質性。將 樣品裝載於管柱上（80%移動相A(10 mM磷酸鈉，pH 6.0)及 20%移動相 B(10 mM磷酸鈉、500 mM NaCl，pH 6.0))，且 以1.0 mL/min之流動速率溶離。 寡醣分佈
以2-胺基苯甲醯胺（2-AB)標記試劑衍生經PNGase F處理 抗體後釋放之寡醣。藉由正相高效液相層析（NPHPLC)分 離螢光標記之募醣，且基於與已知標準物的滯留時間比較 表徵寡醣之不同形式。 首先以PNGaseF消化抗體，以自重鏈之Fc部分裂解N連 接之寡醣。將抗體（200 mg)與2 mL PNGase F及3 mL 10% N-辛基糖苷一起置於500 mL Eppendorf管中。添加磷酸鹽 緩衝鹽水使最終體積達到60 mL。將樣品在37°C下在設定 為700 RPM之Eppendorf恆溫混勻器中培育隔夜。作為對 照，亦使用PNGase F消化批號為AFP04C之阿達木單抗。 在PNGase F處理之後，將樣品在95°C下在設定為750 RPM之Eppendorf恆溫混勻器中培育5分鐘以沈澱出蛋白 質，接著將樣品置於1〇,〇〇〇 RPM下之Eppendorf離心機中 歷時2分鐘，以短暫離心（spin down)沈殿之蛋白質。將含 有寡醣之上清液轉移至500 mL Eppendorf管中且在65°C下 在speed-vac中乾燥。 使用購自Prozyme之2AB標記套組（目錄號GKK-404，批 號132026)以2AB標記寡醣。根據製造商說明書製備標記試 劑。將乙酸（150 mL，於套組中提供）添加至DMSO小瓶（於 151681.doc -419- 201127956 套組中提供）中，且藉由將溶液上下抽吸若干次來混合。 將乙酸/DMSO混合物（100 mL)轉移至2-AB染料小瓶中（即 將使用之前）且混合直至染料完全溶解。接著將染料溶液 添加至還原劑小瓶（於套組中提供）中並充分混合（標記試 劑）。向各乾燥寡醣樣品小瓶中添加標記試劑（5 mL)，且充 分混合。將反應小瓶置於設定為65°C及700至800 RPM之 Eppendorf恆溫混勻器中反應2小時。 在標記反應之後，使用來自Prozyme之GlycoClean S筒 (目錄號GKI-4726)移除過量螢光染料。在添加樣品之前， 將該等筒以1 mL milli-Q水洗滌，隨後以1 mL 30%乙酸溶 液洗務5次。在即將添加樣品之前，向筒中添加1 mL乙腈 (Burdick and Jackson，目錄號AH015-4)。 在所有乙腈均已通過筒之後，將樣品點樣至剛洗滌之圓 盤中央，且使其吸附於圓盤上歷時10分鐘。用1 mL乙腈洗 滌圓盤，隨後以1 mL 96%乙腈洗滌5次。將筒置於1.5 mL Eppendorf管上，且以milli Q水洗滌3次（每次洗滌400 mL) 來溶離2-AB標記之寡醣。 使用連接於Shimadzu HPLC系統之Glycosep N HPLC(目 錄號GKI-4728)管柱分離寡醣。Shimadzu HPLC系統由系統 控制器、脫氣器、二元泵、具有樣品冷卻器之自動取樣器 及螢光偵測器組成。 高溫下之穩定性 抗體緩衝液為5.57 mM磷酸二氫鈉、8.69 mM磷酸氫二 鈉、106.69 mM NaCl、1·07 mM檸檬酸鈉、6.45 mM擰檬 151681.doc -420- 201127956 酸 ' 66.68 mM甘露糖醇、0.1%(w/v)Tween(pH 5.2);或 ι〇 mM組胺酸、1〇 甲硫胺酸、4%甘露糖醇（pH 5.9)，使用 Amicon超離心過濾器。以適當緩衝液將抗體最終濃度調整 至2 mg/mL。接著將抗體溶液過濾滅菌，且在無菌條件下 製備0.25 mL等分試樣。將等分試樣留置於_8(Γ(：、、 25°C或40°C下歷時1、2或3週。在培育期結束時，藉由尺 寸排阻層析及SDS-PAGE分析樣品。 藉由SDS-PAGE在還原性及非還原性條件下分析穩定性 樣品。所用程序與本文所述相同。用膠體藍染色劑 (colloidal blue stain)(Invitri>gen 目錄號 46-7015，46-7016) 對凝膠染色隔夜，且用Milli-Q水脫色直至背景透明。接著 使用 Epson Expression 掃描儀（型號 1680 ， S/N DASX003641)掃描經染色凝膠。為了獲得更高靈敏度，使 用銀染色套組（Owl Scientific)對相同凝膠進行銀染色，且 使用製造商給出之推薦程序。 實例1.2.2.3.C :人類化單株抗體單獨或與化學療法之組合 對人類癌瘤異種移植物生長之功效 人類癌細胞在組織培養燒瓶中活體外生長至活力、 85。/。匯合。對19至25公克之SCID雌性或雄性小鼠（Charles Rivers Labs)在耳朵上做標記且剃毛。接著，在研究第〇 天，以0.2 ml 2χ106個人類腫瘤細胞（與基質膠成1:1)皮下 接種至小鼠右側腹。在將平均腫瘤體積為約15〇至200 mm3 之小队按尺寸匹配分入至各別小鼠籠中之後起始投與 (IP，每週Q3D)媒劑（pbs)、人類化抗體、及/或化學療 151681.doc -421 - 201127956 法。在接種後約第1 〇天開始，藉由一對測徑規每週量測腫 瘤兩次，且根據下式計算腫瘤體積：V=LxW2/2(V :體 積，mm3 ; L :長度，mm ; W :寬度，mm)。可見以單獨 或與化學療法組合之mAb處理之動物的腫瘤體積相對於僅 接收媒劑或同型對照mAb之動物的腫瘤有所減小。 實例1.4 :產生DVD-Ig 使用如本文所述選擇之兩個親本單株抗體建構能夠結合 兩個抗原之DVD-Ig分子，一個親本抗體針對人類抗原A， 且另一親本抗體針對人類抗原B。 實例1.4.1 :產生具有兩個連接子長度之DVD-Ig 使用含有在234及235處具有突變以消除ADCC/CDC效應 功能之μΐ Fc的恆定區。產生四種不同抗A/B DVD-Ig構築 體：2種具有短連接子且2種具有長連接子，各為兩種不同 區域定向：VA-VB-C及VB-VA-C(參看表50)。來源於人類 Cl/Ck或CH1區域之N末端序列的連接子序列如下： 對於DVDAB構築體.：.
輕鏈（若抗A具有λ):短連接子：QPKAAP ;長連接子： QPKAAPSVTLFPP
輕鏈（若抗Α具有κ):短連接子：TVAAP ;長連接子： TVAAPSVFIFPP
重鏈（γΐ):短連接子：ASTKGP ;長連接子： ASTKGPSVFPLAP 對於DVDBA構築體： . 輕鏈（若抗Β具有λ):短連接子：QPKAAP ;長連接子： 151681.doc -422· 201127956
QPKAAPSVTLFPP
輕鏈（若抗B具有k):短連接子：TVAAP ;長連接子： TVAAPSVFIFPP
重鏈（γΐ):短連接子：ASTKGP ;長連接子： ASTKGPSVFPLAP 重鏈及輕鏈構築體經次選殖至pBOS表現載體中，且表 現於COS細胞中，隨後藉由蛋白質A層析純化。對經純化 ^ 物質進行SDS-PAGE及SEC分析。 表50描述用於表現各抗A/B DVD-Ig蛋白的重鏈及轉鏈構 築體。 表50 :抗A/B DVD-Ig構築體
DVD-Ig蛋白 重鏈構築體 輕鏈構築體 DVDABSL DVDABHC-SL DVDABLC-SL DVDABLL DVDABHC-LL DVDABLC-LL DVDBASL DVDBAHC-SL DVDBALC-SL DVDBALL DVDBAHC-LL DVDBALC-LL 實例1.4.2 :針對DVDABSL及DVDABLL之DNA構築體分 子選殖： 為了產生重鏈構築體DVDABHC-LL及DVDABHC-SL， 使用特定引子（對於SL/LL構築體而言，3’引子分別含有短/ 長連接子序列）來PCR擴增A抗體之VH區域；同時使用特定 引子（對於SL/LL構築體而言，5’引子分別含有短/長連接子 序列）來擴增B抗體之VH區域。兩個PCR反應皆根據標準 PCR技術及程序進行。兩個PCR產物經凝膠純化，且一起 用作用於後續重疊PCR反應之重疊模板。藉由使用標準同 源重組法將重疊PCR產物次選殖至Srf I及Sal I雙重消化 151681.doc •423· 201127956 pBOS-hCyl，z非a哺乳動物表現載體（Abbott)中。 為了產生輕鏈構築體DVDABLC-LL及DVDABLC-SL，使 用特定引子（對於SL/LL構築體而言，3'引子分別含有短/長 連接子序列）來PCR擴增A抗體之VL區域；同時使用特定引 子（對於SL/LL構築體而言，5J丨子分別含有短/長連接子序 列）來擴增B抗體之VL區域。兩個PCR反應皆根據標準PCR 技術及程序進行。兩個PCR產物經凝膠純化，且一起用作 用於使用標準PCR條件進行之後續重疊PCR反應之重疊模 板。藉由使用標準同源重組法將重疊PCR產物次選殖至Srf I及Not I雙重消化pBOS-hCk哺乳動物表現載體（Abbott) 中。已使用類似方法產生如下所述之DVDBASL及 DVDBALL： 實例1.4.3 : DVDBASL及DVDBALL之DNA構築體分子選殖 為了產生重鏈構築體DVDBAHC-LL及DVDBAHC-SL， 使用特定引子（對於SL/LL構築體而言，3'引子分別含有短/ 長連接子序列）來PCR擴增抗體B之VH區域；同時使用特定 引子（對於SL/LL構築體而言，5'引子分別含有短/長連接子 序列）來擴增抗體A之VH區域。兩個PCR反應皆根據標準 PCR技術及程序進行。兩個PCR產物經凝膠純化，且一起 用作用於使用標準PCR條件進行之後續重疊PCR反應之重 疊模板。藉由使用標準同源重組法將重疊PCR產物次選殖 至Srf I及Sal I雙重消化pBOS-hCyl，z非a哺乳動物表現載體 (Abbott)中。 為了產生輕鏈構築體DVDBALC-LL及DVDBALC-SL，使 151681.doc •424- 201127956 用特定引子（對於SL/LL構築體而言，3'引子分別含有短/長 連接子序列）來PCR擴增抗體B之VL區域；同時使用特定引 子（對於SL/LL構築體而言，5’引子分別含有短/長連接子序 列）來擴增抗體A之VL區域。兩個PCR反應皆根據標準PCR 技術及程序進行。兩個PCR產物經凝膠純化，且一起用作 用於使用標準PCR條件進行之後續重疊PCR反應之重疊模 板。藉由使用標準同源重組法將重疊PCR產物次選殖至Srf I及Not I雙重消化pBOS-hCk哺乳動物表現載體（Abbott) 中〇 實例1.4.4 :額外DVD-Ig之建構及表現 實例1.4.4.1:製備DVD-Ig載體構築體 可藉由如上文所述製備融合瘤獲得或可藉由定序已知抗 體蛋白質或核酸獲得併入DVD-Ig中之識別特定抗原或其 抗原決定基之特定抗體的親本抗體胺基酸序列。此外，已 知序列可自文獻獲得。可用該等序列藉由使用標準DNA合 成或擴增技術且使用標準重組DNA技術將所要抗體片段組 裝至表現載體中來合成核酸以供在細胞中表現。 舉例而言，自胺基酸序列測定核酸密碼子且藉由Blue Heron Biotechnology, Inc. (w ww.blueheronbio.com) Both ell, WA USA合成寡核苷酸DNA。將寡核苷酸組裝至300至 2,000個鹼基對雙股DNA片段中，選殖至質體載體中且驗 證序列。使用酶促方法組裝經選殖片段產生全基因且次選 殖至表現載體中。（參看 7,306,914 ; 7,297,541 ; 7,279,159 ; 7,150,969 ； 20080115243 ； 20080102475 ； 20080081379 ； 151681.doc -425 - 201127956 20080075690 ； 20080063780 ； 20080050506 ； 20080038777 ； 20080022422 ； 20070289033 ； 20070287170 ； 20070254338 ； 20070243194 ； 20070225227 ； 20070207171 ； 20070150976 ； 20070135620 ； 20070128190 ； 20070104722 ； 20070092484 ； 20070037196 ； 20070028321 ； 20060172404 ； 20060162026 ； 20060153791 ; 20030215458 ; 20030157643)。 將pHybE載體之組（美國專利申請案第61/021，282號）用於 親本抗體及DVD-Ig選殖。使用源自pJP183; pHybE-hCgl，z， 非-a V2之VI選殖具有野生型恆定區之抗體及DVD重鏈。 將源自pJP191; pHybE-hCk V2之V2用於選殖具有κ恆定區 之抗體及DVD輕鏈。使用源自pJP192; pHybE-hCl V2之V3 選殖具有λ恆定區之抗體及DVD輕鏈。使用以λ信號肽及κ 恆定區構造之V4選殖具有λ-κ雜交V區域之DVD輕鏈。使 用以κ信號肽及λ恆定區構造之V5選殖具有κ-λ雜交V區域之 DVD輕鏈。使用源自 pJP183; pHybE-hCgl，z，非-a V2之 V7 選殖具有（234,235 AA)突變恆定區之抗體及DVD重鏈。 參看表51，許多載體用於選殖親本抗體以及DVD-Ig VH 及VL鏈。 表51:用於選殖親本抗體及DVD-Ig之載體 ID 重鏈載體 輕鏈載體 AB001 VI V2 AB002 VI V2 AB003 VI V2 AB004 VI V2 AB005 VI V2 AB006 VI V2 AB007 VI V3 AB008 VI V2 151681.doc -426- 201127956
ID 重鏈載體 輕鏈載體 AB009 VI V2 ABO 10 VI V3 ABO 11 VI V2 AB012 VI V2 AB013 VI V2 ABO 14 VI V2 ABO 15 VI V2 AB016 VI V2 AB033 VI V2 AB034 VI V2 AB035 VI V2 AB039 VI V2 AB047 VI V2 AB062 VI V2 AB063 VI V2 AB067 V7 V3 AB069 VI V2 AB070 VI V2 AB071 V7 V2 AB072 VI V2 AB073 VI V3 AB074 VI V2 AB075 VI V3 AB077 VI V2 AB079 VI V2 AB080 VI V2 DVD001 VI V2 DVD002 VI V2 DVD003 VI V2 DVD004 VI V2 DVD005 VI V5 DVD006 VI V4 DVD007 VI V2 DVD008 VI V2 DYD009 VI V2 DVD010 VI V2 DYD011 VI V2 DVD012 VI V2 DVD013 VI V2 DYD014 VI V2 DVD015 VI V2 DVD016 VI V2 DVD017 VI V2 DVD018 VI V2 DYD019 VI V5 DVD020 VI V4 DVD021 VI V2 151681.doc -427- 201127956 ID 重鏈載體 輕鏈載體 DVD022 VI V2 DVD023 VI V2 DVD024 VI V2 DVD025 VI V2 DVD026 VI V2 DVD027 Y1 V2 DVD028 VI V2 DVD029 VI V5 DVD030 VI V4 DVD031 VI V2 DVD032 VI V2 DVD033 Y1 V2 DVD034 Y1 V2 DVD035 VI V2 DVD036 VI V2 DVD037 VI V2 DVD038 VI V2 DVD039 VI V2 DVD040 VI V2 DVD041 VI V5 DVD042 VI V4 DVD043 VI V2 DVD044 VI V2 DVD045 VI V2 DVD046 VI V2 DVD047 VI V2 DVD048 Y1 V2 DVD049 VI V2 DVD050 VI V2 DVD073 VI V2 DVD074 VI V2 DVD075 VI V2 DVD076 VI V2 DVD077 VI V2 DVD078 VI V2 DVD079 VI V2 DVD080 VI V2 DVD081 VI V2 DVD082 VI V2 DVD083 VI V2 DVD084 VI V2 DVD085 VI V2 DVD086 VI V2 DVD087 VI V2 DVD088 VI V2 DVD089 VI V2 DVD090 VI V2
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IlD 重鏈載體 輕鏈載體 DVD091 VI V2 DVD092 VI V2 DVD093 VI V2 DVD094 VI V2 DVD 107 VI V2 DVD 108 VI V2 DVD131 VI V2 DVD 132 VI V2 DVD135 VI V2 DVD 136 VI V2 DVD 137 VI V2 DVD138 VI V2 DVD 139 VI V2 DVD 140 VI V2 DVD141 VI V2 DVD 142 VI V2 DVD 143 VI V2 DVD 144 VI V2 DVD257 VI V2 DVD258 VI V2 DVD259 VI V2 DVD260 VI V2 DVD299 VI V2 DVD300 VI V2 DVD301 VI V2 DVD302 VI V2 DVD303 VI V2 DVD304 VI V2 DVD305 VI V2 DVD306 VI V2 DVD307 VI V2 DVD308 VI V2 DVD309 VI V2 DVD310 VI V2 DVD385 VI V2 DVD386 VI V2 DVD387 V7 V2 DVD388 VI V2 DVD389 VI V2 DVD390 VI V2 DVD391 V7 V2 DVD392 VI V2 DVD393 VI V2 DVD394 VI V2 DVD395 VI V2 DVD396 VI V2 DVD397 VI V2 151681.doc -429- 201127956 ID 重鏈載體 輕鏈載體 DVD398 VI V2 DVD399 VI V2 DVD400 VI V2 DVD401 VI V2 DVD402 VI V2 DVD403 VI V2 DVD404 VI V2 DVD405 VI V2 DVD406 VI V2 DVD407 VI V2 DVD408 VI V2 DVD409 VI V4 DVD410 VI V5 DVD411 VI V4 DVD412 VI V5 DVD413 VI V4 DVD414 V7 V5 DVD415 VI V4 DVD416 VI V5 DVD417 VI V4 DVD418 V7 V5 DVD419 VI V4 DVD420 VI V5 DVD421 VI V4 DVD422 VI V5 DVD423 VI V4 DVD424 VI V5 DVD441 VI V2 DVD442 VI V2 DVD443 VI V2 DVD444 VI V2 DVD445 VI V2 DVD446 VI V2 DVD447 VI V2 DVD448 VI V2 DVD449 VI V2 DVD450 VI V2 DVD451 V7 V2 DVD452 V7 V2 DVD453 VI V2 DVD454 VI V2 DVD455 VI V2 DVD456 VI V2 DVD457 V7 V2 DVD458 V7 V2 DVD459 VI V2 DVD460 VI V2
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IlD 重鏈載體 輕鏈載體 DVD461 VI V2 DVD462 VI V2 DVD463 VI V2 DVD464 VI V2 DVD465 VI V2 DVD466 VI V2 DVD467 VI V2 DVD468 VI V2 DVD469 VI V2 DVD470 VI V2 DVD471 V7 V2 DVD472 VI V2 DYD473 VI V2 DVD474 VI V2 DYD475 VI V2 DVD476 VI V2 DVD477 V7 V2 DVD478 VI V2 DVD479 VI V2 DVD480 VI V2 DVD481 VI V2 DVD482 VI V2 DVD483 VI V2 DVD484 VI V2 DVD485 VI V2 DYD486 VI V2 DVD487 VI V2 DVD488 VI V2 DVD489 V7 V2 DVD490 VI V2 DVD491 VI V2 DVD492 VI V2 DYD493 VI V2 DVD494 VI V2 DVD495 VI V2 DVD496 VI V2 DVD497 VI V2 DVD498 VI V2 DVD499 VI V2 DVD500 VI V2 DVD501 VI V2 DYD502 VI V2 DVD503 VI V2 DYD504 VI V2 DVD505 VI V2 DVD506 VI V2 DVD507 V7 V2 151681.doc -431 - 201127956 ID 重鏈載體 輕鏈載體 DVD508 VI V2 DVD509 VI V2 DVD510 VI V2 DVD511 VI V4 DVD512 V7 V5 DVD513 VI V4 DVDS 14 VI V5 DVD515 VI V4 DVD516 VI V5 DVD517 VI V4 DVD518 VI V5 DVD519 VI Y4 DVD520 VI V5 DVD521 V7 V4 DVD522 V7 V5 DVD523 VI V4 DVD524 VI V5 DVD525 VI V4 DVD526 VI V5 DVD527 VI V4 DVD528 VI V5 DVD529 VI V4 DVD530 V7 V5 DVD531 VI V4 DVD532 VI V5 DVD533 V7 V4 DVD534 V7 V5 DVD535 VI V2 DVD536 VI V2 DVD537 VI V2 DVD538 VI V2 DVD539 VI V2 DVD540 VI V2 DVD541 VI V2 DVD542 VI V2 DVD543 VI V2 DVD544 VI V2 DVD545 VI V2 DVD546 VI V2 DVD547 VI V2 DVD548 VI V2 DVD549 VI V2 DVD550 VI V2 DVD551 VI V2 DVD552 VI V2 DVD553 VI V2 DVD554 VI V2
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IlD 重鏈載體 輕鏈載體 DVD555 VI V2 DVD556 VI V2 DVD557 VI V2 DVD558 VI V2 DVD559 VI V2 DVD560 VI V2 DVD561 VI V2 DVD562 VI V2 DVD563 VI V2 DVD564 VI V2 DVD565 VI V2 DVD566 VI V2 DVD567 VI V2 DVD568 VI V2 DVD569 VI V2 DVD570 VI V2 DVD571 VI V2 DVD572 VI V2 DVD573 VI V2 DVD574 VI V2 DVD575 VI V2 DVD576 VI V2 DVD577 VI V2 DVD578 VI V2 DVD579 VI V2 DVD580 VI V2 DVD581 VI V2 DVD582 VI V2 DVD583 VI V2 DVD584 VI V2 DVD585 VI V2 DVD586 VI V2 DVD587 VI V2 DVD588 VI V2 DVD589 VI V2 DVD590 VI V2 DVD591 VI V2 DVD592 VI V2 DVD593 VI V2 DVD594 VI V2 DVD595 VI V2 DVD596 VI V2 DVD597 VI V2 DVD598 VI V2 DVD599 VI V2 DVD600 VI V2 DVD601 VI V2 151681.doc -433 - 201127956
IlD 重鏈載體 輕鏈載體 DVD602 VI V2 DVD603 VI V4 DVD604 VI V5 DVD605 VI V4 DVD606 VI V5 DVD607 VI V4 DVD608 VI V5 DVD609 VI V4 DVD610 VI V5 DVD611 VI V2 DVD612 VI V2 DVD613 VI V2 DVD614 VI V2 DVD615 VI V2 DVD616 VI V2 DVD625 VI V2 DVD626 Y1 V2 DYD627 VI V2 DVD628 VI V2 DVD629 Y1 V2 DVD630 VI V2 DVD631 VI V2 DVD632 VI V2 DVD641 VI V2 DVD642 VI V2 DVD643 VI V2 DVD644 VI V2 DVD645 VI V2 DVD646 VI V2 DVD647 VI V2 DVD648 VI V2 DVD649 VI V2 DVD650. VI V2 DVD651 VI V2 DVD652 VI V2 DVD653 VI V2 DVD654 VI V2 DVD655 VI V2 DVD656 VI V2 DVD657 VI V2 DVD658 VI V2 DVD659 VI V2 DVD660 VI V2 DVD661 Y1 V2 DVD662 VI V2 DVD663 VI V2 DVD664 VI V2
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ID 重鏈載體 輕鏈載體 DVD665 VI V2 DVD666 VI V2 DVD667 VI V2 DVD668 VI V2 DVD669 VI V2 DVD670 VI V2 DVD671 VI V2 DVD672 VI V2 DVD673 VI V2 DVD674 VI V2 DVD675 VI V2 DVD676 VI V2 DVD677 VI V2 DVD678 VI V2 DVD679 VI V2 DVD680 VI V2 DVD681 VI V2 DVD682 VI V2 DVD683 VI V2 DVD684 VI V2 DVD685 VI V2 DVD686 VI V2 DVD687 VI V2 DVD688 VI V2 DVD689 VI V2 DVD690 VI V2 DVD691 VI V2 DVD692 VI V2 DVD693 VI V2 DVD694 VI V2 DVD709 VI V2 DVD710 VI V2 DVD711 VI V2 DVD712 VI V2 實例1.4.4.2 :在293細胞中轉染及表現 將DVD-Ig載體構築體轉染至293細胞中以產生DVD-Ig蛋 白質。所用之293短暫轉染程序為Durocher等人（2002) Nucleic Acids Res. 30(2): E9及 Pham 等人（2005) Biotech. Bioengineering 90(3): 332-44中公開之方法的修改形式。 轉染中所用之試劑包括： 151681.doc -435 - 201127956 •在拋棄式錐形瓶中在設定為130 rpm、37°C及5% C02之 含濕氣培育箱中培養HEK 293-6E細胞（穩定表現EBNA1 之人類胚胎腎細胞株；自National Research Council Canada獲得）。 •培養基：FreeStyle 293 表現培養基（Invitrogen 12338-018)加 25 pg/mL 遺傳黴素（geneticin)(G418)(Invitrogen 1013 1-027)及 〇·ι% piuronic F-68(Invitrogen 24040-032)。 •轉染培養基：Freestyle 293表現培養基加10 mM HEPES(Invitrogen 15630-080)。 •聚伸乙基亞胺（PEI)儲備液：以線性25 kDa PEI (Poly sciences)製備且於低於-15 °C下儲存之1 mg/mL 無菌儲備溶液，pH 7.0。 •姨化蛋白饋料培養基：膜化蛋白Nl(Organotechnie, 19554)於FreeStyle 293表現培養基中之5 w/v%無菌儲備 液。 用於轉染之細胞製備：在轉染之前約2至4小時，藉由離心 採集HEK 293-6E細胞，且以每毫升約1，000,000個活細胞
之細胞密度再懸浮於培養基中。對於每次轉染，將40 mL 細胞懸浮液轉移至250 mL拋棄式錐形瓶中且培育2至4小 時。 轉染：將轉染培養基及PEI儲備液預升溫至室溫（RT)。對 於每次轉染，將25 pg質體DNA與50 pg聚伸乙基亞胺（PEI) 在5 mL轉染培養基中合併，且在室溫下培育15至20分鐘以 151681.doc •436- 201127956 形成DNA:PEI複合物。對於BR3-Ig轉染，每次轉染使用25 pg BR3-Ig質體。將各5 mL DNA:PEI複合混合物添加至40 mL先前製備之培養物中，且放回設定為130 rpm，37°C及 5% C02之含濕氣培育箱中。在20至28小時之後，向各轉染 中添加5 mL胰化蛋白饋料培養基且繼續培養6天。 表52含有親本抗體或DVD-Ig構築體之產量數據，表示 為每公升293細胞中的毫克數。 表52 :親本抗體及DVD-Ig構築體於293細胞中之短暫表現 產量
親本抗體或 N末端可變區域 C末端可變區域 表現產量(mg/L) DVD-Ig ID (VD) (VD) AB006 CD-19 9.4 AB001 CD-20 90.2 DVD001 CD-20 CD-19 5.8 DVD002 CD-19 CD-20 2.4 AB001 CD-20 90.2 AB002 CD-3 67.2 DVD003 CD-20 CD-3 4.2 DVD004 CD-3 CD-20 7.4 AB007 CD-80 9.6 AB001 CD-20 90.2 DVD005 CD-20 CD-80 35.4 DVD006 CD-80 CD-20 43.4 AB008 CD-22 50 AB001 CD-20 90.2 DVD007 CD-20 CD-22 0.8 DVD008 CD-22 CD-20 0.22 AB009 CD-40 36.6 AB001 CD-20 90.2 DVD009 CD-20 CD-40 2.6 DVD010 CD-40 CD-20 8 AB002 CD-3 67.2 AB004 HER-2 108.2 DVD011 CD-3 HER-2 30.6 DVD012 HER-2 CD-3 74 AB002 CD-3 67.2 AB006 CD-19 9.4 DVD013 CD-3 CD-19 12.4 DVD014 CD-19 CD-3 7.2 151681.doc -437- 201127956
親本抗體或 DVD-Ig ID N末端可變區域 (VD) c末端可變區域 (VD) 表現產量(mg/L) AB033 EGFR 44.4 AB004 HER-2 108.2 DVD015 EGFR HER-2 42.2 DVD016 HER-2 EGFR 17 AB002 CD-3 67.2 AB033 EGFR 44.4 DVD017 EGFR CD-3 9.6 DVD018 CD-3 EGFR 4 AB033 EGFR 44.4 ABO 11 IG] 71R 28.5 DVD021 EGFR IGF1R 10.4 DVD022 IGF1R EGFR 17.8 AB005 RON 67.4 AB033 EGFR 44.4 DVD024 RON EGFR 19.2 DVD023 EGFR RON 17.8 AB033 EGFR 44.4 AB012 HGF 22.8 DVD025 EGFR HGF 5.8 DVD026 HGF EGFR 2.2 AB004 HER-2 108.2 ABO 10 IGF 1,2 38.6 DVD029 HER-2 IGF 1,2 74.4 DVD030 IGF1，2 HER-2 26.8 AB004 HER-2 108.2 ABO 11 IGI 71R 28.5 DVD031 HER-2 IGF1R 95 DVD032 IGF1R HER-2 41.4 AB005 RON 67.4 AB012 HGF 22.8 DVD033 RON HGF 29.4 DVD034 HGF RON 7.8 ABO 14 VEGF 52.4 AB033 EGFR 44.4 DVD035 VEGF EGFR 6.4 DVD036 EGFR VEGF 5.4 AB014 VEGF 52.4 AB004 HER-2 108.2 DVD037 VEGF HER-2 43.4 DVD038 HER-2 VEGF 41.2 AB001 CD-20 57 AB014 VEGF 52.4 DVD039 VEGF CD-20 0.22 DVD040 CD-20 VEGF 0.48 AB014 VEGF 52.4 AB010 IGF 1,2 38.6 DVD041 VEGF IGF 1,2 39.4 DVD042 IGF 1,2 VEGF 8.8 151681.doc •438- 201127956 親本抗體或 DVD-Ig ID N末端可變區域 (VD) C末端可變區运厂 (VD) 表現產量(mg/L) AB015 DLL-4 57.6 AB014 VEGF 52.4 DVD044 DLL4 VEGF 5.4 DVD043 VEGF DLL4 17.4 AB014 VEGF 52.4 AB012 HGF 22.8 DVD045 VEGF HGF 4 DVD046 HGF VEGF 1.4 AB005 RON 67.4 AB014 VEGF 52.4 DVD048 RON VEGF 14 DVD047 VEGF RON r 18 AB014 VEGF 52.4 ABO 16 NRP1 114.6 DVD049 VEGF NRP1 13 DVD050 NRP1 VEGF 27.2 ABO 15 DLL-4 57.6 AB047 P1GF 23.6 DVD257 DLL4 P1GF 31.2 DVD258 P1GF DLL4 21 AB014 VEGF 52.4 AB047 P1GF 23.6 DVD259 VEGF P1GF 2.2 DVD260 P1GF VEGF 7.8 AB062 ErbB3 24.6 AB033 EGFR 44.4 DVD299 ErbB3 EGFR 4.2 DVD300 EGFR ErbB3 1.6 AB063 ErbB3 37.8 AB033 EGFR 44.4 DVD305 ErbB3 EGFR 5.6 DVD306 EGFR ErbB3 11.2
所有DVD在293細胞中均良好表現。DVD可輕易地經蛋 白質A管柱純化。在多數情形中，可自293細胞之上清液輕 易地獲得>5 mg/L經純化DVD-Ig。 表53 : VEGF/DLL4 DVD-Ig構築體於293細胞中之短暫表 現產量 DVD ID 序列ID 位置 HC連接子 LC連接子 其他DVD區域 表現產量 (mg/L) DVD043 VEGF(序列U N-term. 短 短 DLL4(序列 1) 17.4 DVD044 VEGF(序列D C-term. 短 短 DLL4(序列 1) 5.4 151681.doc -439- 201127956 DVD ID 序列ID 位置 HC連接子 LC連接子 其他DVD區域 表現產量 (mg/L) DVD469 VEGF(序列 1) C-term. 長 長 DLL4(序列 1) 1.6 DVD470 VEGF(序列 1) N-term. 長 長 DLL4(序列 1) 9.2 DVD475 VEGF(序列 1) C-term. 長 短 DLL4(序列 1) 6.2 DVD476 VEGF(序列 1) N-term. 長 短 DLL4(序列 1) 18.2 DVD481 VEGF(序列 1) C-term. 短 長 DLL4(序列 1) 0.9 DVD482 VEGF(序列 1) N-term. 短 長 DLL4(序列 1) 16.8 DVD467 VEGF(序列 2) C-term. 短 短 DLL4(序列 1) 2.4 DVD468 VEGF(序列 2) N-term. 短 短 DLL4(序列 1) 83.6 DVD473 VEGF(序列 2) C-term. 長 長 DLL4(序列 1) 1.8 DVD474 VEGF(序列 2) N-term. 長 長 DLL4(序列 1) 67.8 DVD479 VEGF(序列 2) C-term. 長 短 DLL4(序列 1) 0.8 DVD480 VEGF(序列 2) N-term. 長 短 DLL4(序列 1) 70.2 DVD485 VEGF(序列 2) C-term. 短 長 DLL4(序列 1) 2.6 DVD486 VEGF(序列 2) N-term. 短 長 DLL4(序列 1) 62.6 DVD465 VEGF(序列 3) C-term. 短 短 DLL4(序列 1) 22.4 DVD466 VEGF(序列 3) N-term. 短 短 DLL4(序列 1) 2.7 DVD471 VEGF(序列 3) C-term. 長 長 DLL4(序列 1) 10.6 DVD472 VEGF(序列 3) N-term. 長 長 DLL4(序列 1) 1.4 DVD477 VEGF(序列 3) C-term. 長 短 DLL4(序列 1) 18.2 DVD478 VEGF(序列 3) N-term. 長 短 DLL4(序列 1) 3.2 DVD483 VEGF(序列 3) C-term. 短 長 DLL4(序列 1) 13.6 DVD484 VEGF(序列 3) N-term. 短 長 DLL4(序列 1) 2.4 DVD441 VEGF(序列 1) C-term. 短 短 DLL4(序列 2) 9.2 DVD442 VEGF(序列 1) N-term. 短 短 DLL4(序列 2) 4.4 DVD447 VEGF(序列 1) C-term. 長 長 DLL4(序列 2) 9.2 DVD448 VEGF(序列 1) N-term. 長 長 DLL4(序列 2) 2.8 DVD453 VEGF(序列 1) C-term. 長 短 DLL4(序列 2) 5.0 DVD454 VEGF(序列 1) N-term. 長 短 DLL4(序列 2) 5.4 DVD459 VEGF(序列 1) C-term. 短 長 DLL4(序列 2) 12.0 DVD460 VEGF(序列 1) N-term. 短 長 DLL4(序列 2) 4.6 DVD445 VEGF(序列 2) C-term. 短 短 DLL4(序列 2) 40.0 DVD446 VEGF(序列 2) N-term. 短 短 DLL4(序列 2) 29.8 DVD451 VEGF(序列 2) C-term. 長 長 DLL4(序列 2) 35.0 DVD452 VEGF(序列 2) N-term. 長 長 DLL4(序列 2) 18.0 DVD457 VEGF(序列 2) C-term. 長 短 DLL4(序列 2) 46.8 DVD458 VEGF(序列 2) N-term. 長 短 DLL4(序列 2) 29.6 DVD463 VEGF(序列 2) C-term. 短 長 DLL4(序列 2) 37.6 DVD464 VEGF(序列 2) N-term. 短 長 DLL4(序列 2) 11.0 DVD443 VEGF(序列 3) C-term. 短 短 DLL4(序列 2) 40.4 DVD444 VEGF(序列 3) N-term. 短 短 DLL4(序列 2) 1.1 DVD449 VEGF(序列 3) C-term. 長 長 DLL4(序列 2) 31.6 DVD450 VEGF(序列 3) N-term. 長 長 DLL4(序列 2) 0.7 DVD455 VEGF(序列 3) C-term. 長 短 DLL4(序列 2) 62.6 DVD456 VEGF(序列 3) N-term. 長 短 DLL4(序列 2) 1.8 DVD461 VEGF(序列 3) C-term. 短 長 DLL4(序列 2) 42.0 DVD462 VEGF(序列 3) N-term. 短 長 DLL4(序列 2) 1.0 DVD511 VEGF(序列 1) C-term. 短 短 DLL4(序列 3) 7.8 DVD512 VEGF(序列 1) N-term. 短 短 DLL4(序列 3) 9.0 DVD517 VEGF(序列 1) C-term. 長 長 DLL4(序列 3) 8.2 DVD518 VEGF(序列 1) N-term. 長 長 DLL4(序列 3) 0.3 DVD523 VEGF(序列 1) C-term. 長 短 DLL4(序列 3) 9.4 • 440- 151681.doc 201127956
DVD ID 序列ID 位置 HC連接子 LC連接子 其他DVD區域 表現產量 (mg/L) DVD524 VEGF(序列 1) N-term. 長 短 DLL4(序列 3) 3.2 DVD529 VEGF(序列 1) C-term. 短 長 DLL4(序列 3) 12.4 DVD530 VEGF(序列 1) N-term. 短 長 DLL4(序列 3) 3.0 DVD515 VEGF(序列 2) C-term. 短 短 DLL4(序列 3) 24.0 DVD516 VEGF(序列 2) N-term. 短 短 DLL4(序列 3) 58.6 DVD521 VEGF(序列 2) C-term. 長 長 DLL4(序列 3) 43.4 DVD522 VEGF(序列 2) N-term. 長 長 DLL4(序列 3) 43.4 DVD527 VEGF(序列 2) C-term. 長 短 DLL4(序列 3) 33.0 DVD528 VEGF(序列 2) N-term. 長 短 DLL4(序列 3) 55.6 DVD533 VEGF(序列 2) C-term. 短 長 DLL4(序列 3) 40.8 DVD534 VEGF(序列 2) N-term. 短 長 DLL4(序列 3) 24.8 DVD513 VEGF(序列 3) C-term. 短 短 DLL4(序列 3) 29.6 DVD514 VEGF(序列 3) N-term. 短 短 DLL4(序列 3) 2.0 DVD519 VEGF(序列 3) C-term. 長 長 DLL4(序列 3) 9.0 DVD520 VEGF(序列 3) N-term. 長 長 DLL4(序列 3) 1.0 DVD525 VEGF(序列 3) C-term. 長 短 DLL4(序列 3) 26.8 DVD526 VEGF(序列 3) N-term. 長 短 DLL4(序列 3) 1.2 DVD531 VEGF(序列 3) C-term. 短 長 DLL4(序列 3) 20.2 DVD532 VEGF(序列 3) N-term. 短 長 DLL4(序列 3) 1.6 DVD487 VEGF(序列 1) C-term. 短 短 DLL4(序列 4) 2.1 DVD488 VEGF(序列 1) N-term. 短 短 DLL4(序列 4) 6.6 DVD493 VEGF(序列 1) C-term. 長 長 DLL4(序列 4) 10.4 DVD494 VEGF(序列 1) N-term. 長 長 DLL4(序列 4) 0.4 DVD499 VEGF(序列 1) C-term. 長 短 DLL4(序列 4) 12.2 DVD500 VEGF(序列 1) N-term. 長 短 DLL4(序列 4) 7.4 DVD505 VEGF(序列 1) C-term. 短 長 DLL4(序列 4) 6.2 DVD506 VEGF(序列 1) N-term. 短 長 DLL4(序列 4) 4.0 DVD491 VEGF(序列 2) C-term. 短 短 DLL4(序列 4) 18.2 DVD492 VEGF(序列 2) N-term. 短 短 DLL4(序列 4) 54.6 DVD497 VEGF(序列 2) C-term. 長 長 DLL4(序列 4) 8.6 DVD498 VEGF(序列 2) N-term. 長 長 DLL4(序列 4) 28.0 DVD503 VEGF(序列 2) C-term. 長 短 DLL4(序列 4) 20.0 DVD504 VEGF(序列 2) N-term. 長 短 DLL4(序列 4) 49.0 DVD509 VEGF(序列 2) C-term. 短 長 DLL4(序列 4) 14.2 DVD510 VEGF(序列 2) N-term. 短 長 DLL4(序列 4) 28.8 DVD489 VEGF(序列 3) C-term. 短 短 DLL4(序列 4) 14.8 DVD490 VEGF(序列 3) N-term. 短 短 DLL4(序列 4) 2.4 DVD495 VEGF(序列 3) C-term. 長 長 DLL4(序列 4) 4.8 DVD496 VEGF(序列 3) N-term. 長 長 DLL4 (seq. 4) 0.6 DVD501 VEGF(序列 3) C-term. 長 短 DLL4 (seq. 4) 20.2 DVD502 VEGF(序列 3) N-term. 長 短 DLL4 (seq. 4) 0.9 DVD507 VEGF(序列 3) C-term. 短 長 DLL4 (seq. 4) 5.8 DVD508 VEGF(序列 3) N-term. 短 長 DLL4 (seq. 4) 0.7 所有DVD在293細胞中均良好表現。DVD可輕易地經蛋 白質A管柱純化。在多數情形中，可自293細胞之上清液輕 易地獲得>5 mg/L經純化DVD-Ig。 -441 151681.doc 201127956 實例1.4.5 : A/B DVD-Ig之表徵及前導選擇 在Biacore上針對蛋白質A及蛋白質B分析抗A/B DVD-Ig 之結合親和力。藉由Biacore上之多次結合研究檢驗DVD-Ig之四價特性。同時，分別藉由如本文所述之生物檢定評 定DVD-Ig針對蛋白質A及蛋白質B之中和效能。選擇最佳 保留初始親本mAb之親和力及效能之DVD-Ig分子用於如本 文所述對各mAb的深入物理化學及生物分析（大鼠PK)表 徵。基於分析之集合，使最終前導DVD-Ig進入CHO穩定 細胞株發展中，且來源於CHO之物質用於食蟹猴中之穩定 性、藥物動力學及功效研究，及預調配活性。 實例2:產生及表徵雙重可變區域免疫球蛋白（DVD-Ig) 根據實例1.4.4.1藉由合成編碼DVD-Ig可變重鏈及DVD-Ig可變輕鏈序列之聚核苷酸片段且將片段選殖至pHybC-D2 載體中，產生使用具有已知胺基酸序列之親本抗體的雙重 可變區域免疫球蛋白（DVD-Ig)。如實例1.4.4.2中所述將 DVD-Ig構築體選殖至且表現於293細胞中。根據標準方法 純化DVD-Ig蛋白。如所指示，根據實例1.1.1及1.1.2所述 之方法確定功能特徵。下文提供用於本發明DVD-Ig之 DVD-Ig VH及 VL鏈。 實例2.1 :產生CD-20 及 CD-19 DVD-Ig 151681.doc -442- 201127956 表54
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 112 DVD001H AB001VH AB006VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLQQSGAELVR PGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWI GQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQL SSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGT SVTVSS 113 DVD001L AB001VL AB006VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPDILLTQTPASLAVSLGQRATISCKASQS VDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIP PRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTED PWTFGGGTKLEIKR 114 DVD002H AB006VH AB001VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPQVQLQQPGAE LVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGL EWIGMYPGNGDTSYNQKFKGKATLTADKSSSTAY MQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGT TVTVSA 115 DVD002L AB006VL AB001VL DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPQIVLSQSPAILSPSPGEKVTMTC RASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVP VRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSN PPTFGGGTKLEIKR
實例 2.2:產生 CD-20及 CD-3(序列 1)DVD-Ig 表55
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 116 DVD003H AB001VH AB002VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLQQSGAELAR PGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWI GYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQL SSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVS S 117 DVD003L AB001VL AB002VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPQIVLTQSPAIMSASPGEKVTMTCRASSS VSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFSG SGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFG SGTKLEINR •443 · 151681.doc 201127956
118 DVD004H AB002VH AB001VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQQPGAELVKPG ASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGA IYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSS LTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS A 119 DVD004L AB002VL AB001VL QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWY QQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSY SLTISSMEAEDAATYYCQQWSSNPLTFGSGTKLEI NRTVAAPQIVLSQSPAILSPSPGEKVTMTCRASSS VSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSG SGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFG GGTKLEIKR 實例 2.3:產生 CD-20及 CD-80 DVD-Ig 表56
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 120 DVD005H AB001VH AB007VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLQESGPGLVK PSETLSLTCAVSGGSISGGYGWGWIRQPPGKGLEW IGSFYSSSGNTYYNPSLKSQVTISTDTSKNQFSLK LNSMTAADTAVYYCVRDRLFSVVGMVYNNWFDVWG PGVLVTVSS 121 DVD005L AB001VL AB007VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPESALTQPPSVSGAPGQKVTISCTGSTSN IGGYDLHWYQQLPGTAPKLLIYDINKRPSGISDRF SGSKSGTAASLAITGLQTEDEADYYCQSYDSSLNA QVFGGGTRLTVLG 122 DVD006H AB007VH AB001VH QVQLQESGPGLVKPSETLSLTCAVSGGSISGGYGW GWIRQPPGKGLEWIGSFYSSSGNTYYNPSLKSQVT ISTDTSKNQFSLKLNSMTAADTAVYYCVRDRLFSV VGMVYNNWFDVWGPGVLVTVSSASTKGPQVQLQQP GAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPG RGLEWIGAIYPGMGDTSYNQKFKGKATLTADKSSS TAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWG AGTTVTVSA 123 DVD006L AB007VL AB001VL ESALTQPPSVSGAPGQKVTISCTGSTSNIGGYDLH WYQQLPGTAPKLLIYDINKRPSGISDRFSGSKSGT AASLAITGLQTEDEADYYCQSYDSSLNAQVFGGGT RLTVLGQPKAAPQIVLSQSPAILSPSPGEKVTMTC RASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVP VRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSN PPTFGGGTKLEIKR
實例 2.4 :產生 CD-20及 CD-22 DVD-Ig -444- 151681.doc 201127956 表57
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 124 DVD007H AB001VH AB008VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLVQSGAEVKK PGSSVKVSCFCASGYTFTSYWLHWVRQAPGQGLEWI GYINPRNDYTEYNQNFKDKATITADESTNTAYMEL SSLRSEDTAFYFCARRDITTFYWGQGTTVTVSS 125 DVD007L AB001VL AB008VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPDIQLTQSPSSLSASVGDRVTMSCKSSQS VLYSANHKNYLAWYQQKPGKAPKLLIYWASTRESG VPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQYL SSWTFGGGTKLEIKR 126 DVD008H AB008VH AB001VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWLH WVRQAPGQGLEWIGYINPRNDYTEYNQNFKDKATI TADESTNTAYMELSSLRSEDTAFYFCARRDITTFY WGQGTTVTVSSASTKGPQVQLQQPGAELVKPGASV KMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYP GNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTS EDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA 127 DVD008L AB008VL AB001VL DIQLTQSPSSLSASVGDRVTMSCKSSQSVLYSANH KNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSG SGSGTDFTFTISSLQPEDIATYYCHQYLSSWTFGG GTKLEIKRTVAAPQIVLSQSPAILSPSPGEKVTMT CRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGV PVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTS NPPTFGGGTKLEIKR
實例 2.5:產生CD-20 及 CD-40 DVD-Ig 表58
SEQ ID No. DVD可變 區域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 128 DVD009H AB001VH AB009VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLVESGGGVVQ PGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWV AVISYEESNRYHADSVKGRFTISRDNSKITLYLQM NSLRTEDTAVYYCARDGGIAAPGPDYWGQGTLVTV SS 129 DVD009L AB001VL AB009VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAED7VATYYCQQWTSNPPTFGGGTKLEI KRTVAAPDIVMTQSPLSLTVTPGEPASISCRSSQS LLYSNGYNYLDWYLQKPGQSPQVLISLGSNRASGV PDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQARQ TPFTFGPGTKVDIRR 445- 151681.doc 201127956
130 DVD010H AB009VH AB001VH QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMH WVRQAPGKGLEWVAVISYEESNRYHADSVKGRFTI SRDNSKITLYLQMNSLRTEDTAVYYCARDGGIAAP GPDYWGQGTLVTVSSASTKGPQVQLQQPGAELVKP GASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIG AIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLS SLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTV SA 131 DVD010L AB009VL AB001VL DIVMTQSPLSLTVTPGEPASISCRSSQSLLYSNGY NYLDWYLQKPGQSPQVLISLGSNRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQARQTPFTFGP GTKVDIRRTVAAPQIVLSQSPAILSPSPGEKVTMT CRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGV PVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTS NPPTFGGGTKLEIKR 實例2.6 :產生CD-3(序列1)及HER-2(序列1)DVD-Ig 表59
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 132 DVD011H AB002VH AB004VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 133 DVDOllL AB002VL AB004VL QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWY QQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSY SLTISSMEAEDAATYYCQQWSSNPLTFGSGTKLEI NRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQD VNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF GQGTKVEIKR 134 DVD012H AB004VH AB002VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQSGAELARP GASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIG YINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLS SLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 135 DVD012L AB004VL AB002VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPQIVLTQSPAIMSASPGEKVTMTCRASS SVSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFS GSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTF GSGTKLEINR
實例 2.7 :產生 CD-3(序列 1)及 CD-19 DVD-Ig 15l6Sl.doc 446 * 201127956 表60
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 136 DVD013H AB002VH AB006VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQQSGAELVRPG SSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQ IWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSS LASEDSAVYE^CARRETTTVGRYYYAMDYWGQGTSV TVSS 137 DVD013L AB002VL AB006VL QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWY QQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSY SLTISSMEAEDAATYYCQQWSSNPLTFGSGTKLEI NRTVAAPDILLTQTPASLAVSLGQRATISCKASQS VDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIP PRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTED PWTFGGGTKLEIKR 138 DVD014H AB006VH AB002VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPQVQLQQSGAE LARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGL EWIGYINPSRGYTNYISIQKFKDKATLTTDKSSSTAY MQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTL TVSS 139 DVD014L AB006VL AB002VL DILLTQTPASLAVSLGQRATISCPCASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPQIVLTQSPAIMSASPGEKVTMTC RASSSVSYMNWYQQKSGTSPKRWIYDTSKVASGVP YRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSN PLTFGSGTKLEINR
實例2.8 :產生EGFR(序列2)及HER-2(序列1)DVD-Ig 表61
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 140 DVD015H AB033VH AB004VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 141 DVD015L AB033VL AB004VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTEOAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR •447- 151681.doc 201127956
142 DVD016H AB004VH AB033VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQP SQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLG VIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNS LQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 143 DVD016L AB004VL AB033VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 實例2.9 :產生EGFR(序列2)及CD-3(序列1)DVD-Ig 表62
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 144 DVD017H AB033VH AB002VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQQSGAELARPG ASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGY INPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSS LTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 145 DVD017L VD033VL AB002VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQIVLTQSPAIMSASPGEKVTMTCRASS SVSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFS GSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTF GSGTKLEINR 146 DVD018H AB002VH AB033VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 147 DVD018L AB002VL AB033VL QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWY QQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSY SLTISSMEAEDAATYYCQQWSSNPLTFGSGTKLEI NRTVAAPDILLTQSPVILSVSPGERVSFSCRASQS IGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFS GSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTF GAGTKLELKR 實例2.10 :產生EGFR(序列2)及 IGF1，2 DVD-Ig 448·
151681.doc 201127956 表63
SEQ ID NO DVD可變 區域名稱 外可變區 域名 内可變區域 名 序列 12345678901234567890123456789012345 148 DVD019H AB033VH AB010VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLVQSGAEVKKPG ASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGW MNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSS LRSEDTAVYYCARDPYYYYYGMDVWGQGTTVTVSS 149 DVD019L AB033VL AB010VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQSVLTQPPSVSAAPGQKVTISCSGSSS NIEMNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDR FSGSKSGTSATLGITGLQTGDEADYYCETWDTSLS AGRVFGGGTKLTVLG 150 DVD020H AB010VH AB033VH QVQLVQSGAEVKKPGASVKVSCiCASGYTFTSYDIN WVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTM TRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYY GMDVWGQGTTVTVSSASTKGPQVQLKQSGPGLVQP SQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLG VIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNS LQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 151 DVD020L AB010VL AB033VL QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVS WYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGT SATLGITGLQTGDEADYYCETWDTSLSAGRVFGGG TKLTVLGQPKAAPDILLTQS PVILSVS PGERVS FS CRASQSIGTNIHWYQQRTNGSPRLLIKYASESISG IPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNN NWPTTFGAGTKLELKR
實例2.11 :產生具有連接子組1之EGFR(序列2)及IGF1R (序列 1)DVD-Ig 表64
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 152 DVD021H AB033VH AB011VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFPGyiNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLLESGGGLVQPG GSLRLSCTASGFTFSSYAMNWVRQAPGKGLEWVSA ISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMNS LRAEDTAVYYCAKDLGWSDSYYYYYGMDVWGQGTT VTVSS 153 DVD021L AB033VL AB011VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQFPSSLSASVGDRVTITCRASQ GIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCS FGQGTKLEIKR -449- 151681.doc 201127956
154 DVD022H AB011VH AB033VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPQVQLKQSGP GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKG LEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVF FKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSA 155 DVD022L AB011VL AB033VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 實例2.12 :產生具有連接子組2之EGFR(序列2)及IGF1R (序列 1)DVD-Ig 表65
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 156 DVD611H AB011VH AB033VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPQV QLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWV RQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKD NSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFA YWGQGTLVTVSA 157 DVD611L AB011VL AB033VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPSVFIFPPDILLTQSPVILSVSPGERVS FSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTTFGAGTKLELKR 158 DVD612H AB033VH AB011VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLLESG GGLVQPGGSLRLSCTASGFTFSSYAMNWVRQAPGK GLEWVSAISGSGGTTFYADSVKGRFTISRDNSRTT LYLQMNSLRAEDTAVYYCAKDLGWSDSYYYYYGMD VWGQGTTVTVSS 159 DVD612L AB033VL AB011VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQFPSSLSASVGDRVT ITCRASQGIRNDLGWYQQKPGKAPKRLIYAASRLH RGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQ HNSYPCSFGQGTKLEIKR
實例2.13 :產生具有連接子組3之EGFR(序列2)及IGF1R (序列 1)DVD-Ig 151681.doc -450- 201127956 表66
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 160 DVD613H AB011VH AB033VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPQV QLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWV RQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKD NSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFA YWGQGTLVTVSA 161 DVD613L AB011VL AB033VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 162 DVD614H AB033VH AB011VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLLESG GGLVQPGGSLRLSCTASGFTFSSYAMNWVRQAPGK GLEWVSAISGSGGTTFYADSVKGRFTISRDNSRTT LYLQMNSLRAEDTAVYYCAKDLGWSDSYYYYYGMD VWGQGTTVTVSS 163 DVD614L AB033VL AB011VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQFPSSLSASVGDRVTITCRASQ GIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCS FGQGTKLEIKR
實例2.14 :產生具有連接子組4之EGFR(序列2)及IGF1R (序列 1)DVD-Ig 表67
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 164 DVD615H AB011VH AB033VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPQVQLKQSGP GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKG LEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVF FKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSA 165 DVD615L AB011VL AB033VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPSVFIFPPDILLTQSPVILSVSPGERVS FSCRASQSIGTMIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTTFGAGTKLELKR •451 · 151681.doc 201127956
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 166 DVD616H AB033VH AB011VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLLESGGGLVQPG GSLRLSCTASGFTFSSYAMNWVRQAPGKGLEWVSA ISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMNS LRAEDTAVYYCAKDLGWSDSYYYYYGMDVWGQGTT VTVSS 167 DVD616L AB033VL AB011VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQFPSSLSASVGDRVT ITCRASQGIRNDLGWyQQKPGKAPKRLIYAASRLH RGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQ HNSYPCSFGQGTKLEIKR 實例2.15 :產生具有連接子組1之EGFR(序列2)及 IGF1R(序列 2)DVD-Ig 表68
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 168 DVD603H AB075VH AB033VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTI TADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLE WSTQDHYYYYYMDVWGKGTTVTVSSASTKGPQVQL KQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQ SPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNS KSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYW GQGTLVTVSA 169 DVD603L AB075VL AB033VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWY QQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTA SLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKL TVLGQPKAAPDILLTQSPVILSVSPGERVSFSCRA SQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWP TTFGAGTKLELKR 170 DVD604H AB033VH AB075VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGAEVKKPG SSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG IIPIFGTANYAQKFQGRVTITADKSTSTAYMELSS LRSEDTAVYYCARAPLRFLEWSTQDHYYYYYMDVW GKGTTVTVSS 171 DVD604L AB033VL AB075VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSSELTQDPAVSVALGQTVRITCQGDSL RSYYATWYQQKPGQAPILVIYGENKRPSGIPDRFS GSSSGNTASLTITGAQAEDEADYYCKSRDGSGQHL VFGGGTKLTVLG
實例2.16 :產生具有連接子組2之EGFR(序列2)及IGF1R -452-
151681.doc 201127956 (序列 2)DVD-Ig 表69
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 172 DVD605H AB075VH AB033VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTI TADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLE WSTQDHYYYYYMDVWGKGTTVTVSSASTKGPSVFP LAPQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNY GVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRL SINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYY DYEFAYWGQGTLVTVSA 173 DVD605L AB075VL AB033VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWY QQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTA SLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKL TVLGQPKAAPSVTLFPPDILLTQSPVILSVSPGER VSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASE SISGIPSP.FSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTTFGAGTKLELKR 174 DVD606H AB033VH AB075VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVQSG AEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQ GLEWMGGIIPIFGTANYAQKFQGRVTITADKSTST AYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYY YYYMDVWGKGTTVTVSS 175 DVD606L AB033VL AB075VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPSSELTQDPAVSVALGQTVRI TCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPS GIPDRFSGSSSGNTASLTITGAQAEDEADYYCKSR DGSGQHLVFGGGTKLTVLG
實例2.17 :產生具有連接子組3之EGFR(序列2)及IGF1R (序列 2)DVD-Ig 表70
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 176 DVD607H AB075VH AB033VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTI TADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLE WSTQDHYYYYYMDVWGKGTTVTVSSASTKGPSVFP LAPQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNY GVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRL SINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYY DYEFAYWGQGTLVTVSA •453- 151681.doc 201127956
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 177 DVD607L AB075VL AB033VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWY QQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTA SLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKL TVLGQPKAAPDILLTQSPVILSVSPGERVSFSCRA SQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWP TTFGAGTKLELKR 178 DVD608H AB033VH AB075VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVQSG AEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQ GLEWMGGIIPIFGTANYAQKFQGRVTITADKSTST AYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYY YYYMDVWGKGTTVTVSS 179 DVD608L AB033VL AB075VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD PTLSINSVESED工ADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSSELTQDPAVSVALGQTVRITCQGDSL RSYYATWYQQKPGQAPILVIYGEMKRPSGIPDRFS GSSSGNTASLTITGAQAEDEADYYCKSRDGSGQHL VFGGGTKLTVLG
實例2.18 :產生具有連接子組4之EGFR(序列2)及IGF1R (序列 2)DVD-Ig 表71
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 180 DVD609H AB075VH AB033VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTI TADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLE WSTQDHYYYYYMDVWGKGTTVTVSSASTKGPQVQL KQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQ SPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNS KSQVFFKMNSLQSNDTAIYYCAElALTyYDYEFAYW GQGTLVTVSA 181 DVD609L AB075VL AB033VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWY QQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTA SLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKL TVLGQPKAAPSVTLFPPDILLTQSPVILSVSPGER VSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASE SISGIPSRFSGSGSGTDFTLSINSVESEDIADYYC QQNNNWPTTFGAGTKLELKR 182 DVD610H AB033VH AB075VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGAEVKKPG SSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG IIPIFGTANYAQKFQGRVTITADKSTSTAYMELSS LRSEDTAVYYCARAPLRFLEWSTQDHYYYYYMDVW GKGTTVTVSS •454- 15I681.doc 201127956 183
DVD610L
AB033VL
AB075VL
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPSSELTQDPAVSVALGQTVRI TCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPS GIPDRFSGSSSGNTASLTITGAQAEDEADYYCKSR DGSGQHLVFGGGTKLTVLG 實例2.19 :產生具有連接子組1之EGFR(序列2)及IGF1R (序列 3)DVD-Ig 表72
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 184 DVD625H AB077VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMH WVRQAPGKGiLEWI SVIDTRGAT YYADS VKGRFTIS RDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGM DVWGQGTTVTVSSASTKGPQVQLKQSGPGLVQPSQ SLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI WSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQ SNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 185 DVD625L AB077VL AB033VL EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHW YQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVE 工KRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 186 DVD626H AB033VH AB077VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGGGLVKPG GSLRLSCAASGFTFSSFAMHWVRQAPGKGLEWISV IDTRGATYYADSVKGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARLGNFYYGMDVWGQGTTVTVSS 187 DVD626L AB033VL AB077VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPEIVLTQSPGTLSVSPGERATLSCRASQ SIGSSLHWYQQKPGQAPRLLIKYASQSLSGIPDRF SGSGSGTDFTLTISRLEPEDFAVYYCHQSSRLPHT FGQGTKVEIKR 實例2.20 :產生具有連接子組2之EGFR(序列2)及IGF1R (序列 3)DVD-Ig 455 - 151681.doc 201127956 表73
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 188 DVD627H AB077VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMH WVRQAPGKGLEWISVIDTRGATYYADSVKGRFTIS RDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGM DVWGQGTTVTVSSASTKGPSVFPLAPQVQLKQSGP GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKG LEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVF FKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSA 189 DVD627L AB077VL AB033VL EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHW YQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVE IKRTVAAPSVFIFPPDILLTQSPVILSVSPGERVS FSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTTFGAGTKLELKR 190 DVD628H AB033VH AB077VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVQSG GGLVKPGGSLRLSCAASGFTFSSFAMHWVRQAPGK GLEWISVIDTRGATYYADSVKGRFTISRDNAKNSL YLQMNSLRAEDTAVYYCARLGNFYYGMDVWGQGTT VTVSS 191 DVD628L AB033VL AB077VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPEIVLTQSPGTLSVSPGERAT LSCRASQSIGSSLHWYQQKPGQAPRLLIKYASQSL SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQ SSRLPHTFGQGTKVEIKR 實例2.21 :產生具有連接子組3之EGFR(序列2)及IGF1R (序列 3)DVD-Ig 表74
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 192 DVD629H AB077VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMH WVRQAPGKGLEWISVIDTRGATYYADSVKGRFTIS RDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGM DVWGQGTTVTVSSASTKGPSVFPLAPQVQLKQSGP GLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKG LEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVF FKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTL VTVSA 456.
