TW201039848A - Bispecific anti-ErbB-1/anti-c-Met antibodies - Google Patents
Bispecific anti-ErbB-1/anti-c-Met antibodies Download PDFInfo
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- TW201039848A TW201039848A TW099110596A TW99110596A TW201039848A TW 201039848 A TW201039848 A TW 201039848A TW 099110596 A TW099110596 A TW 099110596A TW 99110596 A TW99110596 A TW 99110596A TW 201039848 A TW201039848 A TW 201039848A
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Description
201039848 t、發明說明： 【發明所屬之技術領域】 本發明係關於針對人類ErbB-l及人類c-Met之雙特異性 抗體、其產生方法、含有該等抗體之醫藥組合物、及其用 途。 【先前技術】
ErbB家族蛋白
ErbB蛋白家族由4個成員組成：ErbB-l，亦稱作表皮生 長因子受體（EGFR) ; ErbB-2，在人類中亦稱作HER2且在 齧齒動物中亦稱作neu ; Er.bB-3，亦稱作HER3 ;及ErbB-4，亦稱作HER4。ErbB家族蛋白係受體酪胺酸激酶且代表 細胞生長、分化及存活之重要介體。
ErbB-l 及抗-ErbB-l 抗體
Erb-Bl(亦稱作ERBB1、人類表皮生長因子受體、EGFR、 HER-1或鳥類成紅細胞白血病病毒（v-erb-b)癌基因同源 物；SEQ ID NO: 16)係由c-erbB原癌基因編碼之170 kDa跨 膜受體，且表現固有的酪胺酸激酶活性（Modjtahedi，H.等 人，Br. J. Cancer 73 (1996) 228-235 ; Herbst, R.S.及 Shin， D,M., Cancer 94 (2002) 1593-161 1)。EGFR亦存在多種亞 型及變體（例如選擇性RNA轉錄物、經截短形式、多態性 等），包括（但不限於）彼等由Swissprot數據庫條目號 P00533-1、P00533-2、P00533-3 及 P00533-4 標識者 ° 已知 EGFR可結合各種配體，包括表皮生長因子（EGF)、轉化生 長因子-α (TGf-α)、雙調蛋白、肝素結合性EGF (hb-EGF)、 146954.doc 201039848 β細胞素、及表皮調節素（Herbst，R.S.及Shin，D.M.， Cancer 94 (2002) 1593-161 1 ; Mendelsohn, J.及 Baselga，J.， Oncogene 19 (2000) 6550-6565)。EGFR經由路胺酸-激酶介 導之信號轉導途徑調節多種細胞過程，包括（但不限於）控 制細胞增殖、分化、細胞存活、細胞凋亡、也管發生、有 絲分裂發生、及轉移之信號轉導途徑之活化（Atalay，G.等 人 ’ Ann. Oncology 14 (2003) 1346-1363 ; Tsao，A.S.及 Herbst，R.S.，Signal 4 (2003) 4-9 ; Herbst, R.S.及 Shin， D.M·, Cancer 94 (2002) 1593-161 1 ; Modjtahedi，H·等人， Br. J. Cancer 73 (1996) 228-235)。 抗-ErbB-1抗體乾向EGFR之細胞外部分，此導致阻斷配 體結合且由此抑制諸如細胞增殖等下游事件（Tsa〇，A §及 Herbst, R.S·，Signal 4 (2003) 4-9)。已研發出包含來自兩個 或更多個不同物種（例如小鼠及人類）之抗體部分之嵌合抗_ ErbB-Ι抗體，例如參見US 5,891，996(小鼠/人類嵌合抗 體 ’ R3)或 US 5,558,864(鼠類抗-EGFR MAb 425 之嵌_ 合及 人類化形式）。同樣，IMC-C225(西妥昔單抗（cetuximab)， Erbitux®，ImClone)係嵌合小鼠/人類抗_EGFR^株抗體（基 於小鼠M225單株抗體，其在人類臨床試驗中產生HAMA& 應），已報導其可在多種異種移植模型中顯示抗腫瘤效 月b。（Herbst, R.S· &Shin,D.M.,Cancer 94 (2002) 1593- 1611)。IMC-C225之效能已歸因為若干種機制，包括抑制 由EGFR信號傳導途徑調節之細胞事件、及可能提高抗體 依賴性細胞毒性（ADCC)活性（Herbst，R_s.及shin, D.M.， 146954.doc 201039848
Cancer 94 (2002) 1593-1611)。在臨床試驗中亦使用 IMC-C225，包括與放療及化療组合（Herbst，R.S.及Shin, D.M., Cancer 94 (2002) 1593-1611)。最近，Abgenix公司（Fremont， CA)研發出用於治療癌症之ABX-EGF。ABX-EGF係全人類 抗 EGFR 單株抗體。（Yang，X.D.等人，Crit. Rev. Oncol./Hematol. 38 (2001) 17-23) ° WO 2006/082515係關於源自大鼠單株抗體ICR62之人類 化抗-EGFR單株抗體，且係關於其用於癌症治療之糖改造 形式。 c-Met及抗- c-Met抗體 MET(間質-上皮轉型因子）係編碼蛋白MET(亦稱作c-Met ;肝細胞生長因子受體HGFR ; HGF受體；擴散因子受 體；SF受體；SEQ ID NO: 15)之原癌基因（Dean, M.等人， Nature 318 (1985) 385-8 ; Chan, A.M.等人，Oncogene 1 (1987) 229-33 ; Bottaro，D.P.等人，Science 251 (1991) 802-4 ; Naldini，L.等人，EMBO J. l〇 (1991) 2867-78 ; Maulik，G.等人 ’ Cytokine Growth Factor Rev. 13 (2002) 41 -59)。MET係胚胎發育及傷口癒合必需之膜受體。肝細 胞生長因子（HGF)係MET受體之唯一已知配體。MET通常 由上皮來源之細胞表現，而HGF之表現受限於間質來源之 細胞。在HGF刺激後，MET誘導若干種生物反應，其共同 引發稱作侵襲性生長之程序。癌症中之異常MET活化與預 後較差有關，其中活性異常的MET誘發腫瘤生長、形成向 腫瘤供應營養之新血管（血管發生）、及癌症向其他器官擴 146954.doc 201039848 散（轉移）。MET在多種類型之人類惡性腫瘤中解除調節， 包括腎癌、肝癌、胃癌、乳癌及腦癌。通常，僅幹細胞及 祖細胞表現MET，其使得該等細胞可侵襲性生長以在胚胎 中生成新組織或在成人中使受損組織再生。然而，人們認 為癌症幹細胞可劫持正常幹細胞表現MET之能力，且由此 使得癌症可持續存留並擴散至體内其他位點。 原癌基因MET之產物係肝細胞生長因子受體且編碼酪胺 酸-激酶活性。對原始單鏈前體蛋白實施轉譯後裂解以產 生α及β亞單元，使其以二硫鍵連接以形成成熟受體。MET 基因中之多種突變與乳突樣腎癌有關。 抗-c-Met抗體可參見（例如）US 5,686,292 ' US 7,476,724、WO 2004/0721 17、WO 2004/108766、WO 2005/016382、WO 2005/063816、WO 2006/015371、WO 2006/10491 1、WO 2007/126799、或 WO 2009/007427。 C-Met結合肽可參見（例如）Matzke，A.等人，Cancer Res 65 (14) (2005) 6105-10及 Tam，Eric，M.等人，J. Mol. Biol. 385 (2009)79-90 ° 多特異性抗體 最近幾年已研發出眾多種重組抗體形式，例如融合（例 如）IgG抗體形式及單鏈結構域之四價雙特異性抗體（例 如，參見 Coloma，M.J.等人，Nature Biotech 15 (1997) 159-163 ; WO 2001/077342 ;及 Morrison，S_L.，Nature Biotech 25 (2007) 1233-1234)。 亦已研發出幾種不再保留抗體核心結構（IgA、IgD、 146954.doc 201039848
IgE、IgG或IgM)之其他新形式，例如雙鏈抗體（diabodies)、 三鏈抗體（triabodies)或四鏈抗體（tetrabodies)、微小抗體、 幾種單鏈形式（scFv、雙scFv)，其能結合兩種或更多種抗 原（Holliger, Ρ·等人，NatureBiotecll 23 (2005) 1 126-1136； Fischer, Ν·, Leger, 0., Pathobiology 74 (2007) 3-14 ; Shen，J.等人，Journal of Immunological Methods 318 (2007) 65-74 ; Wu, C.等人，Nature Biotech. 25 (2007) 1290-1297)。 所有該等形式皆使用連接體來融合抗體核心（IgA、IgD、 IgE、IgG或IgM)與另一結合蛋白（例如scFv)或融合例如兩 個 Fab 片段或 scFv (Fischer, N.，Liger, 0·，Pathobiology 74 (2007) 3-14)。必須牢記，可藉由維持與天然抗體之高 度相似性來保留經由Fc受體結合介導之效應子功能，例如 補體依賴性細胞毒性（CDC)或抗體依賴性細胞毒性 (ADCC)。 WO 2007/024715中報導雙可變結構域免疫球蛋白為經改 造之多價及多特異性結合蛋白。一種製備生物活性抗體二 聚體之方法報導於US 6,897,044中。具有至少四個可變結 構域經由肽連接體彼此連接之多價Fv抗體構成物報導於US 7,129,330中。二聚及多聚抗原結合結構報導於US 2005/0079170中。包含三個或四個Fab片段藉由連接結構 彼此共價結合之三價或四價單特異性抗原結合蛋白，該蛋 白並非天然免疫球蛋白，報導於US 6,5 1 1,663中。在W0 2006/020258中報導四價雙特異性抗體，其可在原核及真 146954.doc 201039848 核細胞中有效表現，且可用於治療性及診斷性方法。一種 自包含兩種類型多肽二聚體之混合物分離經由至少一個鏈 間二硫鍵連接之二聚體與並非經由至少一個鏈間二硫鍵連 接之二聚體或優先合成經由至少一個鏈間二硫鍵連接之二 聚體的方法報導於US 2005/0163782中。雙特異性四價受 體報導於US 5,959,083中。具有三個或更多個功能性抗原 結合位點之經改造之抗體報導於WO 2001/077342中。 多特異性及多價抗原結合多肽報導於WO 1997/001580 中。WO 1992/0〇4〇53報導通常自結合相同抗原決定簇之 IgG類單株抗體製備之均偶合物，其係藉由合成性交聯共 價連接。對抗原具有高親和力之寡聚單株抗體報導於WO 1991/06305中，其中分泌具有兩個或更多個免疫球蛋白單 體之寡聚物（通常為IgG類），該等單體結合在一起形成四 價或六價IgG分子。綿羊源抗體及經改造抗體構成物報導 於US 6,350,860中，其可用於治療具有致病性干擾素γ活性 之疾病。在US 2005/0100543中報導可靶向構成物，其係 雙特異性抗體之多價載體，即可靶向構成物之每個分子皆 可用作兩個或更多個雙特異性抗體之載體。遺傳改造雙特 異性四價抗體報導於WO 1995/009917中。在WO 2007/109254中報導經穩定結合分子，其由經穩定scFv組成 或包含該經穩定scFv。US 2007/0274985係關於包含單鏈 Fab (scFab)片段之抗體形式。
WO 2008/140493係關於抗-ErbB家族成員抗體及包含一 或多個抗-ErbB家族成員抗體之雙特異性抗體。US 146954.doc 201039848 2004/0071696係關於可結合ErbB蛋白家族成員之雙特異性 抗體分子。 WO 20091 1 1 707(A1)係關於使用Met及HER拮抗劑之組 合療法。WO 2009111691(A2A3)係關於使用Met及EGFR拮 抗劑之組合療法。 WO 20040721 17係關於誘導c-Met下調/内化之c-Met抗 體，及其尤其在以ErbB-Ι作為第二抗原之雙特異性抗體中 的潛在用途。 【發明内容】 本發明之第一態樣係特異性結合人類ErbB-Ι及人類c-Met之雙特異性抗體，其包含特異性結合人類ErbB-Ι之第 一抗原結合位點及特異性結合人類c-Met之第二抗原結合 位點，其特徵在於，當在2小時後於流式細胞計數分析中 針對OVCAR-8細胞進行測量時，與不存在抗體時c-Met之 内化相比，該雙特異性抗體顯示c-Met之内化不超過1 5%。 在本發明一實施例中，該抗體係特異性結合人類ErbB-1 及人類c-Met之二價或三價雙特異性抗體，其包含一個或 兩個特異性結合人類ErbB-Ι之抗原結合位點及一個特異性 結合人類c-Met之抗原結合位點。 在本發明一實施例中，該抗體係特異性結合人類ErbB-1 及人類c-Met之三價雙特異性抗體，其包含兩個特異性結 合人類ErbB-Ι之抗原結合位點及一個特異性結合人類c-Met之第三抗原結合位點。 在本發明一實施例中，該抗體係特異性結合人類ErbB-1 146954.doc 201039848 及人類c-Met之二價雙特異性抗體，其包含一個特異性結 合人類ErbB-Ι之抗原結合位點及一個特異性結合人類c_ Met之抗原結合位點。 本發明之一態樣係特異性結合人類ErbB-1及人類c-Met 之雙特異性抗體，其包含特異性結合人類ErbB-1之第一抗 原結合位點及特異性結合人類C-Met之第二抗原結合位 點，其特徵在於 i) 該第一抗原結合位點在重鏈可變結構域中包含SEQ ID NO: 17 之 CDR3H 區、SEQ ID NO: 18 之 CDR2H 區、及SEQ ID NO: 19之CDR1H區，且在輕鏈可變結 構域中包含SEQ ID NO: 20 之 CDR3L 區、SEQ ID NO: 21 之 CDR2L 區、及 SEQ ID NO: 22之 CDR1L 區；且 該第二抗原結合位點在重鏈可變結構域中包含SEQ ID NO: 29 之 CDR3H 區、SEQ ID NO: 30 之 CDR2H 區、及SEQ ID NO: 31之CDR1H區，且在輕鏈可變結 構域中包含 SEQ ID NO: 32 之 CDR3L 區、SEQ ID NO: 33之 CDR2L 區、及 SEQ ID NO: 34之 CDR1L區；
ii) 該第一抗原結合位點在重鏈可變結構域中包含SEQ ID NO: 23 之 CDR3H 區、SEQ ID NO: 24 之 CDR2H 區、及SEQ ID NO: 25之CDR1H區，且在輕鏈可變結 構域中包含SEQ ID NO: 26之CDR3L區、SEQ ID NO: 27iCDR2Lg、&SEQIDNO:28iCDRlI^;a 該第二抗原結合位點在重鏈可變結構域中包含SEQ ID NO: 29 之 CDR3H 區、SEQ ID NO: 30 之 CDR2H 146954.doc -10- 201039848 區、及SEQ ID NO: 31之CDR1H區，且在輕鏈可變結 構域中包含 SEQ ID NO: 32 之 CDR3L 區、SEQ ID NO: 33之 CDR2L 區、及 SEQ ID NO: 34之CDR1L 區。 該雙特異性抗體之特徵較佳在於
0該特異性結合ErbB-1之第一抗原結合位點包含SEQ ID NO: 1之序列作為重鏈可變結構域，且包含SEq ID NO: 2之序列作為輕鏈可變結構域；且 〇 該特異性結合C-Met之第二抗原結合位點包含SEQ ID NO: 5之序列作為重鏈可變結構域，且包含SEq id NO: 6之序列作為輕鏈可變結構域；或 11)該特異性結合ErbB]之第一抗原結合位點包含SEQ ID NO: 3之序列作為重鏈可變結構域，且包含SEq ID NO: 4之序列作為輕鏈可變結構域；且 該特異性結合c-Met之第二抗原結合位點包含SEQ ID NO. 5之序列作為重鏈可變結構域，且包含sEQ ip 〇 NCh 6之序列作為輕鏈可變結構域。 本發明另一態樣係本發明雙特異性抗體，其特徵在於包 含IgGl或IgG3亞類之恆定區。 在一實施例中’本發明該雙特異性抗體之特徵在於，該 抗體在Asn297處經糖鏈糖基化，其中該糖鍵内岩藻糖之量 為65%或更低。 本發明另-態樣係編碼該雙特異性抗體鏈之核酸分子。 本，明之其他態樣係包含該雙特異性抗體之醫藥組合 物、該用於治療癌症之組合物，該雙特異性抗體用於製造 146954.doc 201039848 用於治療癌症之.藥物之用途、藉由將該雙特異性抗體投與 需要治療之患者來治療患有癌症之患者之方法。 由於EGFR及c-Met係導致磷酸化及下游信號傳導級聯活 化之交叉感知受體的一部分，且由於該等受體在腫瘤組織 細胞表面之上調（Bachleitner-Hofmann 等人，Mol. Cane. Ther, 2009，3499-3508)，本發明雙特異性 <ErbB-1-c-Met> 抗體具有有價值的特性，例如抗腫瘤效能及癌細胞抑制。 本發明抗體表現價值極高之特性，例如尤其可抑制表現 兩種受體ErbB 1及c-Met之癌細胞之生長、對患有癌症之患 者有益之抗腫瘤效能。在表現兩種受體ErbB 1及c-Met之癌 細胞上，本發明雙特異性<ErbBl-c-Met>抗體與其親代單 特異性二價<c-Met>抗體相比表現降低之c-Met受體之内 化。 【實施方式】 本發明之第一態樣係特異性結合人類ErbB-1及人類c-Met之雙特異性抗體，其包含特異性結合人類ErbB-Ι之第 一抗原結合位點及特異性結合人類c-Met之第二抗原結合 位點，其特徵在於，當在2小時後於流式細胞計數分析中 對OVCAR-8細胞進行測量時，與不存在該雙特異性抗體時 c-Met之内化相比，該雙特異性抗體顯示c-Met之内化不超 過 15%。 因此本發明係關於特異性結合人類ErbB-1及人類c-Met 之雙特異性抗體，其包含特異性結合人類ErbB-Ι之第一抗 原結合位點及特異性結合人類c-Met之第二抗原結合位 146954.doc -12- 201039848 點，其中該雙特異性抗體導致當在OVCAR-8細胞-抗體培 育1小時後藉由流式細胞計數分析測量時，與不存在抗體 時OVCAR-8細胞上c-Met之内化相比，OVCAR-8細胞上c-Met之内化提高不超過15%。 在一實施例中，該特異性結合人類ErbB-Ι及人類c-Met 之雙特異性抗體包含特異性結合人類ErbB-1之第一抗原結 合位點及特異性結合人類c-Met之第二抗原結合位點，其 特徵在於，當在2小時後於流式細胞計數分析中對OVCAR-8細胞進行測量時，與不存在該雙特異性抗體時c-Met之内 化相比，該雙特異性抗體顯示c-Met之内化不超過10%。 在一實施例中，該特異性結合人類ErbB-Ι及人類c-Met 之雙特異性抗體包含特異性結合人類ErbB-1之第一抗原結 合位點及特異性結合人類c-Met之第二抗原結合位點，其 特徵在於，當在2小時後於流式細胞計數分析中對OVCAR-8細胞進行測量時，與不存在該雙特異性抗體時c-Met之内 化相比，該雙特異性抗體顯示c-Met之内化不超過7%。 在一實施例中，該特異性結合人類ErbB-Ι及人類c-Met 之雙特異性抗體包含特異性結合人類ErbB-1之第一抗原結 合位點及特異性結合人類c-Met之第二抗原結合位點，其 特徵在於，當在2小時後於流式細胞計數分析中對OVCAR-8細胞進行測量時，與不存在該雙特異性抗體時c-Met之内 化相比，該雙特異性抗體顯示c-Met之内化不超過5%。 術語「c-Met之内化」係指相對於不存在抗體時c-Met之 内化，在OVCAR-8細胞（NCI細胞系名稱；購自NCI(國家 146954.doc -13- 201039848 癌症研究所）〇VCAR-8-NCI ; Schilder RJ 等人，Int J Cancer. 1990 年 3 月 15 曰；45(3):416-22 ; Ikediobi ON 等 人，Mol Cancer Ther. 2006 ; 5 ; 2606-12 ; Lorenzi，P_L.等 人，Mol Cancer Ther 2009 ; 8(4):713-24)上由抗體誘導之 c-Met受體内化。該c-Met受體之内化係由本發明雙特異性 抗體誘導，且係在2小時後於流式細胞計數分析（FACS)中 測量，如實例9中所述。在抗體暴露2小時後，與不存在抗 體時c-Met之内化相比，本發明雙特異性抗體在OVCAR-8 細胞上顯示c-Met之内化不超過1 5%。在一實施例中，該抗 體顯示c-Met之内化不超過1 0%。在一實施例中，該抗體顯 示c-Met之内化不超過7%。在一實施例中，該抗體顯示c-Met之内化不超過5%。 本發明另一態樣係特異性結合人類ErbB-1及人類c-Met 之雙特異性抗體，其包含特異性結合人類ErbB-1之第一抗 原結合位點及特異性結合人類c-Met之第二抗原結合位 點，其特徵在於，當在2小時後於流式細胞計數分析中對 OVCAR-8細胞進行測量時，與由（相應）單特異性二價親代 c-Met抗體誘導之c-Met之内化相比，該雙特異性抗體可使 c-Met之内化降低50%或更多（在一實施例中，降低60%或 更多；在另一實施例中，降低70%或更多；在一實施例 中，降低80%或更多）。如下所述計算c-Met之内化之降低 (使用在2小時後於流式細胞計數分析中對OVCAR-8細胞進 行測量之内化％值，而將低於〇之内化％值設定為〇 °/〇内 化，例如對於BsABOl而言（-14%内化設定為0%内化））： 146954.doc -14- 201039848 100Χ(由單特異性二價親代c-Met抗體誘導之c-Met之内化％ -由雙特異性ErbB-1/cMet抗體誘導之c-Met之内化％)/由單 特異性二價親代c-Met抗體誘導之c-Met之内化％。舉例而 言：雙特異性ErbB-1/cMet抗體BsABOl顯示c-Met之内化 為-14%，將其設定為0% ;且單特異性二價親代c-Met抗體 Mab 5D5顯示c-Met之内化為44%。因此，雙特異性ErbB-1/cMet抗體BsABOl顯示c-Met之内化降低100χ(40· 0)/40%= 1 00%(參見實例9中在2小時後於流式細胞計數分析 中對Ο VC AR-8細胞進行測量之内化值）。 本文所用「抗體」係指包含抗原結合位點之結合蛋白。 本文所用術語「結合位點」或「抗原結合位點」表示抗體 分子中實際結合配體且源自抗體之區域。術語「抗原結合 位點」包括抗體重鏈可變結構域（VH)及/或抗體輕鏈可變 結構域（VL)、或VH/VL對，且可源自完整抗體或抗體片 段，例如單鏈Fv、VH結構域及/或VL結構域、Fab、或 (Fab)2。在本發明之一實施例中，抗原結合位點各自包含 抗體重鏈可變結構域（VH)及/或抗體輕鏈可變結構域 (VL)，且較佳係藉由由抗體輕鏈可變結構域（VL)及抗體重 鏈可變結構域（VH)組成之對來形成。 除源自抗體之抗原結合位點外，結合肽（例如，如 Matzke，A.等人，Cancer Res. 65 (14) (2005) 6105-10 中所 述）亦可特異性結合抗原（例如c-Met)。因此本發明另一態 樣係特異性結合人類ErbB-Ι及人類c-Met之雙特異性結合 分子，其包含特異性結合人類ErbB-Ι之抗原結合位點及特 146954.doc -15- 201039848 異性結合人類c-Met之結合肽。因此本發明另一態樣係特 異性結合人類ErbB-Ι及人類c-Met之雙特異性結合分子， 其包含特異性結合人類c-Met之抗原結合位點及特異性結 合人類ErbB-1之結合肽。
Erb-Bl(亦稱作ERBB1、人類表皮生長因子受體、 EGFR、HER-1或鳥類成紅細胞白血病病毒（v-erb-b)癌基因 同源物；SEQ ID NO: 16)係由c-erbB原癌基因編碼之170 kDa跨膜受體，且表現固有的酪胺酸激酶活性（Modjtahedi, Η·等人，Br. J. Cancer 73 (1996) 228-235 ; Herbst，R.S.及 Shin, D.M., Cancer 94 (2002) 1593-161 1)。EGFR亦存在多 種亞型及變體（例如選擇性RNA轉錄物、經截短形式、多 態性等），包括（但不限於）彼等由Swissprot數據庫條目號 P00533-1 ' P00533-2、P00533-3 及 P00533-4標識者。已知 EGFR可結合各種配體，包括表皮生長因子（EGF)、轉化生 長因子-α (TGf-α)、雙調蛋白、肝素結合性EGF (hb-EGF)、β細胞素、及表皮調節素（Herbst, R_S.及Shin， D.M.，Cancer 94 (2002) 1593-161 1 ; Mendelsohn, J.及
Baselga，J·, Oncogene 19 (2000) 6550-6565)。EGFR經由絡 胺酸-激酶介導之信號轉導途徑調節多種細胞過程，包括 (但不限於）控制細胞增殖、分化、細胞存活、細胞凋亡、 血管發生、有絲分裂發生、及轉移之信號轉導途徑之活化 (Atalay，G·等人，Ann. Oncology 14 (2003) 1346-1363 ; Tsao, A.S.及 Herbst, R.S·，Signal 4 (2003) 4-9 ; Herbst, R.S.及 Shin, D.M.，Cancer 94 (2002) 1593-161 1 ； 146954.doc -16- 201039848
Modjtahedi，Η·等人，Br. J. Cancer 73 (1996) 228-235)。
特異性結合人類ErbB-1之抗原結合位點及尤其重鏈可變 結構域（VH)及/或抗體輕鏈可變結構域（VL)可源自a)已知 抗-ErbB-Ι抗體，例如IMC-C225(西妥昔單抗，Erbitux®; ImClone)(Herbst, R_S.及 Shin，D.M.，Cancer 94 (2002) 1593-161 1)、ABX-EGF (Abgenix)(Yang, X.D.等人，Crit. Rev. Oncol./Hematol. 38 (2001) 17-23)、人类員 4 匕 ICR62 (W〇 2006/082515)或其他抗體（例如如 US 5,891,996、US 5,5 5 8,864中所述）；或b)藉由尤其使用人類ErbB-1蛋白或 其核酸或片段實施之重新免疫方法或藉由噬菌體展示法獲 得之新抗-ErbB-Ι抗體。 MET(間質-上皮過渡因子）係編碼蛋白MET之原癌基因 (亦稱作c-Met ;肝細胞生長因子受體HGFR ; HGF受體；擴 散因子受體；SF受體；SEQ ID NO: 15)(Dean, M.等人， Nature 318 (1985) 385-8 ; Chan, A.Μ.等人，Oncogene 1 (1987) 229-33 ; Bottaro，D.P.等人，Science 251 (1991) 802-4 ; Naldini，L.等人，EMBO J. 10 (1991) 2867-78 ; Maulik，G.等人 ’ Cytokine Growth Factor Rev. 13 (2002) 41 -59)。MET係胚胎發育及傷口癒合必需之膜受體。肝細 胞生長因子（HGF)係MET受體之唯一已知配體。MET通常 由上皮來源之細胞表現’而HGF之表現受限於間質來源之 細胞。在HGF刺激後，MET誘導若干種生物反應，其共同 引發稱作侵襲性生長之程序。癌症中之異常MET活化與預 後較差有關，其中活性異常的MET誘發腫瘤生長、形成向 146954.doc •17- 201039848 腫瘤供應營養之新血管（血管發生）、及癌症向其他器官擴 散（轉移）。MET在多種類型之人類惡性腫瘤中解除調節， 包括腎癌、肝癌、胃癌、乳癌及腦癌。通常，僅幹細胞及 祖細胞表現MET，其使得該等細胞可侵襲性生長以在胚胎 中生成新組織或在成人中使受損組織再生。然而，人們認 為癌症幹細胞可劫持正常幹細胞表現MET之能力，且由此 使得癌症可持續存留並擴散至體内其他位點。 特異性結合人類c-Met之抗原結合位點及尤其重鏈可變 結構域（VH)及/或抗體輕鏈可變結構域（VL)可源自a)已知 抗-c-Met抗體（例如如 US 5,686,292、US 7,476,724、WO 2004/0721 17、WO 2004/108766、WO 2005/016382、WO 2005/063816、WO 2006/015371、WO 2006/10491 1、WO 2007/126799、或 WO 2009/007427 中所述）；b)藉由（例如） 尤其使用人類抗-c-Met蛋白或其核酸或片段實施之重新免 疫方法或藉由噬菌體展示法獲得之新抗-c-Met抗體。 本發明另一態樣係特異性結合人類ErbB-Ι及人類C-Met 之雙特異性抗體，其包含特異性結合人類ErbB-1之第一抗 原結合位點及特異性結合人類C-Met之第二抗原結合位 點，其特徵在於
i)該特異性結合ErbB-1之第一抗原結合位點包含SEQ ID NO: 1之序列作為重鏈可變結構域，且包含犯卩 ID NO: 2之序列作為輕鏈可變結構域；且 該特異性結合c-Met之第二抗原結合位點包含SEQ ID NO: 5之序列作為重鏈可變結構域，且包含seQ ID 146954.doc -】8- 201039848 NO: 6之序列作為輕鏈可變結構域，·或 ii)該特異性結合ErbB-11 g β .,.
