TW201107345A - Immunoglobulins - Google Patents

Immunoglobulins Download PDF

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TW201107345A
TW201107345A TW099116859A TW99116859A TW201107345A TW 201107345 A TW201107345 A TW 201107345A TW 099116859 A TW099116859 A TW 099116859A TW 99116859 A TW99116859 A TW 99116859A TW 201107345 A TW201107345 A TW 201107345A
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seq
antigen binding
heavy chain
binding protein
antibody
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TW099116859A
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Claire Ashman
Jonathan Henry Ellis
Paul Andrew Hamblin
Alan Peter Lewis
Martin Anibal Orecchia
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Glaxo Group Ltd
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    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/247—IL-4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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201107345 六、發明說明： 【發明所屬之技術領域】 本發明係關於抗原結合蛋白（特定言之，結合至介白素 13(IL-13)且中和其活性的抗體）、編碼此等抗原結合蛋白 之聚核苦酸、含有該等抗原結合蛋白之醫藥調配物，及此 等抗原結合蛋白用於治療及/或預防發炎相關疾病（諸如哮 喘）的用途。從以下描述中可顯而易見本發明之其他態 樣、目的及優點。 •【先前技術】 介白素-13(IL_13) IL-13為一種抑制炎性細胞激素產生之12 kDa分泌型細 胞激素，其最初被描述為T細胞源細胞激素。結構研究指 示其具有由兩個二硫鍵固定之四螺旋束排列。儘管IL_i3 具有四個潛在糖基化位點，但是對來自大鼠肺之天然IL_ 13的分析已指示其作為未糖基化分子而產生。ns 〇及c〇s _ 7細胞表現人類IL-13證實了此觀測結果（Eisenmesser等 秦人’】 Mol. Biol· 2001 310(1):231-241 ; Moy等人，[編1· Biol. 2001 310(1):219-230 ; Cannon-Carlson等人，Protein Expression and Purification 1998 12(2):239-248)。 IL-13已牽涉哮喘、慢性阻塞性肺病（c〇pD)、過敏性疾 病（包括異位性皮膚炎及過敏性鼻炎））、食道嗜伊紅血球增 多症、腫瘤學適應症（例如B細胞慢性淋巴球性白血病（B_ CLL)及霍奇金氏病（Hodgkin's disease))、發炎性腸病（例如 潰癌性結腸炎、克隆氏病（Crohn’s disease)及不定型結腸 148186.doc 201107345 炎）、牛皮癬及牛皮癖關節炎、急性移植物抗宿主疾病、 糖尿病性腎病變、纖維變性病狀（諸如肺纖維化，例如特 發性肺纖維化（IPF))。 【發明内容】 本發明提供結合至IL-1 3之抗原結合蛋白，例如IL-1 3抗 體，及此等IL-13抗體與IL-4拮抗劑及/或IL-5拮抗劑之組 合。本發明之IL-13抗體與鼠類mAb 6A1相關或來源於鼠類 mAb 6A1，其中CDRH3已突變。6A1鼠類重鏈可變區胺基 酸序列提供為SEQ ID NO: 58。6A1鼠類輕鏈可變區胺基酸 序列提供為SEQ ID NO: 59。 本發明之重鍵可變區（VH)包含下列CDR(如Kabat(^M<ai A ; Sequences of proteins of Immunological Interest NIH, 1987)所定義）： 本發明之重鏈可變區之CDR可包含下列CDR : CDR 根據Kabat HI DTYMH (SEQ ID NO: 1) H2 TIDPANGNTKYVPKFQG (SEQ ID NO: 2) H3 WIYDDYHYDDYYAMDY(SEQ ID NO: 4);或 SVYDDYHYDDYYAMDY(SEQ ID NO: 5);或 SIFDDYHYDDYYAMDY(SEQ ID NO: 6);或 SIYEDYHYDDYYAMDY(SEQ ID NO: 7);或 SIYDDYAYDDYYAMDY(SEQIDNO: 8);或 SIYDDYEYDDYYAMDY(SEQ ID NO: 9);或 SIYDDYQYDDYYAMDY(SEQIDNO: 10);或 SIYDDYRYDDYYAMDY(SEQIDNO: 11);或 SIYDDYSYDDYYAMDY(SEQIDNO: 12);或 148186.doc 201107345 SIYDDYTYDDYYAMDY(SEQIDNO: 13);或 SIYDDYVYDDYYAMDY(SEQIDNO: 14);或 SIYDDYHADDYYAMDY(SEQIDNO: 15);或 SIYDDYHIDDYYAMDY(SEQE)NO: 16);或 SIYDDYHWDDYYAMDY(SEQIDNO: 17);或 SIYDDYHVDDYYAMDY(SEQ ID NO: 18) 本發明之輕鏈可變區包含下列CDR(如Kabat所定義）： CDR 根據Kabat LI RSSQNIVHINGNTYLE(SEQ ID NO: 19) L2 KISDRFS(SEQ ID NO: 20) L3 FQGSHVPWT(SEQ ID NO: 21) 如上表中所示，可依據Kabat編號系統（Kabat等人； Sequences of proteins of Immunological Interest NIH, 1987) 確定抗體之CDR序列，或者其可藉由使用Chothia編號系統 (Al-Lazikani等人，（1997) JMB 273，927-948)、接觸定義 法（contact definition method)(MacCallum R.M.及 Martin A.C.R.及 Thornton J.M, (1996)，Journal of Molecular Biology，262 (5), 73 2-745)或為熟習此項技術者已知用於編 號抗體中之殘基且確定CDR的任何其他已確立方法來確 定。 本文所述之本發明之CDR可經由任一此等方法或藉由將 Chothia與Kabat編號組合使用來定義，舉例而言，CDRH1 可定義為包含FYIKDTYMH(SEQ ID NO: 60)或 GFYIKDTYMH (SEQ ID NO: 61)。 本發明亦提供一種包含連至一或多個抗原決定基結合域 之本發明IL-1 3抗體的抗原結合蛋白，例如包含連至能夠 14S186.doc 201107345 結合至IL-4之抗原決定基結合域之本發明IL_n抗體的抗原 結合蛋白；或包含連至能夠結合至IL_5之抗原決定基結合 域之本發明IL-13抗體的抗原結合蛋白；或包含連至能夠 » 結合至IL-4之第一抗原決定基結合域及能夠結合至扎_5之 第二抗原決定基結合域之本發明IL_13抗體的抗原結合蛋 白。 本發明亦提供一種藉由殘基89(kabat編號）突變成「Q」 (麵酿胺酸）來減少免疫球蛋白單可變域（例如人類VK結構 域抗體）之聚集傾向的方法。在一實施例中，可對SEQ ID NO: 80之抗IL-4結構域抗體使用此方法，產生突變dAb序 列，例如 SEQ ID N〇: 94。 此等突變dAb可單獨存在或作為較大序列之一部分（例如 mAbdAb序列之一部分）存在，從而產生例如包含選自SEq ID NO: 117-134之序列的 dAb。 本發明亦提供具有改良之聚集概況的人類VK dAb，例 如來源於選自以下之生殖系架構（germline framework)的人 類 VK dAb : IGKV1-17、IGKV1D-17、IGKV1/OR2-108、 IGKV1-6 ' IGKV5-2 ' IGKV1D-42 ' IGKV2-24 ' IGKV2-28、IGKV2-30、IGKV2-40、IGKV2D-29、IGKV2D-30 ' IGKV2D-24 及 IGKV6-21，其中該VK dAb 之殘基 89(kabat 編 號）為「Q」（麩醯胺酸）。在一此實施例中，VK dAb包含的 生殖系架構區選自1〇〖¥1-17、10〖¥10-17、10〖¥1/0112-108、IGKV1-6、IGKV5-2、IGKV1D-42 ' IGKV2-24、 IGKV2-28、IGKV2-30、IGKV2-40、IGKV2D-29、IGKV2D- 148186.doc 201107345 30、IGKV2D-24及IGKV6-21之生殖系架構，其中該VK dAb之殘基89(kabat編號）為「Q」（麵酿胺酸）。 在一實施例中，本發明提供一種包含SEq ID NO: 94之 序列的人類dAb。 本發明亦提供一種編碼本文所述之任一種抗原結合蛋白 之重鏈的聚核苷酸序列，及一種編碼本文所述之任一種抗 原結合蛋白之輕鏈的聚核苷酸，此等聚核苷酸代表對應於 等效多肽序列之編碼序列，然而應瞭解此等聚核苷酸序列 可隨起始密碼子、適當信號序列及終止密碼子一起選殖入 表現載體中。 本發明亦提供一種重組轉型或轉染之宿主細胞其包含 一或多種編碼本文所述之任一種抗原結合蛋白之重鏈及輕 鏈的聚核苷酸。 本發明進-步提供一種產生本文所述之任一種抗原結合 蛋白之方法，1玄方法包含在適合培養基(例如無血清培養
基）中培養包含第-及第二載體之宿主細胞的步驟，該第 一載體包含編碼本文所述之任一種抗原結合蛋白之重鍵的 聚核芽酸且該第二載體包含本文所述之任_種抗原結合蛋 白之輕鏈的聚核苷酸。 本發明進-步提供—種包含如本文所述之抗原結合蛋白 及醫藥學上可接受之載劑的醫藥組合物。 在另-態樣中’本發明提供一種藉由投與本發明之抗原 =合蛋白來治療或預防與特異反應性疾病/病症及慢性發 炎性疾病/病症相關之疾病或病症的方法。尤其關注其= 148186.doc 201107345 療哮喘之用途，諸如過敏性哮喘’特定言之，嚴重哮喘 (亦即對當前治療（包括全身投與皮質類固醇）無反應之^ 喘；參見Busse ww等人，j Allergy Clin Immun〇i 2〇〇〇, 106: 1033-1042)、「難治性」哮喘(定義為特徵為儘管投與 最大推薦劑量之處方吸入類固醇但仍無法得到控制之哮喘 表型，參見 Barnes PJ，（1998)，Eur Respir ; 12:12〇8_ 1218)、「脆性」哮喘（定義患有嚴重不穩^哮喘的患者亞 群，其€管投肖高劑量之吸入類固醇，但仍維#寬尖峰呼 氣流量（peak expiratory flow，PEF)變化性，參見jg 等人，（1998) Th〇rax 58:315_321)、夜間哮喘、經前哮 口而、杬類固醇哮喘（參見 Woodc〇ck AJ，（1993) Em j 6:743-747)、類固醇依賴型哮喘（定義為僅可用高劑量口服 類固醇控制之哮喘）、阿斯匹靈誘發性哮喘（aspiHn asthma)、成年發作型哮喘、小兒哮喘。本發明之抗體可用 於預防、降低急性哮喘發作（持續性哮喘（5_似 之頻率或緩和其效應。本發明之抗體亦可用 於降低在治療哮喘中所用之其他藥劑的所需給藥（在投藥 量或給藥頻率方面）。舉例而言’本發明之抗體可用於降 低類固醇治療（諸如皮質類固醇治療）哮喘所需之給藥（「類 口 谛省」）。其他可用本發明之抗體治療之疾病或病症 包括異位性皮膚炎、過敏性鼻炎、克隆氏病、慢性阻塞性 肺病（C0PD)、嗜伊紅血球食道炎、纖維變性疾病或病症 (諸如特發性肺纖維化、進行性全身性硬化（硬皮病）、肝纖 維化）、肝肉芽瘤、血吸蟲病、利什曼體病（丨仏—^仏） 148186.doc 201107345 及細胞週期調節疾病（例 胞白血病）。 如霍奇金氏病 B細胞慢性淋巴細 在另-態樣中，本發 供銥杰，丨—m +货啊抗原結合蛋白用於製 備樂劑之用途’該藥劑 ,法杵另皞ω拉 、，口療或預防特異反應性疾病/ 病症及慢性發炎性疾病/ 、φ味丄α 病症。尤其關注其治療哮喘之用 途’诸如過敏性哮喘， ，Λ由γ a』 特疋5之’嚴重哮喘（亦即對當前 二括全身投與皮質類固醇)無反應之哮喘;參見—
專人 】AHergy Clin τ lln· Immunol 2000, 106: 1033- 10 4 2)、難治性」哮喘（定墓& & (疋義為特徵為儘管投與最大推薦劑 量之處方吸入類固醇但仍無法得到控制之哮喘表型參見 B—n，〇998)，EurRespirJl2:i2〇8 i2i8) '「脆性 (brittle)」哮喘（定義患有嚴重不穩定哮喘的患者亞群其 儘管投與南劑量之@人东 里之及入類固酵，但仍維持寬尖峰呼氣流量 (PEF)變化性，參見 Ayres JG 等人，0998) Thorax 58:315_ 321)、夜間哮喘、經前哮喘、抗類固醇哮喘（參見 Woodcock AJ，（1993) EUr Respir j 6:743_747)、類固醇依賴 型哮喘(定義為僅可用高劑量口服類固醇控制之哮喘）、阿 斯匹莖誘發性哮喘、成年發作型哮喘、小兒哮喘。本發明 之抗體可用於預防、降低急性哮喘發作（持續性哮喘）之頻 率或緩和其效應。本發明之抗體亦可用於降低在治療哮喘 中所用之其他藥劑的所需給藥（在投藥量或給藥頻率方 面）。舉例而言，本發明之抗體可用於降低類固醇治療（諸 如皮質類固醇治療）哮喘所需之給藥（「類固醇節省」）。其 他可用本發明之抗體治療之疾病或病症包括異位性皮膚 J48186.doc 201107345 尺過敏性鼻炎、克隆氏病 '慢性阻塞性肺病（⑺叩）、 嗜伊紅企球食道炎、纖維變性疾病或病症（諸如特發性肺 纖維化、進行性全身性硬化（硬皮病）、肝纖維化）、肝肉芽 瘤、血吸蟲病、利什曼體病及細胞週期調節疾病(例如霍 奇金氏病、B細胞慢性淋巴細胞白血病）。 本發明之其他態樣及優點進一步描述於實施方式及其實 施例中。 定義 如通篇本說明書關於本發明之人類IL_U抗原結合蛋白 所用之術語「結合至人類IL_13」意謂該抗原結合蛋白結 合人類IL-13(下文稱為肌_13)而不結合至或不顯著結合至 其他人類蛋白質(諸如IL_4)。特定言之，本發明之抗原結 合蛋白結合至人類IL-13，因為在Biac〇re分析法（例如描述 於實例3中之BiaC0re分析法）中可見其結合至人類il i3。 然而該術語並不排除本發明之某些抗原結合蛋白亦可與其 他物種之IL-13(例如石蟹獼猴IL_13)交叉反應的事實。 如本文所用之術語「抗原結合蛋白」係指能夠結合且中 和人類IL-13之抗體、抗體片段及其他蛋白質構築體。 術語Fv、Fc、Fd、Fab '或F(ab)2依據其標準含義使用 (參見，例如 Harlow 等人 ’ Antib〇dies a Lab〇ratory
Manual, Cold Spring Harbor Laboratory, (1988))。 「嵌合抗體」係指一類型之工程改造抗體，其含有來源 於供者抗體之天然存在可變區（輕鏈及重鏈）以及來源於受 者抗體之輕鏈及重鏈悝定區。 148186.doc -10- 201107345 人類化抗體」係指一類型之工程改造抗體，其CDR來 源於非人類供者免疫球蛋白，該分子之其餘免疫球蛋白源 部分係來源於一（或多）種人類免疫球蛋白。此外，可改變 架構支樓殘基以保留結合親和力（參見，例如Queen等人， Proc. Natl Acad Sci USA, 86:10029-10032 (1989)；
Hodgson等人，Bio/Technology，9:421 (1991))。適合的人 類受者抗體可為根據與供者抗體之核苷酸及胺基酸序列的 同源性選自以下習知資料庫者：例如KABAT®資料庫、Los Alamos資料庫及瑞士蛋白質資料庫（Swiss Protein database)。特徵為與供者抗體之架構區同源（在胺基酸基 礎上）之人類抗體可適於為插入供者CDR提供重鏈恆定區 及/或重鏈可變架構區。可以類似方式選擇能夠提供輕鏈 怪定區或可變架構區之適合受者抗體。應注意受者抗體重 鏈及輕鏈不必來源於相同受者抗體。先前技術描述產生此 等人類化抗體之若干方式參見例如EP-A-0239400及EP-A-054951 ° 術語「供者抗體」係指一種抗體（單株及/或重組），其向 第一免疫球蛋白搭配物貢獻其可變區、CDR、或其他功能 片段或其類似物之胺基酸序列，從而提供變異的免疫球蛋 白編碼區及由此經表現之變異抗體，該變異抗體具有供者 抗體所特有之抗原特異性及中和活性。 術語「受者抗體」係指與供者抗體異源之抗體（單株及/ 或重組）’其向第一免疫球蛋白搭配物貢獻編碼其重鏈及/ 或輕鏈架構區及/或其重鏈及/或輕鏈恆定區之所有（或任一 148l86.doc -11 - 201107345 部分，但在一些實施例中為所有）胺基酸序列。在某些實 施例中’人類抗體為受者抗體。 「CDR」定義為抗體之互補決定區胺基酸序列，其為免 疫球蛋白重鏈及輕鏈之高變區。參見，例如Kabat等人， Sequences of Proteins 〇f Immun〇1〇gicai ，第 4版， 美國衛生福利部（u.s. Department of Health and Human Services)，國家衛生研究院⑽如㈤insmutes 〇f Health)(1987)。免疫球蛋白之可變部分中存在三個重键及 三個輕鏈CDR(或CDR區卜因此，如本文所用之「cdr」 係指所有三個重鏈CDR或所有三個輕鏈CDR(或所有重鏈 CDR與所有輕鏈CDR(若適當）），抗體之結構及蛋白質摺疊 可意謂其他殘基被視為抗原結合區之一部分且熟習此項技 術者應理解為如此。參見例如Ch〇thia等人，（I%”
Conformations of immunoglobulin hypervariable regions; Nature 342，第 877-883 頁。 ’ 如本文所用之術語「結構域」係指摺疊的蛋白質結構， 其具有不依賴於$白質之其餘料的三級結構。一般而 言，結構域負責蛋白質之個別功能性質且在許多情況下可 添加、移除或轉移至其他蛋白質中而不損失蛋白質及/或 結構域之其餘部分的功能。「抗體單可變域」為包含抗體 可變域所特有之序列的摺疊多肽結構域。其因此包括完全 抗體可變域及經修飾可變域（例如其中一或多個環已經不 為抗體可變域所特有之序列置換)、或已截斷或包含 末端延伸之抗體可變域、以及至少保留全長結構域之結合 i48186.doc -12- 201107345 活性及特異性之可變域摺疊片段。 片-&疫球蛋白單可變域」係指獨立於不同v區或域 纟…m抗原決定基之抗體可變域（vH、vHH、 L)免疫球蛋白單可變域可呈具有其他不同可變區或可 變域之形式（例如，同 门源或異源多聚體）存在，其中該等其
可艾區或可變域不為免疫球蛋白單可變域結合抗原所需 (亦卩”中免疫球蛋白單可變域獨立於其他可變域而結 &原）田用於本文時’術語「結構域抗體」或「dAb」 ” i ^ σ k原之「免疫球蛋白單可變域」相同。免疫球 ^ H @ &人類抗體可變域，㈣包括其他物種之 單可隻域，諸如齧齒動物（例如，如WO 00/29004中所 揭:）、瘦士 f、（nurse shark)及路乾科^繼㈣V仙㈣（奈 二，（an〇b〇dy))。駱駝科vhh為來源於包括駱駝、美洲 羊弘單峰駝及原駝之物種之免疫球蛋白單可變域多 〜X等物種產生天然缺乏輕鏈之重鍵抗體。可根據此項 ’、可用之裇準技術使此等VHH域人類化，且此等結構 域仍然視為本發明之「結構域抗體」。如本文所用，、」
、^科Vhh域。於軟骨魚（包括護士鯊）中鑑別之NARV '類1之免疫球蛋白單可變域。此等結構域亦稱為新 、^,主又體可變區（通常縮寫成V(NAR)或NARV)。對於其 古月參見 Mo1. Immun〇l. 44，656-665 (2006)及 US 20050043519A 〇 2 抗原決定基結合域」係指獨立於不同V區或域而 料^合抗原或抗原決定基的結構域，其可為結構域抗 148l86.doc •13· 201107345 體（dAb) ’例如人類' 駱駝科或鯊免疫球蛋白單可變域， 或其可為來源於非免疫球蛋白骨架之結構域，例如選自由 以下組成之群的非免疫球蛋白骨架：CTLA-4(伊維體 (Evibody));脂質運載蛋白；蛋白質a衍生分子，諸如蛋白 質八之2結構域（親和抗體（Affibody)，SpA)、A結構域（高親 和丨生夕4體/最大抗體（Avimer/Maxibody));熱休克蛋白， 諸如GroEl及GroES ;轉鐵蛋白（運載體（trans_body));錨蛋 白重複蛋白質（DARPin);肽適體（peptide aptamer) ; C型凝 集素結構域（四連接素（Tetranectin));人類γ-晶狀體球蛋白 及人類泛素（親和素（affilins)) ; PDZ結構域；蠍毒素；人 類蛋白酶抑制劑之庫尼茲型結構域（kunitz type d〇main^ 及纖維結合蛋白（黏結素（adnectin));已對其進行蛋白質工 程改造’以達成結合至除天然配位體之外的配位體。 CTLA-4(細胞毒性τ淋巴細胞相關抗原4)為主要在CD4 + T細胞上表現之CD28家族受體。其細胞外域具有類似可變 域的Ig摺疊。對應於抗體CDR之環可經異源序列取代，以 賦予不同結合特性。經工程改造而具有不同結合特異性之 CTLA-4分子亦稱為伊維體（Evib〇dy) ^對於其他詳情，參 見 Journal of Immunological Methods 248 (1-2) 31 45 (2001)。 ’ 脂質運載蛋白為轉運疏水性小分子（諸如類固醇、後膽 色素（bilin)、類視黃素及脂質）之細胞外蛋白質家族。其具 有剛性β摺疊二級結構（在錐形結構之開口端具有多個環/，' 該等環可經工程改造以結合不同靶抗原。抗運載蛋白 148186.doc -14- 201107345 (Anticalin)之尺寸介於ι6〇_18〇個胺基酸之間，且來源於脂 質運載蛋白。對於其他詳情，參見Biochim Biophys Acta 1482: 337-350 (2000)、US 7250297B1 及 US 20070224633。 親和抗體為來源於金黃色葡萄球菌少/ococcws awrws)之蛋白質a的骨架，其可經工程改造以結合至抗 原。該結構域由約5 8個胺基酸之三螺旋束組成。文庫已經 由表面殘基之隨機化產生。對於其他詳情，參見Pr〇tein
Eng_ Des. Sel. 17, 455-462 (2004)及 EP 1641818A1。 高親和性多聚體為來源於A結構域骨架家族之多結構域 蛋白質。約35個胺基酸之天然結構域採用確定之二硫鍵鍵 結結構。藉由改組（shuffling)A結構域家族所展現之天然變 化來產生多樣性。對於其他詳情，參見Nature Biotechnology 23(12)，1556-1561 (2005)及Expert Opinion on Investigational Drugs 16(6)，909-917(2007 年 6 月）。 轉鐵蛋白為單體血清轉運醣蛋白。轉鐵蛋白可藉由在容 坪之表面環中插入肽序列而加以工程改造以結合不同乾抗 原。經工程改造之轉鐵蛋白骨架的實例包括運載體（Transbody)。 對於其他詳情 ，參見j Bi〇i. chem 274， 2406卜 24073 (1999)。 所設計之錨蛋白重複蛋白（DARPin)來源於錨蛋白，錨蛋 白為介導整合膜蛋白（integral membrane pr〇tein)與細胞骨 架（cytoskeleton)連接之蛋白質家族。單個錨蛋白重複為由 兩個α螺旋及一個β轉角（turn)組成之33個殘基基元。其可 藉由隨機化各重複之第-α螺旋及p轉角中之殘基而加以工 148186.doc 201107345 程改造以結合不同靶抗原。其結合界面可藉由增加模組數 而增加（一種親和力成熟法）。對於其他詳情，參見J. Mol. Biol. 332, 489-503 (2003) ； PNAS 100(4), 1700-1705
(2003)及 J. Mol. Biol. 369, 1015-1028 (2007)及 US 20040132028A1 。 纖維結合蛋白為可經工程改造以結合至抗原之骨架。黏 結素（Adnectin)由第III型人類纖維結合蛋白（FN3)之15個重 複單元之第10結構域之天然胺基酸序列主鏈組成。位於β 炎層之一端之三個環可經工程改造以使黏結素（Adnectin) 能夠特異性識別相關治療標靶。對於其他詳情，參見 Protein Eng. Des· Sel. 18, 435-444 (2005)、US 20080139791、 WO 2005056764及 US 6818418B1。 肽適體為由恆定骨架蛋白質組成之組合識別分子，該恆 定骨架蛋白通常為含有在活性位點處插入之限制性可變肽 環的硫氧還蛋白（thioredoxin，TrxA)。對於其他詳情’參 見 Expert Opin. Biol· Ther. 5, 783-797 (2005)。 微體（Microbody)來源於長度為25_50個胺基酸之含有3-4 個半胱胺酸橋（cysteine bridge)之天然存在微蛋白，微蛋白 之實例包括KalataBl及芋螺毒素（conotoxin)及打結素 (knottin)。微蛋白的環可經工程改造以包括多達25個胺基 酸而不影響微蛋白之整體摺疊。對於工程改造之打結素結 構域之其他詳情，參見WO 2008098796。 其他抗原決定基結合域包括已作為骨架用於工程改造不 同靶抗原結合性質的蛋白質’包括人類γ-晶狀體球蛋白及 148186.doc 16· 201107345 人類泛素（親和素（affilins))、人類蛋白酶抑制劑之庫尼兹 (kunitz)型結構域、Ras結合蛋白AF_6之pdz結構域、礙毒 素（卡律蠍毒素（charybdotoxin))、C型凝集素結構域（四連 接素）’該等其他抗原決定基結合域評述於HandbQQk μ
Therapeutic Antibodies 之第 7 章 Non-Antibody Scaffolds (2007，Stefan Dubel編）及 Protein Science 15:14.27 (2006) 中。本發明之抗原決定基結合域可來源於任一此等替代蛋 白質結構域。 如本文所用，術語「抗原結合位點」係指蛋白質上能夠 特異性結合至抗原之位點’其可為單域，例如抗原決定基 結合域，或其可為如標準抗體上可見之成對Vh/^域。在 本發明之一些態樣中，單鏈Fv(ScFv)域可提供抗原結合位 點。 本文中使用的術語「inAbdAb」及厂dAbmAb」係指本發 明之抗原結合蛋白。兩個術語可互換使用且當用於本文中 時意欲具有相同含義。 如本文所用之術語「抗原結合蛋白」係指抗體、抗體片 段（例如結構域抗體（dAb)、ScFv、FAb、FAb2)及其他能夠 結合至IL-13之蛋白質構築體。抗原結合分子可包含至少 一個ig可變域，例如抗體、結構域抗體、Fab、Fab，、 F(ab’）2、Fv、ScFv、雙功能抗體' mAbdAb、親和抗體、 異源結合抗體或雙特異性抗體。在一實施例中，抗原結合 分子為抗體。在另一實施例中，抗原結合分子為dAb，亦 即免疫球蛋白單可變域，諸如Vh、Vhh* Vl，其獨立於不 148186.doc •17· 201107345 同v區或域而特異性結合抗原或抗原決定基。抗原結合分 子能夠結合至兩個標靶，亦即其可為雙靶向蛋白質（dual targeting protein)。抗原結合分子可為抗體與抗原結合片 段之組合’諸如一或多種結構域抗體及/或一或多種連至 單株抗體之ScFv。抗原結合分子亦可包含非Ig結構域，例 如來源於選自由以下組成之群之骨架的結構域：CTLA_ 4(伊維體（Evibody)));脂質運載蛋白；蛋白質a衍生分 子’諸如蛋白質A之Z結構域（親和抗體，SpA)、a結構域 (高親和性多聚體/最大抗體）；熱休克蛋白，諸如Gr〇m及 GroES ’轉鐵蛋白（運載體）；錫蛋白重複蛋白⑴八处⑻； 肽適體；C型凝集素結構域（四連接素）；人類γ_晶狀體球蛋 白及人類泛素（親和素）；PDZ結構域；蠍毒素；人類蛋白 酶抑制劑之庫尼茲型結構域；及纖維結合蛋白（黏結素广 已對其進行蛋白質工程改造以達成結合至比_13。如本文 中所用，「抗原、结合蛋白」能夠结抗及/或中和人類US。 另外’抗原結合蛋白可藉由結合至江_13及防止天然配位 體結合及/或活化受體來阻斷IL_丨3活性。 士本文所用’ IL_13拮抗#|」包括任何能夠降低及或消 除IIM3之至少一種活性的化合物。舉例而言，m拮抗 劑可結合至11^13且彼結合可直接降低或消除m活性， 或飢-U拮抗劑可藉由阻斷至少一種配位體結合受體而 148186.doc 201107345 可結合至IL-4且彼結合可直接降低或消除IL-4活性，或該 IL-4拮抗劑可藉由阻斷至少一種配位體結合受體而間接發 揮作用。 如本文所用，「IL-5拮抗劑」包括任何能夠降低及或消 除IL-5之至少一種活性的化合物。在一實例中，IL-5拮抗 劑可結合至IL-5且彼結合可直接降低或消除IL-5活性，或 該IL-5拮抗劑可藉由阻斷至少一種配位體結合受體而間接 發揮作用。 • 【實施方式】 在一實施例中，本發明之抗原結合蛋白包含重鏈可變 區，該重鏈可變區含有選自由以下組成之清單的CDRH3 : SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 6、SEQ ID NO: 7、SEQ ID NO: 8及 SEQ ID NO: 9、SEQ ID NO: 10、 SEQ ID NO: 11、SEQ ID NO: 12、SEQ ID NO: 13、SEQ ID NO: 14及 SEQ ID NO: 15、SEQ ID NO: 16、SEQ ID NO: 17 及 SEQ ID NO: 18，及適合 CDRH1 及 CDRH2 ;以及 ® 與之成對的輕鏈可變區，該輕鏈可變區含有適合CDRL1、 CDRL2及CDRL3，以形成結合至人類IL-13之抗原結合Fv 單元。在一實施例中，本發明之抗原結合蛋白中和人類 IL-13之活性。