151681.doc 201127956
193 DVD629L AB077VL AB033VL EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHW YQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 194 DVD630H AB033VH AB077VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDMSKSQVFFKMNSLQSNDTMYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVQSG GGLVKPGGSLRLSCAASGFTFSSFAMHWVRQAPGK GLEWISVIDTRGATYYADSVKGRFTISRDNAKNSL YLQMNSLPiVEDTAVYYCARLGNFYYGMDVWGQGTT VTVSS 195 DVD630L AB033VL AB077VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVE;SEDIADYYCQQN_WPTTFGAGTKLE LKRTVAAPE1IVLTQSPGTLSVSPGERATLSCRASQ SIGSSLHWYQQKPGQAPRLLIKYASQSLSGIPDRF SGSGSGTDFTLTISRLEPEDFAVYYCHQSSRLPHT FGQGTKVEIKR
實例2.22 :產生具有連接子組4之EGFR(序列2)及IGF1R (序列 3)DVD-Ig 表75
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 196 DVD631H AB077VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSFAMH WVRQAPGKGLEWISVIDTRGATYYADSVKGRFTIS RDNAKNSLYLQMNSLRAEDTAVYYCARLGNFYYGM DVWGQGTTVTVSSASTKGPQVQLKQSGPGLVQPSQ SLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVI WSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQ SNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 197 DVD631L AB077VL AB033VL EIVLTQSPGTLSVSPGERATLSCRASQSIGSSLHW YQQKPGQAPRLLIKYASQSLSGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCHQSSRLPHTFGQGTKVE IKRTVAAPSVFIFPPDILLTQSPVILSVSPGERVS FSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTTFGAGTKLELKR 198 DVD632H AB033VH AB077VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGGGLVKPG GSLRLSCAASGFTFSSFAMHWVRQAPGKGLEWISV IDTRGATYYADSVKGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARLGNFYYGMDVWGQGTTVTVSS 199 DVD632L AB033VL AB077VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPEIVLTQSPGTLSVSPGERAT LSCRASQSIGSSLHWYQQKPGQAPRLLIKYASQSL SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQ SSRLPHTFGQGTKVEIKR -457« 151681.doc 201127956 實例2·23 :產生具有連接子組1之EGFR(序列2)及RON(序 列 1)DVD-Ig 表76
SEQ 1D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 200 DVD023H AB033VH AB005VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGGGLVKPG GSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAV ISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMMS LRAEDTAVYYCARFSGWPNNYYYYGMDVWGQGTTV TVSS 201 DVD023L AB033VL AB005VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDWMTQSPLSLPVTPGEPASISCRSSQ SLLHSNGFNYVDWYLQKPGQSPHLLIYFGSYRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAL QT P PWT FGQGTKVEIRR 202 DVD024H AB005VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPQVQLKQSGPG LVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGL EWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLV TVSA 203 DVD024L AB005VL AB033VL DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPDILLTQSPVILSVSPGERVSF SCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQN NNWPTTFGAGTKLELKR
實例2.24 :產生具有連接子組2之EGFR(序列2)及RON(序 列 1)DVD-Ig 表77
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 204 DVD535H AB005VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPQVQ LKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVR QSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDN SKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAY WGQGTLVTVSA -458- 151681.doc 201127956
205 DVD535L AB005VL AB033VL DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPSVFIFPPDILLTQSPVILSVS PGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK YASESISGIPSRFSGSGSGTDFTLSINSVESEDIA DYYCQQNNNWPTTFGAGTKLELKR 206 DVD536H AB033VH AB005VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPIAPEVQLVQSG GGLVKPGGSLRLSCAASGFTFSSYAMHWVRQAPGK GLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCARFSGWPNNYYYYGMDV WGQGTTVTVSS 207 DVD536L AB033VL AB005VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDWMTQSPLSLPVTPGEPAS ISCRSSQSLLHSNGFNYVDWYLQKPGQSPHLLIYF GSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQT P PWT FGQGTKVEIRR
實例2.25 :產生具有連接子組3之EGFR(序列2)及RON(序 列 1)DVD-Ig 表78
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 208 DVD537H AB005VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPQVQ LKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVR QSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDN SKSQVFFKI^NSLQSNDTAIYYCARALTYYDYEFAY WGQGTLVTVSA 209 DVD537L AB005VL AB033VL DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPDILLTQSPVILSVSPGERVSF SCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQN NNWPTTFG/^GTKLELKR 210 DVD538H AB033VH AB005VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVQSG GGLVKPGGSLRLSCAASGFTFSSYAMHWVRQAPGK GLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNT LYLQMNSLPAEDTAVYYCARFSGWPNNYYYYGMDV WGQGTTVTVSS •459· 151681.doc 201127956
211 DVD538L
AB033VL
AB005VL
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDWMTQSPLSLPVTPGEPASISCRSSQ SLLHSNGFNYVDWYLQKPGQSPHLLIYFGSYRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAL QTPPWTFGQGTKVEIRR 實例2.26 :產生具有連接子組4之EGFR(序列2)及RON(序 列 1)DVD-Ig 表79
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 212 DVD539H AB005VH AB033VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPQVQLKQSGPG LVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGL EWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLV TVSA 213 DVD539L AB005VL AB033VL DWMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPSVFIFPPDILLTQSPVILSVS PGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK YASESISGIPSRFSGSGSGTDFTLSINSVESEDIA DYYCQQNNNWPTTFGAGTKLELKR 214 DVD540H AB033VH AB005VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVQSGGGLVKPG GSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAV ISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCARFSGWPNNYYYYGMDVWGQGTTV TVSS 215 DVD540L AB033VL AB005VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDVVMTQSPLSLPVTPGEPAS ISCRSSQSLLHSNGFNYVDWYLQKPGQSPHLLIYF GSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPPWTFGQGTKVEIRR
實例2.27 :產生EGFR(序列2)及HGF(序列1)DVD-Ig -460- 151681.doc 201127956 表80
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 216 DVD025H AB033VH AB012VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLVESGGGLVKPG GSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSY ISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVTV SS 217 DVD025L AB033VL AB012VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 218 DVD026H AB012VH AB033VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPQVQLKQSGPGLV QPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEW LGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKM NSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTV SA 219 DVD026L AB012VL AB033VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR
實例 2.28 :產生 EGFR(序列 2)及 e-MET DVD-Ig
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 220 DVD027H AB033VH AB013VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQQSGPELVRPG ASVKWSCPASGYTFTSYWLHWVKKQRPGQGLEWIG MIDPSNSDTRFNPPNFKDKATLNVDRSSNTAYNLL SSLTSADSAVYYCATYGSYVSPLDYWGQGTSVYVS S 221 DVD027L AB033VL AB013VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIMMSQSPSSLTVSVGEKVTVSCKSSQ SLLVTSSQKNYLAWYQQKPQQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTITSVKADDLAVYYCQQY YAYPWTFGDGTKLEIKR 151681.doc •46卜 201127956
222 DVD028H AB013VH AB033VH QVQLQQSGPELVRPGASVKWSCPASGYTFTSYWLH WVKKQRPGQGLEWIGMIDPSNSDTRFNPPNFKDKA TLNVDRSSNTAYNLLSSLTSADSAVYYCATYGSYV SPLDYWGQGTSVYVSSASTKGPQVQLKQSGPGLVQ PSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWL GVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMN SLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVS A 223 DVD028L AB013VL AB033VL DIMMSQSPSSLTVSVGEKVTVSCKSSQSLLVTSSQ KNYLAWYQQKPQQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTITSVKADDLAVYYCQQYYAYPWTFG DGTKLEIKRTVAAPDILLTQSPVILSVSPGERVSF SCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQN NNWPTTFGAGTKLELKR 實例2.29 :產生HER-2(序列 1)及 IGF1，2 DVD-Ig 表82
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 224 DVD029H AB004VH AB010VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLVQSGAEVKKP GASVKVSCKASGYTFTSYDINWVRQATGQGLEWMG WMNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELS SLRSEDTAVYYCARDPYYYYYGMDVWGQGTTVTVS S 225 DVD029L AB004VL AB010VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPQSVLTQPPSVSAAPGQKVTISCSGSSS NIENNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDR FSGSKSGTSATLGITGLQTGDEADYYCETWDTSLS AGRVFGGGTKLTVLG 226 DVD030H AB010VH AB004VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIN WVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTM TRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYY GMDVWGQGTTVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVA RIYPTNGYTRYADSVKGRFTISADTS KNTAYLQMN SLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVS S 227 DVD030L AB010VL AB004VL QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVS WYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGT SATLGITGLQTGDEADYYCETWDTSLSAGRVFGGG TKLTVLGQPKAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHY TTPPTFGQGTKVEIKR
實例 2.30 :產生 HER-2(序列 1)及 IGF1R DVD-Ig •462· 151681.doc 201127956 表83
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345673901234567890123456789012345 228 DVD031H AB004VH AB011VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLLESGGGLVQP GGSLRLSCTASGFTFSSYAMNWVRQAPGKGLEWVS AISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMN SLRAEDTAVYYCAKDLGWSDSYYYYYGMDVWGQGT TVTVSS 229 DVD031L AB004VL AB011VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQFPSSLSASVGDRVTITCRASQ GIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCS FGQGTKLEIKR 230 DVD032H AB011VH AB004VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPEVQLVESGG GLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKG LEWVARIYPTNGYTRYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGT LVTVSS 231 DVD032L AB011VL AB004VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR
實例2·31 :產生RON(序列1)及HGF(序列1)DVD-Ig
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 232 DVD033H AB005VH AB012VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYT^MH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGT TVTVS SASTKGPQVQLVE S GGG LVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL EWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDEYNSGWYVLFDYWGQG TLVTVSS 233 DVD033L AB005VL AB012VL DVVMTQSPL3LPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPDIQMTQSPSSVSASVGDRVTI TCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQS GVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQA NGFPWTFGQGTKVEIKR 151681.doc •463· 201127956 實例2·32 :產生VEGF(序列1)及EGFR(序列2)DVD-Ig 表85
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 236 DVD035H AB014VH AB033VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLKQSGPGL VQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLE WLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFK MNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVT VSA 237 DVD035L AB014VL AB033VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 238 DVD036H AB033VH AB014VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVESGGGLVQPG GSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNS LRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 239 DVD036L AB033VL AB014VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD ETLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR
234 DVD034H AB012VH AB005VH • QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVQSGGGLV KPGGSLRLSCAASGFTFSSYAMHWVRQAPGKGLEW VAVISYDGSNKYYADSV.KGRFTISRDNSKNTLYLQ MNSLRAEDTAVYYCARFSGWPNNYYYYGMDVWGQG TTVTVSS 235 DVD034L AB012VL AB005VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDVVMTQSPLSLPVTPGEPASISCRSSQ SLLHSNGFNYVDWYLQKPGQSPHLLIYFGSYRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAL QTPPWTFGQGTKVEIRR 實例2.33 :產生VEGF(序列1)及HER-2(序列1)DVD-Ig -464- 151681.doc 201127956 表86
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 240 DVD037H AB014VH AB004VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVESGGGL VQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLV TVSS 241 DVD037L AB014VL AB004VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 242 DVD038H AB004VH AB014VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGfCGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 243 DVD038L AB004VL AB014VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR
實例 2.34 :產生 VEGF(序列 1)及 CD-20 DVD-Ig
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 244 DVD039H AB014VH AB001VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLQQPGAEL VKPGASVKT4SCKASGYTFTSYNMHWVKQTPGRGLE WIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYM QLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTT VTVSA 245 DVD039L AB014VL AB001VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPQIVLSQSPAILSPSPGEKVTMTCRASS SVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFS GSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTF GGGTKLEIKR 151681.doc -465 - 201127956
246 DVD040H AB001VH AB014VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPEVQLVESGGGLVQ PGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWV GWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQM NSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTL VTVSS 247 DVD040L AB001VL AB014VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQD ISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTF GQGTKVEIKR 實例 2·35 :產生 VEGF(序列 1)及 IGF1，2 DVD-Ig 表88
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 248 DVD041H AB014VH AB010VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLVQSGAEV KKPGASVKVSCKASGYTFTSYDINWVRQATGQGLE WMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYM ELSSLRSEDTAVYYCARDPYYYYYGMDVWGQGTTV TVSS 249 DVD041L AB014VL AB010VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPQSVLTQPPSVSAAPGQKVTISCSGSSS NIENNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDR FSGSKSGTSATLGITGLQTGDEADYYCETWDTSLS AGRVFGGGTKLTVLG 250 DVD042H AB010VH AB014VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIN WVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTM TRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYY GMDVWGQGTTVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 251 DVD042L AB010VL AB014VL QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVS WYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGT SATLGITGLQTGDEADYYCETWDTSLSAGRVFGGG TKLTVLGQPKAAPDIQMTQSPSSLSASVGDRVTIT CSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYS TVPWTFGQGTKVEIKR
實例2.36 :產生VEGF(序列1)及DLL4(序列1)DVD-Ig •466- 151681.doc 201127956 表89
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 252 DVD043H AB014VH AB015VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVESGGGL VQPGGSLRLSCAASGFTFTDNWISWVRQAPGKGLE WVGYISPNSGFTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARDNFGGYFDYWGQGTLVTV SS 253 DVD043L AB014VL AB015VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR 254 DVD044H AB015VH AB014VH EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYI.QMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWI NTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSL RAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTV SS 255 DVD044L AB015VL AB014VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD' FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPD工QMTQSPSSLSASVGDRVTITCSAS QDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPW TFGQGTKVEIKR
實例2.37 :產生具有連接子組1之VEGF(序列1)及HGF(序 列 1)DVD-Ig 表90
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 256 DVD045H AB014VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWV RQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSH WYFDVWGQGTLVTVSSASTKGPQVQLVESGGGL VKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV SYISSSGSTIYYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLV TVSS 467- 151681.doc 201127956
257 DVD045L AB014VL AB012VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQ QKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK RTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRFGG SGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 258 DVD046H AB012VH AB014VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGWYV LFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQ MNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 259 DVD046L AB012VL AB014VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQ QKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVEIK RTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 實例2·38 :產生具有連接子組2之VEGF(序列1)及HGF(序 列 1)DVD-Ig 表91
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 260 DVD641H AB012VH AB014VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYF DVWGQGTLVTVSS 261 DVD641L AB012VL AB014VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 262 DVD642H AB014VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL VESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQ APGKGLEWVSYISSSGSTIYYADSVKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDEYNSGWYVLF DYWGQGTLVTVSS 468·
151681.doc 201127956
263 DVD642L AB014VL AB012VL
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT ITCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWTFGQGTKVEIKR 實例2.39 :產生具有連接子組3之VEGF(序列1)及HGF(序 列 1)DVD-Ig 表92
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 264 DVD647H AB012VH AB014VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYF DVWGQGTLVTVSS 265 DVD647L AB012VL AB014VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE 工KRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 266 DVD648H AB014VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL VESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQ APGKGLEWVSYISSSGSTIYYADSVKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDEYNSGWYVLF DYWGQGTLVTVSS 267 DVD648L AB014VL AB012VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 實例2.40 :產生具有連接子組4之VEGF(序列1)及HGF(序 列 1)DVD-Ig 469- 151681.doc 201127956 表93
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 268 DVD653H AB012VH AB014VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEW VGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQ MNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGT LVTVSS 269 DVD653L AB012VL AB014VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWT FGQGTKVEIKR 270 DVD654H AB014VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLVESGGGL VKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLE WVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTAVYYCARDEYNSGWYVLFDYWGQGT LVTVSS 271 DVD654L AB014VL AB012VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT ITCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWTFGQGTKVEIKR 實例2.41 :產生VEGF(序列1)及RON(序列1)DVD-Ig 表94
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 272 DVD047H AB014VL AB005VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVQSGGGL VKPGGSLRLSCAASGFTFSSYAMHWVRQAPGKGLE WVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARFSGWPNNYYYYGMDVWGQ GTTVTVSS 273 DVD047L AB014VH AB005VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDWMTQSPLSLPVTPGEPASISCRSSQ SLLHSNGFNYVDWYLQKPGQSPHLLIYFGSYRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAL QT P PWT FGQGTKVEIRR •470, 151681.doc 201127956
實例2.42 :產生VEGF(序列1)及NRP1(序列1)DVD-Ig 表95
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 276 DVD049H AB014VH AB016VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVESGGGL VQPGGSLRLSCAASGFSFSSEPISWVRQAPGKGLE WVSSITGKNGYTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARWGKKVYGMDVWGQGTLVT VSS 277 DVD049L AB014VL AB016VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ SISSYLAWYQQKPGKAPKLLIYGASSRASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYMSVPIT FGQGTKVEIKR 278 DVD050H AB016VH AB014VH EVQLVESGGGLVQPGGSLRLSCAASGFSFSSEPIS WVRQAPGKGLEWVSSITGKNGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGKKVYG MDVWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNS LRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 279 DVD050L AB016VL AB014VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLAW YQQKPGKAPKLLIYGASSRASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYMSVPITFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR
274 DVD048H AB005VH AB014VL EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPEVQLVESGGG LVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGL EWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQ GTLVTVSS 275 DVD048L AB005VL AB014VH DWMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPDIQMTQSPSSLSASVGDRVTI TCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQY STV PWT FGQGTKVE 工 KR 實例2.43 :產生HGF(序列1)及RON(序列2)DVD-Ig 471 - 151681.doc 201127956 表96
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 280 DVD073H AB034VH AB012VH QVQLQESGPGLVKPSEILSLTCTVSGGSISSHYWS WVRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTIS VDTSKNQFSLNLSSVTAADTAVYYCARIPNYYDRS GYYPGYWYFDLWGRGTLVTVSSASTKGPQVQLVES GGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPG KGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARDEYNSGWYVLFDYW GQGTLVTVSS 281 DVD073L AB034VL AB012VL QAVLTQPSSLSAPPGASASLTCTLRSGFNVDSYRI SWYQQKPGSPPQYLLRYKSDSDKQQGSGVPSRFSG SKDASANAGILLISGLQSEDEADYYCMIWHSSAWV FGGGTKLTVLRTVAAPDIQMTQSPSSVSASVGDRV TITCRASQGIS SWLAWYQQKPGKAPNLLIYEAS S L QSGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQ QANGFPWTFGQGTKVEIKR 282 DVD074H AB012VH AB034VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPQVQLQESGPGLV KPSEILSLTCTVSGGSISSHYWSWVRQPPGKGLEW IGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLNL SSVTAADTAVYYCARIPNYYDRSGYYPGYWYFDLW GRGTLVTVSS 283 DVD074L AB012VL AB034VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPQAVLTQPSSLSAPPGASASLTCTLRSG FNVDSYRISWYQQKPGSPPQYLLRYKSDSDKQQGS GVPSRFSGSKDASANAGILLISGLQSEDEADYYCM IWHSSAWVFGGGTKLTVLR
實例2·44 :產生EGFR(序列2)及RON(序列2)DVD-Ig 表97 參
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 284 DVD075H AB034VH AB033VH QVQLQESGPGLVKPSEILSLTCTVSGGSISSHYWS WVRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTIS VDTSKNQFSLNLSSVTAADTAVYYCARIPNYYDRS GYYPGYWYFDLWGRGTLVTVSSASTKGPQVQLKQS GPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPG KGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQ VFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQG TLVTVSA 285 DVD075L AB034VL AB033VL QAVLTQPSSLSAPPGASASLTCTLRSGFNVDSYRI SWYQQKPGSPPQYLLRYKSDSDKQQGSGVPSRFSG SKDASANAGILLISGLQSEDEADYYCMIWHSSAWV FGGGTKLTVLRTVAAPDILLTQSPVILSVSPGERV SFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQ QNNNWPTTFGAGTKLELKR •472· 151681.doc 201127956
實例2.45 :產生VEGF(序列1)及RON(序列2)DVD-Ig 表98
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 288 DVD077H AB034VH AB014VH QVQLQESGPGLVKPSEILSLTCTVSGGSISSHYWS WVRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTIS VDTSKNQFSLNLSSVTAADTAVYYCARIPNYYDRS GYYPGYWYFDLWGRGTLVTVSSASTKGPEVQLVES GGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPG KGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDV WGQGTLVTVSS 289 DVD077L AB034VL AB014VL QAVLTQPSSLSAPPGASASLTCTLRSGFNVDSYRI SWYQQKPGSPPQYLLRYKSDSDKQQGSGVPSRFSG SKDASANAGILLISGLQSEDEADYYCMIWHSSAWV FGGGTKLTVLRTVAAPDIQMTQSPSSLSASVGDRV TITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QYS TVPWT FGQGTKVEIKR 290 DVD078H AB014VH AB034VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLQESGPGL VKPSEILSLTCTVSGGSISSHYWSWVRQPPGKGLE WIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLN LSSVTAADTAVYYCARIPNYYDRSGYYPGYWYFDL WGRGTLVTVSS 291 DVD078L AB014VL AB034VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPQAVLTQPSSLSAPPGASASLTCTLRSG FNVDSYRISWYQQKPGSPPQYLLRYKSDSDKQQGS GVPSRFSGSKDASANAGILLISGLQSEDEADYYCM IWH S SAWVFGGGTKLTVLR
286 DVD076H AB033VH AB034VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQESGPGLVKPS EILSLTCTVSGGSISSHYWSWVRQPPGKGLEWIGY IYYSGSTNYNPSLKSRVTISVDTSKNQFSLNLSSV TAADTAVYYCARIPNYYDRSGYYPGYWYFDLWGRG TLVTVSS 287 DVD076L AB033VL AB034VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTOGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQAVLTQPSSLSAPPGASASLTCTLRSG FNVDSYRISWYQQKPGSPPQYLLRYKSDSDKQQGS GVPSRFSGSKDASANAGILLISGLQSEDEADYYCM IWHSSAWVFGGGTKLTVLR 實例2.46 :產生EGFR(序列1)及HER-2(序列1)DVD-Ig 473 - 151681.doc 201127956 表99
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 292 DVD079H AB003VH AB004VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 293 DVD079L AB003VL AB004VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 294 DVD080H AB004VH AB003VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQESGPGLVKP SETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEW IGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKL SSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS 295 DVD080L AB004VL AB003VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLA FGGGTKVEIKR 實例2.47 :產生EGFR(序列1)及CD3(序列1)DVD-Ig 表100
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 296 DVD081H AB003VH AB002VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLQQSGAELARPG ASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGY INPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSS LTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 297 DVD081L AB003VL AB002VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPQIVLTQS PAIMSAS PGEKVTMTCRAS S SVSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFS GSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTF GSGTKLEINR 474-
151681.doc 201127956
298 DVD082H AB002VH AB003VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQESGPGLVKPS ETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWI GHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLS SVTT^DTAIYYCVRDRVTGAFDIWGQGTMVTVSS 299 DVD082L AB002VL AB003VL QIVLTQSPAIMSASPGEKVTMTCRASSSVSYMNWY QQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSY SLTISSMEAEDAATYYCQQWSSNPLTFGSGTKLEI NRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQD ISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFS GSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAF GGGTKVEIKR 實例 2.48 :產生 EGFR(序列 1)及 IGF1R DVD-Ig 表101
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 300 DVD083H AB003VH AB011VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQF'SLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPEVQLLESGGGLVQPG GSLRLSCTASGFTFSSYAMNViVRQAPGKGLEVJVSA ISGSGGTTFYADSVKGRFTISRDNSRTTLYLQMNS LRAEDTAVYYCAKDLGWSDSYYYYYGMDVWGQGTT VTVSS 301 DVD083L AB003VL AB011VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIQMTQFPSSLSASVGDRVTITCRASQ GIRNDLGWYQQKPGKAPKRLIYAASRLHRGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPCS FGQGTKLEIKR 302 DVD084H AB011VH AB003VH EVQLLESGGGLVQPGGSLRLSCTASGFTFSSYAMN WVRQAPGKGLEWVSAISGSGGTTFYADSVKGRFTI SRDNSRTTLYLQMNSLRAEDTAVYYCAKDLGWSDS YYYYYGMDVWGQGTTVTVSSASTKGPQVQLQESGP GLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPG KGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQ FSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTM VTVSS 303 DVD084L AB011VL AB003VL DIQMTQFPSSLSASVGDRVTITCRASQGIRNDLGW YQQKPGKAPKRLIYAASRLHRGVPSRFSGSGSGTE FTLTISSLQPEDFATYYCLQHNSYPCSFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DISNYLNWYQQKPGKAPKLL工YDASMLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLA FGGGTKVEIKR 實例2.49 :產生EGFR(序列1)及RON(序列1)DVD-Ig 475· 151681.doc 201127956 表102
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 304 DVD085H AB003VH AB005VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPEVQLVQSGGGLVKPG GSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAV ISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCARFSGWPNNYYYYGMDVWGQGTTV TVSS 305 DVD085L AB003VL AB005VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDWMTQSPLSLPVTPGEPASISCRSSQ SLLHSNGFNYVDWYLQKPGQSPHLLIYFGSYRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAL QTPPWTFGQGTKVEIRR 306 DVD086H AB005VH AB003VH EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARFSGWPNN YYYYGMDVWGQGTTVTVSSASTKGPQVQLQESGPG LVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGK GLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQF SLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMV TVSS 307 DVD086L AB005VL AB003VL DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGF NYVDWYLQKPGQSPHLLIYFGSYRASGVPDRFSGS GSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFG QGTKVEIRRTVAAPDIQMTQSPSSLSASVGDRVTI TCQASQDISNYLNWYQQKPGKAPKLLIYDASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHF DHLPLAFGGGTKVEIKR
實例2.50 :產生EGFR(序列1)及RON(序列2)DVD-Ig 表103
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 308 DVD087H AB003VH AB034VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLQESGPGLVKPS EILSLTCTVSGGSISSHYWSWVRQPPGKGLEWIGY IYYSGSTNYNPSLKSRVTISVDTSKNQFSLNLSSV TAADTAVYYCARIPNYYDRSGYYPGYWYFDLWGRG TLVTVSS 309 DVD087L AB003VL AB034VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPQAVLTQPSSLSAPPGASASLTCTLRSG FNVDSYRISWYQQKPGS PPQYLLRYKS DS DKQQGS GVPSRFSGSKDASANAGILLISGLQSEDEADYYCM IWHSSAWVFGGGTKLTVLR •476- 151681.doc 201127956
實例2.51 :產生EGFR(序列1)及HGF(序列1)DVD-Ig 表104
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 312 DVD089H AB003VH AB012VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLVESGGGLVKPG GSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSY ISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVTV SS 313 DVD089L AB003VL AB012VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 314 DVD090H AB012VH AB003VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPQVQLQESGPGLV KPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGL EWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSL KLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTV SS 315 DVD090L AB012VL AB003VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLA FGGGTKVEIKR
310 DVD088H AB034VH AB003VH QVQLQESGPGLVKPSEILSLTCTVSGGSISSHYWS WVRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTIS VDTSKNQFSLNLSSVTAADTAVYYCARIPNYYDRS GYYPGYWYFDLWGRGTLVTVSSASTKGPQVQLQES GPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQS PGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSK TQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQG TMVTVSS 311 DVD088L AB034VL AB003VL QAVLTQPSSLSAPPGASASLTCTLRSGFNVDSYRI SWYQQKPGSPPQYLLRYKSDSDKQQGSGVPSRFSG SKDASANAGILLISGLQSEDEADYYCMIWHSSAWV FGGGTKLTVLRTVAAPDIQMTQSPSSLSASVGDRV TITCQASQDISNYLNWYQQKPGKAPKLLIYDASNL ETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQ HFDHLPLAFGGGTKVEIKR 實例2.52 :產生EGFR(序列 1)及 c-MET DVD_Ig -477· 151681.doc 201127956 表105
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 316 DVD091H AB003VH AB013VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT 工SIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLQQSGPELVRPG ASVKWSCPASGYTFTSYWLHWVKKQRPGQGLEWIG MIDPSNSDTRFNPPNFKDKATLNVDRSSNTAYNLL SSLTSADSAVYYCATYGSYVSPLDYWGQGTSVYVS S 317 DVD091L AB003VL AB013VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIMMSQSPSSLTVSVGEKVTVSCKSSQ SLLVTSSQKNYLAWYQQKPQQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTITSVKADDLAVYYCQQY YAYPWTFGDGTKLEIKR 318 DVD092H AB013VH AB003VH QVQLQQSGPELVRPGASVKWSCPASGYTFTSYWLH WVKKQRPGQGLEWIGMIDPSNSDTRFNPPNFKDKA TLNVDRSSNTAYNLLSSLTSADSAVYYCATYGSYV SPLDYWGQGTSVYVSSASTKGPQVQLQESGPGLVK PSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLE WIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLK LSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVS S 319 DVD092L AB013VL AB003VL DIMMSQSPSSLTVSVGEKVTVSCKSSQSLLVTSSQ KNYLAWYQQKPQQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTITSVKADDLAVYYCQQYYAYPWTFG DGTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTI TCQASQDISNYLNWYQQKPGKAPKLLIYDASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHF DHLPLAFGGGTKVEIKR 實例2.53 :產生EGFR(序列1)及VEGF(序列1)DVD-Ig 表106
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 320 DVD093H AB003VH AB014VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNS LRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 321 DVD093L AB003VL AB014VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR •478·
151681.doc 201127956
322 DVD094H AB014VH AB003VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLQESGPGL VKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKG LEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFS LKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVT VSS 323 DVD094L AB014VL AB003VL DIQMTQSPSSLSASVGDRVT工TCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLA FGGGTKVEIKR 實例2·54 :產生NRP1 (序列2)及VEGF(序列1)DVD-Ig 表107
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 324 DVD107H AB035VH AB014VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMS WVRQAPGKGLEWVSQISPAGGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARELPYYRM SKVMDVQGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEW VGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQ MNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGT LVTVSS 325 DVD107L AB035VL AB014VL DIQMTQSPSSLSASVGDRVTITCRASQYFSSYLAW YQQKPGKAPKLLIYGASSRASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLGSPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 326 DVD108H AB014VH AB035VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLE WVSQISPAGGYTNYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARELPYYRMSKVMDVQGQGT LVTVSS 327 DVD108L AB014VL AB035VL DIQMTQSPSSLSASVGDRVTITCSASQD工SNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE 工KRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ YFSSYLAWYQQKPGKAPKLLIYGASSRASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYLGSPPT FGQGTKVEIKR 實例 2.55 :產生 CD3(序列 2)及 CD-20 DVD-Ig 151681.doc -479· 201127956 表108
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 328 DVD131H AB039VH AB001VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQQPGAELVKPG ASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGA IYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSS LTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS A 329 DVD131L AB039VL AB001VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPQIVLSQSPAILSPSPGEKVTMTCRASSS VSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSG SGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFG GGTKLEIKR 330 DVD132H AB001VH AB039VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMH WVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATL TADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGD WYFNVWGAGTTVTVSAASTKGPQVQLQQSGAELAR PGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWI GYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQL SSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVS S 331 DVD132L AB001VL AB039VL QIVLSQSPAILSPSPGEKVTMTCRASSSVSYIHWF QQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEI KRTVAAPQIVLTQSPAIMSASPGEKVTMTCSASSS VSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRG SGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFG SGTKLEINR 實例2.56 :產生CD-3(序列2)及HER-2(序列1)DVD-Ig 表109
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 332 DVD135H AB039VH AB004VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 333 DVD135L AB039VL AB004VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQD VNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTF GQGTKVEIKR -480·
15168I.doc 201127956
334 DVD136H AB004VH AB039VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQSGAELARP GASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIG YINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLS SLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 335 DVD136L AB004VL AB039VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPQIVLTQSPAIMSASPGEKVTMTCSASS SVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFR GSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTF GSGTKLEINR 實例2.57:產生€0-3(序列2)及€0-19 0¥0-^ 表110
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 336 DVD137H AB039VH AB006VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQQSGAELVRPG SSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQ IWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSS LASEDSAVYFCARRETTTVGRYYYAMDYWGQGTSV TVSS 337 DVD137L AB039VL AB006VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPDILLTQTPASLAVSLGQRATISCKASQS VDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIP PRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTED PWTFGGGTKLEIKR 338 DVD138H AB006VH AB039VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPQVQLQQSGAE LARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGL EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAY MQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTL TVSS 339 DVD138L AB006VL AB039VL DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPQIVLTQSPAIMSASPGEKVTMTC SASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVP AHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSN PFTFGSGTKLEINR 實例2.58 :產生CD-3(序列2)及EGFR(序列2)DVD-Ig •481 · 15168J.doc 201127956 表111
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 340 DVD139H AB039VH AB033VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 341 DVD139L AB039VL AB033VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPDILLTQSPVILSVSPGERVSFSCRASQS IGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFS GSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTF GAGTKLELKR 342 DVD140H AB033VH AB039VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQQSGAELARPG ASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGY INPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSS LTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 343 DVD140L AB033VL AB039VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQIVLTQSPAIMSASPGEKVTMTCSASS SVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFR GSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTF GSGTKLEINR 實例2.59 :產生CD-3(序列2)及EGFR(序列1)DVD-Ig 表112
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 344 DVD141H AB039VH AB003VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYHQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPQVQLQESGPGLVKPS ETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWI GHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLS SVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS 345 DVD141L AB039VL AB003VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQD ISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFS GSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAF GGGTKVEIKR • 482· 151681.doc 201127956
346 DVD142H AB003VH AB039VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLQQSGAELARPG ASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGY INPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSS LTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS 347 DVD142L AB003VL AB039VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPQIVLTQSPAIMSASPGEKVTMTCSASS SVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFR GSGSGTSYSLTISGMEAEDAATYYCQQWSSMPFTF GSGTKLEINR 實例 2.60 :產生EGFR(序列 1)及IGF1，2 DVD-Ig 表113
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 348 DVD143H AB003VH AB010VH QVQLQESGPGJLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLVQSGAEVKKPG ASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGW MNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSS LRSEDTAVYYCARDPYYYYYGMDVWGQGTTVTVSS 349 DVD143L AB003VL AB010VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPQSVLTQPPSVSAAPGQKVTISCSGSSS NIENNHVSWYQQLPGTAPKLLIYDNNKRPSGIPDR FSGSKSGTSATLGITGLQTGDEADYYCETWDTSLS AGRVFGGGTKLTVLG 350 DVD144H AB010VH AB003VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIN WVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTM TRNTSISTAYMELSSLRSEDTAVYYCARDPYYYYY GMDVWGQGTTVTVSSASTKGPQVQLQESGPGLVKP SETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEW IGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKL SSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS 351 DVD144L AB010VL AB003VL QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNHVS WYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGT SATLGITGLQTGDEADYYCETWDTSLSAGRVFGGG TKLTVLGQPKAAPDIQMTQSPSSLSASVGDRVTIT CQASQDISNYLNWYQQKPGKAPKLLIYDASNLETG VPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFD HLPLAFGGGTKVEIKR 實例2.61 :產生DLL_4(序列1)及PLGF(序列1)DVD-Ig •483- 151681.doc 201127956 表114
SEQ 1D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 352 VD257H AB015VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPQVQLQQSGAELVKPGA SVKISCKASGYTFTDYYINWVKLAPGQGLEWIGWI YPGSGNTKYNEKFKGKATLTIDTSSSTAYMQLSSL TSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 353 VD257L AB015VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSS QSLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRE SGVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQ SYHLFTFGSGTKLEIKR 354 VD258H AB047VH AB015VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTFTDNWISWVRQAPGKGLEWVGYISP NSGFTYYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARDNFGGYFDYWGQGTLVTVSS 355 VD258L AB047VL AB015VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQQS YTGTVTFGQGTKVEIKR 實例2.62 :產生具有連接子組1之VEGF(序列1)及PLGF(序 列 1)DVD-Ig 表115
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 356 VD259H AB014VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLQQSGAEL VKPGASVKISCKASGYTFTDYYINWVKLAPGQGLE WIGWIYPGSGNTKYNEKFKGKATLTIDTSSSTAYM QLSSLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 357 VD259L AB014VL AB047VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR •484· 151681.doc 201127956
358 VD260H AB047VH AB014VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINT YTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRA EDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS 359 VD260L AB047VL AB014VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYC)QKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYS TVPWT FGQGT KVEIKR 實例2.63 :產生具有連接子組2之VEGF(序列1)及PLGF(序 列 1)DVD-Ig 表116
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 360 DVD579H AB047VH AB014VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLE WVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYL QMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG TLVTVSS 361 DVD579L AB047VL AB014VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYF TSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYSTVPWTFGQGTKVEIKR 362 DVD580H AB014VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL QQSGAELVKPGASVKISCKASGYTFTDYYINWVKL APGQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDT SSSTAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQG TLLTVSS 363 DVD580L AB014VL AB047VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR
實例2.64 :產生具有連接子組3之VEGF(序列1)及PLGF(序 列 1)DVD-Ig -485- 151681.doc 201127956 表117
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 364 DVD587VH AB047VH AB014VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLE WVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYL QMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG TLVTVSS 365 DVD587VL AB047VL AB014VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYS TVPWT FGQGTKVEIKR 366 DVD588VH AB014VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL QQSGAELVKPGASVKISCKASGYTFTDYYINWVKL APGQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDT SSSTAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQG TLLTVSS 367 DVD588VL AB014VL AB047VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR 實例2.65 :產生具有連接子組4之VEGF(序列1)及PLGF(序 列 1)DVD-Ig 表118
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 368 DVD595VH AB047VH AB014VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKY1SIEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINT YTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRA EDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS 486· 151681.doc 201127956
369 DVD595VL AB047VL AB014VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYF TSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYSTVPWTFGQGTKVEIKR 370 DVD596VH AB014VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLQQSGAEL VKPGASVKISCKASGYTFTDYYINWVKLAPGQGLE WIGWIYPGSGNTKYNEKFKGKATLTIDTSSSTAYM QLSSLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 371 DVD596VL AB014VL AB047VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAI?SVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDETLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR
實例2·66 :產生具有連接子組1之EGFR(序列2)及ErbB3 (序列 1)DVD-Ig 表119
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱· 内可變區域 名稱 序列 12345678901234567890123456789012345 372 VD299H AB062VH AB033VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPQVQLKQSGPGLVQPSQS LSITCTVSG FSLTNYGVHWVRQS PGKGLEWLGVIW SGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQS NDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 373 VD299L AB062VL AB033VL DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDILLTQSPVILSVSPGERVSF SCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQN NNWPTTFGAGTKLELKR 374 VD300H AB033VH AB062VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQQWGAGLLKPS ETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGE INHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSV TAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 375 VD300L AB033VL AB062VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRMYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR -487- 151681.doc 201127956 實例2.67 :產生具有連接子組2之EGFR(序列2)及ErbB3 (序列 1)DVD-Ig 表120
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 376 DVD385H AB062 AB033 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEW工GEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPSVFPLAPQVQLKQSGPG LVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGL EWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLV TVSA 377 DVD385L AB062 AB033 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPSVFIFPPDILLTQSPVILSVS PGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK YASESISGIPSRFSGSGSGTDFTLSINSVESEDIA DYYCQQNNNWPTTFGAGTKLELKR 378 DVD386H AB033 AB062 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPQVQLQQWG AGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGK GLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQF SLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLV TVSS 379 DVD386L AB033 AB062 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIEMTQSPDSLAVSLGERAT 'INCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA VYYCQQYYSTPRTFGQGTKVEIKR
實例2.68 :產生具有連接子組1之EGFR(序列2)及ErbB3 (序列 1)DVD-Ig 表121
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 380 DVD389H AB062 AB033 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPSVFPLAPQVQLKQSGPG LVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGL EWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFF KMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLV TVSA -488· 151681.doc 201127956
381 DVD389L AB062 AB033 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDILLTQSPVILSVSPGERVSF SCRASQSIGTNIHWYQQRTNGSPRLLIKYASESIS GIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQN NNWPTTFGAGTKLELKR 382 DVD390H AB033 AB062 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPQVQLQQWG AGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGK GLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQF SLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLV TVSS 383 DVD390L AB033 AB062 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR
實例2.69 :產生具有連接子組4之EGFR(序列2)及ErbB3 (序列 1)DVD-Ig 表122
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 384 DVD393H AB062 AB033 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPQVQLKQSGPGLVQPSQS LSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIW SGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQS NDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 385 DVD393L AB062 AB033 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPSVFIFPPDILLTQSPVILSVS PGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK YASESISGIPSRFSGSGSGTDFTLSINSVESEDIA DYYCQQNNNWPTTFGAGTKLELKR 386 DVD394H AB033 AB062 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPQVQLQQWGAGLLKPS ETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGE INHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSV TAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 387 DVD394L AB033 AB062 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIEMTQSPDSLAVSLGERAT INCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA VYYCQQYYSTPRTFGQGTKVEIKR • 489- 151681.doc 201127956 實例2.70 :產生EGFR(序列1)及ErbB3(序列1)DVD-Ig 表123
SEQ 1D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 388 DVD301H AB062VH AB003VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPQVQLQESGPGLVKPSET LSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGH IYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSV TAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS 389 DVD301L AB062VL AB003VL DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTI TCQASQDISNYLNWYQQKPGKAPKLLIYDASNLET GVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHF DHLPLAFGGGTKVEIKR 390 DVD302H AB003VH AB062VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPQVQLQQWGAGLLKPS ETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGE IMHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSV TAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 391 DVD302L AB003VL AB062VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR 實例2.71 :產生HGF(序列1)及ErbB3(序列1)DVD-Ig 表124
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 392 DVD303H AB062VH AB012VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPQVQLVESGGGLVKPGGS LRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYIS SSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDEYNSGWYVLFDYWGQGTLVTVSS 393 DVD303L AB062VL AB012VL DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDIQMTQSPSSVSASVGDRVTI TCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQS GVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQA NGFPWTFGQGTKVEIKR -490·
151681.doc 201127956
394 DVD304H AB012VH AB062VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPQVQLQQWGAGLL KPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEW IGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKL SSVTAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 395 DVD304L AB012VL AB062VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR
實例2.72 :產生具有連接子組1之EGFR(序列2)及ErbB3 (序列 2)DVD-Ig 表125
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 396 DVD305H AB063VH AB033VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 397 DVD305L AB063VL AB033VL DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 398 DVD306H AB033VH AB063VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSY ISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 399 DVD306L AB033VL AB063VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR 實例2.73 :產生具有連接子組2之EGFR(序列2)及ErbB3 (序列 2)DVD-Ig 491 - 151681.doc 201127956 表126
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 400 DVD397H AB063 AB033 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPSVFPLAPQVQLKQSG PGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGK GLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQV FFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT LVTVSA 401 DVD397L AB063 AB033 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPSVFIFPPDILLTQSPVILSVSPGERVS FSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTTFGAGTKLELKR 402 DVD398H AB033 AB063 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGK GLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNS LYLQMNSLRDEDTAVYYCARDRGDFDAFDIWGQGT MVTVSS 403 DVD398L AB033 AB063 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCQASQDITNYLNWYQQKPGKAPKLLIYDASNLE TGVPSRFSGSGSGTDFTFTISSLQPEDIATYNCQQ CENFPITFGQGTRLEIKR
實例2.74 :產生具有連接子組3之EGFR(序列2)及ErbB3 (序列 2)DVD-Ig ft 表127
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 404 DVD401H AB063 AB033 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPSVFPLAPQVQLKQSG PGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGK GLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQV FFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT LVTVSA 492· 15l681.doc 201127956
405 DVD401L AB063 AB033 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPDILLTQSPVILSVSPGERVSFSCRASQ SIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRF SGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTT FGAGTKLELKR 406 DVD402H AB033 AB063 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGK GLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNS LYLQMNSLRDEDTAVYYCARDRGDFDAFDIWGQGT MVTVSS 407 DVD402L AB033 AB063 DILLTQSPV:[LSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR
實例2.75 ··產生具有連接子組4之EGFR(序列2)及ErbB3 (序列 2)DVD-Ig 表128
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 408 DVD405H AB063 AB033 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTV3SASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 409 DVD405L AB063 AB033 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPSVFIFPPDILLTQS PVILSVS PGERVS FSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESI SGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQ NNNWPTT FGAGTKLELKR 410 DVD406H AB033 AB063 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSY ISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 411 DVD406L AB033 AB063 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCQASQDITNYLNWYQQKPGKAPKLLIYDASMLE TGVPSRFSGSGSGTDFTFTISSLQPEDIATYNCQQ CENFPITFGQGTRLEIKR • 493 · 151681.doc 201127956 實例2.76 :產生EGFR(序列1)及ErbB3(序列2)DVD-Ig 表129
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 412 DVD307H AB063VH AB003VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPQVQLQESGPGLVKPS ETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWI GHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLS SVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS 413 DVD307L AB063VL AB003VL DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLA FGGGTKVEIKR 414 DVD308H AB003VH AB063VH QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYY WTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLT ISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGA FDIWGQGTMVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSY ISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 415 DVD308L AB003VL AB063VL DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR 實例2.77 :產生HGF(序列1)及ErbB3(序列2)DVD-Ig 表130
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 416 DVD309H AB063VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPQVQLVESGGGLVKPG GSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSY ISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVTV SS 417 DVD309L AB063VL AB012VL DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR •494· 151681.doc 201127956
418 DVD310H AB012VH AB063VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEW VSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQ MNSLRDEDTAVYYCARDRGDFDAFDIWGQGTMVTV SS 419 DVD310L AB012VL AB063VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR
實例2.78 :產生具有連接子組1之VEGF(序列1)及DLL4(序 列 2)DVD-Ig 表131
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 420 DVD441H AB069 AB014 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMSLRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNS LRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 421 DVD441L AB069 AB014 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC SASQDISNYLNVJYQQKPGKAPKVLIYFTSSLHSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYST VPWTFGQGTKVEIKR 422 DVD442H ABO 14 AB069 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLVQSGAEV KKPGASVKISCKASGYSFTAYYIHWVKQAPGQGLE WIGYISSYNGATNYNQKFKGRVTFTTDTSTSTAYM ELRSLRSDDTAVYYCARDYDYDVGMDYWGQGTLVT VSS 423 DVD442L AB014 AB069 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE VPWTFGGGTKVEIKR 實例2.79 :產生具有連接子組2之VEGF(序列1)及DLL4(序 列 2)DVD-Ig -495- 151681.doc 201127956 表132
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 424 DVD447H AB069 AB014 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGK GLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKST AYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVW GQGTLVTVSS 425 DVD447L AB069 AB014 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFT SSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYSTVPWT FGQGTKVEIKR 426 DVD448H AB014 AB069 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPIAPQVQL VQSGAEVKKPGASVKISCKASGYSFTAYYIHWVKQ APGQGLEWIGYISSYNGATNYNQKFKGRVTFTTDT STSTAYMELRSLRSDDTAVYYCARDYDYDVGMDYW GQGTLVTVSS 427 DVD448L AB014 AB069 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQSKEVPWTFGGGTKVEIKR
實例2.80 :產生具有連接子組2之VEGF(序列1)及DLL4(序 列 3)DVD-Ig 癱 表133
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 428 DVD453H AB069 AB014 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGK GLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKST AYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVW GQGTLVTVSS 496- 151681.doc 201127956
429 DVD453L ΑΒ069 AB014 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC SASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYST VPWTFGQGTKVEIKR 430 DVD454H ABO 14 AB069 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL VQSGAEVKKPGASVKISCKASGYSFTAYYIHWVKQ APGQGLEWIGYISSYNGATNYNQKFKGRVTFTTDT STSTAYMELRSLRSDDTAVYYCARDYDYDVGMDYW GQGTLVTVSS 431 DVD454L ABO 14 AB069 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPPCVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE VPWT FGGGTKVEIKR
實例2.81 :產生具有連接子組4之VEGF(序列1)及DLL4(序 列 2)DVD-Ig 表134
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 432 DVD459H AB069 AB014 QVQLVQSGAE：VKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNS LRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSS 433 DVD459L AB069 AB014 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFT SSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYSTVPWTFGQGTKVEIKR 434 DVD460H AB014 AB069 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLVQSGAEV KKPGASVKISCKASGYSFTAYYIHWVKQAPGQGLE WIGYISSYNGATNYNQKFKGRVTFTTDTSTSTAYM ELRSLRSDDTAVYYCARDYDYDVGMDYWGQGTLVT VSS 497· 151681.doc 5 201127956 435
DVD460L AB014 AB069
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQS KEVPWT FGGGTKVEIKR 實例2.82 :產生具有連接子組1之VEGF(序列2)及DLL4(序 列 2)DVD-Ig 表135
SEQ 里D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 436 DVD443H AB069 AB070 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAG ITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 437 DVD443L AB069 AB070 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYT TPPTFGQGTKVEIKR 438 DVD444H AB070 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLVQSGAEVKKP GASVKISCKASGYSFTAYYIHWVKQAPGQGLEWIG YISSYNGATNYNQKFKGRVTFTTDTSTSTAYMELR SLRSDDTAVYYCARDYDYDVGMDYWGQGTLVTVSS 439 DVD444L AB070 AB069 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE VPWTFGGGTKVEIKR 實例2.83 :產生具有連接子組2之VEGF(序列2)及DLL4(序 列 2)DVD-Ig 498- 151681.doc 201127956 表136
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 440 DVD449H AB069 AB070 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPIiAPEVQLVESG GGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGK GLEWVAGITPAGGYTYYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQG TLVTVSS 441 DVD449L AB069 AB070 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSBFSGSGSGTDFTLTISSLQPEDFATY YCQQSYTTPPTFGQGTKVEIKR 442 DVD450H AB070 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WRQAPGKGLEW VAGI T P AGGYT Y Y ADS VKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVQS GAEVKKPGASVKISCKASGYSFTAYYIHWVKQAPG QGLEWIGYISSYNGATNYNQKFKGRVTFTTDTSTS TAYMELRSLRSDDTAVYYCARDYDYDVGMDYWGQG TLVTVSS 443 DVD450L AB070 AB069 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQSKEVPWTFGGGTKVEIKR
實例2.84 :產生具有連接子組3之VEGF(序列2)及DLL4(序 列 2)DVD-Ig 表137
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 444 DVD455H AB069 AB070 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFTIS DYWIHWVRQAPGK GLEWVAGITPAGGYTYYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQG TLVTVSS 499- 151681.doc 201127956
445 DVD455L AB069 AB070 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYT TPPTFGQGTKVEIKR 446 DVD456H AB070 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGIT PAGG YT Y YADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVQS GAEVKKPGASVKISCKASGYSFTAYYIHWVKQAPG QGLEWIGYISSYNGATNYNQKFKGRVTFTTDTSTS TAYMELRSLRSDDTAVYYCARDYDYDVGMDYWGQG TLVTVSS 447 DVD456L AB070 AB069 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE VPWTFGGGTKVEIKR 實例2.85 :產生具有連接子組4之VEGF(序列2)及DLL4(序 列 2)DVD-Ig 表138
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 448 DVD461H AB069 AB070 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAG ITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 449 DVD461L AB069 AB070 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQSYTTPPTFGQGTKVEIKR 450 DVD462H AB070 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLVQSGAEVKKP GASVKISCKASGYSFTAYYIHWVKQAPGQGLEWIG YISSYNGATNYNQKFKGRVTFTTDTSTSTAYMELR SLRSDDTAVYYCARDYDYDVGMDYWGQGTLVTVSS 451 DVD462L AB070 AB069 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQSKEVPWTFGGGTKVEIKR •500·
151681.doc 201127956 實例2.86 :產生具有連接子組1之VEGF(序列2)及DLL4(序 列 3)DVD-Ig 表139
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 452 DVD445H AB069 AB071 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGA IYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVS S 453 DVD445L AB069 AB071 DIVMTQSPDSLAVSLGERATISCRASESVDMYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC RASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNT SPLTFGQGTKVEIKR 454 DVD446H AB071 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGJTLVTVSSASTKGPQVQLVQSGAEVKK PGASVKISCKASGYS FTAYYIHWVKQAPGQGLEWI GYISSYNGATNYNQKFKGRVTFTTDTSTSTAYMEL RSLRSDDTAVYYCARDYDYDVGMDYWGQGTLVTVS S 455 DVD446L AB071 AB069 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE V PWT FGGGTKVEIKR 實例2.87 :產生具有連接子組2之VEGF(序列3)及DLL4(序 列 2)DVD-Ig 表140
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 456 DVD451H AB069 AB071 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGK GLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNT AYLQMNSLEIAEDTAVYYCARWGHSTSPWAMDYWGQ GTLVTVSS •501 · 151681.doc 201127956
457 DVD451L AB069 AB071 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAA SNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQSNTSPLTFGQGTKVEIKR 458 DVD452H AB071 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVQ SGAEVKKPGASVKISCKASGYSFTAYYIHWVKQAP GQGLEWIGYISSYNGATNYNQKFKGRVTFTTDTST STAYMELRSLRSDDTAVYYCARDYDYDVGMDYWGQ GTLVTVSS 459 DVD452L AB071 AB069 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQSKEVPWTFGGGTKVEIKR 實例2.88 :產生具有連接子組3之VEGF(序列3)及DLL4(序 列 2)DVD-Ig 表141
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 460 DVD457H AB069 AB071 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGK GLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQ GTLVTVSS 461 DVD457L AB069 AB071 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTITC RASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNT SPLTFGQGTKVEIKR 462 DVD458H AB071 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVQ SGAEVKKPGASVKISCKASGYSFTAYYIHWVKQAP GQGLEWIGYISSYNGATNYNQKFKGRVTFTTDTST STAYMELRSLRSDDTAVYYCARDYDYDVGMDYWGQ GTLVTVSS 502 ·
151681.doc 201127956 463~ DVD458L AB071 AB069
DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIVMTQSPDSLAVSLGERATISCRASE SVDNYGISFMKWFQQKPGQPPKLLIYAASNQGSGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKE VPWTFGGGTKVEIKR 實例2.89 :產生具有連接子組4之VEGF(序列3)及DLL4(序 列 2)DVD-Ig 表142
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 464 DVD463H AB069 AB071 QVQLVQSGAEVKKPGASVKISCKASGYSFTAYYIH WVKQAPGQGLEWIGYISSYNGATNYNQKFKGRVTF TTDTSTSTAYMELRSLRSDDTAVYYCARDYDYDVG MDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGA IYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVS S 465 DVD463L AB069 AB071 DIVMTQSPDSLAVSLGERATISCRASESVDNYGIS FMKWFQQKPGQPPKLLIYAASNQGSGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGG TKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAA SNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQSNTSPLTFGQGTKVEIKR 466 DVD464H AB071 AB069 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLVQSGAEVKK PGASVKISCKASGYSFTAYYIHWVKQAPGQGLEWI GYISSYNGATNYNQKFKGRVTFTTDTSTSTAYMEL RSLRSDDTAVYYCARDYDYDVGMDYWGQGTLVTVS S 467 DVD464L AB071 AB069 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIVMTQSPDSLAVSLGERAT ISCRASESVDNYGISFMKWFQQKPGQPPKLLIYAA SNQGSGVPDRFSGSGSGTDFTLTISSLQAEDVAVY YCQQSKEVPWTFGGGTKVEIKR 實例2.90 :產生具有連接子組1之VEGF(序列2)及DLL4(序 列 l)DVD_Ig 503 - 151681.doc 201127956 表143
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 468 DVD465H AB015 AB070 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGI TPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 469 DVD465L AB015 AB070 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIQMTQSPSSLSASVGDRVTITCRAS QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPP TFGQGTKVEIKR 470 DVD466H AB070 AB015 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFTDNWISWVRQAPGKGLEWVG YISPNSGFTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARDNFGGYFDYWGQGTLVTVSS 471 DVD466L AB070 AB015 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR
實例2.91 :產生具有連接子組2之VEGF(序列2)及DLL4(序 列 1)DVD-Ig 表 144 #
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 472 DVD471H AB015 AB070 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKG LEWVAGITPAGGYTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGT LVTVSS 473 DVD471L AB015 AB070 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFL YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QSYTTPPTFGQGTKVEIKR •504· 151681.doc 201127956
474 DVD472H AB070 ABO 15 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY 7VMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTFTDNWISWVRQAPG KGLEWVGYISPNSGFTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARDNFGGYFDYWGQGT LVTVSS 475 DVD472L AB070 AB015 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR 實例2·92 :產生具有連接子組3之VEGF(序列2)及DLL4(序 列 1)DVD-Ig
表145
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 476 DVD477H ABO 15 AB070 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKG LEWVAGITPAGGYTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGT LVTVSS 477 DVD477L ABO 15 AB070 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIQMTQSPSSLSASVGDRVTITCRAS QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPP TFGQGTKVEIKR 478 DVD478H AB070 AB015 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTFTDNWISWVRQAPG KGLEWVGYISPNSGFTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARDNFGGYFDYWGQGT LVTVSS 479 DVD478L AB070 AB015 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR 實例2.93 :產生具有連接子組4之VEGF(序列2)及DLL4(序 列 l)DVD_Ig - 505 - 151681.doc 5 201127956 表146
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 480 DVD483H AB015 AB070 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGI TPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 481 DVD483L AB015 AB070 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFL YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QSYTTPPTFGQGTKVEIKR 482 DVD484H AB070 AB015 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFTDNWISWVRQAPGKGLEWVG YISPNSGFTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARDNFGGYFDYWGQGTLVTVSS 483 DVD484L AB070 AB015 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR 實例2.94 :產生具有連接子組1之VEGF(序列3)及DLL4(序 列 1)DVD-Ig 表147
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 484 DVD467H AB015 AB071 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAI YPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 485 DVD467L AB015 AB071 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIQMTQSPSSLSASVGDRVTITCRAS QVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPL TFGQGTKVEIKR 506-
151681.doc 201127956
486 DVD468H AB071 ABO 15 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQ PGGSLRLSCAASGFTFTDNWISWVRQAPGKGLEWV GYISPNSGFTYYADSVKGRFTISADTSKNTAYLQM NSLRAEDTAVYYCARDNFGGYFDYWGQGTLVTVSS 487 DVD468L AB071 AB015 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR 實例2.95 :產生具有連接子組2之VEGF(序列3)及DLL4(序 列 1)DVD-Ig 表148
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 488 DVD473H ABO 15 AB071 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKG LEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQG TLVTVSS 489 DVD473L ABO 15 AB071 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNL ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QSNTSPLTFGQGTKVEIKR 490 DVD474H AB071 AB015 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVE SGGGLVQPGGSLRLSCAASGFTFTDISiWISWVRQAP GKGLEWVGYISPNSGFTYYADSVKGRFTISADTSK NTAYLQMNSLRAEDTAVYYCARDNFGGYFDYWGQG TLVTVSS 491 DVD474L AB071 AB015 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR
實例2.96 :產生具有連接子組3之VEGF(序列3)及DLL4(序 列 1)DVD-Ig •507· 151681.doc 201127956 表149
SEQ ID NO DVD可$區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 492 DVD479H AB015 AB071 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKG LEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQG TLVTVSS 493 DVD479L AB015 AB071 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIQMTQSPSSLSASVGDRVTITCRAS QVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPL TFGQGTKVEIKR 494 DVD480H AB071 AB015 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVE SGGGLVQPGGSLRLSCAASGFTFTDNWISWVRQAP GKGLEWVGYISPNSGFTYYADSVKGRFTISADTSK NTAYLQMNSLRAEDTAVYYCARDNFGGYFDYWGQG TLVTVSS 495 DVD480L AB071 AB015 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR 實例2.97 :產生具有連接子組4之VEGF(序列3)及DLL4(序 列 1)DVD-Ig 表150
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 496 DVD485H ABO 15 AB071 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAI YPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 497 DVD485L AB015 AB071 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNL ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QSNTSPLTFGQGTKVEIKR -508-
151681.doc 201127956
498 DVD486H AB071 ABO 15 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQ PGGSLRLSCAASGFTFTDNWISWVRQAPGKGLEWV GYISPNSGFTYYADSVKGRFTISADTSKNTAYLQM NSLRAEDTAVYYCARDNFGGYFDYWGQGTLVTVSS 499 DVD486L AB071 ABO 15 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR 實例2.98 :產生具有連接子組1之VEGF(序列1)及DLL4(序 列 1)DVD-Ig 表151
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 500 DVD469H ABO 15 AB014 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKG LEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTA YLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWG QGTLVTVSS 501 DVD469L ABO 15 AB014 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QYSTVPWTFGQGTKVEIKR 502 DVD470H AB014 AB015 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWY FDVWGQGTLVTVSSASTKGPSVFPLAPEVQL VESGGGLVQPGGSLRLSCAASGFTFTDNWISWVRQ APGKGLEWVGYISPNSGFTYYADSVKGRFTISADT SKNTAYLQMNSLRAEDTAVYYCARDNFGGYFDYWG QGTLVTVSS 503 DVD470L AB014 AB015 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR
實例2.99 :產生具有連接子組2之VEGF(序列1)及DLL4(序 列 1)DVD-Ig -509- 151681.doc 201127956 表152
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 504 DVD475H AB015 AB014 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKG LEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTA YLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWG QGTLVTVSS 505 DVD475L AB015 AB014 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPDIQMTQSPSSLSASVGDRVTITCSAS QDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPW TFGQGTKVEIKR 506 DVD476H AB014 AB015 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL VESGGGLVQPGGSLRLSCAASGFTFTDNWISWVRQ APGKGLEWVGYISPNSGFTYYADSVKGRFTISADT SKNTAYLQMNSLRAEDTAVYYCARDNFGGYFDYWG QGTLVTVSS 507 DVD476L AB014 AB015 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATTYYCQQSYTGTV TFGQGTKVEIKR 實例2.100 :產生具有連接子組3之VEGF(序列1)及DLL4 (序列 1)DVD-Ig 表153
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 508 DVD481H ABO 15 AB014 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDNWIS WVRQAPGKGLEWVGYISPNSGFTYYADSVKGRFT工 SADTSKNTAYLQMNSLRAEDTAVYYCARDNFGGYF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWI NTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSL RAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTV SS 510-
151681.doc 201127956
509 DVD481L AB015 AB014 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATTYYCQQSYTGTVTFGQGTKV EIKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRV TITCSASQDISNYLNWYQQKPGKAPKVLIYPTSSL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QYSTVPWTFGQGTKVEIKR 510 DVD482H AB014 AB015 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVESGGGL VQPGGSLRLSCAASGFTFTDNWISWVRQAPGKGLE WVGYISPNSGFTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARDNFGGYFDYWGQGTLVTV SS 511 DVD482L AB014 AB015 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATTYYCQ QSYTGTVTFGQGTKVEIKR
實例2.101 :羞生具有連接子組1之VEGF(序列1)及DLL4 (序列 3)DVD-Ig 表154
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 512 DVD487H AB072 AB014 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 513 DVD487L AB072 AB014 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 514 DVD488H AB014 AB072 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLQQSGPEL VKPGASVKMSCKASGYTFTSYVINWVKQKPGQGLE WIGLINPYNDGTKYNEKFKVKATLTSDKSSSTAYM ELSSLTSEDSAVYYCASYYYGSRYYFDYWGQGTTL TVSS 511 - 151681.doc 201127956 5Ϊ5~I DBD488L AB014 AB072
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR 實例2.102 :產生具有連接子組2之VEGF(序列1)及DLL4 (序列 3)DVD-Ig 表155
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 516 DVD493H AB072 AB014 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPG KGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDV WGQGTLVTVSS 517 DVD493L AB072 AB014 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 518 DVD494H AB014 AB072 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL QQSGPELVKPGASVKMSCKASGYTFTSYVINWVKQ KPGQGLEWIGLINPYNDGTKYNEKFKVKATLTSDK SSSTAYMELSSLTSEDSAVYYCASYYYGSRYYFDY WGQGTTLTVSS 519 DVD494L AB014 AB072 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDHINNWLAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQ YWSIPLTFGAGTKLELKR 實例2.103 :產生具有連接子組3之VEGF(序列1)及DLL4 (序列 3)DVD-Ig 512· 151681.doc 201127956 表156
SEQ 【D NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 520 DVD499H AB072 AB014 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPG KGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS TAYLQMNSLIIAEDTAVYYCAKYPHYYGSSHWYFDV WGQGTLVTVSS 521 DVD499L AB072 AB014 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 522 DVD500H AB014 AB072 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGL-EWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL QQSGPELVKPGASVKMSCKASGYTFTSYVINWVKQ KPGQGLEWIGLINPYNDGTKYNEKFKVKATLTSDK SSSTAYMELSSLTSEDSAVYYCASYYYGSRYYFDY WGQGTTLTVSS 523 DVD500L AB014 AB072 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR
實例2.104 :產生具有連接子組4之VEGF(序列1)及DLL4 (序列 3)DVD-Ig 表157
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 524 DVD505H AB072 AB014 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 513- 151681.doc 201127956
525 DVD505L AB072 AB014 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 526 DVD506H AB014 AB072 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLQQSGPEL VKPGASVKMSCKASGYTFTSYVINWVKQKPGQGLE WIGLINPYNDGTKYNEKFKVKATLTSDKSSSTAYM ELSSLTSEDSAVYYCASYYYGSRYYFDYWGQGTTL TVSS 527 DVD506L AB014 AB072 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDHINNWLAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQ YWSIPLTFGAGTKLELKR 實例2.105 :產生具有連接子組1之VEGF(序列2)及DLL4 (序列 3)DVD-Ig 表158
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 528 DVD489H AB072 AB070 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVA GITPAGGYTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVS S 529 DVD489L AB072 AB070 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 530 DVD490H AB070 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLQQSGPELVKP GASVKMSCKASGYTFTSYVINWVKQKPGQGLEWIG LINPYNDGTKYNEKFKVKATLTSDKSSSTAYMELS SLTSEDSAVYYCASYYYGSRYYFDYWGQGTTLTVS S 514-
151681.doc 201127956 531 I DVD490L AB070 AB072
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR 實例2.106 :產生具有連接子組2之VEGF(序列2)及DLL4 (序列 3)DVD-Ig 表159
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 532 DVD495H AB072 AB070 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPG KGLEWVAGITPAGGYTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQ GTLVTVSS 533 DVD495L AB072 AB070 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 534 DVD496H AB070 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQS GPELVKPGASVKMSCKASGYTFTSYVINWVKQKPG QGLEWIGLIMPYNDGTKYNEKFKVKATLTSDKSSS TAYMELSSLTSEDSAVYYCASYYYGSRYYFDYWGQ GTTLTVSS 535 DVD496L AB070 AB072 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDHIN丽LAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQ YWSIPLTFGAGTKLELKR 實例2.107 :產生具有連接子組3之VEGF(序列2)及DLL4 (序列 3)DVD-Ig 515- 151681.doc 201127956 表160
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變® 域名稱 序列 12345678901234567890123456789012345 536 DVD501H AB072 AB070 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPG KGLEWVAGITPAGGYTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQ GTLVTVSS 537 DVD501L AB072 AB070 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 538 DVD502H AB070 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQS GPELVKPGASVKMSCKASGYTFTSYVINWVKQKPG QGLEWIGLINPYNDGTKYNEKFKVKATLTSDKSSS TAYMELSSLTSEDSAVYYCASYYYGSRYYFDYWGQ GTTLTVSS 539 DVD502L AB070 AB072 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR 實例2.108 :產生具有連接子組4之VEGF(序列2)及DLL4 (序列 3)DVD-Ig 表161
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 540 DVD507H AB072 AB070 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVA GITPAGGYTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVS S 516-
151681.doc 201127956
541 DVD507L AB072 AB070 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 542 DVD508H AB070 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLQQSGPELVKP GASVKMSCKASGYTFTSYVINWVKQKPGQGLEWIG LINPYNDGTKYNEKFKVKATLTSDKSSSTAYMELS SLTSEDSAVYYCASYYYGSRYYFDYWGQGTTLTVS S 543 DVD508L AB070 AB072 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDHINNWLAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQ YWSIPLT FGAGTKLELKR
實例2.109 :產生具有連接子組1之VEGF(序列3)及DLL4 (序列 3)DVD-Ig 表162 SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 544 DVD491H AB072 AB071 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVG AIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTV SS 545 DVD491L AB072 AB071 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 546 DVD492H AB071 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLQQSGPELVK PGASVKMSCKASGYTFTSYVINWVKQKPGQGLEWI GLINPYNDGTKYNEKFKVKATLTSDKSSSTAYMEL SSLTSEDSAVYYCASYYYGSRYYFDYWGQGTTLTV SS- 517· 151681.doc 201127956 547~I DVD492L AB071 AB072
DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR 實例2.110 :產生具有連接子組2之VEGF(序列3)及DLL4 (序列 3)DVD-Ig 表163
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 548 DVD497H AB072 AB071 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPG KGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWG QGTLVTVSS 549 DVD497L AB072 AB071 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 550 DVD498H AB071 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQ SGPELVKPGASVKMSCKASGYTFTSYVINWVKQKP GQGLEWIGLINPYNDGTKYNEKFKVKATLTSDKSS STAYMELSSLTSEDSAVYYCASYYYGSRYYFDYWG QGTTLTVSS 551 DVD498L AB071 AB072 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDH工NNWLAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQ YWSIPLTFGAGTKLELKR 實例2.111 :產生具有連接子組3之VEGF(序列3)及DLL4 (序列 3)DVD-Ig 518- 131681.doc 201127956 表164
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 552 DVD503H AB072 AB071 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPG KGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWG QGTLVTVSS 553 DVD503L AB072 AB071 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 554 DVD504H AB071 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQ SGPELVKPGASVKMSCKASGYTFTSYVINWVKQKP GQGLEWIGLINPYNDGTKYNEKFKVKATLTSDKSS STAYMELSSLTSEDSAVYYCASYYYGSRYYFDYWG QGTTLTVSS 555 DVD504L AB071 AB072 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSSSYLSVSLGGRVTITCKASD HINNWLAWYQQKPGNAPRLLISGATSLETGVPSRF SGSGSGKDYTLSITSLQTEDVATYYCQQYWSIPLT FGAGTKLELKR
實例2.112 :產生具有連接子組4之VEGF(序列3)及DLL4 (序列 3)DVD-Ig 表165
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 556 DVD509H AB072 AB071 EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVIN WVKQKPGQGLEWIGLINPYNDGTKYNEKFKVKATL TSDKSSSTAYMELSSLTSEDSAVYYCASYYYGSRY YFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVG AIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTV SS 519- 151681.doc 201127956
557 DVD509L AB072 AB071 DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAW YQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKD YTLSITSLQTEDVATYYCQQYWSIPLTFGAGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 558 DVD510H AB071 AB072 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLQQSGPELVK PGASVKMSCKASGYTFTSYVINWVKQKPGQGLEWI GLINPYNDGTKYNEKFKVKATLTSDKSSSTAYMEL SSLTSEDSAVYYCASYYYGSRYYFDYWGQGTTLTV SS 559 DVD510L AB071 AB072 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSSSYLSVSLGGRVT ITCKASDHINNWLAWYQQKPGNAPRLLISGATSLE TGVPSRFSGSGSGKDYTLSITSLQTEDVMTYCQQ YWSIPLTFGAGTKLELKR 實例2.113 :產生具有連接子組1之VEGF(序列1)及DLL4 (序列 4)DVD-Ig 表166
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 560 DVD511H AB073 AB014 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 561 DVD511L AB073 AB014 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCS ASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTV PWTFGQGTKVEIKR 562 DVD512H AB014 AB073 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLQQSGPEL EKPGASVKISCKASGYSFTGYNMNWVKQSNGKSLE WIGMIDPYFGGTNYISIQKFKGKATLTVDKSSSTAYM QLKSLTSEDSAVYYCARNYDYDGGCFDYWGQGTTL TVSS 520-
151681.doc 201127956 563 DVD512L ABO 14 AB073
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPQAWTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG 實例2.114 :產生具有連接子組2之VEGF(序列1)及DLL4 (序列 4)DVD-Ig 表167
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 564 DVD517H AB073 AB014 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYrcGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPG KGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDV WGQGTLVTVSS 565 DVD517L AB073 AB014 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTS SLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYSTVPWTFGQGTKVEIKR 566 DVD518H AB014 AB073 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL QQSGPELEKPGASVKISCKASGYSFTGYNMNWVKQ SNGKSLEWIGNIDPYFGGTNYNQKFKGKATLTVDK SSSTAYMQLKSLTSEDSAVYYCARNYDYDGGCFDY WGQGTTLTVSS 567 DVD518L AB014 AB073 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPQAWTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG 實例2.115 :產生具有連接子組3之VEGF(序列1)及DLL4 (序列 4)DVD-Ig 521 - 151681.doc 201127956 表168
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 568 DVD523H AB073 AB014 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPG KGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDV WGQGTLVTVSS 569 DVD523L AB073 AB014 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCS ASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTV PWTFGQGTKVEIKR 570 DVD524H AB014 AB073 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPIAPEVQL QQSGPELEKPGASVKISCKASGYSFTGYNMNWVKQ SNGKSLEWIGNIDPYFGGTNYNQKFKGKATLTVDK SSSTAYMQLKSLTSEDSAVYYCARNYDYDGGCFDY WGQGTTLTVSS 571 DVD524L AB014 AB073 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPQAVVTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG 實例2.116 :產生具有連接子組4之VEGF(序列1)及DLL4 (序列 4)DVD-Ig 表169
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 572 DVD529H AB073 AB014 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVG WINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMN SLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLV TVSS 522- 151681.doc 201127956
573 DVD529L ΑΒ073 AB014 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTS SLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYSTVPWTFGQGTKVEIKR 574 DVD530H ABO 14 AB073 EVQLVESGGG.LVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLQQSGPEL EKPGASVKISCKASGYSFTGYNMNWVKQSNGKSLE WIGNIDPYFGGTNYNQKFKGKATLTVDKSSSTAYM QLKSLTSEDSAVYYCARNYDYDGGCFDYWGQGTTL TVSS 575 DVD530L AB014 AB073 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPE：DFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPQAWTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG
實例2.117 :產生具有連接子組1之VEGF(序列2)及DLL4 (序列 4)DVD-Ig 表170
S£Q ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 576 DVD513H AB073 AB070 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLE：WIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVA GITPAGGYTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVS S 577 DVD513L AB073 AB070 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCR ASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTT PPTFGQGTKVEIKR 578 DVD514H AB070 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEVJVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLQQSGPELEKP GASVKISCKASGYSFTGYNMNWVKQSNGKSLEWIG NIDPYFGGTNYNQKFKGKATLTVDKSSSTAYMQLK SLTSEDSAVYYCARNYDYDGGCFDYWGQGTTLTVS S 151681.doc - 523· ；ΐί 201127956 579—DVD514L ΓΑΒ070 AB073
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPQAVVTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG 實例2.118 :產生具有連接子組2之VEGF(序列2)及DLL4 (序列 4)DVD-Ig 表171
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 580 DVD519H AB073 AB070 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPG KGLEWVAGITPAGGYTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQ GTLVTVSS 581 DVD519L AB073 AB070 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSAS FLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQSYTTPPTFGQGTKVEIKR 582 DVD520H AB070 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQS GPELEKPGASVKISCKASGYSFTGYNMNWVKQSNG KSLEWIGNIDPYFGGTNYNQKFKGKATLTVDKSSS TAYMQLKSLTSEDSAVYYCARNYDYDGGCFDYWGQ GTTLTVSS 583 DVD520L AB070 AB073 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRXVAAPSVFIFPPQAVVTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG 實例2.119 :產生具有連接子組3之VEGF(序列2)及DLL4 (序列 4)DVD-Ig -524- 151681.doc 201127956 表172
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 584 DVD525H AB073 AB070 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPG KGLEWVAGITPAGGYTYYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQ GTLVTVSS 585 DVD525L AB073 AB070 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCR ASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTT PPTFGQGTKVEIKR 586 DVD526H AB070 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLE^WVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQS GPELEKPGASVKISCKASGYSFTGYNMNWVKQSNG KSLEWIGNIDPYFGGTNYNQKFKGKATLTVDKSSS TAYMQLKSLTSEDSAVYYCARNYDYDGGCFDYWGQ GTTLTVSS 587 DVD526L AB070 AB073 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPQAVVTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG
實例2.120 :產生具有連接子組4之VEGF(序列2)及DLL4 (序列 4)DVD-Ig 表173
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 588 DVD531H AB073 AB070 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVA GITPAGGYTYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVS S •525· 151681.doc 201127956
589 DVD531L AB073 AB070 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSAS FLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQSYTTPPTFGQGTKVEIKR 590 DVD532H AB070 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLQQSGPELEKP GASVKISCKASGYSFTGYNMNWVKQSNGKSLEWIG NIDPYFGGTNYNQKFKGKATLTVDKSSSTAYMQLK SLTSEDSAVYYCARNYDYDGGCFDYWGQGTTLTVS S 591 DVD532L AB070 AB073 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPQAWTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG 實例2.121 :產生具有連接子組1之VEGF(序列3)及DLL4 (序列 4)DVD-Ig 表174
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 592 DVD515H AB073 AB071 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVG AIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTV SS 593 DVD515L AB073 AB071 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCR ASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTS PLTFGQGTKVEIKR 594 DVD516H AB071 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLQQSGPELEK PGASVKISCKASGYSFTGYNMNWVKQSNGKSLEWI GNIDPYFGGTNYNQKFKGKATLTVDKSSSTAYMQL KSLTSEDSAVYYCARNYDYDGGCFDYWGQGTTLTV SS • 526· 151681.doc 201127956 595DVD516L AB071 AB073
DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPQAWTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG 實例2.122 :產生具有連接子組2之VEGF(序列3)及DLL4 (序列 4)DVD Ig 表175
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 596 DVD521H AB073 AB071 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPG KGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWG QGTLVTVSS 597 DVD521L AB073 AB071 QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAAS NLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQSNTSPLTFGQGTKVEIKR 598 DVD522H AB071 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQ SGPELEKPGASVKISCKASGYSFTGYNMNWVKQSN GKSLEWIGNIDPYFGGTNYNQKFKGKATLTVDKSS STAYMQLKSLTSEDSAVYYCARNYDYDGGCFDYWG QGTTLTVSS 599 DVD522L AB071 AB073 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVE'IFPPQAVVTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGL工GGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG 實例2.123 :產生具有連接子組3之VEGF(序列3)及DLL4 (序列 4)DVD-Ig 527- 151681.doc 201127956 表176
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 600 DVD527H AB073 AB071 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPG KGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKN TAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWG QGTLVTVSS 601 DVD527L AB073 AB071 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPDIQMTQSPSSLSASVGDRVTITCR ASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTS PLTFGQGTKVEIKR 602 DVD528H AB071 AB073 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLQQ SGPELEKPGASVKISCKASGYSFTGYNMNWVKQSN GKSLEWIGNIDPYFGGTNYNQKFKGKATLTVDKSS STAYMQLKSLTSEDSAVYYCARNYDYDGGCFDYWG QGTTLTVSS 603 DVD528L AB071 AB073 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPQAVVTQESALTTSPGETVTLTCRSSTG AVTTSNYANWVQEKPDHLFTGLIGGTNNRAPGVPA RFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNH WVFGGGTKLTVLG
實例2.124 :產生具有連接子組4之VEGF(序列3)及DLL4 (序列 4)DVD-Ig φ 表177
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 604 DVD533H AB073 AB071 EVQLQQSGPELEKPGASVKISCKASGYSFTGYNMN WVKQSNGKSLEWIGNIDPYFGGTNYNQKFKGKATL TVDKSSSTAYMQLKSLTSEDSAVYYCARNYDYDGG CFDYWGQGTTLTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVG AIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTV SS 528- 151681.doc 201127956
605 DVD533L ΑΒ073 ΑΒ071 QAWTQESALTTSPGETVTLTCRSSTGAVTTSNYA NWVQEKPDHLFTGLIGGTNNRAPGVPARFSGSLIG DKAALTITGAQTEDEAIYFCALWYSNHWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASVGD RVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAAS NLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQSNTSPLTFGQGTKVEIKR 606 DVD534H ΑΒ071 ΑΒ073 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLQQSGPELEK PGASVKISCKASGYSFTGYNMNWVKQSNGKSLEWI GNIDPYFGGTNYNQKFKGKATLTVDKSSSTAYMQL KSLTSEDSAVYYCARNYDYDGGCFDYWGQGTTLTV ss 607 DVD534L ΑΒ071 ΑΒ073 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPQAWTQESALTTSPGETVTL TCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNN RAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFC ALWYSNHWVFGGGTKLTVLG
實例2.125 :產生具有連接子組1之HER2(序列1)及ErbB3 (序列 1)DVD-Ig 表178
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 608 DVD387H AB062 AB004 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPSVFPLAPEVQLVESGGG LVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGL EWVARIYPTNGYTRYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTL VTVSS 609 DVD387L AB062 AB004 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPSVFIFPPDIQMTQS PSSLSAS VGDRVTITCRA3QDVNTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFA TYYCQQHYTTPPTFGQGTKVEIKR 610 DVD388H AB004 AB062 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQW GAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPG KGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQ FSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTL VTVSS •529· 15168I.doc 201127956 611
DVD388L AB004 AB062
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIEMTQSPDSLAVSLGERAT INCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA VYYCQQYYSTPRTFGQGTKVEIKR 實例2.126 :產生具有連接子組2之.HER2(序列1)及ErbB3 (序列 1)DVD-Ig 表179
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 612 DVD391H AB062 AB004 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPSVFPLAPEVQLVESGGG LVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGL EWVARIYPTNGYTRYADSVKGRFTISADTSKNTAY LQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTL VTVSS 613 DVD391L AB062 AB004 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTI TCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQH YTTPPTFGQGTKVEIKR 614 DVD392H AB004 AB062 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLFIAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQW GAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPG KGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQ FSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTL VTVSS 615 DVD392L AB004 AB062 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR 實例2.127 :產生具有連接子組3之HER2(序列1)及ErbB3 (序列 1)DVD-Ig -530- 151681.doc 201127956 表180
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 616 DVD395H AB062 AB004 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPEVQLVESGGGLVQPGGS LRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIY PTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLR AEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 617 DVD395L AB062 AB004 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPSVFIFPPDIQMTQSPSSLSAS VGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFA TYYCQQHYTTIPPTFGQGTKVEIKR 618 DVD396H AB004 AB062 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQWGAGLLKP SETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIG EINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSS VTAADTAVYYCARDKWTWYFDLWGRGTLVTVSS 619 DVD396L AB004 AB062 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIEMTQSPDSLAVSLGERAT INCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA VYYCQQYYSTPRTFGQGTKVEIKR
實例2.128 :產生具有連接子組4之HER2(序列1)及ErbB3 (序列 1)DVD-Ig 表181
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 620 DVD683H AB062 AB004 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWS WIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTIS VETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFD LWGRGTLVTVSSASTKGPEVQLVESGGGLVQPGGS LRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIY PTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLR AEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 621 DVD683L AB062 AB004 DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSN RNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFG QGTKVEIKRTVAAPDIQMTQSPSSLSASVGDRVTI TCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQH YTTPPTFGQGTKVEIKR •531 · 151681.doc 201127956
622 DVD684H AB004 AB062 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQWGAGLLKP SETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIG EINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSS VT AADT AVY YCARDKWTW Y FDLWGRGT L VT VS S 623 DVD684L AB004 AB062 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIEMTQSPDSLAVSLGERATINCRSSQ SVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQY YSTPRTFGQGTKVEIKR 實例2.129 :產生具有連接子組1之HER2(序列1)及ErbB3 (序列 2)DVD-Ig 表182
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 624 DVD399H AB063 AB004 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FOIWGQGTMVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 625 DVD399L AB063 AB004 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR 626 DVD400H AB004 AB063 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPIiAPEVQLVES GGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPG KGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKN SLYLQMNSLRDEDTAVYYCARDRGDFDAFDIWGQG TMVTVSS 627 DVD400L AB004 AB063 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCQASQDITNYLNWYQQKPGKAPKLLIYDASNLE TGVPSRFSGSGSGTDFTFTISSLQPEDIATYNCQQ CENFPITFGQGTRLEIKR 實例2.130 :產生具有連接子組2之HER2(序列1)及ErbB3 (序列 2)DVD-Ig - 532-
151681.doc 201127956 表183
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 628 DVD403H AB063 AB004 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 629 DVD403L AB063 AB004 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPED工ATYNCQQCENFPITFGQGTRLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 630 DVD404H AB004 AB063 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPG KGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKN SLYLQMNSLRDEDTAVYYCARDRGDFDAFDIWGQG TMVTVSS 631 DVD404L AB004 AB063 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR
實例2.131 :產生具有連接子組3之HER2(序列1)及ErbB3 (序列 2)DVD-Ig 表184
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 632 DVD407H AB063 AB004 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 151681.doc 533-
S 201127956
633 DVD407L AB063 AB004 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD FTFTISSLQPEDIATYNCQQCENFPITFGQGTRLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR 634 DVD408H AB004 AB063 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVS YISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMN SLRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 635 DVD408L AB004 AB063 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCQASQDITNYLNWYQQKPGKAPKLLIYDASNLE TGVPSRFSGSGSGTDFTFTISSLQPEDIATYNCQQ CENFPITFGQGTRLEIKR 實例2.132 :產生具有連接子組4之HER2(序列1)及ErbB3 (序列 2)DVD-Ig 表185
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 636 DVD685H AB063 AB004 EVQLVESGGGLVQPGGSLRLSCAASGFTFSIYSMN WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRDEDTAVYYCARDRGDFDA FDIWGQGTMVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 637 DVD685L AB063 AB004 DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNW YQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTD E'TFTISSLQPEDIATYMCQQCENFPITFGQGTRLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 638 DVD686H AB004 AB063 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVS YISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMN SLRDEDTAVYYCARDRGDFDAFDIWGQGTMVTVSS 639 DVD686L AB004 AB063 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCQASQ DITNYLNWYQQKPGKAPKLLIYDASNLETGVPSRF SGSGSGTDFTFTISSLQPEDIATYNCQQCENFPIT FGQGTRLEIKR -534-
151681.doc 201127956 實例2.133 :產生具有連接子組1之EGFR(序列2)及ErbB3 (序列 3)DVD-Ig 表186
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 640 DVD409H AB067 AB033 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPPTSRLSINKDNSKSQVFTKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 641 DVD409L AB067 AB033 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVV SWYQQHPGKA]?KLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPDILLTQSPVILSVSPGERVSFS CRASQSIGTNIHWYQQRTNGSPRLLIKYASESISG IPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNN NWPTTFGAGTKLELKR 642 DVD410H AB033 AB067 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEIWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPEVQLLESGGGLVQPG GSLRLSCAASGFTFSHYVMAWVRQAPGKGLEWVSS ISSSGGWTLYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCTRGLKMATIFDYWGQGTLVTVSS 643 DVD410L AB033 AB067 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQSALTQPASVSGSPGQSITISCTGTSS DVGSYNVVSWYQQHPGKAPKLIIYEVSQRPSGVSN RFSGSKSGNTASLTISGLQTEDEADYYCCSYAGSS IFVIFGGGTKVTVLG
實例2.134 :產生具有連接子組2之EGFR(序列2)及ErbB3 (序列 3)DVD-Ig 表187
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 644 DVD413H AB067 AB033 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQSG PGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGK GLEWLGVIWSGGNTDYNTPFTSRLSINKD1S1SKSQV FFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT LVTVSA - 535 - 151681.doc 201127956
645 DVD413L AB067 AB033 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVV SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPSVTLFPPDILLTQSPVILSVSP GERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY ASESISGIPSRFSGSGSGTDFTLSINSVESEDIAD YYCQQNNNWPTTFGAGTKLELKR 646 DVD414H AB033 AB067 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGT L VT VS AASTKGPSVFPLAPE VQLLE S G GGLVQPGGSLRLSCAASGFTFSHYVMAWVRQAPGK GLEWVSSISSSGGWTLYADSVKGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCTRGLKMATIFDYWGQGT LVTVSS 647 DVD414L AB033 AB067 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPQSALTQPASVSGSPGQSITI SCTGTSSDVGSYNVVSWYQQHPGKAPKLIIYEVSQ RPSGVSNRFSGSKSGNTASLTISGLQTEDEADYYC CSYAGSSIFVIFGGGTKVTVLG 實例2.135 :產生具有連接子組3之EGFR(序列2)及ErbB3 (序列 3)DVD-Ig 表188
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 648 DVD417H AB067 AB033 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQSG PGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGK GLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQV FFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGT LVTVSA 649 DVD417L AB067 AB033 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNW SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPDILLTQSPVILSVSPGERVSFS CRASQSIGTNIHWYQQRTNGSPRLLIKYASESISG IPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNN NWPTTFGAGTKLELKR 650 DVD418H AB033 AB067 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKGPSVFPLAPEVQLLESG GGLVQPGGSLRLSCAASGFTFSHYVMAWVRQAPGK GLEWVSSISSSGGWTLYADSVKGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCTRGLKMATIFDYWGQGT LVTVSS 536 _ 151681.doc 201127956 651 DVD418L AB033 AB067
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPQSALTQPASVSGSPGQSITISCTGTSS DVGSYNVVSWYQQHPGKAPKLIIYEVSQRPSGVSN RFSGSKSGNTASLTISGLQTEDEADYYCCSYAGSS IFVIFGGGTKVTVLG 實例2.136:產生具有連接子組4之£0罗11(序列2)及£1^83 (序列 3)DVD-Ig 表189
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 652 DVD421H AB067 AB033 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQPS QSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSL QSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 653 DVD421L AB067 AB033 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNW SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPSVTLFPPDILLTQSPVILSVSP GERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY ASESISGIPSRFSGSGSGTDFTLSINSVESEDIAD YYCQQNNNWPTTFGAGTKLELKR 654 DVD422H AB033 AB067 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVH WVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSIN KDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYE FAYWGQGTLVTVSAASTKQPEVQLLESGGGLVQPG GSLRLSCAASGFTFSHYVMAWVRQAPGKGLEWVSS ISSSGGWTLYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCTRGLKMATIFDYWGQGTLVTVSS 655 DVD422L AB033 AB067 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHW YQQRTNGSIPRLLIKYASESISGIPSRFSGSGSGTD FTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLE LKRTVAAPSVFIFPPQSALTQPASVSGSPGQSITI SCTGTSSDVGSYNVVSWYQQHPGKAPKLIIYEVSQ RPSGVSNRF'SGSKSGNTASLTISGLQTEDEADYYC CSYAGSSIFVIFGGGTKVTVLG 實例2.137 :產生具有連接子組1之HER2(序列1)及ErbB3 (序列 3)DVD-Ig 537· 151681.doc 201127956 表190
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 656 DVD411H AB067 AB004 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 657 DVD411L AB067 AB004 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVV SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHY TTPPTFGQGTKVEIKR 658 DVD412H AB004 AB067 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLLESGGGLVQP GGSLRLSCAASGFTFSHYVMAWVRQAPGKGLEWVS SISSSGGWTLYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCTRGLKMATIFDYWGQGTLVTVSS 659 DVD412L AB004 AB067 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPQSALTQPASVSGSPGQSITISCTGTSS DVGSYNVVSWYQQHPGKAPKLIIYEVSQRPSGVSN RFSGSKSGNTASLTISGLQTEDEADYYCCSYAGSS IFVIFGGGTKVTVLG 實例2.138 :產生具有連接子組2之HER2(序列1)及ErbB3 (序列 3)DVD-Ig 表191
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 660 DVD415H AB067 AB004 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 661 DVD415L AB067 AB004 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVV SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASV GDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFAT YYCQQHYTTPPTFGQGTKVEIKR -538- 151681.doc 201127956
662 DVD416H AB004 AB067 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLLES GGGLVQPGGSLRLSCAASGFTFSHYVMAWVRQAPG KGLEWVSSISSSGGWTLYADSVKGRFTISRDNSKN TLYLQMNSLRAEDTAVYYCTRGLKMATIFDYWGQG TLVTVSS 663 DVD416L AB004 AB067 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE 工 KRTVAAPSVFIFPPQSALTQPASVSGS PGQSITI SCTGTSSDVGSYNWSWYQQHPGKAPKLIIYEVSQ RPSGVSNRFSGSKSGNTASLTISGLQTEDEADYYC CSYAGSSIFVIFGGGTKVTVLG 實例2.139 :產生具有連接子組3之HER2(序列1)及ErbB3
(序列 3)DVD-Ig 表192
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 664 DVD419H AB067 AB004 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVS SIS S SGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 665 DVD419L AB067 AB004 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNW SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHY TTPPTFGQGTKVEIKR 666 DVD420H AB004 AB067 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLLES GGGLVQPGGSLRLSCAASGFTFSHYVMAWVRQAPG KGLEWVSSISSSGGWTLYADSVKGRFTISRDNSKN TLYLQMNSLRAEDTAVYYCTRGLKMATIFDYWGQG TLVTVSS 667 DVD420L AB004 AB067 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPQSALTQPASVSGSPGQSITISCTGTSS DVGSYNVVSWYQQHPGKAPKLIIYEVSQRPSGVSN RFSGSKSGNTASLTISGLQTEDEADYYCCSYAGSS IFVIFGGGTKVTVLG 實例2.140 :產生具有連接子組4之HER2(序列1)及ErbB3 (序列 3)DVD-Ig • 539- 151681.doc 201127956 表193
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 668 DVD423H AB067 AB004 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMA WVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATI FDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 669 DVD423L AB067 AB004 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVV SWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSG NTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGG TKVTVLGQPKAAPSVTLFPPDIQMTQSPSSLSASV GDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFAT YYCQQHYTTPPTFGQGTKVEIKR 670 DVD424H AB004 AB067 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLLESGGGLVQP GGSLRLSCAASGFTFSHYVMAWVRQAPGKGLEWVS SISSSGGWTLYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCTRGLKMATIFDYWGQGTLVTVSS 671 DVD424L AB004 AB067 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPQSALTQPASVSGSPGQSITI SCTGTSSDVGSYNWSWYQQHPGKAPKLIIYEVSQ RPSGVSNRFSGSKSGNTASLTISGLQTEDEADYYC CSYAGSSIFVIFGGGTKVTVLG
實例2.141 :產生具有連接子組1之VEGF(序列1)及PLGF (序列 2)DVD-Ig 表 194 ·
SEQ ID NO DVD可變區 域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 672 DVD541H AB074VH AB014VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINT YTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRA EDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS 673 DVD541L AB074VL AB014VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR •540- 15168】.doc 201127956
674 DVD542H AB014VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLKQSGPGL VQPSQSLSITCTVSGFSLTTYGIHWVRQSPGKGLE WLGVMWSGGDTDYDAAFISRLSISKDNSKSQVFFK MNSLQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 675 DVD542L AB014VL AB074VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR 實例2.142 :產生具有連接子組2之VEGF(序列1)及PLGF (序列 2)DVD-Ig
表195
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 676 DVD549H AB074VH AB014VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLE WVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYL QMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG TLVTVSS 677 DVD549L AB074VL AB014VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 678 DVD550H AB014VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL KQSGPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQ SPGKGLEWLGVMWSGGDTDYDAAFISRLSISKDNS KSQVFFKMNSLQANDTGIYYCARYRFYGMDYWGQG TSVTVSS 679 DVD550L AB014VL AB074VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYL顔 YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR 實例2.143 :產生具有連接子組3之VEGF(序列1)及PLGF (序列 2)DVD-Ig •541 · 151681.doc 201127956 表196
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 680 DVD557H AB074VH AB014VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQS PGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLE WVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYL QMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG TLVTVSS 681 DVD557L AB074VL AB014VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 682 DVD558H AB014VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQL KQSGPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQ SPGKGLEWLGVMWSGGDTDYDAAFISRLSISKDNS KSQVFFKMNSLQANDTGIYYCARYRFYGMDYWGQG TSVTVSS 683 DVD558L AB014VL AB074VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR
實例2.144 :產生具有連接子組4之VEGF(序列1)及PLGF (序列 2)DVD_Ig φ 表197
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 684 DVD565H AB074VH AB014VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINT YTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRA EDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS 542- 151681.doc 201127956
685 DVD565L AB074VL AB014VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPPCVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 686 DVD566H AB014VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPQVQLKQSGPGL VQPSQSLSITCTVSGFSLTTYGIHWVRQSPGKGLE WLGVMWSGGDTDYDAAFISRLSISKDNSKSQVFFK MNSLQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 687 DVD566L AB014VL AB074VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWS T PWT FGGGTKLEIKR
實例2.145 :產生具有連接子组1之VEGF(序列2)及PLGF (序列 2)DVD-Ig 表198
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 688 DVD543H AB074VH AB070VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITP AGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 689 DVD543L AB074VL AB070VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYMRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 690 DVD544H AB070VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRETI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQP SQSLSITCTVSGFSLTTYGIHWVRQSPGKGLEWLG VMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMNS LQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 691 DVD544L AB070VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR • 543 · 151681.doc 201127956 實例2.146 :產生具有連接子組2之VEGF(序列2)及 PLGF(序列 2)DVD-Ig 表199
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 692 DVD551H AB074VH AB070VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLE WVAGITPAGGYTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLV TVSS 693 DVD551L AB074VL AB070VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 694 DVD552H AB070VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQS GPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSPG KGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKSQ VFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTSV TVSS 695 DVD552L AB070VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR
實例2.147 :產生具有連接子組3之VEGF(序列2)及PLGF (序列 2)DVD-Ig 表200
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 696 DVD559H AB074VH AB070VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLE WVAGITPAGGYTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLV TVSS -544- 151681.doc 201127956
697 DVD559L AB074VL AB070VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 698 DVD560H AB070VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQS GPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSPG KGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKSQ VFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTSV TVSS 699 DVD560L AB070VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR
實例2.148 :產生具有連接子組4之VEGF(序列2)及PLGF (序列 2)DVD-Ig 表201
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 700 DVD567H AB074VH AB070VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITP AGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 701 DVD567L AB074VL AB070VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 702 DVD568VH AB070VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQP SQSLSITCTVSGFSLTTYGIHWVRQSPGKGLEWLG VMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMNS LQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 703 DVD568VL AB070VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR - 545 - 151681.doc 201127956 實例2.149 :產生具有連接子组1之VEGF(序列3)及PLGF (序列 2)DVD-Ig 表202
SEQ 1D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 704 DVD545H AB074VH AB071VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYP YSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 705 DVD545L AB074VL AB071VL MQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 706 DVD546H AB071VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQ PSQSLSITCTVSGFSLTTYGIHWVRQSPGKGLEWL GVMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMN SLQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 707 DVD546L AB071VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR
實例2.150 :產生具有連接子組2之VEGF(序列3)及PLGF · (序列 2)DVD-Ig 表203
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 708 DVD553H AB074VH AB071VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLE WVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTL VTVSS •546· 151681.doc 201127956
709 DVD553L AB074VL AB071VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 710 DVD554H AB071VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPIAPQVQLKQ SGPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSP GKGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKS QVFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTS VTVSS 711 DVD554L AB071VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYMRFAWYQQKPGMAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR
實例2.151 :產生具有連接子組3之VEGF(序列3)及PLGF (序列 2)DVD-Ig 表204
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 712 DVD561H AB074VH AB071VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLE WVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTL VTVSS 713 DVD561L AB074VL AB071VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE 工KRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 714 DVD562H AB071VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQ SGPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSP GKGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKS QVFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTS VTVSS • 547· 151681.doc 201127956 715
DVD562L
AB071VL
AB074VL
DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR 實例2.152 :產生具有連接子組4之VEGF(序列3)及PLGF (序列 2)DVD-Ig 表205
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 716 DVD569H AB074VH AB071VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQS PGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYP YSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 717 DVD569L AB074VL AB071VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 718 DVD570H AB071VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQ PSQSLSITCTVSGFSLTTYGIHWVRQSPGKGLEWL GVMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMN SLQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 719 DVD570L AB071VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR 實例2.153 :產生具有連接子組1之HER2(序列1)及PLGF (序列 2)DVD-Ig -548- 151681.doc 201127956 表206
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 720 DVD547H AB074VH AB004VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYP TNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 721 DVD547L AB074VL AB004VL MQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 722 DVD548H AB004VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQP SQSLSITCTVSGFSLTTYGIHWVRQSPGKGLEWLG VMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMNS LQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 723 DVD548L AB004VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSL(2PEDFATYYCQQHYTTE>PTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR
實例2.154 :產生具有連接子組2之HER2(序列1)及PLGF (序列 2)DVD-Ig 表207
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 724 DVD555H AB074VH AB004VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLV TVSS 725 DVD555L AB074VL AB004VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR
J 151681.doc -549- 201127956
726 DVD556H AB004VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQS GPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSPG KGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKSQ VFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTSV TVSS 727 DVD556L AB004VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR
實例2.155 :產生具有連接子組3之HER2(序列1)及PLGF (序列 2)DVD-Ig 表 208 #
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 728 DVD563H AB074VH AB004VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLV TVSS 729 DVD563L AB074VL AB004VL AIQMTQSSSSFSVSLGDRVTITCKASEDIYNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 730 DVD564H AB004VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLKQS GPGLVQPSQSLSITCTVSGFSLTTYGIHWVRQSPG KGLEWLGVMWSGGDTDYDAAFISRLSISKDNSKSQ VFFKMNSLQANDTGIYYCARYRFYGMDYWGQGTSV TVSS 731 DVD564L AB004VL AB074VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPAIQMTQSSSSFSVSLGDRVTITCKASE DIYNRFAWYQQKPGNAPRLLISGAASLEAGVPSRF SGSGSGQDYTLSITSLQTEDVATYYCQQYWSTPWT FGGGTKLEIKR
實例2.156 :產生具有連接子組4之HER2(序列1)及PLGF (序列 2)DVD-Ig - 550- 151681.doc 201127956 表209
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 732 DVD571H AB074VH AB004VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGIH WVRQSPGKGLEWLGVMWSGGDTDYDAAFISRLSIS KDNSKSQVFFKMNSLQANDTGIYYCARYRFYGMDY WGQGTSVTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYP TNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 733 DVD571L AB074VL AB004VL AIQMTQSSSSFSVSLGDRVTITCKASED工YNRFAW YQQKPGNAPRLLISGAASLEAGVPSRFSGSGSGQD YTLSITSLQTEDVATYYCQQYWSTPWTFGGGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR 734 DVD572H AB004VH AB074VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLKQSGPGLVQP VMWSGGDTDYDAAFISRLSISKDNSKSQVFFKMNS LQANDTGIYYCARYRFYGMDYWGQGTSVTVSS 735 DVD572L AB004VL AB004VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPAIQMTQSSSSFSVSLGDRVT ITCKASEDIYNRFAWYQQKPGNAPRLLISGAASLE AGVPSRFSGSGSGQDYTLSITSLQTEDVATYYCQQ YWSTPWTFGGGTKLEIKR
實例2.157 :產生具有連接子組1之PLGF(序列1)及VEGF (序列 2)DVD-Ig 表210
SEQ ID NO DVD可變 區域名稱 外可變區 域名稱 内可變區 域名稱 序列 12345678901234567890123456789012345 736 DVD573H AB047VH AB070VH QVQLQQSGAELVKPGASVKISCiCASGYTFTDYYINWV KLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDT SSSTAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTL LTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASG FTISDYWIHWVRQAPGKGLEWVAGITPAGGYTYYADS VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFV FFLPYAMDYWGQGTLVTVSS 737 DVD573L AB047VL AB070VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMRKS FLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSG TDFTLTISSVQAEDVAVYYCKQSYHLFTFGSGTKLEI KRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQDVS TAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKV EIKR -551 - I51681.doc 201127956
738 DVD574H AB070VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWV RQAPGKGLEWVAGITPAGGYTYYADSVKGRFTISADT SKNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWG QGTLVTVSSASTKGPQVQLQQSGAELVKPGASVKISC KASGYTETDYYINWVKLAPGQGLEWIGWIYPGSGNTK YNEKFKGKATLTIDTSSSTAYMQLSSLTSEDTAVYFC VRDSPFFDYWGQGTLLTVSS 739 DVD574L AB070VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKRTVA APDIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSG SGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGSGTKL EIKR 實例2.158 :產生具有連接子組2之PLGF(序列1)及VEGF (序列 2)DVD-Ig 表211
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内外可變區 域名稱 序列 12345678901234567890123456789012345 740 DVD581H AB047VH AB070VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLE WVAGITPAGGYTYYADSVKGRFTISADTSiCNTAYL QMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLV TVSS 741 DVD581L AB047VL AB070VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQSYTTPPTFGQGTKVEIKR 742 DVD582H AB070VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQS GAELVKPGASVKISCKASGYTFTDYYINWVKLAPG QGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSSS TAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTLL TVSS 743 DVD582L AB070VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR 實例2.159 :產生具有連接子組3之PLGF(序列1)及VEGF (序列 2)DVD-Ig -552- 151681.doc 201127956 表212
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 744 DVD589VH AB047VH AB070VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSS3TAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLE WVAGITPAGGYTYYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARFVFFLPY^DYWGQGTLV TVSS 745 DVD589VL AB047VL AB070VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSY TTPPTFGQGTKVEIKR 746 DVD590VH AB070VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQS GAELVKPGASVKISCKASGYTFTDYYINWVKLAPG QGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSSS TAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTLL TVSS 747 DVD590VL AB070VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR
實例2.160 :產生具有連接子組4之PLGF(序列1)及VEGF (序列 2)DVD-Ig 表213
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 748 DVD597VH AB047VH AB070VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITP AGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 553 - 151681.doc 201127956
749 DVD597VL AB047VL AB070VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQSYTTPPTFGQGTKVEIKR 750 DVD598VH AB070VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLQQSGAELVKP GASVKISCKASGYTFTDYYINWVKLAPGQGLEWIG WIYPGSGNTKYNEKFKGKATLTIDTSSSTAYMQLS SLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 751 DVD598VL AB070VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR 實例2.161 :產生具有連接子組1之PLGF(序列1)及VEGF (序列 3)DVD-Ig 表214
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 752 DVD575H AB047VH AB071VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFOY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYP YSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 753 DVD575L AB047VL AB071VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSN TSPLTFGQGTKVEIKR 754 DVD576H AB071VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLQQSGAELVK PGASVKISCKASGYTFTDYYINWVKLAPGQGLEWI GWIYPGSGNTKYNEKFKGKATLTIDTSSSTAYMQL SSLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 755 DVD576L AB071VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR -554
151681.doc 201127956 實例2.162 :產生具有連接子組2之PLGF(序列1)及VEGF (序列 3)DVD-Ig 表215
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 756 DVD583H AB047VH AB071VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLE WVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYL QMNSLRAE.DTAVYYCARWGHSTSPWAMDYWGQGTL VTVSS 757 DVD583L AB047VL AB071VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYA ASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQSNTSPLTFGQGTKVEIKR 758 DVD584H AB071VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQ SGAELVKPGASVKISCKASGYTFTDYYINWVKLAP GQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSS STAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTL LTVSS 759 DVD584L AB071VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDETLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR 實例2.163 :產生具有連接子組3之PLGF(序列1)及VEGF (序列 3)DVD-Ig 表216
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 760 DVD591VH AB047VH AB071VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLE WVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTL VTVSS •555 - 151681.doc 201127956
761 DVD591VL AB047VL AB071VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSN TSPLTFGQGTKVEIKR 762 DVD592VH AB071VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQ SGAELVKPGASVKISCKASGYTFTDYYINWVKLAP GQGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSS STAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTL LTVSS 763 DVD592VL AB071VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR
實例2.164 :產生具有連接子組4之PLGF(序列1)及VEGF (序列 3)DVD-Ig 表217
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 764 DVD599VH AB047VH AB071VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYP YSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 765 DVD599VL AB047VL AB071VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYA ASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQSNTSPLTFGQGTKVEIKR 766 DVD600VH AB071VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLQQSGAELVK PGASVKISCKASGYTFTDYY工丽VKLAPGQGLEWI GWIYPGSGNTKYNEKFKGKATLTIDTSSSTAYMQL SSLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 767 DVD600VL AB071VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR
- 556- 151681.doc 201127956 實例2.165 :產生具有連接子組1之HER2(序列1)及PLGF (序列 1)DVD-Ig 表218
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 768 DVD577H AB047VH AB004VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYP TNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 769 DVD577L AB047VL AB004VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHY TTPPTFGQGTKVEIKR 770 DVD578H AB004VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQSGAELVKP GASVKISCKASGYTFTDYYINWVKLAPGQGLEWIG WIYPGSGNTKYNEKFKGKATLTIDTSSSTAYMQLS SLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS τη DVD578L AB004VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE 工KRTVAAPD工VLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR
實例2.166:產生具有連接子組2之11£1^2(序列1)及？1^罗 (序列 1)DVD-Ig 表219
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 772 DVD585H AB047VH AB004VH QVQLQQSGAE；LVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLV TVSS - 557- 151681.doc 201127956
773 DVD585L AB047VL AB004VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFAT YYCQQHYTTPPTFGQGTKVEIKR 774 DVD586H AB004VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQS GAELVKPGASVKISCKASGYTFTDYYINWVKLAPG QGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSSS TAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTLL TVSS 775 DVD586L AB004VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR 實例2.167 :產生具有連接子組3之HER2(序列1)及PLGF (序列 1)DVD-Ig 表220
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 776 DVD593VH AB047VH AB004VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPSVFPIAPEVQLVESGGGL VQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYL QMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLV TVSS 777 DVD593VL AB047VL AB004VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPDIQMTQSPSSLSASVGDRVTIT CRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHY TTPPTFGQGTKVEIKR 778 DVD594VH AB004VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLQQS GAELVKPGASVKISCKASGYTFTDYYINWVKLAPG QGLEWIGWIYPGSGNTKYNEKFKGKATLTIDTSSS TAYMQLSSLTSEDTAVYFCVRDSPFFDYWGQGTLL TVSS 558- 151681.doc 201127956
779 DVD594VL AB004VL AB047VL
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIVLTQSPDSLAVSLGERVTMNCKSSQ SLLNSGMRKSFLAWYQQKPGQSPKLLIYWASTRES GVPDRFTGSGSGTDFTLTISSVQAEDVAVYYCKQS YHLFTFGSGTKLEIKR 實例2.168:產生具有連接子組4之11£1^2(序列1)及？1^罗 (序列 1)DVD-Ig 表221
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 780 DVD601VH AB047VH AB004VH QVQLQQSGAELVKPGASVKISCKASGYTFTDYYIN WVKLAPGQGLEWIGWIYPGSGNTKYNEKFKGKATL TIDTSSSTAYMQLSSLTSEDTAVYFCVRDSPFFDY WGQGTLLTVSSASTKGPEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYP TNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRA EDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 781 DVD601VL AB047VL AB004VL DIVLTQSPDSLAVSLGERVTMNCKSSQSLLNSGMR KSFLAWYQQKPGQSPKLLIYWASTRESGVPDRFTG SGSGTDFTLTISSVQAEDVAVYYCKQSYHLFTFGS GTKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASV GDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYS ASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFAT YYCQQHYTTPPTFGQGTKVEIKR 782 DVD602VH AB004VH AB047VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPQVQLQQSGAELVKP GASVKISCKASGYTFTDYYINWVKLAPGQGLEWIG WIYPGSGNTKYNEKFKGKATLTIDTSSSTAYMQLS SLTSEDTAVYFCVRDSPFFDYWGQGTLLTVSS 783 DVD602VL AB004VL AB047VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPDSLAVSLGERVT MNCKSSQSLLNSGMRKSFLAWYQQKPGQSPKLLIY WASTRESGVPDRFTGSGSGTDFTLTISSVQAEDVA VYYCKQSYHLFTFGSGTKLEIKR 實例2.169 :產生具有連接子組1之HGF(序列1)及VEGF(序 列 2)DVD-Ig 559- 151681.doc 201127956 表222
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 784 DVD643H AB012VH AB070VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQA PGKGLEWVAGITPAGGYTYYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYW GQGTLVTVSS 785 DVD643L AB012VL AB070VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 786 DVD644H AB070VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVES GGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPG KGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARDEYNSGWYVLFDYW GQGTLVTVSS 787 DVD644L AB070VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT ITCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWTFGQGTKVEIKR 實例2.170 :產生具有連接子組2之HGF(序列1)及VEGF(序 列 2)DVD-Ig 表223
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 788 DVD649H AB012VH AB070VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQA PGKGLEWVAGITPAGGYTYYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYW GQGTLVTVSS 560- 151681.doc 201127956
789 DVD649L AB012VL AB070VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDirTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 790 DVD650H AB070VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVES GGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPG KGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARDEYNSGWYVLFDYW GQGTLVTVSS 791 DVD650L AB070VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR
實例2.171 :產生具有連接子組3之HGF(序列1)及VEGF(序 列 2)DVD-Ig 表224
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 792 DVD655H AB012VH AB070VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEW VAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQ MNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVT VSS 793 DVD655L AB012VL AB070VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 794 DVD656H AB070VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLVESGGGLVKP GGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVS YISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMN SLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVT VSS 561 - 151681.doc 201127956
