TW202409084A - 針對tigit之抗體 - Google Patents
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Abstract
本發明提供特異性結合至TIGIT之單株抗體。該等單株抗體具有藉由抑制TIGIT與CD155之結合而大量活化T細胞及自然殺手細胞的能力。該等單株抗體在其他應用當中可用於治療癌症及傳染病。
Description
本文尤其係提供特異性結合至免疫檢查點分子,從而引起免疫細胞大量活化的單株抗體以及該等單株抗體在其他應用中用於治療癌症及傳染病之用途。
抗原特異性免疫反應係一種複雜的生物性過程,該過程係由複數層的正向調控物及負向調控物所控制。首先,藉由識別由經抗原呈現細胞上之主要組織相容性複合體(MHC)分子所呈現的T細胞同源肽抗原,T細胞會經由T細胞受體(TCR)而受到刺激。最佳T細胞活化需要由諸如CD28之協同刺激分子所提供的「第二信號」。免疫反應進一步藉由屬於TNF受體超家族之諸如OX40、GITR及4-1BB的協同刺激分子進行正性調節,而藉由諸如PD-1及CTLA-4之檢查點分子進行負性調節。檢查點分子之功能係防止體內免疫系統不當的過度反應;然而,其亦限制了免疫系統有效地對抗癌症及傳染病的能力。已報導,藉由拮抗性單株IgG抗體阻斷PD-1或CTLA-4之功能對人類癌症之免疫療法係有效的(關於綜述,參見Pardoll,
Nat. Rev. Cancer, 12:252-264, 2012;Mahoney等人,
Nat. Rev. Drug Discov. 14:561-584, 2015;Shin等人,
Curr. Opin. Immunol. 33:23-35, 2015;Marquez-Rodas等人
Ann. Transl. Med. 3:267, 2015)。
其他檢查點分子,諸如TIM-3、LAG-3、TIGIT、BTLA及VISTA亦有報導 (Mercier等人,
Front. Immunol. 6:418, 2015)。TIGIT (含Ig及ITIM域的T細胞免疫受體)係胞質尾區中含免疫受體酪胺酸基抑制基元(ITIM)之免疫球蛋白超家族的成員,表現在活化的T細胞及自然殺手(NK)細胞之亞群上(Yu等人,
Nat. Immunol. 10:48-57, 2009)。已知TIGIT與CD155 (亦稱為PVR及necl-5)、CD112 (亦稱為PVRL2及nectin-2)會相互作用,且可能與CD113 (亦稱為PVRL3及nectin-3)相互作用(Mercier等人,同前文獻;Martinet等人,
Nat. Rev. Immunol. 15:243-254, 2015)。已報導,TIGIT與在抗原呈現細胞上表現的高親和力配體CD155之結合會抑制T細胞及NK細胞之功能(Mercier等人,同前文獻;Joller等人
, J. Immunol. 186: 1338-1342, 2011;Stanietsky等人
, Eur. J. Immunol. 43:2138-2150, 2013;Li等人,
J. Biol. Chem. 289:17647-17657, 2014;Zhang等人
Cancer Immunol.
Immunother. 電子出版於2016年2月3日)。亦報導,TIGIT藉由用樹突狀細胞調整細胞介素產生而間接抑制T細胞(Yu等人,同前文獻)。
腫瘤構成高度抑制的微環境,其中浸潤性T細胞被耗竭且NK細胞因諸如PD-1及TIGIT之檢查點分子而沉默,從而避開免疫反應(Johnston等人,
Cancer Cell.26:926-937, 2014;Chauvin等人
, J. Clin. Invest.125:2046-2058, 2015;Inozume等人,
J. Invest. Dermatol. 電子出版於2015年10月12日)。TIGIT在CD8+ T細胞上之高水準表現已報導與AML個體之不良臨床結果有關(Kong等人,
Clin.
Cancer Res. 電子出版於2016年1月13日)。據報導,AML個體之已耗竭的TIGIT+ CD8+ T細胞之功能缺陷因siRNA介導阻斷TIGIT表現而逆轉(Kong等人,同前文獻)。亦報導,效應CD8+ T細胞在HIV感染期間在血液中且在SIV感染期間在淋巴組織中展現較高的TIGIT含量(Chew等人
, PLOS Pathogens, 12:e1005349, 2016)。另外,據報導,離體抗體阻斷TIGIT可恢復病毒特異性CD8+ T細胞效應反應。
本發明尤其提供一種與TIG1、TIG2或TIG3中之任一者競爭結合至人類TIGIT的抗體。抗體TIG1之特徵在於SEQ ID NO: 14之成熟輕鏈可變區及SEQ ID NO: 10之成熟重鏈可變區,抗體TIG2之特徵在於SEQ ID NO: 22之成熟輕鏈可變區及SEQ ID NO: 18之成熟重鏈可變區,且抗體TIG3之特徵在於SEQ ID NO: 30之成熟輕鏈可變區及SEQ ID NO: 26之成熟重鏈可變區,用於特異性結合至TIGIT。一些抗體與TIG1、TIG2或TIG3結合至人類TIGIT上的同一抗原決定基。一些抗體抑制人類TIGIT與CD155之結合。一些抗體包含三個輕鏈CDR及三個重鏈CDR,其基本上來自TIG1的相應的三個輕鏈及三個重鏈CDR。一些抗體包含TIG1、TIG2或TIG3的三個輕鏈CDR及三個重鏈CDR。一些抗體包含TIG1 (SEQ ID NO: 15-17輕鏈及11-13重鏈)、TIG2 (SEQ ID NO: 23-25輕鏈,19-21重鏈)或TIG3 (SEQ ID NO: 31-33輕鏈及27-29重鏈)中之任一者的如由Kabat所定義的三個重鏈CDR及如由Kabat所定義的三個輕鏈CDR。
一些單株抗體結合至包含SEQ ID NO: 1之殘基35及37及/或SEQ ID NO: 1之殘基49及51的人類TIGIT的抗原決定基。一些單株抗體結合至包含SEQ ID NO: 1之殘基35、37、49及51的人類TIGIT的抗原決定基。一些單株抗體結合至由SEQ ID NO: 1之殘基35-51及任一側上不超過五個來自SEQ ID NO: 1之側接胺基酸組成的肽。一些單株抗體結合至由SEQ ID NO: 1之殘基35-51組成的肽。一些此類單株抗體結合至由SEQ ID NO: 1之3至20個相鄰殘基組成的抗原決定基。
一些抗體係嵌合的、人類化的、經鑲飾的(veneered)或人類的。一些抗體具有人類IgG1κ同型。一些抗體具有人類IgG4κ同型。抗體可以係完整抗體或單鏈抗體、Fab或F(ab')
2片段。
本發明進一步提供一種醫藥組合物,其包含以上抗體中之任一者及醫藥學上可接受之載劑。
本發明進一步提供治療個體之癌症或實現癌症預防的方法,其包含向患有癌症或具有患癌症風險之個體投與有效養生法的以上抗體中之任一者。在一些方法中,個體患有急性骨髓性白血病或成人T細胞白血病。
在其他實施例中,本發明涵蓋本文所述之抗體與免疫檢查點抑制劑組合的用途。阻斷免疫檢查點引起抗原特異性T細胞反應放大,已顯示為人類癌症療法中之有前景的方法。作為阻斷候選者之免疫檢查點(配體及受體) (其中一些在各種類型的腫瘤細胞中選擇性上調)的實例包括PD-1 (計劃性細胞死亡蛋白1);PD-L1 (計劃性死亡配體-1);BTLA (B及T淋巴細胞衰減子);CTLA-4 (細胞毒性T淋巴細胞相關抗原4);TIM-3 (T細胞膜蛋白3);LAG-3 (淋巴細胞活化基因3);T細胞活化之V域免疫球蛋白抑制劑(VISTA);CD96;A2aR (腺苷A2a受體);A2bR (腺苷A2b受體);CD73 (胞外-5'-核苷酸酶);CD39 (ENTPD1、NTPDase1);精胺酸酶;吲哚胺-吡咯2,3-雙加氧酶(IDO);色胺酸2,3-雙加氧酶(TDO);及殺手細胞抑制性受體。本文中他處詳細地論述免疫檢查點抑制劑及用其之組合療法。
本發明進一步提供治療經病原體感染之個體的方法,其包含向個體投與有效養生法的以上抗體中之任一者。在一些方法中,病原體係HIV或SIV。在其他方法中,病原體係病毒、細菌、真菌或原蟲。
在其他態樣中,本發明提供一種結合至一或多個包含D51之胺基酸殘基上的TIGIT多肽的抗TIGIT抗體,其中TIGIT多肽具有對應於SEQ ID NO: 1之胺基酸序列。在一些實施例中,抗體係單株抗體。在本文所揭示之實施例中之任一些實施例中,抗體係嵌合的、人類化的或經鑲飾的。在一些實施例中,抗體係人類抗體。在本文所揭示之實施例中之任一些實施例中,抗體不結合至一或多個包含L44、I47或H55之胺基酸殘基。在本文所揭示之實施例中之任一些實施例中,抗體包含SEQ ID NO: 14之成熟輕鏈可變區及SEQ ID NO: 10之成熟重鏈可變區。在本文所揭示之實施例中之任一些實施例中,抗體與TIG1結合至對應於SEQ ID NO: 1之胺基酸序列上的同一抗原決定基。在本文所揭示之實施例中之任一些實施例中,抗體包括包含SEQ ID NO: 15-17之三個輕鏈CDR及包含SEQ ID NO: 11-13之三個重鏈CDR。在本文所揭示之實施例中之任一些實施例中,抗體包含與SEQ ID NO: 35具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 37具有至少90%序列一致性的成熟輕鏈可變區。在一些實施例中,成熟重鏈可變區包含SEQ ID NO: 35之胺基酸序列且成熟輕鏈可變區包含SEQ ID NO: 37之胺基酸序列。在本文所揭示之實施例中之任一些實施例中,成熟重鏈可變區係連接於包含SEQ ID NO: 40之重鏈恆定區,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於包含SEQ ID NO: 41之輕鏈恆定區。
在其他態樣中,本發明提供一種與TIG1、TIG2或TIG3中之任一者競爭結合至人類TIGIT的單株抗體,其中抗體TIG1之特徵在於SEQ ID NO: 14之成熟輕鏈可變區及SEQ ID NO: 10之成熟重鏈可變區,抗體TIG2之特徵在於SEQ ID NO: 22之成熟輕鏈可變區及SEQ ID NO: 18之成熟重鏈可變區,且抗體TIG3之特徵在於SEQ ID NO: 30之成熟輕鏈可變區及SEQ ID NO: 26之成熟重鏈可變區,用於特異性結合至CD155。在一些實施例中,抗體與TIG1、TIG2或TIG3中之任一者結合至人類TIGIT上的同一抗原決定基。在本文所揭示之實施例中之任一些實施例中,抗體抑制CD155與人類TIGIT之結合。在一些實施例中,抗體包含三個輕鏈CDR及三個重鏈CDR,其對應於TIG1、TIG2或TIG3中之任一者的三個輕鏈及三個重鏈CDR。在一些實施例中,抗體包含TIG1、TIG2或TIG3中之任一者的三個重鏈CDR及三個輕鏈CDR。在一些實施例中,抗體包含TIG1 (SEQ ID NO: 15-17輕鏈及11-13重鏈)、TIG2 (SEQ ID NO: 23-25輕鏈,19-21重鏈)或TIG3 (SEQ ID NO: 31-33輕鏈及27-29重鏈)中之任一者的如由Kabat所定義的三個重鏈CDR及如由Kabat所定義的三個輕鏈CDR。在本文所揭示之實施例中之任一些實施例中,抗體係嵌合的、人類化的或經鑲飾的。在一些實施例中,抗體係人類抗體。在本文所揭示之實施例中之任一些實施例中,抗體具有人類IgG1κ同型。在本文所揭示之實施例中之任一些實施例中,抗體係完整抗體。在本文所揭示之實施例中之任一些實施例中,抗體係單鏈抗體、Fab或F(ab')2片段。在本文所揭示之實施例中之任一些實施例中,抗體包含與SEQ ID NO: 35具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 37具有至少90%序列一致性的成熟輕鏈可變區。在一些實施例中,成熟重鏈可變區與SEQ ID NO: 35具有至少95或99%序列一致性且成熟輕鏈可變區與SEQ ID NO: 37具有至少95或99%序列一致性。在一些實施例中,成熟重鏈可變區具有SEQ ID NO: 35之胺基酸序列且成熟輕鏈可變區具有SEQ ID NO: 37之胺基酸序列。在一些實施例中,成熟重鏈可變區係連接於包含SEQ ID NO: 40之重鏈恆定區,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於包含SEQ ID NO: 41之輕鏈恆定區。在一些實施例中,成熟重鏈可變區係連接於包含SEQ ID NO: 60之重鏈恆定區,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於包含SEQ ID NO: 64之輕鏈恆定區。在一些實施例中,成熟重鏈可變區係連接於包含SEQ ID NO: 61之重鏈恆定區,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於包含SEQ ID NO: 64之輕鏈恆定區。在本文所揭示之實施例中之任一些實施例中,抗體包含與SEQ ID NO: 43具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 45具有至少90%序列一致性的成熟輕鏈可變區。在一些實施例中,成熟重鏈可變區與SEQ ID NO: 43具有至少95或99%序列一致性且成熟輕鏈可變區與SEQ ID NO: 45具有至少95或99%序列一致性。在一些實施例中,成熟重鏈可變區具有SEQ ID NO: 43之胺基酸序列且成熟輕鏈可變區具有SEQ ID NO: 45之胺基酸序列。在一些實施例中,成熟重鏈可變區係連接於重鏈恆定區,獲致包含SEQ ID NO: 48之重鏈,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 49之輕鏈。在一些實施例中,成熟重鏈可變區係連接於重鏈恆定區,獲致包含SEQ ID NO: 62之重鏈,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 65之輕鏈。在一些實施例中,成熟重鏈可變區係連接於重鏈恆定區,獲致包含SEQ ID NO: 63之重鏈,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 65之輕鏈。在又其他態樣中,本發明提供一種單株抗體,其結合至包含SEQ ID NO: 1之殘基35及37及/或SEQ ID NO: 1之殘基49及51的抗原決定基。在一些實施例中,抗體結合至包含SEQ ID NO: 1之殘基35、37、49及51的抗原決定基。在一些實施例中,抗體結合至由SEQ ID NO: 1之殘基35-51及任一側上不超過五個來自SEQ ID NO: 1之側接胺基酸組成的肽。在一些實施例中,抗體結合至由SEQ ID NO: 1之殘基35-51組成的肽。在一些實施例中,抗原決定基由SEQ ID NO: 1之3至20個相鄰殘基組成。在本文所揭示之實施例中之任一些實施例中,抗體具有以下性質中之一或多者:(a) 視情況以15-100 ng/ml之IC
