TW201000126A - Glucagon receptor antagonists - Google Patents
Glucagon receptor antagonists Download PDFInfo
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- TW201000126A TW201000126A TW098108296A TW98108296A TW201000126A TW 201000126 A TW201000126 A TW 201000126A TW 098108296 A TW098108296 A TW 098108296A TW 98108296 A TW98108296 A TW 98108296A TW 201000126 A TW201000126 A TW 201000126A
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Description
201000126 六、發明說明: 【發明所屬之技術領域】 本發明係關於抑制升糖素激素與其受體結合之升糖素受 體多肽拮抗劑。特定言之,本發明係關於抑制升糖素與其 爻體結合之高親和力升糖素受體抗體或其Fab片段,及其 用於治療或預防哺乳動物第2型糖尿病(NIDDM)及相關病 症之用途。 【先前技術】 升糖素為由因應低血中葡萄糖含量之胰腺〇1細胞所產生 之29胺基酸肽激素。升糖素結合肝細胞表面上之膜締合升 糖素欠體,其觸發G-蛋白信號轉導級聯,從而活化細胞内 %化AMP且導致經由重新合成(葡糖新生)及肝糖分解(糖原 分解)而釋放葡萄糖。
UnSon等人揭示針對對應於大鼠受體之兩個細胞外部分 之合成肽所產生之多株抗體。在所揭示之檢定中,發現在 大鼠肝臟膜中針對胺基酸殘基126_137及2〇6_219所產生之 多株抗體阻斷升糖素與受體之結合(Uns〇n等人,PNAS第 93卷’第 310-315 頁,1996年 1月)。
Buggy等人揭示單株抗體之製備,認為在活體外檢定中 該單株抗體與升糖素針對受體之激素結合位點競爭(Buggy 等人,Horm· Metab. Res. 28 (1996) 215-219)。在所揭示之 檢定中,經給予名稱CIV395.7A之抗體識別人類及大鼠升 糖素^:體’而不識別小鼠升糖素受體。為研發用於人類治 療性治療之抗體,通常需要在認可大鼠及/或鼠類動物模 138463.doc 201000126 型中進行臨床前功效及安全性研究。因此其將大大促進治 療性抗體之藥物發展且因此對於提供能結合大鼠、鼠類及 人類形式之升糖素叉體之臨床前治療性抗體候選者而言為 非常合乎需要的。
Wdght等人揭示命名融GR_2 ρ6之單株抗體及其^片 段之胺基酸序列。此抗體已在小鼠巾針對人類升糖素受體 而產生且在所揭示之檢定中描述為此受體之競爭性枯抗劑 (WHght等人,Acta Cryst· (2〇〇〇)⑽,π ·)。申請人 已發現hGR-2 F6僅以低親和力結合大鼠及鼠類形式之升糖 素受體’且在糖尿純大鼠活體㈣ 現卿·請之治療功效。詳言之,此抗體不能夠以 汁顯者性降低大鼠模型中之血清葡萄糖(未公開)。 申請人已鑑別需要提供治療性單株抗體,其將以高度親 和力結合升糖素受體且藉此抑制升糖素與其結合,以提供 對糖尿病、較佳2型糖尿病及相關病症之有效治療。此 外,為准許抗體之臨床前藥物研發,明確需要提供可結合 人類、大鼠及鼠類形式之升糖素受體之單株抗體以使得可 進行專性臨床前安全性及功效研究。 【發明内容】 本發明係關於能以高親和力特定結合人類、大鼠及鼠類 來源之天然升糖素受體的新穎單株抗體或其Fab片段。此 外,本發明之發明者提供不僅結合多個來源之升糖素受體 之單株抗體或其Fab片段,而且第一次提供升糖素受體結 合單株抗體,該等單株抗體展示其能夠降低血清葡萄糖之 138463.doc 201000126 活體内功效。 在第一態樣中,本發明係關於一種Fab片段或包含該以卜 片段之人源化單株抗體,其中該Fab片段能夠以小於5〇祕 之Ki結合人類、大鼠及鼠類升糖素受體且抑制升糖素結合 . 各受體。 ^ 在另一意外之發現_,發明者第一次提供能顯著增加活 體内血清GUM濃度之能夠特異性結合升糖素受體之抗體 ❹ 或其Fab片段。在此項技術中已知增加血清GLP-丨含量以增 強β-細胞功能,降低升糖素分泌且延遲胃排空且認為增力曰口 /月GLP 1 3量在療2型糖尿病及相關病狀中極有利。 在第二態樣中,本發明係關於一種醫藥組合物,其包含 有效量之本發明之Fab片段或人源化單株抗體及醫藥學上 可接受之賦形劑。 在第二怨樣中,本發明提供一種在人類中治療丨型或2型 糖尿病及達成體重減輕之方法,其中該方法包含向有需要 • 之患者投與有效量之本發明之Fab片段或人源化單株抗 體。 本發明之第四悲樣包含用作藥物之本發明之Fab片段或 ' 人源化單株抗體。 ,本發明之第五態樣係關於本發明之Fab片段或人源化單 株抗體之用途,其係用於製造用於在人類中治療或預防i 型或2型糖尿病或達成體重減輕之藥物。 【實施方式】 本發明係關於一種Fab片段或包含該Fab片段之人源化單 138463.doc 201000126 株抗體’其中該Fab片段能夠以小於50 nM之Ki結合人類、 大鼠及鼠類升糖素受體且抑制升糖素結合各受體。 本發明亦提供單株抗體,其除人類、大鼠及鼠類來源之 升糖素受體之外亦能以高親和力結合食蟹猴 (cynomol〇gOUS monkey)之升糖素受體。較佳地,因此,
Fab片段或包含該Fab片段之人源化單株抗體亦以小於 nM之Ki抑制升糖素結合食蟹猴升糖素受體。較佳地, 片段或包含該Fab片段之人源化單株抗體具有小於3〇 nM, 更佳地小於20 nM,進一步較佳小於10 nM之對指定升糖素 受體中之每一者的Ki。進一步較佳為Fab片段具有小於2〇 nM之對大鼠、鼠類及食蟹猴受體的活體外幻,及小於5 nM之對人類受體的活體外Ki。更佳地,Fab片段且尤其對 人類升糖素受體之Ki為0.1 nM至15 nM、最佳1 nM至1〇 nM。 本發明之Fab片段或包含該pab片段之人源化單株抗體較 佳具有至少100 nM之對人類及大鼠升糖素受體的功能性結 合親和力(Kb)。進一步較佳為Fab片段或包含該Fab片段之 人源化單株抗體具有至少5 〇 nM、更佳至少1 〇 nM之對此等 文體的功能性結合親和力。在最佳實施例中,Fab片段或 包含該Fab片段之人源化單株抗體具有1 nM至10 nM之對人 類及大鼠升糖素受體的功能性結合親和力。 在尤其意外之發現中,申請人注意到當活體内暴露於具 有本發明鑑別之結合特性的Fab片段或包含該Fab片段之人 源化單株抗體時血清GLP-1增加及血清葡萄糖降低之極快 138463.doc 201000126 速率。為最大化此有利效應,較佳使Fab片段或包含該Fab 片段之人源化單株抗體不明顯結合GLP受體,亦即Ki大於 5000 nM ° 序列之描述: SEQ ID NO: 1至SEQ ID NO: 22係指表1之輕鏈及重鏈 CDR : SEQ ID NO: 23至SEQ ID NO: 3 0係指本文所述之較佳人 類構架區. 參 SEQ ID NO: 31及SEQ ID NO: 32為人類GluR之胺基酸及 cDNA序列: SEQ ID NO: 33及SEQ ID NO: 34為大鼠GluR之胺基酸及 cDNA序列: SEQ ID NO: 35及SEQ ID NO: 36為鼠類GluR之胺基酸及 cDNA序列: SEQ ID NO: 37及SEQ ID NO: 38為食蟹猴GluR之胺基酸 φ 及cDNA序列: SEQ ID NO: 39及 SEQ ID NO: 40為實例 l(Abl)之可變區 胺基酸序列 SEQ ID NO: 41 及 SEQ ID NO: 42為實例 2(Ab2)之可變區 胺基酸序列 SEQ ID NO: 43及 SEQ ID NO: 44為實例 3(Ab3)之可變區 胺基酸序列 SEQ ID NO: 45及 SEQ ID NO: 46為實例 4(Ab4)之可變區 胺基酸序列 138463.doc 201000126 SEQ ID NO: 45及 SEQ ID NO: 47為實例 5(Ab5)之可變區 胺基酸序列 SEQ ID NO: 45及 SEQ ID NO: 48為實例 6(Ab6)之可變區 胺基酸序列 SEQ ID NO: 45及 SEQ ID NO: 49為實例 7(Ab7)之可變區 胺基酸序列 SEQ ID NO: 50係指較佳κ輕鏈IgG4恆定區。 SEQ ID NO: 51係指較佳重鏈CH1恆定結構域。 SEQ ID NO: 5 2係指較佳經修飾人類IgG4 Fc區。 SEQ ID NO: 53 至 SEQ ID NO: 55係指較佳輕鏈 CDR。 SEQ ID NO: 56 至 SEQ ID NO: 68 係指較佳重鏈 CDR。 SEQ ID NO: 59 及 SEQ ID NO: 60 為實例 l(Abl)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO: 61 及 SEQ ID NO: 62 為實例 2(Ab2)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO·· 63 及 SEQ ID NO: 64 為實例 3(Ab3)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO: 65 及 SEQ ID NO: 66 為實例 4(Ab4)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO: 65 及 SEQ ID NO: 67 為實例 5(Ab5)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO: 65 及 SEQ ID NO: 68 為實例 6(Ab6)之輕鏈及 重鏈蛋白質序列。 SEQ ID NO: 65 及 SEQ ID NO: 69 為實例 7(Ab7)之輕鏈及 138463.doc 201000126 重鏈蛋白質序列。 SEQ ID NO: 70及 SEQ ID NO: 71為實例 l(Abl)之輕鏈及 重鏈DNA序列。 SEQ ID NO: 72 及 SEQ ID NO: 73 為實例 2(Ab2)之輕鏈及 重鏈DNA序列。 75為實例3(Ab3)之輕鏈及 77為實例4(Ab4)之輕鏈及 78為實例5(Ab5)之輕鏈及 79為實例6(Ab6)之輕鏈及 SEQ ID NO: 74及 SEQ ID NO: 重鏈DNA序列。 SEQ ID NO: 76及 SEQ ID NO: 重鏈DNA序列。 SEQ ID NO: 76及 SEQ ID NO: 重鏈DNA序列。 SEQ ID NO: 76及 SEQ ID NO: 重鏈DNA序列。 SEQ ID NO: 76 及 SEQ ID NO: 80 為實例 7(Ab7)之輕鏈及 重鏈DNA序列。 φ 定義: 本文亦稱為「GluR」之「升糖素受體」屬於由長胺基末 端細胞外結構域、7個跨膜區段及細胞内C-末端結構域組 •成之2類G蛋白偶合受體族。升糖素受體尤其表現於肝細胞 之表面上,其中該等受體結合升糖素且轉導藉此提供之信 號至細胞中。編碼大鼠及人類來源之升糖素受體之DNA序 列已經分離且揭示於此項技術(EP0658200B1)中。亦已將 鼠類及食蟹猴同系物分離且測序(Burcelin等人,Gene 164 (1995) 305-310) ; McNally等人,Peptides 25 (2004) 1171- 138463.doc 201000126 1178)。 本文關於本發明之抗體或其Fab片段之活性所用之術語 抑制」意謂能夠實質上拮抗升糖素受體之生物活性。此 能力反映於由本文所述之[⑴^升糖素結合檢定計算之幻值 上。 關於本發明之單株抗體所用之術語「人源化」係指具有 至少人類構架及恆定區(CL、CH結構域(例如,chi、 CH2、CH3)及鉸鏈)及來自升糖素受體結合抗體之cDR的 抗體。人類構架包含對應於人類生殖系序列以及具有體細 胞突變之序列的構架。人類構架及恆定區可為完全人類的 或可藉由一或多個胺基酸取代、末端及中間添加及缺失及 其類似者而不同於天然序列。(:1)]^可來自在此申請案中在 任何抗體構架之情況下結合升糖素特異性受體之一或多個 CDR。舉例而言,本發明之人源化抗體之CDR可來自在小 鼠抗體構架之情況下結合升糖素受體之CDR且接著經遺傳 工程處理,以在人類構架之情況下結合升糖素受體。 術語「單株抗體」係指來自單一副本或純系之抗體,包 括例如任何真核、原核或噬菌體純系,而非產生其之方 法。較佳地,本發明之單株抗體以均質或實質上均質之群 體存在。 本文關於本發明之抗體所用之術語「活體内功效」意謂 抗體可在人類或動物模型中賦予積極生物效應之能力。較 佳地’活體内功效係指與對照組反應相比,本發明之抗體 對於企中葡萄糖上升之動物產生葡萄糖正規化作用。可適 138463 .doc -10- 201000126 當使用糖尿病性Zucker糖尿病脂肪大鼠(ZDF)模型(Horm Metab Res_ 2005 Feb;37 (2):79-83)以評定活體内功效,其 中較佳之活體内功效為,當動物暴露於劑量S 3 0 mg/kg之 本發明人源化抗體時,100%血中葡萄糖正規化。更佳之 活體内功效為,當動物暴露於劑量S 1 5 mg/kg之抗體時, 100 %血中葡萄糖正規化,進一步較佳之劑量為$ 10 mg/kg 時100%血中葡萄糖正規化,更佳之劑量為0.1至5 mg/kg之 劑量時100%血中葡萄糖正規化。在最佳實施例中,活體 内功效為,在糖尿病性ZDF大鼠模型中,將動物暴露於劑 量為1至3 mg/kg之本發明人源化抗體時,100%血中葡萄糖 正規化。 術語「葡萄糖正規化」係指在ZDF大鼠模型中,低於 120 mg/dL之平均血漿葡萄糖值,較佳為介於110 mg/dL至 120 mg/dL之平均血漿葡萄糖值。可根據Etgen等人之方法 (Metabolism 2000; 49(5): 684-688)測定血漿葡萄糖,或根 據 D'Orazio 等人之方法(Clin. Chem. Lab. Med. 2006; 44(12): 1486-1490)由全也葡萄糖濃度之轉化計算金漿葡萄 糖。 本文所用之「Fab片段」係指抗體分子可變區内之Fab部 分,其除CL及CH1結構域外,另含有輕鏈及重鏈CDR及構 架序列之胺基酸殘基。 本文將3個重鏈CDR稱為「CDRH1、CDRH2及CDRH3」 且將3個輕鏈CDR稱為「CDRL1、CDRL2及CDRL3」。各結 構域之胺基酸排序係根據熟知之方法進行(Kabat等人, 138463.doc -11 - 201000126
Ann. NY Acad. Sci. 190:382-93 (1971) ; Kabat 等人,
Sequences of Proteins of Immunological Interest,第 5版, U.S. Department of Health and Human Services, NIH公開案 第91-3 242號(1991))。抗原結合結構域或抗原結合結構域 之CDR可來自其他非人類物種,其包括(但不限於)兔子、 小鼠、大鼠或倉鼠。 本發明之發明人已鑑別可組合使用以製備抗體Fab片段 之重鏈及輕鏈CDR序列,該等抗體Fab片段對於鼠類、大 鼠、食蟹猴及人類來源之升糖素受體具有特別高之親和 力。Fab片段較佳包含; SEQ ID NO: 53 SEQ ID NO: 54 SEQ ID NO: 55 SEQ ID NO: 56
(i) 輕鏈 CDRL1 :SXSSSVSYXiH (ii) 輕鏈CDRL2 : T T S X2 L A Η
(iii) 輕鏈CDRL3 : X3 X4 R S T X5 P P T (iv) 重鏈 CDRH1 :GDDITSGYX6X7 (v) 重鏈CDRH2 : YISYSGSTX8YX9PSLKS SEQIDNO: 57 (vi)重鏈CDRH3 : PPX10YYGFGPYAX„ DY SEQIDNO: 58 其中: X =Y或A X6 = W或H Xi =M或I x7 = N、D或 E x2 =N或Y Xg = Y、Q、S或 V x3 =Q或L X9 = N、S或 I X4 =Q或W Xio= G或A 138463.doc -12- 201000126
X5 = L或 I χη= M或 L 更佳地,X為Y或A ; 乂!為1 ; X2為Y ; X3為Q或L ; X4為Q 或W ; X5為L或I;又6為\\^或Η; X7為D或E; X8為Y、Q、S 或V ; X9為S ; X1()為G或A; X11為L。進一步較佳為X為 A ;又!為 I ; χ2為 γ ; 乂3為 q ; χ4為 Q ; X5為 L ; X6為 Η ; X7 為D或E ;又8為丫、q或s ; X9為S ; X10為G或A ; Xn為L。
較佳地,本發明之Fab片段或包含該Fab片段之人源化單 株抗體包含CDR序列: CDRL1 12 3 4 5 6789 10
SASSSVSYIH CDRL2 1234 567 T T S Y L A Η CDRL3 1 2 3 4 5 6 7 8 9
QQRSTLPPT CDRH1 1 23456789 10
GDDITSGYHD CDRH2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
YI SYSGSTYYSPSLKS CDRH3 1 2 3 4 5 6 7 8 9 10 11 12 13 14
PPGYY GFG PYA LDY 其中該Fab片段具有一個、兩個或三個選自由以下胺基 酸取代組成之群的胺基酸取代: CDRL1 : A2Y、I9M ; CDRL2 : Y4N ; CDRL3 : Q1L、Q2W、L6I ; 138463-doc -13· 201000126 CDRHl : H9W、D10E、DION ; CDRH2 : Y9Q、Y9S、Y9V、S11N、Sill ; CDRH3 : G3A、L12M。 更佳地,該Fab片段包含一個、兩個或三個選自以下之 胺基酸取代:CDRHl : D10E ; CDRH2 : Y9Q、Y9S ; CDRH3 : G3A。 本發明之Fab片段或包含該Fab片段之人源化單株抗體較 佳包含選自以下之CDR序列: ⑴具有 SEQ ID NO: 2 之 CDRL1、SEQ ID NO: 4 之 CDRL2、SEQ ID NO: 7之 CDRL3 的輕鏈;及具有 SEQ ID NO: 11 之 CDRHl、SEQ ID NO·· 15 之 CDRH2、SEQ ID NO: 21之CDRH3的重鏈; (ii) 具有 SEQ ID NO: 1 之 CDRL1、SEQ ID NO: 4 之 CDRL2、SEQ ID NO: 6之 CDRL3 的輕鏈;及具有 SEQ ID NO: 10之 CDRHl、SEQ ID NO: 16之 CDRH2、SEQ ID NO: 20之CDRH3的重鏈; (iii) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 8 之CDRL3 的輕鏈;及具有 SEQ ID NO: 11 之 CDRHl、SEQ ID NO: 15之 CDRH2、SEQ ID NO: 21之CDRH3的重鏈; (iv) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO·· 6 之 CDRL3的輕鏈;及具有 SEQ ID NO: 12之 CDRHl、SEQ ID NO: 15 之 CDRH2、SEQ ID NO: 138463.doc -14- 201000126 21之CDRH3的重鏈; (v) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6之 CDRL3 的輕鏈;及具有 SEQ ID NO: 12之 CDRH1、SEQ ID NO: 17之 CDRH2、SEQ ID NO: 21之CDRH3的重鏈; (vi) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6 之 CDRL3 的輕鏈;及具有 SEQ ID NO: 12之 CDRH1、SEQ ID NO: 15之 CDRH2、SEQ ID NO: 參 22之CDRH3的重鏈;及 (vii) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6 之 CDRL3 的輕鏈;及具有 SEQ ID NO: 13 之 CDRH1、SEQ ID NO: 18之 CDRH2、SEQ ID NO: 22之CDRH3的重鏈。 尤其需要本發明之抗體在低血漿濃度下展示活體内功 效。在ZDF大鼠模型中在30 mg/kg之劑量下,較佳在小於 ❹ 1 5 mg/kg,更佳小於5 mg/kg,進一步較佳在0.1 mg/kg至5 mg/kg範圍内之劑量下應觀察到活體内功效。最佳地,本 發明之抗體在ZDF大鼠模型中在約1 mg/kg至3 mg/kg之劑 -量下達成100%葡萄糖正規化。已發現本發明之尤其較佳 - 抗體在活體内ZDF大鼠模型中在3 mg/kg之低劑量下能夠展 示100%葡萄糖正規化。因此本發明較佳包含Fab片段或包 含該Fab片段之人源化單株抗體,其中該Fab片段包含:
(i)具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6之CDRL3的輕鏈;及具有 SEQ ID 138463.doc -15- 201000126 NO: 12之 CDRHl、SEQ ID NO: 15 之 CDRH2、SEQ ID NO: 21之CDRH3的重鏈; (ii) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6之 CDRL3 的輕鏈;及具有 SEQ ID NO: 12之 CDRH1、SEQ ID NO: 17之 CDRH2、SEQ ID NO: 21之CDRH3的重鏈; (iii) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6之 CDRL3 的輕鏈;或具有 SEQ ID NO: 12之 CDRH1、SEQ ID NO: 15之 CDRH2、SEQ ID NO: 22之CDRH3的重鍵;或 (iv) 具有 SEQ ID NO: 3 之 CDRL1、SEQ ID NO: 5 之 CDRL2、SEQ ID NO: 6 之 CDRL3的輕鏈;及具有 SEQ ID NO: 13 之 CDRH1、SEQ ID NO: 18之 CDRH2、SEQ ID NO: 22之CDRH3的重鏈。 在另一較佳實施例中,本發明係關於Fab片段或包含該 Fab片段之人源化單株抗體,其中該Fab片段包含具有SEQ ID NO: 3之 CDRL1、SEQ ID NO: 5之 CDRL2、SEQ ID NO: 6 之 CDRL3 的輕鏈;及具有 SEQ ID NO: 12 之 CDRH1、SEQ ID NO: 17 之 CDRH2、SEQ ID NO: 21 之 CDRH3 的重鏈。已 發現與所述屬内之其他相似抗體相比包含根據此實施例之 Fab片段的抗體具有尤其有利之經長時期維持活體内功效 的特性。 本發明之Fab片段或包含該Fab片段之人源化單株抗體較 佳包含人類來源之輕可變鏈構架區及重可變鏈構架區。此 138463.doc • 16 - 201000126 外,可將多種不同人類構架序列單獨或組合用作本發明之 人源化免疫球蛋白之基礎。較佳地,本發明之Fab片段或 人源化單株抗體之構架區為人類來源的或實質上人類來源 的(至少95%,97%或99%之人類來源)。人類來源之構架區 之序列可經由網站 http://imgt.cines.fr/textes/IMGTindex/FR.html 獲自 ImMunoGenetics(IMGT)或獲自 The immunoglobulin Factsbook. Marie-Paule Lefranc, Gerard Lefranc, Academic Press 2001, ISBN 012441351。舉例而言,生殖系輕鏈構架 可能係選自由以下構架組成之群:All、A17、A18、 A19、A20、A27、A30、LI、L1I、L12、L2、L5、L15、 L6、L8、012、02及08且生殖系重鏈構架區可能係選自由 以下構架區組成之群:又112-5、¥112-26、¥112-70、¥113-20 > VH3-72 ' VHI-46 ' VH3-9 ' VH3-66 ' VH3-74 > VH4-31、VH 1-18、VH 1-69、VI-13-7、VH3-11、VH3-15、 VH3-21、VH3-23、VH3-30、VH3-48、VH4-39、VH4-59 及 VH5-5I。 可將本文所揭示之特異性抗體用作模板或親本抗體以製 造本發明之額外抗體。在一種方法中,將親本抗體CDR接 枝至與親本抗體構架具有高序列一致性之人類構架。新穎 構架與親本抗體中之對應構架的序列一致性一般為至少 80%、至少85%或至少90%。此接枝可導致與親本抗體相 比結合親和力降低。若為此情況,則可基於由Queen等人 公開之特定準則[Queen等人,Proc. Natl. Acad. Sci. USA 88,2869 (1991)]在某些位置處使構架回復突變為親本構 138463.doc 201000126 架。可使用之其他方法包括(例如)Jones等人,Nature, 321:522 (1986) ; Riechmann等人,Nature , 332:323-327 (1988) ; Verhoeyen等人,Science, 239:1534 (1988)。 最佳地,本發明之Fab片段或包含該Fab片段之人源化單 株抗體包含以下輕鏈構架(FR)序列:FR1 SEQ ID NO: 23 ; FR2 SEQ ID NO: 24 ; FR3 SEQ ID NO: 25 ; FR4 SEQ ID NO: 26 ;及重可變鏈構架序列:FR5 SEQ ID NO: 27 ; FR6 SEQ ID NO: 28 ; FR7 SEQ ID NO: 29 ; FR8 SEQ ID NO: 30 ;其中將此等以輕鏈可變序列FR1-CDRL1-FR2-CDRL2-FR3-CDRL3-FR4及重鏈可變序列 FR5-CDRH1-FR6-CDRH2-FR7-CDRH3-FR8排列。
申請人已驚奇地測定到當經由使用活體外競爭性升糖素 結合檢定預測升糖素受體拮抗抗體之活體内功效時,Fab 片段之親和力與活體内功效正性相關。相反,全抗體對升 糖素受體之結合親和力(Ki)並不一定為活體内功效之有效 預測因子。因此製備具有本文所尋求之有利特性之單株抗 體的方法較佳包含選擇在使用異源表現之升糖素受體基因 之活體外競爭性升糖素結合檢定中以小於5 0 nM之Ki結合 各升糖素受體之Fab片段。更佳地,該方法包含選擇對升 糖素受體中之每一者具有小於30 nM,更佳小於20 nM,進 一步較佳小於10 nM之活體外Ki的Fab片段。更佳地,藉由 小於20 nM之對大鼠、鼠類及食蟹猴受體之活體外Ki及小 於5 nM之對人類受體之活體外Ki而選擇Fab片段。更佳 地’所選Fab片段且尤其對人類升糖素受體之Ki為0.1 nM 138463.doc *18· 201000126 至15 nM、最佳丨ηΜι1〇 nM。接著可藉由此項技術中通 常已知之技術將由此方法鑑別之Fab片段適當地表現為用 於治療性用途之全抗體。 將瞭解應用本發明之教示,熟習此項技術者可使用常見 .技術(例如定點突變)以取代本文所揭示之特異性Cdr及構 .. 架序列内之胺基酸且在此情況下產生來自本文所提供之序 列的其他可變區胺基酸序列。可在特定取代位點處引入至 鲁 多全部20個替代性天然存在之胺基酸。接著可適當使用本 文以上所定義之活體外選擇方法以為了具有所主張之交又 反應性及已由本發明之申請人發現指示活體内功效之活體 外Κι的Fab片段而篩檢此等額外可變區胺基酸序列。以此 方式’鑑別適合於製備本發明之人源化抗體之其他Fab片 段。較佳地,構架内之胺基酸取代侷限於本文所揭示之構 架序列中之一或每一者内之一個、兩個或三個位置。較佳 地,CDR内之胺基酸取代侷限於一或每一 CDR内之一至三 Φ 個位置,更佳在一或每一CDR内之一或兩個胺基酸位置處 進行取代。進一步較佳地,在重鏈可變區之CDR中之一或 兩個胺基酸位置進行胺基酸取代。最佳胺基酸取代係在 • CDRH2内之一或兩個胺基酸位置進行。 - Wu等人’ J. Mol_ Biol., 294:151-162中提供用於組合 CDR與構架取代以使用本文中描述為親本抗體之抗體製備 本發明之替代抗體的合適方法。 如本文所用之免疫球蛋白之Fc部分係指來自兩個重鏈之 抗體的恒定區,其經由非共價相互作用及雙硫鍵相關。Fc 138463.doc •19- 201000126 部分可包括鉸鏈區且經由CH2及CH3結構域延伸至抗體之 C-末端。Fc部分可進一步包括一或多個糖基化位點。本發 明之單株抗體可具有選自免疫球蛋白類IgA、IgD、IgG、
IgM及IgE中之任一者之重鏈恒定區。較佳地,本發明之抗 體含有來自人類IgG4 Fc區之Fc部分,此係因為與其他IgG 子型相比其降低之結合FcYR及補體因子的能力。更佳地, 本發明之抗體的IgG4 Fc區含有進一步降低效應功能之取 代[Issacs 等人,(1996) Clin. Exp. Immunol. 106:427-43 3]。此等取代可選自包含以下取代之群中之一或多者: 在殘基233處用脯胺酸取代麩胺酸、在殘基234處用丙胺酸 或纈胺酸取代苯丙胺酸及在殘基235處用丙胺酸或麩胺酸 取代白胺酸(EU編號,Kabat, E.A.等人〇/ iVoie/則 ο/' ,第 5 版 U.S. Dept, of
Health and Human Services, Bethesda,MD, NIH公開案第 91-3242號)。此等殘基對應於SEQ ID NO: 52中之位置15、 16及17及SEQ ID NO: 67中之位置23 5、236及237。此外, 藉由在對應於SEQ ID NO: 52之位置79的殘基297(EU編號) 處用Ala取代Asn以移除IgG4 Fc區中之N-連接糖基化位點 為確保在人源化抗體之情況下消除殘餘效應活性的另一方 式。 此外,供本發明之人源化單株抗體使用之IgG4 Fc部分 較佳含有穩定重鏈二聚體形成且防止半-IgG4 Fc鏈形成之 取代。此建構由在228(EU編號)位置處經脯胺酸(SEQ ID NO: 52中之胺基酸殘基10)取代之絲胺酸組成。在本文所 138463.doc -20- 201000126 討論之抗體的IgG4衍生物以部分中亦可去除存在於天然分 子中之Ο末端離胺酸殘基(SEQ m Ν〇: μ之位置Mg ;經 去除離胺酸稱為消-K)。由SEQ ID NO: 67之胺基酸221至 448提供最佳4〇4?(:部分。 本發明進一步係針對編碼本發明之抗體的經分離核酸序 列,包含彼核豸之載冑,彼核酸視情況與由用冑體轉型之 宿主細胞識狀控料肋作性連接;包含彼載體之宿主 細胞;產生本發明之抗體或其Fab片段的方法,其包含培 養宿主細胞以便表現核酸及視情況自宿主細胞培養基回收 抗體。 在另-實施例中,本發明提供—種醫藥組合物,其包含 本發明之Fab片段或人源化單株抗體。本發明之醫藥組合 物可進#包含醫藥學上可接受之載劑。在該醫藥組合物 中,本發明之Fab片段或人源化單株抗體為活性成份。較 佳地,該醫藥組合物包含本發明之Fab片段或人源化單株 ❹ &體之均質或實質上均質群體。用於治療性用途之組合物 為無菌的且可冷凍乾燥,視情況供有適當稀釋劑。 本發明之另—實施例包含為本發明之任何經分離聚核普 • 酸/任何重組載體之接受者的宿主細胞或細胞培養物,該 •(等)載體包含編碼本發明之HCVR、lcvr、單株抗體或 ㈣片段的序列。宿主細胞包括單__宿主細胞之子代,且 由於天然、偶然或故意突變及/或改變該子代可能不—定 與原始母細胞完全-致(在形態方面或在全部麵補體方 面)。佰主細胞包括用表現本發明之單株抗體或其輕鏈或 138463.doc -21- 201000126 重鏈的一或多個重組載體或聚核苷酸活體内或活體外轉 型、轉導或轉染之細胞。亦可將包含本發明之重組栽體 (穩定併入宿主染色體中或未併入其中)的宿主細胞稱為 「重組宿主細胞」。用於本發明之較佳宿主細胞為CH〇細 胞、NS0細胞、HeLa、SP2/0細胞或COS細胞。用於本發明 之其他宿主細胞包括植物細胞、酵母細胞、其他哺乳動物 細胞及原核細胞。 本發明包含一種製品,該製品包含包裝材料及含於該包 裝材料内之本發明之Fab片段或人源化單株抗體,且其中 包裝材料包含包裝插頁’其指示Fab片段或人源化單株抗 體在患者中中和GluR或降低GluR活性之程度。 生物檢定: 升糖素受體(GlucR)膜製劑 由表現經選殖人類、小鼠、食蟹猴或大鼠升糖素受體之 293HEK細胞製備用於結合研究之膜製劑。首先將各無性 繁殖細胞株生長為懸液培養物且在4〇c下將冷凍細胞小球 再懸浮於由 25 mM Tris、pH 7.5、1 mM MgCl2、CompleteR 無EDTA蛋白酶抑制劑錠劑(R〇che Applied Science)及20 U/ml DNase I(Sigma Chemical Company)組成之膜製劑緩衝 液中。用馬達驅動鐵氟龍玻璃potter_Eivehjem均質機使用 25次衝擊均質化細胞,之後在41下在1800 x g下離心15分 鐘。收集上清液且將小球再懸浮於膜製劑緩衝液中,再均 質且離心。將第二上清液與第一上清液組合且在18〇〇 χ ^ 下再離心15 min至澄清。將澄清之上清液轉移至高速管中 138463.doc -22· 201000126 且在4°C下在25000 x g下離心。將膜小球(P2)再懸浮於膜 製劑缓衝液(在無DNAase之情況下)中,等分試樣,於乾冰 上快速冷凍且在-80°C下儲存直至需要。 藉由閃爍接近檢定(SPA)之[1251】升糖素結合 使競爭性受體/配位體結合實驗適合於閃爍接近檢定 (SPA)形式。在清晰底部不透明96孔微定量板中進行培 育。將化合物於由 25 mM Hepes、pH 7.4、2.5 mM CaCh、 1 mM MgCl2、〇. 1% 無脂肪酸 BSA、0.003% tween-20 及 Complete11無EDTA蛋白酶抑制劑旋劑組成之結合緩衝液中 連續稀釋至3倍。將P2薄膜(以上製備)稀釋於來自各受體 製劑之結合缓衝液中,接著添加至經稀釋化合物中,之後 添加0.15 mg先前用1%無脂肪酸BSA及0.15 nM [1251]-升糖 素(Perkin-Elmer)阻斷之麥胚凝集素(WGA)SPA珠粒(GE Healthcare)。將板用黏著密封帶密封,翻滚混合且在室溫 下培育12小時。與受體結合之放射性(緊密接近WGA SPA 珠粒)於 PE Life and Analytical Sciences Trilux Microbeta板 閃爍計數器上量化且表現為每分鐘計數(CPM)。在不添加 化合物之情況下下測定總結合且藉由添加1 uM升糖素 (Lilly Research Labs)而測定非特異性結合。1 uM之未標記 升糖素的最終濃度能夠完全抑制[1251]_升糖素結合至本底 水準。 [1251]升糖素結合資料分析。 將化合物之濃度曲線之原始CPM資料藉由由個別CPM值 減去非特異性結合且除以總結合信號(亦校正非特異性結 138463.doc •23- 201000126 合)而轉化為百分比抑制。使用4參數(曲線最大值、曲線最 小值、IC50、希爾斜率(Hill slope))非線性回歸常用程式 (XLFit版3.0 : Activity Base, IDBS)分析資料。在各個別受 體物質之檢定中,藉由競爭者抑制之放射性配體結合所測 定之平衡解離常數Ki係基於方程[Ki=IC5〇/(l+D/Kd)]由絕 對IC50值計算,其中D等於用於實驗之放射性配體之濃度 且Kd等於[1251]升糖素之平衡結合親和力常數。 升糖素刺激之cAMP功能拮抗劑檢定。 功能拮抗劑活性係使用相同無性繁殖大鼠、小鼠、食蟹 猴及人類升糖素受體-293HEK細胞株由對次極大劑量之升 糖素所引起之細胞内cAMP增加的劑量依賴性抑制作用而 測定。用來自Perkin Elmer(6760625R)之放大發光接近均 質檢定(Amplified Luminescent Proximity Homogeneous Assay,Alpha Screen)進行細胞内cAMP含量之定量。簡言 之,細胞内產生之cAMP競爭生物素標記之cAMP抗生蛋白 鏈菌素塗佈之供體珠粒及經塗佈之抗cAMP抗體受體珠粒 之結合。細胞内cAMP含量增加時,存在受體珠粒-生物素 標記之cAMP-供體珠粒複合物之分裂。在10 mM Hepes、 pH 7.4中用於含有Mg+2及Ca+2之HBSS中之0.25 mM IBMX 進行功能檢定。將無性繁殖升糖素受體-293HEK細胞以 25 00個細胞/孔及1單位/孔之來自套組的生物素標記之 cAMP懸浮於20 ul之總體積中。將細胞在室溫下用20 ul 3 倍連續稀釋之化合物或3倍連續稀釋之cAMP預先培育30分 鐘用作標準曲線。藉由添加20 ul 300 pM升糖素(3X)(足夠 138463.doc 24· 201000126 產生90%之最大細胞内cAMP之劑量)起始反應。在室溫下 於黑暗中60分鐘之後,藉由每孔添加30 ul溶解缓衝液中止 反應,該溶解缓衝液由於10 mM Hepes、pH 7.4中之1% IGEPAL CA630(Sigma)及 0.1%無脂肪酸BSA(Gibco)製成, 其含有各1單位之套組供體珠粒及受體珠粒。將板包於箔 中以保護供體珠粒及受體珠粒免受光且將其於Titertek震 盪器上中等速度混合30秒。在室溫下培育隔夜之後',經 Packard FusionTM-a儀器讀取該等板。 功能cAMP活性之資料分析。 基於cAMP標準曲線將alpha screen單位轉化為皮莫耳所 產生之cAMP/孔。將在化合物存在下所產生之皮莫耳 cAMP轉化為僅有次極大劑量之升糖素情況下之最大反應 的百分比。在各實驗内,測定以皮莫耳cAMP計之產生 50%響應所需之升糖素的濃度。使用此EC5〇濃度將運作之 間的結果正規化為Kb,其中Kb=(EC50化合物)/[1+(ρΜ所用 升糖素/用於升糖素劑量反應之以pM計之EC50)]。使用4參 數(曲線最大值、曲線最小值、IC5〇、希爾斜率)非線性回 歸常用程式(XLFit 3.0 版:Activity Base,IDBS)分析資 料。 實例: 如此項技術中所已知製造及純化抗體實例Ab-1、Ab-2、 Ab-3、Ab-4、Ab-5、Ab-6 及 Ab-7。將諸如HEK 293 EBNA 或CHO之適當宿主細胞用分泌抗體之表現系統使用最佳預 定輕鏈與重鏈載體比率或編碼輕鏈(SEQ ID NO·· 70、72、 138463.doc -25- 201000126 74、76 中所述)與重鏈(SEQ ID NO: 71、73、75、77、78、 79、80中所述)之單一載體系統瞬間或穩定轉染。使用許 多通常使用技術中之任一者純化已分泌有抗體之澄清培養 基。舉例而言,可便利地將培養基應用於已用相容緩衝液 (諸如磷酸鹽緩衝鹽水(pH 7.4))平衡之蛋白質A或G瓊脂糖 FF管柱。洗滌該管柱以移除非特異性結合組份。結合抗體 係(例如)藉由pH梯度(諸如0.1 Μ磷酸鈉缓衝液pH 6.8至0.1 Μ擰檬酸鈉緩衝液pH 2.5)溶離。抗體部份係(諸如)藉由 SDS-PAGE偵測,且接著集合。視期望用途而定,進一步 純化係可選的。可使用常見技術將抗體濃縮及/或無菌過 濾。可溶性聚集體及多聚體可藉由常見技術而有效移除, 該等技術包括尺寸排斥、疏水性相互作用、離子交換或羥 基磷灰石層析。此等層析步驟之後抗體之純度大於99%。 可將產物在-70°C下即刻冷凍或可冷凍乾燥。 於大腸桿菌(E. coli)中達成Fab表現,其中將Fab分子分 泌至周質空間中。藉由滲透壓衝擊分裂細胞壁,且經 IMAC管柱純化含有His標籤之Fab。 表1陳述用於本發明之抗體實例的CDR組合。全抗體輕 鏈組合藉由三個輕鏈CDR佔據空間之輕鏈構架序列;構架 1(SEQ ID NO: 23)-CDRLl-構架 2(SEQ ID NO: 24)-CDRL2-構架 3(SEQ ID NO: 25)-CDRL3-構架 4(SEQ ID NO: 26)及輕 鏈恆定區(SEQ ID NO: 53)。重鏈構架序列藉由三個重鏈 CDR佔據空間,構架 5(SEQ ID NO: 27)-CDRHl-構架 6(SEQ ID NO: 28)-CDRH2-構架 7(SEQ ID NO·· 29)-CDRH3-構架 138463.doc -26- 201000126 8(SEQ ID NO: 3 0),且接著重鏈 CH1恆定區(SEQ ID NO: 51),之後為在Fab片段中不存在之Ab之Fc結構域(SEQ ID NO: 52,其中 X10=P ; X15=E ; X16=A ; X17=A ; X79=N ; x229 =不存在)。 表1 : 實例 CDRL 1 SEQ ID CDRL 2 SEQ ID CDRL 3 SEQ ID CDRH 1 SEQ ID CDRH 2 SEQ ID CDRH 3 SEQ ID Ab - 1 2 4 7 11 15 21 Ab-2 1 4 6 10 16 20 Ab-3 3 5 8 11 15 21 Ab-4 3 5 6 12 15 21 Ab-5 3 5 6 12 17 21 Ab-6 3 5 6 12 15 22 Ab-7 3 5 6 13 18 22 在以上升糖素受體結合檢定中抗體實例1至7及其Fab片 段全部以小於50 nM之Ki抑制升糖素結合人類、小鼠、食 蟹猴及大鼠升糖素受體。 實例4之抗體(Ab4)的活體外活性 表2.功能cAMP拮抗作用 化合物 大鼠GluR 人類GluR Kb(nM) n Kb (nM) Stdev n Ab4 6.85 1 6.49 0.34 2 此檢定表明在奈莫耳濃度下Ab4結合GluR可阻斷大鼠或 人類升糖素受體細胞株之下游活性且降低細胞之cAMP產 138463.doc -27- 201000126 生。 表3 ·實例4之全抗體及個別Fab之活體外Ki(nM)