795 DVD656L AB070VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDF7VTYYCQQSYTTPPTFGQGTKVE 工KRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT 工TCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWTFGQGTKVEIKR _ 實例2.172 :產生具有連接子組4之HGF(序列1)及VEGF(序 列 2)DVD-Ig 表225
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 796 DVD709VH AB012VH AB070VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEW VAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQ MNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVT VSS 797 DVD709VL AB012VL AB070VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 798 DVD710VH AB070VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPQVQLVESGGGLVKP GGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVS YISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMN SLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLVT VSS 799 DVD710VL AB070VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 實例2.173 :產生具有連接子組1之HGF(序列1)及VEGF(序 列 3)DVD-Ig 562- 151681.doc 201127956 表226
S£Q m NO DVD可變S 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 800 DVD645H AB012VH AB071VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQA PGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDY WGQGTLVTVSS 801 DVD645L AB012VL AB071VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 802 DVD646H AB071VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVE SGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAP GKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAK NSLYLQMNSLI^AEDTAVYYCARDEYNSGWYVLFDY WGQGTLVTVSS 803 DVD646L AB071VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT ITCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWT FGQGT KVEIKR
實例2.174 :產生具有連接子組2之HGF(序列1)及VEGF(序 列 3)DVD-Ig 表227
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 804 DVD651H AB012VH AB071VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPSVFPLAPEVQLV ESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQA PGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDY WGQGTLVTVSS 563 - 151681.doc 201127956
805 DVD651L AB012VL AB071VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 806 DVD652H AB071VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPQVQLVE SGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAP GKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCARDEYNSGWYVLFDY WGQGTLVTVSS 807 DVD652L AB071VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 實例2.175 :產生具有連接子組3之HGF(序列1)及VEGF(序 列 3)DVD-Ig 表228
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 808 DVD657H AB012VH AB071VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEW VGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQ MNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLV TVSS 809 DVD657L AB012VL AB071VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 810 DVD658H AB071VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLVESGGGLVK PGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLV TVSS 564-
151681.doc 201127956
811 DVD658L
AB071VL AB012VL
DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSVSASVGDRVT ITCRASQGISSWLAWYQQKPGKAPNLLIYEASSLQ SGVPSRFGGSGSGTDFTLTISSLQPEDFATYYCQQ ANGFPWTFGQGTKVEIKR 實例2.176:產生具有連接子組4之110[(序列1)及¥£6卩(序 列 3)DVD-Ig 表229
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 812 DVD711VH AB012VH AB071VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMS WIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTI SRDNAKNSLYLQMNSLRAEDTAVYYCARDEYNSGW YVLFDYWGQGTLVTVSSASTKGPEVQLVESGGGLV QPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEW VGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQ MNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLV TVSS 813 DVD711VL AB012VL AB071VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAW YQQKPGKAPNLLIYEASSLQSGVPSRFGGSGSGTD FTLTISSLQPEDFATYYCQQANGFPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 814 DVD712VH AB071VH AB012VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPQVQLVESGGGLVK PGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDEYNSGWYVLFDYWGQGTLV TVSS 815 DVD712VL AB071VL AB012VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPNLLIYEASSLQSGVPSRF GGSGSGTDFTLTISSLQPEDFATYYCQQANGFPWT FGQGTKVEIKR 實例2.177 :產生具有連接子組1之HGF(序列2)及VEGF(序 列 1)DVD-Ig 151681.doc 565 · c： 201127956 表230
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 可變區域名 稱 序列 12345678901234567890123456789012345 816 DVD659H AB079VH AB014VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWI NTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSL RAEDTAVYYCAKYPHYYGSSHWyFDVWGQGTLVTV SS 817 DVD659L AB079VL AB014VL DIQMTQSPSSLSASVGDRVTITCKASENWSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 818 DVD660H AB014VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVQSGAEV KKPGESLKISCKGSGYSFTTYWMHWVRQMPGKGLE WMGEINPTNGHTNYNPSFQGQVTISADKSISTAYL QWSSLKASDTAMYYCARNYVGSIFDYWGQGTLVTV SS 819 DVD660L AB014VL AB079VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NVVSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR 實例2.178 :產生具有連接子組2之HGF(序列2)及VEGF(序 列 1)DVD-Ig 表231
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 820 DVD665H AB079VH AB014VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKG LEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTA YLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWG QGTLVTVSS 566·
151681.doc 201127956
821 DVD665L AB079VL AB014VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGK/^PKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 822 DVD666H AB014VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL VQSGAEVKKPGESLKISCKGSGYSFTTYWMHWVRQ MPGKGLEWMGEINPTNGHTNYNPSFQGQVTISADK SISTAYLQWSSLKASDTAMYYCARNYVGSIFDYWG QGTLVTVSS 823 DVD666L AB014VL AB079VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYTFGQGTKLEIKR
實例2.179 :產生具有連接子組3之HGF(序列2)及VEGF(序 列 1)DVD-Ig 表232
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 824 DVD671VH AB079VH AB014VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI S ADKSIS TAYLQWS S LKAS DTAMY YCARN YVGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKG LEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTA YLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWG QGTLVTVSS 825 DVD671VL AB079VL AB014VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCSASQ DISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWT FGQGTKVEIKR 826 DVD672VH AB014VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQL VQSGAEVKKPGESLKISCKGSGYSFTTYWMHWVRQ MPGKGLEWMGEINPTNGHTNYNPSFQGQVTISADK SISTAYLQWSSLKASDTAMYYCARNYVGSIFDYWG QGTLVTVSS 567· 151681.doc 201127956
827 DVD672VL AB014VL AB079VL
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NVVSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR 實例2.180 :產生具有連接子組4之HGF(序列2)及VEGF(序 列 1)DVD-Ig 表233
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 828 DVD677VH AB079VH AB014VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWI NTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSL RAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTV SS 829 DVD677VL AB079VL AB014VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCSASQDISNYLNWyQQKPGKAPKVLIYFTSSLH SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YSTVPWTFGQGTKVEIKR 830 DVD678VH AB014VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMN WVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGS SHWYFDVWGQGTLVTVSSASTKGPEVQLVQSGAEV KKPGESLKISCKGSGYSFTTYWMHWVRQMPGKGLE WMGEINPTNGHTNYNPSFQGQVTISADKSISTAYL QWSSLKASDTAMYYCARNYVGSIFDYWGQGTLVTV SS 831 DVD678VL AB014VL AB079VL DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNW YQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYT FGQGTKLEIKR 實例2.181 :產生具有連接子組1之HGF(序列2)及VEGF(序 列 2)DVD-Ig * 568 - 151681.doc 201127956 表234
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 832 DVD661H AB079VH AB070VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWS SLKAS DTAMYYCARNYVGS 工 F DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGI TPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 833 DVD661L AB079VL AB070VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 834 DVD662H AB070VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLVQSGAEVKKP GESLKISCKGSGYSFTTYWMHWVRQMPGKGLEWMG EINPTNGHTNYNPSFQGQVTISADKSISTAYLQWS SLKASDTAMYYCARNYVGSIFDYWGQGTLVTVSS 835 DVD662L AB070VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NVVSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR
實例2.182 :產生具有連接子組2之HGF(序列2)及VEGF(序 列 2)DVD-Ig 表235
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 836 DVD667H AB079VH AB070VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFT工SDYWIHWVRQAPGKG LEWVAGITPAGGYTYYADSVKGRFTISADTSKNTA YLQMNSLR?VEDTAVYYCARFVFFLPYAMDYWGQGT LVTVSS 837 DVD667L AB079VL AB070VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR -569- 151681.doc 201127956
838 DVD668H AB070VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPXAPEVQLVQS GAEVKKPGESLKISCKGSGYSFTTYWMHWVRQMPG KGLEWMGEINPTNGHTNYNPSFQGQVTISADKSIS TAYLQWSSLKASDTAMYYCARNYVGSIFDYWGQGT LVTVSS 839 DVD668L AB070VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYTFGQGTKLEIKR 實例2.183 :產生具有連接子組3之HGF(序列2)及VEGF(序 列 2)DVD-Ig 表 236 ·
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 840 DVD673VH AB079VH AB070VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKG LEWVAGITPAGGYTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGT LVTVSS 841 DVD673VL AB079VL AB070VL DIQMTQSPSSLSASVGDRVTITCKASENWSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPT FGQGTKVEIKR 842 DVD674VH AB070VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVQS GAEVKKPGESLKISCKGSGYSFTTYWMHWVRQMPG KGLEWMGEINPTNGHTNYNPSFQGQVTISADKSIS TAYLQWS SLKAS DTAMYYCARNYVGSIFDYWGQGT LVTVSS 843 DVD674VL AB070VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NWSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR
實例2.184:產生具有連接子組4之116罗(序列2)及¥£0罗(序 列 2)DVD-Ig -570- 151681.doc 201127956 表237
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 844 DVD679VH AB079VH AB070VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGI TPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 845 DVD679VL AB079VL AB070VL DIQMTQSPSSLSASVGDRVTITCKASENWSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SYTTPPTFGQGTKVEIKR 846 DVD680VH AB070VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIH WVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPY AMDYWGQGTLVTVSSASTKGPEVQLVQSGAEVKKP GESLKISCKGSGYSFTTYWMHWVRQMPGKGLEWMG EINPTNGHTNYNPSFQGQVTISADKSISTAYLQWS SLKASDTAMYYCARNYVGSIFDYWGQGTLVTVSS 847 DVD680VL AB070VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYTFGQGTKLEIKR
實例2.185 :產生具有連接子組1之HGF(序列2)及VEGF(序 列 3)DVD-Ig 表238
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 848 DVD663H AB079VH AB071VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYMPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAI YPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 849 DVD663L AB079VL AB071VL DIQMTQSPSSLSASVGDRVTITCKASENWSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR -571 - 151681.doc 201127956
850 DVD664H AB071VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLVQSGAEVKK PGESLKISCKGSGYSFTTYWMHWVRQMPGKGLEWM GEINPTNGHTNYNPSFQGQVTISADKSISTAYLQW SSLKASDTAMYYCARNYVGSIFDYWGQGTLVTVSS 851 DVD664L AB071VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NWSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR 實例2.186 :產生具有連接子組2之HGF(序列2)及VEGF(序 列 3)DVD-Ig 表239
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 852 DVD669H AB079VH AB071VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI S ADKSISTAYLQWS SLKAS DTAMYYCARNY VGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKG LEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQG TLVTVSS 853 DVD669L AB079VL AB071VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 854 DVD670H AB071VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVQ SGAEVKKPGESLKISCKGSGYSFTTYWMHWVRQMP GKGLEWMGEINPTNGHTNYNPSFQGQVTISADKSI STAYLQWSSLKASDTAMYYCARNYVGSIFDYWGQG TLVTVSS 855 DVD670L AB071VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT 工 TCKASENWSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYTFGQGTKLEIKR 實例2.187 :產生具有連接子組3之HGF(序列2)及VEGF(序 列 3)DVD-Ig •572-
151681.doc 201127956 表240
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 856 DVD675VH AB079VH AB071VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESGG GLVQPGG3LRLSCAASGFTINASWIHWVRQAPGKG LEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQG TLVTVSS 857 DVD675VL AB079VL AB071VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ VIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLT FGQGTKVEIKR 858 DVD676VH AB071VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVQ SGAEVKKPGESLKISCKGSGYSFTTYWMHWVRQMP GKGLEWMGEINPTNGHTNYNPSFQGQVTISADKSI STAYLQWSSLKASDTAMYYCARNYVGSIFDYWGQG TLVTVSS 859 DVD676VL AB071VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASE NWSYVSWYQQKPGKAPKLLIYGASNRNTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCGQSYNYPYT FGQGTKLEIKR
實例2.188 :產生具有連接子組4之HGF(序列2)及VEGF(序 列 3)DVD_Ig 表241
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 860 DVD681VH AB079VH AB071VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWMH WVRQMPGKGLEWMGEINPTNGHTNYNPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARNYVGSIF DYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPGG SLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAI YPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS -573- 151681.doc 201127956
861 DVD681VL AB079VL AB071VL DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSW YQQKPGKAPKLLIYGASNRNTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCGQSYNYPYTFGQGTKLE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLA SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ SNTSPLTFGQGTKVEIKR 862 DVD682VH AB071VH AB079VH EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIH WVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSP WAMDYWGQGTLVTVSSASTKGPEVQLVQSGAEVKK PGESLKISCKGSGYSFTTYWMHWVRQMPGKGLEWM GEINPTNGHTNYNPSFQGQVTISADKSISTAYLQW SSLKASDTAMYYCARNYVGSIFDYWGQGTLVTVSS 863 DVD682VL AB071VL AB079VL DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAW YQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRN TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQ SYNYPYTFGQGTKLEIKR 實例2.189 :產生具有連接子組1之HER2(序列1)及HER2 (序列 2)DVD-Ig 表242
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 864 DVD687H AB004VH AB080VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVA DVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMN SLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS 865 DVD687L AB004VL AB080VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASQ DVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYT FGQGTKVEIKR 866 DVD688H AB080VH AB004VH EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMD WVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTL SVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFY FDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 867 DVD688L AB080VL AB004VL DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAW YQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR • 574·
151681.doc 201127956 實例2.190 :產生具有連接子組2之]HER2(序列1)及HER2 (序列 2)DVD-Ig 表243
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 868 DVD689H AB004VH AB080VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPG KGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKN TLYLQMNSLPAEDTAVYYCARNLGPSFYFDYWGQG TLVTVSS 869 DVD689L AB004VL AB080VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQFEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRY TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYIYPYTFGQGTKVEIKR 870 DVD690H AB080VH AB004VH’ EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMD WVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTL SVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFY FDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 871 DVD690L AB080VL AB004VL DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAW YQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSAS FLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR 實例2.191 :產生具有連接子組3之HER2(序列1)及HER2 (序列 2)DVD-Ig 表244
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 872 DVD691H AB004VH AB080VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPSVFPLAPEVQLVES GGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPG KGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKN TLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQG TLVTVSS - 575 - 151681.doc 201127956
873 DVD691L AB004VL AB080VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCKASQ DVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYT FGQGTKVEIKR 874 DVD692H AB080VH AB004VH EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMD WVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTL SVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFY FDYWGQGTLVTVSSASTKGPSVFPIAPEVQLVESG GGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGK GLEWVARIYPTNGYTRYADSVKGRFTISADTSKNT AYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSS 875 DVD692L AB080VL AB004VL DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAW YQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVE IKRTVAAPDIQMTQSPSSLSASVGDRVTITCRASQ DVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRF SGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPT FGQGTKVEIKR 實例2.192 :產生具有連接子組4之HER2(序列1)及HER2 (序列 2)DVD-Ig 表245
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 876 DVD693H AB004VH AB080VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIH WVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFY AMDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQP GGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVA DVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMN SLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS 877 DVD693L AB004VL AB080VL DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAW YQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTD FTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT 工TCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRY TGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYIYPYTFGQGTKVEIKR 878 DVD694H AB080VH AB004VH EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMD WVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTL SVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFY FDYWGQGTLVTVSSASTKGPEVQLVESGGGLVQPG GSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVAR IYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNS LRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 879 DVD694L AB080VL AB004VL DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAW YQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ HYTTPPTFGQGTKVEIKR •576·
151681.doc 201127956 實例2.193 :產生具有連接子組1之CD3(序列2)及CD-19(序 列 2)DVD-Ig 表246
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 880 DVD897H AB039VH AB111VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPSVFPLAPEVKLQESG PGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRK GLEWLGVIWGSEGTTYYNSALKSRLTIIKDNSKSQ VPLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQ GTSVTVSS 881 DVD897L AB039VL AB111VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAE；DAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPSVFIFPPDIQMTQTTSSLSASLGDRVTI SCRASQDISKTLNWYQQKPDGTVKLLIYHTSRLHS GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQG NTLPYTFGGGTKLEITR 882 DVD898H AB111VH AB039VH EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVS WIRQPPRKGLEWLGVIWGSEGTTYYNSALKSRLTI IKDNSKSQVPLKMNSLQTDDTAIYYCAKHYYYGGS YAMDYWGQGTSVTVSSASTKGPSVFPLAPQVQLQQ SGAELARPGASVKMSCKASGYTFTRYTMHWVKQRP GQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSS STAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQ GTTLTVSS 883 DVD898L AB111VL AB039VL DIQMTQTTSSLSASLGDRVTISCRASQDISKTLNW YQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLE ITRTVAAPSVFIFPPQIVLTQSPAIMSASPGEKVT MTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLAS GVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQW SSNPFTFGSGTKLEINR 實例2.194:產生具有連接子組1之0〇3(序列3)及€〇-19(序 列 2)DVD-Ig 表247
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 884 DVD899H AB107VH AB111VH EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMN WVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTI SVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDS DWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVKLQ ESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQP PRKGLEWLGVIWGSEGTTYYNSALKSRLTIIKDNS KSQVPLKMNSLQTDDTAIYYCAKHYYYGGSYAMDY WGQGTSVTVSS - 577- 151681.doc 201127956
885 DVD899L AB107VL AB111VL DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNW yQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTD YTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVE IKRTVAAPSVFIFPPDIQMTQTTSSLSASLGDRVT ISCRASQDISKTLNWYQQKPDGTVKLLIYHTSRLH SGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQ GNTLPYTFGGGTKLEITR 886 DVD900H AB111VH AB107VH EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVS WIRQPPRKGLEWLGVIWGSEGTTYYNSALKSRLTI IKDNSKSQVPLKMNSLQTDDTAIYYCAKHYYYGGS YAM D YWGQGT S VT VS S ASTKGPSVFPLAPE VQLVE SGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAP GKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSK NTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDV WGQGTLVTVSS 887 DVD900L AB111VL AB107VL DIQMTQTTSSLSASLGDRVTISCRASQDISKTLNW YQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLE ITRTVAAPSVFIFPPDIQMTQSPSSLSASVGDRVT ITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLE SGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQ GN T L P WT FGQGT KVEIKR 實例2.195 :產生具有連接子組1之CD3(序列2)及CD-19(序 列 3)DVD-Ig 表248
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 888 DVD901H AB039VH AB112VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPSVFPLAPEVQLQESG PELVKPGASVKISCKASGYAFSSSWMNWVIQRPGQ GLEWIGRIYPGDGDTNYNGKFKGKATLTADKSSST AYMQLSSLTSVDSAVYFCARSGFITTVLDFDYWGQ GTTLTVSS 889 DVD901L AB039VL AB112VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPSVFIFPPDIVLTQSPTSLAVSLGQRATI SCRASESVDTFGISFMNWFQQKPGQPPKLLIHAAS NQGSGVPSRFSGSGSGTDFSLNIHPMEEDDSAMYF CQQSKEVPFTFGSGTKLEIKR 890 DVD902H AB112VH AB039VH EVQLQESGPELVKPGASVKISCKASGYAFSSSWMN WVIQRPGQGLEWIGRIYPGDGDTNYNGKFKGKATL TADKSSSTAYMQLSSLTSVDSAVYFCARSGFITTV LDFDYWGQGTTLTVSSASTKGPSVFPLAPQVQLQQ SGAELARPGASVKMSCKASGYTFTRYTMHWVKQRP GQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSS STAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQ GTTLTVSS 578·
151681.doc 201127956
891 DVD902L
AB112VL
AB039VL
DIVLTQSPTSLAVSLGQRATISCRASESVDTFGIS FMNWFQQKPGQPPKLLIHAASNQGSGVPSRFSGSG SGTDFSLNIHPMEEDDSAMYFCQQSKEVPFTFGSG TKLEIKRTVAAPSVFIFPPQIVLTQS PAIMSAS PG EKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYY CQQWSSNPFTFGSGTKLEINR 實例2.196:產生具有連接子組1之€»3(序列3)及0〇-19(序 列 3)DVD-Ig 表249
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 892 DVD903H AB107VH AB112VH EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMN WVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTI SVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDS DWYFDVWGQGTLVTVSSASTKGPSVFPLAPEVQLQ ESGPELVKPGASVKISCKASGYAFSSSWMNWVIQR PGQGLEWIGRIYPGDGDTNYNGKFKGKATLTADKS SSTAYMQLSSLTSVDSAVYFCARSGFITTVLDFDY WGQGTTLTVSS 893 DVD903L AB107VL AB112VL DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNW YQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTD YTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVE IKRTVAAPSVFIFPPDIVLTQSPTSLAVSLGQRAT ISCRASESVDTFGISFMNWFQQKPGQPPKLLIHAA SNQGSGVPSRFSGSGSGTDFSLNIHPMEEDDSAMY FCQQSKEVPFTFGSGTKLEIKR 894 DVD904H AB112VH AB107VH EVQLQESGPELVKPGASVKISCKASGYAFSSSWMN WVIQRPGQGLEWIGRIYPGDGDTNYNGKFKGKATL TADKSSSTAYMQLSSLTSVDSAVYFCARSGFITTV LDFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLVE SGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAP GKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSK NTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDV WGQGTLVTVSS 895 DVD904L AB112VL AB107VL DIVLTQSPTSLAVSLGQRATISCRASESVDTFGIS FMNWFQQKPGQPPKLLIHAASNQGSGVPSRFSGSG SGTDFSLNIHPMEEDDSAMYFCQQSKEVPFTFGSG TKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYT SRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATY YCQQGNTL PWT FGQGTKVEIKR 實例2.197 :產生具有連接子組1之CD3(序列2)及CD-19(序 列 l)DVD Ig 579- 151681.doc 201127956 表250
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 896 DVD913H AB039VH AB006VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPSVFPLAPQVQLQQSG AELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQ GLEWIGQIWPGDGDTNYNGKFKGKATLTADESSST AYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDY WGQGTSVTVSS 897 DVD913L AB039VL AB006VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPSVFIFPPDILLTQTPASLAVSLGQRATI SCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDAS NLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYH CQQSTEDPWTFGGGTKLEIKR 898 DVD914H AB006VH AB039VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPSVFPLAPQVQ LQQSGAELARPGASVKMSCKASGYTFTRYTMHWVK QRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTD KSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDY WGQGTTLTVSS 899 DVD914L AB006VL AB039VL DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPSVFIFPPQIVLTQSPAIMSASPG EKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTS KLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYY CQQWSSNPFTFGSGTKLEINR 實例2.198 :產生具有連接子組1之CD3(序列3)及CD-19(序 列 1)DVD-Ig 表251
S£Q ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 900 DVD915H AB107VH AB006VH EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMN WVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTI SVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDS DWYFDVWGQGTLVTVSSASTKGPSVFPLAPQVQLQ QSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQR PGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADES SSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYA MDYWGQGTSVTVSS 580-
151681.doc 201127956
901 DVD915L AB107VL AB006VL DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNW YQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTD YTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVE IKRTVAAPSVFIFPPDILLTQTPASLAVSLGQRAT ISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDA SNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATY HCQQSTEDPWTFGGGTKLEIKR 902 DVD916H AB006VH AB107VH QVQLQQSGAELVRPGSSVKISCfCASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGK^KGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPSVFPLAPEVQ LVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVR QAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWY FDVWGQGTLVTVSS 903 DVD916L AB006VL AB107VL DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPSVFIFPPDIQMTQSPSSLSASVG DRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYT SRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATY YCQQGNTLPWTFGQGTKVEIKR
實例2.199 :產生具有連接子組1之CD3(序列4)及CD-19(序 列 2)DVD-Ig 表252
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 904 DVD917H AB108VH AB111VH EVQLLESGGGLVQPGGSLKLSCAASGFTFNTYAMN WVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRF TISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFG NSYVSWFAYWGQGTLVTVSSASTKGPSVFPLAPEV KLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWI RQPPRKGLEWLGVIWGSEGTTYYNSALKSRLTIIK DNSKSQVPLKMNSLQTDDTAIYYCAKHYYYGGSYA MDYWGQGTSVTVSS 905 DVD917L AB108VL AB111VL ELWTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYA NWVQQKPGQAPRGLIGGTNKRAPGTPARFSGSLLG GKAALTLSGVQPEDEAEYYCALWYSNLWVFGGGTK LTVLGQPKAAPSVTLFPPDIQMTQTTSSLSASLGD RVTISCRASQDISKTLNWYQQKPDGTVKLLIYHTS RLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYF CQQGNTLPYTFGGGTKLEITR 906 DVD918H AB111VH AB108VH EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVS WIRQPPRKGLEWLGVIWGSEGTTYYNSALKSRLTI IKDNSKSQVPLKMNSLQTDDTAIYYCAKHYYYGGS YAMDYWGQGT SVTVS SASTKGPSVFPLAPEVQLLE SGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQAP GKGLEWVAP.IRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSW FAYWGQGTLVTVSS 581- 151681.doc 201127956
907 DVD918L AB111VL AB108VL
DIQMTQTTSSLSASLGDRVTISCRASQDISKTLNW YQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLE ITRTVAAPSVFIFPPELVVTQEPSLTVSPGGTVTL TCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNK RAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYC ALWYSNLWVFGGGTKLTVLG 實例2.200:產生具有連接子組1之€»3(序列4)及€0-19(序 列 3)DVD-Ig 表253
SEQ ID NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 908 DVD919H AB108VH AB112VH EVQLLESGGGLVQPGGSLKLSCAASGFTFNTYAMN WVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRF TISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFG MSYVSWFAYWGQGTLVTVSSASTKGPSVFPLAPEV QLQESGPELVKPGASVKISCKASGYAFSSSWMNWV IQRPGQGLEWIGRIYPGDGDTNYNGKFKGKATLTA DKSSSTAYMQLSSLTSVDSAVYFCARSGFITTVLD FDYWGQGTTLTVSS 909 DVD919L AB108VL AB112VL ELVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYA NWVQQKPGQAPRGLIGGTNKRAPGTPARFSGSLLG GKAALTLSGVQPEDEAEYYCALWYSNLWVFGGGTK LTVLGQPKAAPSVTLFPPDIVLTQSPTSLAVSLGQ RATISCRASESVDTFGISFMNWFQQKPGQPPKLLI HAASNQGSGVPSRFSGSGSGTDFSLNIHPMEEDDS AMYFCQQSKEVPFTFGSGTKLEIKR 910 DVD920H AB112VH AB108VH EVQLQESGPELVKPGASVKISCKASGYAFSSSWMN WVIQRPGQGLEWIGRIYPGDGDTNYNGKFKGKATL TADKSSSTAYMQLSSLTSVDSAVYFCARSGFITTV LDFDYWGQGTTLTVSSASTKGPSVFPLAPEVQLLE SGGGLVQPGGSLKLSCAASGFTFNTYAMNWVRQAP GKGLEWVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSW FAYWGQGTLVTVSS 911 DVD920L AB112VL AB108VL DIVLTQSPTSLAVSLGQRATISCRASESVDTFGIS FMNWFQQKPGQPPKLLIHAASNQGSGVPSRFSGSG SGTDFSLNIHPMEEDDSAMYFCQQSKEVPFTFGSG TKLEIKRTVAAPSVFIFPPELVVTQEPSLTVSPGG TVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIG GTNKRAPGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCALWYSNLWVFGGGTKLTVLG
實例2.201 :產生具有連接子組1之CD3(序列4)及CD-19(序 列 1)DVD-Ig 582- 151681.doc 201127956 表254
SEQ 1D NO DVD可變區 域名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 912 DVD921H AB108VH AB006VH EVQLLESGGGLVQPGGSLKLSCAASGFTFNTYAMN WVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRF TISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFG NSYVSWFAYWGQGTLVTVSSASTKGPSVFPIAPQV QLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWV KQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTA DESSSTAYMQLSSLASEDSAVYFCARRETTTVGRY YYAMDYWGQGTSVTVSS 913 DVD921L AB108VL AB006VL ELVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYA NWVQQKPGQAPRGLIGGTNKRAPGTPARFSGSLLG GKAALTLSGVQPEDEAEYYCALWYSNLWVFGGGTK LTVLGQPKAAPSVTLFPPDILLTQTPASLAVSLGQ RATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLI YDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDA ATYHCQQSTEDPWTFGGGTKLEIKR 914 DVD922H AB006VH AB108VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPSVFPXAPEVQ LLESGGGLVQPGGSLKLSCAASGFTFNTYAMNWVR QAPGKGLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSY VSW FAYWGQGTLVTVS S 915 DVD922L AB006VL AB108VL DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPSVFIFPPELVVTQEPSLTVSPGG TVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIG GTNKRAPGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCALWYSNLWVFGGGTKLTVLG
實例2.2〇2 :產生具有連接子組2之CD3(序列4)及CD-19(序 列 1)DVD-Ig 表255
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678S01234567890123456789012345 916 DVD1000H AB006VH AB108VH QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMN WVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATL TADESSSTAYMQLSSLASEDSAVYFCARRETTTVG RYYYAMDYWGQGTSVTVSSASTKGPEVQLLESGGG LVQPGGSLKLSCAASGFTFNTYAMNWVRQAPGKGL EWVARIRSKYNNYATYYADSVKDRFTISRDDSKNT AYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWFAYW GQGTLVTVSS 583 - 151681.doc 201127956 917
DVD1000L
AB006VL
AB108VL
DILLTQTPASLAVSLGQRATISCKASQSVDYDGDS YLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSG SGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGG TKLEIKRTVAAPELWTQEPSLTVSPGGTVTLTCR SSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAP GTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALW YSNLWVFGGGTKLTVLG 實例2.203:產生具有連接子組2之€〇3(序列2)及〇〇-19(序 列 2)DVD-Ig 表256
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 918 DVD1005H AB039VH AB111VH QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMH WVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATL TTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYC LDYWGQGTTLTVSSASTKGPEVKLQESGPGLVAPS QSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGV IWGSEGTTYYNSALKSRLTIIKDNSKSQVPLKMNS LQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVS S 919 DVD1005L AB039VL AB111VL QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWY QQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSY SLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEI NRTVAAPDIQMTQTTSSLSASLGDRVTISCRASQD ISKTLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFS GSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTF GGGTKLEITR 920 DVD1006H AB111VH AB039VH EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVS WIRQPPRKGLEWLGVIWGSEGTTYYNSALKSRLTI IKDNSKSQVPLKMNSLQTDDTAIYYCAKHYYYGGS YAMDYWGQGTSVTVSSASTKGPQVQLQQSGAELAR PGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWI GYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQL SSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVS S · 921 DVD1006L AB111VL AB039VL DIQMTQTTSSLSASLGDRVTISCRASQDISKTL陳 YQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLE ITRTVAAPQIVLTQSPAIMSASPGEKVTMTCSASS SVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFR GSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTF GSGTKLEINR 實例2.204:產生具有連接子組1之mCD3及mCD-19 DVD-Ig •584· 15168l.doc 201127956 表257
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 922 DVD1044H AB110VH AB114VH EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMH WVRQAPGRGLESVAYITSSSINIKYADAVKGRFTV SRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNY WGQGTMVTVSSASTKGPEVQLQQSGAELVRPGTSV KLSCKVSGDTITFYYMHFVKQRPGQGLEWIGRIDP EDESTKYSEKFKNKATLTADTSSNTAYLKLSSLTS EDTATYFCIYGGYYFDYWGQGVMVTVSS 923 DVD1044L AB110VL AB114VL DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNW YQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRD SSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLE IKRTVAAPDIQMTQSPASLSTSLGETVTIQCQASE DIYSGLAWYQQKPGKSPQLLIYGASDLQDGVPSRF SGSGSGTQYSLKITSMQTEDEGVYFCQQGLTYPRT FGGGTKLELKR 924 DVD1045H AB114VH AB110VH EVQLQQSGAELVRPGTSVKLSCKVSGDTITFYYMH FVKQRPGQGLEWIGRIDPEDESTKYSEKFKNKATL TADTSSNTAYLKLSSLTSEDTATYFCIYGGYYFDY WGQGVMVTVSSASTKGPEVQLVESGGGLVQPGKSL KLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITS S SINIKYADAVKGRFTVSRDNAKNLLFLQMNILKS EDTAMYYCARFDWDKNYWGQGTMVTVSS 925 DVD1045L AB114VL AB110VL DIQMTQSPASLSTSLGETVTIQCQASEDIYSGLAW YQQKPGKSPQLLIYGASDLQDGVPSRFSGSGSGTQ YSLKITSMQTEDEGVYFCQQGLTYPRTFGGGTKLE LKRTVAAPDIQMTQSPSSLPASLGDRVTINCQASQ DISNYLNWYQQKPGKAPKLLIYYTNKLADGVPSRF SGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWT FGPGTKLEIKR
實例2.205 :產生具有連接子組2之mCD3及mCD-19 DVD-
Ig 表258
SEQ ID NO DVD可變區域 名稱 外可變區域 名稱 内可變區域 名稱 序列 12345678901234567890123456789012345 926 DVD1046H AB110VH AB114VH EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMH WVRQAPGRGLESVAYITSSSINIKYADAVKGRFTV SRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNY WGQGTMVTVSSASTKGPSVFPLAPEVQLQQSGAEL VRPGTSVKLSCKVSGDTITFYYMHFVKQRPGQGLE WIGRIDPEDESTKYSEKFKNKATLTADTSSNTAYL KLSSLTSEDTATYFCIYGGYYFDYWGQGVMVTVSS 927 DVD1046L AB110VL AB114VL DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNW YQQKPGKAPKLLIYYTNKLADGVPSRFSGSGSGRD SS FTISSLESEDIGSYYCQQYYNYPWTFGPGTKLE IKRTVAAPSVFIFPPDIQMTQSPASLSTSLGETVT IQCQASEDIYSGLAWYQQKPGKSPQLLIYGASDLQ DGVPSRFSGSGSGTQYSLKITSMQTEDEGVYFCQQ GLTYPRTFGGGTKLELKR - 585 - 151681.doc 201127956
928 DVD1047H AB114VH AB110VH EVQLQQSGAELVRPGTSVKLSCKVSGDTITFYYMH FVKQRPGQGLEWIGRIDPEDESTKYSEKFKNKATL TADTSSNTAYLKLSSLTSEDTATYFCIYGGYYFDY WGQGVMVTVSSASTKGPSVFPLAPEVQLVESGGGL VQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLE SVAYITSSSINIKYADAVKGRFTVSRDNAKNLLFL QMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS 929 DVD1047L AB114VL AB110VL DIQMTQSPASLSTSLGETVTIQCQASEDIYSGLAW YQQKPGKSPQLLIYGASDLQDGVPSRFSGSGSGTQ YSLKITSMQTEDEGVYFCQQGLTYPRTFGGGTKLE LKRTVAAPSVFIFPPDIQMTQSPSSLPASLGDRVT INCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLA DGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQ YYNYPWTFGPGTKLEIKR 實例2.206 :用於選殖親本抗體及DVD-Ig序列之選殖載體 序列 表259
載體名稱 SEQ ID NO 核苷酸序列 123456789012345678901234567890123456789012345678901 VI 930 GCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT TGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGG GGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGAC CCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGC GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAATGAGCGGCCGCTCGAGGCCGGCAAGGCCGG ATCCCCCGACCTCGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAA TAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGG CAAATCATTTGGTCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCC CCGCCCCGGACGAACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCG GGGCAGTGCATGTAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGC CCTGTTCCACATGTGACACGGGGGGGGACCAAACACAAAGGGGTTCTCTGA CTGTAGTTGACATCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTG GCTTTCATCCTGGAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTG CCTTTATGTGTAACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACAT GTACCTCCCAGGGGCCCAGGAAGACTACGGGAGGCTACACCAACGTCAATC AGAGGGGCCTGTGTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCA ATAGTGTTTATAAGGCCCCCTTGTTAACCCTAAACGGGTAGCATATGCTTC CCGGGTAGTAGTATATACTATCCAGACTAACCCTAATTCAATAGCATATGT -586·
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151681.doc
TACCCAACGGGAAGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTA AGGAACAGCGATATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATG GGGTCAGGATTCCACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGG CTGAAGATCAAGGAGCGGGCAGTGAACTCTCCTGAATCTTCGCCTGCTTCT TCATTCTCCTTCGTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTAA GGTGTATGTGAGGTGCTCGAAAACAAGGTTTCAGGTGACGCCCCCAGAATA AAATTTGGACGGGGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAA CCCTCACAAACCCCTTGGGCAATAAATACTAGTGTAGGAATGAAACATTCT GAATATCTTTAACAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACT GGATGTCCATCTCACACGAATTTATGGCTATGGGCAACACATAATCCTAGT GCAATATGATACTGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACA GGTGAACCATGTTGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGAC GCCGACAGCAGCGGACTCCACTGGTTGTCTCTAACACCCCCGAAAATTAAA CGGGGCTCCACGCCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTT TTTTTGAAATTGTGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTG CGGTTTTGGACTGTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCC GCTAACCACTGCGGTCAAACCACTTGCCCACAAAACCACTAATGGCACCCC GGGGAATACCTGCATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGC TGCGATCTGGAGGACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAG GGTTGTTGGTCCTCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATG TTGCCATGGGTAGCATATACTACCC7\AATATCTGGATAGCATATGCTATCC TAATCTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCAT ATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATTTATATCT GGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAA TCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATG CTATCCTAATAGAGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGG TAGCATATACTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATAT CTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGCATAGGCTATCCT 7\ATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATA TGCTATCCTAATTTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTG GGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAAT CTGTATCCGGGTAGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGA ATTTTCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAA TGTCATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAA TGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTA TCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAG GAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGC GGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAA AGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCT CAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAAT GATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGA CGCCGGGC^AGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTT GGTTGAGTACTCACCAGTCACAGA^AAGCATCTTACGGATGGCATGACAGT AAGAG7\ATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAA CTTACTTCTGACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCA CAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAA TGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGC AACAACGTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCG GCAACAATTAATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCT GCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGG TGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCC CTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGA ACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTA ACTGTCAGACCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCA TTTTTAATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGAC CAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGA AAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTG CTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCA AGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGAT ACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGTVA CTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGC TGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATA GTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACA - 587 - 201127956
GCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGA GCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCC GGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGG AAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGA GCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGC CAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCA CATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGC CTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGA GTCAGTGAGCGAGGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCC CGCGCGTTGGCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTG GAAAGCGGGCAGTGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTA GGCACCCCAGGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAAT TGTGAGCGGATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGC CAAGCTCTAGCTAGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAA GCATGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCA TCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGAC TAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTAT TCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGC TTTGCAAAGATGGATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATG GACCTTCTAGGTCTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTG GGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGG CAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGA TGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATAT AAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCeAG AACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGG TTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGAT TCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTG CGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCG CTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGC TTTCGATAAGTCTCTAGCCATTTA/^AATTTTTGATGACCTGCTGCGACGCT TTTTTTCTGGCAAGATAGTCTTGT7\AATGCGGGCCAAGATCTGCACACTGG TATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCG CACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACG GGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCC GTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGC GTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATG GAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAA AAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCG GGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTC TTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTG GGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGA ATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGT GGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGAGGAATTCTCTAGAG ATCCCTCGACCTCGAGATCCATTGTGCCCGGGCGCCACCATGGAGTTTGGG CTGAGCTGGCTTTTTCTTGTCGCGATTTTAAAAGGTGTCCAGTGC V2 931 ACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGA GAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAAC AGGGGAGAGTGTTGAGCGGCCGCTCGAGGCCGGCAAGGCCGGATCCCCCGA CCTCGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTT GGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATT TGGTCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCCCCGCCCCGG ACGAACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCGGGGCAGTGC ATGTAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGCCCTGTTCCA CATGTGACACGGGGGGGGACCAAACACAAAGGGGTTCTCTGACTGTAGTTG ACATCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTGGCTTTCATC CTGGAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTGCCTTTATGT GTAACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACATGTACCTCCC AGGGGCCCAGGAAGACTACGGGAGGCTACACCAACGTCAATCAGAGGGGCC TGTGTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCAATAGTGTTT
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151681.doc
ATAAGGCCCCCTTGTTAACCCTAAACGGGTAGCATATGCTTCCCGGGTAGT AGTATATACTATCCAGACTAACCCTAATTCAATAGCATATGTTACCCAACG GGAAGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTAAGGAACAGC GATATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATGGGGTCAGGA TTCCACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGGCTGAAGATC AAGGAGCGGGCAGTGAACTCTCCTGAATCTTCGCCTGCTTCTTCATTCTCC TTCGTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTAAGGTGTATGT GAGGTGCTCGAAAACAAGGTTTCAGGTGACGCCCCCAGAATAAAATTTGGA CGGGGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAACCCTCACAA ACCCCTTGGGCAATAAATACTAGTGTAGGAATGT^AACATTCTGAATATCTT TAACAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACTGGATGTCCA TCTCACACGAATTTATGGCTATGGGCAACACATAATCCTAGTGCAATATGA TACTGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACAGGTGAACCA TGTTGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGACGCCGACAGC AGCGGACTCCACTGGTTGTCTCTA^CACCCCCGAAAATTAAACGGGGCTCC ACGCCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTTTTTTTGAAA TTGTGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTGCGGTTTTGG ACTGTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCCGCTAACCAC TGCGGTCAAACCACTTGCCCACAAAACCACTAATGGCACCCCGGGGAATAC CTGCATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGCTGCGATCTG GAGGACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAGGGTTGTTGG TCCTCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATGTTGCCATGG GTAGCATATACTACCCAAATATCTGGATAGCATATGCTATCCT7VATCTATA TCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCC TAATCTATATCTGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCAT AGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCT GGGTAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATGCTATCCTAA TAGAGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATATA CTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCTGGGTAGC ATATGCTATCCTAATCTATATCTGGGTAGCATAGGCTATCCTAATCTATAT CTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCT AATTTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATA TGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCG GGTAGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGAATTTTCTTG AAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGAT AATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGG AACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCAT GAGACAATT^ACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTAT GAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTG CCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGA AGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGG TAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCAC TTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCA AGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTA CTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATT ATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCC7VACTTACTTCT GACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGG GGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCAT ACCAAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTT GCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATT AATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGC CCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGG GTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTAT CGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAG ACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGA CC AAGT T T AC T CAT AT AT AC T T TAG AT T GAT T T AAAAC T T CAT T T T T AAT T TT^AAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCC TTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAA AGGATCTTCTTGAGATCCTTTTTTTC；TGCGCGTAATCTGCTGCTTGCA7\AC AAAAAAACCACCGCTACCAGCGGTGGiTTTGTTTGCCGGATCAAGAGCTACC AACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATAC TGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGC ACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAG •589· 201127956
TGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGA TAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTT GGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGA AAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGG CAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTG GTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATT TTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGC GGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTT TCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTG AGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAG CGAGGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTG GCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTGGAAAGCGGG CAGTGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTAGGCACCCCA GGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGG ATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGCCAAGCTCTA GCTAGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATC TCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCC TAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTT TTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGT AGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTTGCAAAG ATGGATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATGGACCTTCTA GGTCTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTGGGCAGAGCG CACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAAC CGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGT AGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGT AAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCC TTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCC CGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGG AGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCG CCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAA GTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTG GCAAGATAGTCTTGTAT^ATGCGGGCCAAGATCTGCACACTGGTATTTCGGT TTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTC GGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTC TCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGC CCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGA AAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCG GCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTT TCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTC CAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTG GGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGAC TGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCT TTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAG TTTTTTTCTTCCATTTCAGGTGTCGTGAGGAATTCTCTAGAGATCCCTCGA CCTCGAGATCCATTGTGCCCGGGCGCACCATGGACATGCGCGTGCCCGCCC AGCTGCTGGGCCTGCTGCTGCTGTGGTTCCCCGGCTCGCGATGC V3 932 CAACCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCG GGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGA GTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC AGCTACCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGC TGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACA GAATGTTCATGAGCGGCCGCTCGAGGCCGGCAAGGCCGGATCCCCCGACCT CGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGA ATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTGG TCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCCCCGCCCCGGACG AACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCGGGGCAGTGCATG TAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGCCCTGTTCCACAT GTGACACGGGGGGGGACCAAACACAAAGGGGTTCTCTGACTGTAGTTGACA TCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTGGCTTTCATCCTG GAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTGCCTTTATGTGTA ACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACATGTACCTCCCAGG
151681.doc •590· 201127956
151681.doc
GGCCCAGGAAGACTACGGGAGGCTACACCAACGTCAATCAGAGGGGCCTGT GTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCAATAGTGTTTATA AGGCCCCCTTGTTAACCCTAAACGGGTAGCATATGCTTCCCGGGTAGTAGT ATATACTATCCAGACTAACCCTA/vTTCAATAGCATATGTTACCCAACGGGA AGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTAAGGAACAGCGAT ATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATGGGGTCAGGATTC CACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGGCTGAAGATCAAG GAGCGGGCAGTGAACTCTCCTGAATCTTCGCCTGCTTCTTCATTCTCCTTC GTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTAAGGTGTATGTGAG GTGCTCGAAAACAAGGTTTCAGGTGACGCCCCCAGAATAAAATTTGGACGG GGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAACCCTCACAAACC CCTTGGGCAATAAATACTAGTGTAGGAATGAAACATTCTGAATATCTTTAA CAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACTGGATGTCCATCT CACACGAATTTATGGCTATGGGCAACACATAATCCTAGTGCAATATGATAC TGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACAGGTGAACCATGT TGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGACGCCGACAGCAGC GGACTCCACTGGTTGTCTCTAACACCCCCGAAAATTAAACGGGGCTCCACG CCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTTTTTTTGAAATTG TGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTGCGGTTTTGGACT GTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCCGCTAACCACTGC GGTCAAACCACTTGCCCACAAAACCACTAATGGCACCCCGGGGAATACCTG CATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGCTGCGATCTGGAG GACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAGGGTTGTTGGTCC TCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATGTTGCCATGGGTA GCATATACTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCT GGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAA TCTATATCTGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATAGG CTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCTGGG TAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATGCTATCCTAATAG AGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATATACTA CCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCTGGGTAGCATA TGCTATCCTAATCTATATCTGGGT7VGCATAGGCTATCCTAATCTATATCTG GGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAAT TTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGC TATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCGGGT AGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGAATTTTCTTGAAG ACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGATAAT AATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAAC CCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAG ACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAG TATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCT TCCTGTTTTTGCTCACCCAGT^AACGCTGGTGAAAGTAAAAGATGCTGAAGA TCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAA GATCCTTGAGAGTTTTCGCCCCGMGAACGTTTTCCAATGATGAGCACTTT TAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGA GCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTC ACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATG CAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGAC AACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGA TCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACC AAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCG CAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAAT AGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCT TCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTC TCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGT AGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACA GATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCA AGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAA AAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTA ACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGG ATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAA AAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAAC 1 TCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGT •591 · 201127956
TCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACC GCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGG CGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAA GGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGA GCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAG CGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAG GGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTA TCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTT GTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGC CTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCC TGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTGAGC TGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAGCGA GGAAGCGGAAGAGCGCCCAATACGC7\AACCGCCTCTCCCCGCGCGTTGGCC GATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTGGAAAGCGGGCAG TGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTAGGCACCCCAGGC TTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGGATA ACAATTTCACACAGGAAACAGCTATGACCATGATTACGCCAAGCTCTAGCT AGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCA ATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAA CTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTA TTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGT GAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTTGCAAAGATG GATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATGGACCTTCTAGGT CTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCAC ATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGG TGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTG GCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGT CGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAG TGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTG CGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGA GCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGC CCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCG CGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTC TCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCA AGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTT TGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGC GAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCA AGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCC GCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAG ATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCG CTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCC GTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAG GCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGG GGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGA AGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTT TGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTT TTTTCTTCCATTTCAGGTGTCGTGAGGAATTCTCTAGAGATCCCTCGACCT CGAGATCCATTGTGCCCGGGCGCCACCATGACTTGGACCCCACTCCTCTTC CTCACCCTCCTCCTCCACTGCACAGGAAGCTTATCG V4 933 ACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGA GAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAAC AGGGGAGAGTGTTGAGCGGCCGCTCGAGGCCGGCAAGGCCGGATCCCCCGA CCTCGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTT GGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATT TGGTCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCCCCGCCCCGG ACGAACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCGGGGCAGTGC ATGTAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGCCCTGTTCCA CATGTGACACGGGGGGGGACCAAACACAAAGGGGTTCTCTGACTGTAGTTG ACATCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTGGCTTTCATC
151681.doc -592- 201127956
151681.doc
CTGGAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTGCCTTTATGT GTAACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACATGTACCTCCC AGGGGCCCAGGAAGACTACGGGAGGCTACACCAACGTCAATCAGAGGGGCC TGTGTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCAATAGTGTTT ATAAGGCCCCCTTGTTAACCCTA/^ACGGGTAGCATATGCTTCCCGGGTAGT AGTATATACTATCCAGACTAACCCTAATTCAATAGCATATGTTACCCAACG GGAAGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTAAGGAACAGC GATATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATGGGGTCAGGA TTCCACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGGCTGAAGATC AAGGAGCGGGCAGTGAACTCTCCTGAATCTTCGCCTGCTTCTTCATTCTCC TTCGTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTT^AGGTGTATGT GAGGTGCTCGAAAACAAGGTTTCAGGTGACGCCCCCAGAATAAAATTTGGA CGGGGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAACCCTCACAA ACCCCTTGGGCAATAAATACTAGTGTAGGAATGAAACATTCTGT^ATATCTT TAACAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACTGGATGTCCA TCTCACACGAATTTATGGCTATGGGCAACACATAATCCTAGTGCAATATGA TACTGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACAGGTGAACCA TGTTGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGACGCCGACAGC AGCGGACTCCACTGGTTGTCTCTA?\CACCCCCGAAAATTAAACGGGGCTCC ACGCCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTTTTTTTGAAA TTGTGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTGCGGTTTTGG ACTGTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCCGCTAACCAC TGCGGTCAAACCACTTGCCCACAAAACCACTAATGGCACCCCGGGGAATAC CTGCATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGCTGCGATCTG GAGGACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAGGGTTGTTGG TCCTCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATGTTGCCATGG GTAGCATATACTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATA TCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCC TAATCTATATCTGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCAT AGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCT GGGTAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATGCTATCCTAA TAGAGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATATA CTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCTGGGTAGC ATATGCTATCCTAATCTATATCTGGGTAGCATAGGCTATCCTAATCTATAT CTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCT MTTTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATA TGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCG GGTAGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGAATTTTCTTG AAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGAT AATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGG AACCCCTATTTGTTTATTTTTCTMATACATTCAAATATGTATCCGCTCAT GAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTAT GAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTG CCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGA AGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGG TAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCAC TTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCA AGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTA CTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATT ATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCT GACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGG GGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCAT ACCAAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTT GCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATT AATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGC CCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGG GTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTAT CGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAG ACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGA CCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATT TAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCC TTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAA AGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAAC -593 - 201127956
AAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACC AACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATAC TGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGC ACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAG TGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGA TAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTT GGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGA AAGCGCCACGCTTCCCGAAGGGAG7VAAGGCGGACAGGTATCCGGTAAGCGG CAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTG GTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATT TTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGC GGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTT TCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTG AGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAG CGAGGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTG GCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTGGAAAGCGGG CAGTGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTAGGCACCCCA GGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGG ATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGCCAAGCTCTA GCTAGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATC TCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCC TAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTT TTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGT AGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTTGCAAAG ATGGATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATGGACCTTCTA GGTCTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTGGGCAGAGCG CACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAAC CGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGT AGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGT AAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCC TTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCC CGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGG AGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCG CCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAA GTCTCTAGCCATTT7VAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTG GCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGT TTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTC GGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTC TCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGC CCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGA AAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCG GCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTT TCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTC CAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTG GGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGAC TGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCT TTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAG TTTTTTTCTTCCATTTCAGGTGTCGTGAGGAATTCTCTAGAGATCCCTCGA CCTCGAGATCCATTGTGCCCGGGCGCACCATGACTTGGACCCCACTCCTCT TCCTCACCCTCCTCCTCCACTGCACAGGAAGCTTATCG V5 934 CAACCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCG GGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGA GTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC AGCTACCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGC TGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACA GAATGTTCATGAGCGGCCGCTCGAGGCCGGCAAGGCCGGATCCCCCGACCT CGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAATAGTGTGTTGGA ATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGGCAAATCATTTGG TCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCCCCGCCCCGGACG AACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCGGGGCAGTGCATG TAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGCCCTGTTCCACAT
151681.doc -594- 201127956
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GTGACACGGGGGGGGACCAAACACAAAGGGGTTCTCTGACTGTAGTTGACA TCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTGGCTTTCATCCTG GAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTGCCTTTATGTGTA ACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACATGTACCTCCCAGG GGCCCAGGAAGACTACGGGAGGCTACACCAACGTCAATCAGAGGGGCCTGT GTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCAATAGTGTTTATA AGGCCCCCTTGTTAACCCTAAACGGGTAGCATATGCTTCCCGGGTAGTAGT ATATACTATCCAGACTAACCCTAATTCAATAGCATATGTTACCCAACGGGA AGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTAAGGAACAGCGAT ATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATGGGGTCAGGATTC CACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGGCTGAAGATCAAG GAGCGGGCAGTGAACTCTCCTGAATCTTCGCCTGCTTCTTCATTCTCCTTC GTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTAAGGTGTATGTGAG GTGCTCGAAAACAAGGTTTCAGGTGACGCCCCCAGAATAAAATTTGGACGG GGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAACCCTCACAAACC CCTTGGGCAATAAATACTAGTGTAGGAATGAAACATTCTGAATATCTTTAA CAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACTGGATGTCCATCT CACACGAATTTATGGCTATGGGCAACACATAATCCTAGTGCAATATGATAC TGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACAGGTGAACCATGT TGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGACGCCGACAGCAGC GGACTCCACTGGTTGTCTCTAACACCCCCGAAAATTAAACGGGGCTCCACG CCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTTTTTTTGAAATTG TGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTGCGGTTTTGGACT GTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCCGCTAACCACTGC GGTCAAACCACTTGCCCACAAAACCACTAATGGCACCCCGGGGAATACCTG CATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGCTGCGATCTGGAG GACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAGGGTTGTTGGTCC TCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATGTTGCCATGGGTA GCATATACTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCT GGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAA TCTATATCTGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATAGG CTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCTGGG TAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATGCTATCCTAATAG AGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGGTAGCATATACTA CCCAAATATCTGGATAGCATATGCTATCCTAATCTATATCTGGGTAGCATA TGCTATCCTAATCTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTG GGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAAT TTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGC TATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCGGGT AGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGAATTTTCTTGAAG ACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGATAAT AATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAAC CCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAG ACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAG TATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCT TCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGA TCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAA GATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTT TAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGA GCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTC ACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATG CAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGAC AACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGA TCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACC AAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCG CAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAAT AGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCT TCCGGCTGGCTGGTTTATTGCTGATJVAATCTGGAGCCGGTGAGCGTGGGTC TCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGT AGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACA GATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCA AGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAA AAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTA -595 - 201127956
ACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGG ATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAA AAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAAC TCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGT TCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACC GCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGG CGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAA GGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGA GCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAG CGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAG GGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTA TCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTT GTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGC CTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCC TGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTGAGC TGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAGCGA GGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTGGCC GATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTGGAAAGCGGGCAG TGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTAGGCACCCCAGGC TTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGGATA ACAATTTCACACAGGAAACAGCTATGACCATGATTACGCCAAGCTCTAGCT AGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAAGCATGCATCTCA ATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCCGCCCCTAA CTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACTAATTTTTTTTA TTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTAGT GAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTTTGCAAAGATG GATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATGGACCTTCTAGGT CTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCAC ATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGG TGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTG GCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGT CGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAG TGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTG CGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGA GCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGC CCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCG CGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTC TCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCA AGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTT TGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGC GAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCA AGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCC GCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAG ATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCG CTCGGGAGAGCGGGCGGGTGAGTCACCCACACAT^GGAAAAGGGCCTTTCC GTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAG GCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGG GGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGA AGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTT TGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTT TTTTCTTCCATTTCAGGTGTCGTGAGGT^ATTCTCTAGAGATCCCTCGACCT CGAGATCCATTGTGCCCGGGCGCCACCATGGACATGCGCGTGCCCGCCCAG CTGCTGGGCCTGCTGCTGCTGTGGTTCCCCGGCTCGCGATGC V7 935 GCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG AATCACAAGCCCAGCAACACCAAGGTGGACAAG/^AAGTTGAGCCCAAATCT TGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGG GGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGAC CCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC
151681.doc •596· 201127956
151681.doc
AAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGC GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAATGAGCGGCCGCTCGAGGCCGGCAAGGCCGG ATCCCCCGACCTCGACCTCTGGCTAATAAAGGAAATTTATTTTCATTGCAA TAGTGTGTTGGAATTTTTTGTGTCTCTCACTCGGAAGGACATATGGGAGGG CAAATCATTTGGTCGAGATCCCTCGGAGATCTCTAGCTAGAGGATCGATCC CCGCCCCGGACGAACTAAACCTGACTACGACATCTCTGCCCCTTCTTCGCG GGGCAGTGCATGTAATCCCTTCAGTTGGTTGGTACAACTTGCCAACTGGGC CCTGTTCCACATGTGACACGGGGGGGGACCAAACAC7\AAGGGGTTCTCTGA CTGTAGTTGACATCCTTATAAATGGATGTGCACATTTGCCAACACTGAGTG GCTTTCATCCTGGAGCAGACTTTGCAGTCTGTGGACTGCAACACAACATTG CCTTTATGTGTAACTCTTGGCTGAAGCTCTTACACCAATGCTGGGGGACAT GTACCTCCCAGGGGCCCAGGAAGACTACGGGAGGCTACACCT^ACGTCAATC AGAGGGGCCTGTGTAGCTACCGATAAGCGGACCCTCAAGAGGGCATTAGCA ATAGTGTTTATAAGGCCCCCTTGTTAACCCTAAACGGGTAGCATATGCTTC CCGGGTAGTAGTATATACTATCCAGACTAACCCTAATTCAATAGCATATGT TACCCAACGGGAAGCATATGCTATCGAATTAGGGTTAGTAAAAGGGTCCTA AGGAACAGCGATATCTCCCACCCCATGAGCTGTCACGGTTTTATTTACATG GGGTCAGGATTCCACGAGGGTAGTGAACCATTTTAGTCACAAGGGCAGTGG CTGAAGATCAAGGAGCGGGCAGTGi\ACTCTCCTGAATCTTCGCCTGCTTCT TCATTCTCCTTCGTTTAGCTAATAGAATAACTGCTGAGTTGTGAACAGTAA GGTGTATGTGAGGTGCTCGAAAAC；^GGTTTCAGGTGACGCCCCCAGAATA AAATTTGGACGGGGGGTTCAGTGGTGGCATTGTGCTATGACACCAATATAA CCCTCACAAACCCCTTGGGCAATAAATACTAGTGTAGGAATGAAACATTCT GAATATCTTTAACAATAGAAATCCATGGGGTGGGGACAAGCCGTAAAGACT GGATGTCCATCTCACACGAATTTATGGCTATGGGCAACACATAATCCTAGT GCAATATGATACTGGGGTTATTAAGATGTGTCCCAGGCAGGGACCAAGACA GGTGAACCATGTTGTTACACTCTATTTGTAACAAGGGGAAAGAGAGTGGAC GCCGACAGCAGCGGACTCCACTGGTTGTCTCTAACACCCCCGAAAATTAAA CGGGGCTCCACGCCAATGGGGCCCATAAACAAAGACAAGTGGCCACTCTTT TTTTTGAAATTGTGGAGTGGGGGCACGCGTCAGCCCCCACACGCCGCCCTG CGGTTTTGGACTGTAAAATAAGGGTGTAATAACTTGGCTGATTGTAACCCC GCTAACCACTGCGGTCAAACCACTTGCCCACAAAACCACTTVATGGCACCCC GGGGAATACCTGCATAAGTAGGTGGGCGGGCCAAGATAGGGGCGCGATTGC TGCGATCTGGAGGACAAATTACACACACTTGCGCCTGAGCGCCAAGCACAG GGTTGTTGGTCCTCATATTCACGAGGTCGCTGAGAGCACGGTGGGCTAATG TTGCCATGGGTAGCATATACTACCCAAATATCTGGATAGCATATGCTATCC TAATCTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCAT ATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAATTTATATCT GGGTAGCATAGGCTATCCTAATCTATATCTGGGTAGCATATGCTATCCTAA TCTATATCTGGGTAGTATATGCTATCCTAATCTGTATCCGGGTAGCATATG CTATCCTAATAGAGATTAGGGTAGTATATGCTATCCTAATTTATATCTGGG TAGCATATACTACCCAAATATCTGGATAGCATATGCTATCCTAATCTATAT CTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGCATAGGCTATCCT 7\ATCTATATCTGGGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATA TGCTATCCTAATTTATATCTGGGTAGCATAGGCTATCCTAATCTATATCTG GGTAGCATATGCTATCCTAATCTATATCTGGGTAGTATATGCTATCCTAAT CTGTATCCGGGTAGCATATGCTATCCTCATGATAAGCTGTCAAACATGAGA ATTTTCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAA TGTCATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAA TGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTA TCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAG GAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGC GGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAA AGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCT CAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAAT - 597- 201127956 151681.doc
GATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGA CGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTT GGTTGAGTACTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGT AAGAG^TTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAA CTTACTTCTGACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCA CAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAA TGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGC AACAACGTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCG GCAACAATTAATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCT GCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGG TGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCC CTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGA ACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTA ACTGTCAGACCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCA TTTTTAATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGAC CAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGA AAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTG CTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCA AGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGAT ACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAA CTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGC TGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATA GTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACA GCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGA GCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCC GGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGG AAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGA GCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGC CAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCA CATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGC CTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGA GTCAGTGAGCGAGGAAGCGGAAGAGCGCCCAATACGCAAACCGCCTCTCCC CGCGCGTTGGCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGACTG GAAAGCGGGCAGTGAGCGCAACGCAATTAATGTGAGTTAGCTCACTCATTA GGCACCCCAGGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAAT TGTGAGCGGATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGC CAAGCTCTAGCTAGAGGTCGAGTCCCTCCCCAGCAGGCAGAAGTATGCAAA GCATGCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCA TCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGAC TAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTAT TCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGC TTTGCAAAGATGGATAAAGTTTTAAACAGAGAGGAATCTTTGCAGCTAATG GACCTTCTAGGTCTTGAAAGGAGTGGGAATTGGCTCCGGTGCCCGTCAGTG GGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGG CAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGA TGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATAT AAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAG AACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGG TTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGAT TCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTG CGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCG CTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGC TTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCT TTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGG TATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCG CACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACG GGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCC GTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGC GTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATG GAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAA AAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCG GGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTC TTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTG -598- 201127956
GGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGA ATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGT GGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGAGGAATTCTCTAGAG ATCCCTCGACCTCGAGATCCATTGTGCCCGGGCGCCACCATGGAGTTTGGG CTGAGCTGGCTTTTTCTTGTCGCGATTTTAAAAGGTGTCCAGTGC 本發明以全文引用的方式併入分子生物學及藥物傳遞領 域中熟知之技術。此等技術包括（但不限於）以下公開案中 所述之技術：
Ausubel 等人（編），Current Protocols in Molecular Biology, John Wiley &Sons, NY (1993)；
Ausubel, F.M.等人編，Short Protocols In Molecular Biology (第 4版 1999) John Wiley & Sons, NY. (ISBN 0-471- 32938-X)；
Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen及 Ball (編），Wiley，New York (1984)；
Giege，R.及 Ducruix, A. Barrett，Crystallization of Nucleic Acids and Proteins, a Practical Approach,第 2版， 第 20 1 -16 頁，Oxford University Press, New York，New York, (1999)；
Goodson, Medical Applications of Controlled Release, 第 2卷，第 115-138頁（1984);
Hammerling 等人，Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)；
Harlow等人，Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press,第 2版 1988);
Kabat 等人，Sequences of Proteins of Immunological 151681.doc -599- 201127956
Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)；
Kabat，E.A.等人，（1991) Sequences of Proteins of Immunological Interest, 第 5 版，U.S. Department of Health and Human Services，NIH公開案第 91-3242號；
Kontermann 及 Dubel 編，Antibody Engineering (2001) Springer-Verlag. New York。第 790頁（ISBN 3-540-41354-5)。
Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990)；
Lu 及 Weiner 編，Cloning and Expression Vectors for Gene Function Analysis (2001) BioTechniques Press. Westborough，MA.第 298 頁（ISBN 1-881299-21-X);
Medical Applications of Controlled Release, Langer及 Wise (編），CRC Pres” Boca Raton，Fla. (1974);
Old, R. W. & S.B. Primrose, Principles of Gene Manipulation: An Introduction To Genetic Engineering (第 3 版 1985) Blackwell Scientific Publications, Boston. Studies in Microbiology;第 2 卷：第 409 頁（ISBN 0-632· 01318-4)；
Sambrook，J.等人編，Molecular Cloning: A Laboratory
Manual (第 2版 1989) Cold Spring Harbor Laboratory Press, NY.第 1至 3卷（ISBN 0-87969-309-6);
Sustained and Controlled Release Drug Delivery 151681.doc -600- 201127956
Systems，J.R. Robinson編，Marcel Dekker，lnc., New York， 1978 ；
Winnacker, E.L. From Genes To Clones: Introduction To
Gene Technology (1987) VCH Publishers，NY (由 Horst Ibelgaufts翻譯）。第 634頁（ISBN 0-89573-614-4)。 參考文獻併入 本申請案全文可引用之所有引用參考文獻之内容（包括 參考文獻、專利、專利申請案及網站）以及其中所引用之 參考文獻以全文引用的方式明確併入本文中β除非另外說 明，否則本發明之實施將使用此項技術中熟知的免疫學、 分子生物學及細胞生物學之習知技術。 等效物 本發明可在不悖離其精神或基本特徵之情況下以其他特 定形式體現。因此前述實施例在所有態樣中均為說明性而 非限制本文所述之本發明。因此本發明之範疇由隨附申請 專利範圍而非前述描述指定，且因此本文意欲涵蓋申請專 利範圍等效物之含義及範圍内的所有變化。 【圖式簡單說明】 圖1Α為雙重可變區域（DVD)-Ig構築體之示意圖，且展示 自兩個親本抗體產生DVD-Ig之策略； 圖為構桌體DVD1-Ig、DVD2-Ig、及兩個來自融合瘤 純系2D13.E3(抗-IL-la)及13F5.G5(抗-IL-Ιβ)之嵌合單特異 性抗體的示意圖。 151681.doc -601 - 201127956 序列表 <110>美商亞培公司 <120>雙重可變區域免疫球蛋白及其用途 <130> 9380USP1 <140 099126250 <141> 2010-10-22
<150> 12/605,094 <151> 2009-10-23 <150〉12/431,460 〈151> 2009-04-28 <150〉61/199,009 <151〉 2008-11-12 <150〉 61/197, 191 <151〉 2008-10-23 <150〉61/134, 283 <151〉 2008-07-08
〈150> 61/125, 834 <151> 2008-04-29 <160> 935 <170> Patentln version 3. 5 <210〉 1 <211〉 16 <212〉 PRT 〈213〉人造序列 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成肽 <400> 1
Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg 15 10 15 〈210〉 2 〈211〉 17 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400〉 2
Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg 15 10 15
Val <210> 3 〈211〉 9 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 3
Ala Lys Thr Thr Pro Lys Leu Gly Gly 1 5 <210> 4 〈211〉 10 <212〉 PRT <213〉人造序列 151681-序列表.doc 2·
201127956 <220〉 <223〉人造序列之描述：合成肽 <400〉 4
Ser Ala Lys Thr Thr Pro Lys Leu Gly Gly 1 5 10 <210〉 5 〈211〉 6 〈212〉 PRT <213〉人造序列
<220> 〈223>人造序列之描述：合成肽 <400> 5
Ser Ala Lys Thr Thr Pro 1 5 〈210〉 6 <211〉 6 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400〉 6
Arg Ala Asp Ala Ala Pro 1 5 <210〉 7 <211〉 9 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成肽 151681·序列表.doc 201127956 <400〉 7
Arg Ala Asp Ala Ala Pro Thr Val Ser 1 5 <210〉 8 <211> 12 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成肽 <400> 8
Arg Ala Asp Ala Ala Ala Ala Gly Gly Pro Gly Ser 15 10 <210> 9 <211〉 27 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成肽 <400〉 9
Arg Ala Asp Ala Ala Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 15 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 〈210〉 10 〈211〉 18 <212> PRT 〈213>人造序列 <220〉 〈223>人造序列之描述：合成肽 -4 -
15168卜序列表.doc 201127956 <400〉 10
Ser Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala 15 10 15
Arg Val <210〉 11 <211〉 5 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成肽 <400> 11
Ala Asp Ala Ala Pro 1 5 <210〉 12 <211〉 12 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400〉 12
Ala Asp Ala Ala Pro Thr Val Ser lie Phe Pro Pro 1 5 10 <210〉 13 <211〉 5 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 151681-序列表.doc 201127956 <400〉 13
Thr Val Ala Ala Pro 1 5 <210> 14 <211〉 12 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成肽 <400> 14
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro 1 5 10 <210〉 15 <211〉 6 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400〉 15
Gin Pro Lys Ala Ala Pro 1 5 <210〉 16 〈211〉 13 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 16
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro 1 5 10 151681·序列表.doc 201127956 <210〉 17 <211〉 6 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成肽 <400> 17
Ala Lys Thr Thr Pro Pro 1 5
<210〉 18 〈211〉 13 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 18
Ala Lys Thr Thr Pro Pro Ser Val Thr Pro Leu Ala Pro 1 5 10 〈210〉 19 <211> 6 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成肽 <400〉 19
Ala Lys Thr Thr Ala Pro 1 5
<210〉 20 <211〉 13 <212〉 PRT 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 20
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro 1 5 10 <210〉 21 <211> 6 <212> PRT <213〉人造序列
<220〉 <223〉人造序列之描述:合成肽 <400> 21
Ala Ser Thr Lys Gly Pro 1 5 <210〉 22 <211〉 13 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成肽 <400> 22
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 1 5 10 <210> 23 <211> 15 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 151681-序列表.doc 201127956 <400> 23
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 15 10 15 <210〉 24 <211> 15 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 24
Gly Glu Asn Lys Val Glu Tyr Ala Pro Ala Leu Met Ala Leu Ser 1.5 10 15 <210> 25 <211〉 15 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成肽 <400〉 25
Gly Pro Ala Lys Glu Leu Thr Pro Leu Lys Glu Ala Lys Val Ser 15 10 15 <210> 26 <211> 15 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 26
Gly His Glu Ala Ala Ala Val Met Gin Val Gin Tyr Pro Ala Ser -9- 15168卜序列表.doc 201127956 1 δ 10 15 <210〉 27 <211> 5 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成肽 <400> 27
Gly Gly Gly Gly Ser 1 5
<210> 28 <2U> 121 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 28
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 -10- 151681-序列表.doc 201127956
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala 115 120
<210〉 29 <211> 107 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400> 29
Gin lie Val Leu Ser Gin Ser Pro Ala He Leu Ser Pro Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95 -11 - 151681·序列表.doc 201127956
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210〉 30 <211> 119 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 30
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15 φ
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser 115 151681-序列表.doc -12- 201127956 <210〉 31 <211〉 107 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 31
Gin He Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg 100 105 <210〉 32 <211〉 119 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -13- 151681-序列表.doc 201127956 <400> 32
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr He Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly 100 1.05 110
Thr Met Val Thr Val Ser Ser 115 <210> 33 <211> 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 33
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 14-
】51681·序列表.doc 201127956 5 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 34 <211> 120 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 34
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val -15· 151681·序列表.doc 201127956 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 35 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 35
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 4.5
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly -16- 151681-序列表.doc 201127956 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr T}rr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Tlvr Lys Val Glu He Lvs Arg 100 105
<210〉 36 <211> 124 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 36
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -17- 151681-序列表.doc 201127956 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 HO
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210〉 37 <211〉 114 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 37
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro His Leu Leu He Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie • 18· 151681·序列表.doc 201127956 100 105 110
Arg Arg <210〉 38 <211〉 124 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 38
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser -19· 151681-序列表.doc 201127956 115 120 <210> 39 <211〉 112 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 39
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Gin Arg Ala Thr He Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin He Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110 <210> 40 <211〉 127 <212> PRT <213〉人造序列 -20-
151681-序列表doc 201127956 <220〉 〈223>人造序列之描述：合成多肽 <400> 40
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser He Ser Gly Gly 20 25 30
Tyr Gly Trp Gly Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp
lie Gly Ser Phe Tyr Ser Ser Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Gin Val Thr lie Ser Thr Asp Thr Ser Lys Asn Gin Phe 65 70 75 80
Ser Leu Lys Leu Asn Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Leu Phe Ser Val Val Gly Met Val Tyr Asn Asn 100 105 110
Trp Phe Asp Val Trp Gly Pro Gly Val Leu Val Thr Val Ser Ser 115 120 125 〈210〉 41 <211〉 111 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 -21 - 151681·序列表.doc 201127956 <400〉 41
Glu Ser Ala Leu Thr Gin Pro Pro Ser Val Ser Gly Ala Pro Gly Gin 15 10 15
Lys Val Thr lie Ser Cys Thr Gly Ser Thr Ser Asn lie Gly Gly Tyr 20 25 30
Asp Leu His Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 lie Tyr Asp lie Asn Lys Arg Pro Ser Gly lie Ser Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ala Ala Ser Leu Ala lie Thr Gly Leu Gin 65 70 75 80
Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Ser Ser Leu 85 90 95
Asn Ala Gin Val Phe Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 100 105 110 <210> 42 <211> 116 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 42
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 •22- 151681·序列表.doc 201127956
Trp Leu His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp He 35 40 45
Gly Tyr He Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn Gin Asn Phe 50 55 60
Lys Asp Lys Ala Thr lie Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys 85 90 95
Ala Arg Arg Asp lie Thr Thr Phe Tyr Trp Gly Gin Gly Thr Thr Val 100 105 110
Thr Val Ser Ser 115 〈210〉 43 <211〉 113 <212> PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 43
Asp lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 35 40 45 •23· 151681-序列表doc 201127956
Ala Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Tyr Cys His Gin 85 90 95
Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg <210> 44 <211〉 120 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 44
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Glu Glu Ser Asn Arg Tyr His Ala Asp Ser Val 50 55 60 151681-序列表.doc -24- 201127956
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys lie Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Gly Gly lie Ala Ala Pro Gly Pro Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser 115 120
<210> 45 <211> 113 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 45
Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Thr Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu Tyr Ser 20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro Gin Val Leu lie Ser Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80 25· 151681-序列表.doc 201127956
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Arg Gin Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp lie Arg 100 105 110
Arg <210〉 46 <211〉 120 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 46
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -26
151681·序列表.doc 201127956
Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Va.1 Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser 115 120 <210〉 47 <211〉 112 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 47
Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly Gin 15 10 15
Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn Asn 20 25 30
His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45
lie Tyr Asp Asn Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu Gin 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu 85 90 95
Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 •27· 151681·序列表.doc 201127956 <210〉 48 <211> 125 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 48
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125
<210〉 49 <211> 108 <212〉 PRT -28-
151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 49
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 100 105 <210〉 50 <211〉 122 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 50
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly -29· 151681-序列表.doc 201127956 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Tlir Leu Val Thr Val Ser Ser 115 120 <210> 51 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 51
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp •30· 151681-序列表 _doc 201127956 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210> 52 <211> 121 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 52
Gin Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Trp Ser Cys Pro Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Lys Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp 35 40 45 lie Gly Met He Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Pro -31- 151681·序列表.doc 201127956 50 55 60
Asn Phe Lys Asp Lys Ala Thr Leu Asn Val Asp Arg Ser Ser Asn Thr 65 70 75 80
Ala Tyr Asn Leu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr 85 90 95
Tyr Cys Ala Thr Tyr Gly Ser Tyr Val Ser Pro Leu Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Tyr Val Ser Ser 115 120 <210> 53 <211〉 114 〈212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 53
Asp He Met Met Ser Gin Ser Pro Ser Ser Leu Thr Val Ser Val Gly
Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gin Ser Leu Leu Val Thr 20 25 30
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gin Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr •32· 151681·序列表.doc 201127956 65 70 75 80 lie Thr Ser Val Lys Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Asp Gly Thr Lys Leu Glu lie 100 105 110
Lys Arg
<210> 54 <211〉 123 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 54
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys •33- 151681-序列表.doc 201127956 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 55 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 55
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg _34_
151681-序列表,doc 201127956 100 105 <210> 56 <211〉 118 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 56
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser 115 <210〉 57 35· 151681-序列表.doc 201127956 <211〉 109 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 57
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 100 105 〈210〉 58 <211〉 119 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 -36·
151681-序列表.doc 201127956 <400> 58
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Glu 20 25 30
Pro lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Thr Gly Lys Asn Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly Lys Lys Val Tyr Gly Met Asp Val Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser 115 <210> 59 〈211〉 108 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 59
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -37- 151681-序列表.doc 201127956
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Met Ser Val Pro He 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 60 <211〉 119 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 60
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 -38 -
151681·序列表.doc 201127956
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala 115 <210〉 61 <211〉 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述··合成多肽
<400〉 61
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60 -39- 151681-序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210〉 62 <211> 127 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 62
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His 20 25 30
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 •40
151681·序列表.doc 201127956
Arg lie Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210〉 63 <211〉 116 <212> PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 63
Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly Ala 15 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp Ser 20 25 30
Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin Tyr 35 40 45
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly lie 65 70 75 80
Leu Leu lie Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 85 90 95
Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu 100 105 110 -41 151681-序列表 _d〇c 201127956
Thr Val Leu Arg 115 <210〉 64 <211〉 122 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 64
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 φ
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Gin lie Ser Pro Ala Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Glu Leu Pro Tyr Tyr Arg Met Ser Lys Val Met Asp Val Gin 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 •42 151681·序列表.doc 201127956 <210〉 65 <211〉 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 65
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Tyr Phe Ser Ser Tyr 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Leu Gly Ser Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 66 〈211〉 119 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 43- 151681-序列表.doc 201127956 <400> 66
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly, 100 105 110
Thr Thr Leu Thr Val Ser Ser 115 <210〉 67 <211〉 107 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 67
Gin lie Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly -44· 15168卜序列表.doc 201127956 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Gly Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Phe Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 100 105 <210> 68 <211> 116 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 68
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30
Tyr He Asn Trp Val Lys Leu Ala Pro Gly Gin Gly Leu Glu Trp He • 45- 151681-序列表.doc 201127956 35 40 45
Gly Trp He Tyr Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr lie Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95
Val Arg Asp Ser Pro Phe Phe Asp Tyr Trp Gly Gin Gly Thr Leu Leu 100 105 110
Thr Val Ser Ser 115 〈210〉 69 <211〉 113 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 69
Asp He Val Leu Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gin Ser Leu Leu Asn Ser 20 25 30
Gly Met Arg Lys Ser Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45
Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val -46- 151681·序列表 201127956 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Val Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gin 85 90 95
Ser Tyr His Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys loo 105 no
Arg <210〉 70 <211〉 117 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 70
Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30
Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Glu Thr Ser Lys Asn Gin Phe Ser Leu -47- 151681·序列表.doc 201127956 65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110
Val Thr Val Ser Ser 115 <210〉 71 <211> 114 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 71
Asp lie Glu Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr He Asn Cys Arg Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gin Gin Asn Pro Gly Gin 35 40 45
Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin • 48 - 151681·序列表.doc 201127956 85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu He 100 105 110
Lys Arg <210〉 72 <211〉 119 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 72
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser lie Tyr 20 25 30
Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Ser Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Asp Phe Asp Ala Phe Asp He Trp Gly Gin Gly • 49· 151681·序列表.doc 201127956 100 105 110
Thr Met Val Thr Val Ser Ser 115 <210〉 73 <211〉 108 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 73
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Asn Cys Gin Gin Cys Glu Asn Phe Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Arg 100 105 <210> 74 -50-
151681 -序列表.doc 201127956 <211〉 119 <212> PRT 〈213>人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 74
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30
Val Met Ala Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Thr Arg Gly Leu Lys Met Ala Thr lie Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser 115 <210〉 75 <211〉 112 <212〉 PRT <213〉人造序列 -51 · 151681-序列表-doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 75
Gin Ser Ala Leu Thr Gin Pro Ala Ser Val Ser Gly Ser Pro Gly Gin 1 5 10 15
Ser He Thr He Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Val Val Ser Trp Tyr Gin Gin His Pro Gly Lys Ala Pro Lys Leu 35 40 45
He He Tyr Glu Val Ser Gin Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr lie Ser Gly Leu 65 70 75 80
Gin Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95
Ser lie Phe Val lie Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110 <210> 76 <211> 119 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 76
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 -52-
151681 -序列表.d〇c 201127956
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30
Tyr He His Trp Val Lys Gin Ala Pro Gly Gin Gly Leu GIu Trp He 35 40 45
Gly Tyr He Ser Ser Tyr Asn Gly Ala Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Tyr Asp Tyr Asp Val Gly Met Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser 115
<210> 77 <211〉 112 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 77
Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15
Glu Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 -53- 151681-序列表.doc 201127956
Gly lie Ser Phe Met Lys Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie Tyr Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Asp 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80
Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 <210〉 78 <211〉 120 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 78
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Ser Asp Tyr 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Gly He Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 -54- 151681-序列表.doc 201127956
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser 115 120
<210〉 79 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 79
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80 55- 151681-序列表.doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 80 <211〉 121 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 80
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr lie Asn Ala Ser 20 25 30
Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Ala lie Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 100 105 110 •56
151681-序列表d〇c 201127956
Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 〈210〉 81 <211> 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 81
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Val He Arg Arg Ser 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn Thr Ser Pro Leu 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105
<210〉 82 <211〉 120 <212> PRT •57· 151681·序列表.doc 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 82
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 δ 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Val lie Asn Trp Val Lys Gin Lys Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Leu lie Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60
Lys Val Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Ser Tyr Tyr Tyr Gly Ser Arg Tyr Tyr Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210〉 83 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 58-
151681-序列表.doc 201127956 <400〉 83
Asp lie Gin Met Thr Gin Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly 15 10 15
Gly Arg Val Thr lie Thr Cys Lys Ala Ser Asp His lie Asn Asn Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu He 35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser lie Pro Leu 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 100 105
<210〉 84 <211〉 120 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 〈400> 84
Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr -59- 151681·序列表.doc 201127956 20 25 30
Asn Met Asn Trp Yal Lys Gin Ser Asn Gly Lys Ser Leu Glu Trp He 35 40 45
Gly Asn lie Asp Pro Tyr Phe Gly Gly Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Asp Tyr Asp Gly Gly Cys Phe Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 85 <211〉 110 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 85
Gin Ala Val Val Thr Gin Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly -60· 151681·序列表.doc 201127956 35 40 45
Leu lie Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu lie Gly Asp Lys Ala Ala Leu Thr lie Thr Gly Ala 65 70 75 80
Gin Thr Glu Asp Glu Ala lie Tyr Phe Cys Ala Leu Trp Tyr Ser Asn 85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 86 <211> 116 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 86
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr 20 25 30
Gly He His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Met Trp Ser Gly Gly Asp Thr Asp Tyr Asp Ala Ala Phe lie 50 55 60
Ser Arg Leu Ser lie Ser Lys Asp Asn Ser Lys Ser Gin Val Phe Phe • 61 · 151681·序列表.doc 201127956 65 70 75 80
Lys Met Asn Ser Leu Gin Ala Asn Asp Thr Gly lie Tyr Tyr Cys Ala 85 90 95
Arg Tyr Arg Phe Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110
Thr Val Ser Ser 115 <210〉 87 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 87
Ala lie Gin Met Thr Gin Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Glu Asp lie Tyr Asn Arg 20 25 30
Phe Ala Trp Tyr Gin Gin Lys Pro Gly Asn Ala Pro Arg Leu Leu lie 35 40 45
Ser Gly Ala Ala Ser Leu Glu Ala Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Gin Asp Tyr Thr Leu Ser lie Thr Ser Leu Gin Thr 65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Gin Tyr Trp Ser Thr Pro Trp -62· 15168丨·序列表.doc 201127956 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210〉 88 <211> 130 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 88
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala He Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Gly lie He Pro He Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe
Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr 100 105 110
Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val -63- 151681·序列表.doc 201127956 115 120 125
Ser Ser 130 <210〉 89 <211〉 109 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 89
Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly Gin 1 5 10 15
Thr Val Arg lie Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30
Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Va.l lie Tyr 35 40 45
Gly Glu Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser Gly Ser 50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr lie Thr Gly Ala Gin Ala Glu 65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin His 85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 90 -64·
151681-序列表.doc 201127956 <211> 118 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 90
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Ser Val lie Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60
Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110
Thr Val Thr Val Ser Ser 115 <210〉 91 <211〉 108 <212〉 PRT <213〉人造序列 65- 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400〉 91
Glu He Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser He Gly Ser Ser 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Gin Ser Leu Ser Gly He Pro Asp Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro His 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 92 <211〉 118 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 92
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15 •66-
151681-序列表.doc 201127956
Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30
Trp Met His Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45
Gly Glu lie Asn Pro Thr Asn Gly His Thr Asn Tyr Asn Pro Ser Phe 50 55 60
Gin Gly Gin Val Thr He Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80
Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Asn Tyr Val Gly Ser lie Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser 115 <210> 93
<211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 93
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Lys Ala Ser Glu Asn Val Val Ser Tyr 20 25 30 •67- 151681-序列表.doc 201127956
Val Ser Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Asn Arg Asn Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Ser Tyr Asn Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210〉 94 <211> 119 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 94
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30
Thr Met Asp Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser lie Tyr Asn Gin Arg Phe 50 55 60 • 68 -
151681-序列表.doc 201127956
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser 115
<210〉 95 <211> 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 95
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Asp Val Ser lie Gly 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 69· 151681-序列表doc 201127956
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Tyr lie Tyr Pro Tyr 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 100 105 <210〉 96 <211〉 122 <212> PRT <213〉人造序列 <220〉
〈223〉人造序列之描述：合成多肽 <400〉 96
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30
Thr Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Leu lie Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Val Asp Lys Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp 100 105 110 151681·序列表.doc -70· 201127956
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 97 <211〉 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 97
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Arg Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105
<210〉 98 <211〉 125 <212〉 PRT 151681·序列表.doc -71- 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 98
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60
Ser Val Lys Asp Arg Phe Thr He Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80
Ala Tyr Leu Gin Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110
Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210〉 99 <211〉 110 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 72- 151681·序列表.doc 201127956 <400〉 99
Glu Leu Val Val Thr Gin Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 15 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30
Asn Tyr Ala Asn Trp Val Gin Gin Lys Pro Gly Gin Ala Pro Arg Gly 35 40 45
Leu lie Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 65 70 75 80
Gin Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn 85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210〉 100 <211〉 116 <212〉 PRT <213〉人造序列 〈220> <223>人造序列之描述：合成多肽 <400> 100
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Lys 1 5 10 15
Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Gly Tyr -73- 151681 -序列表.d〇c 201127956 20 25 30
Gly Met His Trp Val Arg Gin Ala Pro Gly Arg Gly Leu Glu Ser Val 35 40 45
Ala Tyr He Thr Ser Ser Ser He Asn He Lys Tyr Ala Asp Ala Val 50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Leu Leu Phe 65 70 75 80
Leu Gin Met Asn lie Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95
Ala Arg Phe Asp Trp Asp Lys Asn Tyr Trp Gly Gin Gly Thr Met Val 100 105 110
Thr Val Ser Ser 115 <210> 101 <211〉 108 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 101
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Pro Ala Ser Leu Gly 15 10 15
Asp Arg Val Thr He Asn Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -74-
151681-序列表.doc 201127956 35 40 45
Tyr Tyr Thr Asn Lys Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Arg Asp Ser Ser Phe Thr He Ser Ser Leu Glu Ser 65 70 75 80
Glu Asp lie Gly Ser Tyr Tyr Cys Gin Gin Tyr Tyr Asn Tyr Pro Trp 85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210> 102 <211> 121 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 102
Glu Val Lys Leu Gin Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gin
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr 20 25 30
Gly Val Ser Trp lie Arg Gin Pro Pro Arg Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Gly Ser Glu Gly Thr Thr Tyr Tyr Asn Ser Ala Leu 50 55 60
Lys Ser Arg Leu Thr lie lie Lys Asp Asn Ser Lys Ser Gin Val Pro •75· 151681·序列表.doc 201127956 65 70 75 80
Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala He Tyr Tyr Cys 85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Thr Val Ser Ser 115 120 <210〉 103 φ <211> 108 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 103
Asp lie Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15
Asp Arg Val Thr lie Ser Cys Arg Ala Ser Gin Asp He Ser Lys Thr 20 25 30 ^
Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly Thr Val Lys Leu Leu lie 35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr lie Ser Asn Leu Glu Gin 65 70 75 80
Glu Asp He Ala Thr Tyr Phe Cys Gin Gin Gly Asn Thr Leu Pro Tyr -76· 151681-序列表d〇c 201127956 85 90 95
Thr Phe Gly Gl)r Gly Thr Lys Leu Glu lie Thr Arg 100 105 <210> 104 <211〉 121 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 104
Glu Val Gin Leu Gin Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30
Trp Met Asn Trp Val lie Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Ser Gly Phe lie Thr Thr Val Leu Asp Phe Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Thr Leu Thr Val Ser Ser -77- 151681-序列表.doc 201127956 115 120 <210〉 105 <211〉 112 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 105
Asp lie Val Leu Thr Gin Ser Pro Thr Ser Leu Ala Val Ser Leu Gly 1 5 10 15
Gin Arg Ala Thr lie Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Phe 20 25 30
Gly lie Ser Phe Met Asn Trp Phe Gin Gin Lys Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu lie His Ala Ala Ser Asn Gin Gly Ser Gly Val Pro Ser 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn He His 65 70 75 80
Pro Met Glu Glu Asp Asp Ser Ala Met Tyr Phe Cys Gin Gin Ser Lys 85 90 95
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Lys Arg 100 105 110 <210〉 106 <211〉 116 <212〉 PRT <213〉人造序列 ·78·
151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 106
Glu Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Thr 15 10 15
Ser Val Lys Leu Ser Cys Lys Val Ser Gly Asp Thr lie Thr Phe Tyr 20 25 30
Tyr Met His Phe Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Arg lie Asp Pro Glu Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe 50 55 60
Lys Asn Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80
Leu Lys Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 lie Tyr Gly Gly Tyr Tyr Phe Asp Tyr Trp Gly Gin Gly Val Met Val 100 105 110
Thr Val Ser Ser 115 <210> 107 <211〉 108 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述·合成多肽 -79- 151681·序列表.doc 201127956 <400> 107
Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Thr Ser Leu Gly 15 10 15
Glu Thr Val Thr lie Gin Cys Gin Ala Ser Glu Asp lie Tyr Ser Gly 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ser Pro Gin Leu Leu He 35 40 45
Tyr Gly Ala Ser Asp Leu Gin Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Gin Tyr Ser Leu Lys lie Thr Ser Met Gin Thr 65 70 75 80
Glu Asp Glu Gly Val Tyr Phe Cys Gin Gin Gly Leu Thr Tyr Pro Arg 85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg 100 105 <210〉 108 <211〉 330 <212> PRT <213〉智人 <400> 108
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 •80·
151681·序列表.doc 201127956
Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80
Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125
Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175
Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190
His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205
Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 210 215 220
Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu • 81 - 151681-序列表.doc 201127956 225 230 235 240
Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255
Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320
Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210〉 109 <211> 330 <212> PRT <213〉智人 <400〉 109
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser -82 - 15168卜序列表.doc 201127956 50 5δ 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80
Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125
Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys 130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175
Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190
His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205
Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 210 215 220
Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 83- 151681-序列表doc 201127956
Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255
Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320
Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 110 <211> 106 <212〉 PRT <213〉智人 <400〉 110
Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 15 10 15
Leu Lys Ser Gly Thr Ala Ser Va.l Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30
Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 35 40 45
Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 50 55 60 • 84-
151681·序列表.doc 201127956 %
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 65 70 75 80
His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 85 90 95
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105
<210〉 111 〈211〉 105 <212〉 PRT <213〉智人 <400> 111
Gin Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 1 5 10 15
Glu Leu Gin Ala Asn Lys Ala Thr Leu Val Cys Leu lie Ser Asp Phe 20 25 30
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 35 40 45
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gin Ser Asn Asn Lys 50 55 60
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gin Trp Lys Ser 65 70 75 80
His Arg Ser Tyr Ser Cys Gin Val Thr His Glu Gly Ser Thr Val Glu 85 90 95
Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 -85- 151681-序列表.doc 201127956 <210〉 112 <211〉 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多狀 <400> 112
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp He 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser 130 135 140 86-
151681-序列表.doc 201127956
Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser J5er Tyr Trp 145 150 155 160
Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Gin He Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys 180 185 190
Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala 210 215 220
Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 245 250
<210〉 113 〈211〉 224 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 113
Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30 •87· 151681-序列表.doc 201127956
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp He Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 115 120 125
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 130 135 140
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 145 150 155 160
Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 180 185 190
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 195 200 205
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg -88 - 151681-序列表.doc 201127956 210 215 220 <210> 114 <211〉 251 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 114
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
Ser Val Lys He Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin lie Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro -89- 151681-序列表doc 201127956 130 135 140
Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 145 150 155 160
Ser Tyr Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu 165 170 175
Trp lie Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin 180 185 190
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr 195 200 205
Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 210 215 220
Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 225 230 235 240
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 245 250 <210〉 115 <211〉 224 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 115
Asp He Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr He Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp -90- 151681-序列表.doc 201127956 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 100 105 110
Thr Val Ala Ala Pro Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu 115 120 125
Ser Pro Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser 130 135 140
Ser Val Ser Tyr He His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro 145 150 155 160
Lys Pro Trp lie Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser 180 185 190
Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr 195 200 205 •91 - 151681·序列表doc 201127956
Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210〉 116 <211> 246 〈212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 116
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15 φ
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125 92- 151681-序列表.doc 201127956
Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser 130 135 140
Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr 145 150 155 160
Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys 180 185 190
Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met 195 200 205
Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Thr Leu Thr Val Ser Ser 245 <210> 117 <211〉 219 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 117
Gin lie Val Leu Ser Gin Ser Pro Ala He Leu Ser Pro Ser Pro Gly 15 10 15 •93 151681·序列表.doc 201127956
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 115 120 125
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 130 135 140
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 145 150 155 160
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 165 170 175
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 180 185 190
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr -94-
151681-序列表.doc 201127956 195 200 205
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 <210〉 118 <211〉 246 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400〉 118
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly loo 105 no
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin -95- 151681-序列表.doc 201127956 115 120 125
Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His 145 150 155 160
Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie Gly Ala lie 165 170 175
Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe Lys Gl)r Lys 180 185 190
Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 2⑻ 205
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser 210 215 220
Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr 225 230 235 240
Thr Val Thr Val Ser Ala 245 <210〉 119 <211〉 219 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 〈400> 119
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly •96-
151681-序列表.doc 201127956 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 115 120 125
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 130 135 140
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 145 150 155 160
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 165 170 175
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 180 185 190 •97 151681·序列表 _doc 201127956
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 195 200 205
Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 <210〉 120 <211> 254 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 120
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp He 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 •98
151681·序列表.doc 201127956
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr 130 135 140
Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser He Ser Gly Gly Tyr 145 150 155 160
Gly Trp Gly Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 165 170 175
Gly Ser Phe Tyr Ser Ser Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu 180 185 190
Lys Ser Gin Val Thr He Ser Thr Asp Thr Ser Lys Asn Gin Phe Ser 195 200 205
Leu Lys Leu Asn Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Val Arg Asp Arg Leu Phe Ser Val Val Gly Met Val Tyr Asn Asn Trp 225 230 235 240
Phe Asp Val Trp Gly Pro Gly Val Leu Val Thr Val Ser Ser 245 250 <210〉 121 〈211〉 223 <212〉 PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 99· 151681-序列表.doc 201127956 <400〉 121
Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 5o 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Glu Ser Ala Leu Thr Gin Pro Pro Ser Val Ser Gly Ala Pro Gly Gin 115 120 125
Lys Val Thr lie Ser Cys Thr Gly Ser Thr Ser Asn lie Gly Gly Tyr 130 135 140
Asp Leu His Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp lie Asn Lys Arg Pro Ser Gly He Ser Asp Arg Phe Ser 165 170 175
Gly Ser Lys Ser Gly Thr Ala Ala Ser Leu Ala lie Thr Gly Leu Gin -100-
15168卜序列表.doc 201127956 180 185 190
Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Ser Ser Leu 195 200 205
Asn Ala Gin Val Phe Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 210 215 220
<210〉 122 <211> 254 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 122
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser lie Ser Gly Gly 20 25 30
Tyr Gly Trp Gly Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp
He Gly Ser Phe Tyr Ser Ser Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Gin Val Thr He Ser Thr Asp Thr Ser Lys Asn Gin Phe 65 70 75 80
Ser Leu Lys Leu Asn Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Leu Phe Ser Val Val Gly Met Val Tyr Asn Asn • 101 - 151681-序列表,doc 201127956 100 105 110
Trp Phe Asp Val Trp Gly Pro Gly Val Leu Val Thr Val Ser Ser Ala 115 120 125