50抑制TIGIT與CD155之結合;(b)在表現CD155之抗原呈現細胞存在下,視情況以1.5-3倍量增加如藉由IL-2產生所量測的固有T細胞活化;(c)視情況以1.5-3倍量增加如藉由IL-12產生所量測的抗原特異性T細胞活化;(d)視情況以1.5-3倍量增加如藉由IL-2、IL-6、TNFα或IFNγ中之任一者的產生所量測的自然殺手細胞活化;(e)視情況以1.5-3倍量增加至少一種促炎性細胞介素之T細胞產生;及(f)視情況以1.5-3倍量減少至少一種抗炎性細胞介素之T細胞產生。
在另一態樣中,本發明提供醫藥組合物,其包含本文所述之抗體中之任一者及醫藥學上可接受之載劑。
在其他態樣中,本發明提供用於治療癌症或實現癌症預防的方法,其包含向患有癌症或具有患癌症風險之個體投與有效養生法或治療有效量的本文所揭示之抗體中之任一者。在一些實施例中,癌症係急性骨髓性白血病或成人T細胞白血病。在本文所揭示之實施例中之任一些實施例中,向個體投與由抗體活化的腫瘤浸潤性T細胞。在本文所揭示之實施例中之任一些實施例中,向個體投與誘導針對癌症之免疫反應的疫苗,該免疫反應係藉由抗體增強。在一些實施例中,疫苗包含在癌細胞之表面上表現的抗原或其片段。在本文所揭示之實施例中之任一些實施例中,向個體投與自然殺手細胞,其針對癌症之細胞毒性係藉由抗體增強。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與針對在癌細胞之表面上表現的抗原的第二抗體,藉此第二抗體之針對癌症的效應子介導細胞毒性係藉由抗體增強。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與針對在免疫細胞之表面上表現之抗原的第二抗體。在一些實施例中,免疫細胞係T細胞或自然殺手細胞。在本文所揭示之實施例中之任一些實施例中,抗原係CTLA-4、PD-1或PD-L1。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與一或多種選自由化學療法、輻射、基於細胞之療法及外科手術組成之群的療法。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與一或多種免疫檢查點受體或配體的抑制劑。在一些實施例中,抑制劑係選自由伊匹單抗(ipilimumab)、納武單抗(nivolumab)、派姆單抗(pembrolizumab) (蘭利珠單抗(lambrolizumab))及阿特珠單抗(atezolizumab)組成之群。
在其他態樣中,本發明提供用於治療經病原體感染之個體的方法,其包含向個體投與有效養生法或治療有效量的本文所揭示之抗體中之任一者。在一些實施例中,病原體係病毒、細菌、真菌或原蟲。在一些實施例中,病原體係HIV、SIV、肝炎、疱疹病毒、腺病毒、流感病毒、黃病毒、埃可病毒(echovirus)、鼻病毒、科沙奇病毒(coxsackie virus)、冠狀病毒、呼吸道融合性病毒、腮腺炎病毒、輪狀病毒、麻疹病毒、風疹病毒、小病毒、痘瘡病毒、HTLV病毒、登革熱病毒(dengue virus)、乳突狀瘤病毒、軟疣病毒、脊髓灰白質炎病毒、狂犬病病毒、JC病毒、蟲媒腦炎病毒、衣原體、立克次體細菌(rickettsial bacteria)、分枝桿菌、葡萄球菌、鏈球菌、肺炎球菌、腦膜炎球菌、淋球菌(conococci)、克雷伯氏菌(klebsiella)、變形桿菌、沙雷氏菌(serratia)、假單胞菌、軍團桿菌(legionella)、白喉、沙門氏菌(salmonella)、桿菌、霍亂(cholera)、破傷風、肉毒中毒、炭疽、瘟疫、鉤端螺旋體病及萊姆病(Lyme disease)細菌。在本文所揭示之實施例中之任一些實施例中,用誘導針對病原體之免疫反應的疫苗治療個體,該免疫反應係藉由抗體增強。在一些實施例中,疫苗包含病原體之蛋白質或其片段。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與針對病原體之第二抗體,其中第二抗體之針對病原體的效應子介導細胞毒性係藉由抗體增強。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與抗病毒劑、抗寄生蟲劑、抗細菌劑或抗真菌劑中之一或多者。
在另一態樣中,本發明提供用於幫助治療癌症的方法,其包含向患有癌症的個體投與治療有效量的本文所揭示之抗體中之任一者。在一些實施例中,癌症係急性骨髓性白血病或成人T細胞白血病。在本文所揭示之實施例中之任一些實施例中,向個體投與由抗體活化的腫瘤浸潤性T細胞。在本文所揭示之實施例中之任一些實施例中,向個體投與誘導針對癌症之免疫反應的疫苗,該免疫反應係藉由抗體增強。在一些實施例中,疫苗包含在癌細胞之表面上表現的抗原或其片段。在本文所揭示之實施例中之任一些實施例中,向個體投與自然殺手細胞,其針對癌症之細胞毒性係藉由抗體增強。在本文所揭示之實施例中之任一些實施例中,向個體投與針對在癌細胞之表面上表現的抗原的第二抗體,藉此第二抗體之針對癌症的效應子介導細胞毒性係藉由抗體增強。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與針對在免疫細胞之表面上表現之抗原的第二抗體。在一些實施例中,免疫細胞係T細胞或自然殺手細胞。在本文所揭示之實施例中之任一些實施例中,抗原係CTLA-4、PD-1或PD-L1。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與一或多種選自由化學療法、輻射、基於細胞之療法及外科手術組成之群的療法。在本文所揭示之實施例中之任一些實施例中,向個體進一步投與一或多種免疫檢查點受體或配體的抑制劑。在一些實施例中,一或多種免疫檢查點受體或配體係選自由CTLA-4、PD-1及PD-L1組成之群。在一些實施例中,抑制劑係選自由伊匹單抗、納武單抗、派姆單抗(蘭利珠單抗)及阿特珠單抗組成之群。
除非實施例或態樣之上下文中明確地或清楚地排除,否則本文所述之態樣及實施例中之每一者能夠一起使用。
相關申請案的交叉引用本申請案主張2016年3月4日申請之美國臨時專利申請案第62/304,045號及2016年10月26日申請之美國臨時專利申請案第62/413,025號之優先權,該等臨時專利申請案中之每一者的揭示內容以全文引用的方式併入本文中。
本發明尤其提供特異性結合至TIGIT之細胞外域的單株抗體,TIGIT係胞質尾區中含免疫受體酪胺酸基抑制基元(ITIM)之免疫球蛋白超家族的成員。單株抗體抑制TIGIT與CD155之結合且從而可活化T細胞及/或NK細胞。單株抗體可用於治療癌症及傳染病以及其他應用。
I. 定義通常以經分離形式提供單株抗體或其他生物實體,諸如TIGIT之片段。此意謂著,抗體或其他生物學實體通常係至少50% w/w純的干擾蛋白質及其他由其製造或純化產生的污染物,但是不排除單株抗體與過量醫藥學上可接受的載劑或其他意欲方便其使用的媒劑組合的可能性。有時單株抗體係至少60%、70%、80%、90%、95%或99% w/w純的干擾蛋白質及由其製造或純化產生的污染物。經分離單株抗體或其他生物性實體藥劑常常係在其純化之後剩餘的主要大分子物種。
單株抗體與其目標抗原之特異性結合意謂至少10
6、10
7、10
8、10
9或10
10M
-1之親和力(締合常數或Ka),藉由例如實例15之分析測定。特異性結合之可偵測量值較高且可與至少一種不相關目標發生的非特異性結合區分。特異性結合可以係在特定官能基或特定空間擬合(例如,鎖定及關鍵類型)之間的成鍵結果,而非特異性結合通常係凡得瓦爾力(van der Waals force)之結果。然而,特異性結合不一定隱含著單株抗體結合一個且僅一個目標。
基本抗體結構單元係亞單元之四聚體。各四聚體包括兩對相同的多肽鏈,每對具有一個「輕」鏈(約25 kDa)及一個「重」鏈(約50-70 kDa)。各鏈之胺基端部分包括主要負責抗原識別的具有約100至110個或更多個胺基酸的可變區。此可變區首先與可裂解信號肽有關地表現。無信號肽之可變區有時稱為成熟可變區。因此,舉例而言,輕鏈成熟可變區意謂無輕鏈信號肽之輕鏈可變區。各鏈之羧基端部分界定主要負責效應功能之恆定區。
輕鏈係歸類為κ或λ。重鏈係歸類為γ、μ、α、δ或ε,且抗體之同型分別定義為IgG、IgM、IgA、IgD及IgE。在輕鏈及重鏈內,可變區及恆定區由具有約12個或更多個胺基酸之「J」區連接,其中重鏈亦包括具有約10個或更多個胺基酸之「D」區。(
大體上參見 Fundamental Immunology(Paul, W.編, 第2版, Raven Press, N.Y.,1989), 第7章) (其出於所有目的以全文引用的方式併入本文中)。
各輕鏈/重鏈對之成熟可變區形成抗體結合位點。因此,完整抗體具有兩個結合位點。但在雙官能或雙特異性抗體中除外,兩個結合位點係相同的。鏈均呈現藉由三個高變區連接之相對保守構架區(FR)之相同通式結構,亦稱為互補決定區或CDR。來自各對之兩條鏈之CDR藉由構架區對齊,使得能夠結合於特異性抗原決定基。自N端至C端,輕鏈及重鏈均包含域FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。胺基酸於各域之分配係根據Kabat,
Sequences of Proteins of Immunological Interest(National Institutes of Health, Bethesda, MD, 1987及1991)或Chothia及Lesk
, J. Mol. Biol.196:901-917 (1987);Chothia等人,
Nature342:878-883 (1989)之定義進行。Kabat亦提供一種廣泛使用的編號慣例(Kabat編號),其中給不同重鏈之間或不同輕鏈之間的相應殘基分配相同編號。
術語「抗體」包括完整抗體及其結合片段。因此,除非本文另有規定,否則對抗體之任何提及應理解為係指呈完整形式的抗體或結合片段。片段通常與其所衍生之完整抗體競爭特異性結合至目標,包括單獨重鏈、輕鏈Fab、Fab'、F(ab')
2、F(ab)
c、Dabs、奈米抗體及scFv、雙功能抗體、scFv-Fc、微型抗體、IgNARs、V-NAR、hcIgG、雙scFv、三功能抗體及四功能抗體。片段可藉由重組DNA技術或藉由完整免疫球蛋白之酶促或化學分離來產生。術語「抗體」亦包括雙特異性抗體。雙特異性或雙功能抗體係具有兩個不同重鏈/輕鏈對及兩個不同結合位點的人工雜種抗體(參見例如Songsivilai及Lachmann,
Clin. Exp. Immunol., 79:315-321 (1990);Kostelny等人
, J. Immunol., 148:1547-53 (1992))。
術語「抗原決定基」係指抗原上由抗體結合的位點。抗原決定基可由藉由一或多個蛋白質之三級摺疊並列的相鄰胺基酸或非相鄰胺基酸形成。由相鄰胺基酸形成的抗原決定基(亦稱為線性抗原決定基)通常保留暴露於變性溶劑,而由三級摺疊形成的抗原決定基(亦稱為構形抗原決定基)通常對變性溶劑處理不起作用。抗原決定基在獨特空間構形中通常包括至少3個,且更通常至少5個或8-10個胺基酸。測定抗原決定基之空間構形之方法包括例如X射線晶體學及2維核磁共振。參見例如Epitope Mapping Protocols,
Methods in Molecular Biology, 第66卷, Glenn E. Morris編 (1996)。