化合物 人類 小鼠 大鼠 食蟹猴 人類GLP-1 R GlucR GlucR GlucR GlucR 升糖素 3.13 2.72 12.77 5.78 Ab4 1.34 0.83 1.24 6.00 >5000 Fab4 2.90 2.43 3.30 9.42 ND 此檢定表明在活體外升糖素競爭結合檢定中,Ab4以高 親和力(Ki)結合人類、小鼠、大鼠、食蟹猴來源之升糖素 受體且以低親和力結合人類GLP-1受體。 實例4之抗體(Ab4)的活體内活性 將單次皮下注入實例4之抗體(亦即Ab4)或人類 IgG(hIgG4)對照物給藥約8週大且約400 g重之ZDF大鼠。 各處理組由6隻動物組成。給藥前及在單次皮下3 mg/kg或 15 mg/kg給藥Ab4或15 mg/kg之hlgG對照物之後歷時13曰 每曰獲取血樣以進行葡萄糖量測。給藥前及在3 mg/kg或 15 mg/kg皮下給藥Ab4或15 mg/kg hlgG對照之後2、4、6及 8曰獲取GLP-1分析之血樣。 表4.在向ZDF大鼠單次3 mg/kg或15 mg/kg皮下給藥Ab4 或1 5 mg/kg陰性對照物之後的血中葡萄糖含量。 時間 (日) Ab45 3 mg/kg Ab4, 15 mg/kg 對照物(15 nig/kg hlgG) 平均葡萄糖濃 度(mg/dL) S.D. 平均葡萄糖濃 度(mg/dL) S.D. 平均葡萄糖濃 度(mg/dL) S.D. 0 345.3 37.8 359 29.2 366.5 22.9 1 225.7 53.5 143.8 27.2 374.3 22.4 138463.doc -28- 201000126 2 97.5 4.3 85.7 5.7 389.3 22.3 3 92.0 7.8 89.8 9.6 361 51.5 4 103.7 20.6 90.0 14.2 381.7 69.0 5 105.3 8.9 97.3 5.2 400.8 62.2 6 108.3 13.8 99.3 10.0 401.2 61.3 7 113.7 7.8 97.5 12.2 451.7 45.5 8 135.8 15.5 104.3 11.4 452.8* 33.6 9 151.0 21.1 109.2 7.0 394.3 40.8 10 149.0 9.2 103.0 15.3 418.3 33.3 11 159.3 28.9 106.3 10.3 410.0 34.4 12 151.7 29.9 108.2 9.5 417.7 58.8 13 218.5 88.1 114.8 11.5 443.0 48.9 每組存在6隻大鼠,除去一隻動物量測AQL之一個值 (*),因此 n=5。 表5·在向ZDF大鼠單次3 mg/kg或15 mg/kg皮下給藥Ab4 或15 mg/kg陰性對照物之後的血漿GLP-1含量。 時間 (日) Ab4, 3 mg/kg Ab4, 15 mg/kg 對照物 (15 mg/kg hlgG) 平均 GLP-1 (pM) SD η 平均 GLP-1 (pM) SD n 平均 GLP-1 (pM) SD n 0 <6 N.D. 0 <6 N.D. 0 <6 N.D. 0 2 <6 N.D. 0 10 3 2 <6 N.D. 0 4 15 N.D. 1 13 3 5 <6 N.D. 0 6 21 2 3 29 2 5 <6 N.D. 0 8 36 5 3 112 54 6 <6 N.D. 0 平均值及標準差(sd)僅由彼等具有可計量GLp—i含量之 大鼠測定,且η表示每組之具有可計量GLP4含量之動物的 138463.doc •29· 201000126 數量。若無動物具有可計量GLP-1含量,則結果以小於6 pM列出。N.D.表示值未測定出。
138463.doc •30- 201000126 序列表 <11〇>美國禮來大藥廠 <120> 升糖素受體拮抗劑 <130> X17255 <140> 098108296 <141> 2009-03-13 <150> US 61/039,907 <151> 2008-03-27 <160> 80
<170> Patentln version 3.3 <210> 1 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列: 人源化CDRL 1 <400> 1 Ser Tyr Ser Ser Ser Val Ser Tyr Met His 1 5 10 <210〉 2 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRL l <400> 2 Ser Ala .Ser Ser Ser Val Ser Tyr Met His 1 5 10 <210> 3 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列: 人源化CDRL 1 <400> 3 Ser Ala Ser Ser Ser Val Ser Tyr lie His 138463-序列表.doc 201000126 1 5 <210> <211> 4 7 <212> <213> PRT 人工序列 <220> <223> 合成序列:人源化CDRL2 <400> 4
Thr Thr Ser Asn Leu Ala His 1 5 <210> <211> 5 7 <212> <213> PRT 人工序列 <220> <223> 合成序列:人源化CDRL2 <400> 5
Thr Thr Ser Tyr Leu Ala His 1 5 <210> <211> <212> <213> 6 9 PRT 人工序列 <220> <223> 合成序列:人源化CDRL3 <400> 6
Gin Gin Arg Ser Thr Leu Pro Pro Thr 1 5 <210> <211> <212> <213> 7 9 PRT 人工序列 <220> <223> <400> 合成序列:人源化CDRL3 7
Gin Trp Arg Ser Thr Leu Pro Pro Thr 1 5 2 13 8463-序列表.doc 201000126 <210> 8 <211> 9 <212> PRT <213> 人工序列 <220> <223> 合成序列: 人源化CDRL 3 <400> 8 Leu Gin Arg Ser Thr Leu Pro Pro Thr 1 5 * <210> 9 <211> 9 <212> PRT <213> 人工序列 <220> <223> 合成序列: 人源化CDRL 3 ❹ <400> 9 Gin Gin l Arg Ser Thr lie Pro Pro Thr 1 5 <210> 10 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列: 人源化CDRH 1 <400> 10 Gly Asp Asp lie Thr Ser Gly Tyr Trp Asn 1 5 10 <210> 11 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH 1 <400> 11
Gly Asp Asp lie Thr Ser Gly Tyr Trp Asp 1 5 10 138463-序列表.doc 201000126 <210> 12 <211> <212> <213> 10 PRT 人工序列 <220> <223> 合成序列:人源化CDRH1 <400> 12
Gly Asp Asp lie Thr Ser Gly Tyr His Asp 15 10 <210> 13 <211> <212> <213> 10 PRT 人工序列 <220> <223> 合成序列:人源化CDRH 1 <400> 13
Gly Asp Asp lie Thr Ser Gly Tyr His Glu 15 10 <210> 14 <211> <212> <213> 16 PRT 人工序列 <220> <223> 合成序列:人源化CDRH2 <400> 14
Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> <211> <212> <213> 15 16 PRT 人工序列 <220> <223> 合成序列:人源化CDRH2 <400> 15
Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys Ser 15 10 15 4- 138463·序列表.doc 201000126 <210> 16 <211> 16 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH2 <400> 16
Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr lie Pro Ser Leu Lys Ser 1 5 10 15 <210> 17 <211> 16 <212> PRT <213> 人工序列 <220>
<223> 合成序列:人琢化CDRH2 <400> 17
Tyr lie Ser Tyr Ser Gly Ser Thr Gin Tyr Ser Pro Ser Leu Lys Ser 1 5 10 15 <210> 18 <211> 16 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH2 <400> 18
Tyr lie Ser Tyr Ser Gly Ser Thr Ser Tyr Ser Pro Ser Leu Lys Ser 1 5 10 15 <210> 19 <211> 16 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH2 <400> 19
Tyr lie Ser Tyr Ser Gly Ser Thr Val Tyr Ser Pro Ser Leu Lys Ser 15 10 15 <210> 20 5- 138463·序列表.doc 201000126 <211> 14 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH3 <400> 20
Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met Asp Tyr 1 5 10 <210> 21 <211> 14 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化CDRH3 <400> 21 1 5 <210> 22 <211> 14 <212> PRT <213> 人工序列 <220> <223> 合成序列: :人源化CDRH 3 <400> 22
Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr
Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr 15 10 <210> 23 <211> 23 <212> PRT <213> 智人 <400> 23
Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser 5 10
Val 15
Asp lie Gin Met 1
Asp Arg Val Thr lie Thr Cys 20 <210> 24 138463-序列表.doc 201000126 <211> 15 <212> PRT <213> 智人 <400> 24
Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 15 10 15 <210> 25 <211> 32 <212> PRT <213> 智人 <400> 25
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15
Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 26 <211> 10 <212> PRT <213> 智人 <400> 26
Phe Gly Gly Gly Thr Lys Val Glu lie Lys 15 l〇 <210> 27 <211> 25 <212> PRT <213> 智人 <400> 27
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 20 25 <210> 28 <211> 14 <212> PRT <213> 智人 <400> 28 138463-序列表.doc 10 201000126
Trp lie 1 Arg <210> 29 <211> 32 <212> PRT <213> 智人 <400> 29 Arg Val 1 Thr Leu Ser Ser <210> 30 <211> 11 <212> PRT <213> 智人 <400> 30 Trp Gly Gin 1 <210> 31 <211> 451 <212> PRT <213> 智人 <400> 31 Gin Val Met 20 10 15 25 30 10 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys 20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala Asn 35 40 45
Thr Thr Ala Asn lie Ser Cys Pro Trp Tyr Leu Pro Trp His His Lys 50 55 60
Val Gin His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gin Trp 65 70 75 80 138463·序列表.doc 201000126
Val Arg Gly Pro Arg Gly Gin Pro Trp Arg Asp Ala Ser Gin Cys Gin 85 90 95
Met Asp Gly Glu Glu lie Glu Val Gin Lys Glu Val Ala Lys Met Tyr 100 105 110
Ser Ser Phe Gin Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly 115 120 125
Ala Leu Leu Leu Ala Leu Ala lie Leu Gly Gly Leu Ser Lys Leu His 130 135 140
Cys Thr Arg Asn Ala lie His Ala Asn Leu Phe Ala Ser Phe Val Leu 145 150 155 160
Lys Ala Ser Ser Val Leu Val lie Asp Gly Leu Leu Arg Thr Arg Tyr 165 170 175
Ser Gin Lys lie Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp 180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gin Tyr Gly 195 200 205 lie Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu His 210 215 220
Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser Leu 225 230 235 240
Tyr Leu Gly lie Gly Trp Gly Ala Pro Met Leu Phe Val Val Pro Trp 245 250 255
Ala Val Val Lys Cys Leu Phe Glu Asn Val Gin Cys Trp Thr Ser Asn 260 265 270
Asp Asn Met Gly Phe Trp Trp lie Leu Arg Phe Pro Val Phe Leu Ala 275 280 285 lie Leu lie Asn Phe Phe lie Phe Val Arg lie Val Gin Leu Leu Val 290 295 300 9- 138463-序列表.doc 201000126
Ala Lys Leu Arg Ala Arg Gin Met His His Thr Asp Tyr Lys Phe Arg 305 310 315 320
Leu Ala Lys Ser Thr Leu Thr Leu lie Pro Leu Leu Gly Val His Glu 325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gin Gly Thr Leu Arg 340 345 350
Ser Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gin Gly Leu 355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gin Ser Glu 370 375 380
Leu Arg Arg Arg Trp His Arg Trp Arg Leu Gly Lys Val Leu Trp Glu 385 390 395 400
Glu Arg Asn Thr Ser Asn His Arg Ala Ser Ser Ser Pro Gly His Gly 405 410 415
Pro Pro Ser Lys Glu Leu Gin Phe Gly Arg Gly Gly Gly Ser Gin Asp 420 425 430
Ser Ser Ala Glu Thr Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala Glu 435 440 445
Ser Pro Phe 450 0 12 3 1111 2 2 2 2 V < < < 32 2034
DNA 智人 <400> 32 ggatctggca gcgccgcgaa gacgagcggt caccggcgcc cgacccgagc gcgcccagag 60 gacggcgggg agccaagccg acccccgagc agcgccgcgc gggccctgag gctcaaaggg 120 gcagcttcag gggaggacac cccactggcc aggacgcccc aggctctgct gctctgccac 180 tcagctgccc tcggaggagc gtacacacac accaggactg cattgcccca gtgtgcagcc 240 cctgccagat gtgggaggca gctagctgcc cagaggcatg cccccctgcc agccacagcg 300 acccctgctg ctgttgctgc tgctgctggc ctgccagcca caggtcccct ccgctcaggt 360 10· 138463-序列表.doc 201000126