Ser Thr Lys Gly Pro Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu 130 135 140
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gin Thr Pro Gly Arg 165 170 175
Gly Leu Glu Trp lie Gly Ala He Tyr Pro Gly Asn Gly Asp Thr Ser 180 185 190
Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser 195 200 205
Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr 225 230 235 240
Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 245 250 <210〉 123 <211〉 224 <212> PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 -102-
151681-序列表.doc 201127956 <400〉 123
Glu Ser Ala Leu Thr Gin Pro Pro Ser Val Ser Gly Ala Pro Gly Gin 15 10 15
Lys Val Thr lie Ser Cys Thr Gly Ser Thr Ser Asn lie Gly Gly Tyr 20 25 30
Asp Leu His Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45
lie Tyr Asp lie Asn Lys Arg Pro Ser Gly lie Ser Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ala Ala Ser Leu Ala He Thr Gly Leu Gin 65 70 75 80
Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Ser Ser Leu 85 90 95
Asn Ala Gin Val Phe Gly Gly Gly Thr Arg Leu Thr Val Leu Gly Gin 100 105 110
Pro Lys Ala Ala Pro Gin He Val Leu Ser Gin Ser Pro Ala lie Leu 115 120 125
Ser Pro Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser 130 135 140
Ser Val Ser Tyr lie His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro 145 150 155 160
Lys Pro Trp lie Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val 165 170 175 151681-序列表.doc -103- 201127956
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser 180 185 190
Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr 195 200 205
Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 124 〈211〉 243 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 124
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 -104
151681·序列表.doc 201127956
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser 130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp 145 150 155 160
Leu His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp lie Gly 165 170 175
Tyr He Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn Gin Asn Phe Lys 180 185 190
Asp Lys Ala Thr lie Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr Met 195 ^200 205
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys Ala 210 215 220
Arg Arg Asp He Thr Thr Phe Tyr Trp Gly Gin Gly Thr Thr Val Thr 225 230 235 240
Val Ser Ser <210〉 125 <211〉 225 <212〉 PRT 〈213>人造序列 -105· 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 125
Gin He Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 130 135 140
Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val -106- 151681·序列表.doc 201127956 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 180 185 190
He Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Tyr Cys His Gin 195 200 205
Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys 210 215 220
225 <210〉 126 <211> 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 126
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn Gin Asn Phe 50 55 60
Lys Asp Lys Ala Thr He Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr •107- 151681·序列表-doc 201127956 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys 85 90 95
Ala Arg Arg Asp lie Thr Thr Phe Tyr Trp Gly Gin Gly Thr Thr Val 100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Gin Gin 115 120 125
Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys 130 135 140
Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys 145 150 155 160
Gin Thr Pro Gly Arg Gly Leu Glu Trp lie Gly Ala lie Tyr Pro Gly 165 170 175
Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe Lys Gly Lys Ala Thr Leu 180 185 190
Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu 195 200 205
Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr 210 215 220
Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr 225 230 235 240
Val Ser Ala 108· 151681-序列表.doc 201127956 <210> 127 <211〉 225 <212〉 PRT <213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 127
Asp lie Gin Leu Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30
Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 35 40 45
Ala Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Tyr Cys His Gin 85 90 95
Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Gin lie Val Leu Ser Gin Ser Pro Ala lie 115 120 125
Leu Ser Pro Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser 130 135 140 109- 151681-序列表.doc 201127956
Ser Ser Val Ser Tyr lie His Trp Phe Gin Gin Lys Pro Gly Ser Ser 145 150 155 160
Pro Lys Pro Trp lie Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro 165 170 175
Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie 180 185 190
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp 195 200 205
Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 210 215 220
Arg 225 <210〉 128 <211〉 247 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 128
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1. 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45 •110- 151681·序列表.d〇c 201127956
Gly Ala lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Va.1 Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg Ser 130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly 145 150 155 160
Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 165 170 175
Val He Ser Tyr Glu Glu Ser Asn Arg Tyr His Ala Asp Ser Val Lys 180 185 190
Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys lie Thr Leu Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg Asp Gly Gly lie Ala Ala Pro Gly Pro Asp Tyr Trp Gly Gin Gly -Ill - 151681-序列表.doc 201127956 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 129 <211〉 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 129
Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Thr Val Thr Pro Gly -112-
151681·序列表.doc 201127956 115 120 125
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu Tyr Ser 130 135 140
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 145 150 155 160
Pro Gin Val Leu lie Ser Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 165 170 175
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 180 185 190
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 195 200 205
Arg Gin Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp lie Arg 210 215 220
Arg 225
<210〉 130 <211〉 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 130
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr -113- 151681-序列表.doc 201127956 20 25 30
Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Glu Glu Ser Asn Arg Tyr His Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys lie Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Gly Gly lie Ala Ala Pro Gly Pro Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met 145 150 155 160
His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie Gly Ala 165 170 175 lie Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe Lys Gly 180 185 190
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205 -114- 151681-序列表.doc 201127956
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly 225 230 235 240
Thr Thr Val Thr Val Ser Ala 245
<210〉 131 〈211〉 225 〈212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 131
Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Thr Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu Tyr Ser 20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro Gin Val Leu lie Ser Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95 -115 151681-序列表.doc 201127956
Arg Gin Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp lie Arg 100 105 110
Arg Thr Val Ala Ala Pro Gin lie Val Leu Ser Gin Ser Pro Ala lie 115 120 125
Leu Ser Pro Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser 130 135 140
Ser Ser Val Ser Tyr lie His Trp Phe Gin Gin Lys Pro Gly Ser Ser 145 150 155 160
Pro Lys Pro Trp lie Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro 165 170 175
Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie 180 185 190
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp 195 200 205
Thr Ser Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys 210 215 220
Arg 225 <210〉 132 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 116·
151681·序列表.doc 201127956 <400> 132
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr'Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Ίγτ Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Va.l Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg -117- 151681·序列表.doc 201127956 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210> 133 <211〉 220 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 133
Gin lie Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr He Ser Ser Met Glu Ala Glu -118- 151681·序列表.doc 201127956 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 130 135 140
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 145 150 155 160
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 180 185 190
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 195 200 205
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <21.0〉134 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多狀 •119- 151681·序列表.doc 201127956 <400> 134
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val 130 135 140
Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met 145 150 155 160
His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr 165 170 175 -120 151681·序列表.doc 201127956 lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp 180 185 190
Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin 195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr 225 230 235 240
Leu Thr Val Ser Ser 245 <210> 135 <211> 220 〈212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 135
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 • 121 - 151681-序列表.doc 201127956
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He 145 150 155 160
Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu 195 200 205
Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 220 <210〉 136 <211〉 249 <212〉 PRT <213〉人造序列 122·
151681·序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400〉 136
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser Ser Val Lys 130 135 140 lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr Trp Met Asn 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Gin lie -123 - 151681-序列表.doc 201127956 165 170 175
Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys Gly Lys 180 185 190
Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg 210 215 220
Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Ser Val Thr Val Ser Ser 245 <210> 137 <211〉 224 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 137
Gin lie Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro Gly 15 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp He Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser •124· 151681-序列表.doc 201127956 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Va.1 Ala Ala Pro 100 105 110
Asp He Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 115 120 125
Gin Arg Ala Thr He Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 130 135 140
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 145 150 155 160
Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Val Ser Gly lie Pro Pro 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 180 185 190
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 195 200 205
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 210 215 220
<210> 138 <211> 249 <212> PRT -125· 151681-序列表.doc 201127956 <213〉人造序列 〈220> 〈223>人造序列之描述：合成多肽 <400> 138
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Val Arg Pro Gly Ser 15 l〇 15
Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr 20 25 30
Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Gin He Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp 100 105 110
Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro 130 135 140
Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 145 150 155 160 •126· 151681-序列表.doc 201127956
Arg Tyr Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu 165 170 175
Trp He Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin 180 185 190
Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr 195 200 205
Ala Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 210 215 220
Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Thr Leu Thr Val Ser Ser 245 <210〉 139 <211〉 224 〈212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 139
Asp lie Leu Leu Thr Gin Thr Pro Ala Ser Leu Ala Val Ser Leu Gly 15 10 15
Gin Arg Ala Thr lie Ser Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gin Gin lie Pro Gly Gin Pro Pro 35 40 45 -127- 151681-序列表.doc 201127956
Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Val Ser Gly He Pro Pro 50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn lie His 65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gin Gin Ser Thr 85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 100 105 110
Thr Val Ala Ala Pro Gin lie Val Leu Thr Gin Ser Pro Ala lie Met 115 120 125
Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser 130 135 140
Ser Val Ser Tyr Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro 145 150 155 160
Lys Arg Trp lie Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr 165 170 175
Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser 180 185 190
Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser 195 200 205
Ser Asn Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 220 <210> 140 -128 ·
151681·序列表.doc 201127956 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 140 G：Ln Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gl)r Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr Tyr lie His -129- 151681-序列表.doc 201127956 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245
<210〉 141 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 141
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He -130- 151681·序列表.doc 201127956 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 -131 - 151681-序列表.doc 201127956 <210〉 142 <211〉 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 142
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140 -132-
151681·序列表.doc 201127956
Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 145 150 155 · 160
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175 lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 180 185 190
Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala 210 215 220
Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ala 245
<210〉 143 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 143
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30 -133· 151681-序列表-doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr· Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg -134-
151681·序列表.doc 201127956 210 215 220 <210> 144 <211〉 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多狀 <400> 144
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 S 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys -135· 151681·序列表.doc 201127956 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Tyr lie 165 170 175
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp Lys 180 185 190
Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 210 215 220
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr Leu 225 230 235 240
Thr Val Ser Ser <210〉 145 <211> 220 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 145
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn •136-
15168卜序列表.doc 201127956 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Thr Gin Ser Pro Ala He Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie 145 150 155 160
Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu 195 200 205 -137- 151681_序列表.doc 201127956
Thr Phe Gly Ser Gly Thr Lys Leu Glu He Asn Arg 210 215 220 <210〉 146 <211> 244 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 146
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 15 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu .Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125 •138·
151681·序列表.doc 201127956
Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser 130 135 140 lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His 145 150 155 160
Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie 165 170 175
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu 180 185 190
Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn 195 200 205
Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu 210 215 220
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val 225 230 235 240
Thr Val Ser Ala
〈210〉 147 <211〉 220 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 147
Gin He Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15 -139 151681·序列表.doc 201127956
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys.Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 115 120 125
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 130 135 140 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 145 150 155 160
Lys Tyr Ala Ser Glu Ser He Ser Gly He Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 180 185 190
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr •140- 151681·序列表.doc 201127956 195 200 205
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 2l〇 215 220 <210〉 148 <211> 245 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽
<400> 148
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin •141· 151681-序列表.doc 201127956 115 120 125
Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 130 135 140
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asp lie Asn 145 150 155 160
Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met Gly Trp Met 165 170 175
Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe Gin Gly Arg 180 185 190
Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr Met Glu Leu 195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr 225 230 235 240
Val Thr Val Ser Ser 245 <210> 149 <211〉 225 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 149
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly •142·
151681-序列表.doc 201127956 15 10
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly 115 120 125
Gin Lys Val Thr He Ser Cys Ser Gly Ser Ser Ser Asn He Glu Asn 130 135 140
Asn His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu 145 150 155 160
Leu lie Tyr Asp Asn Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe 165 170 175
Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu 180 185 190 •143· 151681·序列表.doc 201127956
Gin Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser 195 200 205
Leu Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 210 215 220
Gly 225 <210〉 150 <211〉 245 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 150
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -144
151681·序列表.doc 201127956
Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu 130 135 140
Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val 145 150 155 160
His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val 165 170 175 lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg 180 185 190
Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met 195 200 205
Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala 210 215 220
Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ala 245 <210〉 151 <211> 226 <212〉 PRT 〈213>人造序列 145- 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 151
Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly Gin 1 5 10 15
Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn Asn 20 25 30
His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 lie Tyr Asp Asn Asn Lys ,^rg Pro Ser Gly lie Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu Gin 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu 85 90 95
Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie 115 120 125
Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser 130 135 140
Gin Ser He Gly Thr Asn He His Trp Tyr Gin Gin Arg Thr Asn Gly 145 150 155 160
Ser Pro Arg Leu Leu He Lys Tyr Ala Ser Glu Ser He Ser Gly lie • 146-
151681·序列表.doc 201127956 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser 180 185 190 lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin 195 200 205
Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 210 215 220
Lys Arg 225 <210〉 152 <211〉 250 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 152
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe •147· 151681-序列表.doc 201127956 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala lie 165 170 175
Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp 210 215 220
Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 151681-序列表doc -148- 201127956 <210> 153 <211〉 221 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 153
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly I 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn 130 135 140 149- 151681-序列表 d〇c 201127956
Asp Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu 145 150 155 160 lie Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro 195 200 205
Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210> 154 <211〉 250 <212〉 PRT 〈213>人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 154
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60 -150-
151681-序列表.doc 201127956
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu' Val Gin 130 135 140
Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu 145 150 155 160
Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu 165 170 175
Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 180 185 190
Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin 195 200 205
Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr 210 215 220
Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ala -151 - 151681·序列表.doc 201127956 245 250 <210〉 155 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 155
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu lie 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr •152- 151681 ·序列表.doc 201127956 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210〉 156 <211〉 257 <212> PRT <213〉人造序列 <220〉 <223>人造序列之描述：合成多肽 <400〉 156
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val • 153 - 151681-序列表.doc 201127956 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin 130 135 140
Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys 145 150 155 160
Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg 165 170 175
Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly 180 185 190
Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser He Asn 195 200 205
Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin 210 215 220
Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr 225 230 235 240 • 154· 151681·序列表.doc 201127956
Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 245 250 255
Ala <210〉 157 〈211〉 228 <212〉 PRT 〈213>人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 157
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu lie 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110 • 155- 151681·序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Leu Leu Thr Gin Ser Pro 115 120 125
Val He Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Ser lie Asn Ser Val Glu Ser Glu Asp He Ala Asp Tyr Tyr Cys 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210〉 158 <211〉 257 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 158
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15 •156 151681·序列表.doc 201127956
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ser Ala He Ser Gly Ser Gly Gly Thr Thr Phe Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg -157- 151681-序列表.doc 201127956 195 200 205
Thr Thr Leu Tyr Leu Gin Met Asn Ser Leu .\rg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr 225 230 235 240
Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser 245 250 255
Ser <210> 159 <211〉 228 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 159
Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser -158- 151681·序列表.doc 201127956 6δ 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp He Gin Met Thr Gin Phe Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Gly lie Arg Asn Asp Leu Gly Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Arg Leu lie Tyr Ala Ala Ser Arg Leu His Arg 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Leu Gin His Asn Ser Tyr Pro Cys Ser Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu lie Lys Arg 225
<210〉 160 <211〉 257 <212〉 PRT 159- 151681-序列表.doc 201127956 〈213>人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 160
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala He Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin 130 135 140
Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys 145 150 155 160 •160· 151681-序列表doc 201127956
Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg 165 170 175
Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly 180 185 190
Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie Asn 195 200 205
Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin 210 215 220
Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr 225 230 235 240
Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 245 250 255
Ala
〈210〉 161 〈211〉 221 〈212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 161
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30 • 161 - 151681·序列表.doc 201127956
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu lie 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg •162· 151681·序列表.doc 201127956 210 215 220 <210〉 162 <211〉 257 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 162
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val -163- 151681·序列表doc 201127956 130 135 140
Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Tr*p Val Ser Ala He Ser Gly Ser Gly Gly Thr Thr Phe Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Arg 195 200 205
Thr Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr 225 230 235 240
Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser 245 250 255
Ser <210〉 163 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 163
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly •164· 151681·序列表.doc 201127956 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn 130 135 140
Asp Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu 145 150 155 160 lie Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190 •165- 15168丨·序列表.doc 201127956
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro 195 200 205
Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 164 <211〉 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 164
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110 -166 151681-序列表.doc 201127956
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin 130 135 140
Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu 145 150 155 160
Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu 165 170 175
Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 180 185 190
Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin 195 200 205
Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr 210 215 220
Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 <210〉 165 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 167· 151681-序列表.doc 201127956 <400〉 165
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45
Tyr Ala Ala Ser Ai*g Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Pile Pro Pro Asp lie Leu Leu Thr Gin Ser Pro 115 120 125
Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Thr Asn He His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr -168 - 151681·序列表.doc 201127956 180 185 190
Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225
<210〉 166 <211> 250 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 166
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val.He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala -169- 151681-序列表.doc 201127956 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala lie 165 170 175
Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp 210 215 220
Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250
<210〉 167 <211〉 228 〈212〉 PRT 170· 151681·序列表.doc 201127956 <213〉人造序列 <220> <223>人造序列之描述：合成多肽 <400〉 167
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Phe Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Gly lie Arg Asn Asp Leu Gly Trp Tyr Gin Gin Lys Pro 145 150 155 160 -171 - 151681-序列表.doc 201127956
Gly Lys Ala Pro Lys Arg Leu He Tyr Ala Ala Ser Arg Leu His Arg 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Leu Gin His Asn Ser Tyr Pro Cys Ser Phe Gly Gin Gly Thr Lys Leu 210 215 220
Glu He Lys Arg 225 〈210〉 168 <211〉 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 168
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala lie Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Gly lie lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe 50 55 60 •172-
151681-序列表.doc 201127956
Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr 100 105 110
Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Lys Gin Ser Gly 130 135 140
Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val 145 150 155 160
Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser 165 170 175
Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn 180 185 190
Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp 195 200 205
Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn 210 215 220
Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr 225 230 235 240
Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala -173 - 151681·序列表.doc 201127956 245 250 255 <210> 169 <211> 223 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 169
Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly Gin 15 10 15
Thr Val Arg He Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30
Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Val lie Tyr 35 40 45
Gly Glu Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser Gly Ser 50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr lie Thr Gly Ala Gin Ala Glu 65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin His 85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro Lys 100 105 110
Ala Ala Pro Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val 115 120 125
Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie -174-
151681·序列表.doc 201127956 130 135 140
Gly Thr Asn He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg 145 150 155 160
Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg 165 170 175
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser 180 185 190
Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn 195 200 205
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 170 <211〉 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 170
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr -175- 151681·序列表.doc 201127956 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 130 135 140
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala lie Ser 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Gly lie 165 170 175 lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe Gin Gly Arg 180 185 190
Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 210 215 220
Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr Tyr Tyr Tyr 225 230 235 240 176- 15168卜序列表.doc 201127956
Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 245 250 255 <210〉 171 <211〉 222 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 171
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly 115 120 125 151681-序列表.doc -177- 201127956
Gin Thr Val Arg He Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr 130 135 140
Ala Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Val lie 145 150 155 160
Tyr Gly Glu Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe Ser Gly 165 170 175
Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr lie Thr Gly Ala Gin Ala 180 185 190
Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin 195 200 205
His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220 〈210〉 172 <211> 262 〈212〉 PRT 〈213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 172
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala He Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 -178· 151681-序列表.doc 201127956
Gly Gly lie He Pro He Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr 100 105 110
Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gin 130 135 140
Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser 145 150 155 160
Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly 165 170 175
Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly 180 185 190
Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser 195 200 205
Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys 210 215 220
Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg •179· 151681·序列表.doc 201127956 225 230 235 240
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr 245 250 255
Leu Val Thr Val Ser Ala 260 <210〉 173 <211〉 230 <212> PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 173
Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly Gin 15 10 15
Thr Val Arg lie Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30
Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro He Leu Val He Tyr
Gly Glu Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe Ser Gly Ser 50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr lie Thr Gly Ala Gin Ala Glu 65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin His 85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro Lys -180 - 151681·序列表.doc 201127956 100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Leu Leu Thr Gin 115 120 125
Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser 130 135 140
Cys Arg Ala Ser Gin Ser He Gly Thr Asn He His Trp Tyr Gin Gin 145 150 155 160
Arg Thr Asn Gly Ser Pro Arg Leu Leu He Lys Tyr Ala Ser Glu Ser 165 170 175 lie Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 180 185 190
Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp He Ala Asp Tyr 195 200 205
Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr 210 215 220
Lys Leu Glu Leu Lys Arg 225 230 <210〉 174 <211〉 262 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 174
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin -181 - 151681-序列表.doc 201127956 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys 130 135 140
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr 145 150 155 160
Phe Ser Ser Tyr Ala He Ser Trp Val Arg Gin Ala Pro Gly Gin Gly 165 170 175
Leu Glu Trp Met Gly Gly lie lie Pro He Phe Gly Thr Ala Asn Tyr 180 185 190 •182 151681·序列表.doc 201127956
Ala Gin Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr 195 200 205
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr 225 230 235 240
Gin Asp His Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr 245 250 255
Thr Val Thr Val Ser Ser 260 <210> 175 <211〉 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 175
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60 -183· 151681·序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ser Ser Glu Leu Thr Gin Asp Pro 115 120 125
Ala Val Ser Val Ala Leu Gly Gin Thr Val Arg lie Thr Cys Gin Gly 130 135 140
Asp Ser Leu Arg Ser Tyr Tyr Ala Thr Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Gin Ala Pro He Leu Val lie Tyr Gly Glu Asn Lys Arg Pro Ser Gly 165 170 175 lie Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu 180 185 190
Thr lie Thr Gly Ala Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Lys 195 200 205
Ser Arg Asp Gly Ser Gly Gin His Leu Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Gly 225 <210〉 176 184-
151681·序列表.doc 201127956 <211〉 262 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 176
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala lie Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Gly lie lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ala Fro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr 100 105 110
Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Gin 130 135 140
Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser -185· 151681·序列表.doc 201127956 145 150 155 160
Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly 165 170 175
Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly 180 185 190
Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser 195 200 205
Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys 210 215 220
Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala Arg 225 230 235 240
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr 245 250 255
Leu Val Thr Val Ser Ala 260 <210〉 177 <211〉 223 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 177
Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly Gin 1 5 10 15
Thr Val Arg lie Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr Ala -186- 151681-序列表.doc 201127956 20 25 30
Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Val lie Tyr 35 40 45
Gly Glu Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser Gly Ser 50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr He Thr Gly Ala Gin Ala Glu 65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin His 85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro Lys 100 105 110
Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val 115 120 125
Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie 130 135 140
Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg 145 150 155 160
Leu Leu He Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg 165 170 175
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser 180 185 190
Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn 195 200 205 -187- 15168卜序列表.doc 201127956
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 〈210〉 178 <211〉 262 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 178
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15 ^
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 • 188 - 15168卜序列表.doc 201127956
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys 130 135 140
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr 145 150 155 160
Phe Ser Ser Tyr Ala lie Ser Trp Val Arg Gin Ala Pro Gly Gin Gly 165 170 175
Leu Glu Trp Met Gly Gly lie lie Pro lie Phe Gly Thr Ala Asn Tyr 180 185 190
Ala Gin Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr 195 200 205
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr 225 230 235 240
Gin Asp His Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr 245 250 255
Thr Val Thr Val Ser Ser 260 <210> 179 <211〉 222 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 189- 151681-序列表.doc 201127956 <400〉 179
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly 115 120 125
Gin Thr Val Arg lie Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr 130 135 140
Ala Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Val lie 145 150 155 160
Tyr Gly Glu Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe Ser Gly 165 170 175
Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr lie Thr Gly Ala Gin Ala -190· 15168卜序列表.doc 201127956 180 185 190
Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin 195 200 205
His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 210 215 220
<210> 180 <211〉 255 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 180
Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala lie Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Gly lie lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr -191 - 151681-序列表.doc 201127956 100 105 110
Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val 115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu Lys Gin Ser Gly 130 135 140
Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val 145 150 155 160
Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser 165 170 175
Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn 180 185 190
Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser He Asn Lys Asp 195 200 205
Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn 210 215 220
Asp Thr Ala He Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr 225 230 235 240
Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 255 <210〉 181 <211〉 230 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 192- 151681·序列表.doc 201127956 <400> 181
Ser Ser Glu Leu Thr Gin Asp Pro Ala Val Ser Val Ala Leu Gly Gin 15 10 15
Thr Val Arg lie Thr Cys Gin Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30
Thr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro lie Leu Val lie Tyr 35 40 45
Gly Glu Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe Ser Gly Ser 50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr He Thr Gly Ala Gin Ala Glu 65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gin His 85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gin Pro Lys 100 105 110
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Asp lie Leu Leu Thr Gin 115 120 125
Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser 130 135 140
Cys Arg Ala Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin 145 150 155 160
Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser 165 170 175 151681-序列表.doc 193· 201127956 lie Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 180 185 190
Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr 195 200 205
Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr 210 215 220
Lys Leu Glu Leu Lys Arg 225 230
<210〉 182 <211〉 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 182
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80 194-
151681-序列表.doc 201127956
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys 130 135 140
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala lie Ser 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Gly lie 165 170 175 lie Pro lie Phe Gly Thr Ala Asn Tyr Ala Gin Lys Phe Gin Gly Arg 180 185 190
Va.L Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu 195 200 205
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala 210 215 220
Pro Leu Arg Phe Leu Glu Trp Ser Thr Gin Asp His Tyr Tyr Tyr Tyr 225 230 235 240
Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 245 250 255 <210〉 183 -195 15168卜序列表.doc 201127956 <211> 229 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 183
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Ser Ser Glu Leu Thr Gin Asp Pro 115 120 125
Ala Val Ser Val Ala Leu Gly Gin Thr Val Arg He Thr Cys Gin Gly 130 135 140
Asp Ser Leu Arg Ser Tyr Tyr Ala Thr Trp Tyr Gin Gin Lys Pro Gly -196-
151681-序列表.doc 201127956 145 150 155 160
Gin Ala Pro lie Leu Val He Tyr Gly Glu Asn Lys Arg Pro Ser Gly 165 170 175 lie Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu 180 185 190
Thr lie Thr Gly Ala Gin Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Lys 195 200 205
Ser Arg Asp Gly Ser Gly Gin His Leu Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Gly 225 <210> 184 <211〉 243 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 184
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Ser Val He Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys -197· 151681·序列表.doc 201127956 50 55 60
Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu 115 120 125
Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser He 130 135 140
Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp 145 150 155 160
Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp 165 170 175
Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser 180 185 190
He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser 195 200 205
Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr 210 215 220
Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr 225 230 235 240 198· 151681-序列表d〇c 201127956
Val Ser Ala <210〉 185 〈211〉 221 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 185
Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Ser Ser 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Gin Ser Leu Ser Gly He Pro Asp Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro His 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125 •199· 151681·序列表.doc 201127956
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser. Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 186 <211> 243 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 186
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 -200-
151681-序列表.doc 201127956
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Ala Met His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie Ser Val lie 165 170 175
Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Gly 210 215 220
Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr -201 - 151681-序列表.doc 201127956 225 230 235 240
Val Ser Ser <210> 187 <211> 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 187
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro •202· 151681·序列表.doc 201127956 115 120 125
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser He Gly Ser 130 135 140
Ser Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Gin Ser Leu Ser Gly He Pro Asp Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 180 185 190
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro 195 200 205
His Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 188 <211〉 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 188
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie -203 151681·序列表.doc 201127956 35 40 45
Ser Val lie Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60
Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin 130 135 140
Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu 145 150 155 160
Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu 165 170 175
Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 180 185 190
Pro Phe Thr Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin 195 200 205
Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr 210 215 220 -204- 151681·序列表.doc 201127956
Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 〈210〉 189 〈211〉 228 <212〉 PRT <213〉人造序列 <220>
<223〉人造序列之描述：合成多肽 <400> 189
Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Ser Ser 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Gin Ser Leu Ser Gly He Pro Asp Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro His 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110 -205· 151681-序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Leu Leu Thr Gin Ser Pro 115 120 125
Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Arg Leu Leu He Lys Tyr Ala Ser Glu Ser He Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 225 <210〉 190 <211〉 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 190
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15 -206
151681·序列表.doc 201127956
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val 130 135 140
Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Phe Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp He Ser Val lie Asp Thr Arg Gly Ala Thr Tyr Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn -207- 151681·序列表.doc 201127956 195 200 205
Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 〈210〉 191 <211〉 228 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 191
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr -208- 151681-序列表doc 201127956 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Glu lie Val Leu Thr Gin Ser Pro 115 120 125
Gly Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Ser Ser Leu His Trp Tyr Gin Gin Lys Pro 145 150. 155 160
Gly Gin Ala Pro Arg Leu Leu lie Lys Tyr Ala Ser Gin Ser Leu Ser 165 170 175
Gly He Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 195 200 205
His Gin Ser Ser Arg Leu Pro His Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 192 <21.1〉250 <212> PRT <213>人造;^列 <220> <223〉人造序列之描述：合成多肽 -209- 151681·序列表.doc 201127956 <400〉 192
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Ser Val He Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60
Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin 130 135 140
Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu 145 150 155 160
Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu 165 170 175 •210
151681-序列表 doc 201127956
Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr 180 185 190
Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin 195 200 205
Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr 210 215 220
Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 <210〉 193 <211〉 221 <212> PRT 〈213>人造序列 <220〉 〈223>人造序列之描述：合成多肽
<400> 193
Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Ser Ser 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Gin Ser Leu Ser Gly lie Pro Asp Arg Phe Ser Gly 50 55 60 -211 - 151681·序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro His 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu 180 185 190
Ser Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 194 <211〉 250 〈212〉 PRT <213〉人造序列 212-
151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400〉 194
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val 130 135 140
Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Phe Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly •213- 151681-序列表.doc 201127956 165 170 175
Leu Glu Trp lie Ser Val He Asp Thr Arg Gly Ala Thr Tyr Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn 195 200 205
Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ala Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 <210〉 195 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 195
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly -214- 151681·序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Vfil Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Ser 130 135 140
Ser Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Gin Ser Leu Ser Gly lie Pro Asp Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 180 185 190
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro 195 200 205
His Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220
<210> 196 <211〉 243 <212> PRT -215- 151681·序列表-doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400 196
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Ser Val He Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60
Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Leu Gly Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin Leu 115 120 125
Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser lie 130 135 140
Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp 145 150 155 160 -216-
151681·序列表.doc 201127956
Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp 165 170 175
Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser 180 185 190 lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser 195 200 205
Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr 210 215 220
Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu·Val Thr 225 230 235 240
Val Ser Ala <210〉 197 〈211〉 228 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400> 197
Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Ser Ser 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45 -217- 151681-序列表.d〇c 201127956
Lys Tyr Ala Ser Gin Ser Leu Ser Gly He Pro Asp Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gin Ser Ser Arg Leu Pro His 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Leu Leu Thr Gin Ser Pro 115 120 125
Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 130 135 140
Ala Ser Gin Ser He Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr 145 150 155 160
Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser 165 170 175
Gly lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Ser lie Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys 195 200 205
Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 210 215 220
Glu Leu Lys Arg 218·
151681·序列表.doc 201127956 225 <210〉 198 <211> 243 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 198
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro F^e Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg -219- 151681-序列表 doc 201127956 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Ala Met His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie Ser Val lie 165 170 175
Asp Thr Arg Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe 180 185 190
Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Gly 210 215 220
Asn Phe Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr 225 230 235 240
Val Ser Ser <210> 199 〈211〉 228 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 199
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn -220·
151681·序列表.doc 201127956 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Glu lie Val Leu Thr Gin Ser Pro 115 120 125
Gly Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg 130 135 140
Ala Ser Gin Ser lie Gly Ser Ser Leu His Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Gin Ala Pro Arg Leu Leu lie Lys Tyr Ala Ser Gin Ser Leu Ser 165 170 175
Gly lie Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 195 200 205 •221 Μ1681·序列表.doc 201127956
His Gin Ser Ser Arg Leu Pro His Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225 <210> 200 〈211〉 249 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 200
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110 •222· 151681-序列表.doc 201127956
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val lie 165 170 175
Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe 210 215 220
Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Thr Val Thr Val Ser Ser 245 <210〉 201 <211> 227 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 223 - 151681·序列表.doc 201127956 <400〉 201
Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro 115 120 125
Gly Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His 130 135 140
Ser Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin 145 150 155 160
Ser Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val 165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys •224·
151681-序列表.doc 201127956 180 185 190 lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin 195 200 205
Ala Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Arg Arg 225
<210〉 202 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 202
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys • 225 · 151681-序列表.doc 201127956 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 HO
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro 130 135 140
Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 145 150 155 160
Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu 165 170 175
Trp Leu Gly Val He Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro 180 185 190
Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val 195 200 205
Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr 210 215 220
Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ala 245
<210〉 203 <211〉 227 <212〉 PRT 226- 151681·序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 203
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He 100 105 110
Arg Arg Thr Val Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val 115 120 125 lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 130 135 140
Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn 145 150 155 160 •227· 151681-序列表.doc 201127956
Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser He Ser Gly 165 170 175 lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Ser He Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin 195 200 205
Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 210 215 220
Leu Lys Arg 225 <210〉 204 <211〉 256 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 204
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 -228- 151681-序列表.doc 201127956
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser 130 135 140
Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr 145 150 155 160
Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin 165 170 175
Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly 180 185 190
Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys 195 200 205
Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser 210 215 220
Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp 225 230 235 240
Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala -229- 151681·序列表.doc 201127956 245 250 255 <210> 205 <211> 234 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 205
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He 100 105 110
Arg Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp He 115 120 125
Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg -230·
151681-序列表.doc 201127956
130 135 HO
Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn He His 145 150 155 160
Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr 165 170 175
Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp 195 200 205 lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe 210 215 220
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 <210〉 206 <211> 256 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 206
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 1 5 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu -231 - 151681·序列表.doc 201127956 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val 130 135 140
Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Tyr Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175
Leu Glu Trp Val Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys 195 200 205
Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 -232* 151681·序列表.doc 201127956
Val Tyr Tyr Cys Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr 225 230 235 240
Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 255 <210> 207 <211〉 234 <212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述•合成多肽 <400〉 207
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 233 · 151681-序列表.doc 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp Val Val Met Thr Gin Ser Pro 115 120 125
Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser lie Ser Cys Arg 130 135 140
Ser Ser Gin Ser Leu Leu His Ser Asn Gly Phe Asn Tyr Val Asp Trp 145 150 155 160
Tyr Leu Gin Lys Pro Gly Gin Ser Pro His Leu Leu He Tyr Phe Gly 165 170 175
Ser Tyr Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Lys He Ser Arg Val Glu Ala Glu Asp Val 195 200 205
Gly Val Tyr Tyr Cys Met Gin Ala Leu Gin Thr Pro Pro Trp Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu He Arg Arg 225 230 <210〉 208 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 208
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15 -234-
15168卜序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Lys Gin Ser 130 135 140
Gly Pro Gly Leu Val Gin Pro Ser Gin Ser Leu Ser He Thr Cys Thr 145 150 155 160
Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin 165 170 175
Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val He Trp Ser Gly Gly 180 185 190
Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys •235 · 151681·序列表.doc 201127956 195 200 205
Asp Asn Ser Lys Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser 210 215 220
Asn Asp Thr Ala lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp 225 230 235 240
Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 245 250 255 <210〉 209 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 209
Asp Va.1 Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala •236·
151681-序列表.doc 201127956 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Arg Arg Thr Val Ala Ala Pro Asp lie Leu Leu Thr Gin Ser Pro Val 115 120 125 lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 130 135 140
Ser Gin Ser lie Gly Thr Asn lie His Trp Tyr Gin Gin Arg Thr Asn 145 150 155 160
Gly Ser Pro Arg Leu Leu He Lys Tyr Ala Ser Glu Ser lie Ser Gly 165 170 175 lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Ser lie Asn Ser Val Glu Ser Glu Asp He Ala Asp Tyr Tyr Cys Gin 195 200 205
Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 210 215 220
Leu Lys Arg 225 <210> 210 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 •237· 151681 -序列表.doc 201127956 <400〉 210
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val 130 135 140
Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160
Phe Ser Ser Tyr Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly 165 170 175 -238
151681-序列表.doc 201127956
Leu Glu Trp Val Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr 180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys 195 200 205
Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220
Val Tyr Tyr Cys Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr 225 230 235 240
Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 255 <210〉 211 <211> 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 211
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60 •239· 151681-序列表 doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys. Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro 115 120 125
Gly Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His 130 135 140
Ser Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin 145 150 155 160
Ser Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val 165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 180 185 190
He Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin 195 200 205
Ala Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Arg Arg 225 〈210〉 212 -240· 151681·序列表 _doc 201127956 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 212
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro 130 135 140
Ser Gin Ser Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr •241 - 151681-序列表.doc 201127956 145 150 155 160
Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu 165 170 175
Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro 180 185 190
Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val 195 200 205
Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr 210 215 220
Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ala 245 <210〉 213 <211> 234 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 213
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser •242·
151681·序列表.doc 201127956 35 40 45
Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Arg Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp He 115 120 125
Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg 130 135 140
Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asri lie His 145 150 155 160
Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr 165 170 175
Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser Gly Ser Gly 180 185 190
Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser Glu Asp 195 200 205
He Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe 210 215 220 151681·序列表.doc -243- 201127956
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 225 230 <210> 214 <211〉 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 214
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125 • 244·
151681·序列表.doc 201127956
Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val He 165 170 175
Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe 210 215 220
Se:r Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp VaL Trp Gly 225 230 235 240
Gin Gly Thr Thr Val Thr Val Ser Ser
〈210〉 215 〈211〉 234 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 215
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 1 5 10 15 -245 15168卜序列表.doc 201127956
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser He Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu He 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp Val Val Met Thr Gin Ser Pro 115 120 125
Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser lie Ser Cys Arg 130 135 140
Ser Ser Gin Ser Leu Leu His Ser Asn Gly Phe Asn Tyr Val Asp Trp 145 150 155 160
Tyr Leu Gin Lys Pro Gly Gin Ser Pro His Leu Leu lie Tyr Phe Gly 165 170 175
Ser Tyr Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 180 185 190
Gly Thr Asp Phe Thr Leu Lys He Ser Arg Val Glu Ala Glu Asp Val • 246· 151681-序列表.doc 201127956 195 200 205
Gly Val Tyr Tyr Cys Met Gin Ala Leu Gin Thr Pro Pro Trp Thr Phe 210 215 220
Gly Gin Gly Thr Lys Val Glu lie Arg Arg 225 230 <210〉 216 <211〉 247 <212> PRT <213〉人造序列
<220〉 〈223>人造序列之描述：合成多肽 <400〉 216
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly -247- 151681-序列表.doc 201127956 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser 145 150 155 160
Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie 165 170 175
Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210〉 217 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -248- 151681 ·序列表.doc 201127956 <400〉 217
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
He His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175 •249- 151681·序列表.doc 201127956
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 218 <211〉 247 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 218