<弟—抗原結合位點包含SEQ ID NO: 3之序列作為重鏈可變結構域，纟包含seq ID NO: 4之序列作為輕鏈可變結構域；且 該特異性結合c-Met之第二抗原結合位點
包含SEQ ID NO: 5之序列作為重鏈可變結構域，且包含seq① NO: 6之序列作為輕鏈可變結構域。 抗體特異性係指抗體對抗原特定表位之選擇性識別。例 如，天然抗體具有單特異性。本發明「雙特異性抗體」係 具有兩種不同抗原結合特異性之抗體。倘若抗體具有不止 一種特異十生’則所識別表位可能與單一抗原或不丨一種抗 原相關。本發明抗體對兩種不同抗原具有特異性，即作為 第一抗原之ErbB-1及作為第二抗原之c_Met。 本文所用術語「單特異性」抗體表示具有一或多個結合 位點之抗體，δ亥等結合位點各自結合相同抗原上之相同表 位0 本申研案所用術語「價」表示抗體分子中存在特定數量 之結合位點。因此，術語r二價」、「四價」、及「六 4貝」分別表示在抗體分子中存在兩個結合位點、四個結合 位點、及六個結合位點。本發明雙特異性抗體至少為「二 4貝」且可為「三價」或「多價」（例如「四價」或「六 價」）。 本發明抗體之抗原結合位點可含有六個互補決定區 (CDR)，其不同程度地促進結合位點對抗原之親和力。存 146954.doc -19- 201039848 在三個重鏈可變結構域CDR(CDRH1、CDRH2及CDRH3)及 三個輕鏈可變結構域CDR(CDRL1、CDRL2及CDRL3)。 CDR及框架區（FR)之範圍取決於與胺基酸序列之經編譯數 據庫的比對，其中該等區域已根據各序列間之差異加以界 定。本發明範圍内亦包含包括較少CDR(即其中結合特異 性取決於三個、四個或五個CDR)之功能性抗原結合位 點。舉例而言’不足全套6個CDR之CDR數對於結合即已 足夠。在某些情形下，VH或VL結構域即足夠。 在較佳實施例中’本發明抗體另外包含一或多個人源免 疫球蛋白種類之免疫球蛋白恆定區。免疫球蛋白種類包括 IgG、IgM、IgA、IgD、及lgE同種型，且在IgG及IgA情形 下包括其亞型。在一較佳實施例中，本發明抗體具有IgG 型抗體之恆定結構域結構，且具有四個抗原結合位點。此 係藉由（例如）以下方式來完成：連接一個（或兩個）特異性 結合c-Met之完整抗原結合位點（例如單鏈Fab片段或單鏈 Fv)與特異性結合ErbB-1之完整抗體之N或C端重鏈或輕 鏈，從而產生三價雙特異性抗體（或四價雙特異性抗體）。 或者可使用針對人類ErbB-1及人類c-Met之IgG樣雙特異性 二價抗體，其包含免疫球蛋白恆定區，如（例如）以下文獻 中所述：EP 07024867.9、EP 07024864.6、EP 07024865.3 或 Ridgway，J.B., Protein Eng. 9 (1996) 617-621 ； WO 96/02701 1 ; Merchant, A.M.等人，Nature Biotech 16 (1998) 677-681 ; Atwell，S.等人，J. Mol. Biol. 270 (1997) 26-35及 EP 1870459A1。 146954.doc -20· 201039848 本=所用術語「單株抗體」或「單株抗體組合物」係指 具有單一胺基酸組成之抗體分子製劑。 術，吾欣合抗體」係指包含來自一種來源或物種之可變 .區（即結合區）及源自不同來源或物種之怪定區之至少—部 分的抗體，其通常係藉由重組DNA技術來製備。包含鼠類 可反區及人類值定區之嵌合抗體較佳。本發明所涵蓋之其 他較佳形式之「嵌合抗體」係彼等怪定區已相對於原始抗 〇體進行修飾或改變從而尤其在Clq結合及/或。受體㈣ 結合方面獲得本發明特性者。該等嵌合抗體亦稱作「種類 轉換抗體」。嵌合抗體係免疫球蛋白基因之表現產物，該 等免疫球蛋白基因包含編碼免疫球蛋白可變區之dna片段 及編碼免疫球蛋白怪定區之DNA片段。製備丧合抗體之方 法涉及業内熟知之習用重組DNA及基因轉染技術。例如， 參見 Momson，S.L.等人，proc. Natl Acad Sci 仍八 81 (1984) 6851-6855 ; US 5,202,238及 US 5,204,244。 〇 術語「人類化抗體」係指框架區或「互補決定區」 (CDR)已經修飾而包含與親代免疫球蛋白CDR相比具有不 同特異性之免疫球蛋白CDR的抗體。在一較佳實施例中， 將鼠類CDR移植入人類抗體之框架區中以製備「人類化抗 體」。例如，參見Riechmann，L.等人，Nature 332 (1988) 323-327，及Neuberger，M.S·等人，Nature 314 (1985) 268- 270。尤佳CDR對應於嵌合抗體中彼等代表可識別上述抗 原之序列者。本發明所涵蓋之其他形式之「人類化抗體」 係彼等恆定區已相對於原始抗體進行額外修飾或改變從而 146954.doc •21 · 201039848 明特 尤其在Clq結合及/或Fc受體（FcR)結合方面獲得本 性者。 努 本文所用術語「人類抗體」意欲包括具有源自人類種系 免疫球蛋白序列之可變區及恆定區之抗體。人類抗體已為 § 七業内所熟知（van Dijk，M.A.及 van de Winkel j g i
Curr. 〇Pin· Chem· Bio1. 5 (2001) 368-374)。亦可在轉基因 動物（例如小氬）中產生人類抗體，該等轉基因動物在免疫 後能在不產生内源免疫球蛋白之情況下產生全譜系之人類 抗體或所選人類抗體。將人類種系免疫球蛋白基因陣列轉 移至該等種系之突變小鼠中使得可在抗原激發後產生人類 抗體（例如’參見Jakobovits，A.等人，Proc. Natl. Acad. Sci. USA 90 (1993) 255 1-2555 ; Jakobovits，A.等人， Nature 362 (1993) 255-258 ; Brtiggemann，M.等人，Year
Immunol· 7 (1993) 33-40)。人類抗體亦可在噬菌體展示文 庫中產生（Hoogenboom，H.R.及Winter, G.J. Mol. Biol. 227 (1992) 381-388 ; Marks，J.D.等人，J. Mol· Biol. 222 (1991) 581-597)。亦可使用 c〇le，S.P.C.等人及 Boerner, P. 等人之技術來製備人類單株抗體（C〇le, S.p.c·等人， Monoclonal Antibodies and Cancer Therapy, Liss, A.L., (1985) 77-96，及 Boerner，P.等人，j. Immunol. 147 (1991) 86-95)。如已提及之本發明嵌合及人類化抗體，本文所用 術語「人類抗體」亦包含該等恆定區中經修飾從而尤其在 C 1 q結合及/或FcR結合方面獲得本發明特性之抗體，例如 藉由「種類轉換」來修飾，即，使Fc部分發生改變或突變 146954.doc •22· 201039848 (例如自IgGl變為IgG4及/或IgGl/IgG4突變）。 本文所用術語「重組人類抗體」意欲包括所有藉由重組 方式製備、表現、產生或分離之人類抗體，例如自諸如 NS0或CHO細胞等宿主細胞或自人類免疫球蛋白基因之轉 基因動物（例如小鼠）分離之抗體，或使用轉染至宿主細胞 中之重組表現載體表現之抗體。該等重組人類抗體具有重 排形式之可變及恆定區。本發明之重組人類抗體已經活體 Ο
内體細胞超突變。因此，重組抗體之VH& VL區之胺基酸 序列雖然源自且相關於人類種系VH及VL序列，但可能天 然不存在於活體内人類抗體種系譜中。 本文所用「可變結構域」（輕鏈可變結構域（VL)、重鏈 可變區（VH))表不直接參與抗體與抗原結合之輕鏈及重鏈 對中之每一者。人類輕鏈及重鏈可變結構域具有相同一般 、σ構，且每一結構域包含四個序列高度保守之框架區 (FR)，經由三個「超變區」（或互補決定區，cdr)連接。 框架區採終片構形，CDRS可形成連接p_片結構之環。各 鏈中之CDRS藉由框架區保持三維結構，並與另—鍵中之 。抗體重鏈及輕鏈之CDR3區 CDRS—起形成抗原結合位點 在本發明抗體之結合特異性/親和性方面具有特別重要之 作用，由此提供本發明之另—目的。 本文所用術”肖邊區」或「抗體之抗原結合部分或抗 ««中負責與抗原結合之胺基酸殘基。 超變區包含「互補決定區」4「CDRS」之胺基酸殘基。 框木」《FR」區係本文所定義超變區殘基以外的可變 146954.doc •23· 201039848 結構域區。因此，抗體之輕鏈及重鏈自N端至C端包含結 構域 FR1、CDR1、FR2、CDR2、FR3、CDR3 及 FR4。各鏈 上之CDRs係藉由該等框架胺基酸間隔。重鏈之CDR3尤其 為對抗原結合貢獻最大之區域。CDR及FR區係根據Kabat 等人（Sequences of Proteins of Immunological Interest，第 5 版，Public Health Service, National Institutes of Health, 3已11^3(1&,厘0(1991))之標準定義確定。 本文所用術語「結合」或「特異性結合」係指在體外分 析中抗體與抗原（人類ErbB-Ι或人類c-Met)表位之結合，較 佳係在電漿共振分析（BIAcore, GE-Healthcare Uppsala, Sweden)中與純化野生型抗原之結合。結合親和力定義為 術語ka(抗體/抗原複合物中抗體結合之速率常數）、kD(解 離常數）及KD (kD/ka)。結合或特異性結合意指結合親和力 (KD)為 10·8 mol/1或更低，較佳為 10_9 Μ 至 1(T13 mol/1。因 此，本發明雙特異性<ErbBl-c-Met>抗體以1(T8 mol"或更 低、較佳1(Γ9 Μ至1(T13 mol/1之親和力（KD)與各特異性抗原 特異性結合。 可藉由 BIAcore 分析（GE-Healthcare Uppsala, Sweden)來 研究抗體與FcyRIII之結合。結合親和力定義為術語ka(抗 體/抗原複合物中抗體結合之速率常數）、kD(解離常數）及 KD (kD/ka)。 術語「表位」包括能特異性結合抗體之任何多肽決定 簇。在某些實施例中，表位決定簇包括分子之化學活性表 面基團，例如胺基酸、糖側鏈、磷醯基、或磺醯基，且在 146954.doc -24- 201039848 某t實施例中可具有特定的三維結構特徵及/或比電荷特 徵。表位係抗原中結合抗體之區域。 在某二κ知例中，當抗體在蛋白質及/或高分子複合混 合物中優先識別其無抗原時，認為該抗體可特異性結合該 抗原。 Ο
本申咕案117所用術語「悝定區」表示抗體中除可變區以 外之結構域的總和。恆定區並非直接參與抗原結合，而是 表現出各種效應子功能。端視抗體重鏈恆定區之胺基酸序 列，可將抗體分為以下幾類：IgA、IgD、IgE、IgG及
IgM，且其中若干種類可進一步分為多個亞類，例如
IgGl、IgG2、IgG3 及 IgG4、IgA1 及 IgA2。對應於不同抗 體種類之重鏈恆定區分別稱作α、δ、ε、γ、及μ。在所有 五種抗體種類中可發現之輕鏈恆定區稱作κ (“卯的及λ (lambda)。恆定區較佳得自人類來源。 本申明案中所用術語「得自人類來源之恒定區」表示
IgGl、IgG2、IgG3或IgG4亞類人類抗體之重鏈恆定區及/ 或輕鏈κ或λ恆定區。該等恆定區為當前業内所熟知且由 (例如）Kabat，Ε.Α·所闡述（例如’參見J〇hns〇n, G.及Wu， T.T. > Nucleic Acids Res. 28 (2000) 214-218 ； Kabat, E.A. 等人，Proc. Natl. Acad· Sci. USA 72 (1975) 2785-2788)。 在一貫施例中，本發明雙特異性抗體包含IgG i或igG3亞 類（較佳為IgGl亞類）之恆定區，其較佳得自人類來源。在 一實施例中’本發明雙特異性抗體包含IgGl或IgG3亞類 (較佳為IgGl亞類）之Fc部分，其較佳得自人類來源。 146954.doc -25· 201039848
IgG4亞類之抗體顯示降低之Fc受體（FcyRIIIa)結合’同 時其他IgG亞類之抗體顯示較強結合。然而，Pro238、 Asp265、Asp270、Asn297(喪失 Fc碳水化合物）、Pro329、 Leu234、Leu235、Gly236、Gly237、Ile253、Ser254、 Lys28 8、Thr3 07、Gln311、Asn43 4、及His435係在改變後 亦可提供降低之Fc受體結合之殘基（Shields，R.L.等人，】· Biol. Chem. 276 (2001) 6591-6604 ; Lund, J.等人，FASEB J. 9 (1995) 115-1 19 ; Morgan, A.等人，Immunology 86 (1995) 319-324 ; EP 0 307 434)。 在一實施例中，本發明抗體相對於IgGl抗體及全長親代 抗體具有降低之FcR結合，其在FcR結合方面屬於IgG4亞 類或IgGl或IgG2亞類且在S228、L234、L235及/或D265處 具有突變，及/或含有PVA236突變。在一實施例中，全長 親代抗體中之突變係S228P、L234A、L235A、L235E及/或 PVA236。在另一實施例中，全長親代抗體中之突變係 IgG4 S228P及 IgGl L234A及 L235A。 抗體恆定區直接參與ADCC(抗體依賴性細胞介導細胞毒 性）及CDC(補體依賴性細胞毒性）。補體活化（CDC)係藉由 使補體因子Clq與大多數IgG抗體亞類之恆定區結合來起 始。C1 q與抗體之結合係藉由在所謂的結合位點實施所定 義之蛋白質間交互作用來引發。該等恆定區結合位點為當 前業内所知且闡述於（例如）以下文獻中：Lukas, T·，J.等 人，J. Immunol. 127 (1981) 2555-2560 ; Brunhouse, R.及 Cebra, J., J., Mol. Immunol. 16 (1979) 907-917 ; Burton， 146954.doc -26- 201039848 D. ，R.等人，Nature 288 (1980) 338-344 ; Thommesen，J·, E. 等人，Mol. Immunol. 37 (2000) 995-1004 ; Idusogie，E·， E.等人，J. Immunol. 164 (2000) 4178-4184 ; Hezareh, M. 等人，J. Virol. 75 (2001) 12161-12168 ; Morgan，A_等人， Immunology 86 (1995) 3 19-324 ;及EP 0 307 434。該等恆 定區結合位點之特徵在於（例如）胺基酸L234、L235、 D270、N297、E318、K320、K322、P331 及 P329(根據 Kabat之EU索引來編號）。 術語「抗體依賴性細胞毒性（ADCC)」係指人類靶細胞 在效應子細胞存在下由本發明抗體溶解。較佳在效應子細 胞存在下藉由用本發明抗體處理ErB-Ι及c-Met表現細胞之 製劑來測量ADCC，該等效應子細胞例如剛分離之PBMC 或自jk沉棕黃層純化之效應子細胞，例如單核細胞或天然 殺傷（NK)細胞或持久生長NK細胞系。 術語「補體依賴性細胞毒性（CDC)」表示藉由使補體因 子C 1 q與大多數IgG抗體亞類之Fc部分結合來起始之過程。 Clq與抗體之結合係藉由在所謂的結合位點實施所定義之 蛋白質間交互作用來引發。該等Fc部分結合位點為當前業 内已知（參見上文）。該等Fc部分結合位點之特徵在於（例 如）胺基酸 L234、L235、D270、N297、E318、K320、 K322、P331、及P329(根據Kabat之EU索引來編號）。 IgGl、IgG2及IgG3亞類抗體通常顯示包括Clq及C3結合在 内之補體活化，而IgG4不活化補體系統且不結合Clq及/或 C3。 146954.doc -27- 201039848 單株抗體之細胞介導效應子功能可藉由改造其寡糖組份 來增強，如Umana，P.等人，Nature Biotechnol. 17 (1999) 176-180 ;及US 6,602,684所述。IgGl型抗體係最常用治療 性抗體，其為在各CH2結構域中之Asn297處具有保守N-連 接糖基化位點之糠蛋白。與Asn297附接之兩種複雜二天線 (biantennary)寡糖包埋於CH2結構域之間，與多肽骨架形 成廣泛接觸，且其存在為抗體介導諸如抗體依賴性細胞毒 性（ADCC)等效應子功能所必需（Lifely, M. R.等人， Glycobiology 5 (1995) 813-822 ; Jefferis，R.等人，Immunol. Rev· 163 (1998) 59-76 ; Wright，Α·及 Morrison，S. L. ’ Trends Biotechnol. 15 (1997) 26-32)。Umana，P.等人’ Nature Biotechnol. 17 (1999) 176-180 及 WO 99/54342 顯 示，中國倉鼠卵巢（CHO)細胞中β(1，4)-Ν-乙醯葡糖胺基轉 移酶III (「GnTIII」）（一種催化形成二等分型（bisected)寡 糖之糖基轉移酶）之過表現可顯著提高抗體之活體外ADCC 活性。Asn297碳水化合物組成中之改變或其消除亦影響與 FcyR 及 Clq 之結合（Umana, P_等人，Nature Biotechnol. 17 (1999) 176-180 ; Davies, J.等人，Biotechnol· Bioeng. 74 (2001) 288-294 ; Mimura，Y.等人，J. Biol. Chem. 276 (2001) 45539-45547 ; Radaev, S.等人，J. Biol. Chem· 276 (2001) 16478-16483 ; Shields, R.L.等人，J. Biol. Chem. 276 (2001) 659卜6604 ; Shields, R.L.fA，J.Biol.Chem· 277 (2002) 26733-26740 ; Simmons, L.C.等人，J.