gatggacttc ctgtttgaga agtggaagct ctacggtgac cagtgtcacc acaacctgag 420 cctgctgccc cctcccacgg agctggtgtg caacagaacc ttcgacaagt attcctgctg 480 gccggacacc cccgccaata ccacggccaa catctcctgc ccctggtacc tgccttggca 540 ccacaaagtg caacaccgct tcgtgttcaa gagatgcggg cccgacggtc agtgggtgcg 600 tggaccccgg gggcagcctt ggcgtgatgc ctcccagtgc cagatggatg gcgaggagat 660 tgaggtccag aaggaggtgg ccaagatgta cagcagcttc caggtgatgt acacagtggg 720 ctacagcctg tccctggggg ccctgctcct cgccttggcc atcctggggg gcctcagcaa 780 gctgcactgc acccgcaatg ccatccacgc gaatctgttt gcgtccttcg tgctgaaagc 840 cagctccgtg ctggtcattg atgggctgct caggacccgc tacagccaga aaattggcga 900 cgacctcagt gtcagcacct ggctcagtga tggagcggtg gctggctgcc gtgtggccgc 960 ggtgttcatg caatatggca tcgtggccaa ctactgctgg ctgctggtgg agggcctgta 1020 cctgcacaac ctgctgggcc tggccaccct ccccgagagg agcttcttca gcctctacct 1080 gggcatcggc tggggtgccc ccatgctgtt cgtcgtcccc tgggcagtgg tcaagtgtct 1140 gttcgagaac gtccagtgct ggaccagcaa tgacaacatg ggcttctggt ggatcctgcg 1200 gttccccgtc ttcctggcca tcctgatcaa cttcttcatc ttcgtccgca tcgttcagct 1260 gctcgtggcc aagctgcggg cacggcagat gcaccacaca gactacaagt tccggctggc 1320 caagtccacg ctgaccctca tccctctgct gggcgtccac gaagtggtct ttgccttcgt 1380 gacggacgag cacgcccagg gcaccctgcg ctccgccaag ctcttcttcg acctcttcct 1440 cagctccttc cagggcctgc tggtggctgt cctctactgc ttcctcaaca aggaggtgca 1500 gtcggagctg cggcggcgtt ggcaccgctg gcgcctgggc aaagtgctat gggaggagcg 1560 gaacaccagc aaccacaggg cctcatcttc gcccggccac ggccctccca gcaaggagct 1620 gcagtttggg aggggtggtg gcagccagga ttcatctgcg gagaccccct tggctggtgg 1680 cctccctaga ttggctgaga gccccttctg aaccctgctg ggaccccagc tagggctgga 1740 ctctggcacc cagaggcgtc gctggacaac ccagaactgg acgcccagct gaggctgggg 1800 gcgggggagc caacagcagc ccccacctac cccccacccc cagtgtggct gtctgcgaga 1860 ttgggcctcc tctccctgca cctgccttgt ccctggtgca gaggtgagca gaggagtcca 1920 gggcgggagt gggggctgtg ccgtgaactg cgtgccagtg tccccacgta tgtcggcacg 1980 tcccatgtgc atggaaatgt cctccaacaa taaagagctc aagtggtcac cgtg 2034 138463·序列表.doc .11 - 201000126 <210> 33 <211> 458 <212> PRT <213> 氱屬 <400> 33
Gin Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Ser Asp Gin 1 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys 20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Pro Asn 35 40 45
Thr Thr Ala Asn lie Ser Cys Pro Trp Tyr Leu Pro Trp Tyr His Lys 50 55 60
Val Gin His Arg Leu Val Phe Lys Arg Cys Gly Pro Asp Gly Gin Trp 65 70 75 80
Val Arg Gly Pro Arg Gly Gin Ser Trp Arg Asp Ala Ser Gin Cys Gin 85 90 95
Met Asp Asp Asp Glu lie Glu Val Gin Lys Gly Val Ala Lys Met Tyr 100 105 110
Ser Ser Tyr Gin Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly 115 120 125
Ala Leu Leu Leu Ala Leu Val lie Leu Leu Gly Leu Arg Lys Leu His 130 135 140
Cys Thr Arg Asn Tyr lie His Gly Asn Leu Phe Ala Ser Phe Val Leu 145 150 155 160
Lys Ala Gly Ser Val Leu Val lie Asp Trp Leu Leu Lys Thr Arg Tyr 165 170 175
Ser Gin Lys lie Gly Asp Asp Leu Ser Val Ser Val Trp Leu Ser Asp 180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Thr Val 工le Met Gin Tyr Gly 12· 138463-序列表.doc 201000126 195 200 205 lie lie Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Val Tyr Leu Tyr 210 215 220
Ser Leu Leu Ser lie Thr Thr Phe Ser Glu Lys Ser Phe Phe Ser Leu 225 230 235 240
Tyr Leu Cys lie Gly Trp Gly Ser Pro Leu Leu Phe Val lie Pro Trp 245 250 255
Val Val Val Lys Cys Leu Phe Glu Asn Val Gin Cys Trp Thr Ser Asn 260 265 270
Asp Asn Met Gly Phe Trp Trp lie Leu Arg lie Pro Val Leu Leu Ala 275 280 285 m
He Leu lie Asn Phe Phe lie Phe Val Arg lie lie His Leu Leu Val 290 295 300
Ala Lys Leu Arg Ala His Gin Met His Tyr Ala Asp Tyr Lys Phe Arg 305 310 315 320
Leu Ala Arg Ser Thr Leu Thr Leu lie Pro Leu Leu Gly Val His Glu 325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gin Gly Thr Leu Arg 340 345 350
Ser Thr Lys Leu Phe Phe Asp Leu Phe Phe Ser Ser Phe Gin Gly Leu 355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gin Ala Glu 370 375 380
Leu Leu Arg Arg Trp Arg Arg Trp Gin Glu Gly Lys Ala Leu Gin Glu 385 390 395 400
Glu Arg Met Ala Ser Ser His Gly Ser His Met Ala Pro Ala Gly Thr 405 410 415
Cys His Gly Asp Pro Cys Glu Lys Leu Gin Leu Met Ser Ala Gly Ser 420 425 430 -13- 138463-序列表.doc 201000126
Ser Ser Gly Thr Gly Cys Glu 435
Pro Ser Ala 440
Lys Thr Ser Leu Ala Ser 445
Ser Leu 450
Pro Arg Leu Ala Asp Ser Pro Thr 455 <210> 34 <211> 1875 <212> DNA <213> 鼠屬 <400> 34 gaattcgcgg ccgccgccgg gccccagatc ccagtgcgcg aggagcccag tcctagaccc 60 agcaacctga ggagaggtgc acacaccccc aaggacccag gcacccaacc tctgccagat 120 gtgggggggt ggctacccag aggcatgctc ctcacccagc tccactgtcc ctacctgctg 180 ctgctgctgg tggtgctgtc atgtctgcca aaggcaccct ctgcccaggt aatggacttt 240 ttgtttgaga agtggaagct ctatagtgac cagtgccacc acaacctaag cctgctgccc 300 ccacctactg agctggtctg caacagaact ttcgacaagt actcctgctg gcctgacacc 360 cctcccaaca ccactgccaa catttcctgc ccctggtacc taccttggta ccacaaagtg 420 cagcaccgcc tagtgttcaa gaggtgtggg cctgatgggc agtgggttcg agggccacgg 480 gggcagtcat ggcgcgacgc ctcccaatgt cagatggatg atgacgagat cgaggtccag 540 aagggggtag ccaagatgta tagcagctac caggtgatgt acactgtggg ctacagtctg 600 tccctggggg ccttgctcct ggcgctggtc atcctgctgg gcctcaggaa gctgcactgc 660 acccggaact acatccacgg gaacctgttc gcgtccttcg tgctcaaggc tggctctgtg 720 ctggtcattg attggctgct caagacacgc tatagccaga agattggaga tgacctcagt 780 gtgagcgtct ggctcagtga tggggcggtg gctggctgca gagtggccac agtgatcatg 840 cagtacggca tcatagccaa ctactgctgg ttgctggtgg agggtgtgta cctgtacagc 900 ctgctgagca tcaccacctt ctcggagaag agcttcttct ccctctatct gtgcatcggc 960 tggggatctc ccctgctgtt tgtcatcccc tgggtggtgg tcaagtgtct gtttgagaat 1020 gtccagtgct ggaccagcaa tgacaatatg ggattctggt ggatcctgcg tatccctgta 1080 ctcctggcca tactgatcaa ttttttcatc tttgtccgca tcattcatct tcttgtggcc 1140 aagctgcgtg cccatcagat gcactatgct gattacaagt tccggctagc caggtccacg 1200 ctgaccctca ttcctctgct gggagtccac gaagtggtct ttgcctttgt gactgatgag 1260 -14· 138463-序列表.doc 1320 201000126 catgcccagg gcaccctgcg ctccaccaag ctcttttttg acctgttctt cagctccttt cagggtctgc tggtggctgt tctctactgt ttcctcaaca aggaggtgca ggcagagcta ctgcggcgtt ggaggcgatg gcaagaaggc aaagctcttc aggaggaaag gatggccagc agccatggca gccacatggc cccagcaggg acttgtcatg gtgatccctg tgagaaactt cagcttatga gtgcaggcag cagcagtggg actggctgtg agccctctgc gaagacctca ttggccagta gtctcccaag gctggctgac agccccacct gaatctccac tggactccag ccaagttgga ttcagaaagg gcctcacaag acaacccaga aacagatgcc tggccaaggc tgaagaggca aagcagcaag acagcagctt gtactatcca cactccccta acctgtcctg • gccgggtaca ggccacattg atggagtagg ggctggatat gatggagtag ccatgctatg aactatgggt gttcccatga gtgttgccat gttccatgca cacagatatg accttcagta aagagctccc gtagg ❹ <210> 35 <211> 458 <212> PRT <213> 小鼠屬 <400> 35
Gin Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Ser Asp Gin 15 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys 20 25 30
Asn Arg Thr Phe Asp Asn Tyr Ser Cys Trp Pro Asp Thr Pro Pro Asn 35 40 45
Thr Thr Ala Asn lie Ser Cys Pro Trp Tyr Leu Pro Trp Cys His Lys 50 55 60
Val Gin His Arg Leu Val Phe Lys Arg Cys Gly Pro Asp Gly Gin Trp 65 70 75 80
Val Arg Gly Pro Arg Gly Gin Pro Trp Arg Asn Ala Ser Gin Cys Gin 85 90 95
Leu Asp Asp Glu Glu lie Glu Val Gin Lys Gly Val Ala Lys Met Tyr 100 105 110 -15- 1380 1440 1500 1560 1620 1680 1740 1800 1860 1875 138463-序列表.doc 201000126
Ser Ser Gin Gin Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly 115 120 125
Ala Leu Leu Leu Ala Leu Val lie Leu Leu Gly Leu Arg Lys Leu His 130 135 140
Cys Thr Arg Asn Tyr lie His Gly Asn Leu Phe Ala Ser Phe Val Leu 145 150 155 160
Lys Ala Gly Ser Val Leu Val lie Asp Trp Leu Leu Lys Thr Arg Tyr 165 170 175
Ser Gin Lys lie Gly Asp Asp Leu Ser Val Ser Val Trp Leu Ser Asp 180 185 190
Gly Ala Met Ala Gly Cys Arg Val Ala Thr Val lie Met Gin Tyr Gly 195 200 205 lie lie Pro Asn Tyr Cys Trp Leu Leu Val Glu Gly Val Tyr Leu Tyr 210 215 220
Ser Leu Leu Ser Leu Ala Thr Phe Ser Glu Arg Ser Phe Phe Ser Leu 225 230 235 240
Tyr Leu Gly lie Gly Trp Gly Ala Pro Leu Leu Phe Val lie Pro Trp 245 250 255
Val Val Val Lys Cys Leu Phe Glu Asn Val Gin Cys Trp Thr Ser Asn 260 265 270
Asp Asn Met Gly Phe Trp Trp lie Leu Arg lie Pro Val Phe Leu Ala 275 280 285
Leu Leu lie Asn Phe Phe lie Phe Val His lie lie Gin Leu Leu Val 290 295 300
Ala Lys Leu Arg Ala His Gin Met His Tyr Ala Asp Tyr Lys Phe Arg 305 310 315 320
Leu Ala Arg Ser Thr Leu Thr Leu lie Pro Leu Leu Gly Val His Glu 325 330 335 •16· 138463-序列表.doc 201000126
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gin Gly Thr Leu Arg 340 345 350
Ser Thr Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gin Gly Leu 355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gin Ala Glu 370 375 380
Leu Met Arg Arg Trp Arg Gin Trp Gin Glu Gly Lys Ala Leu Gin Glu 385 390 395 400
Glu Arg Leu Ala Ser Ser His Gly Ser His Met Ala Pro Ala Gly Pro 405 410 415
Cys His Gly Asp Pro Cys Glu Lys Leu Gin Leu Met Ser Ala Gly Ser 420 425 430
Ser Ser Gly Thr Gly Cys Val Pro Ser Met Glu Thr Ser Leu Ala Ser 435 440 445