識別相同或重疊抗原決定基的抗體可以在單一免疫分析中鑑別,該單一免疫分析顯示一種抗體與另一抗體競爭結合至目標抗原的能力。抗體之抗原決定基亦可以由與其抗原鍵結以鑑別接觸殘基的抗體的X射線晶體學定義。或者,若抗原中減少或消除一個抗體之結合的所有胺基酸突變減少或消除另一抗體之結合,則兩個抗體具有相同抗原決定基。若減少或消除一個抗體之結合的一些胺基酸突變減少或消除另一抗體之結合,則兩個抗體具有重疊抗原決定基。
抗體之間的競爭藉由如下分析測定:其中在測試條件下,抗體抑制參考抗體與共同抗原的特異性結合(參見例如Junghans等人,
Cancer Res. 50:1495, 1990)。若過量測試抗體(例如,至少2×、3×、4×、5×、6×、7×、8×、9×、10×、15×、20×、25×、30×、35×、40×、45×、50×、60×、70×、80×、90×、100×或更大,包括落在此等值之間的數值)將參考抗體之結合抑制至少50%,但是較佳75%、90%或99%,則測試抗體與參考抗體競爭。在其他實施例中,若過量測試抗體將參考抗體之結合抑制至少約55%、60%、65%、70%中之任一者,或較佳至少約75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%,如在競爭性結合分析中所量測,則測試抗體與參考抗體競爭。藉由競爭分析(競爭抗體)鑑別之抗體包括與參考抗體結合至同一抗原決定基的抗體及結合至足夠靠近參考抗體所結合之抗原決定基之相鄰抗原決定基以產生位阻的抗體。競爭較佳如實例14中般評定。
術語「個體」包括人類及其他哺乳動物個體。在一些情況下,本發明方法可用於實驗動物、獸醫學應用及研發動物疾病模型,包括(但不限於)嚙齒動物,包括小鼠、大鼠、倉鼠,以及靈長類動物,諸如猿猴。在一些實施例中,個體接受預防性或治療性治療或者係接受預防性或治療性治療的候選者。
如本文所用,「對應於(corresponds to)」或係「對應於(corresponding to)」參考胺基酸序列之胺基酸殘基或「與」參考胺基酸序列之胺基酸殘基呈「對應關係(correspondence with)」的相關胺基酸序列之胺基酸殘基指示,相關序列之胺基酸殘基係處於與參考胺基酸序列中所計數之殘基同源或等效的位置處。熟習此項技術者可以判定諸如TIGIT多肽之多肽中之特定胺基酸殘基位置是否對應於同源參考序列之胺基酸殘基位置。舉例而言,TIGIT多肽之序列可以使用已知技術(例如,基本局部比對檢索工具(basic local alignment search tool;BLAST)、ClustalW2、基於結構之序列比對程式(STRAP)或其類似者)與參考序列比對。另外,可以使用參考序列之晶體結構座標來幫助測定同源多肽殘基之三維結構(Stengel等人,
Proc. Natl. Acad. Sci. USA,109:5399-5404, 2012)。在另一態樣中,可以藉由在三級結構水準測定同源性來鑑別等效殘基。使用此類方法,TIGIT多肽變異體之胺基酸殘基可以根據參考序列之相應胺基酸殘基位置編號進行編號。舉例而言,可以使用SEQ ID NO: 1之胺基酸序列來確定相關TIGIT變異體或抗原決定基之各胺基酸殘基的胺基酸殘基位置編號。在一些實施例中,若一個胺基酸序列共用至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性,則其對應於另一胺基酸序列。
出於將胺基酸取代分類為保守或非保守之目的,胺基酸分組如下:I組(疏水性側鏈):met、ala、val、leu、ile;II組(中性親水性側鏈):cys、ser、thr;III組(酸性側鏈):asp、glu;IV組(鹼性側鏈):asn、gln、his、lys、arg;V組(影響鏈取向之殘基):gly、pro;以及VI組(芳族側鏈):trp、tyr、phe。保守取代涉及在相同類別中之胺基酸之間的取代。非保守取代構成此等類別中之一者之成員與另一類別之成員的交換。
藉由Kabat編號慣例與抗體序列最大限度地比對來確定序列一致性百分比。在比對之後,若比較目標抗體區域(例如,重鏈或輕鏈之整個成熟可變區)與參考抗體之相同區域,則目標抗體區域與參考抗體區域之間的序列一致性百分比係目標抗體區域及參考抗體區域兩者中相同胺基酸所佔據的位置之數目除以兩個區域所比對位置之總數(不計間隙)乘以100,從而轉換成百分比。
「包含」一或多種所敍述要素之組合物或方法可包括未具體敍述之其他要素。舉例而言,包含抗體之組合物可單獨或與其他成分組合地含有抗體。
除非根據上下文明顯不同,否則提及範圍時包括範圍內的所有整數及由該等整數界定的所有子範圍。
II.
目標分子除非另外指示,否則TIGIT意謂人類TIGIT。例示性人類序列經指定為Swiss-Prot寄存編號Q495A1。完整的人類TIGIT序列具有244個胺基酸,其中胺基酸1-21係信號肽且22-244構成成熟蛋白(SEQ ID NO: 1)。大約殘基22-141構成細胞外域(SEQ ID NO: 3)。大約殘基142-162構成跨膜域,且大約殘基163-244構成細胞質域。
除非另外指示,否則CD155係指此蛋白質之人類形式。人類CD155之例示性人類序列經指定為Swiss-Prot P15151,其係417個胺基酸之蛋白質,其中大約殘基1-20係信號肽,21-343係細胞外域(SEQ ID NO: 6),344-367係跨膜域,且368-417係細胞質域。
除非根據上下文明顯不同,否則提及以上蛋白質中之一者時至少意謂蛋白質之細胞外域且通常係除可裂解信號肽以外的整個蛋白質。
III. 本發明抗體A.
結合特異性及功能性質 本發明提供結合至TIGIT蛋白質之細胞外域內的抗原決定基的單株抗體。命名為TIG1、TIG2及TIG3之抗體係三個此類例示性小鼠抗體。此等抗體之重鏈及輕鏈成熟可變區之序列分別命名為SEQ ID NO. 10及14、18及22、以及26及30。TIG1、TIG2及TIG3特異性結合至人類TIGIT之細胞外域。
一些本發明抗體與命名為TIG1、TIG2或TIG3之抗體結合至相同或重疊的抗原決定基。其他具有此類結合特異性的抗體可以藉由用包括所要抗原決定基的TIGIT或其部分對小鼠進行免疫,且針對與TIGIT之細胞外域的結合,視情況與TIG1、TIG2或TIG3競爭結合,篩選所得抗體而產生。亦可以針對TIGIT抗原之誘變形式篩選抗體來鑑別針對一系列突變改變與TIG1、TIG2或TIG3顯示相同或類似的結合概況的抗體。突變可以係在TIGIT抗體之整個細胞外域中或在已知抗原決定基所存在的部分中,同時地或以間隔得較開的時間間隔用丙胺酸(若丙胺酸已經存在,則絲胺酸)系統置換取代一種殘基。(以下稱「段落A」)
實例16將SEQ ID NO: 1之殘基35、37、49及51定位為形成TIG1抗體之抗原決定基的殘基。在此等殘基中之任一者處之丙胺酸取代基本上消除抗體之結合。因此,本發明包括結合至人類TIGIT之抗原決定基的其他抗體,該抗原決定基包含SEQ ID NO: 1之殘基35及37及/或SEQ ID NO: 1之殘基49及51,且較佳係包括所有此等殘基之抗原決定基。抗原決定基可以係線性抗原決定基(例如,3-20、3-17或5-10個相鄰殘基)或構形抗原決定基。一些此類抗體結合至由SEQ ID NO: 1之殘基35-51及任一側上不超過1、2、3、4或5個來自SEQ ID NO: 1之側接胺基酸組成的肽。一些此類抗體結合至由SEQ ID NO: 1之殘基35-51組成的肽。一些此類抗體可以藉由用此類肽免疫而產生。實例19亦揭示,除了SEQ ID NO: 1之殘基35、37、49及51之外,SEQ ID NO: 1之殘基90對於人類化(Hu) TIG1抗體與TIGIT之結合亦係關鍵的。在其他實施例中,抗體(諸如HuTIG1抗體)結合至包含對應於SEQ ID NO: 1之胺基酸位置35、37、49、51及/或90的殘基中之一或多者的抗原決定基。在其他實施例中,抗體(諸如HuTIG1抗體)不結合至對應於SEQ ID NO: 1之胺基酸位置34、39、44、47、52、55、86、88、92及/或96的一或多個殘基。
具有所選鼠類抗體(例如TIG1、TIG2或TIG3)之結合特異性的抗體亦可以使用噬菌體呈現方法之變體產生。參見Winter,WO 92/20791。此方法尤其適合於產生人類抗體。在此方法中,使用所選鼠類抗體之重鏈或輕鏈可變區作為起始物質。舉例而言,若選擇輕鏈可變區作為起始物質,則構築如下噬菌體文庫,其中各成員呈現相同輕鏈可變區(亦即,鼠類起始物質)及不同重鏈可變區。重鏈可變區例如可以自重排的人類重鏈可變區之文庫獲得。選擇針對TIGIT顯示強特異性結合(例如,至少10
8且較佳至少10
9M
-1)的噬菌體。此噬菌體之重鏈可變區隨後充當用於構築另一噬菌體文庫的起始物質。在此文庫中,各噬菌體呈現相同重鏈可變區(亦即,自第一呈現文庫鑑別的區域)及不同輕鏈可變區。輕鏈可變區例如可以自重排的人類可變輕鏈區之文庫獲得。再次選擇針對TIGIT顯示強特異性結合的噬菌體。所得抗體通常具有與鼠類起始物質相同或類似的抗原決定基特異性。
一些抗體具有完全或基本上來自TIG1的包含CDR H1、H2及H3的成熟重鏈可變區及包含CDR L1、L2及L3的成熟輕鏈區。一些抗體具有完全或基本上來自TIG2的包含CDR H1、H2及H3的成熟重鏈可變區及包含CDR L1、L2及L3的成熟輕鏈區。一些抗體具有完全或基本上來自TIG3的包含CDR H1、H2及H3的成熟重鏈可變區及包含CDR L1、L2及L3的成熟輕鏈區。CDR可以由任何習知定義進行定義,習知定義包括Kabat、Chothia、Kabat與Chothia複合、AbM或Contact定義,如下表中所示:
其他抗體可以藉由編碼例示性抗體之重鏈及輕鏈的cDNA之突變誘發獲得,例示性抗體諸如TIG1、TIG2或TIG3。在成熟重鏈及/或輕鏈可變區之胺基酸序列方面與TIG1、TIG2或TIG3具有至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%中之任一者的一致性且維持其功能性質,及/或與各別抗體相差少量在功能上不連貫的胺基酸取代(例如,保守取代)、缺失或插入的單株抗體亦包括在本發明中。對於結合可能重要的可變區構架中之胺基酸可以如下文在關於人類化的部分中所述般鑑定。亦包括具有至少一個且較佳所有六個如由Kabat所定義之CDR的單株抗體,該(等) CDR與TIG1、TIG2或TIG3之相應CDR具有約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%中之任一者的一致性。
抗體較佳具有以下特徵中之一或多者:(i)抑制人類TIGIT與人類CD155之結合;(ii)抑制TIGIT與諸如CD112及CD113之其他配體的結合;(iii)增加抗原特異性T細胞反應;(iv)活化自然殺手細胞;(v)刺激固有T細胞活化;及(vi)刺激T細胞及免疫系統之其他細胞的一或多種免疫刺激性細胞介素之產生及/或減少一或多種免疫抑制性細胞介素之產生。用於量測此等性質之例示性分析提供在實例中。
較佳的抗體完全地或部分地抑制TIGIT與CD155之結合。一些抗體可以以下中之任一者之IC
50抑制此類相互作用:約25-300 ng/ml、25-75 ng/ml、25-50 ng/ml、40-75 ng/ml、50-75 ng/ml、50-90 ng/ml、50-100 ng/ml、75-100 ng/ml、50-150、75-175 ng/ml、100-200 ng/ml、125-225 ng/ml、100-250 ng/ml、150-300 ng/ml、175-250 ng/ml、200-300 ng/ml、25-275 ng/ml、250-300 ng/ml、49 +/-10% ng/ml、65 +/-10% ng/ml或76 +/-10% ng/ml,如在實例中所量測。在其他實施例中,抗體可以至少約25 ng/ml、50 ng/ml、75 ng/ml、100 ng/ml、125 ng/ml、150 ng/ml、175 ng/ml、200 ng/ml、225 ng/ml、250 ng/ml、275 ng/ml或300 ng/ml中之任一者或更大的IC
50完全地或部分地抑制TIGIT與CD155之結合,包括落在此等值之間的濃度。一些抗體可以使抗原特異性T細胞反應增加1.5-3倍,諸如約1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或3倍中之任一者或更大,如在實例中所量測。一些抗體可以使NK細胞產生的IL-2、IL-6、TNFα及IFNγ中的1、2、3個或全部增加1.5至3倍,諸如約1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或3倍中之任一者或更大,如在實例中所量測。一些抗體可以使固有T細胞活化增加1.5-3倍,諸如約1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或3倍中之任一者或更大,如在實例中所量測。如動物模型或臨床試驗中所示,一些抗體可以抑制癌症或傳染病。將人類癌細胞注射至諸如小鼠或大鼠之免疫缺陷實驗室動物中的動物癌症模型係廣泛可用的。
相對於起始小鼠抗體,人類化或嵌合抗體延長了活體內半衰期。例如在人類中,所得半衰期可以係10-50天。半衰期可以藉由藥物動力學研究量測,諸如Kim等人,
Eur J of Immunol24:542 (1994)所述。
B.