Immunol. Methods 263 (2002) 133-147) 0 146954.doc • 28 - 201039848 藉由減少岩藻糖之量來增強單株抗體之細胞介導效應子 功能之方法闡述於（例*如）以下文獻中：WO 2005/018572、 WO 2006/1 16260、WO 2006/114700、WO 2004/065540、 WO 2005/01 1735、WO 2005/027966、WO 1997/028267、 US 2006/0134709 ' US 2005/0054048 ' US 2005/0152894 、 WO 2003/035835、WO 2000/061739 ; Niwa，R.等人，J. Immunol. Methods 306 (2005) 151-160 ; Shinkawa, T.等 人，J Biol Chem，278 (2003) 3466-3473 ； WO 03/055993 或 US 2005/0249722 ° 在本發明一實施例中，本發明雙特異性抗體在Asn297處 經糖鏈糖基化（IgGl或IgG3亞類），其中該糖鏈内岩藻糖之 量為65%或更低（根據Kabat進行編號）。在另一實施例中， 該糖鏈内岩藻糖之量介於5%與65%之間，較佳介於20%與 40%之間。本發明「Asn297」意指大致位於Fc區中297位 之胺基酸天冬醯胺。基於抗體間之較小序列差異，Asn297 亦可位於297位上游或下游之數個胺基酸（通常不超過±3個 胺基酸）處，即介於294位與300位之間。 人類IgGl或IgG3之糖基化發生在Asn297處，其為核心岩 藻糖化二天線複雜寡糖糖基化形式，末端為最多2個Gal殘 基。人類IgGl或IgG3亞類之重鏈恆定區詳細報導於以下文 獻中：Kabat, E.A·等人，Sequences of Proteins of Immunological Interest，第 5 版，Public Health Service, National Institutes of Health，Bethesda，MD. (1991);及 Briiggemann，Μ·等人，J. Exp. Med. 166 (1987) 1351- 146954.doc -29· 201039848 1361 ; Love, T.W.等人，Methods Enzymol. 178 (1989) 515-527。該等結構端視末端Gal殘基之量命名為GO、 Gl(a-1，6-或 α-1，3-)或 G2聚糖殘基（Raju，T.S.，Bioprocess Int.l (2003) 44-53)。抗體Fc部分之CHO類糖基化闡述於 (例如）Routier, F.H., Glycoconjugate J. 14 (1997) 201-207 中。以重組方式在未經糖基修飾之CHO宿主細胞中表現之 抗體通常在Asn297處以至少85%之比例經岩藻糖化。全長 親代抗體之經修飾寡糖可為雜合寡糖或複雜寡糖。二等分 型、經還原/未岩藻糖化寡糖較佳為雜合寡糖。在另一實 施例中，二等分型、經還原/未岩藻糖化寡糖為複雜寡 糖。 本發明「岩藻糖之量」意指在Asn297處之糖鏈内’該糖 相對於附接至Asn297之所有糖結構（例如複雜結構、雜合 體結構及高甘露糖結構）之總和之量，其係藉由MALDI-TOF質譜法來測量且計算為平均值。岩藻糖之相對量係含 岩藻糖結構相對於N-糖苷酶F處理樣品中所有確定糖結構 (分別例如複雜結構、雜合體結構及募-及高-甘露糖結構） 之百分比。（例如，參見WO 2008/077546(Α1))。
一實施例係製備在Asn297處經糖鏈糖基化之IgG 1或IgG3 亞類雙特異性抗體之方法’其中岩藻糖在該糖鏈内之量為 65%或更低，且使用以下文獻中所述之程序：WO 2005/044859 ' WO 2004/065540 ' WO 2007/031875 ； Umana，P.等人，Nature Biotechnol. 17 (1999) 176-180 ; WO 99/154342、WO 2005/018572、WO 2006/1 16260、WO 146954.doc 30- 201039848 2006/1 14700、WO 2005/01 1735、WO 2005/027966、WO 97/028267、US 2006/0134709、US 2005/0054048、US 2005/0152894、WO 2003/035835 或 WO 2000/061739。 一實施例係製備在Asn297處經糖鏈糖基化之IgGl或IgG3 亞類雙特異性抗體之方法，其中岩藻糖在該糖鏈内之量為 65%或更低，且使用以下文獻中所述之程序：Niwa，R.等 人，J. Immunol. Methods 306 (2005) 151-160 ; Shinkawa， Τ·等人，J Biol Chem，278 (2003) 3466-3473 ; WO 03/055993 或 US 2005/0249722 。 雙特異性抗體形式 本發明抗體具有兩個或更多個結合位點且為多特異性且 較佳為雙特異性。亦即，抗體甚至在具有兩個以上結合位 點（即抗體為三價或多價）之情形下亦可為雙特異性。本發 明雙特異性抗體包括（例如）多價單鏈抗體、雙鏈抗體及三 鏈抗體、以及具有全長抗體恆定結構域結構之抗體，該結 構經由一或多個肽連接體連接其他抗原結合位點（例如單 鏈Fv、VH結構域及/或VL結構域、Fab、或（Fab)2)。抗體 可為來自單一物種之全長抗體，或為嵌合抗體或人類化抗 體。對於具有兩個以上抗原結合位點之抗體而言，某些結 合位點可相同，只要該蛋白具有針對兩個不同抗原之結合 位點即可。亦即，若第一結合位點對ErbB-Ι具有特異性， 則第二結合位點對c-Met具有特異性，且反之亦然。 在一較佳實施例中，特異性結合人類ErbB -1及人類c-Met之本發明雙特異性抗體包含抗體（較佳為IgGl或IgG3亞 146954.doc -31 · 201039848 類）之Fc區。 二價雙特異性形式
可使用針對人類ErbB-Ι及人類c-Met且包含免疫球蛋白 恆定區之雙特異性二價抗體，如（例如）以下文獻中所述： WO 2009/080251、WO 2009/080252、WO 2009/080253 或 Ridgway, J.B. > Protein Eng. 9 (1996) 617-621 ； WO 96/02701 1 ; Merchant，A.M.等人，Nature Biotech 16 (1998) 677-681 ; Atwell，S.等人，J. Mol. Biol. 270 (1997) 26-35及EP 1870459A1 ° 因此，在本發明一實施例中，本發明雙特異性<ErbB-P c-Met>抗體係二價雙特異性抗體，其包含： a) 全長抗體中特異性結合ErbB-Ι之輕鏈及重鏈；及 b) 全長抗體中特異性結合人類c-Met之輕鏈及重鏈， 其中恆定結構域CL及CH1、及/或可變結構域VL及 VH可彼此替代。 在本發明另一實施例中，本發明雙特異性<ErbB-l-c-Met>抗體係二價雙特異性抗體，其包含： a) 全長抗體中特異性結合人類c-Met之輕鏈及重鏈；及 b) 全長抗體中特異性結合ErbB-1之輕鏈及重鏈， 其中恆定結構域CL及CH1、及/或可變結構域VL及 VH可彼此替代。 下文所述「隆凸-孔洞結合（knob-into-hole)」技術之實 例性示意性結構參見圖2a-c。 為改良該等異二聚二價雙特異性抗-ErbB-1/抗-C-Met抗 146954.doc -32- 201039848 體之產率’可藉由「隆凸-孔洞結合」技術來改變該全長 抗體之CH3結構域’該技術以若干實例詳細闡述於（例如） 以下文獻中.WO 96/02701 1 ; Ridgway, J., B.等人， Protein Eng 9 (1996) 617-621 ;及 Merchant, A_，M.等人， Nat Biotechnol 16 (1998) 677-681。在此方法中，改變兩 個CH3結構域之交互作用表面以增強含有該兩個ch3結構 域之兩條重鏈之異二聚作用。兩個CH3結構域（兩條重鏈 ◎ 中）之每一者皆可為「隆凸」，而另一者為「孔洞」。引 入二硫橋可穩定異二聚體（Merchant, A.，M.等人，Nature
Biotech 16 (1998) 677-681 ; Atwell，S.等人，J. Mol. Biol. 270 (1997) 26-35)並提高產率。 因此在本發明一態樣中，該二價雙特異性抗體之特徵另 外在於： 一條重鏈之CH3結構域及另一條重鏈之CH3結構域各自 在包含抗體CH3結構域間之初始介面之介面處相遇； 〇 其中該介面經改變以促進二價雙特異性抗體之形成，其 中該改變之特徵在於： a) —條重鏈之CH3結構域經改變， 從而使得在二價雙特異性抗體内，在遇到一條重鏈 之CH3結構域之初始介面的另一條重鏈之ch3結構域 的初始介面内， 胺基酸殘基經具有較大側鏈體積之胺基酸殘基替 代’從而在一條重鏈之CH3結構域之介面内生成突 出物’其可定位於另一條重鏈之CH3結構域之介面 146954.doc -33- 201039848 内的腔中， 及 b)另一條重鏈之CH3結構域經改變， 從而使得在二價雙特異性抗體内，在遇到第一 CH3 結構域之初始介面的第二CH3結構域之初始介面 内， 胺基酸殘基經具有較小側鏈體積之胺基酸殘基替 代，由此在第二CH3結構域之介面内生成腔，其中 可定位第一 CH3結構域之介面内之突出物。 該具有較大側鏈體積之胺基酸殘基較佳選自由以下組成 之群：精胺酸（R)、苯丙胺酸（F)、酪胺酸（Y)、色胺酸 (W)。 該具有較小側鏈體積之胺基酸殘基較佳選自由以下組成 之群：丙胺酸（A)、絲胺酸（S)、蘇胺酸（T)、纈胺酸（V)。 在本發明一態樣中，兩個CH3結構域進一步發生以下改 變：在各CH3結構域之相應位置引入半胱胺酸（C)作為胺基 酸，從而可在兩個CH3結構域之間形成二硫橋。 在一較佳實施例中，該二價雙特異性抗體在「隆凸鏈」 之CH3結構域中包含T366W突變且在「孔洞鏈」之CH3結 構域中包含T366S、L368A、Y407V突變。亦可藉由（例如） 在「隆凸鏈」之CH3結構域中引入Y349C突變且在「孔洞 鏈」之CH3結構域中引入E356C突變或S354C突變來使用 CH3結構域之間之另一鏈間二硫橋（Merchant, Α·Μ等人， Nature Biotech 16 (1998) 677-681)。因此在另一較佳實施 146954.doc -34- 201039848 例中，該二價雙特異性抗體在兩個CH3結構域中之一者中 包含Y349C、T366W突變且在兩個CH3結構域中之另一者 中包含E356C、T366S、L368A、Y407V突變；或該二價雙 特異性抗體在兩個CH3結構域中之一者中包含Y349C、 T366W突變且在兩個CH3結構域中之另一者中包含 S354C、T366S、L368A、Y407V 突變（一個 CH3 結構域中之 額外Y349C突變與另一 CH3結構域中之額外E356C或S354C 突變形成鏈間二硫橋）（始終根據Kabat之EU索引來編號）。 但或者或另外，亦可使用其他隆凸-孔洞結合技術，如EP 1870459A1所述。該二價雙特異性抗體之較佳實例係：在 「隆凸鏈」之CH3結構域中具有R409D ; K370E突變且在 「孔洞鏈」之CH3結構域中具有D399K ; E357K突變（始終 根據Kabat之EU索引來編號）。 在另一較佳實施例中，該二價雙特異性抗體在「隆凸 鏈」之CH3結構域中包含T366W突變且在「孔洞鏈」之 CH3結構域中包含T366S、L368A、Y407V突變，且另外在 「隆凸鏈」之CH3結構域中包含R409D ; K370E突變並在 「孔洞鏈」之CH3結構域中包含D399K ; E357K突變。 在另一較佳實施例中，該二價雙特異性抗體在兩個CH3 結構域中之一者中包含Y349C、T366W突變且在兩個CH3 結構域中之另一者中包含S354C、T366S、L368A、Y407V 突變；或該二價雙特異性抗體在兩個CH3結構域中之一者 中包含Y349C、T366W突變且在兩個CH3結構域中之另一 者中包含S354C、T366S、L368A、Y407V突變，且另外在 146954.doc -35· 201039848 「隆凸鏈」之CH3結構域中包含R409D ; K370E突變並在 「孔洞鏈」之CH3結構域中包含D399K ; E357K突變。 三價雙特異性形式 本發明之另一較佳態樣係三價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由兩個抗體重鏈及兩個抗 體輕鏈組成之全長抗體；及 b) —個特異性結合人類c-Met之單鏈Fab片段， 其中該b)中之單鏈Fab片段經由該a)中之全長抗體重 鏈或輕鏈C或N端之肽連接物與該全長抗體融合。 下文所述「隆凸-孔洞結合」技術之實例性示意性結構 參見圖5a。 本發明之另一較佳態樣係三價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由兩個抗體重鏈及兩個抗 體輕鏈組成之全長抗體；及 b) —個特異性結合人類c-Met之單鏈Fv片段， 其中該b)中之單鏈Fv片段經由該a)中之全長抗體重鏈 或輕鏈C或N端之肽連接物與該全長抗體融合。 下文所述「隆凸-孔洞結合」技術之實例性示意性結構 參見圖5b。 在一較佳實施例中，該結合人類c-Met之單鏈Fab或Fv片 段經由該全長抗體重鏈C端之肽連接物與該全長抗體融 合。 本發明之另一較佳態樣係三價雙特異性抗體，其包含 a)特異性結合人類ErbB-1且由兩個抗體重鏈及兩個抗 146954.doc -36- 201039848 體輕鏈組成之全長抗體； b) 由以下組成之多肽： ba) 抗體重鏈可變結構域（VH);或 bb) 抗體重鏈可變結構域（VH)及抗體恆定結構域1 (CH1)， 其中該多肽以該VH結構域之N端經由肽連接物與該 全長抗體兩條重鏈中一條之C端融合； c) 由以下組成之多肽： ca) 抗體輕鏈可變結構域（VL)，或 cb) 抗體輕鏈可變結構域（VL)及抗體輕鏈恆定結構域 (CL)； 其中該多肽以該VL結構域之N端經由肽連接物與該 全長抗體兩條重鏈中另一條之C端融合； 且其中該b)中之多肽之抗體重鏈可變結構域（VH)及 該c)令之多肽之抗體輕鏈可變結構域（VL) 一起形成 特異性結合人類C-Met之抗原結合位點。 該等b)及c)中之肽連接物較佳相同且為具有至少25個胺 基酸、較佳介於30與50個胺基酸之間之肽。 實例性示意性結構參見圖3a_c。 視需要藉由在以下位置之間引入二硫鍵經由鏈間二硫橋 來連接及穩定該b)中之多肽之抗體重鏈可變結構域（VH) 及§亥c)中之多肽之抗體輕鏈可變結構域（VL): Ο重鏈可變結構域44位與輕鏈可變結構域ι〇〇位， U)重鏈可變結構域105位與輕鏈可變結構域43位，或 146954.doc •37· 201039848 iii)重鏈可變結構域1 01位與輕鏈可變結構域1 〇〇位（始終 根據Kabat之EU索引來編號）。 引入非天然二硫橋來進行穩定之技術闡述於（例如）以下 文獻中：WO 94/029350、Rajagopal 等人，Prot. Engin. (1997).1453-59 ; Kobayashi，Η·等人，Nuclear Medicine & Biology 25 (1998) 387-393 ;或 Schmidt，M.等人，
Oncogene 18 (1999) 171 1 -1721。在一實施例中，b)及 c)中 之多肽之可變結構域之間的可選二硫鍵介於重鏈可變結構 域44位與輕鏈可變結構域1 〇〇位之間。在一實施例中，b) 及c)中之多肽之可變結構域之間的可選二硫鍵介於重鏈可 變結構域105位與輕鏈可變結構域43位之間（始終根據 Kabat之EU索引來編號）。在一實施例中，在單鏈Fab片段 之可變結構域VH與VL之間未經該可選二硫鍵穩定之三價 雙特異性抗體較佳。 藉由融合單鏈Fab、Fv片段與重鏈中之一者（圖5a或5 b) 或藉由融合不同多肽與全長抗體之兩個重鏈（圖 3 a-c) ’ 獲 得異二聚三價雙特異性抗體。為改良該等異二聚三價雙特 異性抗-ErbB-l/抗-C-Met抗體之產率，可藉由「隆凸-孔洞 結合」技術來改變該全長抗體之CH3結構域，該技術以若 干個實例詳細闡述於（例如）以下文獻中：WO 96/027011 ;
Ridgway，J.B.等人，Protein Eng 9 (1996) 617-621 ;及 Merchant，A.Μ·等人，Nat Biotechnol 16 (1998) 677-681。 在此方法中，兩個CH3結構域之交互作用表面經改變以增 強含有該兩個CH3結構域之兩條重鏈之異二聚化作用。兩 146954.doc -38- 201039848 個CH3結構域（兩條重鏈中）之每一者皆可為「隆凸」，而 另一者為「孔洞」。引入二硫橋可穩定異二聚體 (Merchant, A.M·等人，Nature Biotech 16 (1998) 677-681 ;
Atwell，S.等人，J. Mol. Biol. 270 (1997) 26-35)並提高產 率ο 因此在本發明一態樣中，該三價雙特異性抗體之特徵另 外在於 全長抗體中一條重鏈之CH3結構域及全長抗體中另一條 重鏈之CH3結構域各自在包含抗體CH3結構域之間之初始 介面的介面處相遇； 其中該介面經改變以促進二價雙特異性抗體之形成，其 中該改變之特徵在於： a) —條重鏈之CH3結構域經改變， 從而使得在二價雙特異性抗體内，在遇到一條重鏈 之CH3結構域之初始介面的另一條重鏈之cjj3結構域 的初始介面内， 胺基酸殘基經具有較大側鏈體積之胺基酸殘基替 代，從而在一條重鏈之CH3結構域之介面内生成突 出物’其可定位於另一條重鏈之CH3結構域之介面 内的腔中， 及 b) 另一條重鏈之CH3結構域經改變， 從而使仟在二價雙特異性抗體内，在遇到第一 CH3 結構域之初始介面的第二CH3結構域之初始介面 146954.doc -39- 201039848 内， 胺基酸殘基經具有較小側鏈體積之胺基酸殘基替 代，由此在第二CH3結構域之介面内生成腔，其中 可定位第一 CH3結構域之介面内之突出物。 該具有較大側鏈體積之胺基酸殘基較佳選自由以下組成 之群：精胺酸（R)、苯丙胺酸（F)、酪胺酸（Y)、色胺酸 (W)。 該具有較小側鏈體積之胺基酸殘基較佳選自由以下組成 之群：丙胺酸（A)、絲胺酸（S)、蘇胺酸（T)、纈胺酸（V)。 在本發明一態樣中，兩個CH3結構域進一步發生以下改 變：在各CH3結構域之相應位置引入半胱胺酸（C)作為胺基 酸，從而可在兩個CH3結構域之間形成二硫橋。 在一較佳實施例中，該三價雙特異性抗體在「隆凸鏈」 之CH3結構域中包含T366W突變且在「孔洞鏈」之CH3結 構域中包含T366S、L368A、Y407V突變。亦可藉由（例如） 在「隆凸鏈」之CH3結構域中引入Y349C突變且在「孔洞 鏈」之CH3結構域中引入E356C突變或S354C突變來使用 CH3結構域之間之另一鏈間二硫橋（Merchant, A.M.等人， Nature Biotech 16 (1998) 677-681)。因此在另一較佳實施 例中，該三價雙特異性抗體在兩個CH3結構域中之一者中 包含Y349C、T3 66W突變且在兩個CH3結構域中之另一者 中包含E356C、T366S、L368A、Y407V突變；或該三價雙 特異性抗體在兩個CH3結構域中之一者中包含Y349C、 T366W突變且在兩個CH3結構域中之另一者中包含 146954.doc -40- 201039848 S354C、T3 66S、L368A、Y407V突變（一個 CH3結構域中之 額外Y349C突變與另一 CH3結構域中之額外E356C或S354C 突變形成鏈間二硫橋）（始終根據Kabat之EU索引來編號）。 但或者或另外，亦可使用其他隆凸-孔洞結合技術，如EP 1870459A1所述。該三價雙特異性抗體之較佳實例係：在 「隆凸鏈」之CH3結構域中具有R409D ; K370E突變且在 「孔洞鏈」之CH3結構域中具有D399K ; E357K突變（始終 根據Kabat之EU索引來編號）。 在另一較佳實施例中，該三價雙特異性抗體在「隆凸 鏈」之CH3結構域中包含T366W突變且在「孔洞鏈」之 CH3結構域中包含T366S、L368A、Y407V突變，且另外在 「隆凸鏈」之CH3結構域中包含R409D ; K370E突變並在 「孔洞鏈」之CH3結構域中包含D399K ; E357K突變。 在另一較佳實施例中，該三價雙特異性抗體在兩個CH3 結構域中之一者中包含Y349C、T366W突變且在兩個CH3 結構域中之另一者中包含S354C、T366S、L368A、Y407V 突變；或該三價雙特異性抗體在兩個CH3結構域中之一者 中包含Y349C、T366W突變且在兩個CH3結構域中之另一 者中包含S3 54C、T366S、L368A、Y407V突變，且另外在 「隆凸鏈」之CH3結構域中包含R409D ; K370E突變並在 「孔洞鏈」之CH3結構域中包含D399K ; E357K突變。 本發明之另一實施例係三價雙特異性抗體，其包含 a)特異性結合人類ErbB-Ι且由以下組成之全長抗體： aa)兩個抗體重鏈，其在N端至C端方向上由以下組 146954.doc •41 - 201039848 成：抗體重鏈可變結構域（VH)、抗體重鏈恆定結構 域1 (CH1)、抗體鉸鏈區(HR)、抗體重鏈恆定結構域 2 (CH2)及抗體重鏈恆定結構域3 (CH3);及 ab)兩個抗體輕鏈，其在N端至C端方向上由以下組 成：抗體輕鏈可變結構域（VL)、及抗體輕鏈恆定結 構域（CL) (VL-CL);及 b) —個特異性結合人類c-Met之單鍵Fab片段， 其中該單鏈Fab片段係由抗體重鏈可變結構域（vH)及 抗體恆定結構域1 (CH1)、抗體輕鏈可變結構域 (VL)、抗體輕鏈恆定結構域（Cl)及連接體組成，且 其中該等抗體結構域及該連接體在N端至C端方向上 具有以下順序中之一種： ba)VH-CHl-連接體-VL-CL，或 bb) VL-CL-連接體 _ VH-CH1 ； 其中該連接體係具有至少30個胺基酸、較佳具有介 於32與50個之間之胺基酸的肽； 且其中該b)中之單鏈Fab片段經由該a)中之全長抗體 的重鏈或輕鏈C或N端（較佳位於重鏈C端）之肽連接物 與該全長抗體融合； 其中該肽連接物係具有至少5個胺基酸、較佳具有介 於10與50個之間之胺基酸之肽。 在此實施例中，三價雙特異性抗體較佳在兩個CH3結構 域中之一者中包含T366W突變且在兩個CH3結構域中之另 一者中包含T366S、L368A、Y407V突變，且該二f擁 #雙特 146954.doc -42- 201039848 異性抗體更佳在兩個CH3結構域中之一者中包含Y349C、 T366W突變且在兩個CH3結構域中之另一者中包含 S354C(或 E356C)、T366S、L368A、Y407V突變。在該實 施例中，三價雙特異性抗體視需要在「隆凸鏈」之CH3結 構域中包含R409D ; K370E突變並在「孔洞鏈」之CH3結 構域中包含D399K ; E357K突變。 本發明之另一實施例係三價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由以下組成之全長抗體： aa) 兩個抗體重鏈，其在N端至C端方向上由以下組 成：抗體重鏈可變結構域（VH)、抗體重鏈恆定 結構域1 (CH1)、抗體鉸鏈區（HR)、抗體重鏈恆 定結構域2 (CH2)及抗體重鏈恆定結構域3 (CH3);及 ab) 兩個抗體輕鏈，其在N端至C端方向上由以下組 成：抗體輕鏈可變結構域（VL)、及抗體輕鏈恆 定結構域（CL) (VL-CL);及 b) —個特異性結合人類c-Met之單鏈Fv片段， 其中該b)中之單鏈Fv片段經由該a)中之全長抗體的重 鏈或輕鏈C或N端（較佳位於重鏈C端）之肽連接物與該 全長抗體融合；且 其中該肽連接物係具有至少5個胺基酸、較佳具有介 於10與50個之間之胺基酸之肽。 在此實施例中，三價雙特異性抗體較佳在兩個CH3結構 域中之一者中包含T366W突變且在兩個CH3結構域中之另 146954.doc -43- 201039848 一者中包含T366S、L3 68A、Y407V突變，且該三價雙特 異性抗體更佳在兩個CH3結構域中之一者中包含Y349C、 T366W突變且在兩個CH3結構域中之另一者中包含 S3 54C(或 E3 56C)、T366S、L3 68A、Y407V突變。在該實 施例中，三價雙特異性抗體視需要在「隆凸鏈」之CH3結 構域中包含R409D ; K370E突變並在「孔洞鏈」之CH3結 構域中包含D399K ; E357K突變。 因此一較佳實施例係三價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由以下組成之全長抗體： aa) 兩個抗體重鏈，其在N端至C端方向上由以下組 成：抗體重鏈可變結構域（VH)、抗體重鏈恆定結 構域1 (CH1)、抗體鉸鏈區（HR)、抗體重鏈恆定 結構域2 (CH2)及抗體重鏈恆定結構域3 (CH3); 及 ab) 兩個抗體輕鏈，其在N端至C端方向上由以下組 成：抗體輕鏈可變結構域（VL)、及抗體輕鏈恆定 結構域（CL) (VL-CL);及 b) —個特異性結合人類c-Met之單鏈Fv片段， 其中該b)中之單鏈Fv片段經由該a)中之全長抗體的重 鏈C端之肽連接物與該全長抗體融合（產生兩個抗體 重鏈-單鏈Fv融合肽）；且 其中該肽連接物係具有至少5個胺基酸之肽。 本發明之另一實施例係三價雙特異性抗體，其包含 a)特異性結合人類ErbB-1且由以下組成之全長抗體： 146954.doc -44 - 201039848 aa) 兩個抗體重鏈，其在N端至C端方向上由以下組 成：抗體重鏈可變結構域（VH)、抗體重鏈恆定結 構域1 (CH1)、抗體鉸鏈區（HR)、抗體重鏈恆定 結構域2 (CH2)及抗體重鏈恆定結構域3 (CH3); 及 ab) 兩個抗體輕鏈，其在N端至C端方向上由以下組 成：抗體輕鏈可變結構域（VL)、及抗體輕鏈恆定 結構域（CL);及 b) 由以下組成之多肽： ba) 抗體重鏈可變結構域（VH);或 bb) 抗體重鏈可變結構域（VH)及抗體恆定結構域1 (CH1)， 其中該多肽以該VH結構域之N端經由肽連接物 與該全長抗體兩條重鏈中一條之C端融合（產生 抗體重鏈-VH融合肽），其中該肽連接物係具有 至少5個胺基酸、較佳具有介於25與50個之間之 胺基酸之肽； c) 由以下組成之多肽： ca) 抗體輕鏈可變結構域（VL)，或 cb) 抗體輕鏈可變結構域（VL)及抗體輕鏈恆定結構 域（CL); 其中該多肽以該VL結構域之N端經由肽連接物 與該全長抗體兩條重鏈中另一條之c端融合（產 生抗體重鏈-VL融合肽）； 146954.doc -45- 201039848 其中該肽連接物與b)中之肽連接物相同； 且其中該b)中之多肽之抗體重鏈可變結構域 (VH)及該c)中之多肽之抗體輕鏈可變結構域 (VL)—起形成特異性結合人類c-Met之抗原結合 位點。 在此實施例中，三價雙特異性抗體較佳在兩個CH3結構 域中之一者中包含T366W突變且在兩個CH3結構域中之另 一者中包含T3 66S、L368A、Y407V突變’且該三價雙特 異性抗體更佳在兩個CH3結構域中之一者中包含Y349C、 T366W突變且在兩個CH3結構域中之另一者中包含 S354C(或 E356C)、T366S、L368A、Y407V 突變。在該實 施例中，三價雙特異性抗體視需要在「隆凸鏈」之CH3結 構域中包含R409D ; K370E突變並在「孔洞鏈」之CH3結 構域中包含D399K ; E357K突變。 在本發明另一態樣中，本發明三價雙特異性抗體包含 a) 結合人類ErbB-1且由兩個抗體重鏈VH-CH1-HR-CH2-CH3及兩個抗體輕鏈VL-CL組成之全長抗體； (其中兩個CH3結構域中之一者較佳包含Y349C、 T366W突變且兩個CH3結構域中之另一者包含 S354C(或 E3 56C)、T366S、L368A、Y407V突變）； b) 由以下組成之多肽： ba) 抗體重鏈可變結構域（VH);或 bb) 抗體重鏈可變結構域（VH)及抗體恆定結構域1 (CH1) ’ 146954.doc 46- 201039848 其中該多肽以該VH結構域之N端經由肽連接物 與該全長抗體兩條重鏈中一條之C端融合； c)由以下組成之多肽： ca) 抗體輕鏈可變結構域（VL)，或 cb) 抗體輕鏈可變結構域（VL)及抗體輕鏈恆定結構 域（CL); 其中該多肽以該V L結構域之N端經由肽連接物與 0 該全長抗體兩條重鏈中另一條之C端融合； 且其中該b)中之多肽之抗體重鏈可變結構域 (VH)及該c)中之多肽之抗體輕鏈可變結構域（vl) 一起形成特異性結合人類c_Met之抗原結合位 點。 