在此實施例之一態樣中，如SEQ ID NO: 1或SEQ ID NO: 60 或 SEQ ID NO·· 61 中所示之 CDRH1 及如 SEQ ID NO·· 2 中 所示之CDRH2亦存在於重鏈可變區中。在此實施例之另一 態樣中，如SEQ ID NO: 19中所示之CDRHL1及如SEQ ID 148186.doc •19- 201107345 NO: 20中所示之CDRL2及如SEQ ID NO: 21中所示之 CDRL3亦存在於輕鏈可變區中。 在另一態樣中，如經由Biacore所量測，抗原結合蛋白結 合至人類IL-13的高親和力為10 nM或10 nM以下，且更特 定而言，2 nM或2 nM以下（例如介於約0·8 nM與2 nM之 間）、1 nM或1 nM以下、或100 pM或100 pM以下（例如介於 約20 pM與約100 pM之間，或介於約20 pM與約80 pM之 間，或介於約20 pM與約60 pM之間）。在一此實施例中， 此係利用捕捉於生物感測器晶片上之抗原結合蛋白、經由 Biacore來量測，例如實例3中所述。 本發明之重鏈可變區可連同允許結合至人類IL-1 3的輕 鏈可變區一起形成習知免疫球蛋白樣式（例如人類IgG、 IgA、IgM等）或形成結合至人類IL-13之任何其他「抗體 樣」形式（例如單鏈FV、雙功能抗體、對於替 代「抗體」形式之概述，參見Holliger及Hudson, Nature Biotechnology，2005，第 23卷，第 9期，1126-1 136))。 本發明之抗原結合蛋白來源於具有如SEQ ID NO: 58及 SEQ ID NO: 59中所述之可變區的鼠類抗體或其非鼠類等 效物，諸如其大鼠、人類、嵌合或人類化變體，舉例而 言，其來源於具有如SEQ ID NO: 22及SEQ ID NO: 24中所 述之重鏈及輕鏈的人類化抗體。 在本發明之一態樣中，提供抗原結合蛋白，例如結合人 類 IL-13 且包含 CDRH3 SIYDDYHYDDYYAMDY(SEQ ID NO: 3)之變體的抗體，其中CDRH3在一或多個下列位置 148186.doc -20- 201107345 (使用Kabat編號）處經下文所示之替代胺基酸取代： a) 位置1中之S95取代為色胺酸（W) b) 位置2中之196取代為纈胺酸（V) c) 位置3中之Y97取代為苯丙胺酸（F) d) 位置4中之D98取代為糙醯胺酸（E) e) 位置7中之H100A取代為丙胺酸（A)，麵胺酸（E)、麩醯胺 酸（Q)、精胺酸（R)、絲胺酸（S)、蘇胺酸（T)或纈胺酸 (V)，及 ® f)位置8中之Y100B取代為丙胺酸（A)、異白胺酸（I)、色胺 酸（W)或纈胺酸（V)。 在本發明之另一態樣中，提供抗原結合蛋白，例如結合 人類IL-13且包含SEQ ID NO: 3中所示之CDRH3的抗體， 其中CDRH3包含一或多個下歹ij取代：S95W、I96V、 Y97F、D98E、H100A_A、H100A_E、H100A Q、H100A R、 H100A_S、H100A_T、H100A_V、Y100B_A、Y100B — I、 Y100B W及 Y100B V。 在一態樣中，本發明之抗原結合蛋白（例如本發明之抗 體）包含的CDRH3序列選自以下所示的CDRH3序列：SEQ ID NO: 4 ' SEQ ID NO: 5 ' SEQ ID NO: 6 ' SEQ ID NO: 7、SEQ ID NO: 8及 SEQ ID NO: 9、SEQ ID NO: 10、SEQ ID NO: 11、SEQ ID NO: 12、SEQ ID NO: 13、SEQ ID NO: 14及 SEQ ID NO: 15、SEQ ID NO: 16、SEQ ID NO: 17及SEQ ID NO: 18。此等抗原結合蛋白可進一步包含下 列CDR序列： 148l86.doc • 21 - 201107345 CDRHl :選自 SEQ ID NO: 1、60及 61 ; CDRH2 ： SEQ ID NO: 2 ； CDRL1 : SEQ ID NO: 19 ; CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 在一實施例中，抗原結合蛋白包含下列CDR : CDRHl ： SEQ ID NO: 1 ； CDRH2 : SEQ ID NO: 2 ; CDRH3 ： SEQ ID NO: 18 ； CDRL1 ： SEQ ID NO: 19 ； CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 在另一實施例中，抗原結合蛋白包含下列CDR : CDRHl ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 17 ； CDRL1 ： SEQ ID NO: 19 ； CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 在另一實施例中，抗原結合蛋白包含下列CDR : CDRHl ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 : SEQ ID NO: 16 ; CDRL1 : SEQ ID NO: 19 ; 148186.doc -22- 201107345 CDRL2 ·· SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 在另一實施例中，抗原結合蛋白包含下列CDR : CDRH1 ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 15 ； CDRL1 : SEQ ID NO: 19 ;
CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 在整篇本說明書中，抗體序列中之胺基酸殘基皆根據 Kabat方案編號。類似地，除非另有指示（例如如SEQ ID NO: 60及61中所示之CDRH3)，否則術語「CDR」、 「CDRL1」、「CDRL2」、「CDRL3」、「CDRH1」、 「CDRH2」、「CDRH3」皆遵循如 Kabat 等人；「Seg o/pro/e/則 NIH, 1987 中所述之
Kabat編號糸統。 在本發明之另一態樣中，提供抗原結合蛋白，諸如人類 化抗體或其抗原結合片段，其包含具有選自以下之序列之 重鏈：8日(5 10]^0:26、8£(^10^^0:28、8£(^10 1^0·· 30 ' SEQ ID NO: 32 ' SEQ ID NO: 34 ' SEQ ID NO: 36 ' SEQ ID NO: 38、SEQ ID NO: 40、SEQ ID NO: 42、SEQ ID NO: 44、SEQ ID NO: 46、SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52、SEQ ID NO: 54、SEQ ID NO: 88、SEQ ID NO·· 89 ' SEQ ID NO: 90及 SEQ ID NO: 91 ; 148186.doc -23- 201107345 及SEQ ID NO: 24之輕鏈。 本發明提供一種抗原結合蛋白，諸如人類化抗體或其抗 原結合片段，其包含選自以下之重鏈：SEQ ID NO: 26、 SEQ ID NO: 28、SEQ ID NO·· 30、SEQ ID NO·· 32、SEQ ID NO: 34、SEQ ID NO: 36、SEQ ID NO: 38、SEQ ID NO: 40、SEQ ID NO: 42、SEQ ID NO: 44、SEQ ID NO: 46、SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52、 SEQ ID NO: 54、SEQ ID NO: 88、SEQ ID NO: 89、SEQ ID NO: 90。 本發明亦提供一種抗原結合蛋白，諸如人類化抗體或其 抗原結合片段，其包含選自以下之輕鏈：SEQ ID NO: 108、SEQ ID NO: 110、SEQ ID NO: 112及 SEQ ID NO: 114。 本發明進一步提供一種抗原結合蛋白，諸如人類化抗體 或其抗原結合片段，其包含具有選自α下之序列之重鏈： SEQ ID NO: 26 ' SEQ ID NO: 28 ' SEQ ID NO: 30 ' SEQ ID NO: 32、SEQ ID NO: 34、SEQ ID NO: 36、SEQ ID NO: 38、SEQ ID NO: 40、SEQ ID NO: 42、SEQ ID NO: 44、SEQ ID NO: 46、SEQ ID NO: 48、SEQ ID NO: 50、 SEQ ID NO: 52、SEQ ID NO: 54、SEQ ID NO: 88、SEQ ID NO: 89 ' SEQ ID NO: 90及 SEQ ID NO: 91 ;及 SEQ ID NO: 108、SEQ ID NO: 110、SEQ ID NO: 112及 SEQ ID NO: 114之輕鍵。 在一實施例中，本發明之抗原結合蛋白包含一種抗體， 148186.doc -24- 201107345
該抗體包含選自以下之重鏈：SEQ ID NO: 26、SEQ ID NO: 28、SEQ ID NO: 30、SEQ ID NO: 32、SEQ ID NO: 34、SEQ ID NO: 36 ' SEQ ID NO: 38、SEQ ID NO: 40、 SEQ ID NO: 42、SEQ ID NO: 44、SEQ ID NO: 46、SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52、SEQ ID NO: 54 ' SEQ ID NO: 88 ' SEQ ID NO: 89 ' SEQ ID NO: 90 及 SEQ ID NO: 91 ;及選自 SEQ ID NO: 24 ' SEQ ID NO: 108、SEQ ID NO: 110、SEQ ID NO: 112及 SEQ ID NO: 114 之輕鏈。 在一實施例中，本發明之抗原結合蛋白包含重鏈及輕 鏈，該重鏈選自 SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52 及 SEQ ID NO: 54 且該輕鏈選自 SEQ ID NO: 24、 SEQ ID NO: 108、SEQ ID NO: 110、SEQ ID NO: 112及 SEQ ID NO·· 114，舉例而言，該抗原結合蛋白包含：SEQ ID NO: 48 之重鏈及 SEQ ID NO: 24 之輕鏈，或 SEQ ID NO: 50之重鏈及SEQ ID NO: 24之輕鏈，或SEQ ID NO: 52之重 鏈及SEQ ID NO: 24之輕鏈，或SEQ ID NO: 54之重鏈及 SEQ ID NO: 24之輕鏈，或 SEQ ID NO: 88之重鏈及 SEQ ID NO: 24 之輕鏈，或 SEQ ID NO: 89 之重鏈及 SEQ ID NO: 24 之輕鏈，或SEQ ID NO: 90之重鏈及SEQ ID NO: 24之輕 鏈，或SEQ ID NO: 91之重鏈及SEQ ID NO: 24之輕鏈，或 SEQ ID NO: 48之重鏈及 SEQ ID NO:108之輕鏈，或 SEQ ID NO: 50之重鏈及 SEQ ID NO: 108之輕鏈，或 SEQ ID NO: 52之重鏈及SEQ ID NO: 108之輕鏈，或SEQ ID NO: 54之 148186.doc -25 - 201107345 重鏈及SEQ ID NO: 108之輕鏈，或SEQ ID NO: 88之重鏈 及SEQ ID NO: 108之輕鏈，或SEQ ID NO: 89之重鏈及SEQ ID NO: 108之輕鏈，或SEQ ID NO: 90之重鏈及SEQ ID NO: 108之輕鏈，或 SEQ ID NO: 91 之重鏈及 SEQ ID NO: 108之輕鏈，或SEQ ID NO: 48之重鏈及SEQ ID NO: 110之 輕鏈，或SEQ ID NO: 50之重鏈及SEQ ID NO: 110之輕 鏈，或SEQ ID NO: 52之重鏈及SEQ ID NO: 110之輕鏈， 或SEQ ID NO: 54之重鏈及SEQ ID NO: 110之輕鏈，或SEQ ID NO: 88之重鏈及SEQ ID NO: 110之輕鏈，或SEQ ID NO: 89 之重鏈及 SEQ ID NO: 110之輕鏈，或 SEQ ID NO: 90之重鏈及SEQ ID NO: 110之輕鏈，或SEQ ID NO: 91之 重鍵及SEQ ID NO: 110之輕鍵。
在一此實施例中，本發明之抗原結合蛋白包含選自SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52及 SEQ ID NO: 54之重鏈及選自 SEQ ID NO: 108及 SEQ ID NO: 110之 輕鏈，舉例而言，該抗原結合蛋白包含SEQ ID NO: 48之 重鏈及SEQ ID NO: 108之輕鏈，或該抗原結合蛋白包含 SEQ ID NO: 48之重鏈及SEQ ID NO: 110之輕鏈，或該抗 原結合蛋白包含SEQ ID NO: 5 0之重鏈及SEQ ID NO: 108 之輕鏈，或該抗原結合蛋白包含SEQ ID NO: 50之重鏈及 SEQ ID NO·· 110之輕鏈，或該抗原結合蛋白包含SEQ ID NO: 52之重鏈及SEQ ID NO: 108之輕鏈，或該抗原結合蛋 白包含SEQ ID NO: 52之重鏈及SEQ ID NO: 110之輕鏈， 或該抗原結合蛋白包含SEQ ID NO: 54之重鏈及SEQ ID 148186.doc -26- 201107345 N〇. 1 08之輕鏈，或該抗原結合蛋白包含SEQ ID NO: 50之 重鏈及SEQ ID NO: 110之輕鏈。 本發明之IL-13抗體可與IL-4及/或IL-5拮抗劑（例如IL_4 抗體或抗原決定基結合域及/或扎_5抗體或抗原決定基結合 域）組合。此等分、子可作為同時投與之各別分子的混合物 而投與，亦即共投與，或彼此在24小時内投與例如彼此 在20小時内，或在15小時内或在12小時内，或在10小時 内，或在8小時内，或在6小時内，或在4小時内，或在2小 時内’或在1小時内，或在30分鐘内投與。 在另一實施例中，拮抗劑作為一種能夠結合至兩種或兩 種以上抗原之分子而存在，舉例而言，本發明提供一種包 3本發明之IL-1 3抗體的抗原結合蛋白，該IL_ 1 3抗體能夠 結合至IL-13且其亦能夠結合至IL_4或其亦能夠結合至IL_ 5 ’或其亦能夠結合至IL-4及IL-5。 在一實施例中，本發明之抗原結合蛋白可為多特異性抗 體，其至少包含CDRH3，且視情況包含本發明之 CDRH1、CDRH2、CDRL1、CDRL2 及 CDRL3 中之一或多 者’其能夠結合至IL-13且其亦能夠結合至一或多種IL 4或 IL-5。在一此實施例中，提供包含CDRH3的多特異性抗 體’或包含能夠結合至IL-4或IL-5之另一抗原結合位點的 如本文定義之抗原結合蛋白。 本發明抗原結合蛋白之一實例為連至一或多個抗原決定 基結合域的抗體，該抗體對IL-13具有特異性且包含如本
文定義之 CDRH1、CDRH2、CDRH3、CDRL1、CDRL2A 148186.doc ·27· 201107345 CDRL3，該等抗原決定基結合域對IL_4或IL 5具有特異 性，例如能夠結合至IL-13及IL_4、或比_13及比_5之雙特 異性杬原結合蛋白，或能夠結合至1]^_13、11^4及11^5之三 特異性抗原結合蛋白。 應瞭解，本文所述之任一種抗原結合蛋白能夠同時結合 兩種或兩種以上抗原，例如使用適合分析法（諸如描述於 實例8中者）、經由化學計量分析所測定。 本發明提供一#包含連至_或多個抗原&定基結合域之 本發明IL-13抗體的抗原結合蛋白，例如包含連至能夠結 合至IL-4之抗原決定基結合域之本發明乩_13抗體的抗原結 合蛋白；或包含連至能夠結合至乩_5之抗原決定基結合域 之本發明IL-13抗體的抗原結合蛋白；或包含連至能夠結 合至IL-4之第一抗原決定基結合域及能夠結合至比乃之第 二抗原決定基結合域之本發明IL_13抗體的抗原結合蛋 白。 抗原決定基結合域可連接至IL_13抗體重鏈之c末端或η 末端或IL-13抗體輕鏈之c末端或n末端。 適合連接子之實例包括長度可為以下的胺基酸序列：i 個fe基酸至150個胺基酸，或丨個胺基酸至14〇個胺基酸， 例如1個胺基酸至130個胺基酸，或丨至12〇個胺基酸，或i 至80個胺基酸，或丨至“個胺基酸，或丨至“個胺基酸，或 1至10個胺基酸，或5至18個胺基酸。此等序列可具有其自 身二級結構，例如本發明之連接子可包含單可變域。一實 知例中之連接子尺寸相當於單可變域。適合連接子尺寸可 148I86.doc -28- 201107345 為1至20埃（angstrom)，例如小於15埃，或小於10埃，或小 於5埃。 在本發明之一實施例中，至少一個抗原決定基結合域經 連接子直接連接至IL-13抗體’該連接子包含1至150個胺 基酸’例如1至20個胺基酸，例如1至1 〇個胺基酸。 此等連接子或此等連接子中之多者可選自SEQ ID NO: 82-87、92至93中所示任一者。 適用於本發明之抗原結合蛋白中之連接子可僅包含或除 _ 其他連接子外亦包含一或多組GS殘基，例如「GSTVAAPS」 (SEQ ID NO: 92)或「TVAAPSGS」（SEQ ID NO: 87)或 「GSTVAAPSGS」（SEQ ID NO: 93)。在一實施例中，連接 子包含 SEQ ID NO: 83。 在一實施例中，抗原決定基結合域經由連接子 「（PAS)n(GS)m」連接至IL-13抗體。在另一實施例中， 抗原決定基結合域經由連接子「（GGGGS)n(GS)m」連接 $ 至IL-13抗體。在另一實施例中，抗原決定基結合域經由 連接子「（TVAAPS)n(GS)m」連接至1L-13抗體。在另一 實施例中，抗原決定基結合域經由連接子 「（GS)m(TVAAPSGS)n」連接至IL-13抗體。在另一實施例 中，抗原決定基結合域經由連接子「（PAVPPP)n(GS)m」 連接至IL-13抗體。在另一實施例中，抗原決定基結合域 經由連接子「（TVSDVP)n(GS)m」連接至IL-13抗體。在 另一實施例中，抗原決定基結合域經由連接子 「（TGLDSP)n(GS)m」連接至IL-13抗體。在所有此等實施 148186.doc -29- 201107345 例中，n=l-10，且 m=0-4。 此等連接子之實例包括（PAS)n(GS)m，其中n=l且m=l ; (PAS)n(GS)m，其中 n=2 且 m=l; (PAS)n(GS)m，其中 n=3 且 m=l ; (PAS)n(GS)m，其中 n=4 且 m=l ; (PAS)n(GS)m，其中 n=2且 m=0 ; (PAS)n(GS)m，其中 n=3 且 m=0 ; (PAS)n(GS)m， 其中n=4且m=0。 此等連接子之實例包括（GGGGS)n(GS)m，其中n=l且 m=l : (GGGGS)n(GS)m，其中 n=2 且 m=l ; (GGGGS)n(GS)m， 其中 n=3 且 m=l ; (GGGGS)n(GS)m，其中 n=4 且 m=l ; (GGGGS)n(GS)m，其中 n=2且 m=0 ; (GGGGS)n(GS)m，其中 n=3 且 m=0 ; (GGGGS)n(GS)m，其中 n=4且 m=0。 此等連接子之實例包括（TVAAPS)n(GS)m，其中n=l且 m=l(SEQ ID NO: 87) ; (TVAAPS)n(GS)m，其中 n=2 且 m=l(SEQ ID NO: 145) ; (TVAAPS)n(GS)m，其中 n=3 且 m=l(SEQ ID NO: 146) ; (TVAAPS)n(GS)m，其中 n=4 且 m=l ; (TVAAPS)n(GS)m，其中 n=2 且 m=0 ; (TVAAPS)n(GS)m， 其中 n=3 且 m=0 ; (TVAAPS)n(GS)m，其中 n=4且 m = 0。 此等連接子之實例包括（GS)m(TVAAPSGS)n，其中n=l且 m=l(SEQ ID NO:139) ; (GS)m(TVAAPSGS)n，其中 n=2 且 m=l(SEQ ID NO:140) ; (GS)m(TVAAPSGS)n，其中 n=3 且 m=l(SEQIDNO:141);或（GS)m(TVAAPSGS)n，其中 n=4且 m=l(SEQ ID NO:142) ; (GS)m(TVAAPSGS)n，其中 n=5 且 m=l(SEQ ID NO:143) ； (GS)m(TVAAPSGS)„ ，其中 n=6且 m=l(SEQ ID NO]44) ; (GS)m(TVAAPSGS)n，其中 n=l 且 148l86.doc -30- 201107345 m=0(SEQ ID NO:87) ; (GS)m(TVAAPSGS)n，其中 n=2 且 m=10 ； (GS)m(TVAAPSGS)n ，其中 n=3 且 m=0 ;或 (GS)m(TVAAPSGS)n，其中 n=0。 此等連接子之實例包括（PAVPPP)n(GS)m，其中n=l且 m=l ; (PAVPPP)n(GS)m，其中 n=2且 m=l(SEQ ID NO·· 65); (PAVPPPMGSU，其中 n=3 且 m=l ; (PAVPPP)„(GS)m，其中 n=4 且 m=l ; (PAVPPP)n(GS)m ，其中 n=2 且 m = 0 ; (PAVPPP)n(GS)m，其中 n=3 且 m=0 ; (PAVPPP)n(GS)m，其中 n=4 且 m=0 ° 此等連接子之實例包括（TVSDVP)n(GS)m，其中n=l且 m=l(SEQ ID NO: 67) ; (TVSDVP)n(GS)m，其中 n=2 且 m=l ; (TVSDVP)n(GS)m，其中 n=3 且 m=l ; (TVSDVP)n(GS)m， 其中 n=4 且 m=l ； (TVSDVP)n(GS)m > 其中 n=2 且 m = 0 ; (TVSDVP)n(GS)m，其中 n=3 且 m=0 ; (TVSDVP)n(GS)m，其 中 n=4 且 m=0。 此等連接子之實例包括（TGLDSP)n(GS)m，其中n=l且 m = l ; (TGLDSP)n(GS)m，其中 n=2 且 m=l ; (TGLDSP)n(GS)m， 其中 n=3 且 m=l ； (TGLDSP)n(GS)m，其中 n=4 且 m=l ； (TGLDSP)n(GS)m，其中 n=2 且 m=0 ; (TGLDSP)n(GS)m，其 中 n=3 且 m=0; (TGLDSP)n(GS)m，其中 n=4且 m=0。 在另一實施例中，抗原決定基結合域與IL-13抗體之間 無連接子。在另一實施例中，抗原決定基結合域經由連接 子「TVAAPS」（SEQ ID NO: 83)連接至IL-13抗體。在另一 實施例中，抗原決定基結合域經由連接子「TVAAPSGS」 148186.doc -31 - 201107345 (SEQ ID NO: 87)連接至IL-13抗體。在另一實施例中，抗 原決定基結合域經由連接子「GS」連接至IL n抗體。在 另一實施例中，抗原決定基結合域經由連接子「astkgpt」 (SEQ ID NO: 84)連接至 IL-13 抗體。 適用於本發明中之抗原決定基結合域為獨立於不同ν區 或域而特異性結合抗原或抗原決定基的結構域，其可為結 構域抗體或可為非免疫球蛋白結構域，例如來源於選自由 以下組成之群之骨架的結構域：CTLA_4(伊維體 (Evibody));脂質運載蛋白；蛋白質A衍生分子，諸如蛋白 質A之Z結構域（親和抗體，SpA)、a結構域（高親和性多聚 體/最大抗體）；熱休克蛋白，諸如Gr〇El及Gr〇Es ;轉鐵蛋 白（運載體广錯蛋白重複蛋白（DARPin);肽適體；c型凝 集素結構域（四連接素）；人類γ_晶狀體球蛋白及人類泛素 (親和素）；PDZ結構域；料素；人類蛋白酶抑制劑之庫 尼茲型結構域；及纖維結合蛋白（黏結素）；已對其進 白質工程改造以達成結合至& # 、 σ I除天然配位體之外的配位體。 在-實施例中，其可為結構域抗體或其他適合結構域，諸 如選自由以下組成之群的結構域：ctla_4、脂質運載蛋 白、SPA、親和抗體、高親和性多聚體、如則、轉鐵蛋 白、GroES及纖維結合蛋白。在一實施例中，其可選 疫球蛋白單可變域' 親和抗F 知疋&去 柷體、錨蛋白重複蛋白（DARpi 及黏結素。在另一實施例中，其可選自親和抗體、錫蛋白 重複蛋白（W)及料素。在另―實施例中，1 構域抗體，例如選自人類、& ^ ^ , A ........ 頁路馬匕科（奈米抗體）、或鯊 148186.doc •32· 201107345 (NARV)結構域抗體之結構域抗體。 此等抗原結合蛋白之實例包括具有作為IL-4拮抗劑之抗 原決定基結合域的本發明IL-1 3抗體，該抗原決定基結合 域連接至重鏈之c末端或η末端，或c末端。實例包括一種 抗原結合蛋白，其包含以下所示之重鏈序列：SEQ ID NO: 26、SEQ ID NO: 28、SEQ ID NO: 30、SEQ ID NO: 32、 SEQ ID NO: 34、SEQ ID NO: 36、SEQ ID NO: 38、SEQ ID NO: 40 ' SEQ ID NO : 42、SEQ ID NO: 44、SEQ ID • NO: 46、SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52、SEQ ID NO: 54、SEQ ID NO: 98、SEQ ID NO: 100、 SEQ ID NO: 102、SEQ ID NO: 104、SEQ ID NO: 106或 SEQ ID NO: 117-138 ;及 SEQ ID NO: 24、SEQ ID NO: 108、SEQ ID NO: 110、SEQ ID NO: 112或 SEQ ID NO: 114 中所示之輕鏈序列，其中重鏈及輕鏈之一或兩者進一步包 含一或多個能夠拮抗IL-4之抗原決定基結合域，例如能夠 結合至IL-4之單可變域。此等抗原決定基結合域可選自 SEQ ID NO_· 78-81 及 94 中所示者。 在一實施例中，本發明之抗原結合構築體包含：SEQ ID NO: 62之重鏈序列及SEQ ID NO: 24之輕鏈序歹ij，或SEQ ID NO: 64之重鏈序列及SEQ ID NO: 24之輕鏈序列，或 SEQ ID NO: 66之重鏈序列及SEQ ID NO: 24之輕鏈序歹ij， 或SEQ ID NO: 68之重鏈序列及SEQ ID NO: 24之輕鏈序 歹|J，或SEQ ID NO: 70之重鏈序列及SEQ ID NO: 24之輕鏈 序列，或SEQ ID NO: 72之重鏈序列及SEQ ID NO: 24之輕 148186.doc -33- 201107345 鏈序歹|J，或SEQ ID NO: 74之重鏈序列及SEQ ID NO: 24之 輕鏈序列，或SEQ ID NO: 76之重鏈序列及SEQ ID NO: 24 之輕鏈序列。 在一實施例中，本發明之抗原結合構築體包含：SEQ ID NO: 94之重鏈序列及SEQ ID NO: 24之輕鏈序列，或SEQ ID NO: 96之重鏈序列及SEQ ID NO: 24之輕鏈序列，或 SEQ ID NO: 98之重鏈序列及SEQ ID NO: 24之輕鏈序列， 或SEQ ID NO: 100之重鏈序列及SEQ ID NO: 24之輕鏈序 列，或SEQ ID NO: 102之重鏈序列及SEQ ID NO: 24之輕 鏈序列，或SEQ ID NO: 104之重鏈序列及SEQ ID NO: 24 之輕鏈序列，或SEQ ID NO: 106之重鏈序列及SEQ ID NO: 2 4之輕鏈序列。 在一實施例中，本發明之抗原結合構築體包含：SEQ ID NO: 62之重鏈序列及SEQ ID NO: 108之輕鏈序列，或SEQ ID NO: 64之重鏈序列及SEQ ID NO: 108之輕鏈序列，或 SEQ ID NO: 66之重鏈序列及SEQ ID NO: 108之輕鏈序 列，或SEQ ID NO: 68之重鏈序列及SEQ ID NO: 108之輕 鏈序列，或SEQ ID NO: 70之重鏈序列及SEQ ID NO: 108 之輕鏈序列，或SEQ ID NO: 72之重鏈序列及SEQ ID NO: 108之輕鏈序列，或SEQ ID NO: 74之重鏈序列及SEQ ID NO: 108之輕鏈序列，或SEQ ID NO: 76之重鏈序列及SEQ ID NO: 108之輕鏈序歹，或SEQ ID NO: 62之重鏈序列及 SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 64之重鏈序 列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 66之重 148186.doc -34- 201107345 鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 68 之重鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 70之重鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 72之重鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 74之重鏈序列及SEQ ID NO: 110之輕鏈序列，或 SEQ ID NO: 76之重鏈序列及SEQ ID NO: 110之輕鏈序 列0