非人類抗體 針對TIGIT之其他非人類單株抗體(例如鼠類、天竺鼠、靈長類動物、兔、雞或大鼠)之產生可以藉由例如用TIGIT或其片段或攜帶TIGIT之細胞對動物進行免疫來實現。參見Harlow及Lane,
Antibodies,
A Laboratory Manual(CSHP NY, 1988) (出於所有目的以引用的方式併入)。此類免疫原可以藉由肽合成或藉由重組性表現自天然來源獲得。視情況,可以與載體蛋白質融合或以其他方式複合來投與免疫原。視情況,可以與佐劑一起投與免疫原。可以使用如下所述的若干類型之佐劑。關於實驗室動物之免疫,弗氏完全佐劑(Complete Freund's adjuvant)、繼之以不完全佐劑係較佳的。通常使用兔或天竺鼠來製造多株抗體。通常使用小鼠來製造單株抗體。篩選出特異性結合至TIGIT的抗體。視情況,進一步篩選結合至TIGIT之特定區域的抗體。此類篩選可以藉由測定抗體與一系列TIGIT之缺失突變體的結合且判定哪些缺失突變體結合至抗體來實現。結合可以例如藉由西方墨點法、FACS或ELISA來評定。
C.
人類化抗體 減少或消除HAMA (人類抗小鼠(亦適用於人類抗大鼠或人類抗兔或人類抗倉鼠等)抗體)反應係合適的治療劑之臨床發展的顯著態樣。參見例如Khaxzaeli等人,
J. Natl. Cancer Inst. (1988), 80:937;Jaffers等人,
Transplantation(1986), 41:572;Shawler等人,
J. Immunol. (1985), 135:1530;Sears等人,
J. Biol. Response Mod. (1984), 3:138;Miller等人,
Blood(1983), 62:988;Hakimi等人,
J. Immunol.(1991), 147:1352;Reichmann等人,
Nature(1988), 332:323;Junghans等人,
Cancer Res. (1990), 50:1495。如本文所述,本發明提供經人類化以使得HAMA反應減少或消除的抗體。此等抗體之變異體可以進一步使用此項技術中已知之常規方法獲得,該等方法中之一些進一步描述於下文中。
人類化抗體係基因工程改造之抗體,其中來自非人類「供體」抗體之CDR移植至人類「接受體」抗體序列中(參見,例如Queen, US 5,530,101及5,585,089;Winter, US 5,225,539;Carter, US 6,407,213;Adair, US 5,859,205、6,881,557;Foote, US 6,881,557)。接受體抗體序列可為例如成熟人類抗體序列、此類序列之複合物、人類抗體序列之共同序列或生殖系區序列。因此,人類化抗體係具有完全或基本上來自供體抗體之一些或所有CDR以及可變區構架序列及恆定區(若存在,則完全或基本上來自人類抗體序列)的抗體。類似地,人類化重鏈具有至少一個、兩個且通常所有三個完全或基本上來自供體抗體重鏈之CDR以及重鏈可變區構架序列及重鏈恆定區(若存在,則基本上來自人類重鏈可變區構架及恆定區序列)。類似地,人類化輕鏈具有至少一個、兩個且通常所有三個完全或基本上來自供體抗體輕鏈之CDR以及輕鏈可變區構架序列及輕鏈恆定區(若存在,則基本上來自人類輕鏈可變區構架及恆定區序列)。除奈米抗體及dAbs以外,人類化抗體包含人類化重鏈及人類化輕鏈。此處如本發明其他地方一樣,當各別CDR之間至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%之相應殘基(如由Kabat所定義)相同時,本發明抗體中之CDR基本上來自參考抗體中之相應CDR;然而,當各別CDR之間至少約65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%之相應殘基(如由Kabat所定義)相同時,本發明抗體中之如由Kabat所定義的CDR H2基本上來自參考抗體中之相應CDR。當至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%之由Kabat定義的相應殘基相同時,抗體鏈之可變區構架序列或抗體鏈之恆定區基本上分別來自人類可變區構架序列或人類恆定區
雖然人類化抗體常常併入了所有六個來自非人類(例如小鼠)抗體之CDR (較佳如由Kabat所定義),但是其亦可以製成所含來自非人類抗體之CDR不到全部的CDR(例如,至少3、4或5個) (例如,Pascalis等人,
J. Immunol. 169:3076, 2002;Vajdos等人,
Journal of Molecular Biology, 320: 415-428, 2002;Iwahashi等人,
Mol. Immunol. 36:1079-1091, 1999;Tamura等人,
Journal of Immunology,164:1432-1441, 2000)。
在一些抗體中,在人類化抗體中僅需要一部分CDR來保留結合,亦即結合所需之CDR殘基的亞群,稱為SDR。不接觸抗原且不在SDR中的CDR殘基可以基於先前研究(例如CDR H2中之殘基H60-H65常常是不需要的)、從處於Chothia高變環外部之Kabat CDR的區域(Chothia,
J. Mol. Biol. 196:901, 1987)、藉由分子模型化及/或憑經驗、或如Gonzales等人,
Mol. Immunol. 41: 863, 2004中所述般鑑別。在缺少一或多個供體CDR殘基或省略整個供體CDR的位置處的此類人類化抗體中,佔據該位置之胺基酸可以係佔據接受體抗體序列中之對應位置(藉由Kabat編號)的胺基酸。在CDR中以此類接受體胺基酸取代供體胺基酸之數目反映了競爭性考慮因素之平衡。此類取代對於減少人類化抗體中之小鼠胺基酸之數目可能是有利的,且因此,對於降低潛在免疫原性可能有利。然而,取代亦會導致親和力改變,且較佳地是避免親和力顯著降低。CDR內之取代位置及待取代之胺基酸亦可以憑經驗選擇。
雖然接受體之序列可以與所選人類構架序列相同,但是無論其來自人類免疫球蛋白抑或人類共同構架,本發明均涵蓋接受體序列可以包含相對於人類免疫球蛋白序列或人類共同構架序列既存的胺基酸取代。此等既存的取代較佳係最少的;通常相對於人類免疫球蛋白序列或共同構架序列僅四個、三個、兩個或一個胺基酸差異。
人類接受體抗體序列可以視情況選自許多已知的人類抗體序列,從而在人類接受體序列可變區構架與供體抗體鏈之相應可變區構架之間得到高序列一致性程度(例如,65-85%一致性)。
某些來自人類可變區構架殘基之胺基酸可基於其對CDR構形及/或與抗原之結合的可能影響加以選擇以用於取代。藉由模型化、特定位置處之胺基酸之特徵的檢查或特定胺基酸之取代或突變誘發之作用的經驗觀察來研究此類可能的影響。
舉例而言,當非人類可變區構架殘基與所選人類可變區構架殘基之間的胺基酸不同時,當合理地預期胺基酸如下時,人類構架胺基酸可以經來自非人類抗體之等效構架胺基酸取代:
(1) 直接非共價結合抗原,
(2) 與CDR區相鄰,
(3) 以其他方式與CDR區相互作用(例如,在CDR區之約6 Å內)。
在彼位置之其他取代候選者係對於人類免疫球蛋白而言不尋常的接受體人類構架胺基酸。此等胺基酸可經來自非人類供體抗體之等效位置之胺基酸或來自更典型人類免疫球蛋白之等效位置之胺基酸取代。在彼位置之其他取代候選者係對於人類免疫球蛋白而言不尋常的接受體人類構架胺基酸。
較佳的人類化抗體具有與SEQ ID NO:35具有至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或小於100%的一致性的成熟重鏈可變區及與SEQ ID NO: 37具有至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或小於100%的一致性的成熟輕鏈可變區。除鑑定為可能對結合重要的殘基(參見段落A)之外,較佳在可變區構架殘基處發生任何變異。任何變異較佳係保守胺基酸取代。較佳的抗體包含具有SEQ ID NO: 35之序列的成熟重鏈可變區及具有SEQ ID NO: 37之序列的成熟輕鏈可變區。關於全長抗體之表現,成熟重鏈可變區較佳與由SEQ ID NO: 40組成或包含SEQ ID NO: 40的重鏈恆定區有關,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區較佳與由SEQ ID NO: 41組成或包含SEQ ID NO: 41的輕鏈恆定區有關。
另一較佳的人類化抗體具有與SEQ ID NO: 43具有至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或小於100%一致性的成熟重鏈可變區及與SEQ ID NO: 45具有至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或小於100%一致性的成熟輕鏈可變區。除鑑定為可能對結合重要的殘基(參見段落A及實例)之外,較佳在可變區構架殘基處發生任何變異。任何變異較佳係保守胺基酸取代。較佳的抗體包含具有SEQ ID NO: 43之序列的成熟重鏈可變區及具有SEQ ID NO: 45之序列的成熟輕鏈可變區。關於全長抗體之表現,成熟重鏈可變區較佳連接至重鏈恆定區,獲致由SEQ ID NO: 48組成或包含SEQ ID NO: 48的重鏈,其條件為C端離胺酸可以存在或可以不存在,且成熟輕鏈可變區較佳連接至輕鏈恆定區,獲致由SEQ ID NO: 49組成或包含SEQ ID NO: 49的輕鏈。
D.
嵌合抗體及面飾化抗體 本發明進一步提供非人類抗體之嵌合及面飾化形式,尤其是實例之TIG1、TIG2及TIG3抗體。
嵌合抗體係非人類抗體(例如小鼠)之輕鏈及重鏈之成熟可變區與人類輕鏈及重鏈恆定區組合的抗體。此類抗體基本上或完全保留非人類抗體之結合特異性,且係約三分之二的人類序列。
面飾化抗體係一種類型之人類化抗體,其保留一些且通常所有的CDR以及非人類抗體之非人類可變區構架殘基中之一些,但是用來自人類抗體序列之相應位置的殘基置換可能有助於B或T細胞抗原決定基的其他可變區構架殘基(例如,暴露的殘基) (Padlan,
Mol. Immunol. 28:489, 1991)。結果係CDR完全或基本上來自非人類抗體且非人類抗體之可變區構架藉由取代而變得更像人類的抗體。本發明中包括TIG1、TIG2或TIG3抗體之面飾化形式。
E.
人類抗體 針對TIGIT之人類抗體藉由下文所述的各種技術提供。藉由競爭性結合實驗、藉由上文Winter之噬菌體呈現方法或以其他方式選擇一些人類抗體以具有與特定小鼠抗體相同的抗原決定基特異性,諸如實例中所述的小鼠單株抗體中之一者。亦可以藉由僅使用TIGIT之片段作為目標抗原,及/或藉由篩選針對TIGIT之一系列缺失突變體的抗體,針對特定抗原決定基特異性篩選人類抗體。
用於產生人類抗體之方法包括Oestberg等人,
Hybridoma2:361-367 (1983);Oestberg, 美國專利第4,634,664號之三源融合瘤(trioma)方法;及Engleman等人,美國專利4,634,666,使用轉殖基因小鼠,包括人類免疫球蛋白基因(參見例如Lonberg等人, WO93/12227 (1993);US 5,877,397、US 5,874,299、US 5,814,318、US 5,789,650、US 5,770,429、US 5,661,016、US 5,633,425、US 5,625,126、US 5,569,825、US 5,545,806;
Nature148, 1547-1553 (1994);
Nature Biotechnology14, 826 (1996);Kucherlapati, WO 91/10741 (1991))及噬菌體呈現方法(參見例如Dower等人, WO 91/17271及McCafferty等人, WO 92/01047;US 5,877,218、US 5,871,907、US 5,858,657、US 5,837,242、US 5,733,743及US 5,565,332)。
F.