四價雙特異性形式 在一實施例中，本發明多特異性抗體係四價，其中特異 性結合人類c-Met之抗原結合位點可抑制c_Met二聚化（例 Q 如，如 WO 2009/007427 中所述）。 在本發月實施例中，該抗體係特異性結合人類ErbB_ 1 及人類c-Met之四價雙特異性抗體，其包含兩個特異性結 合人類ErbB-Ι之抗原結合位點及兩個特異性結合人類& Met之抗原結合位點，其中該等特異性結合人類^彻之抗 原結合位點可抑制c_Met二聚化（例如，如w〇 2〇〇9/〇〇7427 中所述）。 因此’本發明另一態樣係四價雙特異性抗體，其包含 a)特異性結合人類卜跑且由兩個抗體重鏈及兩個抗體 146954.doc •47· 201039848 輕鏈組成之全長抗體；及 b)兩個相同的特異性結合ErbB-l之單鏈Fab片段， 其中5亥b)中之單鏈Fab片段經由該a)中之全長抗體的 重鍵或輕鏈C或N端之肽連接物與該全長抗體融合。 因此’本發明另一態樣係四價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由兩個抗體重鏈及兩個抗 體輕鏈組成之全長抗體；及 b) 兩個相同的特異性結合人類c-Met之單鏈Fab片段， 其中該b)中之單鏈Fab片段經由該3)中之全長抗體的❹ 重鏈或輕鏈C4N端之肽連接物與該全長抗體融合。 貫例性不意性結構參見圖6a。 口此，本發明另一態樣係四價雙特異性抗體，其包含 、異I"生、’.Q合1且由兩個抗體重鏈及兩個抗體輕 鍵組成之全長抗體；及 )兩個相同的特異性結合人類c-Met之單鏈Fv片段， ”中。亥b)中之單鏈Fv片段經由該a)中之全長抗體的重 鏈或輕鏈C或N端之肽連接物與該全長抗體融合。 ◎ 口此，本發明另一態樣係四價雙特異性抗體，其包含 )特異丨生結合人類c_Met且由兩個抗體重鏈及兩個抗體 輕鏈組成之全長抗體；及 b)兩個相同的特異性結合ErbB-l之單鏈Fv片段， “中該b)中之單鏈Fv片段經由該a)中之全長抗體的重 鏈或輕鏈C或N端之肽連接物與該全長抗體融合。 實例性示意性結構參見圖6b。 146954.doc -48- 201039848 在一較佳實施例中’該等結合人類c-Met或人類ErbB-1 之單鏈Fab或Fv片段經由該全長抗體重鏈C端之肽連接物與 該全長抗體融合。 本發明之另一實施例係四價雙特異性抗體，其包含 a) 特異性結合人類ErbB-1且由以下組成之全長抗體： aa) 兩個相同抗體重鏈，其在N端至C端方向上由以 下組成：抗體重鏈可變結構域（VH)、抗體重鏈怪 定結構域1 (CH1)、抗體鉸鏈區（HR)、抗體重鏈 恆定結構域2 (CH2)及抗體重鏈恆定結構域3 (CH3);及 ab) 兩個相同抗體輕鏈，其在N端至C端方向上由以 下組成：抗體輕鏈可變結構域（VL)、及抗體輕鏈 恆定結構域（CL) (VL-CL);及 b) 兩個特異性結合人類c_Met之單鏈Fab片段， 其中該等單鏈Fab片段係由抗體重鏈可變結構域（VH) 及抗體恆定結構域1 (CH1)、抗體輕鏈可變結構域 (VL)、抗體輕鏈恆定結構域（CL)及連接體組成，且 其中該等抗體結構域及該連接體在N端至c端方向上 具有以下順序中之一種： ba) VH-CH1-連接體-VL-CL，或 bb) VL-CL-連接體 _ VH-CH1 ； 其中該連接體係具有至少30個胺基酸、較佳具有介 於32與50個之間之胺基酸的肽； 且其中該b)中之單鏈Fab片段經由該a)中之全長抗體 146954.doc • 49· 201039848 的重鏈或輕鏈C或N端之肽連接物與該全長抗體融 合； 其中該肽連接物係具有至少5個胺基酸、較佳具有介 於10與50個之間之胺基酸之肽。 三價或四價形式中所用術語「全長抗體」表示由兩個 「全長抗體重鏈」及兩個「全長抗體輕鏈」組成之抗體 (參見圖1)。「全長抗體重鏈」係在N端至C端方向上由以 下組成之多肽：抗體重鏈可變結構域（VH)、抗體重鏈恆定 結構域1 (CH1 )、抗體狡鏈區（HR)、抗體重鏈怪定結構域2 (CH2)及抗體重鏈恆定結構域3 (CH3)，縮寫為VH_CH1_ ;且在抗體為IgE亞類之情开多下視需要包括抗 體重鏈恆定結構域4 (CH4)。「全長抗體重鏈」較佳為在]^ 端至C端方向上由VH、CHI、HR、CH2及CH3組成之多 肽。「全長抗體輕鏈」係在N端至C端方向上由以下組成 之多肽：抗體輕鏈可變結構域（VL)、及抗體輕鏈惶定結構 域（CL)，縮寫為VL-CL。抗體輕鍵惺定結構域（cl)可為κ (kappa)或λ (lambda)。兩個全長抗體鏈經由cl結構域與 CH1結構域之間及全長抗體重鏈鉸鏈區之間之多肽内二硫 鍵連接在一起。典型全長抗體之實例係天然抗體，例如 IgG(例如 IgGl 及 IgG2)、IgM、IgA、IgD、及 igE。本發明 全長抗體可來自單一物種（例如人類），或其可為後合抗體 或人類化抗體。本發明全長抗體包含兩個各自由VH& VL 對形成之抗原結合位點’二者可特異性結合相同抗原。該 全長抗體重鏈或輕鏈之C端表示該重鏈或輕鏈€端之最後 146954.doc -50- 201039848 一個胺基酸。該全長抗體重鏈或輕鏈之]^端表示該重鏈或 輕鍵N端之最後一個胺基酸。 本發明所用術語「肽連接物」表示胺基酸序列較佳具有 合成來源之肽。使用本發明該等肽連接物來融合單鏈Fab 片段與全長抗體之C或N端以形成本發明多特異性抗體。 較佳地’ b)中之該等肽連接物係胺基酸序列長度為至少5 個胺基酸、較佳長度為5至1〇〇個、更佳為1〇至5〇個胺基酸 之肽。在一實施例中，該肽連接物係（GxS)n或 (GxS)nGm ’其中G=甘胺酸，S=絲胺酸，且（x=3，n=3、 4、5 或 6，且 m=〇、1、2 或 3)或（x=4，n=2、3、4 或 5 且 m=0、1、2或3) ’較佳地χ=4且n=2或3，更佳地x=4， n=2。較佳地，在VH或VH-CH1多肽及VL或VL-C L多肽（圖 7a-c)經由兩個相同肽連接物與全長抗體c端融合之三價雙 特異性抗體中，該等肽連接物係具有至少25個胺基酸之 肽，較佳為具有30至50個胺基酸之肽，且該肽連接物更佳 為（GxS)n或（GxS)nGm ’其中G=甘胺酸，S=絲胺酸，且 (x=3，n=6、7 或 8，且 m=0、1、2 或 3)或（x=4，n=5、6 或 7 且 m=0、1、2 或 3)，較佳地χ=4且 n=5、6、7。 「單鏈Fab片段」（參見圖2a)係由以下組成之多肽：抗體 重鏈可變結構域（VH)、抗體恆定結構域1 (CH1)、抗體輕 鏈可變結構域（VL)、抗體輕鏈恆定結構域（CL)及連接體， 其中該等抗體結構域及該連接體在N端至C端方向上具有 以下順序中之一種：a) VH-CH1-連接體-VL-CL，b) VL-CL-連接體-VH-CH1，c) VH-CL-連接體-VL-CH1 或 d) VL- 146954.doc 51 201039848 CH1-連接體-VH-CL ;且其中該連接體係具有至少3〇個胺 基酸、較佳具有介於32與50個之間之胺基酸的多肽。經由 CL結構域與CH1結構域之間之天然二硫鍵來穩定該等單鏈
Fab 片段 a) VH-CH1-連接體 _VL_CL、b) VL-CL-連接體-VH-CH1、c) VH-CL-連接體 _vl_ch1 及 d) VL-CH1-連接體-VH- CL。術語「N端」表示N端之最後一個胺基酸。術語「c 端」表示C端之最後一個胺基酸。 術語「連接體」在本發明中係結合單鏈Fab片段來使 用’且表示胺基酸序列較佳具有合成來源之肽。使用本發 明該等肽來連接a) VH-CH1與VL-CL、b) VL-CL與VH-CH1、c) VH-CL 與 VL-CH1 或 d) VL-CH1 與 VH-CL，從而形 成以下本發明單鏈Fab片段：a) VH—CH1-連接體-VL-CL、 b) VL-CL-連接體-VH-CH1、c) VH-CL-連接體-VL-CH1 或 d) VL-CH1-連接體- VH-CL。單鏈Fab片段之内之該連接體 係胺基酸序列長度為至少3〇個胺基酸、長度較佳為32至5〇 個胺基酸之肽。在一實施例中，該連接體係（GxS)n，其中 G=甘胺酸’ S =絲胺酸（X =3，n=8、9或10且m=0、1、2或3) 或（x=4且n=6、7或8且m=0、1、2或3)，較佳地x=4，n=6或 7且m-0、1、2或3，更佳地χ=4 ’ n=7且m=2。在一實施例 中’該連接體係（G4S)6G2。 在一較佳實施例中’在該單鏈Fab片段中，該等抗體結 構域及s亥連接體在N端至C端方向上具有以下順序中之一 種· a) VH-CH1-連接體-VL-CL，或 b) VL-CL-連接體-VH- 146954.doc -52- 201039848 CHI，更佳為VL-CL-連接體_VH_CH1。 在另一較佳實施例中’在該單鏈Fab片段中，該等抗體 結構域及該連接體在N端至c端方向上具有以下順序中之 一種： b) VH-CL-連接體-VL-CH1 或 b) VL_Cm-連接體-VH-CL。 視需要，在該單鏈Fab片段中，除Cl結構域與CH1結構 〇 域之間之天然二硫鍵以外，抗體重鏈可變結構域（VH)及抗 體輕鏈可變結構域（VL)亦藉由在以下位置之間引入二硫鍵 而經二硫鍵穩定： 1)重鏈可變結構域44位與輕鏈可變結構域1 〇〇位， η)重鏈可變結構域105位與輕鏈可變結構域43位，或 ill)重鏈可變結構域101位與輕鏈可變結構域100位（始終 根據Kabat之EU索引來編號）。 該單鏈Fab片段之進一步二硫鍵穩定係藉由在單鏈Fab片 Q 段之可變結構域VH與VL之間引入二硫鍵來達成。引入非 天然二硫橋來穩定單鏈Fv之技術闡述於（例如）以下文獻 中：WO 94/029350 ; Rajagopal，V.等人，Pr〇t Engin (1997) 1453-59 ; Kobayashi，Η.等人，Nuclear Medicine &
Biology 25 (1998) 387-393 ;或 Schmidt, M.等人，
Oncogene 18 (1999) 171 1_mi。在一實施例中，本發明抗 體中所包括單鏈Fab片段可變結構域之間之可選二硫鍵介 於重鏈可變結構域44位與輕鏈可變結構域1〇〇位之間。在 一實施例中’本發明抗體中所包括單鏈Fab片段可變結構 146954.doc -53- 201039848 域之間之可選二硫鍵介於重鏈可變結構域105位與輕鍵可 變結構域43位之間（始終根據Kabat之EU索引來編號）。 在一實施例中，在單鏈Fab片段可變結構域VH與VL之間 未經該可選二硫鍵穩定之單鏈Fab片段較佳。 「單鏈Fv片段」（參見圖2b)係由以下組成之多肽：抗體 重鏈可變結構域（VH)、抗體輕鏈可變結構域（VL)、及單 鏈-Fv-連接體’其中該等抗體結構域及該單鏈_Fv_連接體 在N端至C端方向上具有以下順序中之一種：a) vh-單鏈_
Fv-連接體-VL、b) VL-單鏈-Fv-連接體-VH ;較佳為a) vh- ❹ 單鏈-Fv-連接體-VL ’且其中該單鏈_Fv-連接體係胺基酸序 列長度為至少1 5個胺基酸之多肽，在一實施例中長度為至 少20個胺基酸。術語r n端」表示n端之最後一個胺基 酸。術語「C端」表示C端之最後一個胺基酸。 術語「單鏈—Fv-連接體」在用於單鏈Fv片段中時表示胺 基酸序列較佳具有合成來源之肽。該單鏈-Fv-連接體係胺 基酸序列長度為至少1 5個胺基酸、在一實施例中長度為至 少20個胺基酸且長度較佳介於15與3〇個胺基酸之間之肽。〇 在—實施例中，該單鏈-連接體係（GxS)n，其中G=甘胺 酸 ’ S=絲胺酸，（x = ^n=4、5或 6)4(x=：4 且n==3、4、5或 6) ’較佳地χ=4，n=3、4或5，更佳地χ=4，n=3或4。在一 實施例中，該單鏈Fv_連接體係（GAL或
此外，該等單鏈Fv片段較佳經二硫鍵穩定。該單鏈抗體 之進一步二硫鍵穩定係藉由在單鏈抗體之可變結構域之間 引入二硫鍵來達成，且闡述於（例如）以下文獻中：WO I46954.doc -54- 201039848 94/029350 ; Rajagopal，V.等人，pr〇t 如咖 ι〇 (i997) 1453-59 ; Kobayashi，H.等人，Nuclear & Bi〇l〇gy 25 (1998) 387-393 ;或 Schmidt，M.等人，0nc〇gene 18 (1999) 1711 -1721 。 在經二硫鍵穩定之單鏈Fv片段之一實施例中，本發明抗 體中所包括單鏈Fv片段之可變結構域之間之二硫鍵對各單 鏈Fv片段而言獨立地選自： i)重鏈可變結構域44位與輕鏈可變結構域i 〇〇位， 11)重鏈可變結構域105位與輕鏈可變結構域43位，或 iii)重鏈可變結構域1 〇 1位與輕鏈可變結構域i 〇〇位。 在一實施例中，本發明抗體中所包括單鏈Fv片段之可變 結構域之間之一硫鍵介於重鍵可變結構域44位與輕鍵可變 結構域100位之間。 在一實施例中，本發确雙特異性Heri/C-Met抗體可在不 存在HGF時將A431(ATCC編號CRL-1555)癌症細胞增殖抑 制至少3 0%(在48小時後測量，參見實例7a)。 在一實施例中’本發明雙特異性Herl/c-Met抗體可在不 存在HGF時將A431(ATCC編號CRL-1555)癌症細胞增殖抑 制至少30%(在48小時後測量，參見實例7b)。 本發明抗體係藉由重組方式來產生。因此，本發明一態 樣係編碼本發明抗體之核酸，且另一態樣係包含該編碼本 發明抗體之核酸之細胞。用於重組製造之方法廣泛為當前 業内所知且包含在原核及真核細胞中表現蛋白質及隨後分 離抗體以及通常將其純化至醫藥上可接受之純度。對於上 146954.doc -55- 201039848 述抗體在宿主細胞中之表現’藉由標準方法將編碼各經修 飾輕鏈及重鏈的核酸插入表現載體中。在適宜原核或真核 宿主細胞（例如CHO細胞、NS0細胞、SP2/0細胞、HEK293 細胞、COS細胞、PER.C6細胞、酵母或大腸桿菌（E c〇h) 細胞）中進行表現’且自該等細胞（上清液或溶解後細胞）回 收抗體。重組產生抗體之通用方法已為當前業内所熟知且 闡述於（例如）以下綜述文獻中：Makrides, S.C.，Protein
Expr. Purif. 17 (1999) 183-202; Geisse，S.等人，protein
Expr. Purif. 8 (1996) 271-282 ； Kaufman » R.J. , M〇l. 〇 Biotechnol. 16 (2000) 151-161 ； Werner » R.G. » Drug Res. 48 (1998) 870-880 。 藉由習用免疫球蛋白純化程序以適當方式自培養基分離 雙特異性抗體’該等純化程序為（例如）蛋白質A_瓊脂糖 法、羥基磷灰石層析法、凝膠電泳、透析或親和層析法。 編碼單株抗體之DNA及RNA可使用習用程序容易地分離並 測序。可使用雜交瘤細胞作為該〇]^入及RNA之來源。分離 後，可將DNA立即插入表現載體中，隨後將其轉染至原本Ο 不產生免疫球蛋白之宿主細胞（例如Hek 293細胞、CHO細 胞、或骨髓瘤細胞）中以在宿主細胞中實現重組單株抗體 之合成。 藉由將適宜核苷酸變化引入抗體DNA或藉由核苷酸合成 來製備雙特異性抗體之胺基酸序列變體（或突變體）。然 而’僅此在極有限之範圍内（例如上文所述）實施該等修 飾。舉例而言’該等修飾不改變諸如IgG同種型及抗原結 146954.doc -56 - 201039848 合等上述抗體特徵，但可提高重組產生之產率、增強蛋白 質穩定性或有利於純化。 本申請案中所用術語「宿主細胞」表示可經改造以生成 本發明抗體之任何種類的細胞系統。在一實施例中，使用 HEK293細胞及CHO細胞作為宿主細胞。本文所用表述 「細胞」、「細胞系」及「細胞培養物」可互換使用且所 有該等名稱皆包括其子代。因此，詞語「轉化體」及「轉 〇 化細胞」包括原代個體細胞及源自其之培養物而不考慮轉 移次數。亦應瞭解，所有子代之DNA含量可能因特意或無 意的突變而不完全相同。本發明包括最初轉化細胞中經篩 選具有相同功能或生物活性之變體的子代。 在NS0細胞中之表現闡述於（例如）Barnes，L M等人，
Cytotechnology 32 (2000) 109-123 ; Barnes，L.Μ.等人，
Biotech. Bioeng. 73 (2001) 261-270 中。瞬時表現闡述於 (例如）Dur〇Cher，Υ·等人，Nucl_ Acids. Res, 30 (2002) E9 ◎ 中。可變結構域之選殖闡述於以下文獻_ ·· 〇rlandi, R.等 人，Proc. Natl. Acad· Sci. USA 86 (1989) 3833-3837 ; Carter，P.等人，Proc. Natl. Acad. Sci. USA 89 (1992) 4285-4289，及 Norderhaug，L.等人，J· Irnmunol. Methods 204 (1997) 77-87。較佳瞬時表現系統（HEK 293)闡述於 Schlaeger，E.-J.及 Christensen, Κ·，Cytotechnology 30 (1999) 71-83 ’ 及 Schlaeger，E.-J.，J· Immunol. Methods 194 (1996) 191-199 中。 舉例而言，適用於原核生物之控制序列包括啟動子、 146954.doc -57- 201039848 (視需要）操縱子序列、及核糖體結合位點。已知真核細胞 可利用啟動子、增強子及多聚腺苷酸化信號。 當一核酸與另一核酸序列具有功能性關係時，該核酸係 「可操作連接的」。舉例而言，若前序列或分泌前導序列 之DNA表現為參與多肽分泌之前蛋白，則該前序列或分泌 岫導序列之DNA可操作連接至該多肽之DNA ;若啟動子或 增強子可影響編碼序列之轉錄，則該啟動子或增強子可操 作連接至該編碼序列；或若核糖體結合位點之定位有助於 轉譯，則該核糖體結合位點可操作連接至該編碼序列。一 ^ 般而言，「可操作連接」意指所連接DNA序列係鄰接序列 且在分泌前導序列情況下係鄰接序列且處於閱讀框内。然 而，增強子無需鄰接。藉由在便利的限制位點處接合可完 成連接。若不存在該等位點，則根據習用慣例可使用合成 性寡核苷酸銜接子或連接體。 藉由標準技術實施抗體純化以消除細胞組份或其他污染 物（例如其他細胞核酸或蛋白質），該等技術包括驗/sds處 理、CsC丨區帶法、管柱層析法、瓊脂糖凝膠電泳法、及其❹ 他業内熟知方法。參見Ausubel，F等人編輯，
Protocols in Molecular Biology, Greene Publishing and WUey lnterscience，New Y〇rk (1987)。已有多種不同方法 被人們所接受且廣泛用於蛋白質純化’例如使用微生物蛋 白質實施之親和層析（例如蛋白質A或蛋白質G親和層析卜 離子父換層析（例如陽離子交換（羧曱基樹脂）、陰離子交換 (胺基乙基樹脂）及混合型交換）、嗜硫菌吸附（例如使用 146954.doc -58- 201039848 虡基乙醇及其他SH配體）、疏水作用或芳香族吸附層析（例 如使用苯基-瓊脂糖、氮雜-親芳烴（arenophilic)樹脂、或 間-胺基苯基硼酸）、金屬螯合親和層析（例如使用Ni(n)_及 Cu(II)-親和性材料）、尺寸排除層析及電泳方法（例如凝膠 電泳、毛細管電泳）(Vijayalakshmi，M A，Appi Bi〇chem
Biotech. 75 (1998) 93-102)。 本文所用表述「細胞」、「細胞系」及「細胞培養物」 ◎ T互換使用且所有該等名稱皆包括子代。因此，詞語「轉 化體」及「轉化細胞」包括原代個體細胞及源自其之培養 物而不考慮轉移次數。亦應瞭解，所有子代之含量可 月匕口特思或無思的突變而不完全相同。本發明包括最初轉 化、、’田胞中經篩選具有相同功能或生物活性之變體的子代。 倘若意欲使用獨特名稱，則可根據上下文來確定。 本文所用術語「轉化」係指將載體/核酸轉移至宿主細 胞中之過程。若使用不具有牢固細胞壁障壁之細胞作為宿 ◎ 主細胞，則可藉由例如磷酸鈣沉澱法來實施轉染，如
Graham，F.L.及 van der Eb，A.J·，Virology 52 (1973) 456- 467中所述。然而，亦可使用將dNA引入細胞中之其他方 法，例如細胞核注射或原生質體融合。若使用原核細胞或 含有牢固細胞壁構造之細胞，則一種轉染方法係（例如）使 用氯化鈣進行鈣處理，如C〇hen，S., N.等人，PNAS 69 (1972) 21 10-21 14所述。 本文所用「表現」係指將核酸轉錄為之過程及/或 隨後將經轉錄mRNA(亦稱作轉錄物）轉譯為肽、多狀或蛋 146954.doc -59· 201039848 白質之過程。轉錄物及所編碼多肽共稱為基因產物。若多 核苷酸源自基因組DNA，則在真核細胞中之表現可包括 mRNA之剪接。 載體」係核酸分子，具體而言為自主複製的核酸分 子，其將插入核酸分子轉移至宿主細胞中及/或宿主細胞 之間。該術語包括主要用於將DNA或11]^八插入細胞（例如 染色體整合）之載體、主要用於複製DNA或RNA之複製载 體、及用於DNA或RNA轉錄及/或轉譯之表現載體。該術 語亦包括可提供不止一種上述功能之載體。 Γ表現載體」係在引入適宜宿主細胞時可轉錄並轉譯為 多肽之多核苷酸。「表現系統」通常係指包括可用於產生 期望表現產物之表現載體的適宜宿主細胞。 醫藥組合物 本發明之一態樣係包含本發明抗體之醫藥組合物。本發 明另一態樣係本發明抗體用於製造醫藥組合物之用途。本 發明另一態樣係製造包含本發明抗體之醫藥組合物之方 法。在另一態樣中，本發明提供組合物（例如醫藥組合 物）’其含有與醫藥載劑調配在一起之本發明抗體。 本發明一實施例係本發明雙特異性抗體，其用於治療癌 症。 本發明另一態樣係該醫藥組合物，其用於治療癌症。 本發明另一態樣係本發明抗體之用途，其用於製造治療 癌症之藥物。 本發明另一態樣係藉由將本發明抗體投與需要治療之患 146954.doc -60- 201039848 者來治療癌症患者之方法。 本文所用「醫藥載劑」包括任何及所有溶劑、分 質、包衣、抗細菌及抗真菌試劑、等渗劑及吸收延=1 . &生理上相容之類似試劑。較料，载_合於靜脈内；、、 ㈣ '皮下、非經腸、經脊柱或經表皮投與（例如辟 射或輸注稽由注 本發明組合物可藉由多種業内已知方法來投與。熟習此 ❹㈤支術者應瞭解，投與路徑及/或模式可隨期望效果而變 化。為稭由某些投與路徑投與本發明化合物，需要用某種 材料塗佈該化合物或將該化合物與該材料共投與以防^亥 化合物失活。舉例而言’投與個體之化合物可存於適宜載 劑中’例如脂質體或稀釋劑。醫藥上可接受之稀釋劑包括 鹽水及水性緩衝溶液。醫藥载劑包括無菌水性溶液或分散 液及用於臨時製備無菌可注射溶液或分散液之無菌粉劑。 肩等介貝及試劑於醫藥活性物質中之應用為業内已知。 〇 =文所用片語「非經腸投與」&「以非經腸方式投與」 意指除經腸及局部投與以外的投與模式，通常係藉由注射 士投與且包括(但不限於)靜脈内、肌内、動脈内、鞘内、 莢膜内、眼眶内、心内、真皮内、腹膜腔内、經氣管、皮 下、表皮下、關節内、囊下、蛛網膜下、脊柱内、硬膜外 及胸骨内注射及輸注。 、本文所用術語「癌症」係指增殖性疾病，例如淋巴瘤、 淋巴細胞性白Α病、肺癌、非小細胞肺（NSCL)癌、細支氣 g 胞肺癌 '骨癌、騰腺癌、皮膚癌、頭或頸癌、皮 146954.doc •61- 201039848 膚或眼内黑色素瘤、子宮癌、卵巢癌、直腸癌、肛區癌、 月癌（stomach cancer)、胃癌（gastric cancer)、結腸癌、乳 癌、子宮癌、輸卵管癌、子宮内膜癌、子宮頸癌、陰道 癌、陰戶癌、霍奇金病（Hodgkin's Disease)、食道癌、小 腸癌、内分泌系統癌症、甲狀腺癌、曱狀旁腺癌、腎上腺 癌、軟組織肉瘤、尿道癌、陰莖癌、前列腺癌、膀胱癌、 腎臟或輸尿管癌、腎細胞癌、腎盂癌、間皮瘤、肝細胞 癌、膽管癌、中樞神經系統（CNS)贅瘤、脊椎腫瘤、腦幹 膠質瘤、多形性膠質母細胞冑、星形細胞瘤、許旺細胞瘤 (SChwannoma)、室管膜瘤、髓母細胞瘤、腦膜瘤、扁平細 胞癌垂體腺瘤及尤文肉瘤（Ewings sarcoma)，包括任_ 上述癌症之難治性形式，或一或多種上述癌症之組合。 本發明另一態樣係本發明雙特異性抗體或該醫藥組合 物其用作抗血官生成劑。該抗血管生成劑可用於治療癌 症，尤其可用於治療實體腫瘤及其他血管疾病。 本發明一實施例係本發明雙特異性抗體，其用於治療血 管疾病。 ' 本發明另一態樣係本發明抗體用於製造治療血管疾病之 藥物之用途。 ' 本發明另一態樣係藉由向需要治療之患者投與本發明抗 體來治療患有血管疾病之患者的方法。 術5吾「血管疾病」包括癌症、炎症性疾病、動脈粥樣硬 化、缺灰、創傷、敗血病、c〇pD、哮喘、糖尿病、 AMD、現網膜病變、中風、肥胖症、急性肺損傷、出血、 146954.doc 201039848 血管滲漏（例如細胞因子誘導血管滲漏）、過敏症、格雷夫 氏病（Graves' Disease)、橋本自身免疫性甲狀腺炎 (Hashimoto's Autoimmune Thyroiditis)、自發性血小板缺 乏紫斑症、巨細胞動脈炎、類風濕性關節炎、全身性紅斑 狼瘡（SLE)、狼瘡性腎炎、克羅恩氏病（Crohn's Disease)、 多發性硬化症、潰瘍性結腸炎、尤其實體腫瘤、眼内新生 血管型症候群（例如增殖性視網膜病或老年性黃斑退化症 (AMD))、類風濕性關節炎、及銀屑病（Folkman, J.等人，J. 〇
Biol. Chem. 267 (1992) 10931-10934 ; Klagsbrun，M.等 人，Annu. Rev. Physiol. 53 (1991) 217-239 ;及 Garner, A.,