Ser Leu Pro Arg Leu Ala Asp Ser Pro Thr 450 455 <210> 36 <211> 1944 <212> DNA <213> 小鼠屬 <400> 36 60 120 180 240 300 360 420 480 540 cagggtctcc cttgcaacct gaggagaggt gcacacactc tgaggaccta ggtgtgcaac ctctgccaga tgtggggcgt ggctacccag aggcatgccc ctcacccagc tccactgtcc ccacctgctg ctgctgctgt tggtgctgtc atgtctgcca gaggcaccct ctgcccaggt aatggacttt ttgtttgaga agtggaagct ctatagtgac caatgtcacc acaacctaag cctgctgccc ccacctactg agctggtctg taacagaacc ttcgacaact actcctgctg gcctgacacc cctcccaaca ccactgccaa catttcctgc ccctggtacc taccttggtg ccacaaagtg cagcaccgcc tagtgttcaa gaggtgtggg cccgatgggc agtgggttcg agggccacgg gggcagccgt ggcgcaacgc ctcccaatgt cagttggatg atgaagagat cgaggtccag aagggggtgg ccaagatgta tagcagccag caggtgatgt acaccgtggg -17· 138463·序列表.doc 201000126 ctacagtctg tccctggggg ccttgctcct tgcgctggtc atcctgctgg gcctcaggaa 600 gctgcactgc acccgaaact acatccatgg gaacctgttt gcgtcctttg tgctcaaggc 660 tggctctgtg ttggtcatcg attggctgct gaagacacgg tacagccaga agattggcga 720 tgacctcagt gtgagcgtct ggctcagtga cggggcgatg gccggctgca gagtggccac 780 agtgatcatg cagtacggca tcatacccaa ctattgctgg ttgctggtag agggcgtgta 840 cctgtacagc ctgctgagcc ttgccacctt ctctgagagg agcttctttt ccctctacct 900 gggcattggc tggggtgcgc ccctgctgtt tgtcatcccc tgggtggtgg tcaagtgtct 960 gtttgagaat gttcagtgct ggaccagcaa tgacaacatg ggattctggt ggatcctgcg 1020 tattcctgtc ttcctggcct tactgatcaa ttttttcatc tttgtccaca tcattcaact 1080 tcttgtggcc aagctgcgtg cccatcagat gcactatgct gattacaagt tccggctggc 1140 caggtccacg ctgaccctca tccctctgct gggggtccac gaggtggtct ttgcctttgt 1200 gactgacgag catgcccaag gcaccctgcg ctccaccaag ctcttttttg acctgttcct 1260 cagctccttc cagggtctgc tggtggctgt tctctactgt ttcctcaaca aggaggtgca 1320 ggcagagctg atgcggcgtt ggaggcaatg gcaagaaggc aaagctcttc aggaggaaag 1380 gttggccagc agccatggca gccacatggc cccagcaggg ccttgtcatg gtgatccctg 1440 tgagaaactt cagcttatga gtgcaggcag cagcagtggg actggctgtg tgccctctat 1500 ggagacctcg ctggccagta gtctcccaag gttggctgac agccccacct gaatctccac 1560 ttggagccta ggcaggttgt gttcaagaaa gggcctcaga ggacaaccca gagccagatg 1620 cccggccaag gttgaagagc caaagcagca agacagcagc ttgtactgtg cacactcccc 1680 taacctgtcc tagcctggca caggccacag tgacagagta ggggttggat atgatggaga 1740 agccatgtta tctatgaact ctgagtgttc ccatgtgtgt tgacatggtc cctgtaccca 1800 gatatgtcct tcagtaaaaa gctcgagtgg agctgctgca cagctcgtgg acagcaggct 1860 tgaagccccc agggacgggg tttgggaggc cggggatgag cagcacactc agcaggtgga 1920 gcgctagtgc aacccaggaa agaa 1944 <210> 37 <211> 451 <212> PRT <213> 食蟹猴 <400> 37
Gin Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp Gin 18- 138463·序列表.doc 201000126 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys 20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala Asn 35 40 45
Thr Thr Ala Asn lie Ser Cys Pro Trp Tyr Leu Pro Trp His His Lys 50 55 60
Val Gin His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gin Trp 65 70 75 80
Val Arg Gly Pro Arg Gly Gin Pro Trp Arg Asp Ala Ser Gin Cys Gin 85 90 95 0
Met Asp Gly Glu Glu Leu Glu Val Gin Lys Glu Val Ala Lys Met Tyr 100 105 110
Ser Ser Phe Gin Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly 115 120 125
Ala Leu Leu Leu Ala Leu Ala Val Leu Gly Gly lie Ser Lys Leu His 130 135 140
Cys Thr Arg Asn Ala lie His Ala Asn Leu Phe Val Ser Phe Val Leu 145 150 155 160
Lys Ala Ser Ser Val Leu Val lie Asp Gly Leu Leu Arg Thr Arg Tyr 165 170 175 參
Ser Gin Lys lie Gly Asp Asp Leu Ser Val Ser lie Trp Leu Ser Asp 180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gin Tyr Gly 195 200 205
Val Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu His 210 215 220
Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser Leu 225 230 235 240 19- 138463-序列表.doc 201000126
Tyr Leu Gly lie Gly Trp Gly Ala Pro Met Leu Phe lie lie Pro Trp 245 250 255
Val Val Val Arg Cys Leu Phe Glu Asn lie Gin Cys Trp Thr Ser Asn 260 265 270
Asp Asn Met Gly Phe Trp Trp lie Leu Arg Phe Pro Val Phe Leu Ala 275 280 285 lie Leu lie Asn Phe Phe lie Phe lie Arg lie Val His Leu Leu Val 290 295 300
Ala Lys Leu Arg Ala Arg Glu Met His His Thr Asp Tyr Lys Phe Arg 305 310 315 320
Leu Ala Lys Ser Thr Leu Thr Leu lie Pro Leu Leu Gly Val His Glu 325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gin Gly Thr Leu Arg 340 345 350
Phe Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gin Gly Leu 355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gin Ser Glu 370 375 380
Leu Arg Arg His Trp His Arg Trp Arg Leu Gly Lys Val Leu Gin Glu 385 390 395 400
Glu Arg Gly Thr Ser Asn His Lys Ala Pro Ser Ala Pro Gly Gin Gly 405 410 415
Leu Pro Gly Lys Lys Leu Gin Ser Gly Arg Asp Gly Gly Ser Gin Asp 420 425 430
Ser Ser Ala Glu lie Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala Glu 435 440 445
Ser Pro Phe 450 -20- 138463-序列表.doc 60 60
201000126 <210> 38 <211> 1434 <212> DNA <213> 食蟹猴 <400> 38 atgccgccgt gccagccgcg ccgcccgctg ctgctgctgc tgctgctgct ggcgtgccag ccgcaggcgc cgagcgcgca ggtgatggat tttctgtttg aaaaatggaa actgtatggc gatcagtgcc atcataacct gagcctgctg ccgccgccga ccgaactggt gtgcaaccgc acctttgata aatatagctg ctggccggat accccggcga acaccaccgc gaacattagc tgcccgtggt atctgccgtg gcatcataaa gtgcagcatc gctttgtgtt taaacgctgc ggcccggatg gccagtgggt gcgcggcccg cgcggccagc cgtggcgcga tgcgagccag tgccagatgg atggcgaaga actggaagtg cagaaagaag tggcgaaaat gtatagcagc tttcaggtga tgtataccgt gggctatagc ctgagcctgg gcgcgctgct gctggcgctg gcggtgctgg gcggcattag caaactgcat tgcacccgca acgcgattca tgcgaacctg tttgtgagct ttgtgctgaa agcgagcagc gtgctggtga ttgatggcct gctgcgcacc cgctatagcc agaaaattgg cgatgatctg agcgtgagca tttggctgag cgatggcgcg gtggcgggct gccgcgtggc ggcggtgttt atgcagtatg gcgtggtggc gaactattgc tggctgctgg tggaaggcct gtatctgcat aacctgctgg gcctggcgac cctgccggaa cgcagctttt ttagcctgta tctgggcatt ggctggggcg cgccgatgct gtttattatt ccgtgggtgg tggtgcgctg cctgtttgaa aacattcagt gctggaccag caacgataac atgggctttt ggtggattct gcgctttccg gtgtttctgg cgattctgat taactttttt atttttattc gcattgtgca tctgctggtg gcgaaactgc gcgcgcgcga aatgcatcat accgattata aatttcgcct ggcgaaaagc accctgaccc tgattccgct gctgggcgtg catgaagtgg tgtttgcgtt tgtgaccgat gaacatgcgc agggcaccct gcgctttgcg aaactgtttt ttgatctgtt tctgagcagc tttcagggcc tgctggtggc ggtgctgtat tgctttctga acaaagaagt gcagagcgaa ctgcgccgcc attggcatcg ctggcgcctg ggcaaagtgc tgcaggaaga acgcggcacc agcaaccata aagcgccgag cgcgccgggc cagggcctgc cgggcaaaaa actgcagagc ggccgcgatg gcggcagcca ggatagcagc gcggaaattc cgctggcggg cggcctgccg cgcctggcgg aaagcccgtt ttaa <210> 39 138463-序列表.doc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1434 •21 · 201000126 <211> 106 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變輕鏈 <400> 39
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 Ser Ser Val Ser Tyr Met 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Trp Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 40 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <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 Thr Val Ser Gly Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45 •22- 138463-序列表.doc 201000126
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 41
<211> 106 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變輕鏈 <400> 41
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 Tyr Ser Ser Ser Val Ser Tyr Met 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys 23- 138463-序列表.doc 201000126 100 105 <210> 42 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <400> 42
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asn Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr lie 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 43 <211> 106 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變輕鏈 <400> 43
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 24- 13 8463-序列表.doc 201000126
Asp Arg Val Thr lie Thr Cys Ser Ala Sar Ser Ser Val Ser Tyr lie 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 BO
Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 44 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <400> 44
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 25- 138463-序列表.doc 201000126 85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Set 115 120 <210> 45 <211> 106 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源>{匕可變輕鏈 <400> 45 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 Ser Ser Val Ser Tyr lie 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 7 0 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 46 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 26- 138463·序列表.doc 201000126 <400> 46
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 Asp Asp He Thr Ser Gly 20 25 30
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 47 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <400> 47
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Gin Tyr Ser Pro Ser Leu Lys 27- 138463-序列表.doc 201000126 50 55 60
Ser Arg Val Thr lie Ser Val Asp 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 Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 48 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <400> 48
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr 工le Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110 -28- 138463·序列表.doc 201000126
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 49 <211> 122 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化可變重鏈 <400> 49
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr His Glu Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Ser Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 50 <211> 107 <212> PRT <213> 智人 <400> 50 -
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 15 10 15 •29· 138463·序列表.doc 201000126