在一實施例中，本發明之抗原結合構築體包含：SEQ ID • NO: 96之重鏈序列及SEQ ID NO: 108之輕鏈序歹，或SEQ ID NO: 98之重鏈序列及SEQ ID NO: 108之輕鏈序歹，J，或 SEQ ID NO: 100之重鏈序列及SEQ ID NO: 108之輕鏈序 列，或SEQ ID NO: 102之重鏈序列及SEQ ID NO: 108之輕 鏈序列，或SEQ ID NO: 104之重鏈序列及SEQ ID NO: 108 之輕鏈序列，或SEQ ID NO: 106之重鏈序列及SEQ ID NO: 108之輕鏈序列，或SEQ ID NO: 96之重鏈序列及SEQ ID NO: 110之輕鏈序歹ij，或SEQ ID NO: 98之重鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 100之重鏈序列及 SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 102之重鏈序 列及SEQ ID NO: 110之輕鏈序歹ij，或SEQ ID NO: 104之重 鏈序列及SEQ ID NO: 110之輕鏈序列，或SEQ ID NO: 106 之重鏈序列及SEQ ID NO: 110之輕鏈序列。 在一實施例中，IL-13抗體重鏈係選自SEQ ]:D NO: 48、 SEQ ID NO: 50、SEQ ID NO: 52及 SEQ ID NO: 54 中所示 者。在另一實施例中，重鏈係選自SEQ ID NO: 88-91、 148186.doc -35- 201107345 SEQ ID NO: 96-106 及 SEQ ID NO: 117-138 中所示者。在一 此實施例中，重鏈係選自SEQ ID NO: 96、SEQ ID NO: 98、SEQ ID NO: 100、SEQ ID NO: 102、SEQ ID NO: 104 及 SEQ ID NO: 106。 在一實施例中，抗原結合蛋白將包含連至作為IL-5拮抗 劑之抗原決定基結合域的抗IL-13抗體，其中該抗il- 13抗 體包含選自SEQ ID NO: 3-18(例如SEQ ID NO: 15-18)中所 示者之CDRH3及SEQ ID NO: 24之輕鍵序列。 實例包括一種抗原結合蛋白，其包含SEQ ID NO: 26、 28 ' 30 ' 32 、 34 、 36 ' 38 ' 40 ' 42 、 44 、 46 ' 48 、 50 ' 52 或54中所示之重鏈序列及SEQ ID NO: 24中所示之輕鍵序 列，其中重鏈及輕鍵之一或兩者進一步包含一或多個能夠 抬抗IL - 5之抗原決定基結合域，例如能夠結合至IL - 5之免 疫球蛋白單可變域。 在另一實施例中，抗原結合蛋白將包含SEQ ID NO: 26、28 ' 30、32、34、36 ' 38、40、42、44、46、48、 50、52或54中所示之重鏈序列及SEQ ID NO: 24中所示之 輕鏈序列，其中重鏈及輕鏈之一或兩者進一步包含一或多 個能夠拮抗IL-4之抗原決定基結合域（例如能夠結合至IL_4 之免疫球蛋白單可變域）及一或多個能夠拮抗IL-5之抗原決 定基結合域（例如能夠結合至IL-5之免疫球蛋白單可變 域）。 在一實施例中，本發明之抗原結合蛋白包含至少—個抗 原決定基結合域，其能夠結合人血清白蛋白。 148186.doc -36· 201107345 在一實施例中，存在至少3個抗原結合位點’例如存在4 或5或ό或8或1 〇個抗原結合位點且抗原結合蛋白能夠結合 至少3或4或5或6或8或10種抗原，例如其能夠同時結合3或 4或5或6或8或10種抗原。 在一實施例中，第一抗原決定基結合域連接至蛋白骨架 且第一抗原決定基結合域連接至該第一抗原決定基結合 域，舉例而言，當蛋白骨架為IgG骨架時，第一抗原決定 基結合域可連接至IgG骨架之重鏈的c末端，且彼抗原決定 基結合域可在其c末端連接第二抗原決定基結合域，或舉 例而言，第一抗原決定基結合域可連接至IgG骨架之輕鏈 的C末端，且彼第一抗原決定基結合域可進一步在其c末端 連接至第二抗原決定基結合域，或舉例而言，第一抗原決 定基結合域可連接至IgG骨架之輕鏈的η末端，且彼第一抗 原決定基結合域可進一步在其〇末端連接至第二抗原決定 基結合域，或舉例而言，第一抗原決定基結合域可連接至 IgG骨架之重鏈的η末端’且彼第—抗原決定基結合域可進 步在其η末端連接至第二抗原決定基結合域。 田抗原决d结合域為結構域抗體時，—些結構域抗體 可匹配於骨架内之特定位置。 、用於本發明中之免疫球蛋白單可變域可連接於1 3 Ab之重鏈及/或輕鏈的c末端。此外，一些免疫球蛋白單 可變域可連接至習知抗體之重鏈與輕鏈紅末端。 在其中免疫球蛋白單可變域之N末端融合至抗體怪定域 (Ch3或CL)的構築體甲，肽連接子可有助於免疫球蛋白單 148186.doc -37- 201107345 可變域結合至抗原。實際上，dAb之N末端位於緊靠涉及 抗原結合活性之CDR處。因此，短肽連接子在抗原決定美 結合域與抗體之恆定域之間充當間隔子（spacer)，其可允 許dAb CDR更容易地到達抗原，因此可以高親和力結合。 免疫球蛋白單可變域連接至IgG之環境將視其融合至哪 條抗體鏈而變： 當在抗體叙鏈之C末端融合時’預期各免疫球蛋白單可 變域位於抗體鉸鏈及Fc部分附近。此等免疫球蛋白單可變 域彼此可能相隔較遠。在習知抗體申，Fab片段之間的角 度及各Fab片段與Fc部分之間的角度可顯著不同。就 mAbdAb而言，Fab片段之間的角度可能將不會迥然不同， 而對各Fab片段與以部分之間之角度可能會觀測到一些角 度限制。 _ 當在抗體重鏈之C末端融合時，預期各免疫球蛋白單可 變域位於Fc部分之Ch3域附近。預期此不會影響Fc對&受 體（例，FcYRI、FcyRII、FcyRm及FcRn)之結合性質，因 =此导^體與CH2域喝合（對於FcyRI、以师及^顧類 =體而5 )或與介於Ch2與Ch3域之間的鉸鏈嚙合（例如 :體)。此等抗原結合蛋白之另-特徵為預期兩個免疫球 单可變域在空間上彼此接近且若藉由供給適當連接子 :提供柔順性，則此等免疫球蛋白單可變域可甚至形成同 ::聚種類，因此擴展了 Fc部分的「拉鏈」㈣㈣四級 、，，。構，從而可增強構築體穩定性。 此等結構考慮 可有助於選擇最適合位置以將抗原決定基 148186.doc -38· 201107345 結合域（例如免疫球蛋白單可變域）連接至抗體上。 抗原之尺寸、其定位（於血液中或細胞表面上）、其四級 結構（單體或多聚體）可變化。習知抗體由於存在鉸鏈區而 容易設計成充當接附構築體（adaptor construct)，其中Fab 片段頂端之兩個抗原結合位點的定向可廣泛變化且因此適 應抗原之分子特徵及其環境。相反，連接至無鉸鏈區之抗 體的免疫球蛋白單可變域可能直接或間接地具有較小之結 構柔順性。 瞭解免疫球蛋白單可變域之溶解狀態及結合模式亦為有 盈的。已積累的證據表明’活體外人類dAb可主要呈溶解 之單體、同源二聚體或多聚體形式存在（Reiter等人，
(1999) J Mol Biol 290 第 685-698 頁；Ewert 等人，（2003) J
Mol Biol 325 ’ 第 53 1-553 頁；jespers等人，（2004) j M〇1
Biol 337 第 893-903 頁；Jespers 等人，（2004) Nat Biotechnol 22 第 1161-1165 頁；Martin 等人，（1997) Protein Eng· 10 第 607-614 頁；Sepulvada等人，（2003) J Mol Biol 333 第 355- 365頁）。可清楚地回顧活體内所觀測之。結構域之多聚化 事件’邊如本壤氏蛋白質（Bence-Jones protein)(其為免疫 球蛋白fe鍵之一聚體（Epp等人，（1975) Biochemistry 14第 4943-4952 頁 ’ Huan等人，（1994) Biochemistry 33 第 14848-14857 頁，Huang 等人 ’（1997) Mol immunol 34 第 1291-1301頁））及澱粉狀蛋白纖維（james等人，（2007) J Mol Biol. 367:603-8)。 舉例而言，可能需要將溶解時傾向於二聚合之dAb優先 •39- 148186.doc 201107345 連接至Fc部分的C末端而非輕鏈c末端，因為連接至以之^ 末端將允許彼等dAb在本發明之抗原結合蛋白情形下二聚 合0 本發明之抗原結合蛋白可包含對單一抗原具有特異性之 抗原結合位點，或可具有對兩種或兩種以上抗原，或對單 一抗原上之兩個或兩個以上抗原決定基具有特異性之抗原 結合位點，或可存在的抗原結合位點各對相同或不同抗原 上之不同抗原決定基具有特異性。 本發明之抗原結合蛋白可包含本發明之重鏈可變區及輕 鏈可變區，其可形成天然抗體或其功能片段或其等效物之 、”。構本發明之抗原結合蛋白因此可包含本發明之vh 區，其與適當輕鏈成對時形成全長抗體、（Fab,)2片段、 Fab片段、或其等效物（諸如scFV、雙功能抗體三功能抗 體或四功能抗體、四價雙特異性抗體（Tandab)等）。該抗體 可為 IgGl、igG2、IgG3、或 IgG4 ;或 lgM ; 、邮或
IgD或其經修飾變體。可相應選擇抗體重鏈之恆定域。輕 鏈匣疋域可為κ或λ恆定域。此外，抗原結合蛋白可包含所 有種類之修飾’例如IgG二聚體、不再結合&受體或介導 C1 q、、’°。之Fc突變體。抗原結合蛋白亦可為WO 86/01533 中所述類型之嵌合抗體，其包含抗原結合區及非免疫球蛋 白區。 根據任何所需功能性選擇恆定區。IgGl可藉由結合至補 體而顯不〉谷解能力及/或介導ADCC(抗體依賴型細胞介導 之細胞I性）。若需要非細胞毒性阻斷抗體，則可使用 148186.doc 201107345
IgG4。然而’ IgG4抗體在產生中可顯示不穩定性且因此一 種可選方案為修飾一般而言更穩定之IgGl。EP 0307434中 仏逃建議之修飾，例如位置235及237處之突變。本發明因 此提供一種溶解或非溶解形式之抗原結合蛋白，例如本發 明之抗體。 在某些形式中’本發明之抗體為全長（例如H2L2四聚體） /谷解或非溶解IgG丨抗體，其具有本文所述之任一重鏈可變 區。 在另一態樣中’本發明提供編碼如本文所述之輕鏈及重 鏈可變區的聚核苷酸。 在本發明之一實施例中，抗原結合位點結合至抗原的Kd 為至少約1 mM，例如結合至各種抗原的Kd為至少約i 〇 nM ’至少約1 nM ’至少約5〇〇 ，至少約20〇 pM，至少 勺100 pM或至少約50 pM，如經由BiacoreTM所量測。 在本發明之一實施例中，抗原結合位點結合至抗原的Kd 為至少約1 mM，例如結合至各種抗原的Kd為至少約i 0 nM ’至少約1 nM，至少約5〇〇 pM，至少約200 pM，至少 約100 ρΜ ’或至少約5〇 pM，如經由BiacoreTIV々量測。 在一實施例中，本發明提供抗原結合蛋白，其對人類 IL-13的親和力為包含SEq m NO: 22中所示之重鏈序列及 SEQ ID NO: 24中所示之輕鏈序列之抗比_13抗體的至少2 倍，或至少4倍’或至少6倍，或至少8倍，或至少1〇倍， 如經由Biacore所量測。 如通篇本說明書關於本發明抗原結合蛋白所用之術語 148186.doc 201107345 二和」及其文法變化形式意謂’相較於不存在此等抗原 .。合蛋白時之乩_13活性，存在本發明之抗原結合蛋白時 '生物/舌性凡全或部分降低。中和可歸因於（但不限 ;)、下或夕者.阻斷配位體結合、阻止配位體活化受 體、下調IL-i3受體或影響效應物功能性。中和程度可依 若干方式量測，例如使用如下文實例中所述之分析法，例 如TF1分析法’其可如例如實例4中所述進行。此分析法中 對IL 13、IL-4或此等兩種細胞激素的中和程度係藉由評估 中和抗原結合蛋白之存在對TF1細胞增殖的抑制作用來量 測。 #估中和程度之其他方法（例如評估在中和抗原結合蛋 白存在下之IL-13與其受體之間結合度的減少）在此項技術 中為已知且包括例如Biacore*析法。 在本發明之替代態樣中，提供具有與本文所例示抗體至 ;實質上相當之中和活性的抗原結合蛋白，例如在TF i細 胞增殖分析法中保持AlYl〇〇BAlaLl、AlYlOOBIleLl、 AlYlOOBTrpLl或AlYl〇〇BValLl之中和活性的抗原結合蛋 白’ s亥TF1細胞增殖分析法可如實例4中所述進行。 抗原結合蛋白（例如本發明之抗體）可藉由用包含本發明 之抗原結合蛋白之編碼序列的表現載體轉染宿主細胞產 生。表現載體手重組質體係藉由將抗原結合蛋白之此等編 碼序列定位在與能夠控制宿主細胞中之複製及表現及/或 宿主細胞之分泌的習知調節控制序列操作性連接來產生。 調節序列包括啟動子序列（例如CMV啟動子）及可來源於其 148186.doc -42- 201107345 他已知抗體之信號序列。類似地’可產生具有編碼互補抗 原結合蛋白輕鏈或重鏈之DN A序列的第二表現載體。在某 些實施例中，除編碼序列及可選擇標記以外，此第二表現 載體與第一表現載體相同，以儘可能確保各多肽鏈具有功 能上表現。或者，抗原結合蛋白之重鏈及輕鏈編碼序列可 存在於單個載體上。 經由習知技術，用第一載體與第二載體共轉染（或僅用 單個載體轉染）所選宿主細胞以產生本發明之經轉染宿主 細胞’其包含重組或合成輕鏈與重鏈。接著經由習知技術 培養經轉染細胞，以產生本發明之經工程改造抗原結合蛋 白。藉由適當分析法（諸如ELISA或RIA)自培養物中篩檢包 括相聯結之重組重鏈與/或輕鏈的抗原結合蛋白。類似習 知技術可用於構築其他抗原結合蛋白。 熟習此項技術者可選擇用於本發明之方法及組合物建構 中之選殖及次選殖步驟的適合載體。舉例而言，可使用習 知puc系列之選殖載體。一種載體，pUC19，可自供應機 構（諸如 Amershan^Buckinghamshire，United Kingdom)或 PharmaciaCUppsala，Sweden))購得。另外，能夠輕易複 製、具有豐裕選殖位點及可選擇基因（例如抗生素抗性基 因）且易於操作之任何載體可用於選殖。因此，選殖載體 之選擇不為本發明中之限制因素。 表現載體亦可由適於擴增異源DNa序列之表現的基因 (例如甫礼動物一氫葉酸還原酶基因（dhfr))表徵。其他載 體序列包括poly A信號序列（諸如牛生長激素（BGH)之p〇ly 148186.doc •43· 201107345 A信號序列）及β球蛋白 文中之表現載體可經 成。 啟動子序mbetag，。）。適用於本 由熟習此項技術纟熟知t技術來合 此等載體之組分(例如複製子、選擇基因、增強子、啟 料、信號序列及其類似組分）可自商業或天然來源獲得 或經由用於指導在所選宿主中表現及/或分泌重組舰之 產物的已知程序來合成。為此目的亦可選擇在此項技術中 已知用於哺乳動物、細帛、昆蟲、酵母、及真菌表現的許 多類型的其他適當表現載體。 本發明亦涵蓋經含有本發明抗原結合蛋白之編碼序列之 重組質體轉染的細胞株。適用於此等選殖载體之選殖及其 他祐作的佰主細胞亦為習知的。然而，來自大腸桿菌之各 種菌株的細胞可用於選殖載體之複製及建構本發明抗原結 合蛋白的其他步驟。 適合表現本發明之抗原結合蛋白的宿主細胞或細胞株包 括哺乳動物細胞（諸如NS0、Sp2/〇、CHO(例如；dG44)、 COS、HEK)、纖維母細胞（例如3T3)及骨髓瘤細胞，舉例 而言，本發明之抗原結合蛋白可在CHO或骨髓瘤細胞中表 現。可使用人類細胞，從而使分子能夠經由人類糖基化模 式修飾。或者，可使用其他真核細胞株。適合哺乳動物宿 主細胞之選擇及用於轉型、培養、擴增、篩檢及產物產生 及純化之方法在此項技術t為已知的。參見，例如上文引 用之Sambrook等人。 細菌細胞經證實可適用作適於表現重組Fab或本發明之 148186.doc • 44· 201107345 其他實施例的宿主細胞（參見，例如Pliickthun，A.， Immunol. Rev., 130: 1 5 1 -1 88 (1992))。然而，由於細菌細 胞中所表現的蛋白質易呈未摺疊或不適當摺疊形式或非糖 基化形式，因此需篩檢細菌細胞中所產生之任何重組Fab 以保留抗原結合能力。若細菌細胞所表現之分子呈適當摺 疊形式產生’則彼細菌細胞為所需宿主，或在替代實施例 中，分子可在細菌宿主中表現且隨後再摺疊。舉例而言， 用於表現之大腸桿菌之各種菌株在生物技術領域中作為宿 主細胞已熟知。在此方法中亦可使用枯草芽孢桿菌（凡 wh/D)、鏈黴菌、其他桿菌之各種菌株及 類似物。 需要時，亦可利用熟習此項技術者已知之酵母細胞菌株 以及昆蟲細胞（例如果蠅（Dros〇phiia)及鱗翅目昆蟲 (Lepidoptera))及病毒表現系統作為宿主細胞。參見，例如
Miller 等人，Genetic Engineering，8: 277-298，Plenum
Press (1986)及其令所引用之參考文獻。 可藉以建構載體之一般方法、產生本發明之宿主細胞所 需之轉染方法、及自此宿主細胞中產生本發明抗原結合蛋 白所需之培養方法皆可為f知技術。本發明之培養方法通 4為無血仴培養方法’其一般藉由在無血清懸浮液中培養 ' 同樣本發明之抗原結合蛋白產生後即可根據此項 技術之知準程序（其包括硫酸銨沈澱、親和管柱、管柱層 析法；疑膠電冰法及類似方法)自細胞培養内含物中純 化。此等技術在此項技術之技能範圍内且不限制本發明。 148186.doc -45· 201107345 舉例而言’ WO 99/58679及WO 96/16990中描述變異抗體 之製備。 然而表現抗原結合蛋白之另一方法可利用轉殖基因動物 中之表現’諸如美國專利第4,873,3 16號中所述。此係關於 一種使用動物路蛋白啟動子之表現系統，當以轉殖基因方 式併入哺乳動物中時，其允許雌性動物於其乳中產生所需 重組蛋白質。 在本發明之另一態樣中’提供一種產生本發明之抗體的 方法°玄方法包含培養經編碼本發明抗體之輕鏈及/或重 鏈之載體轉型或轉染的宿主細胞及回收藉此產生之抗體的 步驟。 根據本發明，提供一種產生本發明之抗IL_丨3抗體的方 法，該IL-13抗體結合至人類几_13且中和人類ILn之活 性’該方法包含以下步驟： a) 提供編碼該抗體重鏈之第一載體； b) 提供編碼該抗體輕鏈之第二載體； 0用該第一及第二載體轉型哺乳動物宿主細胞（例如 CHO); d) 在可增進該抗體自該宿主細胞分泌進入該培養基中之條 件下培養步驟（c)之宿主細胞； e) 回收步驟（d)之分泌抗體。 抗體經由所需方法表現後，接著藉由使用適當分析法檢 驗其活體外活性。目前使用習知ELISA分析法形式來定2 及疋里#估抗體與IL-13之結合。另外，亦可使用其他、， I48186.doc -46· 201107345 =分析法驗證中和功效，隨後執行人類臨床研究以評估 抗體於體内的續存(不論常見清除機制）。 治療劑量及持續時間係關於本發明分子在人體循環中的 =持續時間’且可視所治療錄及患者之-般健康狀況 由熟習此項㈣者調整。預計可能需要長期（例如四至六 個月）重複、藥（例如_週—次或每兩週—次）以達成最大治 療功效。 σ
發明治療劑之投藥模式可為將藥劑傳遞至宿主的任何 適當途徑。本發明之抗原結合蛋白及醫藥組合物尤其適用 於非經腸(亦即皮下(s.c.)、勒内、腹膜内、肌肉内、 靜脈内（i.v.)或鼻内）投與。 本發明之治療劑可製備成於醫藥學上可接受之载劑中含 有有效量之本發明抗原結合蛋白作為活性成份的醫藥組合 物。在-實施例中，本發明之預防劑為呈備妥注射形式之 含有抗原結合蛋白的水性懸浮液或溶液。在一實施例中， 懸浮液或溶液在生理pH值下經緩衝。在一實施例中，非經 腸投藥之組合物將包含溶於醫藥學上可接受之载劑令之本 發明抗原結合蛋白或其混合物（c〇cktail)的溶液。在—實施 例中，載劑為水性載劑。可使用多種水性載劑，例如〇 鹽水、0.3%甘胺酸及其類似物.此等溶液可製備為無菌且 —般不含顆粒物質。此等溶液可經由習用、熟知滅菌技術 (例如過濾）進行滅菌。組合物可含有接近生理條件所需之 醫藥學上可接受之助劑，諸如pH值調節劑及緩衝劑等。本 發明抗原結合蛋白在此等醫藥調配物中之濃度可廣泛錄 148I86.doc -47- 201107345 化’亦即’小於約〇·5重量％( 置逋*為或至少約丨重量％)至多 達約15重量％或20重量％，曰士西社 咕 $。且主要基於流體體積、黏度 #、根據所選特定投藥模式選擇。 因此’用於肌肉内注射之本發明醫藥組合物可製備成含 有約i mL無菌緩衝水，及介於約i ng至約i〇〇mg，例如約 ng至約30 mg或約5 mg至約25邮之間的抗原結合蛋 白，例如本發明之抗體。類似地，用於靜脈内輸注之本發 明醫藥組合物可製備成含有約25〇1111無菌林格氏液 (Ringer's solution)、及每毫升林格氏液約1 mg至約3〇 mg 或5 mg至約25 mg之本發明抗原結合蛋白。製備可非經腸 投與之組合物之實際方法為熟知的或對於熟習此項技術者 顯而易知，且更詳細描述於例如Remingt〇n，s Pharmaceutical Science ’ 第 ι5 版，Mack Publishing Company，Easton，Pennsylvania中。對於製備本發明之可靜 脈内投與之抗原結合蛋白調配物，參見Lasmar U及Parkins D 厂 The formulation of Biopharmaceutical products
Pharma. Sci.Tech.today，第 129-137頁，第 3卷（2000年4月 3 日)；Wang，W「Instability, stabilisation and formulation of liquid protein pharmaceuticals」，Int. J. Pharm 185 (1999) 129-188 ； Stability of Protein Pharmaceuticals Part A and B
Ahern T.J.編，Manning M.C,，New York，NY: Plenum Press (1992) ； Akers, M.J. 「Excipient-Drug interactions in Parenteral Formulations」，J. Pharm Sci 91 (2002) 2283- 2300 ; Imamura，K等人’「Effects of types of sugar on 148186.doc -48- 201107345 stabilization of Protein in the dried state」，J Pharm Sci 92 (2003) 266-274 ; Izutsu，Kkojima，S·「Excipient crystalinity and its protein-structure-stabilizing effect during freeze-drying」，J Pharm. Pharmacol，54 (2002) 1033-1039 ; Johnson, R，「Mannitol-sucrose mixtures-versatile formulations for protein lyophilization」，J. Pharm· Sci, 91 (2002) 914-922 及 Ha，E Wang W，Wang Y.j.「Peroxide formation in polysorbate 80 and protein stability」，J_ Pharm Sci, 91, _ 2252-2264,(2002) ’其全部内容以引用的方式併入本文中 且讀者特定參考該等文獻。 在一實施例中’本發明之治療劑當含於醫藥製劑中時， 係呈單位劑量形式存在。熟習此項技術者將輕易地確定適 當治療有效劑量。適用於患者之劑量可根據患者體重計 算’舉例而言，適合劑量的範圍可為約〇.丨至約2〇 mg/kg， 例如約1至約20 mg/kg ’例如約1〇至約20 mg/kg或例如約1 籲 至約I5 mg/kg ’例如約1〇至約is mg/kg。為了有效治療人 類病狀（諸如哮喘或IPF)，本發明之抗原結合蛋白的適合劑 量可在以下範圍内.約〇. 1至約1 〇 〇 〇 m g，例如約〇 · 1至約 500 mg，例如約500 mg，例如約〇」至約1〇〇 mg，或約〇」 至約80 mg，或約0.1至約60 mg，或約〇·〗至約4〇 mg，或例 如約1至約100 mg，或約i至約50 mg，其可非經腸（例如皮 下、靜脈内或肌肉内）投與。需要時，可在由醫師酌情所 選之適當時間間隔下重複此劑量。 本文所述的抗原結合蛋白可凍乾以便儲存且在使用之前 -49- 148186.doc 201107345 於適合載劑中復原。此技術已顯示對習知免疫球蛋白有效 且可使用此項技術已知之凍乾及復原技術。 在另—態樣中，本發明提供—種包含本發明抗原結合蛋 白或其功能片段及醫藥學上可接受之載劑的醫藥組合物以 治療或預防特異反應性疾病/病症及慢性發炎性疾病/病 症，例如哮喘，諸如過敏性哮喘，特定言之，嚴重哮喘 (亦即對當前治療（包括全身投與皮質類固醇）無反應之哮 喘；參見BUsse WW等人，j AUergy CHn2〇〇〇， 1=06: ι〇33_1042)、「難治性」哮喘（定義為特徵為儘管投與 最大推薦劑量之處方吸入類固醇但仍無法得到控制之哮喘i 表型，參見 Barnes PJ (1998)，Eur Respir J 12:1208_1218)、 脆性J哮喘（定義患有嚴重不穩定哮喘的患者亞群其 儘管投與高劑量之吸入類固醇，但仍維持寬尖峰呼氣流量 (PEF)變化性，參見 Ayres JG 等人，（1998) 58:315_ 321)、夜間哮喘、經前哮喘、抗類固醇哮喘（參見 Woodcock AJ，（1993) Eur Respir ; 6:743 747)、類固醇依賴 型哮喘（定義為僅可用高劑量口服類固醇控制之哮喘）、阿鲁 斯匹靈誘發型哮喘、成年發作型哮喘、小兒哮喘。本發明 之抗體可用於預防、降低急性哮喘發作（持續性哮喘）之頻 率或緩和其效應。本發明之抗體亦可用於降低在治療哮喘 中所用之其他藥劑的所需給藥（在投藥量或給藥頻率方 面）。舉例而言，本發明之抗體可用於降低類固醇治療（諸 如皮質類固醇治療）哮喘所需之給藥（「類固醇節省」）。其 他可用本發明之抗體治療之疾病或病症包括異位性皮膚 148186.doc •50· 201107345 人過敏性鼻火、克隆氏病、慢性阻塞性肺病（C〇pD)、 嗜伊紅血球食道炎、纖維變性疾病或病症（諸如特發性肺 纖維化、進行性全身性硬化（硬皮病）、肝纖維化）、肝肉芽 瘤、血吸蟲病、利什曼體病及細胞週期調節疾病（例如霍 奇金氏病、B細胞慢性淋巴細胞白血病）。在一實施例中， 病症為嚴重哮喘。在另一實施例中，病症為纖維變性病 症，諸如IPF。 在另-態樣中，本發明提供-種包含本發明抗原結合蛋 白或其功能片段及醫藥學上可接受之載劑的醫藥組合物以 治療特異反應性疾病/病症及慢性炎性疾病/病症，例如哮 喘，諸如過敏性哮喘，特定言之，嚴重哮喘（亦即對當前 治療化括全身投與皮質類固醇）無反應之哮喘；參見 WW等人 ’ j Allergy Clin. Immun〇i 2000，106: 1033· 1042)、「難治性」哮喘（定義為特徵為儘管投與最大推篇劑 量之處方吸入類固醇但仍無法得到控制 φ -職 Η ⑽8)，EurRespH12:12G8_1218)、「^^ 喘（定義患有嚴重不穩定哮喘的患者亞群，其儘管投與高 劑量之吸入類固醇，但仍維持寬尖峰呼氣流量（pEF)變化 性，參見Ayres JG等人，（1998) Th⑽χ 58 3 15 321)、夜間 哮喘、經前哮喘、抗類固醇哮喘（參見w〇odcockAJ，（1993) Eur^espir J 6:743_747)、類固醇依賴型哮喘（定義為僅可 用问劑里口服類固醇控制之哮喘卜阿斯匹靈誘發型哮 而成年毛作型孝^而、小兒哮嗓。本發明之抗體可用於預 防降低心性哮喘發作（持續性哮喘）之頻率或緩和其效 148186.doc -51· 201107345 應。本發明之抗體亦可用於降低在治療哮喘中所用之其他 藥劑的所需給藥（在投藥量或給藥頻率方面）。舉例而言， 本發明之抗體可用於降低類固醇治療（諸如皮質類固醇治 療）哮喘所需之給藥（「類固醇節省」）。其他可用本發明之 抗體治療之疾病或病症包括異位性皮膚炎、過敏性鼻炎、 克隆氏病、慢性阻塞性肺病（C0PD)、嗜伊紅血球食道 炎、纖維變性疾病或病症（諸如特發性肺纖維化、進行性 全身性硬化（硬皮病）、肝纖維化）、肝肉芽瘤、血吸蟲病、 利什曼體病及細胞週期調節疾病（例如霍奇金氏病、B細胞 慢性淋巴細胞白血病）。在一實施例中，病症為嚴重哮 °而。在另一貫把例中’病症為纖維變性病症，諸如。 應瞭解本文所述序列（SEQ ID NO: 26至SEQ ID NO: 55 及SEQ NO: 62至SEQ ID NO: 146)包括與本文所述序列實 質上一致之序列，例如至少90% 一致之序列，例如至少 91%，或至少92%，或至少93%，或至少94%，或至少 95〇/。’或至少96% ’或至少97%或至少98%，或至少99%_ 致之序列。 對於核酸而言，術語「實質一致性」指示當利用適當核 苦酸插入或缺失進行最佳比對及比較時，兩個核酸或其指 定序列在至少約80%核苷酸，至少約90%至約95%，咬至 少約98%至約99.5%核苷酸上一致。或者，當區段在選擇 性雜交條件下與互補股雜交時，存在實質一致性。 對於核苷酸及胺基酸序列而言，術語「一致」指示當利 用適當插入或缺失進行最佳比對及比較時，兩個核酸或胺 148186.doc -52· 201107345 基酸序列之間的一致性程度。或者，當DNA區段在選擇性 雜父條件下與互補股雜交時，存在實質一致性。 在考慮兩個序列最佳比對所需引入之間隙數及各間隙之 長度的情況下，兩個序列之間的一致性百分比為該等序列 所共有之相同位置數的函數（亦即一致性％=相同位置數/總 位置數X 100)。如下文非限制性實例中所述，可使用數學 演算法比較序列及確定兩個序列之間的一致性百分比。 可使用GCG套裝軟體中之gap程式、使用 NWSgapdna.CMP矩陣及間隙權重4〇、5〇、60 ' 70或80及 長度權重1、2、3、4、5或ό確定兩個核苷酸序列之間的一 致性百分比。亦可使用已併入ALIGN程式（2.0版）中之Ε.
Meyers及 W. Miller之演算法（c〇mpUt_ Appl. Biosci., 4:11_ 17 (1988))、使用 PAM120 權重殘基表（weight residue table)、間隙長度罰分12及間隙罰分4確定兩個核苷酸或胺 基酸序列之間的一致性百分比。此外，可使用已併入gcg 套襄軟體之GAP程式中的Needleman及Wunsch(J. Mol.