Vascular diseases > Pathobiology of ocular disease, A dynamic approach，Garner，A.及 Klintworth，G. K.(編輯）， 第 2版，Marcel Dekker, New York (1994) 1625-1710)。 該等組合物亦可含有佐劑，例如防腐劑、潤濕劑、乳化 劑及分散劑。可藉由上述消毒程序及藉由引入各種抗細菌 ❹ 及抗真菌劑來確保防止存在微生物’該等抗細菌及抗真菌 劑為（例如）對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸及諸 如此類。亦可期望該等組合物包括等滲劑，例如糖、氯化 鈉及諸如此類。另外，可藉由引入延遲吸收之試劑（例如 單硬脂酸鋁及明膠）來實現可注射醫藥形式之長效吸收。 不管選擇何種投與路徑，可藉由熟習此項技術者已知之 習用方法將可以適宜水合形式使用之本發明化合物及/或 本發明醫藥組合物調配為醫藥上可接受之劑型。 本發明醫藥組合物中活性成份之實際劑量程度可改變， I46954.doc -63- 201039848 以獲侍活性成份可有效地 達成期望仏疼處 特疋心者、組合物及投與模式 運U望/口療反應且對患者旦 決於各種藥代動力學因辛 里。所選劑量程度取 活性、才H 括本發明所用特定組合物之 率、二、：径、投與時間、所用特定化合物之排泄速 率、治療持續時間、盥所用 ^ 物…、 疋化合物組合使用之其他藥 ΓΓ體:及，或材料、所治療患者之年齡、性別、體 知的類—般健康狀況及先前病史、及醫學領域熟 知的類似因素。 組合物之無菌及流動性 L勒性私度應使其可藉由注射器來遞 、’、除水以外’載劑較佳為等渗緩衝鹽水溶液。 例如’可藉由使用諸如卵磁炉莖4十 , 卯H月曰4包衣、藉由在分散物情 形下維持所需粒徑及藉由使 祠r W使用表面活性劑來維持適當流動 性。在許多情形下，組合物中 T孕乂佳匕括專，參劑，例如糖、 多元醇（例如甘露醇或山梨醇）、及氯化鈉。 現在已發現，針對人類ErbB]及人類c_Met之本發明雙 特異性抗體具有有價值的特徵，例如生物或醫藥活性。 提供以下實例、序列表及圖來幫助理解本發明，本發明 之實際範圍陳述於隨附申請專利範圍中。應瞭解，可對各 程序貫施修改而不偏離本發明之精神。 胺基酸序列說明 SEQ ID NO: 1重鏈可變結構域西妥昔單抗 SEQ Π) NO: 2輕鏈可變結構域<ErbB_1；>西妥昔單抗 SEQ ID NO: 3重鏈可變結構人類化ICR62 SEQ ID NO: 4輕鏈可變結構人類化ICR62 146954.doc -64- 201039848 Ο SEQ ID NO: 5 SEQ ID NO: 6 SEQ ID NO: 7 SEQ ID NO: 8 SEQ ID NO: 9 SEQ ID NO: 10 SEQ ID NO: 11 SEQ ID NO: 12 SEQ ID NO: 13 SEQ ID NO: 14 SEQ ID NO: 15 重鏈可變結構域<c-Met> Mab 5D5 輕鏈可變結構域<c-Met> Mab 5D5 重鍵 <c-Met> Mab 5D5 輕鍵 <c-Met> Mab 5D5 重鏈<c-Met> Fab 5D5 輕鏈 <c-Met> Fab 5D5 人類IgGl之重鏈恆定區 人類IgG3之重鏈恆定區 人類輕鏈κ怪定區 人類輕鏈λ十亙定區 人類c-Met SEQ ID NO: 16 人類 ErbB-1 SEQ ID NO·· 17 重鏈CDR3H，<ErbB-l>西妥昔單抗 SEQ ID NO: 18 重鏈 CDR2H，<ErbB-l>西妥昔單抗 SEQ ID NO: 19 重鏈 CDR1H，<ErbB-l> 西妥昔單抗 SEQ ID NO: 20 輕鏈 CDR3L，<ErbB-l>西妥昔單抗 SEQ ID NO: 21 輕鏈 CDR2L，<ErbB-l>西妥昔單抗 SEQ ID NO: 22 輕鏈 CDR1L，<ErbB-l> 西妥昔單抗 SEQ ID NO: 23 重鏈 CDR3H，<ErbB-l> 人類化 ICR62 SEQ ID NO: 24 重鏈 CDR2H，<ErbB-l> 人類化 ICR62 SEQ ID NO: 25 重鏈 CDR1H，<ErbB-l> 人類化 ICR62 SEQ ID NO: 26 輕鏈 CDR3L，<ErbB-l> 人類化 ICR62 SEQ ID NO: 27 輕鏈 CDR2L，<ErbB-l> 人類化 ICR62 SEQ ID NO: 28 輕鏈 CDR1L，<ErbB-l> 人類化 ICR62 146954.doc -65- 201039848 SEQ ID NO: 29 重鏈 CDR3H，^C-Met> Mab 5D5 SEQ ID NO: 30 重鏈 CDR2H，<C-Met> Mab 5D5 SEQ ID NO: 31 重鏈CDR1H，^C-Met> Mab 5D5 SEQ ID NO: 32 輕鏈 CDR3L，^C-Met> Mab 5D5 SEQ ID NO: 33 輕鏈 CDR2L，“-Met> Mab 5D5 SEQ ID NO: 34 輕鏈 CDR1L，“-Met> Mab 5D5 實驗程序 實例 材料及方法 重組DNA技術 使用標準方法來處理，如以下文獻中所述： Sambrook，J.等人，Molecular d〇ning: A laboratory manual ; Cold Spring Harbor Laboratory P^ss, Cold Spring Harbor, New York，1 989。根據製造商說明書來使用分子生物學試 劑。 DNA及蛋白質序列分析及序列資料管理 關於人類免疫球蛋白輕鏈及重鏈核苷酸序列之一般資訊 闡述於以下文獻中：Kabat，E.，A.等人，（1991) Sequences of Proteins of Immunological Interest ’ 第 5版 ’ NIH出版號 91-3242。根據EU編號法對抗體鏈之胺基酸進行編號 (Edelman, G.M·等人，PNAS 63 (1969) 78-85 ; Kabat, E.A. 等人，(1991) Sequences 〇f Proteins of Immunological Interest，第 5版，NIH 出版號 91-3242)。使用 GCG(Genetics Computer Group，Madison ’ Wisconsin)之軟體包（10.2版） 146954.doc -66 - 201039848 及 Infomax之 Vector NTI Advance suite(8.0版）來對序列實 施創建、製圖、分析、注釋及說明。 DNA測序 藉由用 SequiServe (Vaterstetten，Germany)及 Geneart AG (Regensburg，Germany)實施雙鏈測序法來測定DNA之序. 列。 基因合成 藉由 Geneart AG (Regensburg, Germany)自藉由自動化基 f% 因合成產生之合成性募核苷酸及PCR產物來製備期望基因 片段。將兩側具有單數個限制性内切核酸酶裂解位點之基 因片段選殖至pGA18 (ampR)質粒中。質粒DNA係自經轉化 細菌純化且藉由UV光譜法來測定濃度。藉由DNA測序來 確認亞選殖基因片段之DNA序列。以類似方式藉由使用兩 側BamHI及Xbal限制性位點之基因合成來製備DNA序列， 該DNA序列編碼經修飾「隆凸-孔洞結合」<ErbB-l>抗體 q 重鏈，該抗體重鏈在CH3結構域中具有S354C&T366W突 變且具有/不具有藉由肽連接物連接的0端<c-Met>5D5 scFab VH區；以及「隆凸-孔洞結合」〈ΕΑΒ-1〉抗體重 鏈，該重鏈具有Y349C、T366S、L368A及Y407V突變且具
• 有/不具有藉由肽連接物連接之(：端<c-Met>5D5 scFab VL 區。最後，使用兩側BamHI及Xbal限制性位點來合成編碼 <ErbB-l>抗體及<c-Met>5D5抗體之未經修飾重鏈及輕鏈 的DNA序列。所有構成物皆經設計而具有編碼前導肽 (MGWSCIILFLVATATGVHS)之5,端口贴序列’該前導肽 146954.doc •67- 201039848 乾向真核細胞中之分泌蛋白。 表現質粒之構建 使用Roche表現載體來構建編碼所有重鏈及輕鏈scFv融 合蛋白之表現質粒。該載體係由以下元件組成： -作為選擇標記之抗潮黴素基因， 笑潑斯坦-巴爾病毒（Epstein-Barr virus) (EBV)之複製 起點oriP， •來自載體PUC18之複製起點，其容許此質粒在大腸桿 菌中複製， -在大腸桿菌中賦予氨苄西林抗性之β_内醯胺酶基因， _ 來自人類巨細胞病毒（HCMV)之立即早期增強子及啟 動子， -人類1 -免疫球蛋白多聚腺苷酸化（「多聚Α」）信號序 列，及 -獨特的BamHI及Xbal限制性位點。 包含重鏈或輕鏈構成物以及具有C端VH及VL結構域之 「隆凸-孔洞結合」構成物的免疫球蛋白融合基因係藉由 基因合成來製備且將其選殖至所述pGA 1 8 (ampR)質粒中。 用 BamHI及 Xbal 限制性酶（R0che Molecular Biochemicals) 來消化具有合成DNA片段及Roche表現載體之pG18 (ampR) 質粒且實施瓊脂糖凝膠電泳。然後將編碼重鏈及輕鏈之經 純化DNA片段接合至經分離Roche表現載體BamHI/XbaI片 段，從而產生隶終表現載體。將最終表現載體轉化至大腸 才干讀細胞中，分離表現質粒DNA (Miniprep)且對其實施限 146954.doc -68- 201039848 制性酶分析及DNA測序。使正確純系在150 ml LB-Amp培 養基中生長，再次分離質粒DNA (Maxiprep)並藉由DNA測 序來確認序列完整性。 免疫球蛋白變體在HEK293細胞中之瞬時表現 根據製造商說明書藉由使用FreeStyleTM 293表現系統 (Invitrogen，USA)瞬時轉染人類胚腎293-F細胞來表現重組 免疫球蛋白變體。簡言之，在Freestyle™ 293表現培養基 中在37°C/8% C02下培養懸浮FreeStyle™ 293-F細胞，且在 轉染當天將細胞以1-2χ106活細胞/ml之密度接種於新鮮培 養基中。在Opti-MEM® I培養基（Invitrogen，USA)中使用 325 μΐ 293fectin™ (Invitrogen，Germany)及 250 pg 重鏈及 輕鏈質粒DNA以1:1莫耳比及250 ml之最終轉染體積來製備 DNA-293fectin™複合物。在 Opti-MEM® I培養基（Invitrogen， USA)中使用 325 μΐ 293fectinTM (Invitrogen，Germany)及 250 pg「隆凸-孔洞結合」重鏈1及2及輕鏈質粒DNA以1:1:2之 莫耳比及250 ml之最終轉染體積來製備「隆凸-孔洞結合」 DNA-293fectin複合物。在轉染後7天藉由以14000 g離心30 分鐘來收穫含有抗體之細胞培養上清液且經由無菌濾器 (0.22 μπι)過濾。在純化前將上清液儲存在-20°C下。 雙特異性抗體及對照抗體之純化 藉由使用 Protein A-Sepharose™ (GE Healthcare, Sweden) 之親和層析及Superdex200尺寸排除層析自細胞培養上清 液純化三價雙特異性抗體及對照抗體。簡言之，將無菌過 濾細胞培養上清液施加至經PBS緩衝液（10 mM Na2HP〇4、 146954.doc -69- 201039848 1 mM ΚΗ2Ρ〇4、137 mM NaCl 及 2.7 mM KCl，pH 7.4)平衡 之HiTrap ProteinA HP (5 ml)管柱上。用平衡緩衝液洗去 未結合蛋白。用0.1 Μ檸檬酸鹽緩衝液（pH 2.8)洗脫抗體及 抗體變體，且用0.1 ml 1 M Tris (pH 8.5)來中和含有蛋白 質之流份。然後，彙集所洗脫蛋白質流份，用Amicon Ultra離心過濾裝置（MWCO: 30 K，Millipore)濃縮至3 ml體 積並裝載至經20 mM Histidin、140 mM NaCl (pH 6.0)平衡 之 Superdex200 HiLoad 120 ml 16/60凝膠過濾管柱（GE Healthcare, Sweden)上。彙集含有經純化雙特異性抗體及 〇 對照抗體以及低於5%之高分子量凝集體之流份且以1.0 mg/ml之等份儲存於- 80°C下。藉由用木瓜蛋白酶消化經純 化5D5單株抗體且隨後藉由蛋白A層析移除摻雜的Fc結構 域來產生 Fab 片段。在經 20 mM Histidin、140 mM NaCl (pH 6.0)平衡之 Superdex200 HiLoad 120 ml 16/60 凝膠過遽 管柱（GE Healthcare, Sweden)上進一步純化未結合Fab片 段，將其彙集且以1.0 mg/ml等份儲存於-80°C下。 純化蛋白質之分析 Θ 藉由在280 nm下測量光密度（OD)使用基於胺基酸序列計 算出之莫耳消光係數來確定經純化蛋白質樣品之蛋白質濃 度。藉由在存在及不存在還原劑（5 mM 1，4-二硫蘇糖醇）時 使用考馬斯亮藍（Coomassie brilliant blue)染色實施SDS-P AGE來分析雙特異性抗體及對照抗體之純度及分子量。
根據製造商說明書來使用NuPAGE® Pre-Cast凝膠系統 (Invitrogen，USA)(4-20% Tris-甘胺酸凝膠）。在 200 mM 146954.doc -70- 201039848 ΚΗ2Ρ〇4、250 mM KCl (pH 7.0)運行緩衝液中於25°C下使 用Superdex 200分析型尺寸排除管柱（GE Healthcare， Sweden)藉由高效SEC來分析雙特異性抗體及對照抗體樣 品之凝集體含量。以0.5 ml/min之流速將25 pg蛋白質注入 管柱上且經50分鐘實施等度洗脫。對於穩定性分析，將1 mg/ml濃度之純化蛋白質在4°C及40。(：下培育7天且隨後藉 由高效SEC來評估。在藉由用肽-N-糖苷酶F (Roche Molecular Biochemicals)實施酶處理移除N-聚糖後，藉由 奈升電噴霧Q-TOF質譜來驗證經還原雙特異性抗體輕鏈及 重鏈之胺基酸骨架之完整性。 c-Met攝酸化分析 在實施HGF刺激前一天以5xl〇e5/孔將A549細胞接種於6 孔板中之含有0.5% FCS(胎牛血清）之RPMI中。第二天，經 一小時用含有0.2% BSA(牛血清白蛋白）之RPMI替代生長 培養基。然後將5 pg/mL雙特異性抗體添加至培養基中且 將細胞培育10分鐘，之後再經10分鐘以50 ng/mL之終濃度 添加HGF。用含有1 mM釩酸鈉之冰冷PBS將細胞洗滌一 次，之後將其置於冰上並在細胞培養板中用100 pL溶解緩 衝液（50 mM Tris-Cl ρΗ7·5、150 mM NaC卜 1% NP40、 0.5% DOC、抑肽酶、0.5 mM PMSF、1 mM釩酸鈉）進行溶 解。將細胞溶解產物轉移至埃彭道夫（eppendorf)管中並在 冰上使溶解繼續進行30分鐘。使用BCA方法（Pierce)來測 定蛋白質濃度。在4-12% Bis-Tris NuPage 凝膠（Invitrogen) 上分離30-50 pg溶解產物且將凝膠上之蛋白質轉移至硝酸 146954.doc -71 - 201039848 纖維素膜上。用含有5% BSA之TBS-T將膜封閉1小時且根 據製造商說明書用針對Y1230、1234、1235之填酸化特異 性c-Met抗體（44-888, Biosource)進行顯影。用結合未磷酸 化c-Met之抗體（AF276, R&D)再次探測免疫印跡。 ErbBl/Herl磷酸化分析 在添加抗體的前一天以5χ 10e5/孔將A43 1細胞接種於6孔 板中之含有10% FCS(胎牛血清）之RPMI中。第二天’將5 pg/mL對照抗體或雙特異性抗體添加至培養基中且將細胞 再培育1小時。用含有1 mM釩酸鈉之冰冷PB S將細胞洗滌 一次，之後將其置於冰上並在細胞培養板中用100 溶解 缓衝液（50 mM Tris-Cl ρΗ7·5、150 mM NaCl、1% NP40、 0·5°/〇 DOC、抑肽酶、0.5 mM PMSF、1 mM飢酸鈉）進行溶 解。將細胞溶解物轉移至埃彭道夫管中並在冰上使溶解進 行30分鐘。使用BCA方法（Pierce)來測定蛋白質濃度。在4-12% Bis-Tris NuPage凝膠（Invitrogen)上分離 30-50 pg溶解 產物且將凝膠上之蛋白質轉移至硝酸纖維素膜上。用含有 5% BS A之TBS-T將膜封閉1小時且根據製造商說明書用針 對Y1 173之磷酸化特異性EGFR抗體（sc-12351，Santa Cruz) 進行顯影。用結合未填酸化EGFR之抗體（〇6-847，uPstate) 再次探測免疫印跡。 AKT磷酸化分析 在添加抗體的前一天以5 X 10e5/孔將A43 1細胞接種於6孔 板中之含有10% FCS(胎牛血清）之RPMI中。第二天，將5 pg/mL對照抗體或雙特異性抗體添加至培養基中且將細胞 146954.doc -72- 201039848 再培育1小時。然後用25 ng/mL HGF (R&D, 294-HGN)將細 胞亞群再刺激15 min。用含有1 mM釩酸鈉之冰冷PBS將細 胞洗滌一次，之後將其置於冰上並在細胞培養板中用1 00 pL 溶解緩衝液（50 mM Tris-Cl pH7.5、150 mM NaCM、1% NP40、0.5% DOC、抑肽酶、0.5 mM PMSF、1 mM 釩酸鈉） 進行溶解。將細胞溶解物轉移至埃彭道夫管中並在冰上使 溶解進行30分鐘。使用BCA方法（Pierce)來測定蛋白質濃 度。在4-12%Bis-TrisNuPage 凝膠（Invitrogen)上分離 30-50 pg溶解產物且將凝膠上之蛋白質轉移至硝酸纖維素膜上。 用含有5% BSA之TBS-T將膜封閉1小時且根據製造商說明 書用針對Thr308之磷酸化特異性AKT抗體（Cell Signaling, 9275)進行顯影。用結合肌動蛋白之抗體（Abeam，ab20272) 再次探測免疫印跡。 ERK1/2磷酸化分析 在添加抗體的前一天以5xl 0e5/孔將A431細胞接種於6孔 板中之含有10% FCS(胎牛血清）之RPMI中。第二天，將5 pg/mL對照抗體或雙特異性抗體添加至培養基中且將細胞 再培育1小時。然後用25 ng/mL HGF (R&D, 294-HGN)將細 胞亞群再刺激15 min。用含有1 mM鈒酸納之冰冷PBS將細 胞洗滌一次，之後將其置於冰上並在細胞培養板中用100 pL溶解缓衝液（50 mM Tris-Cl ρΗ7·5、150 mM NaCM、1% NP40、0.5% DOC、抑肽酶、0.5 mM PMSF、1 mM釩酸鈉） 進行溶解。將細胞溶解物轉移至埃彭道夫管中並在冰上使 溶解進行30分鐘。使用BCA方法（Pierce)來測定蛋白質濃 146954.doc -73- 201039848 度。在4-12% Bis-Tris NuPage 凝膠（Invitrogen)上分離 30-50 pg溶解產物且將凝膠上之蛋白質轉移至硝酸纖維素膜上。 用含有5% BSA之TBS-T將膜封閉1小時且根據製造商說明 書用針對Thr202/Tyr204之磷酸化特異性Erkl/2抗體 (CellSignaling, Nr.9106)進行顯影。用結合肌動蛋白之抗 體（Abeam，ab20272)再次探測免疫印跡。 細胞-細胞擴散分析（擴散分析） 在化合物處理前一天以200 μΐ^總體積將A549(4000細胞/ 孔）或A43 1(8000細胞/孔）接種於96孔E-板（Roche, 05232368001)中之含有0.5% FCS之RPMI中。用實時細胞 分析機過夜監測細胞黏附及細胞生長，每1 5 min掃描一次 以監測阻抗。第二天，將細胞與5 pL之各抗體稀釋液在 PBS中一起預培育，且每5分鐘掃描一次。在30分鐘後，添 加2.5 μί具有20 ng/mL終濃度之HGF溶液並使實驗繼續再 進行72小時。經1 80分鐘每分鐘掃描一次來監測即時變 化，之後在剩餘時間内每1 5分鐘掃描一次。 流式細胞計數分析（FACS) a)結合分析 分離並計數c-Met及ErbB-Ι表現細胞。以1.5xl0e5/孔將 細胞接種於96孔錐形板中。使細胞旋轉沉降（1 500 rpm， 4°C, 5 min)且在冰上及50 pL各雙特異性抗體存於含有2% FCS(胎牛血清）之PBS中之系歹ij稀釋液中培育30 min。再次 使細胞旋轉沉降並用200 pL含有2% FCS之PBS洗滌一次， 之後再次與在含有2% FCS的PBS中稀釋之針對人類Fc且偶 146954.doc -74- 201039848 合藻紅蛋白之抗體（Jackson Immunoresearch，1091 16098)— 起培育30 min。使細胞旋轉沉降且用200 pL含有2% FCS之 PBS洗滌兩次，使其再懸浮於BD細胞固定溶液（BD Biosciences)中且在冰上培育至少10 min。藉由流式細胞計 數術（FACS Canto，BD)測定細胞之平均螢光強度（mfi)。藉 由至少兩次一式兩份的獨立染色來測定mfi。使用Flow Jo 軟體（TreeStar)進一步處理流式細胞計數譜圖。使用XLFit 4.0 (IDBS)及劑量反應一點式模型205來測定半最大結合。 b)内化分析 分離並計數細胞。將5x10e5個細胞置於埃彭道夫管中之 50 μίν完全培養基中且與5 gg/mL之各雙特異性抗體在37°C 下一起培育。在指定時間點後將細胞儲存在冰上，直至時 程結束。此後，將細胞轉移至FACS管中，旋轉沉降（1500 rpm，4°C，5min) ’ 用 PBS+2% FCS洗滌且與在含有 2% FCS 之PBS中稀釋之50 μι針對人類Fc且偶合藻紅蛋白之第二抗 體（Jackson Immunoresearch，1091 16098) —起培育 30 分鐘。 再次使細胞旋轉沉降’用PBS+2% FCS洗滌並藉由流式細 胞計數術（FACS Canto, BD)測定螢光強度。
Cell Titer Glow分析 使用cell titer glow分析（Promega)來量化細胞活力及增 殖。根據製造商說明書來實施分析。簡言之，在96孔板中 以100 μί之總體積將細胞培養期望時間段。對於增殖分 析’自培育器中移出細胞且將其於室溫下置放3〇 min 〇 添 加100 pL cell titer glow試劑且將多孔板置於定軌振盪器上 146954.doc 75· 201039848 並保持2 min。在15 min後於微量板讀數器（Tecan)上量化 發光。
Wst-Ι分析 根據終點法分析來實施Wst-1活力及細胞增殖分析，從 而檢測代謝活性細胞數。簡言之，將20 μί Wst-Ι試劑 (Roche，1 1644807001)添加至200 pL培養基中。將96孔板 再培育30 min至1 h直至染料顯著顯影。在微量板讀數器 (Tecan)上於45 0 nm波長下量化染色強度。 雙特異性<£1^丑1-卜]\161>抗體之設計 以下所表現及純化之所有雙特異性<ErbB 1 -c-Met>抗體 皆包含IgGl亞類之恆定區或至少Fc部分（SEQ ID NO: 11之 人類IgGl恆定區），其最後如下文所述經修飾。 在表1中：已經或可根據上述通用方法來表現並純化三 價雙特異性<ErbBl-c-Met>抗體，其係基於全長ErbB-Ι抗 體（西妥昔單抗或人類化ICR62)及一個來自C-Met抗體 (cMet 5D5)之單鏈Fab片段（基本結構示意圖參見圖5a)，且 具有表1中所示之各特徵。西妥昔單抗或人類化ICR62之相 應VH及VL闡述於序列表中。 146954.doc 76- 201039848 表1 : 分子名稱 雙特異性抗體之scFab-Ab-命名 BsABOl BsAB03 特徵: 隆凸-孔洞結合突變 S354C: T366W/ Y349'C: T366'S: L368'A: Υ407Ύ S354C: T366W/ Y349'C: T366'S: L368'A: Υ407Ύ 全長抗體骨架源自： 西妥昔單抗 人類化ICR62 單鏈Fab片段，源自： cMet 5D5 (人類化） cMet 5D5 (人類化） 附接至抗體之scFab之位置 C端隆凸重鏈 C端隆凸重鏈 連接體(ScFab) (g4s)5gg (g4s)5gg 肽連接物 (G4S)2 (G4s)2 ScFab 二硫鍵 VH44/VL100穩定 - 實例1 : 雙特異性抗體與ErbB-Ι及c-Met之結合 (表面電漿共振） 使用標準結合分析在25°C下測定結合親和力，例如表面 電聚共振技術（BIAcore®，GE-Healthcare Uppsala, Sweden)。 對於親和力測量，在SPR儀器（Biacore T100)上藉由標準胺 偶合及封阻化學方法使30 pg/ml抗Fey抗體（來自山羊， Jackson Immuno Research)偶合至CM-5感受器晶片表面。 在偶聯後，在25°C下以5 pL/min之流速注入單或雙特異性 ErbB Ι/cMet抗體且隨後以30 pL/min注入人類ErbB 1或c-Met ECD之連續稀釋液（0 nM至1000 nM)。使用PBS/0.1% BSA作為結合實驗之運行緩衝液。然後用1〇 mM甘胺酸- 146954.doc • 77· 201039848 HCl (pH 2.0)溶液之60s脈衝使晶片再生。 表：如藉由表面電漿共振所測定之雙特異性抗體結合 ErbBl/cMet之結合特徵。 結合特異性 BsABOl 『Moll c-Met ka(l/Ms) l,10E+04 kd (1/s) 5,80E-05 KD(M) 5,50E-09 ErbB-1 ka (1/Ms) l,54E+06 kd (1/s) 8,84E-04 KD(M) 5,75E-10 實例2 : 雙特異性Herl/c-Met抗體形式對HGF誘導c-Met受體磷酸 化之抑制 為確認雙特異性Herl/c-Met抗體中c-Met部分之功能性， 實施c-Met磷酸化分析。在此實驗中，用雙特異性抗體或 親代對照抗體處理A549肺癌細胞或A43 1結直腸癌細胞， 之後暴露於HGF中。親代抗體或雙特異性抗體之結合可導 致對受體磷酸化之抑制。或者，亦可使用具有自分泌HGF 環之細胞（例如U87MG)且在存在或不存在親代抗體或雙特 異性抗體時評價c-Met受體磷酸化。 實例3 : 在用Herl/cMet雙特異性抗體處理後分析Herl受體磷酸化 為確認雙特異性Herl/cMet抗體中EGFR結合部分之功能 性，將A431與親代EGFR抗體或雙特異性Herl/cMet抗體一 146954.doc •78- 201039848 起培育。親代抗體或雙特異性抗體而非無關IgG對照抗體 之結合可導致受體磷酸化之抑制。或者，亦可在存在或不 存在親代抗體或雙特異性抗體時使用經EGF刺激可誘導 ErbB 1 /Her 1受體鱗峻化之細胞。 實例4 : 在用Herl/cMet雙特異性抗體處理後分析pi3IC信號傳導 EGFR以及c-Met受體可經由PI3K途徑傳導信號，該途徑 傳遞促有絲分裂信號。為證實同時靶向EGFR及c-Met受 體’可監測AKT之磷酸化，其係PI3K途徑中之下游靶。出 於此目的’將未經刺激細胞、經EGF或HGF處理之細胞、 或經兩種細胞因子處理之細胞並行地與非特異性親代對照 抗體或雙特異性抗體一起培育。或者，亦可評價過表現 ErbBl/Herl及/或具有自分泌HGF環之細胞，該HGF環可活 化c-Met信號傳導。AKT係PI3K途徑中之主要下游信號傳 導組份，且此蛋白質之磷酸化係經由此途徑傳導信號之關 鍵指示。 實例5 : 在用Herl/cMet雙特異性抗體處理後分析MAPK信號傳導 ErbBl/Herl及c-Met受體可經由MAPK途徑傳導信號。為 證實靶向ErbBl/Herl及c-Met受體，可監測ERK1/2之磷酸 化，其係MAPK途徑中之主要下游靶。出於此目的，將未 經刺激細胞、經EGF或HGF處理之細胞、或經兩種細胞因 子處理之細胞並行地與非特異性親代對照抗體或雙特異性 抗體一起培育。或者，亦可評價過表現ErbBl/Herl及/或具 146954.doc -79- 201039848 有自分泌HGF環之細胞，該HGF環可活化c-Met信號傳導。 實例6 : 雙特異性Herl/c-Met抗體形式對HGF誘導HUVEC增殖之 抑制 可實施HUVEC增殖分析來證實HGF之血管生成及促有絲 分裂效應。向HUVEC中添加HGF可導致細胞增殖增強，此 可由c-Met結合抗體以劑量依賴性方式來抑制。 實例7 : 雙特異性Herl/c-Met抗體對A431增殖之抑制 a) A43 1細胞顯示Herl之高細胞表面含量及c-Met之中高 細胞表面表現，如流式細胞計數術所獨立地確認。在48小 時後，在CellTiterGlowTM分析中測量雙特異性Herl/c-Met 抗體對A431增殖之抑制。結果展示於圖8a中。對照為PBS 緩衝液。 第二次測量顯示EGFR抗體西妥昔單抗之29%抑制（與設 定為0°/。抑制之緩衝液對照相比）。雙特異性Herl/c-Met BsABOl (BsAb)抗體對癌症細胞增殖產生更顯著之抑制 (38%抑制）。單價c-Met抗體單臂5D5 (OA5D5)顯示對增殖 無任何影響。EGFR抗體西妥昔單抗及單價c_Met抗體單臂 5D5 (OA5D5)之組合產生顯著性較低之降低（2〇%抑制）。 b) A43 1主要依賴於EGFR信號傳導《為模擬出現活性 EGFR _ c-Met-受體信號傳導網絡之情景，根據勾中所述在 經HGF調整之培養基存在下實施進一步增殖分析（在48小 時後實施CellTiterGlowTM分析）。結果展示於圖8b中。 146954.doc -80- 201039848 第二次測量顯示，EGFR抗體西妥昔單抗（0%抑制）及單 價c-Met抗體單臂5D5 (OA5D5)(l%抑制）幾乎沒有抑制效 應。雙特異性Herl/c-Met抗體BsABOl (BsAb)(39%抑制）顯 示可顯著抑制A43 1細胞之癌症細胞增殖。EGFR抗體西妥 昔單抗與單價c-Met抗體單臂5D5 (OA5D5)之組合以顯著性 較低之程度使細胞增殖降低（20%抑制）。 實例8 : 分析在癌細胞系DU145中雙特異性Herl/c-Met抗體形式對 HGF誘導細胞-細胞擴散（擴散）之抑制 HGF誘導擴散誘導細胞之形態改變，從而導致細胞變 圓、細胞產生偽足樣突出、紡錘體樣結構及獲得一定運動 性。雙特異性Herl/cMet抗體抑制HGF誘導之細胞-細胞擴 散。 實例9 : 在表現ErbB-Ι及c-Met之癌細胞系中分析抗體介導之受體 内化 已顯示將細胞與特異性結合Her 1或c-Met之抗體一起培 育可誘發受體内化。為評價雙特異性抗體之内化能力，將 實驗設置設計為研究抗體誘導之受體内化。出於此目的， 在37°C下將OVCAR-8細胞（NCI細胞系名稱；購自NCI(國 家癌症研究所）〇VCAR-8-NCI ; Schilder RJ等人，Int J Cancer. 1990 年 3 月 15 日；45(3):416-22 ; Ikediobi ON 等 人，Mol Cancer Ther. 2006 ; 5 ; 2606-12 ; Lorenzi, P.L.等 人，Mol Cancer Ther 2009 ; 8(4):713-24)(其表現Herl 以及 146954.doc -81 · 201039848 c-Met，如藉由流式細胞計數術所確認-參見圖7b)與各_級 抗體一起培育不同時間段（例如0、30、60、120分鐘吲、 0.5、1、2小時（h))。藉由將細胞快速冷卻至4°C來终止細 胞過程。使用特異性結合一級抗體Fc之二級螢光體偶合抗 體來檢測與細胞表面結合之抗體。抗體-受體複合物之内 化耗盡了細胞表面之抗體-受體複合物且導致平均螢光強 度降低。在Ovcar-8細胞中研究内化。結果展示於下表及 圖9中。經由各抗體之内化來測量各受體之内化°/〇(在圖9 中，雙特異性 <ErbBl-cMet> 抗體 BsABOl 稱作 cMet/HERl， 親代單特異性二價抗體稱作<HER1 >及<cMet>)。 表：在2小時（2 h)後在OVCAR-8細胞上，使用FACS分析測 量之雙特異性Her Ι/cMet抗體與親代單特異性二價c-Met抗 體之c-Met受體内化％的比較。將在〇 h(=不存在抗體時）細 胞表面上c-Met受體之測量％設定為細胞表面上C-Met受體 之 100%。 抗體 在2 h後測量之在2 h後’OVCAR-8細胞上c_Met OVCAR-8細胞表 之内化％ 面上c-Met受體之 （ATCC編號CRL-1555) % (=100-細胞表面上之抗體％) A)單特異性 <〇1^技>親代抗體