Gin Leu Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30
Tyr Pro Arg 35
Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 40 45
Ser Gly Asn 50
Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 55 60
Thr Tyr Ser 65
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 70 75 80
Lys His Lys
Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95
Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 51 <211> 98 <212> PRT <213> 智人 <400> 51 Ala Ser Thr 1
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 5 10 15
Ser Thr Ser
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30
Phe Pro Glu 35
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 40 45
Gly Val His 50
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 55 60
Leu Ser Ser 65
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 70 75 80
Tyr Thr Cys
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95
Arg Val 138463·序列表.doc -30- 201000126 <210> 52 <211> 229 <212> PRT <213> 人工序列 <220> <223> 合成序列:經修飾人類IgG4 Fc序列 > > > > 0 12 3 2 2 2 2 2 2 2 2 VARIANT (10)..(10) Xaa 為 Ser 或 Pro <220> <221> VARIANT <222> (15)..(15) <223> Xaa 為 Pro 或 Glu ο >>>> >>>> 0 12 3 0 12 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 <<<< <<<< VARIANT (16)..(16) Xaa 為 Ala 或 Val 或 Phe VARIANT (17)..(17) Xaa 為 Ala 或 Glu 或 Leu <220> <221> VARIANT <222> (79)..(79) <223> Xaa 為 Ala 或 Asn <220> <221> VARIANT <222> (229)..(229) <223> Xaa為Lys或去除 <400> 52 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Xaa Cys Pro Ala Pro Xaa Xaa 15 10 15
Xaa Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 20 25 30
Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 35 40 45
Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val 50 55 60 138463-序列表.doc .31 201000126
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Xaa 65 70 75
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp 85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 100 105 110
Ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu 115 120 125
Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn 130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 145 150 155
Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 180 185 190
Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys 195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 210 215 220
Ser 80 Leu Ser Pro Gin Ala 160 Thr Leu Ser Ser
Leu Ser Leu Gly Xaa 225 <210> 53 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列:輕鏈CDRl <220> <221> VARIANT <222> (2)..(2) <223> Xaa 為 Tyr 或 Ala 138463-序列表.doc •32· 201000126 <220> <221> VARIANT <222> (9) - - (9) <223> Xaa 為 Met 或 lie <400> 53
Ser Xaa Ser Ser Ser Val Ser Tyr Xaa His 15 10 <210> 54 <211> 7 <212> PRT <213> 人工序列 <220> <223> 合成序列:輕鏈CDR2 <220>
<221> VARIANT <222> (4)..(4) <223> Xaa 為 Asn 或 Tyr <400> 54
Thr Thr Ser Xaa Leu Ala His 1 5 <210> 55 <211> 9 <212> PRT <213> 人工序列 <220> <223> 合成序列: :輕鏈CDR3 <220> <221> VARIANT <222> ⑴··(1) <223> Xaa 為 Gin 或 Leu <220> <221> VARIANT <222> (2)..(2) <223> Xaa 為 Gin 或 Trp <220> <221> VARIANT <222> (6) . . (6) <223> Xaa 為 Leu 或 lie <400> 55 -33- 138463-序列表.doc 201000126
Xaa Xaa Arg Ser Thr Xaa Pro Pro Thr 1 5 <210> 56 <211> 10 <212> PRT <213> 人工序列 <220> <223> 合成序列:重鏈CDR1 <220> <221> VARIANT <222> (9)..(9) <223> Xaa 為 Tip 或 His <220>
<221> VARIANT <222> (10)..(10) <223> Xaa 為 Asn、Asp 或 Glu <400> 56
Gly Asp Asp lie Thr Ser Gly Tyr Xaa Xaa 15 10 <210> 57 <211> 16 <212> PRT <213> 人工序列 <220> <223> 合成序列:重鏈CDR2 <220> <221> VARIANT <222> (9)..(9) <223> Xaa 為 Tyr、Gin、Ser 或 Val <220> <221> VARIANT <222> (11)·.(11) <223> Xaa 為 Asn、Ser 或 lie <400> 57
Tyr lie Ser Tyr Ser Gly Ser Thr Xaa Tyr Xaa Pro Ser Leu Lys Ser 15 10 15 <210> 58 <211> 14 34- 138463-序列表.doc 201000126 <212> PRT <213> 人工序列 <220> <223> 合成序列:重鏈CDR3 <220> <221> VARIANT <222> (3)..(3) <223> Xaa 為 Gly 或 Ala <220> <221> VARIANT <222> (12)..(12) <223> Xaa 為 Met 或 Leu <400> 58
Pro Pro Xaa Tyr Tyr Gly Phe Gly Pro Tyr Ala Xaa Asp Tyr 15 10
<210> 59 <211> 213 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體輕鏈 <400> 59
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 Ser Ser Val Ser Tyr Met 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Trp Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro •35· 138463·序列表.doc 201000126 100 105 110
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205
Asn Arg Gly Glu Cys 210 <210> 60 <211> 448 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體重鏈 <400> 60
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asp Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys 50 55 60 36· 138463-序列表.doc 201000126
Ser Arg Val Thr lie Ser Val Asp 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 Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu 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 Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 37· 138463-序列表.doc 201000126 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 61 <211> 213 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體輕鏈 <400> 61
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 Tyr Ser Ser Ser Val Ser Tyr Met 20 25 30 •38 138463·序列表.doc 201000126
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu 工le Lys Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 ❿
Asn Arg Gly Glu Cys 210 <210> 62 <211> 448 <212> PRT <213> 人工序列 <220> <223>合成序列:人源化單株抗體重鏈 <400> 62 -39- 138463-序列表.d〇c 201000126
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asn Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr lie 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met 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 Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 -40- 138463-序列表.doc 201000126
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp * 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 ❹
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 63 -41 - 138463-序列表.doc 201000126 <211> 213 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗逋輕鏈 <400> 63
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 Ser Ser Val Ser Tyr lie 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys '130 135 140
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 -42· 13 8463-序列表.doc 201000126
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205
Asn Arg Gly Glu Cys 210 <210> 64 <211> 448 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體重鏈 <400> 64
Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15 ❹
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp lie Thr Ser Gly 20 25 30
Tyr Trp Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys 50 55 60
Ser Arg Val Thr 65 lie Ser Val Asp Thr Ser 70
Lys Asn Gin Phe Ser Leu 75 80
Lys Leu Ser Ser
Val Thr Ala Ala Asp Thr 85 90
Ala Val Tyr Tyr Cys Ala 95
Arg Pro Pro Gly❹ 100 Gly Gin Gly Thr 115
Tyr Tyr Gly Phe Gly Pro 105
Leu Val Thr Val Ser Ser 120
Tyr Ala Leu Asp Tyr Trp 110
Ala Ser Thr Lys Gly Pro 125
Ser Val Phe Pro 130
Leu Ala Pro Cys Ser Arg 135
Ser Thr Ser Glu Ser Thr 140
Ala Ala Leu Gly 145
Cys Leu Val Lys Asp Tyr 150
Phe Pro Glu Pro Val Thr 155 160 -43 - 138463-序列表.doc 201000126
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380 • 44· 138463-序列表.doc 201000126
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 65 <211> 213 <212> PRT <213〉 人工序列
<220> <223> 合成序列:人源化單株抗體輕鏈 <400> 65
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 Ser Ser Val Ser Tyr lie 20 25 30
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro Glu 65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Arg Ser Thr Leu Pro Pro Thr 85 90 95
Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro 100 105 110
Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125 45- 13 8463-序列表.doc 201000126
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140
Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160
Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190
Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205
Asn Arg Gly Glu Cys 210 <210> 66 <211> 448 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體重鏈 <400> 66
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 Asp Asp lie Thr Sar Gly 20 25 30
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 • 46· 138463-序列表.doc 201000126
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp 100 105 110
Gly Gin Gly Thr Leu Val Thr Val 115 120
Ser Ser Ala Ser Thr Lys Gly Pro 125
Ser Val 130
Phe Pro Leu Ala Pro Cys 135
Ser Arg Ser Thr Ser Glu Ser Thr 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 . 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 47- 138463·序列表.doc 201000126
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr 工le Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 67 <211> 448 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體重鏈 <400> 67
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Gin Tyr Ser Pro Ser Leu Lys 50 55 60 48- 13 8463-序列表.d0c 201000126
Ser Arg Val Thr lie Ser Val Asp 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 Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu 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 Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