Biol· 48·444-453 (1970))演算法、使用 Bi〇ssum 62矩陣或 PAM250矩陣及間隙權重16、14、12、10、8、6或4及長度 權重1、2、3、4、5或ό確定兩個胺基酸序列之間的一致性 百分比。 舉例而言’本發明之聚核苷酸序列可與SEq ID Ν〇: 25 之〆考序列致，亦即10 0 % —致，或其相較於該參考序 列可包括多達某整數個核苷酸變異。此等變異係選自由以 下組成之群：至少一個核苷酸缺失、取代（包括轉移及易 148186.doc -53- 201107345 位）或插入’且其中該等變異可發生於參考核苷酸序列之5， 或3末端位置處或彼等末端位置之間的任何位置處㈠固別地 散置於參考序列之核苦酸中或以一或多個鄰接群散置於參 考序列内）。如下確定核苷酸變異數：以各別一致性百分 比之百分比數值（除以100)乘SEQ ID N〇: 25中之核苷酸總 數且自SEQ ID NO: 25中之核苷酸之該總數中減去彼乘 積，或： nn < xn-(xn · y) > 其中nn為核苷酸變異數’仙為SEq id NO: 25中之核苷酸 總數，且y對於50%為0.50 ,對於6〇%為〇 60 ,對於7〇%為 0.70，對於80%為〇.8〇，對於85%為〇 85，對於9〇%為 0.90，對於95%為0.95，對於97%為〇 97或對於1〇〇%為 1.00，且其中xn與y之任何非整數乘積在自χη中將其減去 之前向下捨入至最接近之整數。SEQ m Ν〇: 25之聚核苷 酸序列的變異可在此編碼序列中產生無意義（n〇nsense)、 5吳義（missense)或讀框轉移（frameshjft)突變且藉此使發生 此等變異後之聚核苷酸所編碼的多肽變異。 類似地，在另一實例中，本發明之多肽序列可與由SEQ ID NO: 24編碼之參考序列一致，亦即1〇〇%一致，或其相 較於該參考序列可包括多達某整數個胺基酸變異，從而一 致性％小於100%。此等變異係選自由以下組成之群：至少 一個胺基酸缺失、取代（包括保守及非保守取代）或插入， 且其中該等變異可發生於參考多肽序列之胺基或羧基末端 位置處或彼荨末端位置之間的任何位置處（個別地散置於 148186.doc -54- 201107345 參考序列之胺基酸中或以-或多個鄰接群散置於參考 内)。既定一致性%之胺基酸變異數係藉由以各別一致性百 分比之百分比數值（除以_乘SEQ ID N〇: 24所編碼之: 肽序列中之胺基酸總數且接著自SEQ ID N〇: 24所編碼1 多肽序列之該胺基酸總數中減去彼乘積來確定，咬 na < xa-(xa · y),
其中na為胺基酸變異數’ xa為SEQ ID N〇: 24所編碼之多 肽序列之胺基酸總數，且y例如對於7〇%為〇·7〇，對於 為0.80’對於85%為0.85等，且其之任何非整數乘0 積在自xa中將其減去之前向下捨入至最接近之整數。 下列實例說明但不限制本發明。 實例 實例1 -建構重組抗IL -13抗體 藉由重組人類IL- 1 3免疫小鼠來產生初始鼠類mAb。收 集有反應動物之脾且與骨髓瘤細胞融合中以產生融合瘤。 針對結合來篩檢融合瘤上清液物質。使用標準技術單選殖 相關融合瘤。所得鼠類抗體（6A1)包含SEQ ID NO: 58及 SEQ ID NO: 59中所示之可變區。此鼠類抗體及此抗體 A1L1(SEQ ID NO: 22及24)之人類化形式的其他詳情描述 於WO 2006/003407中’該文獻以引用的方式併入本文中。 抗IL-13 mAb抗體A1L1在若干下列實例中作為比較抗體使 用。 產生包含SEQ ID NO: 22中所示之重鏈之人類化抗體的 許多變體。此等變體在抗體之CDRH3區（SEQ ID NO: 3)皆 148186.doc •55· 201107345 不相同。 藉由建立重疊寡核苷酸來重新製備本發明抗體之基本 DNA表現構築體SEQ ID NO: 23(重鏈）及SEQ ID NO: 25(輕 鍵）’該等重疊寡核苷酸包括用於選殖入Rld及Rln哺乳動 物表現載體中之限制性位點以及人類信號序列。引入Hind III及Spe I限制性位點以框住含有用於選殖入Rid中之信號 序列（SEQ ID NO: 56)的VH域，該Rid含有人類γΐ恆定區。 引入Hind III及BsiW I限制性位點以框住含有用於選殖入 Rln中之k號序列（seq ID NO: 56)的VL域，該Rln含有人類 κ恆定區。使用亦包括人類恆定區之ρττ載體產生替代構築 體。適當時，使用定點突變誘發（SDM)產生不同人類化構 築體。 實例2-抗體表現於hek 293 6Ε細胞中 將分別編碼重鏈及輕鏈之pTT質體短暫共轉染於ΗΕΚ 293 6E細胞中且小規模表現以產生抗體。評估直接來自組 織培養液上清液中的抗體。使用固定蛋白質A管柱純化其 他抗體且藉由讀取280 nm下之吸光度進行定量且需要時， 在下述實例所述中之分析法中評估該純化的抗體物質。 當用代碼（亦即AlYlOOBTrpLl)提及抗體時，係指藉由 所述第一及第二質體之共轉染及表現所產生之mAb ,例如 「AlYlOOBTrpLl」係關於藉由將含有AlYlOOBTrp序列之 質體與含有L1序列之質體共轉染於適合細胞株中所產生的 mAb。 實例3-抗IL-13人類化mAb之Biacore分析 148186.doc -56- 201107345 動力學分析 在ProteOn XPR3 6(Biorad)上進行CDRH3突變體之初始篩 檢。方法如下：藉由一級胺偶聯使抗人類IgG(Biacore BR-1008-3 9)固定在GLM晶片上，接著CDRH3突變體抗體捕捉 於此表面上且IL13在256、64、16、4、1 nM下通過（0 nM 進樣（亦即僅用緩衝液）用作雙重參照）。使用3 M MgCl2再 生捕捉表面，移除所結合CDRH3突變體抗體為另一輪捕捉 及分析物進樣作準備。使用機器固有軟體針對1:1模型擬 ® 合數據。所有研究皆使用直接來自組織培養液上清液中之 抗體，作為純化物質之親本抗體除外。 篩檢鑑別似乎比親本分子具有更佳動力學概況之多種抗 體，接著使用類似方法在Biacore T100上分析此等相同樣 品以證實結果，其中藉由一級胺偶聯使抗人類IgG捕捉抗 體固定在CM5晶片上，IL13在256、64、16、4、1及0.25 nM下通過表面（0 nM用作雙重參照），用3 M :MgCl2再生且 針對T1 00固有之1:1模型擬合數據。表1詳述來自ProteOn 篩檢及T100操作之所選構築體的總親和力（平衡解離常數 KD)。 表1 分子 ProteOn K〇(pM) Biacore Κ〇(ρΜ) AlS95TrpLl 不可分析 216 AlI96ValLl 395 696 AlY97PheLl 683 618 AlD98GluLl 873 779 AlHlOOAAlaLl 不可分析 172 148186.doc •57· 201107345 A1H100A GluLl 110 195 AlHlOOAGlnLl 195 278 AlHlOOAArgLl 256 307 A1H100A SerLl 131 174 AlHlOOAThrLl 158 211 A1H100A ValLl 112 152 A1Y100B AlaLl 75 83 A1Y100B IleLl 75 73 AlYlOOBTrpLl 68 95 A1L1 〜450-600* 366 *A1L1在ProteOn篩檢期間操作了若干次因此為所得數值之 範圍。 數據強調了 Y1 00B殘基處之若干突變似乎會改良總親和 力。據此，使用ProteOn、使用如前所述之相同方法且再 次使用直接來自組織培養液上清液中之抗體來測試不存在 於初始篩檢中之此殘基處的突變。在所測試之突變中， A1Y100B ValLl似乎改良總親和力（平衡解離常數KD)，相 較於0·390-0·460 nM之親本值，所得值為0.166 nM。當使 用如前所述之相同方法在Biacore T100上測試Y100B Val 時，相較於0.346 nM之親本值，所量測之平衡解離常數KD 為 0.025 nM。 根據迄今使用直接來自組織培養液上清液中之抗體突變 體所進行之研究，產生A1Y100BL1突變體Ala、lie及Trp的 純化抗體。此等純化抗體（包括在此階段未純化之 A1Y100B ValLl突變體）皆使用如前所述之相同方法在 Biacore T100上操作。表2展示得自此實驗之數據。 148186.doc -58- 201107345 表2 分子 kaCM^s1) kd(s-1) KD(nM) AlYlOOBValLl(上清液） 1.018E+6 3.455E-5 0.034 A1Y100B AlaLl 9.599E+5 3.004E-5 0.031 A1Y100B IleLl 1.149E+6 5.584E-5 0.049 AlYlOOBTrpLl 2.572E+6 1.627E-4 0.063 A1L1 1.267E+6 4.560E-4 0.360 實驗證實突變體相較於親本分子確實會改良對IL13之結 合親和力。 若純化A1Y100BL1突變體產生的結合親和力優於獲自組 Φ 織培養液上清液中之彼等者，則純化A1Y100B ValLl且與 親和力亦改良之其他純化A1Y100BL1突變體一起使用前述 方法、使用Biacore T100機器操作。表3展示得自此實驗之 數據。此實驗與表2中數據良好吻合且證實Y100B突變使 親和力改良。 表3 分子 ka(M-1s-1) kd(s-1) K„(nM) A1Y100B IleLl(純化） 9.886E+5 4.214E-5 0.043 AlYlOOBValLl(純化） 7.757E+5 2.123E-5 0.027 A1Y100B AlaLl(純化） 8.096E+5 2.583E-5 0.032 AlY100BTrpLl〇Mt) 2.385E+6 1.253E-4 0.053 A1L1 (純化） 1.128E+6 3.677E-4 0.326 實例4-在細胞增殖生物分析法中對大腸桿菌所表現之重組 人類IL-13之中和 TF-1細胞回應於許多不同細胞激素（包括人類IL-13)而增 殖。此等細胞對於IL-1 3之增殖反應因此可用於量測IL-1 3 之生物活性且隨後已開發一種分析法以測定mAb中和IL-1 3 148186.doc -59- 201107345 之效能（抑制IL -13生物活性）。 該分析法在無菌條件下於無菌96孔組織培養盤中進行且 所有測試孔皆一式三份進行。將14 ng/ml經重組大腸桿菌 表現之人類IL-13與各種稀釋度之mAb(通常自93.4 nM以3 倍稀釋度滴定至0.014 nM)在37°C下一起預培育1小時。無 關特異性之抗體作為陰性對照以類似方式滴定。接著將此 等樣品添加至無菌96孔組織培養盤中之50 μΐ TF-1細胞（每 毫升2xl〇5個細胞之濃度）中。因此最終1〇〇 μ1分析體積含 有各種稀釋度之mAb(46.7 nM以3倍稀釋度滴定至0.007 nM 之最終濃度）、重組大腸桿菌表現之人類IL-13(7 ng/ml之最 終濃度）及TF-1細胞（每毫升1 X 1 〇5個細胞之最終濃度）。分 析盤在含濕氣C〇2培育箱中在37°C下培育約3天。接著使用 購自Promega之「CellTitre 96®非放射性細胞增殖分析法」 (產品目錄第G4100號）如製造商說明書中所述來測定細胞 增殖量。96孔盤中之樣品的吸光度於讀盤器中在570 nm下 讀取。 mAb中和重組大腸桿菌所表現之人類IL_丨3生物活性的 能力表述為將一定量之人類IL-1 3(7 ng/ml)之生物活性中和 50%所需之mAb的濃度（=ND5。）。所需mAb之濃度越低，則 中和能力越強。使用Microsoft Excel中之Robosage來計算 本文提供之ND50數據（表4)。數據之圖形表示可見於圖1 中。 148186.doc -60- 201107345 表4 分子 NDso(nM) 標準誤差(nM) A1L1 9.77 34.82 AlYlOOBAlaLl 0.92 0.08 AlYlOOBIleLl 1.10 0.21 AlYlOOBTrpLl 1.25 0.34 實例5-建構及表現包含CDRH3變體抗IL-13 mAb之mAb-dAb 使用標準分子生物學技術，將編碼A1抗體之CDRH3變 ^ 體重鍵可變區之各序列的基因自現有構築體轉移至含有 hlgG 1恒定區的表現載體中’該higG 1恒定區在其c末端經 由TVAAPS或ASTKGPS連接子融合至抗人類il-4結構域抗 體（DOM9-112-210)。所建構重鏈之詳情列於表5中。 表5
分子編號 名稱 描述 蛋白質 SeqlD DNA SeqlD BPC1624 AlYlOOBAlaH-TVAAPS-210 L1 H 鏈=AlY100BAlaH 鏈-TVAAPS連接子_ DOM9-112-210dAb 62 63 L 鏈=L1 24 25 BPC1625 AlYlOOBIle H-TVAAPS-210L1 H 鏈=AlY100BIleH鏈-TVAAPS 連接子-DOM9-112-210 dAb 64 65 L 鍵=L1 24 25 BPC1626 AlYlOOBTrpH- TVAAPS-210L1 H 鏈=AlY100BTrpH鏈-TVAAPS 連接子-DOM9-112-210 dAb 66 67 L 鏈=L1 24 25 148186.doc -61 - 201107345 BPC1627 AlYlOOBVal H-TVAAPS-210L1 H鏈=AlY100BValH 鏈-TVAAPS 連接子-DOM9-112-210 dAb 68 69 L 鏈=L1 24 25 BPC1628 AlYlOOBAla H-ASTKGPS-210 LI H 鍵=AlY100BAlaH 鏈-ASTKGPS連接子-DOM9-112-210dAb 70 71 L 鍵=L1 24 25 BPC1629 A1 YlOOBIle H-ASTKGPS-210 LI H 鏈=AlY100BIleH鏈-ASTKGPS連接子-DOM9-112-210dAb 72 73 L 鏈=L1 24 25 BPC1630 AlYlOOBTrpH-ASTKGPS-210 LI H鏈=AlY100BTrpH鏈· ASTKGPS連接子-DOM9-112-210dAb 74 75 ( L 鏈=L1 24 25 BPC1631 AlYlOOBVal H-ASTKGPS-210L1 H鏈=AlY100BValH鏈- ASTKGPS連接子- DOM9-112-210dAb 76 77 L 鏈=L1 24 25 在 HEK293 細月包中表現 BPC1624、BPC1625、BPC1626及 8?01627。簡而言之，用預先經293【6〇1:111試劑（11^1；1'〇呂611# 51-0031)培育之重鏈及輕鏈表現質體共轉染250 ml(1.5xl06 · 個細胞/毫升）HEK293細胞。此等細胞於振盪培育箱中、在 37°C、5% C02及95%相對濕度下置放。24小時後添加胰化 蛋白饋料培養基且細胞再生長5天。離心收集上清液且無 菌過濾。使用固定蛋白質A管柱、經由親和層析法來純化 所表現之分子且藉由量測280 nm下之吸光度來測定濃度。 經由尺寸排阻層析法（size exclusion chromatography)測定 純化樣品中之聚集蛋白質的含量。純化蛋白質之產量及聚 148186.doc •62· 201107345 集程度展示於表5b中。 表5b BPC 名稱 產量 聚集物％ BPC1624 586Y100BA H-TVAAPS-210 0.81 mg 3.6% BPC 1625 586Y100BIH-TVAAPS-210 0.944 mg 6.7% BPC 1626 586Y100BW H-TVAAPS-210 1.14 mg 5.5% BPC 1627 5 86Y100BV H-TVAAPS-210 1.26 mg 8.4% 實例6_包含CDRH3變體抗IL-13 mAb之mAb-dAb之中和活 性數據 在TF-1細胞增殖生物分析法中測試包含CDRH3變體抗 IL-13 mAb的mAb-dAb對大腸桿菌所表現之重組人類IL-13 的中和程度。 該分析法在無菌條件下於無菌96孔組織培養盤中進行且 所有測試孔皆一式三份進行。將約20 ng/ml經重組大腸桿 菌表現之人類IL-13與各種稀釋度之mAbdAb(通常自50 nM 以3倍稀釋度滴定至0.02 nM)(彼等mAbdAb於HEK細胞中製 備且如實例5中所述純化）以50 μΐ總體積在3 7°C下預培育1 小時。無關特異性之抗體作為陰性對照以類似方式滴定 (數據未示）。接著將此等樣品添加至無菌96孔組織培養盤 中之50 μΐ TF-1細胞（每毫升2xl〇5個細胞之濃度）中。因此 最終100 μΐ分析體積含有各種稀釋度之mAbdAb(25 nM以3 倍稀釋度滴定至0.01 nM之最終濃度）、重組大腸桿菌表現 之人類IL-13(10 ng/ml之最終濃度）及TF-1細胞（每毫升 1 X 105個細胞之最終濃度）。分析盤在含濕氣C〇2培育箱中 在37。(3下培育約3天。接著使用Promega之「CellTitre 96® 148186.doc • 63- 201107345 非放射性細胞增殖分析法」（產品目錄第G4100號）如製造 商說明書中所述來測定細胞增殖量。96孔盤中之樣品的吸 光度於讀盤器中在570 nm下讀取。 mAbdAb中和重組大腸桿菌表現之人類IL-13生物活性的 能力表述為將一定量之人類IL-13(10 ng/ml)的生物活性中 和50%所需之mAb-dAb的濃度（=ND5〇)。所需mAbdAb之濃 度越低，則中和能力越強。使用GraphPad Prism來計算本 文提供之ND50數據（表6)。此等數據圖示於圖2中。 表6
抗體ID 描述 NDse(人類 IL-13) BPC 1624 A1 YlOOBAla H-TVAAPS-210L1 0.553 nM BPC 1625 A1 YlOOBIle H-TVAAPS-210L1 0.542 nM BPC1626 AlYlOOBTrp H-TVAAPS-210L1 0.681 nM BPC 1627 AlYlOOBVal H-TVAAPS-210L1 0.615 nM A1L1 抗IL-13抗體 2.524 nM 實例7-在CHOEla表現系統中表現包含CDRH3變體抗IL-13 mAb 之 mAb-dAb 亦於CHOEla細胞中表現如表5中所示之分子BPC 1624至 1 63 1。將編碼重鏈及輕鏈之DNA載體共電穿孔進入懸浮 CHO細胞中》細胞在37°C、5% C02、130 rpm下在MR1基 本選擇性培養基中於搖瓶中傳代直至細胞活力且細胞數提 高。接著將CHO細胞接種於MR1基本x2選擇性培養基中且 在34°C、5% C02、130 rpm下培育8至12天。離心集結細胞 且無菌過濾、上清液。 使用固定蛋白質A管柱、經由親和層析法來純化所表現 148186.doc -64- 201107345 之物質且藉由量測280 nm下之吸光度來測定產量。經由尺 寸排阻層析法測定聚集物含量。經由製備型尺寸排阻層析 法移除聚集物且再評估產量。表7列出自此表現系統獲得 之聚集物之產量及含量。 表7 分子 表現體積 ㈣ 產量(mg) (蛋白質A預清 洗後） 聚集物(％) (蛋白質A預清 洗後） 最終產量 (mg) 最終聚集物 (%) BPC1628 850 80.70 17.1% 39.50 2.6% BPC1629 850 77.90 20.3% 35.25 2.8% BPC1630 850 69.30 15.7% 38.00 3.3% BPC1631 850 61.47 20.3% 30.00 2.3% BPC1624 850 88.65 15.2% 45.00 2.6% BPC1625 850 77.49 16.2% 37.49 2.3% BPC1626 850 65.16 12.6% 30.80 3.1% BPC1627 850 73.26 15.2% 34.44 1.9% 實例8-抗原結合蛋白之化學計量評估（使用BiacoreTM) 此實例為預示性的。其為進行可測試本發明之抗原結合 蛋白的另一分析法提供指導。 藉由一級胺偶聯將抗人類IgG固定在CM5生物感測器晶 片上。抗原結合蛋白捕捉於此表面上，隨後，單一濃度之 IL-13或IL-4或IL-5通過，此濃度足以飽和結合表面且所觀 測之結合信號達到完全R-max。接著使用既定公式計算化 學計量： 化學計量=Rmax><Mw(配位體）/Mw(分析物）xR(所固定或捕 捉之配位體） 當計算一種以上分析物同時結合之化學計量時，使不同 148186.doc -65- 201107345 抗原以飽和抗原濃度依序通過且如上計算化學計量。該研 究可在25°C下使用HBS-ΕΡ操作緩衝液在Biac〇re 3〇〇〇上進 行。 實例9-對經改良之人類化變體mAb的劑量預測 開發抗體-配位體結合PK-PD模型，以基於結合親和力及 預測之人類潛在治療劑量對不同單株抗體（mAb)候選劑評 級。 出於此目的，將預測之人類潛在治療劑量定義為在每月 靜脈内投與mAb後對肺（作用部位）中之靶IL_丨3提供穩定狀 態之90%抑制持續1 h的劑量^假定各分子之分子量相同且 等於mAb之標準分子量，亦即15〇 kDa。此外，在缺乏不 同候選劑之動物或人類藥物動力學數據的情況下，A1L1 抗體之人類藥物動力學推定至所有候選劑。 對各種mAb使用相同的抗體_配位體結合pK_PD模型以及 關於乾濃度、粗轉換（target turnover)、把組織：血聚比率 及mAb組織穿透之相同假定。經由該模型所提供之評級因 此僅基於分子之結合親和力（此為唯一不同之參數）。在此 等條件下’預測4種候選劑（AlYlOOBlleLl 、 AlYlOOBValLl、AlYl〇〇BAlaLl 及 AlYlOOBTrpLl)之人類 潛在治療劑量以得到勝過對A1L1預測之人類潛在治療劑 量的實質改良。 實例10-含有變體IL-4 dAb之抗IL13/IL4 mAbdAb 10.1建構及表現 使用聚集預測算法研究抗IL-4 dAb(DOM9-155-154， 148186.doc -66- 201107345 SEQ ID NO: 80)之有聚集傾向的殘基。Kabat位置89處之白 胺酸殘基被鑑別為促進聚集之關鍵殘基。 為了降低含有此dAb之mAbdAb的聚集潛力，此胺基酸 殘基被取代為其他胺基酸以產生許多mAb-dAb變體。使用 編碼現有niAbdAb構築體之重鏈的DNA表現載體、經由定 點突變誘發來產生表現構築體。包含突變dAb序列之所得 新mAbdAb重鏈的蛋白質序列於SEQ ID NO: 117-134中給 出。 在位置89處合併另一突變之其他重鏈序列為SEQ ID NO: 96-106。此等分子詳述於實例11中。 表8提供所表現之分子清單。 表8
標識符 替代名稱 連接子 分子描述 蛋白質 SEQ ID NO: BPC1090 829H- (TVAAPS)2GS-154 (89G) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89G) 117 L鏈：抗人_11^13 mAb輕鏈 24 BPC1091 829H- (TVAAPS)2GS-154(89S) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89S) 118 L鍵：抗人類IL-13 mAb輕鍵 24 BPC1092 829H- (TVAAPS)2GS-154 (89H) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89H) 119 L鍵：抗人類IL-13 mAb輕鍵 24 148186.doc -67- 201107345 標識符 替代名稱 連接子 分子描述 蛋白質 SEQ ID NO: BPC1093 829H- (TVAAPS)2GS-154 (89M) (tvaaps)2gs H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89M) 120 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1094 829H- (TVAAPS)2GS-154 (89A) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89A) 121 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1095 829H- (TVAAPS)2GS-154 (89T) (tvaaps)2gs H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89T) 122 L键：抗人類IL-13 mAb輕鍵 24 BPC1108 829H- (TVAAPS)2GS-154 (89C) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_Y-(TVAAPS)2GS-DOM9-155-154 (89C) 123 L键：抗人類IL-13 mAb輕鏈 24 BPC1109 829H- (TVAAPS)2GS-154 (89R) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89R) 124 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1110 829H- (TVAAPS)2GS-154 (89W) (tvaaps)2gs H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89W) 125 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1111 829H- (TVAAPS)2GS-154 (89E) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89E) 126 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1112 829H- (TVAAPS)2GS-154 (89K) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89K) 127 148186.doc -68- 201107345 標識符 替代名稱 連接子 '· .‘ - 、 _ 分子描述 蛋白質 SEQ ID NO: L鏈：抗人類IL-13mAb輕鏈 24 BPC1113 829Η- (TVAAPS)2GS-154 (89D) (TVAAPS)2GS H链：抗人類IL-13 mAb重鍵 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89D) 128 L鍵：抗人類IL-13 mAb輕鏈 24 BPC1114 829H- (TVAAPS)2GS-154 (89N) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89N) 129 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1115 829H- (TVAAPS)2GS-154 (89Y) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89Y) 130 L鏈：抗人類IL-13 mAb輕鍵 24 BPC1116 829H- (TVAAPS)2GS-154 (89V) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89V) 131 L鏈：抗人類IL-13 mAb輕鍵 24 BPC1117 829H- (TVAAPS)2GS- 154(891) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (891) 132 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1118 829H- (TVAAPS)2GS-154(89F) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89F) 133 L鏈：抗人類IL-13 mAb輕鏈 24 BPC1119 829H- (TVAAPS)2GS-154(89P) (TVAAPS)2GS H鏈：抗人類IL-13 mAb重鏈 Y100B_V-(TVAAPS)2GS-DOM9-155-154 (89P) 134 L鏈：抗人類IL-13 mAb輕鏈 24
10.2分子表現於HEK 293 6E細胞中
將分別編碼重鏈及輕鏈之pTT質體短暫共轉染入HEK 148186.doc -69- 201107345 293 6E細胞中且小規模表現以產生抗體分子。轉染長達24 小時後將胰化蛋白饋料添加至各細胞培養液中且3天後收 集細胞。評估直接來自組織培養液上清液中之抗體分子且 使用Gyrolab工作站進行定量。 定量細胞上清液中之抗體分子的Gy rolab工作站方法 使用Gyrolab Bioaffy工作站（Gyros)、經由定量免疫分析 法來定量來自組織培養液上清液中之由HEK 2936E小規模 短暫轉染所產生的抗體（0.75-2.0 ml)。使用固定在塗有抗 生蛋白鏈菌素之粒子上的生物素標記抗IgG親和抗體分子 (Abeam)、在光碟（CD)微型實驗室（Gyros)上、經由Fc區捕 捉抗體。將親和抗體試劑短暫渦旋且用PBS-吐溫20(0.01% v/v)稀釋至0.1 mg/ml之最終工作濃度（working concentration)。接著使用雷射誘導螢光、經由標記ALEXA 647之Fab2抗人類IgG κ輕鏈分子偵測抗體。藉由短暫渦旋 且藉由在13000 rpm下離心4分鐘來製備標記ALEXA 647之 偵測劑。將標記之Fab2偵測劑添加至未標記Fab2中，使用 Rexcip F偵測試劑稀釋劑（Gyros)分別稀釋至75 nM及1.5 μΜ之最終濃度。相對於抗CD23單株抗體標準曲線，抗體 定量範圍介於0.244-250 pg/ml之間。藉由組織培養基 (Freestyle 293表現培養基，氧化異丙稀F68(Pluronic F68) 及遺傳黴素（Geneticin)，Invitrogen))連續稀釋抗體來產生 抗CD23(1 mg/ml)標準曲線。 在一些情況下，使用固定蛋白質A管柱純化抗體分子且 藉由讀取280 nm下之吸光度進行定量，且需要時，在下述 148186.doc -70- 201107345 實例所述之分析法中評估該純化抗體分子。
10.3 IL-4結合 ELISA 使用下列方法測試此等mAbdAb在直接結合ELISA中對 IL-4之結合。 用含於NaHC〇3中之5 pg/ml人類IL_4(在GSK製備）塗佈％ 孔咼結合培養盤且在4 °C下儲存隔夜。用含有〇. 〇 5 %之吐 溫-20的Tris緩衝鹽水（TBST)洗滌培養盤兩次。在各孔中添 加100 μί阻斷溶液（含有丨％ BSA之TBST緩衝液）且培養盤 在室溫下培育至少1小時。越過培養盤的經純化mAbdAb於 阻斷溶液中連續稀釋。在】小時培育之後，洗滌培養盤3 次。山羊抗人類κ輕鏈特異性過氧化酶結合抗體（Sigma A7164)於阻斷溶液中稀釋至丄^/mL且向各孔中添加⑽ pL。培養盤培育1小時。再進行3次洗滌步驟之後，向各孔 中添加50 μΐ OPD(鄰苯二胺二鹽酸鹽）SigmaFast受質溶液 且約5分鐘後藉由添加25吣之3 M硫酸終止反應。使用鹼 性終點方案、使用VersaMax可調微定量盤讀取器 (Molecular Devices)在49〇⑴^下讀取吸光度。 除均為純化物質之陽性對照物（抗IL_4 mAb)及抗江丨3陰 性對照物mAb外，實驗使用直接來自組織培養液上清液中 之mAbdAb來進行。此等數據展示於圖17中。 ELIS^#果顯示，此等短暫表現之抗IL13 mAb-抗IL4 dAb大部分結合IL_4，但觀測到IL_4結合活性的一些變 化，、屯化的陽性對照物抗IL-4 mAb亦顯示結合至il-4，而 純化的陰性對照物mAb顯示不結合至人類il_4。 148186.doc 201107345 實例11-建構及測試包含CDRH3變體抗IL-13 mAb及突變 dAb之抗原結合蛋白（BPC1085、BPC1086 及 BPC1087) 11.1建構及表現 使用編碼由抗IL-13 mAb及抗IL-4 dAb組成之重鏈的質 體作為基本構築體以產生替代質體構築體。需要兩步選殖 策略。在步驟1中，使用Hind III及Spe I、經由限制性選殖 將編碼Η鏈之抗IL13 mAb組分之VH的DNA序列置換為編碼 另一人類化抗IL13抗體之VH(SEQ ID NO: 54)的DNA序 列。在步驟2中，經由定點突變绣發使編碼mAbdAb之抗 IL4 dAb(D〇M9-155-154，SEQ ID NO: 80)組分中之Kabat 位置89處之白胺酸的密碼子突變成麩醯胺酸。由此產生之 所有重鏈DNA序列皆於SEQ ID NO: 96、98及100中給出。 表9提供所建構及所表現之分子清單。 表9-所建構及所表現之抗體概述 標識符 替代名稱 連接子 分子描述 蛋白質 SEQ ID NO: BPC1085 829H- GS(TVAAPSGS)2-154 (89Q)或 829H- GS(TVAAPSGS)2- 256 GS(TVAAPSGS)2 Η鏈：抗人類IL-13 mAb 重鏈 YlOOB+V-GSCTVAAPSGSh-DOM+lSSI 96 L鏈：抗人類IL-13 mAb輕鍵 24 BPC1086 829H- GS(TVAAPSGS)3-154 (89Q)或 829H-GS(TVAAPSGS)3-256 GS(TVAAPSGS)3 Η鏈：抗人類IL-13 mAb 重鏈YlOOBj-GSCTVAAPSGSh-DOMllSSJSG 98 L鏈：抗人類IL-13 mAb輕鏈 24 148186.doc -72· 201107345 BPC1087 829H- GS(TVAAPSGS)4 Η鏈：抗人類IL-13 100 GS(TVAAPSGS)4- mAb 重鏈Y100B_V- 154 (89Q)或 829H- GS(TVAAPSGS)4- GS(TVAAPSGS)4- DOM9-155-256 256 L鏈：抗人類IL-13 24 mAb輕鏈 使用 293fectin(Invitrogen，12347019)將編碼 BPC1085、 8卩(：1086及8?(：1087 111八5(1八13之重鏈及輕鏈表現質體共轉 染入HEK 2936E細胞中。24小時後將胰化蛋白饋料添加至 各細胞培養液中且72小時後收集細胞。在結合分析法測試 • 之前使用蛋白質A管柱純化抗體。 使用蛋白質A親和法純化BPC1085、BPC1086及BPC1087 mAbdAb。在AKTA Xpress系統上使用1 ml蛋白質A管柱 (GE Healthcare)，用 PBS(Gibco/Invitrogen)平衡管柱且使 用Pierce IgG溶離物溶離抗體。使用1 Μ參（羥曱基）胺基甲 烧緩衝液（一般而言5-10% ν/ν)中和溶離份。彙集抗體溶離 份且經由尺寸排阻層析法分析聚集度且使用分光光度計藉 ^ 由在280 nm下讀取OD進行定量。 對此等抗體與描述於表1〇中之類似mAbdAb(2222、 2223、2230及223 1)進行比較。此等類似mAbdAb包含： i) 與 BPC108 5、BPC1086及 BPC1087 中所用之 dAb—致的 dAb，例外之處為位置89，在BPC2222、BPC2223、 BPC2230 及 BPC223 1 中，其為「L」且在 BPC1085、 BPC1086 及 BPC1087 中，其為「Q」， ii) 相同連接子， iii) 與 BPC1085、BPC1086及 BPC1087 中所用之 IL-13 mAb 148186.doc -73- 201107345 序列一致的IL-13 mAb序列，例外之處為位置100B ’ 在 BPC2222、BPC2223、BPC2230及 BPC2231 中，其 為「Y」且在BPC1085、6及7中，其為「V」。 表10 : 標識符 mAb 連接子 dAb 重綠 輕鏈' BPC2222 A1L1 GS(TVAAPSGS)i DOM9-155-154 135 24 BPC2223 A1L1 GS(TVAAPSGS)2 DOM9-155-154 136 24 BPC2230 A1L1 GS(TVAAPSGS)3 DOM9-155-154 137 24 BPC2231 A1L1 GS(TVAAPSGS)4 DOM9-155-154 138 24 使用蛋白質A親和法純化BPC2222、2223、2230及2231 # mAbdAb。在AKTA Xpress系統上使用1 ml蛋白質A管柱 (GE Healthcare)，用 PBS(Gibco/Invitrogen)平衡管柱且使 用Pierce IgG溶離物溶離抗體。使用1 Μ參（羥曱基）胺基曱 烷緩衝液（一般而言5-10% ν/ν)中和溶離份》彙集抗體溶離 份且經由尺寸排阻層析法分析聚集度且使用分光光度計藉 由在280 nm下讀取OD進行定量。 BPC2222、2223、2230及2231顯示聚集度介於30-40%之 間，聚集物溶離早於10分鐘。 如經由尺寸排阻層析法所評估，構築體BPC1085、1086 及1087相較於BPC2222、2223、2230及2231顯示較低聚集 度。此等分子之SEC概況展示於圖3-9中。