Mab 5D5 54 44 B)雙特異性<£出61-cMet>抗體
BsABOl 114 -η 146954.doc -82- 201039848 實例ίο 雙特異性Herl/c-Met抗體之糖改造形式之製備 在MPSV啟動子及合成性多聚A位點上游之控制下將雙 特異性Herl/c-Met抗體之DNA序列亞選殖至哺乳動物表現 載體中，各載體具有EBVOriP序列。 雙特異性抗體係使用磷酸鈣轉染方法藉由用哺乳動物雙 特異性抗體表現載體共轉染HEK293-EBNA細胞來產生。 藉由磷酸鈣方法來轉染指數性生長之HEK293-EBNA細 胞。對於糖改造抗體之產生，用兩種額外質粒共轉染細 胞，一種用於融合GnTIII多肽表現（GnT-III表現載體），且 一種用於甘露糖苷酶Π表現（高爾基體甘露糖苷酶II表現載 體），其比率分別為4:4:1:1。在T燒瓶中使用補加有10% FCS之DMEM培養基使細胞以黏附單層培養物形式生長， 且在其鋪滿50%至80%時進行轉染。對於T150燒瓶之轉 染，在轉染前24小時將1·5χ107個細胞接種於25 ml補加有 FCS(最終濃度為10% V/V)之DMEM培養基中，且將細胞在 3 7°C下於具有5% C02氣氛之培育器中置放過夜。對於欲轉 染之各T150燒瓶，藉由混合94 pg總質粒載體DNA(輕鏈與 重鏈表現載體各一半）、終體積為469 μΐ之水及469 μΐ 1 Μ CaCl2溶液來製備DNA、CaCl2與水之溶液。向此溶液中添 加 938 μΐ 50 mM HEPES、280 mM NaCl、1.5 mM Na2HP04 溶液（pH 7.05)，立即混合10秒且在室溫下靜置20秒。用10 ml補加有2% FCS之DMEM稀釋懸浮液，且將其添加至 T150中來代替已有培養基。然後添加另外13 ml轉染培養 146954.doc -83- 201039848 基。在37°C及5% C02下將細胞培育約17至20小時，然後將 培養基替換為25 ml DMEM，10% FCS。在轉染後第7天藉 由以21〇xg離心15 min來收穫經調整培養基，對溶液實施 無菌過濾（0.22 μιη濾器）且以0.01% w/v之終濃度添加疊氮 化鈉，並保持在4°C下。 所分泌非岩藻糖化雙特異性糖改造抗體係藉由以下方式 來純化：實施蛋白A親和層析，之後實施陽離子交換層 析，且最後在 Superdex 200 管柱（AmershamPharmacia)上實 施尺寸排除層析步驟，且將緩衝液更換為2 5 mM磷酸鉀、 125 mM氯化鈉、100 mM甘胺酸溶液（pH 6.7)並收集純淨的 單體IgGl抗體。使用分光光度計根據在280 nm下之吸光度 來估計抗體濃度。 藉由所述MALDI/TOF-MS來分析附接至抗體Fc區域之募 糖。藉由PNGaseF消化自抗體酶促釋放寡糖，其中使抗體 固定在PVDF膜上或固定在溶液中。所得含有所釋放寡糖 之消化溶液直接經製備用於MALDI/TOF-MS分析，或經 EndoH糖苷酶進一步消化，之後製備為用於MALDI/TOF-MS分析之樣品。 實例11 雙特異性Herl/c-Met抗體糖結構之分析 為確定含有岩藤糖與非岩藻糖（無岩澡糖）之寡糖結構之 相對比率，藉由MALDI-Tof-質譜法來分析純化抗體材料 之經釋放聚糖。為此，在37°C下將抗體樣品（約50 pg)與存 於0.1 Μ磷酸鈉緩衝液（pH 6.0)中之5 mU N-糖苷酶 146954.doc -84- 201039848 F(Prozyme編號GKE-5010B)—起培育過夜，以自蛋白質骨 架中釋放募糖。隨後，使用NuTip-Carbon吸量管管嘴（得 自 Glygen: NuTipl-ΙΟ μ1，目錄Nr編號 NT1CAR)》離所釋 放聚糖結構並進行除鹽。在第一步驟中，藉由依次用3 1 M NaOH、20 pL純水（例如得自Baker之HPLC梯度級，編 號4218)、3 pL 3 0% v/v乙酸及20 μΐ純水（同上）洗滌來準備 NuTip-Carbcm吸量管管嘴以供結合寡糖。為此，將各溶液 裝載至NuTip-Carbon吸量管管嘴中之層析材料頂部且加壓 使其經過管嘴。此後，藉由將上述N-糖苷酶F消化物上下 抽吸四至五次來使對應於1〇料抗體之聚糖結構結合至 NuTip-Carbon吸量管管嘴中之材料上。以上述方式用2〇 μί純水洗滌與NuTip-Carbon吸量管管嘴中之材料結合之聚 糖，且分別用0.5 μί 10%及2.0 pL 20%乙腈逐步洗脫。在 此步驟中，將各洗脫溶液填充於0.5 mL反應容器中且各自 上下抽吸四至五次。合併兩種洗脫液以供藉由MALDI-Tof 質譜法來分析。在此測量中，在MALDI靶上混合0.4 pL經 合併洗脫液與1.6 pL SDHB基質溶液（2.5-二羥基苯甲酸/2-羥基-5-曱氧基苯曱酸[61'111<^〇31仂1^8編號209813]，以5 mg/ml溶於20%乙醇/5 mM NaCl中）且用經適當調整之 Bruker Ultraflex TOF/TOF儀器加以分析。以例行方式記錄 單次實驗之50-300次脈衝並進行加和。藉由flex分析軟體 (Bruker Daltonics)評估所得譜圖並確定所檢測各峰之質 量。隨後，藉由比較各結構（例如分別具有或不具有岩藻 糖之複雜結構、雜合體結構及寡-或高-甘露糖結構）質量之 146954.doc -85- 201039848 藻糖或無岩藻糖 汁算值與理論預期值來將各峰分為含有岩 (非岩藻糖）之聚糖結構。 為確定雜合體結構之比率，同時㈣娜酶 切酶Η消化抗體樣品1姻酶F自蛋白質骨架釋放所有 連接聚糖結構（複雜結構、雜合體結構及寡及高甘露糖 結構），且糖皆内切酶Η另外在聚糖還原端之兩個仙版 殘基之間裂解所有雜合體型聚糖。隨後藉由缝附_ 譜法以與上述用於N_糖苷_F消化樣品相 分析該消化物。藉由比較N_糖苦酶F消化物與經 苷酶F/内切酶Η消化物之模式’使用指定糖結構之信號的 降低程度來估計雜合體結構之相對含量。 根據個別糖結構峰高度與所檢測所有糖結構峰高度之和 之比來計算各種糖結構之相對含量。岩藻糖含量係含岩藻 糖結構相對於Ν-糖苷酶F處理樣品中所鑒定所有糖結構（分 別例如複雜結構、雜合體結構及募-及高-甘露糖結構）之百 分比。非岩藻糖化程度係無岩藻糖結構相對於Ν·糖苦酶F 處理樣品中所鑒定所有糖結構（分別例如複雜結構、雜合 體結構及寡-及高-甘露糖結構）之百分比。 實例12 : 在用Herl/cMet雙特異性抗體處理後分析細胞遷移 活性c-Met信號傳導之一重要態樣係誘導遷移及侵入程 序。c-Met抑制性抗體之效能可藉由測量對HGF誘導細胞 遷移之抑制來確定。出於此目的，在不存在或存在雙特異 性抗體或IgG對照抗體時用HGF處理HGF可誘導癌細胞系 146954.doc • 86- 201039848 A431，且在Acea實時細胞分析儀上使用具有阻抗讀數器之 CIM板以時間依賴性方式測量穿過8 μιη管孔之遷移細胞 數。 實例13
雙特異性Herl/c-Met抗體之體外ADCC 本發明Herl/cMet雙特異性抗體在表現兩種受體之細胞 上顯示降低之内化（與相應單特異性親代c-Met抗體相比）。 内化降低強有力地支持對該等抗體進行糖改造之理論，此 乃因延長抗體-受體複合物在細胞表面上之暴露時間使得 更有可能被Nk細胞所識別。内化降低及糖改造可理解為抗 體依賴性細胞毒性（ADCC)相對於親代抗體有所增強。證 實該等效應之體外實驗設置可設計為使用在細胞表面上表 現Herl及cMet二者之癌細胞（例如A43 1)及效應子細胞（例 如Nk細胞系或PBMC細胞系）。使腫瘤細胞與親代單特異性 抗體或雙特異性抗體一起預培育最多24 h，之後添加效應 子細胞系。量化細胞溶解且使得可辨別單-與雙特異性抗 體。 用胰蛋白酶/EDTA(Gibco編號25300-054)收集指數生長 期之靶細胞（例如PC-3，DSMZ編號ACC 465，前列腺腺 癌，在Ham's F12營養混合物+2 mM L-内醯胺基-L-麩胺酿 胺+ 10% FCS中培養）。在實施洗滌步驟並檢查細胞數量及 活力後，在37°C下於細胞培育器中用約黃綠素（Invitrogen 編號C3 100MP ;在1個小瓶中，鈣黃綠素再懸浮於50 μΐ DMS0中，可用於標記存於5 ml培養基中之5χ106個細胞） 146954.doc -87- 201039848 將所需等份樣品標記30 min。此後，用AIM-V培養基將細 胞洗滌三次，檢查細胞數量及活力並將細胞數量調整至 3xl05/ml ° 同時，根據製造商方案（洗滌步驟：1><400 §及2<3 50 §， 每次10 min)藉由密度梯度離心法（Histopaque-1077，Sigma 編號H8 889)來準備作為效應子細胞之PBMC。檢查細胞數 量及活力並將細胞數量調節至1.5 X 107/ml。 將100 μΐ經鈣黃綠素染色之靶細胞平鋪於圓底96孔板 中，添加50 μΐ經稀釋抗體及50 μΐ效應子細胞。在某些實 驗中將把細胞與Redimune® NF液體（ZLB Behring)混合， 濃度為 1 〇 mg/ml Redimune。 使用自發溶解作為對照，其係藉由在不存在抗體之情形 下共培養靶細胞及效應子細胞來測定；且使用最大溶解作 為對照，其係僅藉由把細胞之1% Triton X-100溶解來測 定。在3 7°C下於加濕細胞培育器中將板培育4小時。 根據製造商說明書使用細胞毒性檢測套組（LDH檢測套 組，Roche編號1 644 793)藉由測量自受損細胞釋放之LDH 來評價靶細胞之殺滅。簡言之，將1 00 μΐ來自各孔之上清 液與1 〇〇 μΐ來自套組之受質於透明平底96孔板中混合。在 ELISA讀數器中於490 nm下經至少10 min測定受質顏色反 應之Vmax值。如下所述計算特定抗體介導殺滅百分比： ((A-SR)/(MR-SR)xlOO，其中A係在特定抗體濃度下之平均 Vmax，SR係自發釋放之平均Vmax且MR係最大釋放之平 均 Vmax。 146954.doc -88 - 201039848 實例14 雙特異性Herl/cMet抗體在具有旁分泌HGF環之皮下異種 移植模型中之體内效能 經Mrc-5細胞共注射之皮下A549模型模擬c-Met之旁分泌 活化環。A549在細胞表面上表現c-Met以及Herl。將A549 及Mrc-5細胞在標準細胞培養條件下維持於對數生長期。 以10:1之比注射A549及Mrc-5細胞，且將lxl〇7個A549細胞 及1 X 106個Mrc-5細胞移植入SCID米色鼠中。在出現腫瘤且 尺寸到達100-150 mm3後開始處理。用20 mg/kg(抗體/小 鼠）之負荷劑量處理小鼠，且隨後每週一次用1 〇 mg/kg(抗 體/小鼠）處理。每週兩次測量腫瘤體積且並行監測動物體 重。比較單一處理及單一抗體之組合與使用雙特異性抗體 之治療。 實例15 雙特異性Herl/cMet抗體在具有旁分泌HGF環之皮下異種 移植模型中之體内效能 經Mrc-5細胞共注射之皮下A43 1模型模擬c_Met之旁分泌 活化環。A43 1在細胞表面上表現c-Met以及Herl。將A43 1 及Mrc-5細胞在標準細胞培養條件下維持於對數生長期。 以10:1之比注射A431及Mrc-5細胞’且將lxl〇7個A43i細胞 及lx 106個Mrc-5細胞移植入SCID米色鼠中。在出現腫瘤且 尺寸到達100-150 mm3後開始處理。用2〇 mg/kg(抗體/小 鼠）之負荷劑量處理小鼠，且隨後每週一次用1〇 mg/kg(抗 體/小鼠）處理。每週兩次測量腫瘤體積且並行監測動物體 146954.doc •89- 201039848 重。比較單一處理及單一抗體之組合與使用雙特異性抗體 之治療。 實例16 雙特異性Herl/cMet抗體對Ovcar-8增殖之抑制 a) Ovcar-8細胞顯示Her 1之高細胞表面含量及c-Met之中 高細胞表面表現，如流式細胞計數術所獨立地確認。在48 小時後，在CellTiterGlowTM分析中測量雙特異性Herl/cMet抗體對 Ovcar-8 增殖之 抑制。 結果展 示於圖 1 0a 中 。對 照為PBS缓衝液。 EGFR抗體西妥昔單抗未顯示抑制（與設定為0°/。抑制之緩 衝液對照相比）。雙特異性Herl/c-Met BsABOl (BsAb)抗體 對癌症細胞增殖產生較小但顯著之抑制（8%抑制）。單價c-Met抗體單臂5D5 (OA5D5)對增殖未顯示任何效應。EGFR 抗體西妥昔單抗與單價c-Met抗體單臂5D5 (OA5D5)之組合 幾乎不降低增殖（2%抑制）。 b) 可用HGF進一步刺激Ovcar-8。為模擬出現活性EGFR -c-Met-受體信號傳導網絡之情景，根據a)中所述在經HGF 調整之培養基存在下實施進一步增殖分析（在48小時後實 施CellTiterGlowTM分析）。結果展示於圖10b中。
添加HGF可導致增殖增強（10%)。與僅用HGF處理之細 胞（其設定為〇%抑制）相比，EGFR抗體西妥昔單抗以及單 價c-Met抗體單臂5D5 (OA5D5)僅對增殖顯示較小抑制效應 (2%、7%)。雙特異性Herl/c-Met抗體BsABOl (BsAb)( 15% 抑制）顯示可顯著抑制〇vcar-8細胞之癌症細胞增殖。EGFR 146954.doc •90- 201039848 抗體西妥昔單抗與單價c-Met抗體單臂5D5 (OA5D5)之組合 以顯著性較低之程度使細胞增殖降低（10%抑制）。 【圖式簡單說明】 圖1 不含CH4結構域之全長抗體的示意性結構，其可 以兩對重鏈及輕鏈特異性結合第一抗原1，該等 重鏈及輕鏈以典型順序包含可變結構域及恆定 結構域。 圖2a-c二價雙特異性<ErbB-l/c-Met^^體之示意性結 構，其包含：a)全長抗體中特異性結合人類 ErbB-Ι之輕鏈及重鏈；及b)全長抗體中特異性結 合人類c-Met之輕鏈及重鏈，其中恆定結構域CL 及CH1、及/或可變結構域VL及VH彼此替代，該 等鍵經隆凸-孔洞結合技術修飾。 圖3 本發明三價雙特異性<ErbB-l/c-Met>抗體之示意 圖，其包含特異性結合ErbB-Ι之全長抗體，該 全長抗體上融合有 a) 圖3a:兩個多肽VH及VL(VH及VL結構域二 者一起形成特異性結合c-Met之抗原結合位點）； b) 圖3b:兩個多肽VH-CH1及VL-CL(二者中之 VH及VL結構域一起形成特異性結合c-Met之抗 原結合位點）； 圖3c :本發明三價雙特異性抗體之示意圖，其 包含特異性結合ErbB-Ι之全長抗體，該全長抗 體上融合有兩個多肽VH及VL(VH及VL結構域二 146954.doc -91 - 201039848 者一起形成特異性結合c-Met之抗原結合位點）且 具有「隆凸及孔洞」； 圖3d :本發明三價雙特異性抗體之示意圖，其 包含特異性結合ErbB-Ι之全長抗體，該全長抗 體融合有兩個多肽VH及VL(VH及VL結構域二者 一起形成特異性結合c-Met之抗原結合位點，其 中該VH及VL結構域在VH44位與VL100位之間包 含鏈間二硫橋）且具有「隆凸及孔洞」。 圖4 4a ··四種可能的單鏈Fab片段之示意性結構 4b ··兩種單鏈F v片段之示意性結構 圖5 三價雙特異性〈ErbB-l/c-Met：^^體之示意性結 構，其包含全長抗體及一個單鏈Fab片段（圖5a) 或一個單鏈Fv片段（圖5b)-具有隆凸及孔洞之雙 特異性三價抗體之實例。 圖6 四價雙特異性<ErbB-l/c-Met：MJl體之示意性結 構，其包含全長抗體及兩個單鏈Fab片段（圖6a) 或兩個單鏈Fv片段（圖6b) - c-Met結合位點源自 c-Met二聚化抑制性抗體。 圖7a 在表皮樣癌細胞系A43 1中ErbB 1/2/3及c-Met之細 胞表面表現之流式細胞計數分析。 圖7b 在卵巢癌細胞系OVCAR-8中ErbBl/2/3及c-Met之 細胞表面表現之流式細胞計數分析。 圖8a 在癌細胞系A43 1中之增殖分析-與親代單特異性 <HERl>&<c-MetMiL體相比，本發明雙特異性 146954.doc -92· 201039848 <HERl/c-Met>抗體BsABOl (BsAb)對癌症細胞增 殖之抑制。 圖8b 在癌細胞系A43 1中在HGF存在下之增殖分析-與親代單特異性<HER1>及<c-Met>抗體相比， 本發明雙特異性<HERl/c-Met>抗體BsABOl (BsAb)對癌症細胞增殖之抑制。 圖9 在OVCAR-8癌細胞中之内化分析，在第0、 30、60及120分鐘（=0、0.5、1及2小時）測量。 圖1 Oa 在OVCAR-8癌細胞中之增殖分析。與親代單特 異性<«^111>及<(>]\^1>抗體相比，本發明雙特 異性 <HERl/c-Met>抗體 BsABOl (BsAb)對癌症 細胞增殖之抑制。 圖10b 在癌細胞系A43 1中在HGF存在下之增殖分析-與親代單特異性<HER1>及<c-Met>抗體相比， 本發明雙特異性<HERl/c-Met>抗體BsABOl (Bs Ab)對癌症細胞增殖之抑制。 146954.doc -93- 201039848 序列表 <110>瑞士商羅齊克雷雅公司 <120>雙特異性抗-Ert)B-l^c_Met抗體
<130> 26066 FT <140> 099110596 <141〉 2010-04-06 <150> 09005109.5 <151> 2009-04-07 <160> 34 <170> Patentln version 3.2 〇 <210> 1 <211> 119
<212> PRT <213〉小家鼠(mus musculus) <40〇> 1
Gin Val Gin Leu Lys Gin Ser Gly Pro Gly Leu Val Gin Pro Ser Gin 15 10 15
Ser Leu Ser lie Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30
Gly Val His Trp Val Arg Gin Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60
Ser Arg Leu Ser lie Asn Lys Asp Asn Ser Lys Ser Gin Val Phe Phe 65 70 75 80
Lys Met Asn Ser Leu Gin Ser Asn Asp Thr Ala He Tyr Tyr Cys Ala 85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gin Gly
100 105 HO 146954-序列表.doc 201039848
Thr Leu Val Thr Val Ser Ala 115 <210> 2 <211> 107 <212> PRT <213>小家鼠 <400> 2
Asp lie Leu Leu Thr Gin Ser Pro Val lie Leu Ser Val Ser Pro Gly 15 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Asn 20 25 30 lie His Trp Tyr Gin Gin Arg Thr Asn Gly Ser Pro Arg Leu Leu lie 35 40 45
Lys Tyr Ala Ser Glu Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser lie Asn Ser Val Glu Ser 65 70 75 80
Glu Asp lie Ala Asp Tyr Tyr Cys Gin Gin Asn Asn Asn Trp Pro Thr 85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 3 <211> 120 <212> PRT <213〉人工的 <220> <223〉重鏈可變結攤或<£比8-1>人類化ICR62 <400> 3
Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 15 10 15 -2- 146954-序列表.doc 201039848
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30
Lys He His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45
Gly Tyr Phe Asn Pro Asn Ser Gly Tyr Ser Thr Tyr Ala Gin Lys Phe 50 55 60
Gin Gly Arg Val Thr He Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
Ala Arg Leu Ser Pro Gly Gly Tyr Tyr Val Met Asp Ala Trp Gly Gin 100 105 110
Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 4 <211> 108 <212> PRT <213〉人工的 <220> <223>輕鏈可變結P^<ErbB-l>人類化ICR62 〇 <400> 4
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp hrq Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Asn Asn Tyr 20 25 30
Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu lie 35 40 45
Tyr Asn Thr Asn Asn Leu Gin Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 146954-序列表.doc 201039848
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Phe Pro Thr 85 90 95
Phe Gly Gin Gly Thr Lys Leu Glu 工le Lys Arg Thr 100 105 <210> 5 <211> 119 <212〉 PRT <213> 人工的 <220> <223〉重鏈可變結構域<c-Met> Mab 5D5 <400> 5
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Met lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser 4- 146954-序列表 doc 115 201039848 <210> 6 <211> 113 <212> PRT <213> ΛΧέβ <220> <223〉可變結構域<c-Met> Mab 5D5 <400> 6
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ser Ser Gin Ser Leu Leu Tyr Thr 20 25 30
O
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 35 40 45
Ala Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys <210> 7 <211> 449 <212> PRT <213>人工的 <220> <223> 重鏈 cMet Mab 5D5 146954-序列表.doc 201039848 <400> 7
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Met lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe 50 55 60
Lys Asp Arg Phe Thr lie Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205 146954-序列表.doc 201039848
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 o
Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335
Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350 〇
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380
Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 146954·序列表.doc 201039848
Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430
Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445
Lys <210> 8 <211> 220 <212> PRT <213〉人工的 <220> <223〉$至鏈 cMet Mab 5D5 <400> 8
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15
Asp Arg Val Thr lie Thr Cys Lys Ser Ser Gin Ser Leu Leu Tyr Thr 20 25 30
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 35 40 45
Ala Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125 146954-序列表.doc 201039848
Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160
Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205 ❹
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 9 <211> 226 <212〉 PRT <213〉人工的 <220> <223> 重鏈 cMet Fab 5D5 <400> 9
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Trp Leu His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Gly Met lie Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe 50 55 60
Lys Asp Arg Phe Thr He Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 146954-序列表.doc 201039848
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gin Gly 100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175
Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190
Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn His Lys Pro 195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220