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 •250
151681·序列表.doc 201127956
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 130 135 140
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 145 150 155 160
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 165 170 175
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 180 185 190
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 195 200 205
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 210 215 220
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ala 245 <210> 219 <211〉 221 <212> PRT <213〉人造序列 251 - 151681-序列表.doc 201127956 <220> <223〉人造序列之描述：合成多肽 <400> 219
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160
He Lys Tyr Ala Ser Glu Ser He Ser Gly lie Pro Ser Arg Phe Ser -252- 151681-序列表.doc 201127956 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser He Asn Ser Val Glu 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220
<210> 220 <211> 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 220
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala - 253 - 151681·序列表.doc 201127956 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Pro Glu Leu Val Arg Pro Gly Ala Ser Val Lys 130 135 140
Trp Ser Cys Pro Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Leu His 145 150 155 160
Trp Val Lys Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp He Gly Met 165 170 175 lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Pro Asn Phe Lys 180 185 190
Asp Lys Ala Thr Leu Asn Val Asp Arg Ser Ser Asn Thr Ala Tyr Asn 195 200 205
Leu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220
Thr Tyr Gly Ser Tyr Val Ser Pro Leu Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Ser Val Tyr Val Ser Ser 245
<210〉 221 <211〉 227 <212〉 PRT 151681-序列表.doc -254- 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 221
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30
lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly He Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Met Met Ser Gin Ser Pro Ser Ser Leu Thr Val Ser Val 115 120 125
Gly Glu Lys Val Thr Val Ser Cys Lys Ser Ser Gin Ser Leu Leu Val 130 135 140
Thr Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gin 145 150 155 160 -255 - 151681·序列表.doc 201127956
Gin Ser Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly 165 170 175
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr He Thr Ser Val Lys Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gin 195 200 205
Gin Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Asp Gly Thr Lys Leu Glu 210 215 220
He Lys Arg 225 〈210〉 222 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 <400〉 222
Gin Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Arg Pro Gly Ala 1 5 10 15
Ser Val Lys Trp Ser Cys Pro Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Lys Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp 35 40 45
He Gly Met He Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Pro 50 55 60 * •256-
151681·序列表.doc 201127956
Asn Phe Lys Asp Lys Ala Thr Leu Asn Val Asp Arg Ser Ser Asn Thr 65 70 75 80
Ala Tyr Asn Leu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr 85 90 95
Tyr Cys Ala Thr Tyr Gly Ser Tyr Val Ser Pro Leu Asp Tyr Trp Gly 100 105 110
Gin Gly Thr Ser Val Tyr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin 115 120 125
Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin Ser 130 135 140
Leu Ser He Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly 145 150 155 160
Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly 165 170 175
Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser 180 185 190
Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe Lys 195 200 205
Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala Arg 210 215 220
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ala 257 - 151681-序列表.doc 245 201127956 <210> 223 <211〉 227 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 223
Asp lie Met Met Ser Gin Ser Pro Ser Ser Leu Thr Val Ser Val Gly 15 10 15
Glu Lys Val Thr Val Ser Gys Lys Ser Ser Gin Ser Leu Leu Val Thr 20 25 30
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gin Gin 35 40 45
Ser Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Thr Ser Val Lys Ala Asp Asp Leu Ala Val Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Asp Gly Thr Lys Leu Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Asp He Leu Leu Thr Gin Ser Pro Val 115 120 125 lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala • 258·
151681·序列表.doc 201127956 130 135 140
Ser Gin Ser lie Gly Thr Asn He His Trp Tyr Gin Gin Arg Thr Asn 145 150 155 160
Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser lie Ser Gly 165 170 175 lie Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Ser He Asn Ser Val Glu Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin 195 200 205
Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 210 215 220
Leu Lys Arg 225 <210〉 224 <211〉 246 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 224
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val • 259- 151681·序列表.doc 201127956 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 130 135 140
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asp lie 145 150 155 160
Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met Gly Trp 165 170 175
Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe Gin Gly 180 185 190
Arg Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr Met Glu 195 200 205
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 210 215 220 260- 151681-序列表.doc 201127956
Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 225 230 235 240
Thr Val Thr Val Ser Ser 245 <210〉 225 <211〉 225 〈212〉 PRT <213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 225
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110 -261 - 151681-序列表.doc 201127956
Pro Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly 115 120 125
Gin Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn 130 135 140
Asn His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu 145 150 155 160
Leu He Tyr Asp Asn Asn Lys Arg Pro Ser Gly lie Pro Asp Arg Phe 165 170 175
Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu 180 185 190
Gin Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser 195 200 205
Leu Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 2l〇 215 220
Gly 225 <210〉 226 <211〉 246 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 226
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala i 5 10 15 -262
151681·序列表.doc 201127956
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser He Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr He 145 150 155 160
His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg 165 170 175 lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin -263 - 151681·序列表 _doc 201127956 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg 210 215 220
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr 225 230 235 240
Leu Val Thr Val Ser Ser 245 <210> 227 <211> 226 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400〉 227
Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly Gin 15 10 15
Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn Asn 20 25 30
His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45
He Tyr Asp Asn Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu Gin 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu •264-
151681·序列表.doc 201127956 85 90 95
Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110
Gin Pro Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser 130 135 140
Gin Asp Val Asn Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
His Tyr Thr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie 2l〇 215 220
Lys Arg 225 <210〉 228 <211〉 251 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -265- 151681·序列表.doc 201127956 <400〉 228
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala 165 170 175 -266
151681-序列表.doc 201127956 lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys Gly 180 185 190
Arg Phe Thr He Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val 225 230 235 240
Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 <210〉 229 <211> 221 〈212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 229
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 -267. 151681-序列表.doc 201127956
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn 130 135 140
Asp Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu 145 150 155 160
He Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro 195 200 205
Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 210 215 220 <210〉 230 <211〉 251 〈212〉 PRT 〈213〉人造序列 -268-
151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 230
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Yal Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin 130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He 145 150 155 160
Lys Asp Thr Tyr He His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu -269· 151681-序列表.doc 201127956 165 170 175
Glu Trp Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala 180 185 190
Asp Ser Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn 195 200 205
Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 231 <211〉 221 <212> PRT <213〉人造序列 <220〉 、 <223〉人造序列之描述：合成多肽 <400〉 231
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Va.1 Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly •270- 151681-序列表.doc 201127956 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220
<210〉 232 <211〉 252 <212〉 PRT 271 15168卜序列表_doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 232
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val He Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro 130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 272 - 151681_ 序列表.doc 201127956
Asp Tyr Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu 165 170 175
Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp 180 185 190
Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser 195 200 205
Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220
Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 233 〈211〉 227 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 233
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45 -273 - 151681-序列表.doc 201127956
Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Arg Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala 130 135 140
Ser Gin Gly He Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Asn Leu Leu He Tyr Glu Ala Ser Ser Leu Gin Ser Gly 165 170 175
Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin 195 200 205
Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Lys Arg -274· 151681·序列表.doc 201127956 225 <210〉 234 <211> 252 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 234
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly -275 - 151681-序列表.doc 201127956 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 145 150 155 160
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 180 185 190
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 225 230 235 240
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 <210> 235 <211〉 227 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 235
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp •276-
151681·序列表.doc 201127956 30 20 25
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro 115 120 125
Gly Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His 130 135 140
Ser Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin 145 150 155 160
Ser Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val 165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu kys 180 185 190 lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin 195 200 205 •277- 151681·序列表.doc 201127956
Ala Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Arg Arg 225 <210〉 236 <211〉 248 <212〉 PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽
<400〉 236
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 -278
151681-序列表.doc 201127956
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser 130 135 140
Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn 145 150 155 160
Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp 165 170 175
Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe 180 185 190
Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe 195 200 205
Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys 210 215 220
Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ala 245 <210〉 237 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 279- 151681-序列表doc 201127956 <400〉 237
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro 115 120 125
Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr 130 135 140
Asn lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu 145 150 155 160 lie Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu •280·
151681-序列表doc 201127956 180 185 190
Ser Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro 195 200 205
Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 210 215 220 <210> 238 <211> 248 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 238
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser He Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly -281 - 151681-序列表doc 201127956 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp He 165 170 175
Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg 180 185 190
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr 210 215 220
Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 239 <211> 221 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -282-
151681-序列表.doc 201127956 <400> 239
Asp lie Leu Leu Thr Gin Ser Pro Val He Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Ti*p Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175 •283 151681·序列表.doc 201127956
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 240 <211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 240
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -284-
151681·序列表doc 201127956
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp 145 150 155 160
Thr Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 241 <211〉 221 <212〉 PRT <213〉人造序列 285- 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述：合成多肽 <400> 241
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser • 286 - 151681·序列表.doc 201127956 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 21〇 215 220
<211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 242
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg He Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -287· 151681·序列表.doc 201127956 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175
He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 180 185 190
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245
<210〉 243 <211〉 221 <212> PRT 288- 151681-序列表.doc 201127956 <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400> 243
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30
Va'l Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 289 · 151681-序列表.doc 201127956 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 244 <211〉 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 244
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 290· 151681-序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly 130 135 140
Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser 145 150 155 160
Tyr Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp 165 170 175 lie Gly Ala He Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys 180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala 195 200 205
Tyr Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp 225 230 235 240
Gly Ala Gly Thr Thr Val Thr Val Ser Ala 245 250 <210〉 245 291 · 151681·序列表.doc 201127956 <211〉 220 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 245
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Fhe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr 130 135 140
He His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie -292- 151681·序列表.doc 201127956 145 150 155 160
Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro 195 200 205
Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 246 <211> 250 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 246
Gin Val Gin Leu Gin Gin Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asn Met His Trp Val Lys Gin Thr Pro Gly Arg Gly Leu Glu Trp lie 35 40 45
Gly Ala He Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gin Lys Phe 50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr -293- 151681·序列表.doc 201127956 65 70 75 80
Met· Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Glu 115 120 125
Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser 130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly 145 150 155 160
Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 165 170 175
Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 180 185 190
Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu 195 200 205
Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 -294-
151681-序列表.doc 201127956 <210> 247 <211〉 220 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 247
Gin lie Val Leu Ser Gin Ser Pro Ala lie Leu Ser Pro Ser Pro Gly 1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr lie 20 25 30
His Trp Phe Gin Gin Lys Pro Gly Ser Ser Pro Lys Pro Trp lie Tyr 35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Arg Val Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Thr Ser Asn Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 130 135 140 -295- 151681-序列表.doc 201127956
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 145 150 155 160
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 180 185 190
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 195 200· 205
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 248 <211〉 249 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 248
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 •296·
151681-序列表 _doc 201127956
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 130 135 140
Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser 145 150 155 160
Tyr Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp 165 170 175
Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys 180 185 190
Phe Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser He Ser Thr Ala 195 200 205
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Thr Val Thr Val Ser Ser -297- 151681·序列表.doc 245 201127956 <210〉 249 <211> 22δ <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 249
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly 115 120 125
Gin Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn •298·
151681·序列表.doc 201127956 130 135 140
Asn His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu 145 150 155 160
Leu He Tyr Asp Asn Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe 165 170 175
Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly He Thr Gly Leu 180 185 190
Gin Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser 195 200 205
Leu Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 210 215 220
Gly 225 <210〉 250 <211> 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述·合成多肽 <400〉 250
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Asp lie Asn Trp Val Arg Gin Ala Thr Gly Gin Gly Leu Glu Trp Met •299· 151681·序列表.doc 201127956 35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr Met Thr Arg Asn Thr Ser lie Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val 115 120 125
Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met 145 150 155 160
Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 165 170 175 lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 180 185 190
Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin 195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 210 215 220 -300- 151681-序列表.doc 201127956
Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Leu Val Thr Val Ser Ser 245 <210> 251 <211〉 226 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 251
Gin Ser Val Leu Thr Gin Pro Pro Ser Val Ser Ala Ala Pro Gly Gin 15 10 15
Lys Val Thr lie Ser Cys Ser Gly Ser Ser Ser Asn lie Glu Asn Asn 20 25 30
His Val Ser Trp Tyr Gin Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45
lie Tyr Asp Asn Asn Lys Arg Pro Ser Gly He Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly lie Thr Gly Leu Gin 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Glu Thr Trp Asp Thr Ser Leu 85 90 95
Ser Ala Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 •301 · 151681-序列表.doc 201127956
Gin Pro Lys Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser 115 120 125
Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser 130 135 140
Gin Asp He Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys 145 150 155 160
Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val 165 170 175
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 180 185 190 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 195 200 205
Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 210 215 220
Lys Arg 225 <210> 252 <211> 247 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 252
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -302- 151681·序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 145 150 155 160
Asn Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Gly Tyr He Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala - 303 · 151681-序列表.doc 201127956 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245 <210> 253 <211〉 222 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 253
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp -304· 151681·序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly 195 200 205
Thr Val Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 254 <211〉 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 254
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -305 - 151681-序列表doc 201127956 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Asn 20 25 30
Trp He Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Tyr lie Ser Pro Asn Ser Gly Phe Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Asn Phe Gly Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin Leu 115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu 130 135 140
Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp 145 150 155 160
Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn 165 170 175
Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe 180 185 190 -306-
151681·序列表.doc 201127956
Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn 195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro 210 215 220
His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245
<210〉 255 <211〉 222 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 255
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser Thr Ala 20 25 30
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 -307- 151681·序列表.doc 201127956
Glu Asp Phe Ala Thr Thr Tyr Tyr Cys Gin Gin Ser Tyr Thr Gly Thr 85 90 95
Val Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110
Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 115 120 125
Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser 130 135 140
Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val 145 150 155 160
Leu He Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe 165 170 175
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 180 185 190
Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val 195 200 205
Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 2i〇 215 220 <210> 256 <211〉 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 308-
151681-序列表.doc 201127956 <400〉 256
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp 145 150 155 160
Tyr Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ser Tyr lie Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser •309- 151681·序列表-doc 201127956 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 257 <211〉 221 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400> 257
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro •310- 151681·序列表 doc 201127956 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 258 <211〉 251 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 311 · 151681-序列表.doc 201127956 <400> 258
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr He Ser Ser Ser Gly Ser Thr He Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 145 150 155 160
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175 -312 151681-序列表.doc 201127956
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 180 185 190
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 259 <211> 221 <212〉 PRT <213〉人造序列 〈220〉 <2之3>人造序列之描述：合成多肽
<400〉 259
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60 313· 151681-序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp He Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 260 <211〉 258 <212> PRT <213>人造序列 314· 151681-序列表.doc 201127956 <220〉 <223〉人造序列之描述··合成多肽 <400> 260
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 δ 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro -315- 151681-序列表.doc 201127956 165 170 175
Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu 180 185 190
Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp 195 200 205
Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser 225 230 235 240
Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 245 250 255
Ser Ser <210〉 261 <211〉 228 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 261
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie -316-
151681-序列表,doc 201127956 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe He Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp krg Val Thr lie Thr Cys Ser 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220 317- 151681-序列表.doc 201127956
Glu lie Lys Arg 225 <210〉 262 <211〉 258 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 262
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 151681·序列表.doc -318· 201127956
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly 130 135 140
Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 145 150 155 160
Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser Trp He Arg Gin Ala 165 170 175
Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser 180 185 190
Thr He Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg 195 200 205
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly 225 230 235 240
Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 245 250 255
Ser Ser <210〉 263 <211> 228 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 319- 151681·序列表.doc 201127956 <400〉 263
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg 130 135 140
Ala Ser Gin Gly lie Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr •320· 151681-序列表,doc 201127956 180 185 190
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210〉 264 <211〉 258 <212> PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 264
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -321 - 151681-序列表.doc 201127956 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Ser Val Phe Pro Leu Ala Pro Glu Val Gin Leu Val Glu Ser Gly Gly 130 135 140
Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 145 150 155 160
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro 165 170 175
Gly Lys Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu 180 185 190
Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp 195 200 205
Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu 210 215 220
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser 225 230 235 240
Ser His Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val 245 250 255
Ser Ser -322- 151681·序列表.doc 201127956 <210> 265 <211> 221 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 265
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Sex Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140 323 - 151681-序列表.doc 201127956
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160
He Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210> 266 <211> 258 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 266
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 -324-
151681-序列表.doc 201127956
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Gin Val Gin Leu Val Glu Ser Gly 130 135 140
Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 145 150 155 160
Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser Trp lie Arg Gin Ala 165 170 175
Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr He Ser Ser Ser Gly Ser 180 185 190
Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg 195 200 205
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala 210 215 220
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly 225 230 235 240
Trp Tyr Val Leu.Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val •325- 151681-序列表.doc 201127956 245 250 255
Ser Ser <210〉 267 <211〉 221 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 267
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val - 326·
151681-序列表.doc 201127956 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 268 <211> 251 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述··合成多肽 <400〉 268
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val •327· 151681·序列表.doc 201127956 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Glu Val Gin Leu Val Glu Ser Gly Gljr Gly Leu Val Gin Pro Gly Gly 130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 145 150 155 160
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 165 170 175
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 180 185 190
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 195 200 205
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220 •328-
151681-序列表.doc 201127956
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 269 <211> 228 <212〉 PRT 〈213〉人造序列 <220〉
<223〉人造序列之描述：合成多肽 <400〉 269
Asp He Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110 151681-序列表.doc 329-
S 201127956
Pro Ser Val Phe lie Phe Pro Pro Asp lie Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser 130 135 140
Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser 165 170 175
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu lie Lys Arg 225
<210〉 270 <211〉 251 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 270
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -330- 15168卜序列表.doc 201127956
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp 145 150 155 160
Tyr Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu •331 - 151681·序列表 _d〇c 201127956 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr 225 230 235 240
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 271 <211〉 228 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 271
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp •332- 151681·序列表.doc 201127956 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Ser Val Phe lie Phe Pro Pro Asp He Gin Met Thr Gin Ser Pro 115 120 125
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg 130 135 140
Ala Ser Gin Gly He Ser Sef Trp Leu Ala Trp Tyr Gin Gin Lys Pro 145 150 155 160
Gly Lys Ala Pro Asn Leu Leu lie Tyr Glu Ala Ser Ser Leu Gin Ser 165 170 175
Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 180 185 190
Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 195 200 205
Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val 210 215 220
Glu He Lys Arg 225 <210〉 272 <211> 253 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 • 333 · 151681·序列表.doc 201127956 <400> 272
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser 145 150 155 160
Tyr Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175 •334
151681-序列表.doc 201127956
Val Ala Val He Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met 225 230 235 240
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 <210〉 273 <211> 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400> 273
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 335 - 151681·序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro 115 120 125
Gly Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His 130 135 140
Ser Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin 145 150 155 160
Ser Pro His Leu Leu lie Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val 165 170 175
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 180 185 190 lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin 195 200 205
Ala Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220
He Arg Arg 225 <210〉 274 •336- 151681·序列表.doc 201127956 <211> 253 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 274
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val He Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro 130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr • 337- 151681·序列表.doc 201127956 145 150 155 160
Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu 165 170 175
Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala 180 185 190
Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr 195 200 205
Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220
Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe 225 230 235 240
Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250
<210> 275 〈211〉 227 <232> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 275
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser -338- 151681-序列表.doc 201127956 35 40 45
Pro His Leu Leu He Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Arg Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Ser Ala 130 135 140
Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly 145 150 155 160
Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin 195 200 205
Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 339- 15168〗-序列表.doc 201127956 lie Lys Arg 225 <210> 276 <211〉 248 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 276
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 ^
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp He Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 151681·序列表.doc -340- 201127956
Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser 145 150 155 160
Glu Pro lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp 165 170 175
Val Ser Ser lie Thr Gly Lys Asn Gly Tyr Thr Tyr Tyr Ala Asp Ser 180 185 190
Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala 195 200 205
Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220
Cys Ala Arg Trp Gly Lys Lys Val Tyr Gly Met Asp Val Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser
<210〉 277 〈211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 277
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 •341 _ 151681-序列表.doc 201127956
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser He Ser Ser 130 135 140
Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Met Ser Val Pro -342- 151681-序列表doc 201127956 195 200 205 lie Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210〉 278 <211> 248 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 278
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Glu 20 25 30
Pro lie Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ser lie Thr Gly Lys Asn Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp Gly Lys Lys Val Tyr Gly Met Asp Val Trp Gly G：Ln Gly loo 105 no
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin -343 - 151681·序列表.doc 201127956 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp lie 165 170 175
Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg 180 185 190
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala L)rs Tyr 210 215 220
Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val Trp Gly Gin 225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser 245 <210〉 279 <211〉 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 279
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly • 344. 151681-序列表.doc 201127956 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Met Ser Val Pro lie 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu 145 150 155 160 lie Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190 • 345 - 151681·序列表d〇c 201127956
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 210 215 220 <210〉 280 <211> 255 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 280
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His 20 25 30
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg lie Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 100 105 110 -346·
151681·序列表.doc 201127956
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125
Ser Thr Lys Gly Pro Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 145 150 155 160
Thr Phe Ser Asp Tyr Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr 180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala 195 200 205
Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val 225 230 235 240
Leu Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 281 <211〉 229 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 347- 151681·序列表.doc 201127956 <400> 281
Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly Ala 15 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp Ser 20 25 30
Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin Tyr 35 40 45
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly lie 65 70 75 80
Leu Leu lie Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 85 90 95
Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu 100 105 110
Thr Val Leu Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 130 135 140
Arg Ala Ser Gin Gly He Ser Ser Trp Leu Ala Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Asn Leu Leu He Tyr Glu Ala Ser Ser Leu Gin 165 170 175
Ser Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe -348-
151681-序列表.doc 201127956 180 185 190
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Ala Asn Gly Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225
<210〉 282 <211〉 255 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 282
Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala vSer Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys - 349 - 151681·序列表.doc 201127956 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 130 135 140
He Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His 145 150 155 160
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 165 170 175
Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 180 185 190
Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 195 200 205
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 210 215 220
Arg lie Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 225 230 235 240
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250 255
<210> 283 <211> 229 〈212〉 PRT 350- 151681-序列表.doc 201127956 <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 283
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu lie 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly 115 120 125
Ala Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp 130 135 140
Ser Tyr Arg He Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin 145 150 155 160 351 - 151681-序列表.doc 201127956
Tyr Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly 180 185 190
He Leu Leu He Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr 195 200 205
Cys Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Arg 225 <210> 284 <211〉 252 <212〉 PRT 〈213>人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 284
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His 20 25 30
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 -352-
151681·序列表.doc 201127956
Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg He Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125
Ser Thr Lys Gly Pro Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu 130 135 140
Val Gin Pro Ser Gin Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe 145 150 155 160
Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp Leu Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr 180 185 190
Asn Thr Pro Phe Thr Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys 195 200 205
Ser Gin Val Phe Phe Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala 210 215 220 lie Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala 225 230 235 240
Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala • 353. 151681·序列表 doc 201127956 245 250 <210> 285 <211> 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 285
Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly Ala 15 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp Ser 20 25 30
Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin Tyr 35 40 45
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly lie 65 70 75 80
Leu Leu He Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 85 90 95
Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu 100 105 110
Thr Val Leu Arg Thr Val Ala Ala Pro Asp lie Leu Leu Thr Gin Ser 115 120 125
Pro Val lie Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys -354- 151681-序列表.doc 201127956 130 135 140
Arg Ala Ser Gin Ser He Gly Thr Asn lie His Trp Tyr Gin Gin Arg 145 150 155 160
Thr Asn Gly Ser Pro Arg Leu Leu lie Lys Tyr Ala Ser Glu Ser He 165 170 175
Ser Gly He Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Ser lie Asn Ser Va.1 Glu Ser Glu Asp lie Ala Asp Tyr Tyr 195 200 205
Cys Gin Gin Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys 210 215 220
Leu Glu Leu Lys Arg 225 〈210〉 286 <211> 252 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 286
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu • 355 - 151681-序列表.doc 201127956 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala lie Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu lie Leu Ser 130 135 140
Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His Tyr Trp Ser 145 150 155 160
Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Tyr lie 165 170 175
Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val 180 185 190
Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Asn Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg lie Pro 210 215 220 356· 151681·序列表.doc 201127956
Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp Tyr Phe Asp 〇〇ς 230 235 240
Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 287 <211〉 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 287
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105 110 - 357- 151681-序列表.doc 201127956
Pro Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly 115 120 125
Ala Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp 130 135 140
Ser Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin 145 150 155 160
Tyr Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly 180 185 190 lie Leu Leu lie Ser Gly Leu Girt Ser Glu Asp Glu Ala Asp Tyr Tyr 195 200 205
Cys Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Arg 225 <210> 288 <211〉 256 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 288
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 •358
151681-序列表.doc 201127956 lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His 20 25 30
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg lie Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125
Ser Thr Lys Gly Pro Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu 130 135 140
Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr 145 150 155 160
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys 165 170 175
Gly Leu Glu Trp Val Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr 180 185 190
Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser - 359 · 151681·序列表.doc 201127956 195 200 205
Lys Ser Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220
Ala Val Tyr Tyr Cys Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His 225 230 235 240
Trp Tyr Phe Asp Val Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210〉 289 <211〉 229 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 289
Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly Ala 15 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp Ser 20 25 30
Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin Tyr 35 40 45
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly lie 65 70 75 80
Leu Leu lie Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys •360· 151681-序列表.doc 201127956 85 90 95
Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu 100 105 110
Thr Val Leu Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys 130 135 140
Ser Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Val Leu lie Tyr Phe Thr Ser Ser Leu His 165 170 175
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 195 200 205
Cys Gin Gin Tyr Ser Thr Val Pro Trp Thr Phe Gly Gin Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225 <210〉 290 <211〉 256 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 -361 - 151681-序列表.doc 201127956 <400〉 290
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30
Gly Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Trp lie Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110
Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125
Pro Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser 130 135 140
Glu lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser 145 150 155 160
His Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp 165 170 175 • 362
151681-序列表.doc 201127956 lie Gly Tyr lie Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu 180 185 190
Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Glri Phe Ser 195 200 205
Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 210 215 220
Ala Arg He Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr 225 230 235 240
Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250 255 <210> 291 <211> 229 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽
<400〉 291
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Ser Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 •363 · 151681-序列表.doc 201127956
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Thr Val Pro Trp 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly 115 120 125
Ala Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp 130 135 140
Ser Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin 145 150 155 160
Tyr Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly 180 185 190 lie Leu Leu He Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr 195 200 205
Cys Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Arg 225 〈210〉 292 364-
151681·序列表.doc 201127956 <211〉 245 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 292
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser He Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 HO
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Asn He Lys Asp Thr Tyr He His •365 · 151681·序列表.doc 201127956 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg lie 165 170 175
Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp 210 215 220
Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu 225 230 235 240
Val Thr Val Ser Ser 245 <210> 293 <211〉 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 293
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -366- 151681·序列表.doc 201127956 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp He Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Asn Thr 130 135 140
Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro 195 200 205
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 367- 151681-序列表.doc 201127956 <210〉 294 <211> 245 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 294
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn lie Lys Asp Thr 20 25 30
Tyr lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Arg lie Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gin 100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val 115 120 125
Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu 130 135 140 368·
151681·序列表.doc 201127956
Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr 145 150 155 160
Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp lie 165 170 175
Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 180 185 190
Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe Ser Leu 195 200 205
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val 210 215 220
Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly Thr Met 225 230 235 240
Val Thr Val Ser Ser 245 <210> 295 <211> 221 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 295
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp Val Asn Thr Ala 20 25 30 -369- 151681-序列表.doc 201127956
Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin His Tyr Thr Thr Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160
He Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin 180 185 190
Pro Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro 195 200 205
Leu Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg -370- 151681·序列表.doc 201127956 210 215 220 <210〉 296 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 296
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp He Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser He Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Lys -371 - 151681·序列表.doc 201127956 130 135 140
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His 145 150 155 160
Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie Gly Tyr lie 165 170 175
Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe Lys Asp Lys 180 185 190
Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu 195 200 205
Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr 210 215 220
Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly Thr Thr Leu 225 230 235 240
Thr Val Ser Ser <210> 297 <211〉 220 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 297
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr -372-
151681-序列表.doc 201127956 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin He Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro 115 120 125
Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr 130 135 140
Met Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie 145 150 155 160
Tyr Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala 180 185 190
Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu 195 200 205 •373 · 151681-序列表·doc 201127956
Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg 210 215 220 <210〉 298 <211〉 244 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 298
Gin Val Gin Leu Gin Gin Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Thr Met His Trp Val Lys Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gin Lys Phe 50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80
Met Gin Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125 151681-序列表.doc -374- 201127956
Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser 130 135 140
Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp Tyr Tyr 145 150 155 160
Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp lie Gly 165 170 175
His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser 180 185 190
Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe Ser Leu Lys 195 200 205
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr Cys Val Arg 210 215 220
Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly Thr Met Val 225 230 235 240
Thr Val Ser Ser
<210> 299 <211〉 220 <212〉 PRT 〈213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 299
Gin lie Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15 •375 151681-序列表.doc 201127956
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30
Asn Trp Tyr Gin Gin Lys Ser Gly Thr Ser Pro Lys Arg Trp lie Tyr 35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Tyr Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr lie Ser Ser Met Glu Ala Glu 65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Trp Ser Ser Asn Pro Leu Thr 85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg Thr Val Ala Ala Pro 100 105 110
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 115 120 125
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 130 135 140
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 145 150 155 160
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 165 170 175
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 180 185 190
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu -376- 151681·序列表.doc 201127956 195 200 205
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 2l〇 215 220 <210〉 300 <211〉 250 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽
<400〉 300
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp He Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin • 377- 151681-序列表.doc 201127956 115 120 125
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 145 150 155 160
Trp Va.l Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala He 165 170 175
Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp 210 215 220
Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 225 230 235 240
Gly Gin Gly Thr Thr Val Thr Val Ser Ser 245 250 <210〉 301 <211〉 221 <212〉 PRT 〈213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 301
Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -378- 151681-序列表.doc 15 201127956
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn 130 135 140
Asp Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu 145 150 155 160
He Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin 180 185 190 151681·序列表.doc -379- 201127956
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro 195 200 205
Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg 210 215 220 <210〉 302 <211〉 250 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 302
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala lie Ser Gly Ser Gly Gly Thr Thr Phe Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Arg Thr Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Asp Leu Gly Trp Ser Asp Ser Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110 -380- 151681·序列表.doc 201127956
Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys 130 135 140
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val 145 150 155 160
Ser Ser Gly Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys 165 170 175
Gly Leu Glu Trp He Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr 180 185 190
Asn Pro Ser Leu Lys Ser Arg Leu Thr He Ser He Asp Thr Ser Lys 195 200 205
Thr Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala 210 215 220
lie Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp 225 230 235 240
Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210〉 303 <211> 221 <212> PRT <213〉人造序列 <220〉 〈223>人造序列之描述：合成多肽 381- 151681·序列表.doc 201127956 <400> 303
Asp lie Gin Met Thr Gin Phe Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30
Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45
Tyr Ala Ala Ser Arg Leu His Arg Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Cys 85 90 95
Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 115 120 125
Gly Asp Arg -Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn 130 135 140
Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 145 150 155 160 lie Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin -382- 151681-序列表.doc 201127956 180 185 190 *Pro Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro 195 200 205
Leu Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 210 215 220
<210> 304 〈211〉 249 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 304
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly - 383 - 151681-序列表 201127956 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gin 115 120 125
Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Pile Thr Phe Ser Ser Tyr Ala Met His 145 150 155 160
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val lie 165 170 175
Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190
Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe 210 215 220
Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly 225 230 235 240
Gin Gly Thr Thr Val Thr Val Ser Ser 245 <210> 305 <211〉 227 <212〉 PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 384- 151681-序列表.doc 201127956 <400〉 305
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Se:r Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro 115 120 125
Gly Glu Pro Ala Ser He Ser Cys Arg Ser Ser Gin Ser Leu Leu His 130 135 140
Ser Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin 145 150 155 160
Ser Pro His Leu Leu He Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val 165 170 175 -385 151681-序列表.doc 201127956
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 180 185 190 lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin 195 200 205
Ala Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 210 215 220 lie Arg Arg 225 <210〉 306 <211> 249 <212> PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 306
Glu Val Gin Leu Val Gin Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val lie Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 386- 151681-序列表.doc 201127956
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Phe Ser Gly Trp Pro Asn Asn Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110
Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125
Gly Pro Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro 130 135 140
Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser 145 150 155 160
Ser Gly Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly 165 170 175
Leu Glu Trp lie Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn 180 185 190
Pro Ser Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr 195 200 205
Gin Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie 210 215 220
Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly 225 230 235 240
Gin Gly Thr Met Val Thr Val Ser Ser 245 <210〉 307 387- 151681·序列表.doc 201127956 <211〉 227 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 307
Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Ser 20 25 30
Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro His Leu Leu He Tyr Phe Gly Ser Tyr Arg Ala Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95
Leu Gin Thr Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Arg Arg Thr Val Ala Ala Pro Asp He Gin Met Thr Gin Ser Pro Ser 115 120 125
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Gin Ala 130 135 140
Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Gly -388- 151681-序列表.doc 201127956 145 150 155 160
Lys Ala Pro Lys Leu Leu He Tyr Asp Ala Ser Asn Leu Glu Thr Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe 180 185 190
Thr lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Phe Cys Gin 195 200 205
His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu 210 215 220
He Lys Arg 225 <210〉 308 <211〉 252 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 308
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 δ 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser • 389- 151681-序列表.doc 201127956 50 55 60
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala lie Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu lie Leu Ser 130 135 140
Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser His Tyr Trp Ser 145 150 155 160
Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly Tyr lie 165 170 175
Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val 180 185 190
Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Asn Leu Ser 195 200 205
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg lie Pro 210 215 220
Asn Tyr T>t Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp Tyr Phe Asp 225 230 235 240 390-
151681-序列表.doc 201127956
Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 245 250 <210〉 309 <211> 229 <212> PRT 〈213〉人造序列 <220> <223〉人造序列之描述：合成多肽 <400〉 309
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp lie Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110
Pro Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly 115 120 125 -391 · 151681·序列表.doc 201127956
Ala Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp 130 135 140
Ser Tyr Arg lie Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin 145 150 155 160
Tyr Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly 165 170 175
Val Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly 180 185 190
lie Leu Leu lie Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr 195 200 205
Cys Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys 210 215 220
Leu Thr Val Leu Arg 225
<210〉 310 <211〉 252 <212> PRT <213〉人造序列 <220> 〈223>人造序列之描述：合成多肽 <400> 310
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 lie Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Ser His 20 25 30 151681-序列表.doc - 392- 201127956
Tyr Trp Ser Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80
Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg He Pro Asn Tyr Tyr Asp Arg Ser Gly Tyr Tyr Pro Gly Tyr Trp 100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125
Ser Thr Lys Gly Pro Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu 130 135 140
Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 145 150 155 160
Ser Val Ser Ser Gly Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro 165 170 175
Gly Lys Gly Leu Glu Trp lie Gly His lie Tyr Tyr Ser Gly Asn Thr 180 185 190
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr 195 200 205
Ser Lys Thr Gin Phe Ser Leu Ljrs Leu Ser Ser Val Thr Ala Ala Asp • 393 - 151681-序列表doc 201127956 210 215 220
Thr Ala He Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp 225 230 235 240
He Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 245 250 <210〉 311 <211〉 229 <212〉 PRT <213〉人造序列
<220〉 <223〉人造序列之描述：合成多肽 <400〉 311
Gin Ala Val Leu Thr Gin Pro Ser Ser Leu Ser Ala Pro Pro Gly Ala 15 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Ser Gly Phe Asn Val Asp Ser 20 25 30
Tyr Arg He Ser Trp Tyr Gin Gin Lys Pro Gly Ser Pro Pro Gin Tyr
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gin Gin Gly Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Lys Asp Ala Ser Ala Asn Ala Gly lie 65 70 75 80
Leu Leu lie Ser Gly Leu Gin Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 85 90 95
Met lie Trp His Ser Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu -394· 151681-序列表.doc 201127956 100 105 110
Thr Val Leu Arg Thr Val Ala Ala Pro Asp lie Gin Met Thr Gin Ser 115 120 125
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys 130 135 140
Gin Ala Ser Gin Asp lie Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys 145 150 155 160
Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr Asp Ala Ser Asn Leu Glu 165 170 175
Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 180 185 190
Thr Phe Thr lie Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Phe 195 200 205
Cys Gin His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys 210 215 220
Val Glu lie Lys Arg 225 <210〉 312 〈211〉 247 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 312
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu -395- 151681-序列表.doc 201127956 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30
Asp Tyr Tyr Trp Thr Trp He Arg Gin Ser Pro Gly Lys Gly Leu Glu 35 40 45
Trp He Gly His He Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60
Leu Lys Ser Arg Leu Thr He Ser He Asp Thr Ser Lys Thr Gin Phe 65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala He Tyr Tyr 85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp He Trp Gly Gin Gly 100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Gin Val Gin 115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg 130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ser 145 150 155 160
Trp He Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr lie 165 170 175
Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val Lys Gly Arg 180 185 190 •396· 151681-序列表.doc 201127956
Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met 195 200 205
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 210 215 220
Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp Gly Gin Gly 225 230 235 240
Thr Leu Val Thr Val Ser Ser 245
<210> 313 <211> 221 <212> PRT <213〉人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400〉 313
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80 397· 151681·序列表.doc 201127956
Glu Asp He Ala Thr Tyr Phe Cys Gin His Phe Asp His Leu Pro Leu 85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110
Pro Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val 115 120 125
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser 130 135 140
Trp Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu 145 150 155 160 lie Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly 165 170 175
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 180 185 190
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Gly Phe Pro 195 200 205
Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 210 215 220 <210> 314 〈211〉 247 <212〉 PRT <213〉人造序列 <220> <223〉人造序列之描述：合成多肽 •398 .