11.2 IL-4結合 ELISA 根據實例10.3中所述方法測試純化BPC 1085、BPC 1086 及BPC1087 mAbdAb在直接結合ELISA中對IL-4之結合。 此等數據展示於圖10中。ELISA結果證實此等純化 148186.doc • 74- 201107345 mAbdAb結合至IL-4。陽性對照物抗il_4 mAb及BPC2231亦 顯示結合至IL-4，而陰性對照物mAb(抗IL-13 mAb)顯示不 結合至人類IL-4。此指示在此ELISA中當連接子長度自 GS(TVAAPSGS)增加至 gS(TVAAPSGS)2-4 時，dAb 效能增 加。 11.3在TF-1細胞增殖生物分析法中對IL_4之中和 在TF-1細胞生物分析法中測試純化bPC1085、BPC1086 及BPC1087對人類IL-4之中和程度。 TF-1細胞回應於許多不同細胞激素（包括人類IL 4)而增 殖。此等細胞對於IL-4之增殖反應因此可用於量測IL_4之 生物活性且隨後已開發一種分析法以測定mAbdAb中和化_ 4之效能（抑制IL-4生物活性）。 該分析法在無菌條件下於無菌96孔組織培養盤中進行且 所有/則式孔白式兩伤進行。將約2.2 ng/ml經重組大腸桿 菌表現之人類IL-4與各種稀釋度之mAbdAb(通常為56〇 nM 以3倍稀釋度滴定至0·009 nM)wl2〇 y總體積在37它下預 坨月1小時。無關特異性之抗體作為陰性對照（抗IL 1 3 mAb)以類似方式滴定。接著將5〇 μΐ此等樣品添加至含於 無菌96孔組織培養盤中之5〇 μι ΤΙΜ細胞（每毫升“⑺5個細 肊之/辰度）中。因此最終1〇〇 μ1分析體積含有各種稀釋度之 mAb(270 ηΜ以3倍稀釋度滴定至〇 〇〇5 _之最終濃幻重 組大腸桿菌表現之人類IL_4(u ng/ml之最終濃度）及叫 細胞（每毫升lxl〇5個細胞之最終濃度）。分析盤在含濕氣 〇2培月相中在37 C下培育約4天。接著使用Pr〇mega之 14E186.doc -75- 201107345 「CellTitre 96®非放射性細胞增殖分析法」（產品目錄第 G4 100號）、如製造商說明書中所述來測定細胞增殖量。％ 孔盤中之樣品的吸光度於讀盤器中在57〇 nm下讀取。此等 數據輸入Excel試算表，對一式兩份測試孔之值求平均值 且減去平均背景值（無mAb-dAb及無IL-4測試孔）。 mAbdAb中和重組經大腸桿菌表現之人類il-4生物活性 的能力表述為將一定量之人類IL_4(1丨ng/ml)的生物活性 中和50%所需之mAb-dAb濃度（=ND50)。所需mAbdAb之濃 度越低，則中和能力越強。使用Excel中之R〇b〇sage函數 來計算本文提供之ND5〇數據（表u)。此等數據圖示於圖U 中。 抗 IL-4 mAb及 DOM9-155_i54(SEq ID N〇 : 8〇)作為中和 人類及石蟹獼猴IL-4的陽性對照物而包括於TF_丨細胞生物 斤中另外對無關抗原具有特異性之dAb(模擬dAb) 亦作為令和人類或石蟹獼猴IL-4的陰性對照物而包括於 TF-1細胞生物分析法中。 此等測忒重複右干次且圖i i展示此等實驗之一的結果。 根據數據集計算叫。值。⑧5。值為能夠將IL_4之生物活性 中和观之mAbdAb、或mAb或㈣的濃度。 平均ND50值及測試次數（η)展示於表U中。 I48186.doc •76· 201107345 表11 分子 .平均NDS0值及標準偏差(η1νπ 重趨次數 BPC1085 9.21 3 BPC1086 4.32 3 BPC1087 3.59 3 抗IL-4 mAb 1.95 2 DOM9-155-154 0.98 2 陰性對照dAb 不中和 2 此等數據證實，純化BPC1085、BPC1086及BPC1087 mAbdAb中和人類及石蟹獼猴il-4之生物活性。抗IL-4 mAb及DOM9-155-154亦中和了人類及石蟹獼猴IL-4之生物 活性，而陰性dAb(模擬dAb)在相同生物分析法中未展示中 和作用。 所有三種mAbdAb皆展示良好效能，且根據中和分析法 顯而易見dAb效能隨連接子長度增加而增加的明顯趨勢（儘 管較粗糙的ELISA未偵測此效能差異）。陰性對照物抗IL-4 mAb在相同生物分析法中未展示中和作用。 11.5在TF-1細胞增殖生物分析法中對人類1L_13之中和 在如下所述之TF-1細胞生物分析法中測試純化 BPC1085、BPC1086 及 BPC1087對人類 IL-13之中和程度。 TF-1細胞回應於許多不同細胞激素（包括人類1L_13)而增 殖。此等細胞對於IL-13之增殖反應因此可用於量測IL_13 之生物活性且隨後已開發一種分析法以測定mAbdAb中和 IL-13之效能（抑制IL-1 3生物活性）。 該分析法在無菌條件下於無菌96孔組織培養盤中進行且 148186.doc -77· 201107345 所有測試孔皆一式兩份進行。將約14 ng/ml經重組大腸桿 菌表現之人類IL-4與各種稀釋度（通常為560 nM以3倍稀釋 度滴定至0.009 nM)之mAbdAb以120 μΐ總體積在37。(：下預 培育1小時。無關特異性之抗體及dAb作為陰性對照物（分 別為抗IL-4 mAb及DOM9-1 5 5-1 54)以類似方式滴定。接著 將5 0 μΐ此等樣品添加至含於無菌96孔組織培養盤中之5〇 μΐ TF-1細胞（每毫升2χ105個細胞之濃度）中。因此最終1〇〇 分析體積含有各種稀釋度之niAbdAb(270 ηΜ以3倍稀釋 度滴定至0.005 ηΜ之最終濃度）、重組大腸桿菌表現之人 類IL-1 3(7 ng/ml之最終濃度）及tf- 1細胞（每亳升1 χ丨〇5個細 胞之最終濃度）。分析盤在含濕氣C〇2培育箱中在37。〇下培 育約4天。接著使用promega之「celiTitre 96®非放射性細 胞增殖分析法」（產品目錄第G4100號）、如製造商說明書 中所述來測定細胞增殖量。96孔盤中之樣品的吸光度於讀 盤器中在570 nm下讀取。此等數據輸入Exce丨試算表，對 一式兩份測試孔之值求平均值且減去平均背景值（無mAb_ dAb及無IL-13測試孔）〇 mAbdAb中和重組大腸桿菌表現之人類IL_ i 3生物活性的 月匕力表述為將一定置之人類IL-13(7 ng/ml)的生物活性中和 50%所需之mAb-dAb濃度（=ND5〇)。所需mAbdA.b之濃度越 低’則中和能力越強。使用Excel中之Robosage函數來計 算本文提供之NDso數據（表12)〇此等數據圖示於圖中。 抗 IL-13 mAb(SEQ ID NO: 22 & 24)作為中和人類 IL-13 的陽性對照物而包括於TF-1細胞生物分析法中。另外，抗 148186.doc -78- 201107345 IL-4 mAb亦作為陰性對照物而包括在内。 圖12展示TF-1細胞中和分析法之結果。根據數據集計算 NDso值。NDso值為能夠將几_13之生物活性中和5〇%之 mAbdAb或mAb或dAb的濃度。 平均ND5〇值及測試次數展示於表12中。 表12 分子 平均NDS((值及標準偏差(nM) 重複次數 BPC1085 0.88 1 BPC1086 1.01 1 BPC1087 1.14 1 抗IL-13 mAb 5.01 1 抗IL-4 mAb 不中和 1 此等數據證實，純化BPC1085、BPC1086及BPC1087 mAbdAb中和重組人類及石蟹獼猴il-13之生物活性。陰性 對照物抗IL-4 mAb在相同生物分析法中未展示中和作用。 實例12抗IL-13 mAb輕鍵之再人類化 12.1再人類化 將鼠類抗體6A1 (其輕鏈於SEQ ID NO: 59中表示）之輕鏈 CDR再接枝於新架構上以改良某些抗IL_13 mAb-抗IL-4 dAb分子（BPC1085)之表現。使用基於PCR之策略及重疊寡 核苷酸來重新建構密碼子優化之輕鏈可變區序列（概述於 表13中）。PCR引子設計成合併信號序列（SEQ ID NO: 56) 且包括Hindlll及BsiWI限制性位點，該等Hindlll及BsiWI 限制性位點設計成框住V L域且允許選殖入含有人類JC C區 的pTT及Rln哺乳動物表現載體中。表13概述已建構之再人 148186.doc -79- 201107345 類化輕鍵。 表13 輕鏈名稱 描述 主鏈 反突變 核苷酶序列 SEQIDNO: 联基酸¥列 SEQroNO: P0 抗DL-13 808VL κ輕鏈 IGKV1_39+JK2 N/A 108 109 P1 抗IL-13 809VL κ輕鏈 IGKV1 一39+JK2 I2V+Q3L 110 111 〇〇 IGKV3 20+JK2 N/A 112 113 Q1 IGKV3_20+JK2 I2V、V3L、 L4M、E1D、 R45K、I58V 114 115 • 12.2分子表現於HEK 293 6E細胞中 首先以mAb形式檢驗再人類化輕鏈之表現性質。使用 293fectin(Invitrogen，12347019)將編碼 A1Y100BVAL1 (SEQ ID NO: 54)重鏈、現有輕鏈（SEQ ID NO: 24)及再人 類化輕鏈之質體短暫共轉染入HEK 293 6E細胞中。小規模 (2x0.75 ml培養體積）表現質體以產生抗體。24小時後將胰 化蛋白饋料添加至細胞培養液中且再過72小時後收集細 胞。表14概述已建構及表現之所有mAb。 表14 抗體ID 分子描述 蛋白質 SEO ID NO: A1Y100BVAL1 Η鏈：抗人類IL-13 Y100b_V mAb 54 L鏈：586抗人類IL-13 mAb 24 BPC3208 Η鏈：抗人類IL-13 Y100b_V mAb 54 L鏈：P0再人類化抗人類IL-13 mAb 108 BPC3211 H鏈：抗人類IL-13 Y100b_V mAb 54 148186.doc • 80 · 201107345 L鏈：Π再人類化抗人類IL-13 mAb 110 BPC3219 Η鏈：抗人類IL-13 Y100b_V mAb 54 L鏈：Q0再人類化抗人類IL-13 mAb 112 BPC3220 Η鏈：抗人類IL-13 Y100b_V mAb 54 L鏈：Q1再人類化抗人類IL-13 mAb 114 使用Gyro lab工作站、經由定量免疫分析法評估直接來 自組織培養液上清液中之抗體的表現。含有再人類化輕鍵 (分別表示為P0及P1)之抗體BPC3208及BPC3211相較於 A1Y100BVAL1 mAb展示改良之表現產量。Q0及Q1輕鏈 (3?〇3219及6?。3220)不改良抗化-13 mAb之表現。表現數 據呈現於表15中。
表15 •Ά’...：...： ：.，；/ A;;l? /. . . . V ' ' .Λ · - · ... - . . . / 、 砷聦Xi*洙申太總灰量〜g): A1Y100BVAL1 19.9 BPC3208 111.0 BPC3211 115.0 BPC3219 16.0 BPC3220 18.3 12.3 mAb-dAb表現於 HEK 293 6E細胞中 因為BPC3 208及BPC3211之再人類化輕鏈使抗IL-13 mAb 之表現改良，所以其在抗IL-13mAb-抗IL-4dAb之情形下檢 驗。使用 293fectin(Invitrogen，12347019)將再人類化輕鍵 P0 及 P1 及 586(L1)輕鏈與 829H-GS(TVAAPSGS)2-256 重鏈 (SEQ ID NO: 96，詳情概述於表16中）共轉染入HEK 293 6E細胞中。質體在50至500 ml規模上受表現以產生抗體分 子。24小時後將胰化蛋白饋料添加至細胞培養液中且再過 48小時後收集細胞。使用固定蛋白質A管柱純化抗體且藉 148186.doc •81 - 201107345 由讀取280 nm下之吸光度進行定量且需要時，在下述實例 所述之分析法中評估該純化抗體分子。如圖13及14中所說 明，經由尺寸排阻層析法（SEC)分析BPC3214及BPC3215。 表16 抗體ID 替代名稱 連接子 分子描述 蛋白質 SEQ ID NO： DNA SEQ ID NO: BPC1085 829H- GS(TVAAPSGS)2 -256 GS(TVAAPSGS)2 H鏈：抗人類IL-13 mAb重鏈 Y100B V-GS(TVAAPSGS)2-DOM9-155-256 96 97 L鏈：586抗人類 IL-13 mAb輕鏈 24 25 BPC3214 808H- GS(TVAAPSGS)2 -256 GS(TVAAPSGS)2 H鏈：抗人類IL-13 mAb重鏈 Y100B V-GS(TVAAPSGS)2-DOM9-155-256 96 97 L鏈：P0再人類化 抗人類IL-13 mAb 108 109 BPC3215 809H- GS(TVAAPSGS)2 -256 gs(tvaapsgs)2 H鏈：抗人類IL-13 mAb重鍵 Y100B V-GS(TVAAPSGS)2-DOM9-155-256 96 97 L鏈：PI再人類化 抗人類IL-13 mAb 110 111 與以mAb形式觀測之結果一致，含有再人類化輕鏈之 mAbdAb(BPC3214及 BPC3215)相較於 BPC1085 展示改良之 表現。代表性表現數據概述於表Π中。 表17 抗體ID 純化m 乂 bdAb之產查(pg/ml) BPC1085 5.6 BPC3214 9.8 BPC3215 7.2 148186.doc -82- 201107345
12.4 人類 IL-13 結合 ELISA 經由直接結合ELISA測試純化BPC3214及BPC3215相較 於BPC1085(描述於實例10中）對人類il-13的結合。抗IL_i3 mAb A1Y100BVAL1及抗IL-4 mAb亦分別作為陽性及陰性 對照物加以檢驗。用5 pg/ml經重組大腸桿菌表現之人類 IL-13(批號：GRITS3丨061)以50微升/孔塗佈96孔高結合培 養盤且在+4°C下培育隔夜。隨後所有步驟皆在室溫下進 行。用含有〇·〇5°/。吐溫20之磷酸鹽緩衝鹽水洗滌該等培養 盤3次。向各孔中添加1〇〇 #阻斷溶液（含有1% bsa、 0 · 0 5 %吐溫-2 0之填酸鹽緩衝鹽水）且在室溫下培育該等培 養盤至少1小時。接著進行另一洗滌步驟。越過培養盤之 純化抗體於阻斷溶液中連續稀釋。培育1小時之後，洗務 培養盤。山羊抗人類κ輕鏈特異性過氧化酶結合抗體 (Sigma A7 164)於阻斷溶液中稀釋至〇·75 gg/mL且向各孔中 添加50 μί。將該等培養盤培育1小時。再進行兩次洗滌步 驟之後，向各孔中添加50 μΐ 〇PD(鄰苯二胺二鹽酸 鹽）SigmaFast受質溶液且藉由添加5〇吣之3 Μ硫酸終止反 應。使用驗性終點方案、使用VersaMax微定量盤讀取器 (Molecular Devices)在490 nm下讀取吸光度。此等數據展 示於圖I5中。直接結合ELISA證實BPC3214及BPC3215結 合至人類IL-13。BPC3214及BPC3215展示與BPC1085類似 之IL-13結合效能。陽性對照物抗仄七mAb A1Y100BVAL1 亦展示結合至重組IL-1 3，而陰性對照物抗il-4 mAb顯示 不結合至人類IL-13。 148186.doc -83· 201107345
12.5 人類 IL-4 結合 ELISA 在直接結合ELISA中亦測試純化BPC3214及BPC3215對 重組大腸桿菌表現之人類IL-4的結合。如實例4中所述進 行ELISA，用5 pg/ml經重組大腸桿菌表現之人類IL-4以50 微升/孔塗佈96孔高結合培養盤且在+4°C下培育隔夜。此 等數據展示於圖16中。直接結合ELISA證實BPC3214及 BPC3215結合至人類IL-4。亦檢驗BPC1085。BPC3214展 示與BPC1085類似之IL-4結合效能。陽性對照物抗IL-4 mAb亦展示結合至重組IL-4，而陰性對照物抗IL-13mAb A1Y100BVAL1顯示不結合至人類IL-4。 實例 13-包含初始 IL-13 mAb CDRH3 之 mAbdAb (BPC2222、 BPC2223 及 BPC2230-2231)對 IL-13 及 IL-4 之結合親和力， 如經由BIAcoreTM分析所評估 方法 蛋白質A藉由一級胺偶聯固定在C1晶片上；此表面用作 欲測試之抗體分子的捕捉表面。重組大腸桿菌表現之人類 IL 13在256、64、16、4及1 nM下使用，重組大腸桿菌表現 之人類IL4在64、16、4、1及0.25 nM下使用，0 nM(亦即 僅用緩衝液）用作IL4與IL13結合之結合曲線的雙重參照。 用100 mM磷酸再生蛋白質A表面。使用HBS-EP作為操作 緩衝液在25°C下操作該分析法。針對Biacore T100分析軟 體固有之1:1模型擬合數據。 結合至人類IL 13之結果展示於表1 8中且結合至人類IL4 之結果展示於表19中。 148186.doc -84- 201107345 表18 分子名稱 分子描述 ka(M/s) kd(l/s) KD(nM) BPC2222 586H-GSTVAAPSGS-154 1.31E+06 4.93E-04 0.376 BPC2223 586H-GS(TVAAPSGS)2-154 1.32E+06 4.90E-04 0.372 BPC2230 586H-GS(TVAAPSGS)3-154 1.31E+06 4.88E-04 0.373 BPC2231 586H-GS(TVAAPSSGS)4-154 1.30E+06 5.13E-04 0.394 表19 分子名稱 分子描述. ka(M/s) kd(l/s) KD(nM) BPC2222 586H-TVAAPSGS-154 1.06E+05 1.09E-04 1.027 BPC2223 586H-TVAAPSGSx2-154 8.59E+06 1.56E-04 0.018 BPC2230* 586H-TVAAPSGSx3-154 2.48E+07 2.48E-04 0.010 BPC2231* 586H-TVAAPSSGSx4-154 4.03E+07 2.31E-04 0.006
*6?€2230及2231之結合速率（〇111&{6)超出別&(：〇^之靈敏 度，但未能精確分析此數據之事實說明，與IL4可能以快 結合速率、高親和力相互作用。 實例 14-包含初始 IL-13 mAb CDRH3 之 mAbdAb (BPC2222、 BPC2231)及包含變體抗 IL-13 mAb CDRH3 之 mAbdAb (BPC1085-1087)對IL-13及IL-4的結合親和力，如經由 BIAcoreTM分析所評估 方法 蛋白質A藉由一級胺偶聯固定在CM5晶片上；此表面用 作欲測試之抗體分子的捕捉表面。重組大腸桿菌表現之人 類IL13僅在256 nM下使用，重組大腸桿菌表現之人類IL4 在64、1 6、4、1 nM下使用，0 nM(亦即僅用緩衝液）用作 IL4與IL13結合之結合曲線的雙重參照。用50 mM NaOH再 生蛋白質A表面。使用HBS-EP作為操作緩衝液在25°C下操 148186.doc -85- 201107345 作該分析法。針對Biacore ΊΊ00分析軟體固有之1:1模型擬 合數據。 結合至人類IL13之結果展示於表20中，且結合至人類 IL4之結果展示於表21中。 表20 分子名稱 ka(M/s) kd(l/s) Κ〇(ηΜ) BPC2222 1.64E+05 5.15E-05 0.314 BPC2231 5.36E+08 1.16E-03 0.002 BPC1085 1.87E+07 8.97E-04 0.048 BPC1086 7.99E+07 1.64E-03 0.021 BPC1087 9.86E+07 1.79E-03 0.018 BPC1086及BPC1087之結合速率超出Biacore之靈敏度， 但未能精確分析此數據之事實說明，與IL4可能以快結合 速率、高親和力相互作用。 表21 分子名稱 ka(M/s) kd(l/s) Κ〇(ηΜ) BPC2222 1.44E+06 4.44E-04 0.308 BPC2231 1.56E+06 4.95E-04 0.316 BPC1085 1.20E+06 6.39E-05 0.053 BPC1086 1.28E+06 6.57E-05 0.051 BPC1087 1.13E+06 6.42E-05 0.057 實例15-包含許多變體抗IL-13 mAb CDRH3之mAbdAb (BPC1085、BPC1090-BPC1095、及 BPC1108-BPC1119)對 IL-4的結合親和力，如經由BIAcoreTM分析所評估 方法（人類IL-4結合親和力） 蛋白質A藉由一級胺偶聯固定在CM5晶片上，此表面用 148186.doc • 86 - 201107345 作欲測試之抗體分子的捕捉表面。 重組大腸桿菌表現之人類IL4在64、16、4、1及0.25 nM 下使用。所有結合曲線皆以0 nM進樣（亦即僅用緩衝液）作 為雙重參照。 用50 mM NaOH再生蛋白質A表面。使用HBS-EP作為操 作緩衝液在25°C下操作該分析法。針對Biacore T100分析 軟體固有之1:1模型擬合數據。 結合至人類IL4之結果展示於表22中。 9表22
分子名稱 ka (M/s) kd (1/s) Κ〇(ηΜ) BPC1085 1.07E+07 8.34E-04 0.078 BPC1090 4.34E+06 4.16E-04 0.096 BPC1091 6.05E+06 1.02E-03 0.168 BPC1092 2.27E+06 3.89E-03 1.713 BPC1093 3.84E+06 2.11E-04 0.055 BPC1094 1.46E+06 3.04E-03 2.078 BPC1095 6.78E+06 3.18E-02 4.687 BPC1108 4.38E+06 1.23E-03 0.281 BPC1109 1.20E+06 1.77E-01 147.300 BPC1110 1.07E+06 1.73E-03 1.626 BPC1111 2.98E+06 1.11E-04 0.037 BPC1112* 1.I4E+08 3.31E+00 28.980 BPC1113 未顯示結合 未顯示結合 未顯示結合 BPC1114 3.89E+06 2.55E-03 0.656 BPC1115** 1.44E+08 3.29E-01 2.292 BPC1116 6.82E+06 2.74E-03 0.402 BPC1117 3.95E+06 9.13E-04 0.231 BPC1118 6.39E+06 2.58E-03 0.405 BPC1119 未顯示結合 未顯示結合 未顯示結合 148186.doc -87- 201107345 *BPC1112數據具有正解離速率（off-rate)，此係由於機器可 能因解離速率如此之迅速而不能計算真實解離速率所致， 此外，此構築體之結合速率超出Biacore可量測之程度，但 構築體對IL4之結合極其不良。 *BPC1115亦具有不可能存在之結合速率，其在BIAcore計 算親和力之範圍外。 實例16-包含再人類化輕鏈之mAbdAb(BPC3214及 BPC3215)相較於包含初始輕鏈之mAbdAb(BPC1085)對IL-13的結合親和力，如經由BIAcoreTM分析所評估 方法（人類及石蟹獼猴IL-13結合親和力） 蛋白質A藉由一級胺偶聯固定在CM5晶片上；此表面用 作欲測試之抗體分子的捕捉表面。 重組大腸桿菌表現之人類IL 13及石蟹獮猴IL1 3在64、 16、4、1及0.25 nM下使用。所有結合曲線皆以0 nM進樣 (亦即僅用缓衝液）作為雙重參照。 用50 mM NaOH再生蛋白質A表面。使用HBS-EP作為操 作緩衝液在25°C下操作該分析法。針對Biacore T100分析 軟體固有之1:1模型擬合數據。 結合至人類及石蟹獼猴IL13之結果展示於表23中。 表23 分子名稱 ka (M/s) kd (1/s) KD(nM) 註解 結合至人類IL13 BPC3214 7.749E+05 7.18E-05 0.093 BPC3215 8.220E+05 5.23E-05 0.064 BPC1085 8.652E+05 6.34E-05 0.073 148186.doc •88· 201107345 結合至石蟹獼猴IL13 ' BPC3214* 3.214E+05 5.07E-06 0.015770 ------- 不可此存在之解離技率 BPC3215* 3.283E+05 3.13E-06 0.009546 —_乏能存在之解離讳率 BPC1085* 3.552E+05 5.19E-10 0.000001 不可能存在之解離 *石蟹獼猴IL13結合至BPC3214、BPC3215及BPC1085之解 離速率（ka)超出BiacoreTlOO之靈敏度，此指示解離速率極 慢且相互作用可能具有極高親和力。 實例17-對含有或不含有突變dAb之mAbdAb的著重點研究 將許多mAbdAb置於PBS或50 mM乙酸鹽緩衝液中且在 φ 37°C下培育多達14天。接著針對可見沈澱物之存在、可溶 性聚集物及黏附直至濃度穩定性對其進行分析。 結果說明，包含突變dAb之mAbdAb(BPC2222、2223、 223 0、2231)在表現上類似於包含非突變dAb之mAbdAb (BPC1 085、1086、1087)，如依據溶液中蛋白質濃度無變 化所指示，兩類mAbdAb在PBS與乙酸鹽緩衝液中、在37°C 下之兩週培育期間均顯示穩定。此外，注意到溶液中之聚 集物的含量無變化或變化極小且未觀測到沈澱物。 # 實例18-PK評估 在各別研究中研究BPC1085、BPC1086及BPC1087靜脈 内投與大鼠之後的藥物動力學。亦研究BPC1085靜脈内投 與石蟹獼猴後的PK。 發現所有三種分子在大鼠中及BPC 1085在猴中之PK與標 準mAb之PK—致。 148186.doc -89- 201107345 序列概述（表24) 描述 序列標識符(SEQ ID NO) 胺基酸序列 聚核苷酸序列 抗IL13A1，CDRH1 1 - 抗IL13A1，CDRH2 2 - 抗IL13A卜 CDRH3 3 - CDRH3替代物 4 • CDRH3替代物 5 _ CDRH3替代物 6 _ CDRH3替代物 7 _ CDRH3替代物 8 CDRH3替代物 9 _ CDRH3替代物 10 - CDRH3替代物 11 - CDkH3替代物 12 . CDRH3替代物 13 - CDRH3替代物 14 - CDRH3替代物 15 - CDRH3替代物 16 - CDRH3替代物 17 CDRH3替代物 18 • 抗IL13 LI，CDRL1 19 - 抗IL13 LI，CDRL2 20 抗IL13 U，CDRL3 21 - 抗IL13 A1 (重鏈） 22 23 抗IL13 L1 (輕鏈） 24 25 抗IL13人類化變體A1 S95 Trp (重鏈） 26 27 抗IL13人類化變體Al 196 Val (重鏈） 28 29 抗IL13人類化變體A1 Y97 Phe (重鏈） 30 31 抗IL13人類化變體Al D98 Glu (重鍵） 32 33 抗IL13人類化變體Al HlOOAAla (重鏈） 34 35 抗IL13人類化變體Al HlOOAGlu (重鏈） 36 37 抗IL13人類化變體Al HlOOAGln (重鏈） 38 39 148186.doc -90- 201107345
抗IL13人類化變體A1 HlOOAArg (重鏈） 40 41 抗IL13人類化變體A1 HlOOASer (重鏈） 42 43 抗IL13人類化變體A1 HlOOAThr (重鏈） 44 45 抗IL13人類化變體A1 H100A Val (重鏈） 46 47 抗IL13人類化變體A1 YlOOBAla (重鏈） 48 49 抗IL13人類化變體A1 Y100B lie (重鏈） 50 51 抗IL13人類化變體A1 Y100B Trp (重鏈） 52 53 抗IL13人類化變體A1 Υ100Β Val (重鏈） 54 55 信號序列 56 人類IL13 57 _ 鼠類6A1 VH 58 鼠類6A1 VL 59 替代 CDRH1 (Chothia 及 Kabat編號） 60 _ 替代 CDRH1 (Chothia及 Kabat 編號） 61 一 A1 YlOOBAla H-TVAAPS-210 (重鏈） 62 63 Al Y100BIleH-TVAAPS-210 (重鏈） 64 65 AlYlOOBTrp H-TVAAPS -210 (重鏈） 66 67 AlYlOOBVal H-TVAAPS-210 (重鏈） 68 69 A:lYlOOBAla H-ASTKGPS-210 (重鏈） 70 71 Al YlOOBIle H-ASTKGPS-210 (重鏈） 72 73 AlYlOOBTrp H-ASTKGPS-210 (重鏈） 74 75 AlYlOOBVal H-ASTKGPS-210 (重鏈） 76 77 DOM9-155-25 78 DOM9-155-147 79 DOM9-155-154 80 DOM9-112-210 81 連接子 82 連接子 83 連接子 84 連接子 85 連接子 86 連接子 87 147-TVAAPS-586 Y100B V重鏈 88 147-ASTKG-586 Y100B V重鏈 89 148186.doc •91 · 201107345 154-TVAAPS-586 Y100B V 重鏈 90 154-ASTKG -586 Y100B V重鏈 91 連接子 92 連接子 93 DOM9-155-154 L89Q(aka DOM9-155-256) 94 95 829H-GS(TVAAPSGS)2-154 L89Q 96 97 829H-GS(TVAAPSGS)3-154 L89Q 98 99 829H-GS(TVAAPSGS)4-154 L89Q 100 101 829H-(TVAAPS)2GS-154 L89Q 102 103 829H-(TVAAPS)3GS-154 L89Q 104 105 829H-(TVAAPS)4GS-154 L89Q 106 107 PO 108 109 PI 110 111 〇〇 112 113 01 114 115 586H-TVAAPS-154 (H鏈） 116 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89G) 117 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89S) 118 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89H) 119 抗人類 IL-13mAb 重鏈丫10(«_乂-(7^八八？8)2〇8-DOM9-155-154(89M) 120 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89A) 121 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89T) 122 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89C) 123 抗人類 IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89R) 124 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS-DOM9-155-154(89W) 125 148186.doc -92- 201107345 抗人類IL-13 mAb 重鏈Υ100B_V-(TVAAPS)2GS- 126 DOM9-155-154(89E) 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS- 127 DOM9-155-154(89K) 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS- 128 DOM9-155-154(89D) 抗人類 IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS- 129 DOM9-155-154(89N) 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS- 130 DOM9-155-154(89Y) 抗人類IL-13 mAb 重鏈Y100B_V-(TVAAPS)2GS- 131 DOM9-155-154(89V) 抗人類IL-13 mAb重鏈Y100B—V-(TVAAPS)2GS- 132 DOM9-155-154(891) 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS- 133 DOM9-155-154(89F) 抗人類IL-13 mAb重鏈Y100B_V-(TVAAPS)2GS- 134 DOM9-155-154(89P) 抗IL-13 mAb重鏈GS(TVAAPSGS)!-DOM9-155-154 135 抗IL-13 mAb重鏈GS(TVAAPSGS)2-DOM9-155-154 136 _ 抗IL-13 mAb 重鏈GS(TVAAPSGS)3-DOM9-155-154 137 _ 抗IL-13 mAb 重鏈GS(TVAAPSGS)4-DOM9-l 55-154 138 GS(TVAAPSGS), 139 gs(tvaapsgs)2 140 gs(tvaapsgs)3 141 GS(TVAAPSGS)4 142 gs(tvaapsgs)5 143 GS(TVAAPSGS)6 144 (TVAAPSMGS), 145 (TVAAPS)3(GS)i 146 148186.doc 93- 201107345 序列 SEQ ID NO: 1
DTYMH SEQ ID NO: 2
TIDPANGNTKYVPKFQG SEQ ID NO: 3
SIYDDYHYDDYYAMDY SEQ ID NO: 4
WIYDDYHYDDYYAMDY SEQ ID NO: 5
SVYDDYHYDDYYAMDY SEQ ID NO: 6
SIFDDYHYDDYYAMDY SEQ ID NO: 7
S1YEDYHYDDYYAMDY SEQ ID NO: 8
SIYDDYAYDDYYAMDY SEQ ID NO: 9
SIYDDYEYDDYYAMDY SEQ ID NO: 10
SIYDDYQYDDYYAMDY SEQ ID NO: 11
SIYDDYRYDDYYAMDY -94- 148186.doc 201107345 SEQ ID NO: 12
SIYDDYSYDDYYAMDY SEQ ID NO: 13
SIYDDYTYDDYYAMDY SEQ ID NO: 14
SIYDDYVYDDYYAMDY SEQ ID NO: 15
SIYDDYHADDYYAMDY SEQ ID NO: 16
SIYDDYHIDDYYAMDY SEQ ID NO: 17
SIYDDYHWDDYYAMDY SEQ ID NO: 18
S1YDDYHVDDYYAMDY SEQ ID NO: 19
RSSQNIVHINGNTYLE SEQ ID NO: 20
KISDRFS SEQ ID NO: 21
FQGSHVPWT SEQ ID NO: 22
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG -95- 148186.doc 201107345
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 23
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 24
DIVMTQSPLSLPVTPGEPASISCRSSQNIVHINGNTYLEWYLQKPGQSPRLLIYKISDRFSGVPD
RFSGSGSGTDFTLKISRVEADDVGIYYCFQGSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK
VYACEVTHQGLSSPVTKSFNRGEC •96-
148186.doc 201107345 SEQ ID NO: 25
GACATCGTGATGACCCAGTCTCCTCTGAGCCTCCCCGTGACCCCCGGCGAACCAGCCAGCATCTC
CTGCAGAAGCAGCCAGAACATCGTGCACATCAACGGCAACACCTACCTGGAGTGGTACCTGCAAA
AGCCCGGCCAGAGCCCCAGGCTGCTGATCTACAAGATCAGCGACAGGTTCAGCGGCGTGCCCGAT
AGGTTCAGCGGCAGCGGCAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTGGAGGCCGACGA
CGTGGGCATCTACTACTGCTTCCAGGGCAGCCACGTCCCCTGGACTTTCGGACAGGGCACCAAGC
TGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTG
AAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCA
GTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACAGCA
AGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG
GTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGC SEQ ID NO; 26
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARWIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 27
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGTGGATCTACGACGACTACCACTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC -97- 148186.doc 201107345
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 28
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLE測GTIDPANGNTKYVPKFQ GRVTITADESTSTAYMELSSLRSEDTAVYYCARSVYDDYHYDDYYAiyiDYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 29
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCGTCTACGACGACTACCACTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCT^AGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG -98·
148186.doc 201107345
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 30
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIFDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 31
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTTTGACGACTACCACTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGA.CCCACZ\CCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT -99- 148186.doc 201107345
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 32
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYEDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 33
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGAGGACTACCACTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC •100·
I48186.doc 201107345
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 34
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWiyiGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYAYDDYY/^MDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 35
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACGCGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG -101 - 148186.doc 201107345
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 36
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYEYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSViyiHEALHNHYTQKSLSLSPGK SEQ ID NO: 37
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACGAGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACT^GAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT •102·
148186.doc 201107345
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO: 38
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYiyiHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYQYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 39
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCAGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAG/W^ACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -103· 148186.doc 201107345 SEQ ID NO: 40
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYRYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 41
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACAGGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -104-
148186.doc 201107345 SEQ ID NO: 42
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYSYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 43
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACTCCTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -105- 148186.doc 201107345 SEQ ID NO: 44
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYTYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM.
ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 45
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACACGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG 106·
148186.doc 201107345 SEQ ID NO: 46
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYVYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 47
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACGTGTACGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACC7VAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCAC7VAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -107- 148186.doc 201107345 SEQ ID NO: 48
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHADDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 49
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGCGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG •108·
148186.doc 201107345 SEQ ID NO: 50
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHIDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 51
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACATTGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -109- 148186.doc 201107345 SEQ ID NO: 52
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHWDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 53
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACTGGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG •110·
148186.doc 201107345 SEQ ID NO: 54
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 55
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGTCGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG -Ill - 148186.doc 201107345 SEQ ID NO: 56
MGWSCIILFLVATATGVHS SEQ ID NO: 57
GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM
LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN SEQ ID NO: 58 eiqlqqsvaelvrpgasvrlsctasgfyikdtymhwviqrpeqglewigtidpangntkyvpkfq
GKATITADTSSNTAYLRLSSLTSEDTAIYYCARSIYDDYHYDDYYAMDYWGQGTSVTVSS SEQ ID NO: 59
DVLMTQTPLSLPVSLGDQASISCRSSQNIVHINGNTYLEWYLQKPGQSPKLLIYKISDRFSGVPD
RFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGGGTKLEIK SEQ ID NO: 60
FYIKDTYMH SEQ ID NO: 61
GFYIKDTYMH SEQ ID 62: AlYlOOBAla H-TVAAPS-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHADDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTETY
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS •112- 148186.doc 201107345 SEQ ID 63: AlYlOOBAla H-TVAAPS-210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGCGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCTAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
ACCGTGGCCGCCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGG
CAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGGTCA
GGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACCTAC
TACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTACCT
GCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCAGGT
TCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC SEQ ID 64: A1 YlOOBIle H-TVAAPS-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHIDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM -113 - 148186.doc 201107345
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTETY
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID 65: AlYlOOBIle H-TVAAPS-210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACATTGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCTAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
ACCGTGGCCGCCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGG
CAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGGTCA
GGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACCTAC
TACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTACCT
GCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCAGGT
TCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC -114-
148186.doc 201107345 SEQ ID 66: AlYlOOBTrp H-TVAAPS-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHWDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTETY
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS
SEQ ID 67: AlYlOOBTrp H-TVAAPS-210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACTGGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCTAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
ACCGTGGCCGCCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGG -115- 148186.doc 201107345
CAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGGTCA
GGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACCTAC
TACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTACCT
GCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCAGGT
TCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC SEQ ID 68: AlYlOOBVal H-TVAAPS-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTETY
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID 69: A1 YlOOBVal H-TVAAPS-210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGTCGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA -116-
148186.doc 201107345
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
ACCGTGGCCGCCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGG
CAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGGTCA
GGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACCTAC
TACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTACCT
GCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCAGGT
TCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC
SEQ ID 70: AlYlOOBAla H-ASTKGPS-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHADDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTET
YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID 71: AlYlOOBAla H-ASTKGPS-210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGCGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG •117· 148186.doc 201107345
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
GCCAGCACCAAGGGCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGG
CGGCAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGG
TCAGGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACC
TACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTA
CCTGCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCA
GGTTCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC 8£〇10 72:入1丫10(^116 11-入81^0?3-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHIDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTET
YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID 73: AlYlOOBIle H- ASTKGPS -210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACATTGACGACT -118·
148186.doc 201107345
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
GCCAGCACCAAGGGCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGG
CGGCAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGG
TCAGGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACC
TACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTA
CCTGCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCA
GGTTCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC 8£〇10 74:八1丫10(^1>?11-八8丁〖0?8-210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHWDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTET
YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS 119· 148186.doc 201107345 SEQ ID 75: AlYlOOBTrp H- ASTKGPS -210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACTGGGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
GCCAGCACCAAGGGCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGG
CGGCAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGG
TCAGGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACC
TACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTA
CCTGCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCA
GGTTCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC SEQ ID 76: AlYlOOBVal H- ASTKGPS -210(蛋白質序列）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM -120-
148186.doc 201107345
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSEVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTET
YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID 77: AlYlOOBVal H- ASTKGPS -210(DNA序列）
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTGAGCTG
CAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCTCCTGGCCAGG
GCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTACGTGCCCAAGTTCCAG
GGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCCTGAG
GTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATCTACGACGACTACCACGTCGACGACT
ACTACGCCATGGACTACTGGGGACAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGC
CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTG
CCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCG
GCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC
GTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACAC
CAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTG
CCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGGTGAA
GTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGT
ACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAG
GAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGC
CAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGA
ACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAG
AGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTT
CTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCT
CCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAG
GCCAGCACCAAGGGCCCCTCGGAAGTGCAGCTCCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGG
CGGCAGCCTGAGGCTGAGCTGCGCCGCTAGCGGCTTCACCTTCAGGAACTTCGGCATGGGCTGGG
TCAGGCAGGCCCCCGGCAAGGGCCTGGAGTGGGTCAGCTGGATCATCAGCTCCGGCACCGAGACC
TACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCCGCGACAACAGCAAGAACACCCTGTA
CCTGCAGATGAACAGCCTGAGGGCCGAGGACACCGCCGTCTACTACTGCGCCAAGAGCCTGGGCA
GGTTCGACTACTGGGGACAGGGGACCCTGGTGACTGTGAGCAGC -121 - 148186.doc 201107345 SEQ ID NO: 78=DOM9-155- 25
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASTLDSGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO: 79=DOM9-155-147
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLYEGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO: 80=DOM9-155-154
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO: 81=DOM9-112-210
EVQLLESGGGLVQPGGSLRLSCAASGFTFRNFGMGWVRQAPGKGLEWVSWIISSGTETYYADSVK
GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSLGRFDYWGQGTLVTVSS SEQ ID NO: 82(G4S 連接子）
GGGGS SEQ ID NO: 83(連接子）
TVAAPS SEQ ID NO: 84(連接子）
ASTKGPT SEQ ID NO: 85(連接子）
ASTKGPS SEQ ID NO: 86(連接子）
GS SEQ ID NO: 87(連接子）
TVAAPSGS -122- 148186.doc 201107345 SEQ ID NO: 88=147-TVAAPS-586 Y100B V (重鏈）
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLYEGVPSRFSGS
GSGTDFTLTISSLQPEDFTVTYYCLQEGWGPPTFGQGTKVEIKRGSTVAAPSQVQLVQSGAEVKKP
GSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQGRVTITADESTSTA
YMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN
VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP
VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 89=147-ASTKG-586 Y100B V (重鏈）
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLYEGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKRGSASTKGPSQVQLVQSGAEVKK PGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQGRVTITADESTST AYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNPCALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDS DGS FFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 90=154 TVAAPS-586 Y100B V (重鏈）
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKRGSTVAAPSQVQLVQSGAEVKKP
GSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQGRVTITADESTSTA
YMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN
VNHKPSOTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP
VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK -123· 148186.doc 201107345 SEQ ID NO: 91 = 154-ASTKG-586 Y100B V (重鏈）
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKRGSASTKGPSQVQLVQSGAEVKK
PGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQGRVTITADESTST
AYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKST
SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA
PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 92(連接子）
GSTVAAPS SEQ ID NO: 93(連接子）
GSTVAAPSGS SEQ ID NO: 94 DOM9-155-154 L89Q(aka DOM9-155-256)
DIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR SEQ ID NO: 95 DOM9-155 154 L89Q(aka DOM9-155-256)
GACATCCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACC
ATTACCTGCAGGGCCAGCAGGCCCATCAGCGACTGGCTGCACTGGTACCAACAGAAGCCC
GGCAAGGCTCCCT^AGCTGCTGATCGCCTGGGCCAGCAGCCTGCAGGGAGGCGTGCCCAGC
AGGTTTAGCGGCAGCGGCAGCGGCACCGACTTCACCCTCACCATCTCTTCCCTGCAGCCC
GAGGACTTCGCCACCTACTACTGCCAGCAGGAGGGCTGGGGGCCCCCTACTTTCGGCCAG
GGCACCAAGGTGGAGATCAAGAGG SEQ ID NO: 96
829H-GS(TVAAPSGS)2-154 L89Q -124· 148186.doc 201107345
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPMIGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAiyiDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSTVAAPSGSTVAAPSGSDIQMTQS
PSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGSGS
GTDFTLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR
SEQ ID NO: 97
829H-GS(TVAAPSGS)2-154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTT^ACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGG
GAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG •125- 148186.doc 201107345
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAGGGATCTACCGTGGCA
GCACCATCCGGATCTACCGTAGCAGCACCATCCGGATCCGACATCCAGATGACCCAGAGC
CCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACCATTACCTGCAGGGCCAGCAGG
CCCATCAGCGACTGGCTGCACTGGTACCAACAGAAGCCCGGCAAGGCTCCCAAGCTGCTG
ATCGCCTGGGCCAGCAGCCTGCAGGGAGGCGTGCCCAGCAGGTTTAGCGGCAGCGGCAGC
GGCACCGACTTCACCCTCACCATCTCTTCCCTGCAGCCCGAGGACTTCGCCACCTACTAC
TGCCAGCAGGAGGGCTGGGGGCCCCCTACTTTCGGCCAGGGCACCAAGGTGGAGATCAAG
AGG SEQ ID NO: 98
829H-GS(TVAAPSGS)3-154 L89Q
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSTVAAPSGSTVAAPSGSTVAAPSG
SDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVP
SRFSGSGSGTDFTLTISSLQPEDFTVTYYCQQEGWGPPTFGQGTKVEIKR SEQ ID NO: 99
829H-GS(TVAAPSGS)3154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC -126- 148186.doc 201107345
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGG
GAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCC7VAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGC7VAGGGATCTACCGTGGCA
GCACCATCAGGATCTACCGTGGCAGCACCATCAGGTTCAACAGTAGCTGCTCCTTCTGGA
TCCGACATCCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTG
ACCATTACCTGCAGGGCCAGCAGGCCCATCAGCGACTGGCTGCACTGGTACCAACAGAAG
CCCGGCAAGGCTCCCAAGCTGCTGATCGCCTGGGCCAGCAGCCTGCAGGGAGGCGTGCCC
AGCAGGTTTAGCGGCAGCGGCAGCGGCACCGACTTCACCCTCACCATCTCTTCCCTGCAG
CCCGAGGACTTCGCCACCTACTACTGCCAGCAGGAGGGCTGGGGGCCCCCTACTTTCGGC
CAGGGCACCAAGGTGGAGATCAAGAGG SEQ ID NO: 100
829H-GS(TVAAPSGS)4-154 L89Q
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSTVAAPSGSTVAAPSGSTVAAPSG
STVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR -127· 148186.doc 201107345 SEQ ID NO: 101
829H-GS(TVAAPSGS)4-154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGG
GAGGAGCAGTACT^CAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAGGGATCTACCGTGGCA
GCACCATCAGGATCTACCGTGGCAGCACCATCAGGTTCAACAGTAGCTGCTCCTTCTGGT
TCAACAGTAGCTGCTCCTTCTGGATCCGACATCCAGATGACCCAGAGCCCCAGCAGCCTG
AGCGCCAGCGTGGGCGACAGGGTGACCATTACCTGCAGGGCCAGCAGGCCCATCAGCGAC
TGGCTGCACTGGTACCAACAGAAGCCCGGCAAGGCTCCCAAGCTGCTGATCGCCTGGGCC
AGCAGCCTGCAGGGAGGCGTGCCCAGCAGGTTTAGCGGCAGCGGCAGCGGCACCGACTTC
ACCCTCACCATCTCTTCCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGGAG
GGCTGGGGGCCCCCTACTTTCGGCCAGGGCACCAAGGTGGAGATCAAGAGG -128- 148186.doc 201107345
SEQ ID NO: 102 829H-(TVAAPS)2GS-154 L89Q
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTVAAPSTVAAPSGSDIQMTQSPSSL
SASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGSGSGTDF
TLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR
SEQ ID NO: 103 829H-(TVAAPS)2GS-154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACC7\AGCCCAGG
GAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTAC7\AGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC -129- 148186.doc 201107345
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAGACCGTGGCAGCACCA
TCCACCGTAGCAGCACCATCCGGATCCGACATCCAGATGACCCAGAGCCCCAGCAGCCTG
AGCGCCAGCGTGGGCGACAGGGTGACCATTACCTGCAGGGCCAGCAGGCCCATCAGCGAC
TGGCTGCACTGGTACCAACAGAAGCCCGGCAAGGCTCCCAAGCTGCTGATCGCCTGGGCC
AGCAGCCTGCAGGGAGGCGTGCCCAGCAGGTTTAGCGGCAGCGGCAGCGGCACCGACTTC
ACCCTCACCATCTCTTCCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGGAG
GGCTGGGGGCCCCCTACTTTCGGCCAGGGCACCAAGGTGGAG'ATCAAGAGG
SEQ ID NO: 104 829H-(TVAAPS)3GS-154 L89Q
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTVAAPSTVAAPSTVAAPSGSDIQMT
QSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGS
GSGTDFTLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR
SEQ ID NO: 105 829H-(TVAAPS)3GS-154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA -130- 148186.doc 201107345
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGG
GAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAGACCGTGGCAGCACCA
TCAACCGTGGCAGCACCATCAACAGTAGCTGCTCCTTCTGGATCCGACATCCAGATGACC
CAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACCATTACCTGCAGGGCC
AGCAGGCCCATCAGCGACTGGCTGCACTGGTACCAACAG7U\GCCCGGCAAGGCTCCCAAG
CTGCTGATCGCCTGGGCCAGCAGCCTGCAGGGAGGCGTGCCCAGCAGGTTTAGCGGCAGC
GGCAGCGGCACCGACTTCACCCTCACCATCTCTTCCCTGCAGCCCGAGGACTTCGCCACC
TACTACTGCCAGCAGGAGGGCTGGGGGCCCCCTACTTTCGGCCAGGGCACCAAGGTGGAG
ATCAAGAGG
SEQ ID NO: 106 829H-(TVAAPS)4GS-154 L89Q
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKY
VPKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTVAAPSTVAAPSTVAAPSTVAAPSG
SDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGGVP .131 - 148186.doc 201107345
SRFSGSGSGTDFTLTISSLQPEDFATYYCQQEGWGPPTFGQGTKVEIKR
SEQ ID NO: 107 829H-(TVAAPS)4GS-154 L89Q
CAGGTGCAGCTCGTGCAGAGCGGCGCCGAAGTGAAAAAGCCCGGCAGCAGCGTGAAGGTG
AGCTGCAAGGCCTCCGGCTTCTACATCAAGGACACCTACATGCACTGGGTCAGGCAGGCT
CCTGGCCAGGGCCTGGAGTGGATGGGCACTATCGACCCCGCCAACGGCAACACCAAGTAC
GTGCCCAAGTTCCAGGGCAGGGTGACCATCACCGCCGATGAGAGCACCAGCACCGCCTAC
ATGGAACTGAGCAGCCTGAGGTCTGAGGACACCGCCGTGTACTATTGCGCCAGGAGCATC
TACGACGACTACCACGTCGACGACTACTACGCCATGGACTACTGGGGACAGGGCACACTA
GTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGC
AAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAA
CCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCC
GTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC
CTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAGGTGGAGCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCC
GAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATG
ATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAG
GTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGG
GAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT
TGGCTGAACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATC
GAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCC
CCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTC
TACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG
ACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTG
GACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTG
CACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCTGGCAAGACCGTGGCAGCACCA
TCAACCGTGGCAGCACCATCAACAGTAGCTGCTCCTTCTACAGTAGCTGCTCCTTCTGGA
TCCGACATCCAGATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTG
ACCATTACCTGCAGGGCCAGCAGGCCCATCAGCGACTGGCTGCACTGGTACCAACAGAAG
CCCGGCAAGGCTCCCAAGCTGCTGATCGCCTGGGCCAGCAGCCTGCAGGGAGGCGTGCCC
AGCAGGTTTAGCGGCAGCGGCAGCGGCACCGACTTCACCCTCACCATCTCTTCCCTGCAG
CCCGAGGACTTCGCCACCTACTACTGCCAGCAGGAGGGCTGGGGGCCCCCTACTTTCGGC
CAGGGCACCAAGGTGGAGATCAAGAGG -132-
148186.doc 201107345 SEQ ID NO: 108
DIQMTQSPSSLSASVGDRVTITCRSSQNIVHINGNTYLEWYQQKPGPCAPKLLIYKISDRFSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCFQGSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 109
ATGGGCTGGTCCTGCATCATCCTGTTTCTGGTGGCCACCGCCACCGGCGTGCACAGCGACATCCA
GATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACTATCACCTGCAGGA
GCAGCCAGAACATCGTGCACATCAACGGCAACACCTACCTCGAGTGGTACCAGCAGAAACCCGGG
AAGGCCCCCAAGCTGCTGATCTACAAGATCAGCGACAGGTTCAGCGGCGTGCCCAGCAGGTTTAG
CGGCTCCGGCTCAGGCACCGATTTCACCCTGACCATTAGCAGCCTGCAGCCCGAGGACTTCGCCA
CCTACTACTGCTTCCAGGGCTCTCACGTCCCCTGGACCTTCGGCCAGGGCACCAAGCTGGAGATC
AAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTGAAGAGCGG
CACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG
TGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACTCC
ACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGC
CTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC SEQ ID NO: 110
DVLMTQSPSSLSASVGDRVTITCRSSQNIVHINGNTYLEWYQQKPGKAPKLLIYKISDRFSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCFQGSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 111
ATGGGCTGGTCCTGCATCATCCTGTTTCTGGTGGCCACCGCCACCGGCGTGCACAGCGACGTGCT
GATGACCCAGAGCCCCAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACTATCACCTGCAGGA
GCAGCCAGAACATCGTGCACATCAACGGCAACACCTACCTCGAGTGGTACCAGCAGAAACCCGGG
AAGGCCCCCAAGCTGCTGATCTACAAGATCAGCGACAGGTTCAGCGGCGTGCCCAGCAGGTTTAG
CGGCTCCGGCTCAGGCACCGATTTCACCCTGACCATTAGCAGCCTGCAGCCCGAGGACTTCGCCA
CCTACTACTGCTTCCAGGGCTCTCACGTCCCCTGGACCTTCGGCCAGGGCACCAAGCTGGAGATC
AAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTGAAGAGCGG
CACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG -133 - 148186.doc 201107345
TGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACTCC
ACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGC
CTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC SEQ ID NO: 112
EIVLTQSPGTLSLSPGERATLSCRSSQNIVHINGNTYLEWYQQKPGQAPRLLIYKISDRFSGIPD
RFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK
VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 113
ATGGGCTGGTCCTGCATCATCCTGTTTCTGGTGGCCACCGCCACCGGCGTGCACAGCGAGATCGT
GCTGACCCAGAGCCCTGGCACACTGAGCCTGAGCCCCGGAGAGAGGGCCACCCTGAGCTGCAGGT
CTAGCCAGAACATCGTGCACATCAACGGCAACACCTACCTGGAGTGGTATCAGCAGAAGCCCGGC
CAGGCCCCCAGGCTGCTGATCTACAAGATCAGCGACAGGTTCAGCGGCATCCCCGACAGGTTTAG
CGGCAGCGGCAGCGGCACCGACTTCACCCTGACCATTAGCAGGCTGGAGCCCGAGGACTTCGCCG
TGTACTACTGCTTCCAGGGGAGCCACGTGCCCTGGACCTTCGGCCAGGGCACCAAGCTCGAAATC
AAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTGAAGAGCGG
CACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG
TGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACTCC
ACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGC
CTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC SEQ ID NO: 114
DVLMTQSPGTLSLSPGERATLSCRSSQNIVHINGNTYLEWYQQKPGQAPKLLIYKISDRFSGVPD
RFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK
VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 115
GACGTGCTGATGACCCAGAGCCCTGGCACACTGAGCCTGAGCCCCGGAGAGAGGGCCACCCTGAG
CTGCAGGTCTAGCCAGAACATCGTGCACATCAACGGCAACACCTACCTGGAGTGGTATCAGCAGA
AGCCCGGCCAGGCCCCCAAGCTGCTGATCTACAAGATCAGCGACAGGTTCAGCGGCGTGCCCGAC
AGGTTTAGCGGCAGCGGCAGCGGCACCGACTTCACCCTGACCATTAGCAGGCTGGAGCCCGAGGA -134·
148186.doc 201107345
CTTCGCCGTGTACTACTGCTTCCAGGGGAGCCACGTGCCCTGGACCTTCGGCCAGGGCACCAAGC
TCGAAATCAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTG
AAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCA
GTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACAGCA
AGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG
GTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGC SEQ ID NO:116=586H-TVAAPS154(H鏈）
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQGG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO:117
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAiyiDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQEGWGPPTFGQGTKVEIKR SEQ ID NO:118
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ GRVTITADESTSTAYMELSSLRSEDTAVYYCARS工YDDYHVDDYYAMDYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT -135- 148186.doc 201107345
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQEGWGPPTFGQGTKVEIKR SEQ ID NO:119
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQEGWGPPTFGQGTKVEIKR SEQ ID NO:120
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCMQEGWGPPTFGQGTKVEIKR SEQ ID NO:121
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE -136- 148186.doc 201107345
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSPIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQEGWGPPTFGQGTKVEIKR SEQ ID NO:122
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCTQEGWGPPTFGQGTKVEIKR SEQ ID NO:123
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDMLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCQEGWGPPTFGQGTKVEIKR SEQ ID NO:124
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVNIHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCRQEGWGPPTFGQGTKVEIKR -137- 148186.doc 201107345 SEQ ID NO:125
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM 工SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCWQEGWGPPTFGQGTKVEIKR SEQ ID NO:126
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCEQEGWGPPTFGQGTKVEIKR SEQ ID NO:127
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCKQEGWGPPTFGQGTKVEIKR SEQ ID NO:128
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG •138· 148186.doc 201107345
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSMTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYMSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCDQEGWGPPTFGQGTKVEIKR SEQ ID NO:129
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDETLTISSLQPEDFATYYCNQEGWGPPTFGQGTKVEIKR SEQ ID NO:130
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCYQEGWGPPTFGQGTKVEIKR SEQ ID NO:131
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK -139- 148186.doc 201107345
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCVQEGWGPPTFGQGTKVEIKR SEQ ID NO:132
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAiyiDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCIQEGWGPPTFGQGTKVEIKR SEQ ID NO:133
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQEGWGPPTFGQGTKVEIKR SEQ ID NO:134
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHVDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSViyiHEALHNHYTQKSLSLSPGK
TVAAPSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWA •140- 148186.doc 201107345
SSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCPQEGWGPPTFGQGTKVEIKR SEQ ID NO:135
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
GSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLLIAWASSLQ
GGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO:136
QVQLVQSGAEVKKE?GSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
GSTVAAPSGSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQKPGKAPKLL
IAWASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKVEIKR SEQ ID NO:137
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHYDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
GSTVAAPSGSTVAAPSGSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISDWLHWYQQK
PGKAPKLLIAWASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQEGWGPPTFGQGTKV
EIKR -141 - I48186.doc 201107345 SEQ ID NO:138
QVQLVQSGAEVKKPGSSVKVSCKASGFYIKDTYMHWVRQAPGQGLEWMGTIDPANGNTKYVPKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARSIYDDYHyDDYYAMDYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
GSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGSDIQMTQSPSSLSASVGDRVTITCRASRPISD
WLHWYQQKPGKAPKLLIAWASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQEGWGPP
TFGQGTKVEIKR SEQ ID NO:139
GSTVAAPSGS SEQ ID NO:140
GSTVAAPSGSTVAAPSGS SEQ ID NO:141
GSTVAAPSGSTVAAPSGSTVAAPSGS SEQ ID NO:142
GSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGS SEQ ID NO:143
GSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGS SEQ ID NO:144
GSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGSTVAAPSGS SEQ ID NO:145
TVAAPSTVAAPSGS SEQ ID NO:146
TVAAPSTVAAPSTVAAPSGS 142- 148186.doc 201107345 【圖式簡單說明】 圖1 :曲線圖展示包含Y100B變體之mAbdAb在TF-1細胞 增殖分析法中中和人類IL-13之能力； 圖2 :曲線圖展示包含Y100B變體之mAbdAb在TF-1細胞 增殖分析法中中和人類IL-13之能力； 圖 3 : BPC2222 之 SEC 跡線； 圖 4 : BPC2223 之 SEC跡線； 圖 5 : BPC2230之 SEC跡線；
圖 6 : BPC2231 之 SEC跡線； 圖 7 : BPC1085之 SEC跡線； 圖 8 : BPC1086之 SEC跡線； 圖 9 : BPC1087之 SEC 跡線； 圖10 :曲線圖展示純化mAbdAb(BPC1085、BPC1086及 BPC1087)對人類IL-4之結合，如ELISA所測定。IL-4對照 物mAb標示為「帕考珠單抗（pascolizumab)」； 圖11:曲線圖展示純化〇1八匕(1>13(：6?(：1085、8?(：1086及 BPC1087)在TF-1細胞生物分析法中對人類IL-4之中和程 度。IL-4對照物mAb標示為「帕考珠單抗」； 圖12 :曲線圖展示純化mAbdAb(BPC1085、BPC1086及 BPC1087)在TF-1細胞生物分析法中對人類IL-13之中和程 度。IL-4對照物mAb標示為「帕考珠單抗」； 圖 13 : BPC3214之 SEC概況； 圖 14 : BPC3215之 SEC概況； 圖 15 :曲線圖展示純化 mAbdAb BPC3214、BPC3215、 148186.doc -143 - 201107345 BPC1085 及對照物 mAb A1Y100BVAL1 及抗 IL-4 mAb 對人 類IL-13之結合，如ELISA所測定。IL-4對照物mAb標示為 「帕考珠單抗」； 圖 16 :曲線圖展示純化 mAbdAb BPC3214、BPC3215、 BPC1085 及對照 mAb A1Y100BVAL1 及抗 IL-4 mAb 對人類 IL-4之結合，如ELISA所測定。IL-4對照mAb標示為「帕 考珠單抗」；及 圖17:曲線圖展示短暫表現之mAbdAb對重組大腸桿菌 表現之人類IL-4之結合，如ELIS A所測定。IL-4對照物 mAb標示為「帕考珠單抗」。 148186.doc • 144· 201107345 序列表 <100>英商葛蘭素集團有限公司 <120>免疫球蛋白 <130> PB63682 <140〉 099116859 <141> 2010-05-26 <150> 61/181,833 <151> 2009-05-28
<150> 61/288,930 <151> 2009-12-22 <160〉 146 <170> FastSEQ for Windows Version 4.0 <210> 1 <211〉 5 <212> PRT <213〉小鼠屬 <220> φ <400> 1
Asp Thr Tyr Met His 1 5 <210〉 2 <211〉 17 <212> PRT <213〉小鼠屬 <400> 2
Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe Gin 14S186-序列表.doc 201107345 15 10 15
Gly <210〉 3 <211> 16 <212〉 PRT <213〉小鼠屬 <400〉 3
Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210> 4 <211〉 16 <212> PRT <213〉人工序列 <220〉 <223〉突變 CDR <400〉 4
Trp lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 5 <211> 16 <212> PRT <213〉人工序列 <220> <223〉突變 CDR <400〉 5
Ser Val Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15
<210> 6 <211〉 16 〈212〉 PRT 148186-序列表.doc 201107345 〈213>人工序列 <220〉 <223〉突變 CDR <400> 6
Ser lie Phe Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 7 <211> 16 <212〉 PRT <213〉人工序列
〈223> 突變 CDR <400〉 7
Ser He Tyr Glu Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 8 (211> 16 <212〉 PRT <213〉人工序列 <220> <223〉突變 CDR <400> 8
Ser He Tyr Asp Asp Tyr Ala Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 9 <211> 16 <212〉 PRT <213〉人工序列 <220>
<223〉突變 CDR 148186-序列表.doc 201107345 <400〉 9
Ser lie Tyr Asp Asp Tyr Glu Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210> 10 <211〉 16 <212〉 PRT <213〉人工序列 <220> 〈223> 突變 CDR <400〉 10
Ser lie Tyr Asp Asp Tyr Gin Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 11 <211〉 16 <212> PRT <213〉人工序列 <220〉 〈223> 突變 CDR <400> 11
Ser lie Tyr Asp Asp Tyr Arg Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 12 〈211〉 16 <212〉 PRT <213〉人工序列 <220〉 <223〉突變 CDR <400〉 12
Ser lie Tyr Asp Asp Tyr Ser Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 4- 148186·序列表.doc 201107345 <210> 13 <211〉 16 <212> PRT 〈213〉人工序列 <220> <223〉突變 CDR <400〉 13
Ser lie Tyr Asp Asp Tyr Thr Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210〉 14 <211〉 16
<212〉 PRT <213〉人工序列 <220> <223〉突變 CDR <400> 14
Ser lie Tyr Asp Asp Tyr Val Tyr Asp Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210> 15 <211> 16 <212> PRT <213〉人工序列 <220> <223〉突變 CDR <400> 15
Ser He Tyr Asp Asp Tyr His Ala Asp Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <210〉 16 <211〉 16 <212〉 PRT <2,13>人工序列 148186-序列表.doc 201107345 <220〉 <223〉突變 CDR <400> 16
Ser lie Tyr Asp Asp Tyr His lie Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 〈210〉 17 <211〉 16 <212> PRT <213〉人工序列 <220> <223〉突變 CDR <400〉 17
Ser lie Tyr Asp Asp Tyr His Trp Asp Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 15 〈210〉 18 <211〉 16 <212〉 PRT <213〉人工序列 <220〉 <223〉突變 CDR <400〉 18
Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met Asp Tyr 15 10 15 <210〉 19 <211> 16 <212〉 PRT <213〉小鼠屬 <400〉 19
Arg Ser Ser Gin Asn lie Val His lie Asn Gly Asn Thr Tyr Leu Glu 15 10 15 -6- 148186-序列表.doc 201107345 <210〉 20 <211> 7 <212> PRT <213〉小鼠屬 <400〉 20
Lys lie Ser Asp Arg Phe Ser 1 5 <210〉 21 <211〉 9 <212> PRT <213〉小鼠屬
<400> 21 F)he Gin Gly Ser His Val Pro Trp Thr 1 5 <：210> 22 <211> 455 <：212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 22
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 148186-序列表.doc 201107345 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 148186-序列表.doc 201107345 <210> 23 <211〉 1365 <212〉 DNA <213〉人工序列 <220> <223〉人類化 <400> 23
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accactacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ocggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 24 <211> 219 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400> 24
Asp lie Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 148丨86·序列表.doc 201107345 15 10 15
Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Asn He Val His lie 20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro Arg Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Asp Asp Val Gly lie Tyr Tyr Cys Phe Gin Gly 85 90 95
Ser His Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210〉 25 <211〉 657 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400> 25 gacatcgtga tgacccagtc tcctctgagc ctccccgtga cccccggcga accagccagc 60 atctcctgca gaagcagcca gaacatcgtg cacatcaacg gcaacaccta cctggagtgg 120 tacctgcaaa agcccggcca gagccccagg ctgctgatct acaagatcag cgacaggttc 180 agcggcgtgc ccgataggtt cagcggcagc ggcagcggca ccgacttcac cctgaagatc 240 agcagggtgg aggccgacga cgtgggcatc tactactgct tccagggcag ccacgtcccc 300 tggactttcg gacagggcac caagctggag attaagcgta cggtggccgc ccccagcgtg 360 • 10- 148186-序列表.doc 201107345 ttcatcttcc cccccagcga tgagcagctg aagagcggca ccgccagcgt ggtgtgtctg 420 ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa tgccctgcag 480 agcggcaaca gccaggagag cgtgaccgag caggacagca aggactccac ctacagcctg 540 agcagcaccc tgaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgtgag 600 gtgacccacc agggcctgtc cagccccgtg accaagagct tcaaccgggg cgagtgc 657 <210〉 26 <211> 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400> 26
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Trp lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro -11 - 148186·序列表.doc 201107345 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Lea Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 27 <211〉 1365 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400> 27 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 -12· 148186·序列表.doc 201107345
atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggtggatc 300 1;acgacgact accactacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ocggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 28 <211> 455 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 28
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser Val Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr -13 - 148186-序列表,doc 201107345 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 -14- 148186·序列表.doc 201107345 <210〉 29 <211> 1365 <212〉 DNA <213〉人工序列 <220> <223〉人類化 <400〉 29
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcgtc 300 tacgacgact accactacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga. gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 iiagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 30 <211> 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 30
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser -15- 148186·序列表.doc 201107345 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Phe Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys -16- 148186·序列表.doc 201107345 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455
<210〉 31 <211> 1365 〈212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 31 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tttgacgact accactacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 ijtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 -17- 148186-序列表.doc 201107345 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 32 <211〉 455 <212〉 PRT 〈213〉人工序列 <220〉 〈223>人類化 <400〉 32
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Glu Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys •18· 148186·序列表.doc 201107345 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 33 〈211〉 1365 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 33 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct; 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgaggact accactacga cgactactac gccatggact actggggaca gggcacacta 360 -19- 148186-序列表.doc 201107345 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca* cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 34 <211> 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 34
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Ala Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser -20-
148186-序列表.doc 201107345 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Va.1 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 35 •21 - 148186-序列表.doc 201107345 <211> 1365 <212〉 DNA <213〉人工序列 <220> <223〉人類化 <400〉 35 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact acgcgtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 36 <211> 455 <212> PRT 〈213〉人工序列 <220> <223〉人類化 <400> 36
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr •22 148186·序列表.doc 201107345 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Glu Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350 GLu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp -23- 148186-序列表.doc 201107345 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 37 <211〉 1365 <212> DNA <213〉人工序列 <220〉 <223〉人類化 <400> 37 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact acgagtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 -24-
148186-序列表.doc 201107345 1365 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag <：210> 38 <211> 455 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400〉 38
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Gin Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val -25- 148186-序列表.doc 201107345 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 39 <211> 1365 〈212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400> 39 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accagtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 -26- 148186-序列表.doc 201107345 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgeiagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365
<210〉 40 <211> 455 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 40
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Arg Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp^Tyr Phe Pro Glu -27- 148186-序列表,doc 201107345 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser As'n Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455
<210> 41 <211〉 1365 <212〉 DNA 28· 148】86-序列表.doc 201107345 <213〉人工序列 <220〉 <223〉人類化 <400〉 41
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact acaggtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 tgLCCCcagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 42 <211〉 455 〈212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 42
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met •29· 148186-序列表.doc 201107345 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr Ser Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys -30- 148186-序列表.doc 201107345 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 43 <：211> 1365 <：212> DNA <213〉人工序列
<220> <223〉人類化 <400〉 43 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact actcctacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 •31 - 148186-序列表.doc 201107345 <210〉 44 <211〉 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 44
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Thr Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp -32· 148186-序列表.doc 201107345 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn GLy Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 45 <211〉 1365 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400> 45 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact acacgtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 -33- 148丨86·序列表.doc 201107345 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgteiag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 46 <211〉 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 46
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr Val Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His -34- 148186-序列表.doc 201107345 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 〈210〉 47 <211> 1365 <212> DNA <213〉人工序列 -35- 148186-序列表.doc 201107345 <220〉 <223〉人類化 <400〉 47 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact acgtgtacga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210> 48 <211> 455 <212〉 PRT 〈213>人工序列 <220〉 <223〉人類化 <400〉 48
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe -36· 148186-序列表.doc 201107345 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Ala Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser -37- 148186-序列表.doc 201107345 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 49 <211〉 1365 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400>_ 49 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgcgga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210〉 50 <211> 455 38- 148丨86-序列表.doc 201107345 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400> 50