W
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 -49- 138463-序列表 _doc 201000126
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn 385 390
Tyr Lys Thr Thr Pro Pro Val Leu 395 400
Asp Ser Asp Gly Ser Phe Phe Leu 405
Tyr Ser Arg Leu Thr Val Asp Lys 410 415
Ser Arg Trp Gin Glu Gly Asn Val 420
Phe Ser Cys Ser Val Met His Glu 425 430
Ala Leu His Asn His Tyr Thr Gin 435 440
Lys Ser Leu Ser Leu Ser Leu Gly 445 <210> 68 <211> 448 <212> PRT <213> 人工序列 <220> <22;3> 合成序列:人源化單株抗體重鏈 <400> 68
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 Asp Asp lie Thr Ser Gly 20 25 30 •50· 13 8463·序列表.doc 201000126
Tyr His Asp Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr He Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu 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 ❹
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255 -51 - 138463-序列表.doc 201000126
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 69 <211> 448 <212> PRT <213> 人工序列 <220> <223> 合成序列:人源化單株抗體重鏈 •52· 138463-序列表.doc 201000126 <400> 69
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 Asp Asp lie Thr Ser Gly 20 25 30
Tyr His Glu Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45
Gly Tyr lie Ser Tyr Ser Gly Ser Thr Ser Tyr Ser 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
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu 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 Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175
Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 53· 138463-序列表.doc 201000126
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp 260 265 270
Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350
Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 • 54- 13 8463-序列表.doc 201000126 <210> 70 <211> 639 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQIDNO:59之人源化單株抗體輕鏈之DNA序列 <400> 70 gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60 attacctgca gcgcgagcag cagcgtgagc tatatgcatt ggtatcagca gaaaccgggc 120 aaagcgccga aactgctgat ttataccacc agcaacctgg cgcatggcgt gccgagccgc 180 tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240 gattttgcga cctattattg ccagtggcgc agcaccctgc cgccgacctt tggcggcggc 300 accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360 gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420 cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480 agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540 agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600 agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639 ❹ <210> 71 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQIDNO:60之人源化單株抗體重鏈之DNA序列
<400> 71 caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60 acctgcaccg tgagcggcga tgatattacc agcggctatt gggattggat tcgccagccg 120 ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180 ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240 aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300 tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360 agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420 55- 138463·序列表.doc 201000126 agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480 gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540 agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600 aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660 gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720 agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780 gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840 gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900 acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960 tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020 gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080 accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140 gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200 gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260 gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320 aaaagcctga gcctgagcct gggc 1344 <210> 72 <211> 639 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQ Π)NO: 61之人源化單株抗體輕鏈之DNA序列 <400> 72 gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60 attacctgca gctatagcag cagcgtgagc tatatgcatt ggtatcagca gaaaccgggc 120 aaagcgccga aactgctgat ttataccacc agcaacctgg cgcatggcgt gccgagccgc 180 tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240 gattttgcga cctattattg ccagcagcgc agcaccctgc cgccgacctt tggcggcggc 300 accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360 gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420 56· 13 8463-序列表.doc 201000126 cgcgaagcga agcgtgaccg agcaaagcgg agcagcccgg aagtgcagtg aacaggatag attatgaaaa tgaccaaaag gaaagtggat caaagatagc acataaagtg ctttaaccgc aacgcgctgc acctatagcc tatgcgtgcg ggcgaatgc agagcggcaa tgagcagcac aagtgaccca cagccaggaa cctgaccctg tcagggcctg 480 540 600 639 <210> 73 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQ ID NO: 62之人源化單株抗體重鏈之DNA序列
<400> 73 caggtgcagc acctgcaccg ccgggcaaag ccgagcctga aaactgagca tattatggct agcagcgcga agcgaaagca gtgagctgga agcagcggcc aaaacctata gaaagcaaat agcgtgtttc gtgacctgcg gtggatggcg acctatcgcg tataaatgca gcgaaaggcc accaaaaacc tgcaggaaag tgagcggcga gcctggaatg aaagccgcgt gcgtgaccgc ttggcccgta gcaccaaagg ccgcggcgct acagcggcgc tgtatagcct cctgcaacgt atggcccgcc tgtttccgcc tggtggtgga tggaagtgca tggtgagcgt aagtgagcaa agccgcgcga aggtgagcct cggcccgggc tgatattacc gattggctat gaccattagc ggcggatacc tgcgatggat cccgagcgtg gggctgcctg gctgaccagc gagcagcgtg ggatcataaa gtgcccgccg gaaaccgaaa tgtgagccag taacgcgaaa gctgaccgtg caaaggcctg accgcaggtg gacctgcctg ctggtgaaac agcggctatt attagctata gtggatacca gcggtgtatt tattggggcc tttccgctgg gtgaaagatt ggcgtgcata gtgaccgtgc ccgagcaaca tgcccggcgc gataccctga gaagatccgg accaaaccgc ctgcatcagg ccgagcagca tataccctgc gtgaaaggct cgagcgaaac ggaactggat gcggcagcac gcaaaaacca attgcgcgcg agggcaccct cgccgtgcag attttccgga cctttccggc cgagcagcag ccaaagtgga cggaagcggc tgattagccg aagtgcagtt gcgaagaaca attggctgaa ttgaaaaaac cgccgagcca tttatccgag cctgagcctg tcgccagccg ctattatatt gtttagcctg cccgccgggc ggtgaccgtg ccgcagcacc accggtgacc ggtgctgcag cctgggcacc taaacgcgtg gggcggcccg caccccggaa taactggtat gtttaacagc cggcaaagaa cattagcaaa ggaagaaatg cgatattgcg 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 57- 138463·序列表.doc 201000126 gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200 gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260 gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320 aaaagcctga gcctgagcct gggc 1344 <210> 74 <211> 639 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQIDNO:63之人源化單株抗體輕鏈之DNA序列 <400> 74 gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60 attacctgca gcgcgagcag cagcgtgagc tatattcatt ggtatcagca gaaaccgggc 120 aaagcgccga aactgctgat ttataccacc agctatctgg cgcatggcgt gccgagccgc 180 tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240 gattttgcga cctattattg cctgcagcgc agcaccctgc cgccgacctt tggcggcggc 300 accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360 gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420 cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480 agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540 agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600 agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639 <210> 75 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQIDNO:64之人源化單株抗體重鏈之DNA序列 <400> 75 caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60 acctgcaccg tgagcggcga tgatattacc agcggctatt gggattggat tcgccagccg 120 ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180 -58 - 138463·序列表.doc 201000126 ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240 aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300 tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360 agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420 agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480 gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540 agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600 aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660 gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720 agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780 gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840 gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900 acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960 tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020 gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080 accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140 gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200 gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260 gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320 aaaagcctga gcctgagcct gggc 1344