Thr His 225 <210> 10 <211> 220 <212> PRT <213〉人工的 <22〇> <223> $S®cMet Fab 5D5 <400> 10
Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 10· M6954-序列表.doc 201039848 5 10 15
Asp Arg Val Thr lie Thr Cys Lys Ser Ser Gin Ser Leu Leu Tyr Thr 20 25 30
Ser Ser Gin Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys 35 40 45
Ala Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125
Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160
Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 -11 - 146954-序列表.doc 201039848 <210> 11 <211> 330 <212> PRT <213> 智人 <400> 11
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80
Tyr lie Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125
Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 -12- 146954-序列表.doc 201039848
Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190
His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205
Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 210 215 220
Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240
Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255
O
Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 o
Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 12 <211> 377 <212> PRT <213〉智人 <400> 12
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 -13- 146954-序列表.doc 201039848
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro 100 105 110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg 115 120 125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys 130 135 140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 165 170 175
Pro Lys Asp Thr Leu Met 工le Ser Arg Thr Pro Glu Val Thr Cys Val 180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Lys Trp Tyr 195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 210 215 220
Gin Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His 225 230 235 240 -14· 146954-序列表.doc 201039848
Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 245 250 255
Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin 260 265 270
Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 275 280 285
Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 290 295 300
Ser Asp lie Ala Val Glu Trp Glu Ser Ser Gly Gin Pro Glu Asn Asn 305 310 315 320
O
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn lie 340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gin 355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys 370 375 <210〉 13 <211> 107 <212〉 PRT <213> 智人 <400> 13
Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 15 10 15
Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30
Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 15- 146954·序列表.doc 201039848 35 40 45
Ser Gly Asn 50
Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 55 60
Thr Tyr Ser 65
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 70 75 80
Lys His Lys
Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95
Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 14 <211> 104 <212> PRT <213〉智人 <400> 14 Pro Lys Ala 1
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 5 10 15
Leu Gin Ala
Asn Lys Ala Thr Leu Val Cys Leu lie Ser Asp Phe Tyr 20 25 30
Pro Gly Ala 35
Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 40 45
Ala Gly Val 50
Glu Thr Thr Thr Pro Ser Lys Gin Ser Asn Asn Lys Tyr 55 60
Ala Ala Ser 65
Ser Tyr Leu Ser Leu Thr Pro Glu Gin Trp Lys Ser His 70 75 80
Arg Ser Tyr
Ser Cys Gin Val Thr His Glu Gly Ser Thr Val Glu Lys 85 90 95
Thr Val Ala
Pro Thr Glu Cys Ser 100 146954-序列表.doc -16- 201039848 <210> 15 <211> 1390 <212> PRT <213〉智人 <400> 15
Met Lys Ala Pro Ala Val Leu Ala Pro Gly lie Leu Val Leu Leu Phe 15 10 15
Thr Leu Val Gin Arg Ser Asn Gly Glu Cys Lys Glu Ala Leu Ala Lys 20 25 30
Ser Glu Met Asn Val Asn Met Lys Tyr Gin Leu Pro Asn Phe Thr Ala 35 40 45
Glu Thr Pro lie Gin Asn Val lie Leu His Glu His His lie Phe Leu 50 55 60
Gly Ala Thr Asn Tyr lie Tyr Val Leu Asn Glu Glu Asp Leu Gin Lys 65 Ί0 75 80
Val Ala Glu Tyr Lys Thr Gly Pro Val Leu Glu His Pro Asp Cys Phe 85 90 95
Pro Cys Gin Asp Cys Ser Ser Lys Ala Asn Leu Ser Gly Gly Val Trp 100 105 110
Lys Asp Asn lie Asn Met Ala Leu Val Val Asp Thr Tyr Tyr Asp Asp 115 120 125 o
Gin Leu lie Ser Cys Gly Ser Val Asn Arg Gly Thr Cys Gin Arg His 130 135 140
Val Phe Pro His Asn His Thr Ala Asp lie Gin Ser Glu Val His Cys 145 150 155 160 lie Phe Ser Pro Gin lie Glu Glu Pro Ser Gin Cys Pro Asp Cys Val 165 170 175
Val Ser Ala Leu Gly Ala Lys Val Leu Ser Ser Val Lys Asp Arg Phe 17- U6954-序列表.doc 201039848 190 180 lie Asn Phe Phe Val Gly Asn Thr 195 200 His Pro Leu His Ser lie Ser Val 210 215 Gly Phe Met Phe Leu Thr Asp Gin 225 230 Phe Arg Asp Ser Tyr Pro lie Lys 245 Asn Phe lie Tyr Phe Leu Thr Val 260 Thr Phe His Thr Arg lie lie Arg 275 280 His Ser Tyr Met Glu Met Pro Leu 290 295 Lys Lys Arg Ser Thr Lys Lys Glu 305 310 Tyr Val Ser Lys Pro Gly Ala Gin 325 Leu Asn Asp Asp lie Leu Phe Gly 340 Ser Ala Glu Pro Met Asp Arg Ser 355 360 Tyr Val Asn Asp Phe Phe Asn Lys 370 375 Cys Leu Gin His Phe Tyr Gly Pro 385 390
Asn Ser Ser Tyr Phe Pro Asp 205
Arg Leu Lys Glu Thr Lys Asp 220
Tyr lie Asp Val Leu Pro Glu 235 240
Val His Ala Phe Glu Ser Asn 250 255
Arg Glu Thr Leu Asp Ala Gin 270
Cys Ser lie Asn Ser Gly Leu 285
Cys lie Leu Thr Glu Lys Arg 300
Phe Asn lie Leu Gin Ala Ala 315 320
Ala Arg Gin lie Gly Ala Ser 330 335
Phe Ala Gin Ser Lys Pro Asp 350
Met Cys Ala Phe Pro lie Lys 365
Val Asn Lys Asn Asn Val Arg 380
His Glu His Cys Phe Asn Arg 395 400 146954-序列表.doc -Ϊ8- 201039848
Thr Leu Leu Arg Asn Ser Ser Gly Cys Glu Ala Arg Arg Asp Glu Tyr 405 410 415
Arg Thr Glu Phe Thr Thr Ala Leu Gin Arg Val Asp Leu Phe Met Gly 420 425 430
Gin Phe Ser Glu Val Leu Leu Thr Ser lie Ser Thr Phe lie Lys Gly 435 440 445
Asp Leu Thr lie Ala Asn Leu Gly Thr Ser Glu Gly Arg Phe Met Gin 450 455 460
Val Val Val Ser Arg Ser Gly Pro Ser Thr Pro His Val Asn Phe Leu 465 470 475 480
Leu Asp Ser His Pro Val Ser Pro Glu Val lie Val Glu His Thr Leu 485 490 495
Asn Gin Asn Gly Tyr Thr Leu Val lie Thr Gly Lys Lys lie Thr Lys 500 505 510 lie Pro Leu Asn Gly Leu Gly Cys Arg His Phe Gin Ser Cys Ser Gin 515 520 525
Cys Leu Ser Ala Pro Pro Phe Val Gin Cys Gly Trp Cys His Asp Lys 530 535 540
Cys Val Arg Ser Glu Glu Cys Leu Ser Gly Thr Trp Thr Gin Gin lie 545 550 555 560
Cys Leu Pro Ala lie Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu 565 570 575
Gly Gly Thr Arg Leu Thr lie Cys Gly Trp Asp Phe Gly Phe Arg Arg 580 585 590
Asn Asn Lys Phe Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu 595 600 605 19- 146954-序列表.doc 201039848
Ser Cys Thr Leu Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys 610 615 620
Thr Val Gly Pro Ala Met Asn Lys His Phe Asn Met Ser lie lie lie 625 630 635 640
Ser Asn Gly His Gly Thr Thr Gin Tyr Ser Thr Phe Ser Tyr Val Asp 645 650 655
Pro Val lie Thr Ser lie Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly 660 665 670
Thr Leu Leu Thr Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Arg 675 680 685
His 工le Ser lie Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn 690 695 700
Ser lie Leu Glu Cys Tyr Thr Pro Ala Gin Thr lie Ser Thr Glu Phe 705 710 715 720
Ala Val Lys Leu Lys lie Asp Leu Ala Asn Arg Glu Thr Ser lie Phe 725 730 735
Ser Tyr Arg Glu Asp Pro lie Val Tyr Glu He His Pro Thr Lys Ser 740 745 750
Phe lie Ser Gly Gly Ser Thr lie Thr Gly Val Gly Lys Asn Leu Asn 755 760 765
Ser Val Ser Val Pro Arg Met Val lie Asn Val His Glu Ala Gly Arg 770 775 780
Asn Phe Thr Val Ala Cys Gin His Arg Ser Asn Ser Glu lie lie Cys 785 790 795 800
Cys Thr Thr Pro Ser Leu Gin Gin Leu Asn Leu Gin Leu Pro Leu Lys 805 810 815 20- 146954·序列表.doc 201039848
Thr Lys Ala Phe Phe Met Leu Asp Gly lie Leu Ser Lys Tyr Phe Asp 820 825 830
Leu lie Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys Pro Val 835 840 845
Met lie Ser Met Gly Asn Glu Asn Val Leu Glu lie Lys Gly Asn Asp 850 855 860
He Asp Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly Asn Lys 865 870 875 880
Ser Cys Glu Asn lie His Leu His Ser Glu Ala Val Leu Cys Thr Val 885 890 895
Pro Asn Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn lie Glu Trp Lys 900 905 910
Gin Ala lie Ser Ser Thr Val Leu Gly Lys Val lie Val Gin Pro Asp 915 920 925
Gin Asn Phe Thr Gly Leu lie Ala Gly Val Val Ser lie Ser Thr Ala 930 935 940
Leu Leu Leu Leu Leu Gly Phe Phe Leu Trp Leu Lys Lys Arg Lys Gin 945 950 955 960 工le Lys Asp Leu Gly Ser Glu Leu Val Arg Tyr Asp Ala Arg Val His 965 970 975 ❹
Thr Pro His Leu Asp Arg Leu Val Ser Ala Arg Ser Val Ser Pro Thr 980 985 990
Thr Glu Met Val Ser Asn Glu Ser Val Asp Tyr Arg Ala Thr Phe Pro 995 1000 1005
Glu Asp Gin Phe Pro Asn Ser Ser Gin Asn Gly Ser Cys Arg Gin 1010 1015 1020
Val Gin Tyr Pro Leu Thr Asp Met Ser Pro lie Leu Thr Ser Gly -21- 146954-序列表.doc 201039848 1025 1030 1035
Asp Ser Asp lie Ser Ser Pro Leu Leu Gin Asn Thr Val His lie 1040 1045 1050
Asp Leu 1055 Ser Ala Leu Asn Pro 1060 Glu Leu Val Gin Ala 1065 Val Gin His Val Val 1070 lie Gly Pro Ser Ser 1075 Leu lie Val His Phe 1080 Asn Glu Val lie Gly Arg Gly His Phe Gly Cys Val Tyr His Gly Thr Leu Leu 1085 1090 1095
Asp Asn Asp Gly Lys Lys lie His Cys Ala Val Lys Ser Leu Asn 1100 1105 1110
Arg He 1115 Thr Asp lie Gly Glu 1120 Val Ser Gin Phe Leu 1125 Thr Glu Gly lie lie 1130 Met Lys Asp Phe Ser 1135 His Pro Asn Val Leu 1140 Ser Leu Leu Gly lie 1145 Cys Leu Arg Ser Glu 1150 Gly Ser Pro Leu Val 1155 Val Leu Pro
Tyr Met Lys His Gly Asp Leu Arg Asn Phe lie Arg Asn Glu Thr 1160 1165 1170
His Asn Pro Thr Val Lys Asp Leu lie Gly Phe Gly Leu Gin Val 1175 1180 1185
Ala Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe Val His Arg 1190 1195 1200
Asp Leu Ala Ala Arg Asn Cys Met Leu Asp Glu Lys Phe Thr Val 1205 1210 1215
Lys Val Ala Asp Phe Gly Leu Ala Arg Asp Met Tyr Asp Lys Glu 1220 1225 1230 22· 146954-序列表.doc 201039848
Tyr Tyr Ser Val His Asn Lys Thr Gly Ala Lys Leu Pro Val Lys 1235 1240 1245
Trp Met Ala Leu Glu Ser Leu Gin Thr Gin Lys Phe Thr Thr Lys 1250 1255 1260
Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Leu Met Thr 1265 1270 1275
Arg Gly Ala Pro Pro Tyr Pro Asp Val Asn Thr Phe Asp lie Thr 1280 1285 1290
Val Tyr Leu Leu Gin Gly Arg Arg Leu Leu Gin Pro Glu Tyr Cys 1295 1300 1305
Pro Asp Pro Leu Tyr Glu Val Met Leu Lys Cys Trp His Pro Lys 1310 1315 1320
Ala Glu Met Arg Pro Ser Phe Ser Glu Leu Val Ser Arg lie Ser 1325 1330 1335
Ala lie Phe Ser Thr Phe lie Gly Glu His Tyr Val His Val Asn 1340 1345 1350
Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr Pro Ser Leu 1355 1360 1365
Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp Thr Arg Pro 1370 1375 1380
Ala Ser Phe Trp Glu Thr Ser 1385 1390 <210> 16 <211> 1210 <212> PRT <213> 智人 <400> 16 -23· 146954-序列表.doc 201039848
Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 15 10 15
Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gin 20 25 30
Gly Thr Ser Asn Lys Leu Thr Gin Leu Gly Thr Phe Glu Asp His Phe 35 40 45
Leu Ser Leu Gin Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60
Leu Glu lie Thr Tyr Val Gin Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80
Thr 工le Gin Glu Val Ala Gly Tyr Val Leu lie Ala Leu Asn Thr Val 85 90 95
Glu Arg lie Pro Leu Glu Asn Leu Gin lie lie Arg Gly Asn Met Tyr 100 105 110
Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125
Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gin Glu lie Leu 130 135 140
His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160
Ser lie Gin Trp Arg Asp lie Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175
Ser Met Asp Phe Gin Asn His Leu Gly Ser Cys Gin Lys Cys Asp Pro 180 185 190
Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gin 195 200 205
Lys Leu Thr Lys lie lie Cys Ala Gin Gin Cys Ser Gly Arg Cys Arg 24- 146954-序列表.doc 201039848 210 215 220
Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gin Cys Ala Ala Gly Cys 225 230 235 240
Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255
Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270
Thr Thr Tyr Gin Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285
Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300
Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320
Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335
Cys Asn Gly lie Gly lie Gly Glu Phe Lys Asp Ser Leu Ser lie Asn 340 345 350
Ala Thr Asn lie Lys His Phe Lys Asn Cys Thr Ser lie Ser Gly Asp 355 360 365
Leu His lie Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380
Pro Pro Leu Asp Pro Gin Glu Leu Asp lie Leu Lys Thr Val Lys Glu 385 390 395 400 lie Thr Gly Phe Leu Leu lie Gin Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415