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His lie Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 F^o Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr •39- 148186-序列表.doc 201107345 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 51 <211〉 1365 〈212〉 DNA <213〉人工序列 <220> <223〉人類化 <400〉 51 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacattga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 •40· 148186-序列表.doc 201107345 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 c-ctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365
<210〉 52 <211〉 455 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400> 52
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Trp Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser •41 · 148186-序列表.doc 201107345 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys 450 455 <210〉 53 〈211〉 1365 <212> DNA <213〉人工序列 <220〉 <223〉人類化 -42- 148186-序列表.doc 201107345 <400〉 53
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accactggga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta. cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210> 54 <211> 455 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 54
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr • 43· 148丨86-序列表.doc 201107345 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asa Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser -44-
148186-序列表,doc 201107345
Cys
Leu 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445 Ser Leu Ser Pro Gly Lys 450 455 <210〉 55 <211> 1365 <212> DNA <213〉人工序列<220〉 <223〉人類化
<400〉 55 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaag 1365 <210> 56 <211> 19 <212〉 PRT <213〉人工序列 148丨86-序列表.doc 45 · 201107345 <220> <223〉信號序列 <400〉 56
Met Gly Trp Ser Cys He lie Leu Phe Leu Val Ala Thr Ala Thr Gly 15 10 15
Val His Ser <210〉 57 〈211〉 112 <212〉 PRT <213〉智人 <400〉 57
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu lie Glu Glu Leu 15 10 15
Val Asn lie Thr Gin Asn Gin Lys Ala Pro Leu Cys Asn Gly Ser Met 20 25 30
Val Trp Ser lie Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu 35 40 45
Ser Leu lie Asn Val Ser Gly Cys Ser Ala lie Glu Lys Thr Gin Arg 50 55 60
Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gin Phe Ser 65 70 75 80
Ser Leu His Val Arg Asp Thr Lys He Glu Val Ala Gin Phe Val Lys 85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Arg Phe Asn 100 105 110 <210> 58 <211〉 125 <212〉 PRT <213〉小鼠屬 <400〉 58
Glu lie Gin Leu Gin Gin Ser Val Ala Glu Leu Val Arg Pro Gly Ala 15 10 15
Ser Val Arg Leu Ser Cys Thr Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val He Gin Arg Pro Glu Gin Gly Leu Glu Trp He •46- 148186·序列表.doc 201107345 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Lys Ala Thr lie Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80
Leu Arg Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala lie Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser 115 120 125
<210〉 59 <：211> 112 <212〉 PRT <213〉小鼠屬 <400> 59
Asp Val Leu Met Thr Gin Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15
Asp Gin Ala Ser lie Ser Cys Arg Ser Ser Gin Asn He Val His lie 20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gin Lys Pro Gly Gin Ser 35 40 45
Pro Lys Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gin Gly
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu He Lys 100 105 110 <210〉 60 <211〉 9 <212〉 PRT <213〉人工序列 <220> <223〉突變 CDR <400〉 60 -47· 148186·序列表.doc 201107345
Phe Tyr lie Lys Asp Thr Tyr Met His <210〉 61 <211〉 10 <212〉 PRT <213〉人工序列 <220〉 〈223> 突變 CDR <400〉 61
Gly Phe Tyr He Lys Asp Thr Tyr Met His 1 5 10 <210〉 62 〈211〉 577 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 62
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Ala Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 • 48· 148186-序列表doc 201107345
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Glu Val Gin 450 455 460
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 465 470 475 480
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met Gly 485 490 495 •49- 148186-序列表.doc 201107345
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp lie 500 505 510 lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 515 520 525
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 530 535 540
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser 545 550 555 560
Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 565 570 575
Ser 〈210〉 63 <211〉 1731 〈212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 63 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgcgga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ctagcgccag cacceiagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 • 50-
148丨86-序列表.doc 201107345 ^[acaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggccgccccc 1380 tcggaagtgc agctcctgga gagcggcggc ggcctggtgc agcccggcgg cagcctgagg 1440 ctgagctgcg ccgctagcgg cttcaccttc aggaacttcg gcatgggctg ggtcaggcag 1500 gcccccggca agggcctgga gtgggtcagc tggatcatca gctccggcac cgagacctac 1560 tacgccgaca gcgtgaaggg caggttcacc atcagccgcg acaacagcaa gaacaccctg 1620 tacctgcaga tgaacagcct gagggccgag gacaccgccg tctactactg cgccaagagc 1680 ctgggcaggt tcgactactg gggacagggg accctggtga ctgtgagcag c 1731 <210〉 64 <211> 577 <212〉 PRT 〈213>人工序列 <220〉
<223〉人類化 <400〉 64
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His lie Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Veil Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205 •51 - 148186·序列表.doc 201107345
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Glu Val Gin 450 455 460
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 465 470 475 480
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met Gly 485 490 495
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp lie 500 505 510
He Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 515 520 525
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 530 535 540
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser 545 550 555 560 -52- 148186-序列表.doc 201107345
Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 565 570 575
Ser 〈210〉 65 〈211〉 1731 <212> DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 65
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacattga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ctagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggccgccccc 1380 tcggaagtgc agctcctgga gagcggcggc ggcctggtgc agcccggcgg cagcctgagg 1440 otgagctgcg ccgctagcgg cttcaccttc aggaacttcg gcatgggctg ggtcaggcag 1500 gcccccggca agggcctgga gtgggtcagc tggatcatca gctccggcac cgagacctac 1560 tacgccgaca gcgtgaaggg caggttcacc atcagccgcg acaacagcaa gaacaccctg 1620 tacctgcaga tgaacagcct gagggccgag gacaccgccg tctactactg cgccaagagc 1680 ctgggcaggt tcgactactg gggacagggg accctggtga ctgtgagcag c 1731 53· 148186·序列表.doc 201107345 <210> 66 <211> 577 〈212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 66
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Trp Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270 -54- 148186·序列表.doc 201107345
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Glu Val Gin 450 455 460
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 465 470 475 480
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met Gly 485 490 495
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp lie 500 505 510 lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 515 520 525
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 530 535 540
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser 545 550 555 560
Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 565 570 575
Ser <210〉 67 <211〉 1731 55- 148186-序列表.doc 201107345 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 67 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accactggga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ctagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggccgccccc 1380 tcggaagtgc agctcctgga gagcggcggc ggcctggtgc agcccggcgg cagcctgagg 1440 ctgagctgcg ccgctagcgg cttcaccttc aggaacttcg gcatgggctg ggtcaggcag 1500 gcccccggca agggcctgga gtgggtcagc tggatcatca gctccggcac cgagacctac 1560 tacgccgaca gcgtgaaggg caggttcacc atcagccgcg acaacagcaa gaacaccctg 1620 tacctgcaga tgaacagcct gagggccgag gacaccgccg tctactactg cgccaagagc 1680 ctgggcaggt tcgactactg gggacagggg accctggtga ctgtgagcag c 1731 <210〉 68 <211> 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 56- 148186-序列表.doc 201107345 <400〉 68
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu H5 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335 -57- 148186-序列表.doc 201107345
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Glu Val Gin 450 455 460
Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg 465 470 475 480
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met Gly 485 490 495
Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp lie 500 505 510 lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 515 520 525
Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin Met 530 535 540
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ser 545 550 555 560
Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 565 570 575
Ser <210〉 69 <211〉 1731 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 69 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 • 58 - 148186-序列表.doc 201107345 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960
tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggccgccccc 1380 tcggaagtgc agctcctgga gagcggcggc ggcctggtgc agcccggcgg cagcctgagg 1440 ctgagctgcg ccgctagcgg cttcaccttc aggaacttcg gcatgggctg ggtcaggcag 1500 gcccccggca agggcctgga gtgggtcagc tggatcatca gctccggcac cgagacctac 1560 tacgccgaca gcgtgaaggg caggttcacc atcagccgcg acaacagcaa gaacaccctg 1620 i：acctgcaga tgaacagcct gagggccgag gacaccgccg tctactactg cgccaagagc 1680 ctgggcaggt tcgactactg gggacagggg accctggtga ctgtgagcag c 1731 <210〉 70 0 <211> 578 <：212> PRT <213〉人工序列 <220> <223〉人類化 <400> 70 Gin Val Gin Leu 1 Ser Val Lys Val
Ser Thr
Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly 5 10 15
Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp 20 25 30
Tyr Met His Tip 35
Val Arg Gin Ala Pro Gly 40
Gin Gly Leu Glu Trp Met 45 -59 148186-序列表.doc 201107345
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Ala Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400 •60- 148丨86-序列表,doc 201107345
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Ala Ser Thr Lys Gly Pro Ser Glu Val 450 455 460
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met 485 490 495
Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp 500 505 510
lie lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly 515 520 525
Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 530 535 540
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 1545 550 555 560
Ser Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 565 570 575
Ser Ser <210> 71 <：211> 1734 <；212> DNA <213〉人工序列
<：220> <223〉人類化 <：400> 71 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 eigctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgcgga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 •61 · 148186-序列表.doc 201107345 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg atatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaaggccag caccaagggc 1380 ccctcggaag tgcagctcct ggagagcggc ggcggcctgg tgcagcccgg cggcagcctg 1440 aggctgagct gcgccgctag cggcttcacc ttcaggaact tcggcatggg ctgggtcagg 1500 caggcccccg gcaagggcct ggagtgggtc agctggatca tcagctccgg caccgagacc 1560 tactacgccg acagcgtgaa gggcaggttc accatcagcc gcgacaacag caagaacacc 1620 ctgtacctgc agatgaacag cctgagggcc gaggacaccg ccgtctacta ctgcgccaag 1680 agcctgggca ggttcgacta ctggggacag gggaccctgg tgactgtgag cage 1734 <210〉 72 <211〉 578 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 72
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His lie Asp Asp Tyr Tyr Ala Met 100 105 110 -62· 148186·序列表.doc 201107345
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Ala Ser Thr Lys Gly Pro Ser Glu Val 450 455 460 -63- 148186-序列表.doc 201107345
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met 485 490 495
Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp 500 505 510 lie lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly 515 520 525
Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 530 535 540
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 545 550 555 560
Ser Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 565 570 575
Ser Ser <210> 73 <211> 1734 〈212〉 DNA <213〉人工序列 <220〉 〈223>人類化 <400〉 73 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacattga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 •64- 148186-序列表.doc 201107345 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg atatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaaggccag caccaagggc 1380 ccctcggaag tgcagctcct ggagagcggc ggcggcctgg tgcagcccgg cggcagcctg 1440 aggctgagct gcgccgctag cggcttcacc ttcaggaact tcggcatggg ctgggtcagg 1500 caggcccccg gcaagggcct ggagtgggtc agctggatca tcagctccgg caccgagacc 1560 tactacgccg acagcgtgaa gggcaggttc accatcagcc gcgacaacag caagaacacc 1620 ctgtacctgc agatgaacag cctgagggcc gaggacaccg ccgtctacta ctgcgccaag 1680 agcctgggca ggttcgacta ctggggacag gggaccctgg tgactgtgag cage 1734
<210> 74 <211〉 578 <212> PRT <213〉人工序列 <220> <223〉人類化 <400> 74
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Pile Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Cly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Grin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Trp Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 -65· 148丨86-序列表.doc 201107345
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Ala Ser Thr Lys Gly Pro Ser Glu Val 450 455 460
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met 485 490 495
Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp 500 505 510
He lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly 515 520 525 -66-
148186-序列表.doc 201107345
Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 530 535 540
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys f)45 550 555 560
Ser Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 565 570 575
Ser Ser <210〉 75 <211> 1734 <212〉 DNA <213>人工序列
<220〉 <223〉人類化 <400> 75
caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accactggga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg atatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaaggccag caccaagggc 1380 ccctcggaag tgcagctcct ggagagcggc ggcggcctgg tgcagcccgg cggcagcctg 1440 aggctgagct gcgccgctag cggcttcacc ttcaggaact tcggcatggg ctgggtcagg 1500 -67· 148186·序列表.doc 201107345 caggcccccg gcaagggcct ggagtgggtc agctggatca tcagctccgg caccgagacc 1560 tactacgccg acagcgtgaa gggcaggttc accatcagcc gcgacaacag caagaacacc 1620 ctgtacctgc agatgaacag cctgagggcc gaggacaccg ccgtctacta ctgcgccaag 1680 agcctgggca ggttcgacta ctggggacag gggaccctgg tgactgtgag cage 1734 <210〉 76 <211> 578 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400> 76
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 -68 - 148186·序列表.doc 201107345
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Ala Ser Thr Lys Gly Pro Ser Glu Val 450 455 460
Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu 465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe Gly Met 485 490 495
Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Trp 500 505 510 lie lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val Lys Gly 515 520 525
Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 530 535 540
Met Asn Ser Leu Arg Ala Glii Asp Thr Ala Val Tyr Tyr Cys Ala Lys 545 550 555 560
Ser Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 565 570 575
Ser Ser 69- 148186-序列表.doc 201107345 <210〉 77 <211> 1734 <212> DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 77 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg atatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaaggccag caccaagggc 1380 ccctcggaag tgcagctcct ggagagcggc ggcggcctgg tgcagcccgg cggcagcctg 1440 aggctgagct gcgccgctag cggcttcacc ttcaggaact tcggcatggg ctgggtcagg 1500 caggcccccg gcaagggcct ggagtgggtc agctggatca tcagctccgg caccgagacc 1560 tactacgccg acagcgtgaa gggcaggttc accatcagcc gcgacaacag caagaacacc 1620 ctgtacctgc agatgaacag cctgagggcc gaggacaccg ccgtctacta ctgcgccaag 1680 agcctgggca ggttcgacta ctggggacag gggaccctgg tgactgtgag cage 1734
<210〉 78 <211> 108 <212〉 PRT 70- 148186·序列表.doe 201107345 <213〉智人 <400〉 78
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Ala Trp Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <；210> 79 <211> 108 <：212> PRT <213〉智人 <400〉 79
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie
Ala Trp Ala Ser Ser Leu Tyr Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leii Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105
<210〉 80 <211〉 108 <212〉 PRT -71 - 148186-序列表.doc 201107345 <213〉智人 <400〉 80
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 81 <211〉 116 <212〉 PRT <213〉智人 <400> 81
Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Phe 20 25 30
Gly Met Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Trp lie lie Ser Ser Gly Thr Glu Thr Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Lys Ser Leu Gly Arg Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110
Thr Val Ser Ser 115 <210〉 82 -72-
148186-序列表.doc 201107345 <211〉 5 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400〉 82
Gly Gly Gly Gly Ser 1 5
<210〉 83 〈211〉 6 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400> 83
Thr Val Ala Ala Pro Ser 1 5 <210〉 84 <211〉 7 <212> PRT <213〉人工序列 • <220〉 <223〉連接子 <400> 84
Ala Ser Thr Lys Gly Pro Thr 1 5 <210> 85 〈211〉 7 <212> PRT <213〉人工序列 <220> •73 148186-序列表.doc 201107345 <223〉連接子 <400> 85
Ala Ser Thr Lys Gly Pro Ser 1 5 〈210〉 86 <211〉 2 <212〉 PRT <213〉人工序列 <220〉 〈223>連接子 <400> 86 Gly Ser <210〉 87 <211〉 8 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400〉 87
Thr Val Ala Ala Pro Ser Gly Ser 1 5 <210〉 88 <211〉 571 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400〉 88
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -74· 148186-序列表.doc 201107345 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Ala Trp Ala Ser Ser Leu Tyr Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Gly Ser Thr Val 100 105 110
Ala Ala Pro Ser Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys 115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr 130 135 140 lie Lys Asp Thr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly 145 150 155 160
Leu Glu Trp Met Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr 165 170 175
Val Pro Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr 180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 195 200 205
Val Tyr Tyr Cys Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp 210 215 220
Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 225 230 235 240
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr 290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin 305 310 315 320
Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 325 330 335
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 340 345 350
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro -75- 148丨86-序列表.doc 201107345 355 360 365
Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415
Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430
Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445
Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys 450 455 460
Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp 465 470 475 480
Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 485 490 495
Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly 530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560
Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 565 570 <210〉 89 <211〉 572 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400〉 89
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -76·
148186-序列表.doc 201107345 35 40 45
Ala Trp Ala Ser Ser Leu Tyr Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Gly Ser Ala Ser 100 105 110
Thr Lys Gly Pro Ser Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val 115 120 125
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe 130 135 140
Tyr lie Lys Asp Thr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin 145 150 155 160
Gly Leu Glu Trp Met Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys 165 170 175
Tyr Val Pro Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser 180 185 190
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp 210 215 220
Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 245 250 255
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 260 265 270
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 275 280 285
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu 290 295 300
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 305 310 315 320
Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 325 330 335
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 340 345 350
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 355 360 365
Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 370 375 380
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe •77- 148186-序列表.doc 201107345 385 390 395 400
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 405 410 415
Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 420 425 430
Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 435 440 445
Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala 450 455 460
Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 465 470 475 480
Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 485 490 495
Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 500 505 510
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 515 520 525
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 530 535 540
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 545 550 555 560
Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 565 570 <210> 90 <211〉 571 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400> 90
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro -78- 148186-序列表.doc 201107345 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Gly Ser Thr Val 100 105 110
Ala Ala Pro Ser Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys 115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr 130 135 140
He Lys Asp Thr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly 145 150 155 160
Leu Glu Trp Met Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr 165 170 175
Val Pro Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr 180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 195 200 205
Val Tyr Tyr Cys Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp 210 215 220
Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser 225 230 235 240
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr 290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin 305 310 315 320
Thr Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 325 330 335
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 340 345 350
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365
Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415
Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val -79· 148186·序列表.doc 201107345 420 425 430
Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445
Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys ALa Lys 450 455 460
Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp 465 470 475 480
Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 485 490 495
Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly 530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560
Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 565 570 〈210〉 91 <211〉 572 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400〉 91
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45
Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Gly Ser Ala Ser -80- 148186-序列表.doc 201107345 100 105 110
Thr Lys Gly Pro Ser Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val 115 120 125
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe 130 135 140
Tyr He Lys Asp Thr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin 145 150 155 160
Gly Leu Glu Trp Met Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys 165 170 175
Tyr Val Pro Lys Phe Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser 180 185 190
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 195 200 205
Ala Val Tyr Tyr Cys Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp 210 215 220
Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 225 230 235 240
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 245 250 255
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 260 265 270
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 275 280 285
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu 290 295 300
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 305 310 315 320
Gin Thr Tyr He Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 325 330 335
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 340 345 350
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 355 360 365
Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val 370 375 380
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 385 390 395 400
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 405 410 415
Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 420 425 430
Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 435 440 445
Ser Asn Lys Ala Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala -81- 148】86-序列表,doc 201107345 450 455 460
Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 465 470 475 480
Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 485 490 495
Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 500 505 510
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 515 520 525
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 530 535 540
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 545 550 555 560
Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 565 570 <210〉 92 <211> 8 〈212〉 PRT <213〉人工序列 <220〉 <223〉連接子 <400> 92
Gly Ser Thr Val Ala Ala Pro Ser 1 5 <210> 93 〈211〉 10 <212> PRT 〈213>人工序列 <220> <223〉連接子 <400〉 93
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser 1 5 10 -82-
148186-序列表,d〇c 201107345 <210〉 94 <211〉 108 <212> PRT <213〉智人 <220〉 <223〉突變 dAb <：400> 94
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr He Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp 20 25 30
Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45
Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Glu Gly Trp Gly Pro Pro 85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 <210〉 95 <211〉 324 〈212〉 DNA <213〉智人 <400〉 95 gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagggtgacc 60 attacctgca gggccagcag gcccatcagc gactggctgc actggtacca acagaagccc 120 ggcaaggctc ccaagctgct gatcgcctgg gccagcagcc tgcagggagg cgtgcccagc 180 aggtttagcg gcagcggcag cggcaccgac ttcaccctca ccatctcttc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag gagggctggg ggccccctac tttcggccag 300 ggcaccaagg tggagatcaa gagg 324 <210> 96 <211> 581 <212〉 PRT <213〉人工序列 83- 148〗86-序列表.doc 201107345 <220〉 <223〉人類化 <400〉 96
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300 -84-
148丨86-序列表.doc 201107345
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser 465 470 475 480
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 485 490 495
Arg Ala Ser Arg Pro He Ser Asp Trp Leu His Trp Tyr Gin Gin Lys 500 505 510
Pro Gly Lys Ala Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin 515 520 525
Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 530 535 540
Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 545 550 555 560
Cys Gin Gin Glu Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys 565 570 575
Val Glu He Lys Arg 580 〈210〉 97 <211> 1743 <212〉 DNA <213〉人工序列 <220> -85- 148186-序列表.doc 201107345 <223〉人類化 <400〉 97 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagggatc taccgtggca 1380 gcaccatccg gatctaccgt agcagcacca tccggatccg acatccagat gacccagagc 1440 cccagcagcc tgagcgccag cgtgggcgac agggtgacca ttacctgcag ggccagcagg 1500 cccatcagcg actggctgca ctggtaccaa cagaagcccg gcaaggctcc caagctgctg 1560 atcgcctggg ccagcagcct gcagggaggc gtgcccagca ggtttagcgg cagcggcagc 1620 ggcaccgact tcaccctcac catctcttcc ctgcagcccg aggacttcgc cacctactac 1680 tgccagcagg agggctgggg gccccctact ttcggccagg gcaccaaggt ggagatcaag 1740 agg 1743 〈210〉 98 <211〉 589 <212> PRT <213〉人工序列 <220〉 <223〉人類化 -86 - 148186-序列表.doc 201107345 <400> 98
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gill Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pi"〇 Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg -87- 148186-序列表.doc 201107345 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380
He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser Gly 465 470 475 480
Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 485 490 495
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp 500 505 510
Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 515 520 525 lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser 530 535 540
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 545 550 555 560
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Glu Gly Trp Gly Pro 565 570 575
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 580 585 <210〉 99 <211> 1767 <212〉 DNA <213〉人工序列 <220> <223〉人類化 <400> 99 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 •88· 148186-序列表.doc 201107345
agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagggatc taccgtggca 1380 gcaccatcag gatctaccgt ggcagcacca tcaggttcaa cagtagctgc tccttctgga 1440 tccgacatcc agatgaccca gagccccagc agcctgagcg ccagcgtggg cgacagggtg 1500 accattacct gcagggccag caggcccatc agcgactggc tgcactggta ccaacagaag 1560 cccggcaagg ctcccaagct gctgatcgcc tgggccagca gcctgcaggg aggcgtgccc 1620 ajgcaggttta gcggcagcgg cagcggcacc gacttcaccc tcaccatctc ttccctgcag 1680 cccgaggact tcgccaccta ctactgccag caggagggct gggggccccc tactttcggc 1740 cagggcacca aggtggagat caagagg 1767 • <210〉 100 <211> 597 <212> PRT 〈213>人工序列 <220> <223〉人類化 <400> 100 Gin Val Gin Leu Val Gin 1 5 Ser Val Lys Val Ser Cys
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser . 10 15
Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30 -89- 148:丨86·序列表.doc 201107345
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 • 90· 148186·序列表.doc 201107345 lie Ala Va.1 Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser Gly 465 470 475 480
Ser Thr Val Ala Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser 485 490 495
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 500 505 510
Arg Ala Ser Arg Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys 515 520 525
Pro Gly Lys Ala Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin 530 535 540
Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 545 550 555 560
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 565 570 575
Cys Gin Gin Glu Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys 580 585 590
Val Glu lie Lys Arg 595 <210〉 101 <211> 1791 <212〉 DNA <213〉人工序列 <220> <223〉人類化 <400〉 101 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 -91 · 148186-序列表.doc 201107345 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtcceiaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagggatc taccgtggca 1380 gcaccatcag gatctaccgt ggcagcacca tcaggttcaa cagtagctgc tccttctggt 1440 tcaacagtag ctgctccttc tggatccgac atccagatga cccagagccc cagcagcctg 1500 agcgccagcg tgggcgacag ggtgaccatt acctgcaggg ccagcaggcc catcagcgac 1560 tggctgcact ggtaccaaca gaagcccggc aaggctccca agctgctgat cgcctgggcc 1620 agcagcctgc agggaggcgt gcccagcagg tttagcggca gcggcagcgg caccgacttc 1680 accctcacca tctcttccct gcagcccgag gacttcgcca cctactactg ccagcaggag 1740 ggctgggggc cccctacttt cggccagggc accaaggtgg agatcaagag g 1791 <210〉 102 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 102
Gin Va.1 Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe -92- 148186·序列表.doc 201107345 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser -93· 148丨86-序列表.doc 201107345 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr· lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 103 <211〉 1731 〈212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 103 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 -94- 148186·序列表.doc 201107345 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggcagcacca 1380 tccaccgtag cagcaccatc cggatccgac atccagatga cccagagccc cagcagcctg 1440
agcgccagcg tgggcgacag ggtgaccatt acctgcaggg ccagcaggcc catcagcgac 1500 tggctgcact ggtaccaaca gaagcccggc aaggctccca agctgctgat cgcctgggcc 1560
Eigcagcctgc agggaggcgt gcccagcagg tttagcggca gcggcagcgg caccgacttc 1620 eiccctcacca tctcttccct gcagcccgag gacttcgcca cctactactg ccagcaggag 1680 ggctgggggc cccctacttt cggccagggc accaaggtgg agatcaagag g 1731 <210> 104 <211> 583 <212〉 PRT <213〉人工序列 <220> 〈223>人類化 • <400〉 104
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30 ·
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 A.La Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met -95· 148186-序列表.doc 201107345 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asa Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 .350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala • 96· 148〗86-序列表.doc 201107345 450 455 460
Ala Pro Ser Thr Val Ala Ala Pro Ser Gly Ser Asp lie Gin Met Thr 465 470 475 480
Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie 485 490 495
Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp Leu His Trp Tyr Gin 500 505 510
Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He Ala Trp Ala Ser Ser 515 520 525
Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 530 535 540
Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr 545 550 555 560
Tyr Tyr Cys Gin Gin Glu Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly 565 570 575
Thr Lys Val Glu lie Lys Arg 580 <210〉 105 <211〉 1749 <212> DNA <213〉人工序列 <220> <223〉人類化 <400> 105 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 900 -97· 148186-序列表.doc 201107345 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggcagcacca 1380 tcaaccgtgg cagcaccatc aacagtagct gctccttctg gatccgacat ccagatgacc 1440 cagagcccca gcagcctgag cgccagcgtg ggcgacaggg tgaccattac ctgcagggcc 1500 agcaggccca tcagcgactg gctgcactgg taccaacaga agcccggcaa ggctcccaag 1560 ctgctgatcg cctgggccag cagcctgcag ggaggcgtgc ccagcaggtt tagcggcagc 1620 ggcagcggca ccgacttcac cctcaccatc tcttccctgc agcccgagga cttcgccacc 1680 tactactgcc agcaggaggg ctgggggccc cctactttcg gccagggcac caaggtggag 1740 atcaagagg 1749 <210〉 106 <211> 589 <212〉 PRT <213〉人工序列 <220> <223〉人類化 <400〉 106
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 -98- 148186·序列表.doc 201107345
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro Lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Thr Val Ala Ala Pro Ser Thr Val Ala Ala Pro Ser Gly 465 470 475 480
Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 485 490 495 -99- 148丨86-序列表.doc 201107345
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp 500 505 510
Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 515 520 525 lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser 530 535 540
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin 545 550 555 560
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Glu Gly Trp Gly Pro 565 570 575
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 580 585 <210> 107 <211> 1767 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 107 caggtgcagc tcgtgcagag cggcgccgaa gtgaaaaagc ccggcagcag cgtgaaggtg 60 agctgcaagg cctccggctt ctacatcaag gacacctaca tgcactgggt caggcaggct 120 cctggccagg gcctggagtg gatgggcact atcgaccccg ccaacggcaa caccaagtac 180 gtgcccaagt tccagggcag ggtgaccatc accgccgatg agagcaccag caccgcctac 240 atggaactga gcagcctgag gtctgaggac accgccgtgt actattgcgc caggagcatc 300 tacgacgact accacgtcga cgactactac gccatggact actggggaca gggcacacta 360 gtgaccgtgt ccagcgccag caccaagggc cccagcgtgt tccccctggc ccccagcagc 420 aagagcacca gcggcggcac agccgccctg ggctgcctgg tgaaggacta cttccccgaa 480 ccggtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcaccc agacctacat ctgtaacgtg aaccacaagc ccagcaacac caaggtggac 660 aagaaggtgg agcccaagag ctgtgacaag acccacacct gccccccctg ccctgccccc 720 gagctgctgg gaggccccag cgtgttcctg ttccccccca agcctaagga caccctgatg 780 atcagcagaa cccccgaggt gacctgtgtg gtggtggatg tgagccacga ggaccctgag 840 gtgaagttca actggtacgt ggacggcgtg gaggtgcaca atgccaagac ceiagcccagg 900 gaggagcagt acaacagcac ctaccgggtg gtgtccgtgc tgaccgtgct gcaccaggat 960 tggctgaacg gcaaggagta caagtgtaag gtgtccaaca aggccctgcc tgcccctatc 1020 gagaaaacca tcagcaaggc caagggccag cccagagagc cccaggtgta caccctgccc 1080 cctagcagag atgagctgac caagaaccag gtgtccctga cctgcctggt gaagggcttc 1140 taccccagcg acatcgccgt ggagtgggag agcaacggcc agcccgagaa caactacaag 1200 -100- 148186-序列表.doc 201107345 accacccccc ctgtgctgga cagcgatggc agcttcttcc tgtacagcaa gctgaccgtg 1260 gacaagagca gatggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaggccctg 1320 cacaatcact acacccagaa gagcctgagc ctgtcccctg gcaagaccgt ggcagcacca 1380 tcaaccgtgg cagcaccatc aacagtagct gctccttcta cagtagctgc tccttctgga 1440 tccgacatcc agatgaccca gagccccagc agcctgagcg ccagcgtggg cgacagggtg 1500 accattacct gcagggccag caggcccatc agcgactggc tgcactggta ccaacagaag 1560 cccggcaagg ctcccaagct gctgatcgcc tgggccagca gcctgcaggg aggcgtgccc 1620 agcaggttta gcggcagcgg cagcggcacc gacttcaccc tcaccatctc ttccctgcag 1680 cccgaggact tcgccaccta ctactgccag caggagggct gggggccccc tactttcggc 1740 cagggcacca aggtggagat caagagg 1767 <210〉 108 <211〉 219 <212〉 PRT <213〉人工序列
<220〉 <223〉人類化 <400〉 108
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ser Ser Gin Asn lie Val His lie 20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gin Gin Lys Pro Gly Lys Ala 35 40 45
Pro Lys Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly Val Pro , 50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He ^ 65 70 75 80
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gin Gly 85 90 95
Ser His Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu -101 - 148丨86·序列表.doc 201107345 180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210〉 109 <211> 714 <212> DNA <213〉人工序列 <220〉 〈223>人類化 <400〉 109 atgggctggt cctgcatcat cctgtttctg gtggccaccg ccaccggcgt gcacagcgac 60 atccagatga cccagagccc cagcagcctg agcgccagcg tgggcgacag ggtgactatc 120 acctgcagga gcagccagaa catcgtgcac atcaacggca acacctacct cgagtggtac 180 cagcagaaac ccgggaaggc ccccaagctg ctgatctaca agatcagcga caggttcagc 240 ggcgtgccca gcaggtttag cggctccggc tcaggcaccg atttcaccct gaccattagc 300 agcctgcagc ccgaggactt cgccacctac tactgcttcc agggctctca cgtcccctgg 360 accttcggcc agggcaccaa gctggagatc aagcgtacgg tggccgcccc cagcgtgttc 420 atcttccccc ccagcgatga gcagctgaag agcggcaccg ccagcgtggt gtgtctgctg 480 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaatgc cctgcagagc 540 ggcaacagcc aggagagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 600 agcaccctga ccctgagcaa ggccgactac gagaagcaca aggtgtacgc ctgtgaggtg 660 acccaccagg gcctgtccag ccccgtgacc aagagcttca accggggcga gtgc 714 <210〉 110 <211〉 219 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 110
Asp Val Leu Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Arg Ser Ser Gin Asn lie Val His lie 20 25 30 -102- 148丨86-序列表.doc 201107345
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gin Gin Lys Pro Gly Lys Ala 35 40 45
Pro Lys Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly Val Pro 50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 65 70 75 80
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gin Gly 85 90 95
Ser His Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin
145 150 155 160
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 〈210〉 111 <211> 714 <212> DNA <213〉人工序列 <220> 〈223>人類化 <400> 111 atgggctggt cctgcatcat cctgtttctg gtggccaccg ccaccggcgt gcacagcgac 60 gtgctgatga cccagagccc cagcagcctg agcgccagcg tgggcgacag ggtgactatc 120 acctgcagga gcagccagaa catcgtgcac atcaacggca acacctacct cgagtggtac 180 cagcagaaac ccgggaaggc ccccaagctg ctgatctaca agatcagcga caggttcagc 240 ggcgtgccca gcaggtttag cggctccggc tcaggcaccg atttcaccct gaccattagc 300 agcctgcagc ccgaggactt cgccacctac tactgcttcc agggctctca cgtcccctgg 360 accttcggcc agggcaccaa gctggagatc aagcgtacgg tggccgcccc cagcgtgttc 420 atcttccccc ccagcgatga gcagctgaag agcggcaccg ccagcgtggt gtgtctgctg 480 -103- 148丨86-序列表.doc 201107345 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaatgc cctgcagagc 540 ggcaacagcc aggagagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 600 agcaccctga ccctgagcaa ggccgactac gagaagcaca aggtgtacgc ctgtgaggtg 660 acccaccagg gcctgtccag ccccgtgacc aagagcttca accggggcga gtgc 714 <210〉 112 <211> 219 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 112
Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gin Asn lie Val His lie 20 25 30 .