恆定區之選擇 嵌合抗體、人類化(包括面飾化)抗體或人類抗體之重鏈及輕鏈可變區可與人類恆定區之至少一部分有關。恆定區之選擇部分視是否需要抗體依賴性補體及/或細胞介導之細胞毒性而定。舉例而言,人類同型IgG1及IgG3具有補體介導之細胞毒性,而人類同型IgG2及IgG4則不具有。輕鏈恆定區可以係λ或κ。關於針對不表現TIGIT之癌症或病原體的免疫療法,人類IgG2或IgG4或具有降低的效應功能之減毒形式的人類IgG1常常係較佳的。關於人類IgG4,在重鏈上包括經S228P (Eu編號)工程改造之突變以防止Fab臂交換常常係較佳的。然而,對於表現TIGIT之癌細胞(例如,T細胞或NK細胞之腫瘤)的消除或對於免疫抑制,人類IgG1或IgG3常常係較佳的。
人類恆定區在不同個體之間會顯示同種異型變異及同源同種異型(isoallotypic)變異,亦即在不同個體中在一或多個多形位置處恆定區可不同。同源同種異型與同種異型之不同之處在於識別同源同種異型之血清結合至一或多個其他同型之非多形區。提及人類恆定區時包括具有任何天然同種異型性或天然同種異型性中佔據多形位置之殘基的任何排列的恆定區。
在一定比例的或全部的分子中,輕鏈及/或重鏈之胺基或羧基端處之一個或若干個胺基酸,諸如重鏈之C端離胺酸,可缺失或衍生。可在恆定區中進行取代以降低或增大效應功能,諸如補體介導之細胞毒性或ADCC (參見,例如Winter等人,美國專利第5,624,821號;Tso等人,美國專利第5,834,597號;及Lazar等人,
Proc. Natl. Acad. Sci. USA103:4005, 2006),或用以延長在人類中之半衰期(參見,例如Hinton等人,
J. Biol. Chem.279:6213, 2004)。例示性取代包括在位置250處之Gln及/或位置處428 (Eu編號)之Leu,以便提高抗體之半衰期。
一些本發明抗體藉由引入恆定區突變進行工程改造,從而相比於不含突變之相同抗體,具有降低的效應功能,諸如CDC及ADCC或ADCP。較佳地,相比於不含突變之抗體,此等效應功能中之每一者或全部降低至少50%、75%、90%或95%。本發明實例顯示如何量測CDC。其他分析由Shields等人, 2001
J. Biol. Chem., 第276卷, 第6591-6604頁;Chappel等人, 1993
J. Biol. Chem.,第268卷, 第25124-25131頁;Lazar等人, 2006
PNAS, 103; 4005-4010描述。
位置234、235、236及/或237中之任何或所有位置的取代降低了對Fcγ受體,尤其是對FcγRI受體的親和力(參見例如US 6,624,821)。丙胺酸係用於取代的較佳殘基且L234A/L235A係用於降低效應功能的較佳雙重突變。具有降低的效應功能的其他突變組合包括L234A/L235A/G237A、E233P/L234V/L235A/G236、A327G/A330S/P331S、K322A、L234A及L235A、L234F/L235E/P331S。視情況,人類IgG2中之位置234、236及/或237經丙胺酸取代且位置235經麩醯胺酸取代。(參見例如US 5,624,821。)EU索引位置330及331處之補體C1q結合位點中之兩個胺基酸取代減少補體結合(參見Tao等人,
J. Exp. Med. 178:661 (1993)及Canfield及Morrison
, J. Exp. Med.173:1483 (1991))。取代到位置233-236處之人類IgG1或IgG2殘基以及位置327、330及331處之IgG4殘基中大大降低了ADCC及CDC (參見例如Armour KL.等人, 1999
Eur J Immunol. 29(8):2613-24;及Shields RL.等人, 2001
. J Biol Chem. 276(9):6591-604)。N297A、N297Q或N297G (Eu編號)突變減少糖基化且從而降低效應功能。
G.
重組抗體之表現 嵌合抗體、人類化(包括面飾化)抗體及人類抗體通常藉由重組性表現產生。重組性聚核苷酸構築體通常包括可操作地連接於抗體鏈之編碼序列的表現控制序列,包括天然相關或異源啟動子區。較佳地,表現控制序列係載體中能夠轉型或轉染真核宿主細胞之真核啟動子系統。一旦載體已併入至適當宿主中,宿主就維持在適合高水準表現核苷酸序列且收集及純化重組抗體的條件下。
哺乳動物細胞係用於表現編碼免疫球蛋白或其片段之核苷酸區段的較佳宿主。參見Winnacker, From Genes to Clones, (VCH出版社, NY, 1987)。能夠分泌完整異源蛋白質之多個適合的宿主細胞株已在此項技術中研發出,且包括CHO細胞株、各種COS細胞株、HeLa細胞、HEK293細胞、L細胞及非產抗體骨髓瘤,包括Sp2/0及NS0。較佳地,細胞係非人類的。用於此等細胞之表現載體可包括表現控制序列,諸如複製起點、啟動子、強化子(Queen等人,
Immunol. Rev.89:49 (1986)),及必需的處理資訊的位點,諸如核糖體結合位點、RNA剪接位點、聚腺苷酸化位點以及轉錄終止子序列。較佳表現控制序列係來源於內源基因、巨細胞病毒、SV40、腺病毒、牛乳突狀瘤病毒及其類似者之啟動子。參見Co等人,
J. Immunol. 148:1149 (1992)。
一旦表現,抗體就可根據此項技術之標準程序純化,包括HPLC純化、管柱層析、凝膠電泳及其類似者(通常參見,Scopes, Protein Purification (Springer-Verlag, NY, 1982))。
IV. 治療應用抗體可用於增強免疫反應來治療癌症及傳染病。可藉由本發明抗體治療之病症包括(但不限於)癌症,包括血液科惡性疾病及實體腫瘤。此類癌症可以表現或可以不表現TIGIT或CD155。針對TIGIT之抗體可有效針對不表現TIGIT之癌症,因為抑制TIGIT與CD155之相互作用刺激了針對此類癌症之免疫反應。血液科惡性疾病之實例包括白血病、淋巴瘤及骨髓瘤,包括急性骨髓性白血病、成人T細胞白血病、T細胞大顆粒淋巴細胞白血病、急性淋巴母細胞白血病、慢性淋巴球性白血病、慢性骨髓性白血病、急性單核細胞性白血病、霍奇金氏(Hodgkin's)及非霍奇金氏淋巴瘤及多發性骨髓瘤。實體腫瘤之實例包括(但不限於)卵巢癌、子宮內膜癌、乳癌、肺癌(小細胞或非小細胞)、結腸癌、前列腺癌、子宮頸癌、胰臟癌、胃癌、食道癌、肝細胞癌(肝癌)、腎細胞癌(腎癌)、頭頸部腫瘤、間皮瘤、黑素瘤、肉瘤及腦腫瘤(例如,神經膠質瘤,諸如神經膠母細胞瘤)。
本發明方法可以在輔助環境(adjuvant setting)下實踐。「輔助環境」係指個體具有增生性疾病史,尤其是癌症病史,且一般(但不一定)已對療法起反應的臨床環境,療法包括(但不限於)外科手術、放射線療法及/或化學療法。然而,因為增生性疾病史,所以此等個體視為具有發展出彼疾病之風險。「輔助環境」中之治療或投藥係指後續治療模式。在一些實施例中,本文提供一種用於治療癌症或實現癌症預防的方法,其包含在輔助環境中向患有癌症或具有患癌症風險之個體投與治療有效量的本文所揭示之抗體中之任一者。
本文所提供之方法亦可在「新輔助環境(neoadjuvant setting)」中實踐,亦即,該方法可以在主要/確定性療法之前進行。在一些態樣中,個體先前已經過治療。在其他態樣中,個體先前未經過治療。在一些態樣中,治療係第一線療法。在一些實施例中,本文提供一種用於治療癌症或實現癌症預防的方法,其包含在新輔助環境中向患有癌症或具有患癌症風險之個體投與治療有效量的本文所揭示之抗體中之任一者。
可藉由本發明抗體治療之其他病症包括病毒、細菌、真菌、原蟲及其他病原體的傳染性疾病,例如,肝炎(A、B或C)、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II及CMV、埃-巴二氏病毒(Epstein Barr virus))、腺病毒、流感病毒、黃病毒、埃可病毒(echovirus)、鼻病毒、科沙奇病毒(coxsackie virus)、冠狀病毒、呼吸道融合性病毒、腮腺炎病毒、輪狀病毒、麻疹病毒、風疹病毒、小病毒、痘瘡病毒、HTLV病毒、登革熱病毒(dengue virus)、乳突狀瘤病毒、軟疣病毒、脊髓灰白質炎病毒、狂犬病病毒、JC病毒、HIV、SIV及蟲媒腦炎病毒、衣原體、立克次體細菌(rickettsial bacteria)、分枝桿菌、葡萄球菌、鏈球菌、肺炎球菌、腦膜炎球菌及淋球菌(conococci)、克雷伯氏菌(klebsiella)、變形桿菌、沙雷氏菌(serratia)、假單胞菌、軍團桿菌(legionella)、白喉、沙門氏菌(salmonella)、桿菌、霍亂(cholera)、破傷風、肉毒中毒、炭疽、瘟疫、鉤端螺旋體病及萊姆病(Lymes disease)細菌。
A.