<210> 76 <211> 639 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQIDNO:65之人源化單株抗體輕鏈之DNA序列 60 120 180 <400> 76 gatattcaga attacctgca aaagcgccga tgacccagag gcgcgagcag aactgctgat cccgagcagc cagcgtgagc ttataccacc ctgagcgcga tatattcatt agctatctgg gcgtgggcga ggtatcagca cgcatggcgt tcgcgtgacc gaaaccgggc gccgagccgc -59· 138463-序列表.doc 240 201000126 tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa gattttgcga cctattattg ccagcagcgc agcaccctgc cgccgacctt tggcggcggc accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc <210> 77 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQ ID NO: 66之人源化單株抗體重鏈之DNA序列 <400> 77 caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 13 8463-序列表.doc 60- 300 360 420 480 540 600 639 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 201000126 acctatcgcg tataaatgca gcgaaaggcc accaaaaacc gtggaatggg gatagcgatg gaaggcaacg aaaagcctga tggtgagcgt aagtgagcaa agccgcgcga aggtgagcct aaagcaacgg gcagcttttt tgtttagctg gcctgagcct gctgaccgtg caaaggcctg accgcaggtg gacctgcctg ccagccggaa tctgtatagc cagcgtgatg gggc ctgcatcagg ccgagcagca tataccctgc gtgaaaggct aacaactata cgcctgaccg catgaagcgc attggctgaa ttgaaaaaac cgccgagcca tttatccgag aaaccacccc tggataaaag tgcataacca cggcaaagaa cattagcaaa ggaagaaatg cgatattgcg gccggtgctg ccgctggcag ttatacccag 960 1020 1080 1140 1200 1260 1320 1344
<210> 78 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:编碼SEQ ED NO: 67之人源化單株抗體重鏈之DNA序列 <400> 78 caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ccagtatagc ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 138463-序列表.doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 -61 - 900 960 201000126 acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag aaaagcctga gcctgagcct gggc <210> 79 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQ ID NO: 68之人源化單株抗«重鏈之DNA序列 <400> 79 caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccggcg tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 138463-序列表_(1(^ 62- 1020 1080 1140 1200 1260 1320 1344 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 960
201000126 acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag aaaagcctga gcctgagcct gggc <210> 80 <211> 1344 <212> DNA <213> 人工序列 <220> <223> 合成序列:編碼SEQ ID NO: 69之人源化單株抗體重鏈之DNA序列 1020 1080 1140 1200 1260 1320 1344 <400> 80 caggtgcagc acctgcaccg ccgggcaaag ccgagcctga aaactgagca tattatggct agcagcgcga agcgaaagca gtgagctgga agcagcggcc aaaacctata gaaagcaaat agcgtgtttc gtgacctgcg gtggatggcg tgcaggaaag tgagcggcga gcctggaatg aaagccgcgt gcgtgaccgc ttggcccgta gcaccaaagg ccgcggcgct acagcggcgc tgtatagcct cctgcaacgt atggcccgcc tgtttccgcc tggtggtgga tggaagtgca cggcccgggc tgatattacc gattggctat gaccattagc ggcggatacc tgcgctggat cccgagcgtg gggctgcctg gctgaccagc gagcagcgtg ggatcataaa gtgcccgccg gaaaccgaaa tgtgagccag taacgcgaaa ctggtgaaac agcggctatc attagctata gtggatacca gcggtgtatt tattggggcc tttccgctgg gtgaaagatt ggcgtgcata gtgaccgtgc ccgagcaaca tgcccggcgc gataccctga gaagatccgg accaaaccgc cgagcgaaac atgaatggat gcggcagcac gcaaaaacca attgcgcgcg agggcaccct cgccgtgcag attttccgga cctttccggc cgagcagcag ccaaagtgga cggaagcggc tgattagccg aagtgcagtt gcgaagaaca cctgagcctg tcgccagccg cagctatagc gtttagcctg cccgccggcg ggtgaccgtg ccgcagcacc accggtgacc ggtgctgcag cctgggcacc taaacgcgtg gggcggcccg caccccggaa taactggtat gtttaacagc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 63- 138463-序列表.doc 201000126 acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960 tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020 gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080 accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140 gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200 gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260 gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320 aaaagcctga gcctgagcct gggc 1344 64- 138463-序列表.doc
Claims (1)
- 201000126 七、申請專利範圍: 1. 一種Fab片段或包含該Fab片段之人源化單株抗體,其中 該Fab片段之Ki小於50 nM,可與人類、大鼠及鼠類升糖 素受體結合且抑制升糖素與各受體結合。 2. 如請求項1之Fab片段或包含該Fab片段之人源化單株抗 體,其中該Fab片段之Ki小於50 nM,可抑制升糖素與食 蟹猴升糖素受體結合。3. 如請求項1或請求項2之Fab片段或包含該Fab片段之人源 化單株抗體,其中該Fab片段包含; SEQ ID NO: 53 SEQ ID NO: 54 SEQ ID NO: 55 SEQ ID NO: 56 (i) 輕鏈 CDRL1 :SXSSSVSYXiH (ii) 輕鏈CDRL2 : T T S X2 L A Η (iii) 輕鏈CDRL3 : X3 X4 R S Τ Χ5 Ρ Ρ Τ (iv) 重鏈CDRH1 : GDDITSGYX6X7 (v)重鏈 CDRH2 : YISYSGSTX8YX9PSLKS SEQ ID NO: 57 (vi)重鏈 CDRH3 : PPX10YYGFGPYAXUDY SEQ ID NO: 58 其中: X = :Y或A Χό = W或Η X 1 ·= :Μ或I Xj ~ Ν、D或 Ε X2 = :Ν或Υ X» ^ Υ、Q、S或 V X3 = :Q或L X9 = Ν、S或 I x4 = :Q或W Xl 0 = G或A X5 = :L或I Χι 1~ Μ或L。 4.如請求項3之Fab片段或包含該Fab片段之人源化單株抗 體,其中: 138463.doc 201000126 X = A Χβ = H Xl = I X7 = D或E x2 = Y Χδ = γ、Q 或 S x3 = :Q X9 ~ S x4 = :Q Xio= G或A x5 = :L Xll = L 0 5.如請求項請求項2之Fab片段或包含該Fab片段之人源 化單株抗體,其中該Fab片段包含CDR序列: CDRLl 1 2 3 4 5 6 7 8 9 10 S A S S S V S Y I H CDRL2 1 2 3 4 5 6 7 T T S Y L A H CDRL3 1 2 3 4 5 6 7 8 9 Q Q R S T L P P T CDRH1 1 2 3 4 5 6 7 8 9 10 G D D I T S G Y H D CDRH2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Y I S Y S G S T Y Y S P S L K S CDRH3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 P P G Y Y G F G P Y A L D Y 其中該Fab片段具有一、二或三個選自由以下胺基酸 取代組成之群的胺基酸取代: CDRL1 : A2Y、I9M ; CDRL2: Y4N; CDRL3 : Q1L、Q2W、L6I ; CDRH1 : H9W、D10E、D10N ; 138463.doc -2- 201000126 CDRH2 : Y9Q、Y9S、Y9V、S11N、Sill ; CDRH3 : G3A、L12M。 6.如請求項1或請求項2之Fab片段或包含該Fab片段之人源 化單株抗體,其中該Fab片段包含: (i)輕鏈CDRL1 : SASSSVSYIH (SEQIDNO: 3) ⑼輕鏈CDRL2:TTSYLAH (SEQIDNO: 5) ’ (iii)輕鏈CDRL3:QQRSTLPPT (SEQIDNO:6) (iv)重鏈CDRH1:GDDITSGYHD (SEQIDNO: 12) ❹ (v)重鏈CDRH2 : YISYSGSTYYSPSLKS (SEQIDNO: 15) (vi)重鏈CDRH3 :PPGYYGFGPYALDY(SEQIDNO:21)。 7.如請求項1或請求項2之Fab片段或包含該Fab片段之人源 化單株抗艎,其中該Fab片段包含: (i)輕鏈CDRL1 : SASSSVSYIH (SEQIDNO:3) (ii)輕鍵CDRL2:TTSYLAH (SEQIDNO: 5) (iii)輕鍵CDRL3:QQRSTLPPT (SEQIDNO:6) A (iv)重鍵CDRH1:GDDITSGYHD 9 (SEQIDNO: 12) (v) 重鍵CDRH2 : YISYSGSTQYSPSLKS (SEQIDNO: 17) (vi) 重鏈CDRH3 :PPGYYGFGPYALDY(SEQIDNO:21)。 8.如請求項1或請求項2之Fab片段或包含該Fab片段之人源 化單株抗體,其中該Fab片段包含: (i)輕鍵CDRL1 : SASSSVSYIH (SEQIDNO: 3) (ii)輕鏈CDRL2:TTSYLAH (SEQIDNO: 5) (iii)輕鍵CDRL3 : QQRSTLPPT (SEQIDNO:6) (iv)重鏈CDRH1:GDDITSGYHD (SEQIDNO: 12) 138463.doc 201000126 (V)重鏈CDRH2: YISYSGSTYYSPSLKS (SEQIDNO: 15) (vi)重鏈CDRH3 : PPAYYGFGPYALDY (SEQEDNO:22)。 9. 如請求項1或請求項2之Fab片段或包含該Fab片段之人源 化單株抗體,其中該Fab片段包含: (i)輕鍵CDRL1 : SASSSVSYIH (SEQEDNO:3) ⑼輕鏈CDRL2 : TTSYLAH (SEQBDNO:5) (iii) 輕鍵CDRL3 : QQRSTLPPT (SEQIDNO:6) (iv) 重鏈CDRH1 : GDDITSGYHE (SEQIDNO: 13) (v) 重鏈CDRH2: YISYSGSTSYSPSLKS (SEQBDNO: 18) ⑽重鏈CDRH3 : PPAYYGFGPYALDY (SEQIDNO:22)。 10. 如請求項1或2之Fab片段或包含該Fab片段之人源化單株 抗體,其中該Fab片段包含輕可變鏈構架區:構架1 SEQ ID NO: 23、構架 2 SEQ ID NO: 24、構架3 SEQ ID NO: 25、構架4 SEQ ID NO: 26,及重可變鏈構架區:構架5 SEQ ID NO: 27、構架 6 SEQ ID NO: 28、構架 7 SEQ ID NO: 29、構架 8 SEQ ID NO: 30。 11. 一種人源化單株抗體,其包含: ⑴兩個SEQ ID NO: 65之輕鏈及兩個SEQ ID NO: 66之 重鏈; (ii) 兩個SEQ ID NO: 65之輕鍵及兩個SEQ ID NO: 67之 重鏈; (iii) 兩個 SEQ ID NO: 65之輕鏈及兩個 SEQ ID NO: 68 之重鏈;或 (iv) 兩個SEQ ID NO: 65之輕鏈及兩個SEQ ID NO: 69 138463.doc 201000126 之重鍵。 12. —種載體,其包含編碼如請求項1至11中任—項之 段或包含該Fab片段之人源化單株抗體之核酸序列。 13. —種宿主細胞,其包含編碼如請求項丨至^中任一項之 . Fab片段或包含該Fab片段之人源化單株抗體之異源聚核 苷酸序列。 14. 一種醫藥組合物,其包含有效量之如請求項丨至丨丨中任 φ 一項之Fab片段或包含該Fab片段之人源化單株抗體及醫 藥學上可接受之賦形劑。 15. 如請求項1或2之Fab片段或包含該Fab片段之人源化單株 抗體’其係作為藥物。 16. 如請求項1或2之Fab片段或包含該Fab片段之人源化單株 抗體’其係用於治療人類第丨型或第2型糖尿病,或用於 人體減重。 17. —種如請求項1至^中任一項之Fab片段或包含該^讣片 φ 段之人源化單株抗體用於製備藥物之用途,其中該藥物 係用於製造用於治療或預防人類第1型或第2型糖尿病, 或用於人體減重。 138463.doc 201000126 四、指定代表圖: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件符號簡單說明: 五、本案若有化學式時,請揭示最能顯示發明特徵的化學式: (無) 138463.doc -2-
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BR112012005208A2 (pt) * | 2009-09-08 | 2016-11-22 | Neopharm Co Ltd | antiocorpos contra o receptor de glucagon e seu uso |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
JO3756B1 (ar) | 2010-11-23 | 2021-01-31 | Regeneron Pharma | اجسام مضادة بشرية لمستقبلات الجلوكاجون |
US8771696B2 (en) | 2010-11-23 | 2014-07-08 | Regeneron Pharmaceuticals, Inc. | Method of reducing the severity of stress hyperglycemia with human antibodies to the glucagon receptor |
ES2865068T3 (es) | 2011-01-14 | 2021-10-14 | Univ California | Anticuerpos terapéuticos contra la proteína ROR-1 y métodos para usarlos |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013059531A1 (en) * | 2011-10-20 | 2013-04-25 | Genentech, Inc. | Anti-gcgr antibodies and uses thereof |
JP2015505828A (ja) | 2011-12-02 | 2015-02-26 | イーライ リリー アンド カンパニー | 抗グルカゴン抗体およびその使用 |
CA2911412A1 (en) * | 2013-05-07 | 2014-11-13 | Rinat Neuroscience Corp. | Anti-glucagon receptor antibodies and methods of use thereof |
EP3151855B1 (en) * | 2014-06-08 | 2021-11-24 | REMD Biotherapeutics, Inc. | Methods for treating type 1 diabetes using glucagon receptor antagonistic antibodies |
KR20190044079A (ko) | 2016-08-30 | 2019-04-29 | 리제너론 파마슈티칼스 인코포레이티드 | 글루카곤 수용체 신호전달을 간섭함에 의한 중증 인슐린 저항성의 치료 방법 |
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EP3573651A4 (en) | 2017-01-27 | 2020-10-14 | NGM Biopharmaceuticals, Inc. | GLUCAGON RECEPTOR BINDING PROTEINS AND METHODS OF USE |
US20210130480A1 (en) | 2017-08-22 | 2021-05-06 | Regeneron Pharmaceuticals, Inc. | Methods of treating urea cycle disorders by interfering with glucagon receptor signaling |
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WO2006005469A2 (en) | 2004-07-15 | 2006-01-19 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with glucagon receptor (gcgr) |
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