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gin Gin Lys Pro Gly Gin Ala 35 40 45
Pro Arg Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly lie Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 65 70 75 80
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gin Gly 85 90 95
Ser His Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 •104· 148186·序列表.doc 201107345 <210〉 113 <211〉 714 <212> DNA <213〉人工序列 <220> <223〉人類化 <400> 113 atgggctggt cctgcatcat cctgtttctg gtggccaccg ccaccggcgt gcacagcgag 60 atcgtgctga cccagagccc tggcacactg agcctgagcc ccggagagag ggccaccctg 120 agctgcaggt ctagccagaa catcgtgcac atcaacggca acacctacct ggagtggtat 180 oagcagaagc ccggccaggc ccccaggctg ctgatctaca agatcagcga caggttcagc 240 ggcatccccg acaggtttag cggcagcggc agcggcaccg acttcaccct gaccattagc 300
aggctggagc ccgaggactt cgccgtgtac tactgcttcc aggggagcca cgtgccctgg 360 accttcggcc agggcaccaa gctcgaaatc aagcgtacgg tggccgcccc cagcgtgttc 420 atcttccccc ccagcgatga gcagctgaag agcggcaccg ccagcgtggt gtgtctgctg 480 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaatgc cctgcagagc 540 ggcaacagcc aggagagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 600 agcaccctga ccctgagcaa ggccgactac gagaagcaca aggtgtacgc ctgtgaggtg 660 acccaccagg gcctgtccag ccccgtgacc aagagcttca accggggcga gtgc 714 <210> 114 <211〉 219 <212> PRT <213〉人工序列 <220> <223〉人類化
<400> 114
Asp Val Leu Met Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gin Asn lie Val His lie 20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gin Gin Lys Pro Gly Gin Ala 35 40 45
Pro Lys Leu Leu lie Tyr Lys lie Ser Asp Arg Phe Ser Gly Val Pro 50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 65 70 75 80 -105- 148:186-序列表.doc 201107345
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Phe Gin Gly 85 90 95
Ser His Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160
Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 115 <211〉 657 <212〉 DNA <213〉人工序列 <220〉 <223〉人類化 <400〉 115 gacgtgctga tgacccagag ccctggcaca ctgagcctga gccccggaga gagggccacc 60 ctgagctgca ggtctagcca gaacatcgtg cacatcaacg gcaacaccta cctggagtgg 120 tatcagcaga agcccggcca ggcccccaag ctgctgatct acaagatcag cgacaggttc 180 agcggcgtgc ccgacaggtt tagcggcagc ggcagcggca ccgacttcac cctgaccatt 240 agcaggctgg agcccgagga cttcgccgtg tactactgct tccaggggag ccacgtgccc 300 tggaccttcg gccagggcac caagctcgaa atcaagcgta cggtggccgc ccccagcgtg 360 ttcatcttcc cccccagcga tgagcagctg aagagcggca ccgccagcgt ggtgtgtctg 420 ctgaacaact tctacccccg ggaggccaag gtgcagtgga aggtggacaa tgccctgcag 480 agcggcaaca gccaggagag cgtgaccgag caggacagca aggactccac ctacagcctg 540 agcagcaccc tgaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgtgag 600 gtgacccacc agggcctgtc cagccccgtg accaagagct tcaaccgggg cgagtgc 657 <210〉 116 <211> 571 106- 148186-序列表.doc 201107345 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400> 116
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285 -107- 148186-序列表.doc 201107345
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Gly Ser Asp 450 455 460 lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 465 470 475 480
Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp Trp Leu 485 490 495
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He Ala 500 505 510
Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser Gly Ser 515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro Glu 530 535 540
Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro Pro Thr 545 550 555 560
Phe Gly Gin Gly Thr Lys Val Glu He Lys Arg 565 570 <210> 117 <211> 577 <212〉 PRT <213〉人工序列 <220〉 108-
148186·序列表.doc 201107345 <223〉人類化 <400〉 117
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala. Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Alai Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 FJro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320 •109· 148丨86-序列表.doc 201107345
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu.Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 118 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 •110· 148186-序列表.doc 201107345 <400〉 118
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335 -Ill - 148丨86-序列表.doc 201107345
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu. His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 119 <211〉 577 <212〉 PRT <213〉人工序列 <220> <223>人類化 <400〉 119 •112·
148186-序列表.doc 201107345
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Crly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350 -113- 148:186·序列表.doc 201107345
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr He Thr Cys Arg Ala Ser Arg 485 490 495
Pro He Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210> 120 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 〈223>人類化 <400〉 120
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15 -114- 148186-序列表.doc 201107345
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr. lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365 -115 - 148186-序列表.doc 201107345
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Met Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 121 <211> 577 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 121
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30 •116· 148186-序列表.doc 201107345
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255 A；sp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 -117- 148186-序列表.doc 201107345 lie Ala Val Glu Trp Glu 385 390 Thr Thr Pro Pro Val Leu 405 Lys Leu Thr Val Asp Lys 420 Cys Ser Val Met His Glu 435 Leu Ser Leu Ser Pro Gly 450 Ala Pro Ser Gly Ser Asp 465 470 Ser Ala Ser Val Gly Asp 485 Pro lie Ser Asp Trp Leu 500 Pro Lys Leu Leu lie Ala 515 Ser Arg Phe Ser Gly Ser 530 Ser Ser Leu 545 Gly Trp Gly
Gin Pro Glu 550 Pro Pro Thr 565
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 410 415
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser 440 445
Lys Thr Val Ala Ala Pro Ser Thr Val Ala 455 460 lie Gin Met Thr Gin Ser Pro Ser Ser Leu 475 480
Arg Val Thr He Thr Cys Arg Ala Ser Arg 490 495
His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 505 510
Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Thr He 535 540
Asp Phe Ala Thr Tyr Tyr Cys Ala Gin Glu 555 560
Phe Gly Gin Gly Thr Lys Val Glu He Lys 570 575
Arg <210〉 122 〈211〉 577 〈212〉 PRT 〈213〉人工序列 <220〉 <223〉人類化 <400> 122
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 •118· 148186·序列表.doc 201107345
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400 -119- 148186-序列表.doc 201107345
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Thr Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 123 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 123
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60 -120- 148186-序列表.doc 201107345
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr ALa Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415 -121 - 148Ϊ86·序列表.doc 201107345
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro He Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Cys Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu He Lys 565 570 575
Arg <210〉 124 <211> 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 124
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 -122- 148186·序列表.doc 201107345
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro Il.e Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leii Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430 123· 148)86-序列表.doc 201107345
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu He Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 125 <211> 577 〈212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 125
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 •124· 148186-序列表.doc 201107345
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140 C-ly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445 -125- 148186-序列表.doc 201107345
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Trp Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210> 126 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 126
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110 -126- 148186-序列表.doc 201107345
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460 •127· 148丨86-序列表.doc 201107345
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala .500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Glu Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 127 <211〉 577 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 127
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125 •128- 148丨86·序列表.doc 201107345
Lys Gly Pro Ser Val Phe Pro Leu 130 135 Gly Gly Thr Ala Ala Leu Gly Cys 145 150 Pro Val Thr Val Ser Trp Asn Ser 165 Thr Phe Pro Ala Val Leu Gin Ser 180 Val Val Thr Val Pro Ser Ser Ser 195 200 Asn Val Asn His Lys Pro Ser Asn 210 215 Pro Lys Ser Cys Asp Lys Thr His 225 230 Glu Leu Leu Gly Gly Pro Ser Val 245 Asp Thr Leu Met lie Ser Arg Thr 260 Asp Val Ser His Glu Asp Pro Glu 275 280 Gly Val Glu Val His Asn Ala Lys 290 295 Asn Ser Thr Tyr Arg Val Val Ser 305 310 Trp Leu Asn Gly Lys Glu Tyr Lys 325 Pro Ala Pro lie Glu Lys Thr lie 340 Glu Pro Gin Val Tyr Thr Leu Pro 355 360 Asn Gin Val Ser Leu Thr Cys Leu 370 375 lie Ala Val Glu Trp Glu Ser Asn 385 390 Thr Thr Pro Pro Val Leu Asp Ser 405 Lys Leu Thr Val Asp Lys Ser Arg 420 Cys Ser Val Met His Glu Ala Leu 435 440 Leu Ser Leu Ser Pro Gly Lys Thr 450 455 Ala Pro Ser Gly Ser Asp lie Gin 465 470
Ala Pro Ser Ser Lys Ser Thr Ser 140
Leu Val Lys Asp Tyr Phe Pro Glu 155 160
Gly Ala Leu Thr Ser Gly Val His 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser 185 190
Leu Gly Thr Gin Thr Tyr lie Cys 205
Thr Lys Val Asp Lys Lys Val Glu 220
Thr Cys Pro Pro Cys Pro Ala Pro 235 240
Phe Leu Phe Pro Pro Lys Pro Lys 250 255
Pro Glu Val Thr Cys Val Val Val 265 270
Val Lys Phe Asn Trp Tyr Val Asp 285
Thr Lys Pro Arg Glu Glu Gin Tyr 300
Yal Leu Thr Val Leu His Gin Asp 315 320
Cys Lys Val Ser Asn Lys Ala Leu 330 335
Ser Lys Ala Lys Gly Gin Pro Arg 345 350
Pro Ser Arg Asp Glu Leu Thr Lys 365
Val Lys Gly Phe Tyr Pro Ser Asp 380
Gly Gin Pro Glu Asn Asn Tyr Lys 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser 410 415
Trp Gin Gin Gly Asn Val Phe Ser 425 430
His Asn His Tyr Thr Gin Lys Ser 445
Val Ala Ala Pro Ser Thr Val Ala 460
Met Thr Gin Ser Pro Ser Ser Leu 475 480 148186-序列表.doc -129- 201107345
Val Gly Asp Arg 485 Asp Trp Leu His 500 Leu He Ala Trp Ser Gly Ser Gly 535 Gin Pro Glu Asp 550 Pro Pro Thr Phe 565
Leu Gin Gly 525 Asp Phe Thr Leu Thr lie 540 Phe Ala Thr Tyr Tyr Cys 555 Thr Lys Val
Ser Ala Ser
Pro lie Ser
Pro Lys Leu 515
Ser Arg Phe 530
Ser Ser Leu 545
Gly Trp Gly Arg
Val Thr He 490
Trp Tyr Gin 505
Ala Ser Ser 520
Ser Gly Thr
Gly Gin Gly 570
Thr Cys Arg Gin Lys Pro
Ala Ser Arg 495
Gly Lys Ala 510
Gly Val Pro
Lys Gin Glu 560
Glu lie Lys 575 <210> 128 <211> 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 128 Gin Val Gin Leu Val 1 5 Ser Val Lys Val Ser 20 Tyr Met His Trp Val 35 Gly Thr He Asp Pro 50 Gin Gly Arg Val Thr 65 Met Glu Leu Ser Ser 85 Ala Arg Ser lie Tyr 100 Asp Tyr Trp Gly Gin 115 Lys Gly Pro Ser Val 130
Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 10 15
Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 25 30
Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 40 45
Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 55 60 lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 70 75 80
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 90 95
Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 135 140 •130· 148186-序列表.doc 201107345
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
As;n Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495 -131 - 148186-序列表.doc 201107345
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Asp Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210> 129 <211〉 577 <212〉 PRT <213>人工序列 <220〉 <223〉人類化 <400> 129
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 -132- 148186-序列表.doc 201107345
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Fro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510 •133· 148丨86·序列表.doc 201107345
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Asn Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 130 <211〉 577 <212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 130
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 -134- 148丨86-序列表.doc 201107345
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525 -135· 148186-序列表.doc 201107345
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Tyr Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 131 <211> 577 <212> PRT <213〉人工序列 <220> <223〉人類化 <400〉 131
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 -136- 148186-序列表.doc 201107345
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Va.l Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 530 535 540 -137- 148186-序列表.doc 201107345
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Val Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg <210〉 132 <211〉 577 <212> PRT 〈213〉人工序列 <220〉 <223〉人類化 <400> 132
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205 -138- 148186-序列表.doc 201107345
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510 F^o Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys lie Gin Glu 545 550 555 560 •139· 148:丨86-序列表.doc 201107345
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg 〈210〉 133 <211〉 577 〈212〉 PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 133
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220 •140- 148】86-序列表,doc 201107345
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380
He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575 • 141 - 148186·序列表.doc 201107345
Arg <210> 134 <211〉 577 <212> PRT <213〉人工序列 <220〉 <223〉人類化 <400〉 134
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Val Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 •142- 148丨86·序列表.doc 201107345
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380
He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Thr Val Ala Ala Pro Ser Thr Val Ala 450 455 460
Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu 465 470 475 480
Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg 485 490 495
Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala 500 505 510
Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro 515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 530 535 540
Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Pro Gin Glu 545 550 555 560
Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 565 570 575
Arg 143- 148186-序列表.doc 201107345 <210〉 135 <211〉 573 <212〉 PRT 〈213>人工序列 <220> <223〉人類化 <400〉 135
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr He Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255 144- 148186-序列表.doc 201107345
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 465 470 475 480
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp 485 490 495
Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 500 505 510 lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser 515 520 525
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 530 535 540
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro 545 550 555 560
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 565 570 〈210〉 136 <211> 581 145- 148186-序列表.doc 201107345 <212> PRT 〈213>人工序列 <220〉 <223〉人類化 <400〉 136
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285 -146· 148186-序列表.doc 201107345
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leii His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser 465 470 475 480
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 485 490 495
Arg Ala Ser Arg Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys 500 505 510
Pro Gly Lys Ala Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin 515 520 525
Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 530 535 540
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 545 550 555 560
Cys Leu Gin Glu Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys 565 570 575
Val Glu lie Lys Arg 580 〈210〉 137 <211〉 589 <212> PRT <213〉人工序列 •147- 148186-序列表_如。 201107345 <220〉 〈223>人類化 <400〉 137
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr lie Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser lie Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 .160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300 •148- 148186·序列表 _doc 201107345
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser Gly 465 470 475 480
Ser Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 485 490 495
Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Arg Pro lie Ser Asp 500 505 510
Trp Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu 515 520 525 lie Ala Trp Ala Ser Ser Leu Gin Gly Gly Val Pro Ser Arg Phe Ser 530 535 540
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin 545 550 555 560
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin Glu Gly Trp Gly Pro 565 570 575
Pro Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 580 585 <210〉 138 <211> 597 〈212〉 PRT <213〉人工序列 <220> •149- 148丨86-序列表.doc 201107345 <223〉人類化 <400> 138
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Tyr lie Lys Asp Thr 20 25 30
Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Thr He Asp Pro Ala Asn Gly Asn Thr Lys Tyr Val Pro Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Ser He Tyr Asp Asp Tyr His Tyr Asp Asp Tyr Tyr Ala Met 100 105 110
Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175
Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys 195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu 210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255
Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 305 310 315 320 -150- 148186·序列表.doc 201107345
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 325 330 335
Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 340 345 350
Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 355 360 365
Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser 420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser 435 440 445
Leu Ser Leu Ser Pro Gly Lys Gly Ser Thr Val Ala Ala Pro Ser Gly 450 455 460
Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser Gly 465 470 475 480
Ser Thr Val Ala Ala Pro Ser Gly Ser Asp lie Gin Met Thr Gin Ser 485 490 495
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr lie Thr Cys 500 505 510
Arg Ala Ser Arg Pro lie Ser Asp Trp Leu His Trp Tyr Gin Gin Lys 515 520 525
Pro Gly Lys Ala Pro Lys Leu Leu lie Ala Trp Ala Ser Ser Leu Gin 530 535 540
Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 545 550 555 560
Thr Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr 565 570 575
Cys Leu Gin Glu Gly Trp Gly Pro Pro Thr Phe Gly Gin Gly Thr Lys 580 585 590
Val Glu lie Lys Arg 595 〈210〉 139 <211> 10 <212> PRT 〈213〉人工序列 <220〉 151 - 148186·序列表.doc 201107345 <223〉連接子 <400> 139
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser 1 5 10 <210〉 140 <211> 18 <212〉 PRT <213〉人工序列 <220〉 <223〉連接子 <400〉 140
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 15 10 15
Gly Ser <210〉 141 <211〉 26 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400> 141
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 15 10 15
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser .20 25 <210〉 142 <211> 34 <212〉 PRT <213〉人工序列 -152- 148186-序列表.doc 201107345 <220〉 <223〉連接子 <400〉 142
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 15 10 15
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 20 25 30
Gly Ser
<210〉 143 <211〉 42 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400〉 143
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 15 10 15
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 20 25 30
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser 35 40
<210> 144 <211> 50 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400> 144
Giy Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 1 5 10 15 -153 - 148186-序列表,d〇c 201107345
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 20 25 30
Gly Ser Thr Val Ala Ala Pro Ser Gly Ser Thr Val Ala Ala Pro Ser 35 40 45
Gly Ser 50 <210〉 145 <211〉 14 〈212〉 PRT <213〉人工序列 <220〉 <223〉連接子 <400〉 145
Thr Val Ala Ala Pro Ser Thr Val Ala Ala Pro Ser Gly Ser 1 5 10 <210> 146 <211> 20 <212> PRT <213〉人工序列 <220〉 <223〉連接子 <400> 146
Thr Val Ala Ala Pro Ser Thr Val Ala Ala Pro Ser Thr Val Ala Ala 1 5 10 15
Pro Ser Gly Ser 20 -154- 148186·序列表,doc

Claims (1)

  1. 201107345 七、申請專利範圍： 1. 一種抗原結合蛋白，其結合人類IL-13且其包含CDRH3 SIYDDYHYDDYYAMDY(SEQ ID NO: 3)，其中 CDRH3 包 含一或多個下列取代： g) 位置1中之S95取代為色胺酸（W) h) 位置2中之196取代為纈胺酸（V) i) 位置3中之Y97取代為苯丙胺酸（F) j) 位置4中之D9 8取代為鞑醯胺酸（E) 鲁 k)位置7中之H100A取代為丙胺酸（A)、麩胺酸（E)、麩醯 胺酸（Q)、精胺酸（R)、絲胺酸（S)、蘇胺酸（T)或纈胺酸 (V)及 1)位置8中之Y100B取代為丙胺酸（A)、異白胺酸（I)、色 胺酸（W)或纈胺酸（V)。 2. 如請求項1之抗原結合蛋白，其中CDRH3之位置8中之 Y100B取代為選自以下之胺基酸：丙胺酸（A)、異白胺酸 (I)、色胺酸（W)或纈胺酸（V)。 籲3.如請求項1或2之抗原結合蛋白，其結合人類IL-13且其包 含選自以下所示的CDRH3序列：SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 6、SEQ ID NO: 7、SEQ ID NO: 8及 SEQ ID NO: 9、SEQ ID NO: 10、SEQ ID NO: 11、SEQ ID NO: 12、SEQ ID NO: 13、SEQ ID NO: 14及 SEQ ID NO: 15、SEQ ID NO: 16、SEQ ID NO: 17及 SEQ ID NO: 18。 4.如請求項1或2之抗原結合蛋白，其中該抗原結合蛋白進 148186 201107345 一步包含下列CDR序列： CDRH1 ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRL1 : SEQ ID NO:19 ; CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 其中該抗原結合蛋白包 5. 如請求項1或2之抗原結合蛋白， 含下列CDR : CDRH1 ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 18 ； CDRL1 ： SEQ ID NO: 19 ； CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 其中該抗原結合蛋白包 6. 如請求項1或2之抗原結合蛋白， 含下列CDR : CDRH1 ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 17 ； CDRL1 ； SEQ ID NO: 19 ； CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 ，其中該抗原結合蛋白包 7. 如請求項1或2之抗原結合蛋白 含下列CDR : 148186 201107345 CDRHl ： SEQ ID NO: 1 ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 16 ； CDRL1 ： SEQ ID NO: 19 ； CDRL2 : SEQ ID NO: 20 ;及 CDRL3 : SEQ ID NO: 21。 8. 如請求項1或2之抗原結合蛋白，其中該抗原結合蛋白包 含下列CDR : _ CDRHl ： SEQ ID NO:l ； CDRH2 ： SEQ ID NO: 2 ； CDRH3 ： SEQ ID NO: 15 ； CDRL1 ： SEQ ID NO:19 ； CDRL2 : SEQ ID NO:20 ;及 CDRL3 ·_ SEQ ID NO:21。 9. 如請求項1或2之抗原結合蛋白，其中該抗原結合蛋白包 含抗體。 10_如請求項1或2之抗體，其中該抗體為人類化抗體。 11. 如請求項1或2之抗原結合蛋白，其中該抗體為IgG同型 抗體。 12. 如請求項1或2之抗原結合蛋白，其包含選自以下之重 鏈：SEQ ID NO: 26、SEQ ID NO: 28、SEQ ID NO: 30、 SEQ ID NO: 32、SEQ ID NO: 34、SEQ ID NO: 36、SEQ ID NO: 38、SEQ ID NO: 40、SEQ ID NO: 42、SEQ ID NO: 44、SEQ ID NO: 46、SEQ ID NO: 48、SEQ ID NO: 148186 201107345 50、SEQ ID NO: 52及 SEQ ID NO: 54 ;及 SEQ ID NO: 24、108、110、112及 114之輕鏈。 13. 如請求項12之抗原結合蛋白，其包含選自SEQ ID NO: 48、SEQ ID NO: 50、SEQ ID NO: 52及 SEQ ID NO: 54之 重鏈；及SEQ ID NO: 108及110之輕鏈。 14. 如請求項13之抗原結合蛋白，其包含SEQ ID NO·· 54之重 鏈及SEQ ID NO: 108之輕鏈。 15. 如請求項13之抗原結合蛋白，其包含SEQ ID NO: 54之重 鏈及SEQ ID NO: 110之輕鏈。 16. 如請求項1或2之抗體，其包含突變Fc區，從而降低該抗 體之ADCC及/或補體活化作用。 17. 如請求項1或2之抗原結合蛋白，其能夠結合至IL-13且其 亦能夠結合至IL-4及IL-5中至少一者。 18. 如請求項17之抗原結合蛋白，其包含至少一種選自SEQ ID NO: 78、79、80、81 及 94之 dAb。 19. 如請求項18之抗原結合蛋白，其包含選自以下任一者之 重鏈：SEQ ID NO: 62、64、66、68、70、72、74、76、 96、98、100、102、104、106 及 117-138 ;及 SEQ ID NO: 24、108、110、112及 114之輕鏈。 20. 如請求項19之抗原結合蛋白，其包含選自以下任一者之 重鏈：SEQ ID NO: 96、98、100、102、104、106 ;及 SEQ ID NO: 24、108及 110之輕鏈。 21. 如請求項20之抗原結合蛋白，其包含：SEQ ID NO: 96之 重鏈及SEQ ID NO: 24之輕鏈，或SEQ ID NO: 96之重鏈 148186 201107345 及SEQ ID NO: 108之輕鏈，或SEQ ID NO: 96之重鏈及 SEQ ID NO: 110之輕鏈，或 SEQ ID NO: 98之重鏈及 SEQ ID NO: 24之輕鏈，或SEQ ID NO: 98之重鏈及SEQ ID NO: 108 之輕鏈，或 SEQ ID NO: 98 之重鏈及 SEQ ID NO: 110 之輕鏈，或 SEQ ID NO: 100 之重鏈及 SEQ ID NO: 24 之輕鏈’或SEQ ID NO: 100之重鏈及SEQ ID NO: 108之 輕鏈，或SEQ ID NO: 100之重鏈及SEQ ID NO: 110之輕 鍵。 22. —種重組轉型或轉染之宿主細胞，其包含第一及第二載 體’該第一載體包含編碼如請求項1至2 [中任一項之抗 原結合蛋白之重鏈的聚核苷酸且該第二載體包含編碼如 請求項1至21中任一項之抗原結合蛋白之輕鏈的聚核苷 酸。 23_ —種醫藥組合物，其包含如請求項i至21中任一項之抗 原結合蛋白及醫藥學上可接受之載劑。 24.:種如請求項壬一項之抗原結合蛋白的用途， 係用於製備供治療或預防以下病症的藥劑：過敏性哮 1 '嚴重哮喘、難治性哮喘、脆性哮喘、夜間哮喘、經 刖哮喘、抗類固醇哮喘、類固醇依賴型哮喘、阿斯匹靈 誘發型哮喘、成年發作型哮喘、小兒哮喘、異位性皮膚 尺過敏I·生鼻火、克隆氏病（Cr〇hn,s d心咖）、c〇pD ; 纖維變性疾病或病症， 庇者如特發性肺纖維化、進行性全 身性硬化、肝纖維化；肝兩 鬥牙瘤、血吸蟲病、利什曼體 病（leishmaniasis);細胞週期哨伙 巧期5周即疾病，諸如霍奇金氏病 148186 201107345 (Hodgkins disease)、B細胞慢性淋巴細胞白血病。 25. —種降低免疫球蛋白單可變域之聚集的方法，其包含步 驟： a) 量測免疫球蛋白單可變域之聚集程度； b) 使kabat位置89突變成麩醯胺酸； c) 量測該突變免疫球蛋白單可變域之聚集程度； 其中保留結合活性，且該突變免疫球蛋白單可變域之聚 集程度低於未突變免疫球蛋白單可變域之聚集程度。 26. —種人類VK dAb，其來源於選自以下之生殖系架構： IGKV1-17、IGKV1D-17、IGKV1/OR2-108、IGKV1-6、 IGKV5-2 、IGKV1D-42 、IGKV2-24 、IGKV2-28 、 IGKV2-30 ' IGKV2-40、IGKV2D-29、IGKV2D-30、 IGKV2D-24及IGKV6-21，其中該人類VK dAb之殘基 89(kabat編號）為麩醯胺酸。 27. —種免疫球蛋白單可變域，其包含SEQ ID NO: 94之序 列。 148186
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