Leu His Ala Phe Glu Asn Leu Glu lie lie Arg Gly Arg Thr Lys Gin 420 425 430 -25- 146954-序列表.doc 201039848
His Gly Gin Phe Ser Leu Ala Val Val Ser Leu Asn lie Thr Ser Leu 435 440 445
Gly Leu Arg Ser Leu Lys Glu lie Ser Asp Gly Asp Val lie lie Ser 450 455 460
Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr lie Asn Trp Lys Lys Leu 465 470 475 480
Phe Gly Thr Ser Gly Gin Lys Thr Lys lie lie Ser Asn Arg Gly Glu 485 490 495
Asn Ser Cys Lys Ala Thr Gly Gin Val Cys His Ala Leu Cys Ser Pro 500 505 510
Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525
Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540
Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys lie Gin Cys His Pro 545 550 555 560
Glu Cys Leu Pro Gin Ala Met Asn lie Thr Cys Thr Gly Arg Gly Pro 565 570 575
Asp Asn Cys lie Gin Cys Ma His Tyr lie Asp Gly Pro His Cys Val 580 585 590
Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605
Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620
Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 -26- 146954-序列表.doc 201039848
Pro Lys lie Pro Ser lie Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655
Leu Leu Val Val Ala Leu Gly lie Gly Leu Phe Met Arg Arg Arg His 660 665 670 lie Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gin Glu Arg Glu Leu 675 680 685
Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gin Ala Leu Leu 690. 695 700
Arg He Leu Lys Glu Thr Glu Phe Lys Lys lie Lys Val Leu Gly Ser 705 710 715 720
G
Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp lie Pro Glu Gly Glu 725 730 735
Lys Val Lys lie Pro Val Ala lie Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750
Pro Lys Ala Asn Lys Glu lie Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765
Val Asp Asn Pro His Val Cys Arg Leu Leu Gly lie Cys Leu Thr Ser 770 775 780
Thr Val Gin Leu lie Thr Gin Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800
Tyr Val Arg Glu His Lys Asp Asn lie Gly Ser Gin Tyr Leu Leu Asn 805 810 ‘815
Trp Cys Val Gin lie Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830
Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 27- 146954·序列表.doc 201039848
Gin His Val Lys lie Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860
Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro lie Lys Trp 865 870 875 880
Met Ala Leu Glu Ser lie Leu His Arg lie Tyr Thr His Gin Ser Asp 885 890 895
Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910
Lys Pro Tyr Asp Gly lie Pro Ala Ser Glu lie Ser Ser 工le Leu Glu 915 920 925
Lys Gly Glu Arg Leu Pro Gin Pro Pro lie Cys Thr lie Asp Val Tyr 930 935 940
Met lie Met Val Lys Cys Trp Met lie Asp Ala Asp Ser Arg Pro Lys 945 950 955 960
Phe Arg Glu Leu lie 工le Glu Phe Ser Lys Met Ala Arg Asp Pro Gin 965 970 975
Arg Tyr Leu Val lie Gin Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990
Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005
Asp Val Val Asp Ala Asp Glu Tyr Leu lie Pro Gin Gin Gly Phe 1010 1015 1020
Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035
Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys lie Asp Arg Asn 1040 1045 1050
Gly Leu Gin Ser Cys Pro lie Lys Glu Asp Ser Phe Leu Gin Arg 28- 146954-序列表.doc 201039848 1055 1060 1065
Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser lie Asp 1070 1075 1080
Asp Thr Phe Leu Pro Val Pro Glu Tyr lie Asn Gin Ser Val Pro 1085 1090 1095
Lys Arg Pro Ala Gly Ser Val Gin Asn Pro Val Tyr His Asn Gin 1100 1105 1110
Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gin Asp Pro 1115 1120 1125
His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gin 1130 1135 1140
Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155
Gin Lys Gly Ser His Gin lie Ser Leu Asp Asn Pro Asp Tyr Gin 1160 1165 1170
Gin Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly lie Phe Lys 1175 1180 1185
Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gin 1190 1195 1200
Ser Ser Glu Phe lie Gly Ala 1205 1210 <210> 17 <211> 11 <212> PRT <213〉小家鼠 <400> 17
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 15 10 29· 146954·序列表.doc 201039848 <210> <211> 18 16 <212> <213> PRT 小家鼠 <400> 18
Val lie Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser 1 5 10 15 <210> <211> 19 5 <212> <213> PRT 小家鼠 <400> 19
Asn Tyr Gly Val His 1 5 <210> <211> 20 9 <212> <213> PRT 小家鼠 <400> 20
Gin Gin Asn Asn Asn Trp Pro Thr Thr 1 5 <210> <211> 21 7 <212> <213> PRT 小家鼠 <400> 21
Tyr Ala Ser Glu Ser lie Ser 1 5 <21〇> <211> 22 11 <212> <213> PRT 小家鼠 <4〇〇> 22
Arg Ala Ser Gin Ser lie Gly Thr Asn lie His 30- 146954-序列表.doc 201039848 15 10 <210> 23 <211> 11 <212> PRT <213〉人工的 <220> <223> 重鏈 CDR3H, <ErbB-l>XMit ICR62 <400> 23
Leu Ser Pro Gly Gly Tyr Tyr Val Met Asp Ala 15 10 <210> 24 <211> 17
<212> PRT <213> 人工的 <220> <223〉重鏈 CDR2H, <ErbB-l>A^化工CR62 <400> 24
Tyr Phe Asn Pro Asn Ser Gly Tyr Ser Thr Tyr Ala Gin Lys Phe Gin 15 10 15
Gly <210> 25 <211〉 5 <212> PRT <213> 人工的 <220〉 <223> 重鏈CDR1H, <ErbB-1>人類化工CR62 <400> 25 Asp Tyr Lys lie His 1 5 <210> 26 <211> 8 <212> PRT <213> 人工的 -31 - 146954-序列表.doc 201039848 <220> <223〉輕鏈 CDR3L, <ErbB-l>人類化 ICR62 <400> 26
Leu Gin His Asn Ser Phe Pro Thr 1 5 <210> 27 <211> 7 <212> PRT <213〉人工的 <22〇> <223〉輕鏈 CDR2L, <ErbB-l>人類化 ICR62 <40〇> 27
Asn Thr Asn Asn Leu Gin Thr 1 5 <210> 28 <211> 11 <212> PRT <213〉人工的 <220> <223〉輕鍵 CDR1L, <ErbB-l>人類化 ICR62 <400> 28
Arg Ala Ser Gin Gly lie Asn Asn Tyr Leu Asn 15 10 <210> 29 <211> 10 <212> PRT <213〉人工的 <220> <223〉重鏈 CDR3H,〈c-Met〉Mab 5D5 <400> 29
Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr 15 10 <210> 30 02- 146954-序列表.doc 201039848 <211> 17 <212〉 PRT <213> 人工的 <220> <223> 重鏈 CDR2H, <c-Met> Mab 5D5 <400> 30 Met He ：Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe Lys 1 5 10 15 Asp <210> 31 <211> 5 <212> PRT <213> 人工的
<220> <223> 重鏈CDR1H, <c-Met> Mab 5D5 <400> 31
Ser Tyr Trp Leu His 1 5 <210> 32 <211> 9 <212> PRT <213> 人工的 <220> <223〉$至鏈 CDR3L, <c-Met> Mab 5D5 <400> 32
Gin Gin Tyr Tyr Ala Tyr Pro Trp Thr 1 5 <210〉 33 <211> 7 <212> PRT <213〉人工的 <220> <223> 輕鍵 CDR2L, <c-Met> Mab 5D5 33- 146954-序列表.doc 201039848 <400> 33
Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 34 <211〉 17 <212> PRT <213〉人工的 <220> <223> 輕鏈 CDR1L, <c-Met> Mab 5D5 <4〇〇> 34
Lys Ser Ser Gin Ser Leu Leu Tyr Thr Ser Ser Gin Lys Asn Tyr Leu 15 10 15
Ala -34- 146954-序列表.doc
Claims (1)
- 201039848 七、申請專利範圍： 1. 一種雙特異性抗體，其特異性結合人類ErbB-l及人類c-Met，其包含特異性結合人類ErbB-Ι之第一抗原結合位 點及特異性結合人類c-Met之第二抗原結合位點，其特徵 在於在流式細胞計數分析中在2小時後對OVCAR-8細胞 測量時，與該雙特異性抗體不存在下c-Met之内化相比， 該雙特異性抗體顯示c-Met之内化不超過15%。 2. 如請求項1之雙特異性抗體，其特徵在於其為二價或三 〇 價抗體，包含一個或兩個特異性結合人類ErbB-1之抗原 結合位點及一個特異性結合人類c-Met之第三抗原結合位 點。 3. 如請求項2之抗體，其特徵在於包含 a) 特異性結合ErbB-1且由兩個抗體重鏈及兩個抗體輕 鏈組成之全長抗體；及 b) —個特異性結合人類c-Met之單鏈Fab片段， 其中b)中該單鏈Fab片段經由a)中該全長抗體重鏈或輕鏈 ❹ C或N端之肽連接物與該全長抗體融合。 4. 一種雙特異性抗體，其特異性結合人類ErbB-l及人類c-Met，其包含特異性結合人類ErbB-l之第一抗原結合位 點及特異性結合人類c-Met之第二抗原結合位點，其特徵 在於 i) 該第一抗原結合位點在重鏈可變結構域中包含SEQ ID NO: 17 之 CDR3H 區、SEQ ID NO: 18 之 CDR2H 區、及SEQ ID N〇：19之CDR1H區，且在輕鏈可變結 146954.doc 201039848 構域中包含 SEQ ID NO: 20 之 CDR3L 區、SEQ ID NO: 21 之 CDR2L 區、及 SEQ ID NO: 58之 CDR1L 區或 SEQ ID NO: 22之 CDR1L 區；及 該第二抗原結合位點在重鏈可變結構域中包含Seq ID NO: 30 之 CDR3H 區、SEQ ID NO: 31 之 CDR2H 區、及SEQ ID NO: 32之CDR1H區，且在輕鏈可變結 構域中包含 SEQ ID NO: 33 之 CDR3L 區、SEQ ID NO: 34之 CDR2L 區、及 SEQ ID NO: 35之 CDR1L 區； ii)該第一抗原結合位點在該重鏈可變結構域中包含 SEQ ID NO: 23 之 CDR3H 區、SEQ ID NO: 24 之 CDR2H區、及SEQ ID NO: 25之CDR1H區，且在該輕 鏈可變結構域中包含SEQ ID NO: 26之CDR3L區、 SEQ ID NO: 27 之 CDR2L 區、及 SEQ ID NO: 28 之 CDRlI^4SEQIDNO:29：^CDRlLg;& 該第二抗原結合位點在該重鏈可變結構域中包含 SEQ ID NO: 30 之 CDR3H 區、SEQ ID NO: 31 之 CDR2H區、及SEQ ID NO: 32之CDR1H區，且在該輕 鏈可變結構域中包含SEQ ID NO: 33之CDR3L區、 SEQ ID NO: 34 之 CDR2L 區、及 SEQ ID NO: 35 之 CDR1L 區。 5.如請求項4之雙特異性抗體，其特徵在於 i)該特異性結合ErbB-1之第一抗原結合位點包含序列 SEQ ID NO: 1作為重鏈可變結構域，且包含序列SEQ ID NO: 2作為輕鏈可變結構域；及 146954.doc 201039848 °亥特異性結合e_Met之第二抗原結合位點包含序列 Q ID NO. 5作為重鍵可變結構域，且包含序列seq ID NO: 6作為輕鏈可變結構域；或 U) °亥知'異性結合El*bB-1之第一抗原結合位點包含序列 SEQ ID NO: 3作為重鏈可變結構域，且包含序列SEQ ID NO: 4作為輕鏈可變結構域；及 该特異性結合c_Met2第二抗原結合位點包含序列 SEQ ID NO’· 5作為重鏈可變結構域，且包含序列SEQ ID NO: 6作為輕鏈可變結構域。 6.如請求項1至5中任一項之雙特異性抗體，其特徵在於包 含IgGl或IgG3亞類之恆定區。 7_如請求項1至5中任一項之雙特異性抗體，其特徵在於該 抗體係在Asn297經糖鏈糖基化，其中該糖鏈内岩藻糖之 量為65%或更低。 8· —種核酸，其編碼如請求項丨至7中任一項之雙特異性抗 體。 9. —種醫藥組合物，其包含如請求項丨至7中任一項之雙特 異性抗體。 10. 如請求項9之醫藥組合物，其用於治療癌症。 11. 如請求項1至5中任一項之雙特異性抗體，其用於治療癌 症。 12. —種如請求項1至7中任一項之雙特異性抗體之用途，其 用於製造治療癌症之藥物。 146954.doc
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| EP2014681A1 (en) | 2007-07-12 | 2009-01-14 | Pierre Fabre Medicament | Novel antibodies inhibiting c-met dimerization, and uses thereof |
| CA2694488A1 (en) * | 2007-07-31 | 2009-02-05 | Medimmune, Llc | Multispecific epitope binding proteins and uses thereof |
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| MX2010009669A (es) | 2008-03-06 | 2010-09-22 | Genentech Inc | Terapia de combinacion con antagonistas de c-met y egfr. |
| BRPI0910482A2 (pt) * | 2008-04-29 | 2019-09-24 | Abbott Lab | imunoglobinas de domínio variável duplo e usos das mesmas |
| US20100260668A1 (en) * | 2008-04-29 | 2010-10-14 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
| TW201008580A (en) * | 2008-06-03 | 2010-03-01 | Abbott Lab | Dual variable domain immunoglobulin and uses thereof |
-
2010
- 2010-03-30 CA CA2757426A patent/CA2757426A1/en not_active Abandoned
- 2010-03-30 EP EP10711846A patent/EP2417160A1/en not_active Withdrawn
- 2010-03-30 CN CN2010800134576A patent/CN102361884A/zh active Pending
- 2010-03-30 KR KR1020117023690A patent/KR20110124368A/ko not_active Ceased
- 2010-03-30 WO PCT/EP2010/002006 patent/WO2010115553A1/en not_active Ceased
- 2010-03-30 WO PCT/EP2010/002003 patent/WO2010115551A1/en not_active Ceased
- 2010-03-30 BR BRPI1014474A patent/BRPI1014474A2/pt not_active IP Right Cessation
- 2010-03-30 JP JP2012503895A patent/JP5612663B2/ja not_active Expired - Fee Related
- 2010-03-30 KR KR1020117023688A patent/KR20110126748A/ko not_active Ceased
- 2010-03-30 BR BRPI1014449A patent/BRPI1014449A2/pt not_active IP Right Cessation
- 2010-03-30 AU AU2010233993A patent/AU2010233993A1/en not_active Abandoned
- 2010-03-30 MX MX2011010158A patent/MX2011010158A/es active IP Right Grant
- 2010-03-30 AU AU2010233995A patent/AU2010233995A1/en not_active Abandoned
- 2010-03-30 SG SG2011072634A patent/SG175080A1/en unknown
- 2010-03-30 SG SG2011072618A patent/SG175078A1/en unknown
- 2010-03-30 CN CN2010800134595A patent/CN102361883A/zh active Pending
- 2010-03-30 JP JP2012503897A patent/JP5497887B2/ja not_active Expired - Fee Related
- 2010-03-30 MX MX2011010169A patent/MX2011010169A/es unknown
- 2010-03-30 EP EP10713827A patent/EP2417164A1/en not_active Withdrawn
- 2010-03-30 CA CA2757669A patent/CA2757669A1/en not_active Abandoned
- 2010-04-02 US US12/753,141 patent/US20100254988A1/en not_active Abandoned
- 2010-04-02 US US12/753,145 patent/US20100254989A1/en not_active Abandoned
- 2010-04-05 AR ARP100101124A patent/AR076195A1/es unknown
- 2010-04-05 AR ARP100101123A patent/AR076194A1/es unknown
- 2010-04-06 TW TW099110596A patent/TW201039848A/zh unknown
- 2010-04-06 TW TW099110598A patent/TW201039849A/zh unknown
-
2011
- 2011-08-25 IL IL214847A patent/IL214847A0/en unknown
- 2011-08-29 IL IL214885A patent/IL214885A0/en unknown
-
2013
- 2013-02-22 US US13/774,192 patent/US20130156772A1/en not_active Abandoned
- 2013-04-10 US US13/860,353 patent/US20130273054A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20130273054A1 (en) | 2013-10-17 |
| US20130156772A1 (en) | 2013-06-20 |
| IL214847A0 (en) | 2011-11-30 |
| AR076195A1 (es) | 2011-05-26 |
| CA2757426A1 (en) | 2010-10-14 |
| IL214885A0 (en) | 2011-11-30 |
| JP5497887B2 (ja) | 2014-05-21 |
| EP2417160A1 (en) | 2012-02-15 |
| AR076194A1 (es) | 2011-05-26 |
| SG175080A1 (en) | 2011-11-28 |
| WO2010115553A1 (en) | 2010-10-14 |
| BRPI1014449A2 (pt) | 2017-06-27 |
| BRPI1014474A2 (pt) | 2017-06-27 |
| KR20110126748A (ko) | 2011-11-23 |
| JP5612663B2 (ja) | 2014-10-22 |
| EP2417164A1 (en) | 2012-02-15 |
| CN102361884A (zh) | 2012-02-22 |
| WO2010115551A1 (en) | 2010-10-14 |
| CN102361883A (zh) | 2012-02-22 |
| JP2012522525A (ja) | 2012-09-27 |
| US20100254989A1 (en) | 2010-10-07 |
| SG175078A1 (en) | 2011-11-28 |
| CA2757669A1 (en) | 2010-10-14 |
| JP2012522523A (ja) | 2012-09-27 |
| KR20110124368A (ko) | 2011-11-16 |
| US20100254988A1 (en) | 2010-10-07 |
| MX2011010158A (es) | 2011-10-17 |
| AU2010233995A1 (en) | 2011-09-08 |
| MX2011010169A (es) | 2011-10-11 |
| TW201039849A (en) | 2010-11-16 |
| AU2010233993A1 (en) | 2011-09-08 |
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