151681-序列表.doc 201127956 <400〉 314
Glri Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30
Tyr Met Ser Trp lie Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Tyr lie Ser Ser Ser Gly Ser Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Va.l Tyr Tyr Cys 85 90 95
Ala Arg Asp Glu Tyr Asn Ser Gly Trp Tyr Val Leu Phe Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 130 135 140
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 145 150 155 160
Asp Tyr Tyr Trp Thr Trp lie Arg Gin Ser Pro Gly Lys Gly Leu Glu 165 170 175
Trp Ilo, Gly His lie Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser •399- 151681·序列表doc 201127956 180 185 190
Leu Lys Ser Arg Leu Thr lie Ser lie Asp Thr Ser Lys Thr Gin Phe 195 200 205
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala He Tyr Tyr 210 215 220
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp lie Trp Gly Gin Gly 225 230 235 240
Thr Met Val Thr Val Ser Ser 245 <210〉 315 <211> 221 <212〉 PRT <213>人造序列 <220〉 <223〉人造序列之描述：合成多肽 <400> 315
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Asn Leu Leu He 35 40 45
Tyr Glu Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Gly Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro -400· 151681-序列表.doc

Claims (1)

  1. 201127956 七、申請專利範圍： 1. 一種包含多肽键之結合蛋白，其中該多肽鏈包含VD1-(Xl)n-VD2-C-(X2)n，其中； VD1為第一重鏈可變區域； VD2為第二重鏈可變區域； C為重鍵惶定區域； XI為連接子，其限制條件為XI不為CH1 ; X2為Fc區， (Xl)n 為（X1)0 或（Xl)l ;及 (X2)n為（X2)0或（X2)l ; 其中該結合蛋白能夠結合選自由以下組成之群的抗原 對：CD-20與 CD-19 ; CD-20與 CD-80 ; CD-20與 CD-22 ; CD-20 與 CD-40 ; CD-3 與 HER-2 ; CD-3 與 CD-19 ; EGFR 與 HER-2 ; EGFR 與 CD-3 ; EGFR 與 IGF1，2 ; EGFR 與 IGF1R ; EGFR與 RON ; EGFR與 HGF ; EGFR與 c-MET ; HER-2 與 IGF1，2 ; HER-2 與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ; VEGF 與 HER_2 ; VEGF 與 CD-20 ; VEGF 與 IGF1,2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF與 NRP1 ; CD-20與 CD3 ; DLL-4與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2與 ErbB3 ; c-Met與 ErB3 ; PLGF與 HER-2 ;及 HER-2與 HER-2。 2. 如請求項1之結合蛋白，其中VD1及VD2包含選自由以下 組成之群的胺基酸序列：SEQ ID NO: 28、30、32、34、 36 、 38 、 40 、 42 、 44 、 46 、 48 、 50 ' 52 、 54 、 56 、 58 、 151681.doc 201127956 60、62 ' 64、66、68、70、72、74、76、78、80、82、 84、86、88、90、92、94、96、98、100、102、104及 106 〇 3· —種包含多肽鏈之結合蛋白，其中該多肽鏈包含VD1-(Xl)n-VD2-C-(X2)n，其中； VD1為第一輕鏈可變區域； VD2為第二輕鏈可變區域； C為輕鏈恆定區域； XI為連接子，其限制條件為XI不為CH1 ; X2不包含Fc區； (Xl)n為（Xl)〇或（Xl)i ;及 (X2)n為（X2)0或（X2)l ; 其中該結合蛋白能夠結合選自由以下組成之群的抗原 對：CD-20與 CD-19 ; CD-20與 CD-80 ; CD-20與 CD-22 ; CD-20 與 CD-40 ; CD-3 與 HER-2 ; CD-3 與 CD-19 ; EGFR 與 HER-2 ; EGFR 與 CD-3 ; EGFR 與 IGF 1，2 ; EGFR 與 IGF1R ; EGFR與 RON ; EGFR與 HGF ; EGFR與 c-MET ; HER-2 與 IGF1，2 ; HER-2 與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ; VEGF 與 HER-2 ; VEGF 與 CD-20 ; VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD-20 與 CD3 ; DLL-4 與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2與 ErbB3 ; c-Met與 ErB3 ; PLGF與 HER-2 ;及 HER-2與 HER-2。 4.如請求項3之結合蛋白，其中該VD1輕鏈可變區域及該 151681.doc 201127956 VD2輕鏈可變區域包含選自由以下組成之群的胺基酸序 列：SEQ ID NO: 29、31、33、35、37、39、41、43、 45 、 47 、 49 、 51 、 53 、 55 、 57 、 59 、 61 、 63 、 65 、 67 、 69 、 71 、 73 、 75 、 77 、 79 、 81 、 83 、 85 、 87 、 89 、 91 、 93、95、97、99、101、i〇3、i〇5及1〇7。 5. 如請求項1或3之結合蛋白，其中η為〇。 6. —種結合蛋白’其包含第一及第二多肽鏈，其中該第一 多肽鏈包含第一 VDl-(Xi)n_VD2_C-(X2)n，其中 VD1為第一重鍵可變區域； VD2為第二重鏈可變區域； C為重鏈恆定區域； XI為連接子’其限制條件為X1不為CH1 ;及 X2為Fc區；及 其中该第二多肽鏈包含第二vDi_(xi)n_vD2-C-(X2)n，其中 VD1為第一輕鏈可變區域； VD2為第二輕鏈可變區域； C為輕鏈恆定區域； X1為連接子’其限制條件為X丨不為Chi ; X2不包含Fc區； (Xl)n為（Xl)〇或（χι)ι ;及 (Χ2)η為（Χ2)0或（X2)l ’其中該結合蛋白能夠結合選自 由以下組成之群的抗原對：^⑼與CD_19 ; CD_2〇與 CD-80 ; CD-20 與 CD-22 ; CD-20 與 CD-40 ; CD-3 與 HER- 151681.doc 201127956 2 ; CD-3 與 CD-19 ; EGFR 與 HER-2 ; EGFR 與 CD-3 ; EGFR與 IGF1，2 ; EGFR與 IGF1R ; EGFR與 R〇N ; EGFR與 HGF ; EGFR 與 c-MET ; HER-2 與 IGF 1，2 ; HER-2 與 IGF1R ; RON與 HGF ; VEGF 與 EGFR ; VEGF 與 HER-2 ; VEGF 與 CD-20 ; VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD-20 與 CD3 ; DLL-4 與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2 與 ErbB3 ; c-Met 與 ErB3 ; PLGF 與 HER-2 ;及 HER-2與 HER-2。 7. 如請求項6之結合蛋白，其中該VD1及該VD2重鏈可變區 域包含選自由以下組成之群的胺基酸序列：SEQ ID NO : 28、30、32、34、36、38、40、42、44、46、48、 50 、 52 、 54 、 56 、 58 、 60 、 62 ' 64 、 66 、 68 、 70 、 72 、 74、76、78、80、82、84、86 ' 88、90、92、94、96、 98、100、102、104及106，且其中該VD1及該VD2輕鏈 可變區域包含選自由以下組成之群的胺基酸序列：SEQ ID NO: 29、31、33、35、37、39、41、43、45、47、 49 、 51 、 53 、 55 、 57 、 59 、 61 、 63 、 65 、 67 、 69 、 71 、 73、75、77、79、81、83、85、87、89、91、93、95、 97 ' 99 ' 101 、 103 、 105及107 〇 8. 如請求項1、3或6之結合蛋白，其中XI或X2為選自由 SEQ ID NO 1-26組成之群的胺基酸序列。 9. 如請求項6之結合蛋白，其中該結合蛋白包含兩個第一 多肽鏈及兩個第二多肽鏈。 151681.doc • 4- 201127956 10.如請求項i、3或6之結合蛋白，其中該Fc區係選自由原 生序列Fc區及變異序列Fc區組成之群。 Π.如請求項10之結合蛋白，其中該以區係選自由來自 IgGl、IgG2、IgG3、IgG4、IgA、IgM、IgE及 IgD 的 Fc 區 組成之群》 12·如請求項1、3或6之結合蛋白，其中該第一多肽鏈之該 VD1及該第二多肽鏈之該VD1係分別自相同第一親本抗 體及第二親本抗體或其抗原結合部分獲得。 13.如請求項丨、3或6之結合蛋白，其中該第一多肽鏈之該 VD1及該第二多肽鏈之該vD1係分別自不同第一親本抗 體及第二親本抗體或其抗原結合部分獲得。 14_如請求項i、3或6之結合蛋白，其中該第一多肽鏈之該 VD2及g亥第二多肽鏈之該VD2係分別自相同第一親本抗 體及第二親本抗體或其抗原結合部分獲得。 15,如請求項丨、3或6之結合蛋白，其中該第一多肽鏈之該 VD2及該第二多肽鏈之該VD2係分別自不同第一親本抗 體及第二親本抗體或其抗原結合部分獲得。 16_如請求項13之結合蛋白，其中該第一親本抗體及該第二 親本抗體結合該抗原上的不同抗原決定基。 17. 如凊求項13之結合蛋白，其中該第一親本抗體或其抗原 結合部分結合該第一抗原之效能不同於該第二親本抗體 或其抗原結合部分結合該第二抗原之效能。 18. 如請求項13之結合蛋白’其中該第一親本抗體或其抗原 結合部分結合該第-抗原之親和力不同於該第二親本抗 151681.doc 201127956 體戈其抗原結合部分結合該第二抗原之親和力。 19. 如請求項13之結合蛋白，其中該第一親本抗體或其抗原 結合部分，及該第二親本抗體或其抗原結合部分係選自 由人類抗體、CDR移植抗體及人類化抗體組成之群。 20. 如請求項13之結合蛋白，其中該第一親本抗體或其抗原 5。卩分、及该第一親本抗體或其抗原結合部分係選自 由以下組成之群：Fab片段；F(ab，）2片段，即包含兩個在 欽鍵&由一硫橋鍵連接的Fab片段之二價片段；由vh及 CH1區域組成之Fd片段；由抗體單臂之VL及VH區域組 成之Fv片段；dAb片段；分離之互補決定區（CDR);單鏈 抗體；及微型雙功能抗體。 21. 如請求項1、3或6之結合蛋白，其中該結合蛋白具有至 少一種由該第一親本抗體或其抗原結合部分或該第二親 本抗體或其抗原結合部分展現之所要特性。 22. 如請求項21之結合蛋白，其中該所要特性係選自一或多 種抗體參數。 23·如請求項21之結合蛋白，其中該等抗體參數係選自由以 下組成之群：抗原特異性、對抗原之親和力、效能、生 物功能、抗原決定基識別性、穩定性、溶解度、生產效 率、免疫原性、藥物動力學、生物可用性、組織交又反 應性及直系同源抗原結合性。 24· —種能夠結合兩個抗原之結合蛋白，其包含四個多狀 鏈，其中兩個多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中 VD1為第一重鏈可變區域； 151681.doc 201127956 VD2為第二重鏈可變區域； C為重鏈恆定區域； X1為連接子，其限制條件為XI不為CH1 ;及 X2為Fc區；及 其中兩個多肽鏈包含VDl-(Xi)n-VD2-C-(X2)n，其中 VD1為第一輕鏈可變區域； VD2為第二輕鏈可變區域；
    C為輕鏈恆定區域； X1為連接子，其限制條件為X丨不為CH1 ; X2不包含Fc區； (Xl)n為（Xl)〇或（χι)ι ;及 (Χ2)η為（Χ2)0或（X2)l ; 其中該VD1重鏈可變區域及該VD2重鏈可變區域包含選自由 以下組成之群的胺基酸序列：SEQ ID NO: 28、30、32、 34、36、38、40、42、44、46、48 ' 50、52、54、56 ' 58、60、62、64 ' 66、68 ' 70、72、74 ' 76 ' 78 ' 80、 82、84、86、88、90 ' 92、94、96、98、100、102、104及 106，且其中該VD 1及該VD2輕鏈可變區域包含選自由以下 組成之群的胺基酸序列：SEQ ID NO: 29、31、33、35、 37 、 39 、 41 、 43 、 45 、 47 ' 49 、 51 、 53 、 55 、 57 、 59 、 61 、 63 、 65 、 67 、 69 、 71 、 73 、 75 、 77 、 79 、 81 、 83 、 85 、 87 、 89、91、93 ' 95、97 ' 99、101 ' 103 ' 105及107 ° 25. —種能夠結合兩個抗原之結合蛋白，其包含四個多肽 鏈，其中兩個多肽鏈包含VDl-(Xl)n-VD2-C-(X2)n，其中 151681.doc 201127956 VD1為第一重鏈可變區域； VD2為第二重鏈可變區域； C為重鍵怪定區域； XI為連接子，其限制條件為XI不為CH1 ; X 2為F c區， (Xl)n為（X1)0或（Xl)l ;及 (X2)n為（X2)0或（X2)l ;及 其中兩個多肽鏈包含乂01-(又1)11-¥02-(：-(义2)11，其中 VD1為第一輕鏈可變區域； VD2為第二輕鏈可變區域； C為輕鏈恆定區域； XI為連接子，其限制條件為XI不為CH1 ; X2不包含Fc區； (Xl)n為（Xl)〇或（χιρ ;且 (X2)n為（X2)0 或（Χ2)1 ; 其中該DVD-Ig結合至少一種選自由以下組成之群的抗 原：CD-20、CD_19、CD-80、CD-22、CD-40、CD-3、 人類表皮生長因子受體2(HER_2)、表皮生長因子受體 (EGFR)、胰島素樣生長因子丨’叩郎以）、胰島素樣生長 因子受體（IGF1R)、巨噬細胞刺激蛋白受體酪胺酸激酶 (RON)、肝細胞生長因子（HGF)、間葉細胞_上皮過渡因 子（c-MET)、血管内皮生長因子（VEGF)、果蠅δ同系物 4(DLL4)、神經纖毛蛋白1(NRpi)、胎盤生長因子 (PLGF)、及v_erb_b2禽類紅血球胚細胞白血病病毒致癌 151681.doc 201127956 26. 27.
    28. 基因同系物3(ErbB3)。 如凊求項1、3、6、24或25之結合蛋白，1中 /、肀如表面電 ，：、振所量測’該結合蛋白對該一或多個目標具有選 自由以下組成之群的締合速率常數(κ〇η):至少約1〇2 丨· 至少約1〇3 ;至少約1〇4 Μ· v ;至少約1〇5 M二： 及至少約。 ’ 如睛求項1、3、6、24或25之結合蛋白，其中 及子:、振所量測’該結合蛋白對該一或多個目標具有選 自由以下組成之群的解離速率常數(K〇ff):至多約1〇·3 ^ .至 多約10 4 S·1 ;至多約1〇_5 s·〗；及至多約1〇、丨。 如明求項1、3、6、24或25之結合蛋白’其中該結合蛋 白對該-或多個目標具有選自由以下組成之 數㈣：至多約ΠΤ、；至多約10_8Μ;至多約ι〇_9μ: 至多約10-10 Μ ;至多約10_" μ ;至多約10-12 Μ ;及至夕 ίο·13 Μ • 29. 30. 31. 一種結合蛋白結合物，其包含如請求項1、3、6、24或 25中任一項之結合蛋白，該結合蛋白結合物另外包含選 自由以下組成之群的藥劑：免疫黏附分子、顯影劑、治 療劑及細胞毒性劑。 如明求項29之結合蛋白結合物，其中該藥劑為選自由放 射性標記物、酶、螢光標記物、發光標記物、生物發光 標記物、磁性標記物及生物素組成之群的顯影劑。 如明求項30之結合蛋白結合物，其中該顯影劑為選自由 以下組成之群的放射性標記物：3η、！4C、ay、9〇γ、 151681.doc 201127956 Tc、丨丨丨In、丨25I、uy、丨77Lu、丨66H〇及 mSm。 32·如明求項3〇之結合蛋白結合物其中該藥劑為選自由以 下組成之群的治療劑或細胞毒性劑：抗代謝物、烷基化 实1抗生素、生長因子、細胞激素、抗血管生成劑、抗 有’糸刀裂劑、蒽環黴素（anthracycline)、毒素及細胞凋亡 劑。 如凊求項1、3、6、24或25之結合蛋白，其中該結合蛋 白為結晶結合蛋白。 34. 如請求項33之結合蛋白，其中該晶體為無載劑醫藥控制 釋放晶體。 35. 如請求項33之結合蛋白，其中該結合蛋白具有比該結合 蛋白之可溶性對應物長的活體内半衰期。 36·如咕求項33之結合蛋白，其中該結合蛋白保留生物活 性。 37. 種經分離核酸’其編碼如請求項1、3、6、24或25中 任一項之結合蛋白胺基酸序列。 38. —種載體，其包含如請求項37之經分離核酸。 39. 如請求項38之載體，其中該載體係選自由pcDNA、 pTT、pTT3、pEFBOS ' pBV、pJV、pCDNA3.1 TOPO、 pEF6 TOP〇及pBJ組成之群。 40. —種宿主細胞，其包含如請求項μ之載體。 41. 如請求項40之宿主細胞，其中該宿主細胞為原核細胞。 42. 如請求項41之宿主細胞，其中該宿主細胞為大腸桿菌。 43. 如請求項40之宿主細胞’其中該宿主細胞為真核細胞。 151681.doc -10· 201127956 44 ·如請求項43之宿主細胞，其中該真核細胞係選自由原生 生物細胞、動物細胞、植物細胞及真菌細胞組成之群。 45. 如請求項43之宿主細胞’其中該真核細胞為選自由哺乳 動物細胞、禽類細胞及昆蟲細胞組成之群的動物細胞。 46. 如請求項45之宿主細胞’其中該宿主細胞為CHO細胞。 47. 如請求項45之宿主細胞，其中該宿主細胞為COS。 48. 如請求項43之宿主細胞，其中該宿主細胞為酵母細胞。 49. 如請求項48之宿主細胞’其中該酵母細胞為釀酒酵母 {Saccharomyces cerevisiae) ° 50. 如請求項45之宿主細胞’其中該宿主細胞為昆蟲Sf9細 胞0 51· —種產生結合蛋白之方法，其包含在足以產生結合蛋白 之條件下，在培養基中培養如請求項4〇至5〇中任一項之 宿主細胞。 50% 75% 90%
    52.如凊求項51之方法，其中所產生之該結合蛋白中有 至750/0為雙重特異性四價結合蛋白。 53·如請求項51之方法，其中所產生之該結合蛋白中有 至90%為雙重特異性四價結合蛋白。 54.如凊求項51之方法，其中所產生之該結合蛋白中有 至95%為雙重特異性四價結合蛋白。 55_ -種蛋白質，其係根據如請求項51之方法產生。 56. —種醫藥組合物，复 ，、匕3如Μ求項：1至36及55中任一項 之蛋白及醫藥學上可接受之載劑。 57·如請求項56之醫 ^具另外包含至少一種額外治 151681.doc 201127956 療劑。 58·如請求項57之醫藥組合物，其中該額外治療劑係選自由 以下組成之群：治療劑、顯影劑、細胞毒性劑、血管生 成抑制劑、激酶抑制劑、協同刺激分子阻斷劑、黏附分 子阻斷劑、抗細胞激素抗體或其功能片段、甲胺二; (methotrexate)、環孢靈（cycl〇sp〇咖）、雷帕黴素 (rapamycin)、FK5〇6、可偵測標記物或報導體、_结 抗劑、抗風濕藥、肌肉鬆弛劑、麻醉藥、非類固醇消： 藥物（NSAID)、止痛劑、麻醉劑、鎮靜劑、局部麻醉 劑、神經肌肉阻斷劑、抗微生物劑、抗牛皮癬藥、皮質 類固醇、同化類固醇、紅血球生成素、免疫癖:疫= 白免疫抑制背J、生長激素、激素替代藥物、放射性藥 物、抗抑鬱劑、抗精神病藥、興奮劑 '哮喘藥物、_ 效劑吸入類固醇、腎上腺素或其類似物、細胞激素及 細胞激素括抗劑。 59. —種如請求項1至36及55中任一項之結合蛋白之用途， 其係用於製造治療個體之疾病或病症之藥物。 60. 如請求項59之用途，其中該病症係選自包含以下之群： 類風濕性關節炎、骨關節炎、青少年慢性關節炎、敗血 性關節炎、萊姆關節炎（Lyme arthritis)、牛皮癬性關節 炎、反應性關節炎、脊椎關節病、全身性紅斑狼瘡症、 克羅恩氏病（Crohn's disease)、潰瘍性結腸炎、發炎性腸 病、胰島素依賴性糖尿病、曱狀腺炎、哮喘、過敏性疾 病、牛皮癣、皮膚炎硬皮病、移植物抗宿主疾病、器官 151681.doc 201127956 移植排斥反應、與器官移植有關之急性或慢性免疫疾 病、肉狀瘤病、動脈粥樣硬化、散播性血管内凝血、川 崎氏病（K_sakiis disease)、格雷氏病（Grave，s disease)、腎病症候群、慢性疲勞症候群、韋袼納氏肉芽 腫病（Wegener's granui〇matosis)、亨偌·絲奇恩賴紫癜 (Henoch-Schoenlein purpurea)、腎顯微性血管炎、慢性 活動型肝炎、葡萄膜炎、敗血性休克、中毒性休克症候 群、敗血症症候群、惡病質、感染性疾病、寄生蟲病、 後天免疫缺乏症候群、急性橫貫性脊蟫炎、亨廷頓氏舞 蹈病（Huntington’s chorea)、帕金森氏病（Parkins〇nis disease)、阿茲海默氏病（Alzheimer's disease)、中風、原 發性膽汁性肝硬化、溶血性貧血、惡性病、心臟衰竭、 心肌梗塞、乂迪森氏病（Addison's disease)、偶發性I型 多腺體分泌不足症及II型多腺體分泌不足症、施密特氏 症候群（Schmidt’s syndrome)、成人（急性）呼吸窘迫症候 群、脫髮、斑形脫髮、血清陰性關節病、關節病、萊特 爾氏病（Reiter's disease)、牛皮癖性關節病、潰瘍性結腸 炎關節病、腸病性滑膜炎、與披衣菌(Chlamydia)、耶氏 桿菌（yersinia)及沙門氏菌（salmonella)相關之關節病、脊 椎關郎病、動脈粥樣瘤病/動脈硬化、異位性過敏、自體 免疫大皰病、尋常天疱瘡、葉狀天疱瘡、類天疮瘡、線 狀IgA病、自體免疫溶血性貧血、庫姆氏陽性溶血性貧 血（Coombs positive haemolytic anaemia)、後天惡性貧 血、青少年惡性貧血、肌痛腦炎/皇家自由病（Royal Free 151681.doc 201127956 • )陵性皮膚黏膜念珠菌病、巨細胞動脈炎、原 發性硬化性肝炎、原因不明性自體免疫肝炎、後天免疫 缺乏疾病症候群、後天免疫缺乏相關疾病、B型肝炎、C 型肝炎、常見變異性免疫缺乏（常見變異性低？球蛋白血 症）、擴張性心肌病、雌性不孕症、卵巢功能衰竭、卵巢 早衰、纖維變性肺病、原因不明性纖維性肺泡炎、發炎 後間質性肺病、間質性肺炎、結締組織病相關之間質性 肺病、混合結締組織病相關之肺病、全身性硬化症相關 之間質性肺病、類風濕性關節炎相關之間質性肺病、全 身性紅斑狼瘡症相關之肺病、皮肌炎/多發性肌炎相關之 肺病、休格連氏病相關之肺病（Sj0gren,s associated lung disease)、僵直性脊椎炎相關之肺病、血 管炎擴散性肺病、含鐵血黃素沈積症（haem〇sider〇sis)相 關之肺病、藥物誘發之間質性肺病、纖維化、放射性纖 維化、閉塞性細支氣管炎、慢性嗜伊紅血球性肺炎、淋 巴球浸潤性肺病、感染後間質性肺病、痛風性關節炎、 自體免疫性肝炎、丨型自體免疫性肝炎（經典自體免疫或 類狼瘡性肝炎）、2型自體免疫性肝炎（抗LKM抗體肝 炎）、自體免疫介導之低血糖症、B型胰島素抗性伴發黑 色棘皮病、副甲狀腺低能症、與器官移植有關之急性免 疫疾病、與器官移植有關之慢性免疫疾病、骨性關節 病、原發性硬化性膽管炎、1型牛皮癬、2型牛皮癣、特 發性白血球減少病、自體免疫性嗜中性球減少症、n〇s 型腎病、血管球性腎炎、腎顯微性血管炎、萊姆病_ 151681.doc -14- 201127956 disease)、盤狀紅斑狼瘡、特發性或1<〇8型雄性不育症、 精子自體免疫、多發性硬化症（所有次型）、交感性眼 炎、結締組織病繼發之肺循環血壓過高、 万巴士禮氏症 候群（Goodpasture’s syndrome)、結節性多動脈炎之肺表 現形式、急性風濕熱、類風濕性脊椎炎、史提爾氏病 (Still’s disease)、全身性硬化症、休格連氏症候群、高 安氏病（Takayasu’s disease)/動脈炎、自體免疫性血小板 φ 減少症、特發性血小板減少症、自體免疫性甲狀腺病、 曱狀腺機能亢進症、曱狀腺腫性自體免疫性甲狀腺低能 症（橋本氏病（Hashimoto's disease))、萎縮性自體免疫性 曱狀腺低能症、原發性黏液水腫、晶狀體源性葡萄膜 炎、原發性血管炎、白斑病急性肝病、慢性肝病、酒精 性肝硬化、酒精誘發之肝損傷、膽汁鬱滯、特質性肝 病、藥物誘發之肝炎、非酒精性脂肪變性肝炎、過敏症 及哮喘、B群鏈球菌（GBS)感染、精神障礙（例如抑鬱症 • 及精神分裂症）、Th2型及Thl型介導之疾病、急性及慢 性疼痛（不同形式之疼痛）、及諸如肺癌、乳癌、胃癌、 膀胱癌、結腸癌、胰腺癌' 卵巢癌、前列腺癌及直腸癌 之癌症及造血系統惡性疾病（白血病及淋巴瘤）、無β脂蛋 白血症、手足發紺、急性及慢性寄生或感染過程、急性 白血病、急性淋巴母細胞白血病（ALL)、急性骨髓白血 病（AML)、急性或慢性細菌感染、急性胰腺炎、急性腎 衰竭、腺癌、心房異位搏動' AIDS癡呆複合症、酒精誘 發之肝炎、過敏性結膜炎、過敏性接觸性皮膚炎、過敏 151681.doc 201127956 性鼻炎、同種異體移植排斥反應、心卜抗胰蛋白酶缺 乏、肌肉萎縮性側索硬化、貧血、心絞痛、前角細胞退 化、抗cd3療法、抗磷脂症候群、抗受體過敏反應、主 動脈及周圍動脈瘤、主動脈剝離、動脈性高血壓、動脈 硬化症、動靜脈瘺、共濟失調、心房纖維性顫動（持續性 或陣發性）、心房撲動、房室傳導阻滯、B細胞淋巴瘤、 骨移植物排斥反應、骨髓移植（BMT)排斥反應、束枝傳 導阻滯、伯基特淋巴瘤（Burkitt's lymphoma)、燒傷、心 律不整、心臟頓抑症候群、心臟腫瘤、心肌病、心肺繞 道發炎反應、軟骨移植排斥反應、小腦皮質退化、小腦 病症、奈亂性或多灶性房性心動過速、與化學療法有關 之病症、慢性髓細胞白血病（CML)、慢性酒精中毒、慢 性發炎性病變、慢性淋巴細胞性白血病（CLl)、慢性阻 塞性肺病（COPD)、慢性水揚酸中毒、結腸直腸癌、充血 性心臟衰竭、結膜炎、接觸性皮膚炎、肺原性心臟病、 冠狀動脈疾病、庫賈氏病（Creutzfeldt-Jakob disease)、 培養物陰性敗血症、囊腫性纖維化、細胞激素療法相關 之病症、拳擊員癡呆、脫髓鞘疾病、出血性登革熱 (dengue hemorrhagic fever)、皮膚炎、皮膚病病狀、糖 尿病（diabete、diabetes mellitus)、糖尿病性動脈硬化 病、泛發性路易體疾病（Diffuse Lewy body disease)、擴 張型充血性心肌病、基底神經節病症、中年唐氏症候群 (Down’s Syndrome in middle age)、由阻斷CNS多巴胺受 體之藥物誘發的藥物誘發之運動障礙、藥物敏感、濕 151681.doc •16· 201127956 疹、腦脊髓炎、心内膜炎、内分泌病、會厭炎、EB病毒 感染（epstein-barr virus infection)、肢端紅痛症、錐體外 及小服病症、豕族性谨血淋巴組織細胞瘤病、胚胎胸腺 移植排斥反應、弗里德賴希氏共濟失調（Friedreich，s ataxia)、功能性周圍動脈病症、真菌性敗血症、氣性壞 痕、月潰瘍、腎小球腎炎、任何器官或組織的移植物排 斥反應、革蘭氏陰性敗血症（gram negative sepsis)、革蘭 氏陽性敗血症、胞内生物體引起之肉芽腫、毛細胞白血 病、哈洛弗登-史巴茲氏蒼白球色素退化症 (Hallervorden-Spatz disease)、喬本氏甲狀腺炎 (hashimoto's thyroiditis)、枯草熱、心臟移植排斥反應、 血色素沈著症、血液透析、溶血性尿毒癥候群/溶栓性血 小板減少性紫癜、出血、A型肝炎、希氏束心律不整 (His bundle arrythmias)、HIV 感染/HIV神經病、霍奇金 病（Hodgkin’s disease)、過動性運動病症、過敏反應、過 敏性^炎^高血壓、運動不足運動病症、下丘腦-垂體· #上腺軸評估、特發性艾迪森氏病、特發性肺:纖'ϋ -、-抗體介導之細胞毒性、衰弱、嬰兒脊髓性肌萎縮症、主 動脈發炎、a型流感、電離輻射曝露、虹膜睫狀體炎/葡 萄膜炎/視神經炎、缺血再灌注損傷、缺血性中風、青少 年類風濕性關節炎、青少年脊髓性肌萎縮症、卡波西氏 肉瘤（Kaposi’s sarcoma)、腎臟移植排斥反應、退伍軍人 病（legionella)、利什曼體病（iejshmaniasis)、麻風病、皮 質脊髓系統病變、脂性水腫、肝移植排斥反應、淋巴水 I5168I.doc •17· 201127956 腫、瘧疾、惡性淋巴瘤、惡性組織細胞增多病、惡性黑 素瘤、腦膜炎、腦膜炎球菌企症、代謝性/特發性疾病、 偏頭痛、粒線體多系統病症、混合結締組織病、單株球 蛋白症、多發性骨髓瘤、多系統退化（曼切、代哲因-托 馬斯、史德爾格及馬查多-約瑟夫（!^1^1〇6』61·^- Thomas Shi-Drager and Machado-Joseph))、重症肌無 力、禽細胞内分枝桿菌（mycobacterium avium intracellulare) > 結核分枝桿菌（Mycobacterium tuberculosis)、骨髓發育不良症候群、心肌梗塞、心肌缺 血病症、鼻咽癌、新生兒慢性肺病、腎炎、腎病、神經 退化性疾病、I型神經性肌肉萎縮、嗜中性球減少性發 熱、非霍奇金淋巴瘤（non-hodgkins lymphoma)、腹主動 脈及其分支堵塞、阻塞性動脈病症、okt3療法、睪丸炎/ 副睪丸炎、睪丸炎/輸精管復通術、器官腫大、骨質疏鬆 症、胰腺移植排斥反應、胰腺癌、副腫瘤症候群/惡性高 血鈣症、副甲狀腺移植排斥反應、骨盆腔炎疾病、常年 性鼻炎、心包疾病、周圍動脈粥樣硬化疾病、周圍血管 疾病、腹膜炎、惡性貧血、卡氏肺囊蟲肺炎 (pneumocystis carinii pneumonia)、肺炎、p〇ems症候群 (多發性神經病、器官腫大、内分泌病、單株球蛋白症及 皮膚變化症候群）、灌注後症候群、泵後症候群、ΜΙ,〇 切開術後症候群、子癇前症、進行性核上性麻療、原發 性肺高血壓、放射性療法、雷諾現象（Raynaud，s phenomenon)及疾病、雷諾病（Raynoud，s disease)、雷弗 151681.doc 201127956 素姆氏病（Refsum’s disease)、規則性qrs波狹窄型心動 過速、腎血管性南血壓、再灌注損傷、限制型心肌病、 肉瘤、硬皮病、老年性舞蹈病、路易體型老年癡呆 (Senile Dementia of Lewy body type)、血清陰性關節 病、休克、鐮形細胞性貧血、皮膚同種異體移植排斥反 應、皮膚變化症候群、小腸移植排斥反應、實體腫瘤、 特異性心律不整、脊椎共濟失調、脊髓小腦退化、鏈球 菌肌炎、小腦結構病變、亞急性硬化性全腦炎、昏厥、 心血管系統梅毒、全身性過敏、全身性發炎反應症候 群、全身發作型青少年類風濕性關節炎、T細胞或FAB ALL、毛細管擴張、血栓閉塞性血管炎、血小板減少 症、中毒、移植、外傷/出血、ΙΠ型過敏反應、IV型過 敏、不穩定型心絞痛、尿毒癥、尿膿毒病、蓴麻疹、心 臟瓣膜病、靜脈曲張' 血管炎、靜脈疾病、靜脈血栓形 成、心室纖維性顫動、病毒及真菌感染、病毒性腦炎/無 菌性腦膜炎、病毒相關之嗜血細胞症候群、韋尼克_科爾 薩科夫症候群（Wernicke-Korsakoff syndrome)、威爾遜氏 病（Wilson’s disease)、任何器官或組織的異種移植物排 斥反應、急性冠狀動脈症候群、急性特發性多發性神經 炎、急性發炎性脫髓鞘性多神經根神經病、急性局部缺 血、成人史爾氏病（adult Still’s disease)、斑形脫髮、 全身性過敏反應、抗磷脂抗體症候群、再生不全性貧 血、動脈硬化、異位性濕疹、異位性皮膚炎、自體免疫 性皮膚炎、與鏈球菌感染有關之自體免疫病症、自體免 151681.doc •19- 201127956 疫性腸病、自體免疫性聽力損失、自體免疫淋巴組織增 生症候群（ALPS)、自體免疫性心肌炎、自體免疫性卵巢 早衰、瞼炎、支氣管擴張、大皰性類天疱瘡、心血管疾 病、災難性抗磷脂症候群、乳糜瀉、頸椎關節強硬、慢 性局部缺血、瘢痕性類天疱瘡、具有多發性硬化症風險 之臨床單一症候群（cis)、結膜炎、兒童期初發型精神病 症、慢性阻塞性肺病（C0PD)、淚囊炎、皮肌炎、糖尿病 性視網膜病變、糖尿病、椎間盤突出症、椎間盤脫垂、 藥物誘發之免疫性溶血性貧血、心内膜炎、子宮内膜異 位、眼内炎、上鞏膜炎、多形性紅斑、重症多形性紅 斑、妊娠期類天疱瘡、格·巴二氏症候群（Guillain_BarM syndr〇me)(GBS)、枯草熱、休斯症候群（Hughes syndrome)、特發性帕金森氏病、特發性間質性肺炎、 IgE介導之過敏症、免疫性溶血性貧血、包涵體肌炎、 感染性眼部發炎疾病、發炎性脫髓鞘疾病、發炎性心臟 病、發炎性腎病、IPF/UIP、虹膜炎、角膜炎、乾燥性角 膜結膜炎、庫斯毛爾氏病（Kussmaul disease)或庫斯毛爾_ 米爾氏病（Kussmaul-Meier disease)、蘭德里麻療 (Landry’s paralySis)、朗格罕氏細胞組織細胞增多病 (Langerhan’s cell histiocytosis)、網狀青斑、黃斑變性、 顯微性多血管炎、白赫鐵列夫症（morbus bechterev)、運 動神經元病症、黏膜類天疱瘡、多器官衰竭、重症肌無 力、骨髓發育不良症候群、心肌炎、神經根病症、神經 病、非A非B型肝炎、視神經炎、骨質溶解、卵巢癌、少 151681.doc -20- 201127956 關節型JRA(pauciarticular JRA)、周邊動脈閉塞性疾病 (PAOD)、周圍血管疾病（PVD)、周圍動脈疾病（pad)、靜 脈炎、結節性多動脈炎（或結節性動脈周圍炎）、多軟骨 炎、風濕性多肌痛、白髮症、多關節型JRA、多發性内 分泌缺乏症候群、多發性肌炎、風濕性多肌痛（PMR)、 泵後症候群、原發性帕金森氏症、前列腺癌及直腸癌及 造企性惡性病（白血病及淋巴瘤）、前列腺炎、純紅血球 發育不全、原發性腎上腺機能不全、復發性視神經脊髓 炎、再狹窄、風濕性心臟病、saph〇(滑膜炎、痤瘡、膿 皰病、骨肥厚及骨炎）、硬皮病、繼發性澱粉樣變性病、 休克肺、鞏膜炎、坐骨神經痛、繼發性腎上腺機能不 全、聚矽氧相關之結締組織疾病、史奈登-威爾金森皮膚 病（sneddon-wilkinson dermatosis)、強直性脊椎炎、史蒂 芬-瓊森症候群（Stevens-Johnson syndrome，SJS)、全身 性發炎反應症候群、顳動脈炎、弓形蟲性視網膜炎 '中 毒性表皮壞死溶解、橫貫性脊髓炎、TRAPS(腫瘤壞死因 子受體）、1型過敏反應、II型糖尿病、蓴麻疹、尋常性 間質性肺炎（UIP)、血管炎、春季結膜炎、病毒性視網膜 炎、沃格特-小柳-原田症候群（v〇gt_K〇yanagi_Harada Syndi:〇me)(VKH症候群）、濕式黃斑變性、傷口癒合、耶 氏桿菌及沙門氏菌相關之關節病。 61 _如請求項60之用途，其中該藥物係藉由至少一種選自以 下之模式向該個體投與：非經腸、皮下、肌肉内、靜脈 内、關節内、支氣管内、腹内、囊内、軟骨内、腔内、 151681.doc •21- 201127956 體腔内、小腦内、腦室内、結腸内、子宮頸内、胃内、 肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜 内、前列腺内、肺内、直腸内、腎内、視網膜内、脊椎 内、滑膜内、胸腔内、子宮内、膀胱内、快速注射、經 陰道、經直腸、經頻、舌下、鼻内及經皮。 62. —種產生能夠結合兩個抗原之雙重可變區域免疫球蛋白 之方法，其包含以下步驟 a) 獲得能夠結合第一抗原之第_親本抗體或其抗原結 合部分； b) 獲得能夠結合第二抗原之第二親本抗體或其抗原結 合部分； c) 建構包含VDl-(Xl)n-VD2-C-(X2)n之第一多肽鏈及第 三多肽鏈，其中 VD1為獲自該第一親本抗體或其抗原結合部分之第— 重鏈可變區域； VD2為獲自該第一親本抗體或其抗原結合部分之第二 重鏈可變區域； C為重鍵丨亙定區域， X1為連接子，其限制條件為X1不為CH1 ; X2為Fc區； (Xl)n為（X1)0或（Xl)l ;及 (X2)n為（X2)0或（X2)l ;及 d) 建構包含VDl-(Xl)n-VD2-C-(X2)n之第二多肽鏈及 第四多肽鏈，其中 151681.doc •22· 201127956 VD1為獲自該第一親本抗體或其抗原結合部分之第一 輕鏈可變區域； VD2為獲自該第二親本抗體或其抗原結合部分之第二 輕鏈可變區域； C為輕鏈恆定區域； XI為連接子，其限制條件為XI不為CH1 ; X2不包含Fc區； ^ (Xl)n為（X1)0或（Xl)l ;及 (X2)n為（X2)0或（X2)l ;及 e)表現該第一多肽鏈、該第二多肽鏈、該第三多肽鏈 及該第四多肽鏈； 因此產生能夠結合該第一抗原及該第二抗原之雙重可變 區域免疫球蛋白’其中該結合蛋白能夠結合選自由以下 組成之群的抗原對：CD-20與CD-19 ; CD-20與CD-80 ; CD-20 與 CD-22 ; CD-20 與 CD-40 ; CD-3 與 HER-2 ; CD-3 φ 與 CD-19 ; EGFR 與 HER-2 ; EGFR 與 CD-3 ; EGFR 與 IGF1，2，EGFR與 IGF1R ; EGFR與 RON ; EGFR與 HGF ; EGFR與 c-MET ; HER-2與 IGF1,2 ; HER-2與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ; VEGF 與 HER-2 ; VEGF 與 CD-20 ; VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD-20 與 CD3 ; DLL-4 與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2與 ErbB3 ; c-Met與 ErB3 ; PLGF與 HER-2 ;及 HER-2與 HER-2。 151681.doc 23· 201127956 63 ·如請求項62之方法’其中該VD1重鏈可變區域及該VD2 重鍵可變區域包含選自由以下組成之群的胺基酸序列： SEQ ID NO: 28、30、32、34、36、38、40、42、44、 46 、 48 、 50 、 52 、 54 、 56 、 58 、 60 、 62 、 64 、 66 、 68 、 70、72、74、76、78、80、82、84、86、88、90、92、 94、96、98、100、102、104及 106，且其中該 VD1 輊鏈 可變區域及該VD2輕鏈可變區域包含選自由以下組成之 群的胺基酸序列：SEQ ID NO: 29、31、33、35、37、 39 、 41 、 43 、 45 、 47 、 49 、 51 、 53 、 55 、 57 、 59 、 61 、 63、65、67、69、71、73、75、77、79、81、83、85、 87、89、91、93、95、97、99、101、103、105及107。 64. 如請求項62之方法，其中該第一親本抗體或其抗原結合 部分、及該第二親本抗體或其抗原結合部分係選自由人 類抗體、CDR移植抗體及人類化抗體組成之群。 65. 如請求項62之方法，其中該第一親本抗體或其抗原結合 刀、及§亥第一親本抗體或其抗原結合部分係選自由以 下組成之群：Fab片段；F(ab')2片段，即包含兩個在鉸鍵 區由二硫橋鍵連接的Fab片段之二價片段；由VH區域及 CH1區域組成之Fd片段；由抗體單臂之vl區域及vh區 域組成之Fv片段；dAb片段；分離之互補決定區（CE)r); 單鏈抗體；及微型雙功能抗體。 66. 如請求項62之方法，其中該第一親本抗體或其抗原結合 部分具有至少一種由該雙重可變區域免疫球蛋白展現之 所要特性。 151681.doc •24· 201127956 67. 如研求項62之方法，其中該第二親本抗體或其抗原結合 部刀〃、有至少一種由該雙重可變區域免疫球蛋白展現之 所要特性。 68. 如凊求項62之方法，其中該以區係選自由原生序列卜區 及變異序列Fc區組成之群。 月长項62之方法，其中該fc區係選自由來自工gGi、 邮2、IgG3、IgG4、IgA、IgM、IgE 及 IgD 的 Fc 區組成之 群。 7〇·如叫求項66之方法，其中該所要特性係選自一或多種抗 體參數。 或多種抗 71_如凊求項67之方法，其中該所要特性係選自 體參數。 清求項70之方法，其中該等抗體參數係選自由以下組 群抗原特異性、對抗原之親和力、效能、生物功 能、抗原決定基識別性、穩定性、溶解度、生產效率、 免疫原性、藥物動力學、生物可用性、組織交叉反應性 及直系同源抗原結合性。 73·如請求項71之方法，其中該等抗體參數係選自由以下組 f之群：抗原特異性、對抗原之親和力、效能、生物功 忐、抗原決定基識別性、穩定性、溶解度、生產效率、 =原性、藥物動力學、生物可用性、組織交叉反應性 及直系同源抗原結合性。 74·^求項62之方法，其中該第—親本抗體或其抗原結合 。刀結合該第__抗原之親和力不同於該第二親本抗體或 151681.doc -25- 201127956 其抗原結合部分結合該第二抗原之親和力。 75·如請求項62之方法，其 ,Η ^ Λ α Α 第一親本抗體或其抗原結合 口 Ρ为結合該第一抗原之效能 双I不问於该第二親本抗體或其 抗原結合部分結合該第二抗原之效能。 76. -種產生能夠結合兩個抗原且具有所要特性之雙重可變 區域免疫球蛋白之方法，其包含以下步驟 a)獲得能夠結合第一抗原且具有至少一種由該雙重可 變區域免疫球蛋白展現之所要特性的第—親本抗體或其 抗原結合部分； b) 獲得能夠結合第二抗原且具有至少一種由該雙重可 變區域免疫球蛋白展現之所要特性的第二親本抗體或其 抗原結合部分； c) 建構包含VDl-(Xl)n_VD2-C-(X2)n之第一多肽鏈及第 三多肽鏈，其中； VD1為獲自該第一親本抗體或其抗原結合部分之第一 重鏈可變區域； VD2為獲自該第二親本抗體或其抗原結合部分之第二 重鏈可變區域； C為重鏈恆定區域； XI為連接子，其限制條件為XI不為CH1 ; X2為Fc區； (Xl)n為（X1)0 或（Xl)l ;及 (X2)n為（X2)0或（X2)l ; d)建構包含VDl-(Xl)n-VD2-C-(X2)n之第二多肽鏈及 151681.doc •26· 201127956 第四多肽鏈，其中； VD1為獲自該第一親本抗體或其抗原結合部分之第一 輕鏈可變區域； VD2為獲自該第二親本抗體或其抗原結合部分之第二 輕鏈可變區域； C為輕鏈恆定區域； XI為連接子，其限制條件為XI不為CH1 ;
    X2不包含Fc區； (Xl)n為（X1)0或（Xl)l ;及 (X2)n為（X2)0或（X2)l ; e)表現該第一多肽鏈、該第二多肽鏈、該第三多肽鏈 及該第四多狀鍵； 因此產生能夠結合該第一抗原及該第二抗原且具有所要 特性之雙重可變區域免疫球蛋白，其中該結合蛋白能夠 結合選自由以下組成之群的抗原對：CD-20與CD-19 ; CD-20與 CD-80 ; CD-20與 CD-22 ; CD-20與 CD-40 ; CD-3 與 HER-2 ; CD-3 與 CD-19 ; EGFR與 HER-2 ; EGFR與 CD-3 ; EGFR 與 IGF1，2 ; EGFR 與 IGF1R ; EGFR 與 RON ; EGFR與 HGF ; EGFR與 c-MET ; HER-2 與 IGF1，2 ; HER-2 與 IGF1R ; RON 與 HGF ; VEGF 與 EGFR ; VEGF 與 HER-2 ; VEGF 與 CD-20 ; VEGF 與 IGF1，2 ; VEGF 與 DLL4 ; VEGF 與 HGF ; VEGF 與 RON ; VEGF 與 NRP1 ; CD-20 與 CD3 ; DLL-4與 PLGF ; VEGF 與 PLGF ; ErbB3 與 EGFR ; ErbB3 與 HGF ; HER-2 與 ErbB3 ; c-Met與 ErB3 ; PLGF 與 I51681.doc •27· 201127956 HER-2 ;及 HER-2與 HER-2 0 77. —種改良如請求項6之結合蛋白之特徵的方法，該方法 包含以下步驟： (a)在改變之前測定該結合蛋白之特徵； (a) 改變重鏈及/或輕鏈之（χι)ι的長度及/或序列，藉此 提供經改變之重鏈及/或輕鏈； (b) 測疋包含該經改變重鏈及該經改變輕鏈之該經改變 結合蛋白的經改良特徵。 78. —種改良如請求項6之結合蛋白之特徵的方法該方法 包含以下步驟： (a) 在改變之前測定該結合蛋白之特徵； (b) 改變該第一多肽鏈及該第二多肽鏈，使得vdi_ (Xl)n-VD2-C-(X2)n 變為 VD2侦）n VDi c调n，藉此 提供經改變之重鍵及輕鍵； (c)測定包含該經改變重鏈 久β經改變輕鏈之該經改變 結合蛋白的經改良特徵。 79.
    -種改良如請求項6之結合蛋白之特徵的方法該方法 包含以下步驟： (a) 在改變之前測定該結合蛋白之特徵； (b) 改變該第一多肽鏈及/或 X弟一多肽鏈，使得該重鏈 及/或輕鏈之VD1或VD2中僅—者之序列改變；及 (c) 測定包含該經改變重鏈 。亥冱改變輕鏈之該經改變 、-。σ蛋白之特徵。 80.如請求項77至78中任一項之方 击其中該特徵係選自由 151681.doc -28- 201127956 、 成之群.與目標蛋白之結合性、來自宿主細胞之 表見產量、活體外半衰期、活體内半衰期、穩定性、溶 解度、及改良之效應功能。 81. 82. 83.
    84. 85. 86. • 87· 88. 89. 青求項77之方法，其中該經改變重鏈之該（χι)ι的長 增加。 月托項77或80之方法，其中該經改變重鏈之該（XI)!的 長度減少。 长項77或8〇之方法，其中該經改變輕鏈之該 長度増加。 月长項77或80之方法，其中該經改變輕鏈之該（XI)丨的 長度減少。 人广求項77或80之方法，其中該經改變重鏈之該（XI)丨包 3，自由SEQ ID Ν0:21或22組成之群的胺基酸。 月长項77或80之方法，其中該經改變輕鏈之該（XI)〗包 含選自由 EQ ID NO: 13或14組成之群的胺基酸。 月求項77或80之方法，其中該經改變重鏈之該（χι)ι SEQ iD N 且該經改變輕鍵之該（χι)ι為seq ι〇 NO:l4 〇 月托項77或80之方法，其中該經改變重鏈之該（XI)!為 ID Ν〇:21且該經改變輕鏈之該（χι)1為SEq ID NO:l4。 如°月求項77或80之方法，其中該經改變重鍵之該（χι)ι為 SEQ Jrj χτ Ν〇:22且該經改變輕鏈之該（xi)l為SEQ ID NO:l3 〇 151681.doc -29- 201127956 90.如請求項77或80之方法，其中該經改變重鏈之該（XI )〗為 SEQ ID NO:21且該經改變輕鏈之該（XI)1為SEQ ID NO:13。
    151681.doc •30-
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