抗體之投與 本文所述之抗體係以有效養生法投與,有效養生法意指延遲病症發作、降低嚴重度、抑制進一步惡化及/或改善至少一種體徵或症狀的劑量、投與途徑及投與頻率。若個體已患上病症,則養生法可稱作治療有效養生法。若個體係相對於一般群體而言具有高得病風險,但是尚未經歷症狀,則養生法可稱作預防性有效養生法。在一些情況下,可以在個別個體中相對於同一個體的歷史對照或過去的經歷觀察到治療性或預防性功效。在其他情況下,可以在臨床前或臨床試驗中在經治療個體群體中相對於未經治療個體之對照群體證明治療性或預防性功效。
在一些態樣中,本文所述方法中之任一者包括向有需要之個體投與治療有效量的本文所述抗體中之一或多者。如本文所用,抗癌療法(諸如本文所述抗TIGIT抗體中之任一者)之「治療有效量」或「治療有效劑量」係足以實現有利結果或所要結果的量。對於治療用途而言,有利結果或所要結果包括諸如以下之臨床結果:減少由癌症引起之一或多種症狀、提高患癌症個體之生活品質、降低治療癌症所需之其他藥物的劑量、增強另一藥物之作用(諸如經由靶向)、延緩疾病進展及/或延長存活期。有效劑量可在一或多次投藥中投與。出於本發明之目的,抗癌療法之有效劑量係足以直接地或間接地完成治療性或預防性治療的量。如在臨床背景下所瞭解,抗癌療法之治療有效劑量可以或可以不結合另一抗癌療法達成。
本文所述抗體中之任一者的例示性劑量係約0.1-20 mg/kg或0.5-5 mg/kg體重(例如,約0.5 mg/kg、1 mg/kg、2 mg/kg、3 mg/kg、4 mg/kg、5 mg/kg、6 mg/kg、7 mg/kg、8 mg/kg、9 mg/kg、10 mg/kg、11 mg/kg、12 mg/kg、13 mg/kg、14 mg/kg、15 mg/kg、16 mg/kg、17 mg/kg、18 mg/kg、19 mg/kg或20 mg/kg)或10-1500 mg (諸如以下中之任一者:小於10 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、80 mg、90 mg、100 mg、150 mg、200 mg、250 mg、300 mg、350 mg、400 mg、450 mg、500 mg、550 mg、600 mg、650 mg、700 mg、750 mg、800 mg、850 mg、900 mg、950 mg、1000 mg、1100 mg、1200 mg、1300 mg、1400 mg或1500 mg或更大,包括在此等數值之間的值)作為固定劑量。 無論治療係預防性或治療性且無論病症係急性或慢性,劑量均視個體之病狀及對先前治療之反應(若存在)以及其他因素而定。
投藥可以係非經腸、靜脈內、經口、皮下、動脈內、顱內、鞘內、腹膜內、瘤內、局部、鼻內或肌肉內。藉由靜脈內或皮下投藥而投藥於全身循環中係較佳的。靜脈內投藥可以係例如藉由經諸如30-90 min之時段輸注。
投藥頻率視循環中之抗體之半衰期、個體之病狀及投藥途徑以及其他因素而定。響應於個體病狀之改變或待治療病症之進展,頻率可以係每天、每週、每月、每季度或不規律的時間間隔。在連續的治療過程中,例示性靜脈內投藥頻率係介於每週與每季度之間,但是更頻繁或較不頻繁的給藥亦係可能的。對於皮下投藥,例示性給藥頻率係每天至每月,但是更頻繁或較不頻繁的給藥亦係可能的。
所投與劑量之數目視病症係急性或慢性及病症對治療之反應而定。關於急性病症或慢性病症之急性惡化,1個與10個劑量之間常常係足夠的。有時候,視情況呈分開形式的單一單次劑量對於急性病症或慢性病症之急性惡化而言就已足夠。針對急性病症或急性惡化之復發,治療可以重複。關於慢性病症,抗體可以按常規時間間隔投與,例如每週、每兩週、每月、每季度、每六個月,持續至少1、5或10年,或個體一生。
包括抗TIGIT抗體之治療可以緩解疾病,此係藉由使患癌症個體之中值無進展存活期或總存活時間相較於對照個體增加至少約30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%,但是較佳增加至少約50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、 74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或甚至100%,或使此等時間中之任一者增加2週、1、2或3個月,或較佳增加4或6個月或甚至9個月或一年。另外或替代地,包括抗TIGIT抗體之治療可以使個體之完全反應率、部分反應率或客觀反應率(完全+部分)相較於對照個體增加至少約30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%,但是較佳增加至少約50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或甚至100%。除了抗TIGIT抗體以外,對照個體接受與接受抗TIGIT抗體之個體相同的治療。因此,若接受抗TIGIT抗體之個體接受單獨的安慰劑或安慰劑與除抗TIGIT抗體以外的一些化學治療劑之組合,則對照個體亦可以接受這些。
本文所揭示之抗TIGIT抗體可以使CD155表現細胞(諸如(但不限於)K562細胞)的NK細胞介導之細胞毒性相對於在不存在本文所揭示之抗TIGIT抗體中之一者的情況下CD155表現細胞之NK細胞介導的細胞毒性之量增強以下中之任一者:約10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%或更大。
通常,在臨床試驗(例如II期、II/III期或III期試驗)中,經抗TIGIT抗體治療之個體的中值無進展存活期及/或反應率相對於對照組個體的增加係統計學上顯著的,例如處於p=0.05或0.01或甚至0.001水準。完全及部分反應率係藉由癌症臨床試驗中常用的客觀標準測定,例如如國家癌症研究院(National Cancer Institute)及/或食品與藥物管理局(Food and Drug Administration)所列的或所認可的,且尤其可以包括例如腫瘤體積、腫瘤數目、轉移、存活時間及生活品質量測。
用於非經腸投與之醫藥組合物較佳係無菌的且基本上等張的且在GMP條件下製造。醫藥組合物可以單位劑型(亦即,單次投藥之劑量)提供。醫藥組合物可以使用一或多種生理學上可接受之載劑、稀釋劑、賦形劑或助劑來調配。調配視所選投藥途徑而定。對於注射,抗體可在水溶液中調配,較佳在生理學上相容的緩衝液中,諸如漢克氏溶液(Hank's solution)、林格氏溶液(Ringer's solution),或生理鹽水或乙酸鹽緩衝液(以降低注射位點處之不適)。溶液可含有調配劑,諸如懸浮劑、穩定劑及/或分散劑。或者,抗體可以呈凍乾形式,在使用之前用適合媒劑復原,例如無菌無熱原質水。液體調配物中之抗體之濃度可以在例如約10-150 mg/ml之範圍內變化。在一些調配物中,濃度係約25-50 mg/ml。
B.
組合療法 本發明涵蓋抗TIGIT抗體與一或多種活性治療劑(例如化學治療劑)或其他預防或治療模式(例如,輻射)組合的用途。在此類組合療法中,各種活性劑經常具有不同的互補作用機制。此類組合療法可藉由允許試劑中之一或多者之劑量減少,藉此減少或消除與試劑中之一或多者相關之不良作用而尤其有利。此外,此類組合療法可對潛在疾病、病症或病狀具有協同的治療或預防作用。
如本文所用,「組合」係意謂包括可以分開投與的療法,例如針對單獨投藥分開調配(例如,可以在套組中提供),及可以按單一調配物(亦即,「共調配物」)一起投與的療法。
在某些實施例中,本文所揭示之抗TIGIT抗體中之任一者係依序投與或施用,例如其中先投與一種藥劑,然後投與一或多種其他藥劑。在其他實施例中,抗體係同時投與,例如其中兩種或更多種藥劑在相同時間或大致相同時間投與;兩種或更多種藥劑可存在於兩種或更多種單獨的調配物中或組合成單一調配物(亦即共調配物)。不論兩種或更多種藥劑是否依序或同時投與,出於本發明之目的均認為其應組合投與。
本發明之抗體可以與至少一種其他(活性)藥劑以任何在各情況下適合之方式組合使用。在一個實施例中,使採用至少一種活性劑及至少一種本發明之抗TIGIT抗體的治療維持一段時間。在另一實施例中,減弱或中斷用至少一種活性劑治療(例如,當個體穩定時),同時按恆定給藥方案維持用本發明之抗TIGIT抗體治療。在另一實施例中,減弱或中斷用至少一種活性劑治療(例如,當個體穩定時),同時減弱用本發明之抗TIGIT抗體治療(例如較低劑量、較不頻繁給藥或較短治療療程)。在另一實施例中,減弱或中斷用至少一種活性劑治療(例如,當個體穩定時),且增強用本發明之抗TIGIT抗體治療(例如較高劑量、較頻繁給藥或較長治療療程)。在另一實施例中,維持用至少一種活性劑治療且減弱或中斷用本發明之抗TIGIT抗體治療(例如較低劑量、較不頻繁給予或較短治療療程)。在另一實施例中,減弱或中斷用至少一種活性劑治療及用本發明之抗TIGIT抗體治療(例如較低劑量、較不頻繁給予或較短治療療程)。
用本發明抗體治療可以與可有效針對待治療病症之其他治療組合。當用於治療增生性病狀、癌症、腫瘤或癌前期疾病、病症或病狀時,本發明抗體可以與化學療法、輻射(例如,局部輻射療法或全身輻射療法)、幹細胞治療、外科手術或用其他生物製品治療組合。
在某些實施例中,本發明提供用於腫瘤生長之腫瘤抑制的方法,其包含與信號轉導抑制劑(STI)組合投與本文所揭示之抗TIGIT抗體以達成腫瘤生長之累加或協同抑制。如本文所用,術語「信號轉導抑制劑」係指選擇性抑制信號傳導路徑中之一或多個步驟的藥劑。本發明之信號轉導抑制劑(STI)包括:(i) BCR-Abl激酶抑制劑(例如,甲磺酸伊馬替尼(imatinib mesylate) (格列衛(GLEEVEC)));(ii)表皮生長因子(EGF)受體抑制劑,包括激酶抑制劑及抗體;(iii) HER-2/neu受體抑制劑(例如,赫賽汀(HERCEPTIN));(iv) Akt家族激酶或Akt路徑之抑制劑(例如,雷帕黴素(rapamycin));(v)細胞循環激酶抑制劑(例如,夫拉平度(flavopiridol));及(vi)磷脂醯肌醇激酶抑制劑。參與免疫調節之藥劑亦可以與本文所揭示之抗TIGIT抗體組合使用來抑制癌症患者中之腫瘤生長。
化學治療劑之實例包括(但不限於)烷基化劑,諸如噻替派(thiotepa)及環磷醯胺;磺酸烷基酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶(aziridine),諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);乙烯亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三伸乙基三聚氰胺(triethylenemelamine)、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基三聚氰胺(trimethylolomelamime);氮芥,諸如氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、二氯甲基二乙胺(mechlorethamine)、二氯甲基二乙胺氧化物鹽酸鹽、美法侖(melphalan)、新恩比興(novembichin)、膽固醇對苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲洛磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲(nitrosureas),諸如卡莫司汀(carmustine)、氯脲黴素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysins)、放線菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博來黴素(bleomycins)、放線菌素C (cactinomycin)、卡奇黴素(calicheamicin)、卡拉比辛(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycins)、更生黴素(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、小紅莓(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤(methotrexate)及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如卡普睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸;醋葡醛內酯(aceglatone);醛磷醯胺醣苷(aldophosphamide glycoside);胺基乙醯丙酸;安吖啶(amsacrine);倍思塔布(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;磨菇多糖(lentinan);氯尼達明(lonidamine);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);雷佐生(razoxane);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);甲托辛(gacytosine);阿拉伯糖苷(Ara-C);環磷醯胺;噻替派;類毒素(亦即紫杉烷(taxane)),例如太平洋紫杉醇(paclitaxel)、紫杉醇(taxol)及多西他賽(doxetaxel);氯芥苯丁酸;吉西他濱(gemcitabine);6-硫鳥嘌呤;巰基嘌呤;甲胺喋呤;鉑及鉑配位複合物,諸如順鉑(cisplatin)及卡鉑(carboplatin);長春鹼(vinblastine);依託泊苷(etoposide) (VP-16);異環磷醯胺;絲裂黴素C;米托蒽醌;長春新鹼(vincristine);長春瑞濱(vinorelbine);溫諾平(navelbine);諾安托(novantrone);替尼泊苷(teniposide);柔紅黴素(daunomycin);胺基喋呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);CPT11;拓樸異構酶抑制劑(topoisomerase inhibitor);喜樹鹼(camptothecins)、二氟甲基鳥胺酸(DMFO);視黃酸;埃斯波黴素(esperamicins);卡培他濱(capecitabine);抗代謝物(例如硫唑嘌呤(azathioprine));蒽環黴素(anthracycline);植物鹼(包括例如,長春花屬生物鹼(vinca alkaloid));及以上中之任一者的醫藥學上可接受之鹽、酸或衍生物。
化學治療劑亦包括用來調節或抑制對腫瘤之激素作用的抗激素劑,諸如抗雌激素,包括例如他莫昔芬(tamoxifen)、雷諾昔酚(raloxifene)、芳香酶抑制4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、奧那司酮(onapristone)及托瑞米芬(toremifene);及抗雄激素,諸如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);及以上中之任一者的醫藥學上可接受之鹽、酸或衍生物。在某些實施例中,組合療法包含投與激素或相關激素劑。
其他可與本文所揭示之抗TIGIT抗體組合使用的治療模式包括放射線療法、針對腫瘤抗原之單株抗體、單株抗體與毒素之複合物、T細胞佐劑、骨髓移植或抗原呈現細胞(例如樹突狀細胞療法)或基於細胞-細胞之療法。如本文所用之術語「基於細胞之療法」係指出於達成所要治療作用的目的,涉及細胞引入的任何療法,所要治療作用諸如修復受損的或飽滿的成人細胞群體或組織,或者增強針對病原體或增殖性細胞(諸如癌細胞)的免疫反應。在其他實施例中,基於細胞之療法包括引入能夠分化成達成所要治療作用所需的特定細胞類型的非分化細胞(諸如幹細胞或其他多能或全能細胞),所要治療作用諸如修復受損的或飽滿的成人細胞群體或組織,或者增強針對病原體或增殖性細胞(諸如癌細胞)的免疫反應。在一些實施例中,本發明抗體亦可以與視情況已離體擴增或針對腫瘤加以選擇的腫瘤浸潤性T細胞或自然殺手細胞一起投與。本發明抗體有助於此等細胞之活化。
較佳組合係本發明抗體與第二抗體,第二抗體係定向於較佳在相對於對照正常組織而言的癌細胞上表現的表面抗原。可以與本發明抗體一起以組合療法投與來治療癌症的抗體的一些實例包括針對HER2抗原之Herceptin® (曲妥珠單抗(trastuzumab))、針對VEGF之Avastin® (貝伐單抗(bevacizumab))或針對EGF受體之抗體,諸如(Erbitux®,西妥昔單抗(cetuximab))及Vectibix® (帕尼單抗(panitumumab))。可以投與的其他藥劑包括PD-1、PD-L1、CTLA-4、4-1BB、BTLA、VISTA、TIM-3及LAG-3中之任一者的抗體或其他抑制劑;或其他下游信號傳導抑制劑,例如mTOR及GSK3β抑制劑;及細胞介素,例如干擾素-γ、IL-2及IL-15。其他藥劑之一些特定實例包括:伊匹單抗、帕佐泮尼(pazopanib)、舒尼替尼(sunitinib)、達沙替尼(dasatinib)、派姆單抗、INCR024360、達拉菲尼(dabrafenib)、曲美替尼(trametinib)、阿特珠單抗(MPDL3280A)、特羅凱(tarceva)、考比替尼(cobimetinib)及納武單抗。用於組合療法之第二抗體或其他藥劑的選擇視待治療之癌症而定。視情況,針對抗原之表現或優先表現測試癌症以指導適當抗體之選擇。第二抗體之同型較佳係人類IgG1,以便促進效應功能,諸如ADCC、CDC及吞噬作用。
本發明抗體亦可以與誘出針對癌症之免疫反應的疫苗一起投與。此類免疫反應藉由本發明抗體而增強。疫苗可以包括在癌症之表面上表現的抗原或其可有效誘導免疫反應的片段,視情況與載劑分子相連。
本發明涵蓋與免疫檢查點抑制劑組合使用本文所述之抗TIGIT抗體。
作為所有癌症之特徵的極大數目之基因及表觀遺傳改變提供了免疫系統可用於區分腫瘤細胞與其正常對應物的一組不同抗原。在T細胞之情況下,經由T細胞受體(TCR)之抗原識別引發的反應的最終幅度(例如細胞介素產生或增殖之程度)及品質(例如所產生之免疫反應之類型,諸如細胞介素產生模式)係藉由協同刺激信號與抑制信號(免疫檢查點)之間的平衡來調節。在正常生理條件下,免疫檢查點對於自體免疫之預防(亦即自身耐受性之維持)以及對於當免疫系統對病原性感染作出反應時使組織免受損傷而言係至關重要的。免疫檢查點蛋白之表現可藉由腫瘤失調作為重要免疫耐受機制。
作為阻斷候選者之免疫檢查點(配體及受體) (其中一些在各種類型的腫瘤細胞中選擇性上調)的實例包括PD-1 (計劃性細胞死亡蛋白1);PD-L1 (計劃性死亡配體-1);BTLA (B及T淋巴細胞衰減子);CTLA-4 (細胞毒性T淋巴細胞相關抗原4);TIM-3 (T細胞膜蛋白3);LAG-3 (淋巴細胞活化基因3);T細胞活化之V域免疫球蛋白抑制劑(VISTA);CD96;A2aR (腺苷A2a受體);A2bR (腺苷A2b受體);CD73 (胞外-5'-核苷酸酶);CD39 (ENTPD1、NTPDase1);精胺酸酶;吲哚胺-吡咯2,3-雙加氧酶(IDO);色胺酸2,3-雙加氧酶(TDO);及殺手細胞抑制性受體,其可以基於其結構特徵分成兩類:i)殺手細胞免疫球蛋白樣受體(KIR),及ii) C型凝集素受體(II型跨膜受體家族之成員)。其他定義較不明確之免疫檢查點已描述於文獻中,包括受體(例如2B4 (亦稱為CD244)受體)及配體(例如某些B7家族抑制配體,諸如B7-H3 (亦稱為CD276)及B7-H4 (亦稱為B7-S1、B7x及VCTN1))。參見Pardoll, (2012年4月)
Nature Rev. Cancer12:252-64。
本發明涵蓋本文所揭示之抗TIGIT抗體中之任一者與前述免疫檢查點受體及配體以及即將描述之免疫檢查點受體及配體之抑制劑的組合的用途。目前可獲得免疫檢查點之某些調節劑,而其他調節劑則處於後階段發展中。舉例而言,當其在2011年經批准用於治療黑素瘤時,完全人類化CTLA-4單株抗體伊匹單抗(YERVOY;Bristol-Myers Squibb)成為在美國得到管理批准的第一種免疫檢查點抑制劑。包含CTLA-4及抗體(CTLA-4-Ig;阿巴西普(abatcept) (ORENCIA;Bristol-Myers Squibb))之融合蛋白已用於治療類風濕性關節炎,且其他融合蛋白已顯示出在對埃-巴二氏病毒敏感之腎移植患者中有效。抗PD-1抗體處於發展中(例如,納武單抗(Bristol-Myers Squibb)及派姆單抗(蘭利珠單抗) (Merck)),且抗PD-L1抗體亦正在進行評估(例如,MPDL3280A (Roche))。納武單抗及派姆單抗已顯示出在患有黑素瘤、肺癌及腎癌之患者中的前景。
可以使用類似組合療法來治療或預防傳染病,諸如病毒、細菌、真菌及寄生蟲性疾病、病症及病況,以及與其相關的病症。舉例而言,本發明抗體可以與針對病原體之抗體或針對病原體之疫苗(諸如針對勞斯肉瘤病毒(rous sarcoma virus)之帕利珠單抗(palivizumab))組合。疫苗可以係病原體之蛋白質或其可有效誘導免疫反應之片段。本發明抗體增強抗體或疫苗針對病原體之免疫反應。本發明抗體亦可以與離體擴增之T細胞或自然殺手細胞一起投與。
此類組合療法包括靶向各種病毒生命週期階段且具有不同作用機制之抗病毒劑,包括(但不限於)以下:病毒脫殼之抑制劑(例如金剛胺(amantadine)及金剛乙胺(rimantidine));逆轉錄酶抑制劑(例如阿昔洛韋(acyclovir)、齊多夫定(zidovudine)及拉米夫定(lamivudine));靶向整合酶之藥劑;阻斷轉錄因子與病毒DNA之連接之藥劑;影響轉譯之藥劑(例如反義分子) (例如福米韋生(fomivirsen));調節轉譯/核糖核酸酶功能之藥劑;蛋白酶抑制劑;病毒裝配調節劑(例如利福平(rifampicin));抗逆轉錄病毒劑,諸如核苷類似物逆轉錄酶抑制劑(例如疊氮胸苷(AZT)、ddl、ddC、3TC、d4T);非核苷逆轉錄酶抑制劑(例如依法韋侖(efavirenz)、奈韋拉平(nevirapine));核苷酸類似物逆轉錄酶抑制劑;及防止病毒粒子釋放之藥劑(例如紮那米韋(zanamivir)及奧司他韋(oseltamivir))。某些病毒感染(例如HIV)之治療及/或預防經常需要一組抗病毒劑(「混合物」)。
預期與本文所揭示之抗TIGIT抗體中之任一者組合使用的其他抗病毒劑包括(但不限於)以下:阿巴卡韋(abacavir)、阿丹弗(adefovir)、三環癸胺(amantadine)、安普那韋(amprenavir)、安普利近(ampligen)、阿比朵爾(arbidol)、阿紮那韋(atazanavir)、阿托伐他汀鈣(atripla)、波普瑞韋爾特(boceprevirertet)、西多福韋(cidofovir)、可比韋(combivir)、地瑞那韋(darunavir)、地拉韋啶(delavirdine)、地達諾新(didanosine)、多可沙諾(docosanol)、依度尿苷(edoxudine)、安卓西他賓(emtricitabine)、恩夫韋地(enfuvirtide)、恩替卡韋(entecavir)、泛昔洛韋(famciclovir)、夫沙那韋(fosamprenavir)、膦甲酸鹽(foscarnet)、膦乙酸鹽(fosfonet)、更昔洛韋(ganciclovir)、伊巴他濱(ibacitabine)、異丙肌苷(imunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韋(indinavir)、肌苷(inosine)、各種干擾素(例如聚乙二醇化干擾素α-2a)、洛匹那韋(lopinavir)、洛韋胺(loviride)、馬拉維若(maraviroc)、嗎啉脒胍(moroxydine)、美替沙腙(methisazone)、奈非那韋(nelfinavir)、多吉美(nexavir)、噴昔洛韋(penciclovir)、帕拉米韋(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、雷特格韋(raltegravir)、利巴韋林(ribavirin)、利托那韋(ritonavir)、普拉咪定(pyramidine)、沙奎那韋(saquinavir)、司他夫定(stavudine)、特拉匹偉(telaprevir)、田諾弗(tenofovir)、替拉那韋(tipranavir)、曲氟尿苷(trifluridine)、三協唯(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada)、伐昔洛韋(valaciclovir)、纈更昔洛韋(valganciclovir)、維克利諾(vicriviroc)、阿糖腺苷(vidarabine)、韋拉咪定(viramidine)及紮西他濱(zalcitabine)。
本發明涵蓋本文所揭示之抗TIGIT抗體中之任一者與抗寄生蟲劑組合的用途。此類藥劑包括(但不限於)腐絕(thiabendazole)、雙羥萘酸噻嘧啶(pyrantel pamoate)、甲苯達唑(mebendazole)、吡喹酮(praziquantel)、氯硝柳胺(niclosamide)、雙硫酸醇(bithionol)、奧沙尼喹(oxamniquine)、美曲磷酯(metrifonate)、伊佛黴素(ivermectin)、阿苯達唑(albendazole)、依氟鳥胺酸(eflornithine)、美拉胂醇(melarsoprol)、潘他米丁(pentamidine)、苄硝唑(benznidazole)、硝呋莫司(nifurtimox)及硝基咪唑。熟習此項技術者瞭解可用於治療寄生蟲病症之其他藥劑。
本發明之實施例涵蓋本文所揭示之抗TIGIT抗體中之任一者與用於治療或預防細菌病症之藥劑之組合的用途。抗細菌劑可以各種方式分類,包括基於作用機制、基於化學結構及基於活性譜。抗細菌劑之實例包括靶向細菌細胞壁(例如頭胞菌素(cephalosporin)及青黴素(penicillin))或細胞膜(例如多黏菌素(polymyxin))、或干擾必需細菌酶(例如磺醯胺、利福黴素(rifamycin)及喹啉)之抗細菌劑。大多數靶向蛋白質合成之抗細菌劑(例如四環素(tetracycline)及巨環內酯(macrolide))係抑制細菌的,而諸如胺基醣苷之藥劑係殺細菌的。抗細菌劑之另一分類方式係基於其目標特異性;「窄譜」藥劑靶向特定類型之細菌(例如革蘭氏陽性(Gram-positive)細菌,諸如鏈球菌),而「廣譜」藥劑具有針對較寬範圍之細菌的活性。熟習此項技術者瞭解適合於在特定細菌感染中使用之抗細菌劑的類型。
本發明之實施例涵蓋本文所揭示之抗TIGIT抗體中之任一者與用於治療或預防真菌病症之藥劑之組合的用途。抗真菌劑包括多烯(例如兩性黴素(amphotericin)、制黴菌素(nystatin)及鏈黴菌素(pimaricin));唑類(例如氟康唑(fluconazole)、伊曲康唑(itraconazole)及酮康唑(ketoconazole));烯丙胺(例如萘替芬(naftifine)及特比萘芬(terbinafine))及嗎啉(例如阿莫羅芬(amorolfine));及抗代謝物(例如5-氟胞嘧啶)。
本發明涵蓋上述藥劑(及各類藥劑之成員)之醫藥學上可接受之鹽、酸或衍生物。
針對TIGIT之抗體可以與經描述作為醫藥組合物之組分用於共同療法中之第二抗體或藥劑中之任一者組合。在醫藥組合物中,藥劑可以與如所述的一或多種醫藥學上可接受之載劑組合。
V. 其他應用在臨床診斷或治療之情況下或在研究中,可以使用抗TIGIT抗體偵測TIGIT。舉例而言,可以使用抗體偵測TIGIT在T細胞、自然殺手細胞及癌細胞上的存在情況作為個體患有能夠治療之癌症或傳染病的一指示。TIGIT在患有癌症或傳染病之個體的T細胞、自然殺手細胞及/或癌細胞上之表現亦提供癌症或傳染病能夠用本發明抗體治療的指示。抗體亦可以作為研究試劑出售,用於實驗室研究,偵測T細胞、自然殺手細胞及癌細胞及其對各種刺激之反應。在此類用途中,單株抗體可以用螢光分子、自旋標記分子、酶或放射性同位素標記,且可以含有對TIGIT進行分析所需的所有試劑的套組形式提供。抗體亦可以用於純化TIGIT,例如藉由親和層析。
VI. 套組針對TIGIT之抗體可以與經描述作為套組之組分用於共同療法中之第二抗體或藥劑中之任一者組合。本文所揭示之發明提供一或多種套組,其含有本文所揭示之抗體中之一或多者以及一或多種醫藥學上可接受之賦形劑或載劑(諸如(但不限於)磷酸鹽緩衝鹽水溶液、水、無菌水、聚乙二醇、聚乙烯吡咯啶酮、卵磷脂、花生油、芝麻油、乳液,諸如油/水乳液或水/油乳液、微乳液、奈米載劑及各種類型的濕潤劑)。亦可在本發明之套組中與載劑、稀釋劑或賦形劑一起包括添加劑,諸如醇、油、二醇、防腐劑、調味劑、著色劑、懸浮劑及其類似者。在一個實施例中,適合用於本文所揭示之抗體組合物中之醫藥學上可接受之載劑係無菌的、不含病原體的、及/或在其他方面對於向個體投與係安全的,不存在相關感染及其他過度不良副作用之風險。在套組中,各別藥劑可以在單獨的小瓶中提供,含有用於組合、然後投與的說明書或用於分開投與的說明書。套組亦可以包括用於恰當處理及儲存本文所揭示之抗TIGIT抗體中之任一者的書面說明書。
預期本說明書通篇中所給出的每一個最大數值限制包括每一個較低的數值限制,如同該等較低的數值限制明確地書寫在本文中一樣。本說明書通篇中所給出的每一個最小數值限制包括每一個較高的數值限制,如同該等較高的數值限制明確地書寫在本文中一樣。本說明書通篇中所給出之每一個數值範圍將包括落在此類較寬數值範圍內之每一個較窄數值範圍,如同該等較窄數值範圍全部明確地書寫在本文中一般。
上文或下文引用之所有專利申請、網站、其他公開案、寄存編號及其類似物出於所有目的以全文引用的方式併入本文中,其引用程度如同各個別物件特別且個別地指示為以引用的方式併入一般。若序列之不同版本與不同時間的寄存編號相關,則意謂在本申請案之有效申請日時與寄存編號相關之版本。有效申請日意指早於實際申請日或提及寄存編號(若適用)之優先權申請案之申請日。同樣,除非另外指明,否則若在不同時間公開不同版本的公開案、網站或其類似物,則意謂在本申請案之有效申請日時最近公開之版本。除非另外特別指示,否則本發明之任何特徵、步驟、要素、實施例或態樣可與任何其他特徵、步驟、要素、實施例或態樣組合使用。
儘管出於清楚及理解之目的已藉助於說明及實例相當詳細地描述本發明,但顯而易見可在所附申請專利範圍之範疇內實踐某些改變及修改。
實例以下實例論述針對人類TIGIT之單株抗體的產生、表徵及人類化,且亦提供可以藉以測定本申請案中所述之抗體的結合特徵的例示性方法。
實例 1 :重組性人類 TIGIT 蛋白質之表現在此工作中用標準分子生物學技術進行基因選殖、突變誘發及質體構築,諸如Sambrook及Russel (
Molecular Cloning, A Laboratory Manual,第3版, 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY)、Kostelny等人(
Int. J. Cancer93:556-565, 2001)及Cole等人(
J. Immunol.159:3613-3621, 1997)中所述的彼等技術。
用於製造與人類免疫球蛋白γ1鏈之Fc區融合的人類TIGIT之胞外區(hTIGIT-Fc;SEQ ID NO:59)的哺乳動物表現載體pFCm404 (圖1)含有以下遺傳組分。自圖1中之pFCm404的SalI位點順時針前進,質體含有用於hTIGIT-Fc的轉錄單元,從人類巨細胞病毒(CMV)主要即刻早期啟動子及強化子(CMV-P,圖1中)開始。CMV啟動子之後係信號肽(sp;SEQ ID NO: 2)之編碼區、人類TIGIT (hTIGIT;SEQ ID NO: 3)之胞外區、多肽連接子(SEQ ID NO: 4)及人類γ1 Fc區(SEQ ID NO: 5),且隨後係人類γ1重鏈基因之聚腺苷酸化位點。hTIGIT-Fc基因之後係SV40早期啟動子(SV40-P)、用於抵抗嘌呤黴素的嘌呤黴素N-乙醯基-轉移酶基因(puro)及含有SV40聚腺苷酸化位點(SV40-A)的區段。最後,pFCm404含有質體pUC19之一部分,包含細菌複製起點(pUC ori)及β內醯胺酶基因(β內醯胺酶)。圖中之箭頭表示轉錄方向。圖中指出了相關的限制酶位點。
將pFCm404中的人類TIGIT之胞外區之編碼區替換為編碼人類CD155 (hCD155;SEQ ID NO: 6)之胞外區的DNA片段,引起新表現載體pFCm406之產生(圖1)。與人類γ1 Fc區融合的人類CD155之胞外區(hCD155-Fc;SEQ ID NO: 7)係自pFCm406表現。
將pFCm404中在AgeI與EagI位點之間的γ1 Fc區之編碼區替換為編碼FLAG肽(FLAG;SEQ ID NO: 8)之DNA片段,繼之以人類CD55之糖基化磷脂醯肌醇鍵聯信號(GPI;SEQ ID NO: 9),引起新表現載體pFCm407之產生(圖1)。與FLAG及GPI融合的人類TIGIT之胞外區(hTIGIT-GPI)編碼的pFCm406係在細胞表面上表現。
為獲得在培養上清液中穩定地產生hTIGIT-Fc及hCD155-Fc的細胞株,將表現載體pFCm404及pFCm406分別引入小鼠骨髓瘤細胞株NS0 (European Collection of Animal Cell Cultures, Salisbury, Wiltshire, UK)之染色體中。使NS0細胞在37℃下在7.5% CO
2培育箱中在含有10%胎牛血清(FBS)的DME培養基中生長。藉由如Bebbington等人(
Bio/Technology10: 169-175, 1992)所述的電穿孔,穩定轉染至NS0中。在轉染之前,使用FspI使表現載體線性化。用10 μg線性化質體轉染約10
7個細胞,將其懸浮於含有10% FBS的DME培養基中,且塗鋪於若干96孔盤中。24小時後,施用選擇培養基(含有10% FBS及3 μg/ml嘌呤黴素的DME培養基)。在開始選擇之後約10天,藉由ELISA分析培養上清液中Fc融合蛋白之產生情況,使用山羊抗人類γ鏈抗體進行塗佈且使用HRP結合的山羊抗人類γ鏈偵測Fc融合蛋白。
產生高含量Fc融合蛋白之NS0穩定轉染物在融合瘤-SFM培養基(Thermo Fisher Scientific, Waltham, MA)中適應且擴增,且在滾瓶中生長至耗竭。在離心及過濾之後,將培養上清液加載至蛋白質A瓊脂糖凝膠管柱(GE Healthcare, Piscataway, NJ)上。用磷酸鹽緩衝鹽水(PBS)洗滌管柱,然後用0.1 M甘胺酸鹽酸鹽(pH 3.0)溶離Fc融合蛋白。在用1 M Tris-HCl (pH 8)中和之後,藉由透析將經溶離之Fc融合蛋白的緩衝劑改為PBS。
為獲得在表面上表現hTIGIT-GPI的細胞株,將表現載體pFCm407穩定地轉染至NS0細胞中。使用大鼠抗FLAG單株抗體及Fc特異性抗體經PE標記之山羊抗大鼠IgG,藉由流動式細胞測量術監測hTIGIT-GPI在細胞表面上之表現。使用在細胞表面上表現高含量hTIGIT-GPI的NS0細胞株(NS0-hTIGIT)篩選抗TIGIT抗體。
實例 2 :抗 TIGIT 單株抗體之產生及表徵產生抗人類TIGIT單株抗體之小鼠融合瘤係在JN Biosciences (Mountain View, CA),遵循標準融合瘤技術,諸如GenomONE CF EX細胞融合試劑(Cosmo Bio, Carlsbad, CA)產生。至於免疫原,係使用人類TIGIT-Fc融合蛋白及NS0-hTIGIT細胞。
分泌在融合瘤細胞之培養上清液中的小鼠抗體經歷一系列篩選以鑑別具有以下性質的抗體:(1)結合至經純化之hTIGIT-Fc融合蛋白,(2)結合至NS0-hTIGIT細胞,(3)不結合至NS0細胞,(4)結合至源自經植物血球凝集素處理的人類外周血液單核細胞的CD3+ T細胞及(5)阻斷hCD155-Fc融合蛋白與NS0-hTIGIT細胞之結合。結合至hTIGIT-Fc的第一性質係藉由ELISA,使用針對小鼠κ及λ輕鏈的HRP結合的山羊抗體(SouthernBiotech, Birmingham, AL)來測試,以便鑑別小鼠抗TIGIT抗體。第二、第三及第四性質係藉由流動式細胞測量術,使用經PE標記的山羊抗小鼠γ鏈抗體(SouthernBiotech)來檢查,以便偵測細胞結合的小鼠抗體。第五性質藉由流動式細胞測量術如下所述分析。發現三種小鼠單株抗體(TIG1、TIG2及TIG3)具有所有這五種性質。藉由如上所述之蛋白質A管柱層析,自融合瘤細胞之培養上清液純化TIG1、TIG2及TIG3單株抗體。TIG1、TIG2及TIG3之同型分別係小鼠IgG2b/κ、IgG2a/κ及IgG2a/κ。
藉由流動式細胞測量術分析TIG1、TIG2及TIG3阻斷TIGIT與CD155之間的相互作用的活性。將NS0-hTIGIT細胞與亞飽和濃度之hCD155-Fc一起在存在(或不存在)各種濃度之抗TIGIT單株抗體作為競爭者的情況下培育。用Fc特異性抗體經DyLight488標記之山羊抗人類IgG (Jackson ImmunoResearch, West Grove, PA)進行hCD155-Fc結合至NS0-hTIGIT細胞的偵測。如圖2中所示,TIG1、TIG2及TIG3以劑量依賴性方式抑制hCD155-Fc與NS0-hTIGIT細胞之結合。阻斷hCD155-Fc與NS0-hTIGIT細胞之間的相互作用的半數最大抑制濃度(IC
50)於TIG1係49 ng/ml,於TIG2係197 ng/ml,且於TIG3係460 ng/ml。阻斷CD155與TIGIT之超過95%之結合所需的抗體濃度於TIG1係0.63 μg/ml,於TIG2係1.25 μg/ml,且於TIG3係2.5 μg/ml。
實例 3 :抗 TIGIT 單株抗體之 V 基因定序按照Tsurushita等人(Methods 36:69-83, 2005)中所述的程序測定小鼠抗TIGIT抗體之重鏈及輕鏈可變區(分別係VH及VL)序列。使用TRIzol試劑(Invitrogen, Carlsbad, CA),根據供應商之方案,自約10
7個細胞提取全部RNA。使用SMARTer RACE cDNA擴增套組(Clontech, Mountain View, CA),根據供應商之方案合成用於5'-RACE之寡聚dT預致敏的cDNA。藉由聚合酶鏈反應(PCR),用Phusion DNA聚合酶(Thermo Fisher Scientific, Waltham, MA),使用特異性黏接至小鼠重鏈或輕鏈恆定區之3'引子(Tsurushita等人,同前文獻)及SMARTer RACE cDNA擴增套組中所提供之5'引子來擴增VH及VL cDNA。使用CloneJet PCR選殖套組(Thermo Fisher Scientific)選殖經擴增之VH及VL基因且用CloneJet PCR選殖套組中所提供的引子使其經歷定序。對若干VH及VL純系進行定序且鑑別與典型的小鼠重鏈及輕鏈可變區同源的獨特序列。
TIG1之成熟VH之胺基酸序列(SEQ ID NO: 10)顯示於圖3中。TIG1 VH之CDR1、2及3胺基酸序列分別係NFGMH (SEQ ID NO:11)、FISSGSSSIYYADTVKG (SEQ ID NO:12)及MRLDYYAMDY (SEQ ID NO:13)。
TIG1之成熟VL之胺基酸序列(SEQ ID NO: 14)顯示於圖4中。TIG1 VL之CDR1、2及3胺基酸序列分別係RASKSISKYLA (SEQ ID NO:15)、SGSTLQS (SEQ ID NO:16)及QQHNEYPWT (SEQ ID NO:17)。
成熟TIG2 VH之胺基酸序列(SEQ ID NO: 18)顯示於圖5中。TIG2 VH之CDR1、2及3胺基酸序列分別係EYTMH (SEQ ID NO:19)、GINPNNGGTSYNQKFKG (SEQ ID NO:20)及PGWYNYAMDY (SEQ ID NO:21)。
成熟TIG2 VL之胺基酸序列(SEQ ID NO: 22)顯示於圖6中。TIG2 VL之CDR1、2及3胺基酸序列分別係KASQGVSTAVA (SEQ ID NO:23)、SASYRYT (SEQ ID NO:24)及QQHYITPWT (SEQ ID NO:25)。
成熟TIG3 VH之胺基酸序列(SEQ ID NO: 26)顯示於圖7中。TIG3 VH之CDR1、2及3胺基酸序列分別係DYDMS (SEQ ID NO:27)、YISDGGYNTYYPDTVKG (SEQ ID NO:28)及QILLRYYFDY (SEQ ID NO:29)。
成熟TIG3 VL之胺基酸序列(SEQ ID NO: 30)顯示於圖8中。TIG3 VL之CDR1、2及3胺基酸序列分別係KSSQSLLYSSNQKNYLA (SEQ ID NO:31)、WASTRES (SEQ ID NO:32)及QQYHSYPWT (SEQ ID NO:33)。
圖3至圖8中CDR序列之分配及胺基酸位置之編號係根據Kabat等人(1991)。在圖中,CDR1、CDR2及CDR3序列加底線。
實例 4 :人類化 TIG1 抗體之構築及表現如Queen等人(
Proc. Natl. Acad. Sci. USA.86:10029-10033, 1989)所述,根據Tsurushita等人(
Methods36:69-83, 2005)之程序進行TIG1 VH及VL之人類化。簡言之,首先使用JN Biosciences之專用算法構築TIG1之可變區的三維分子模型。隨後,使用分子模型鑑別對於TIG1之互補決定區(CDR)之結構的形成而言重要的構架胺基酸殘基。平行地,分別選擇與TIG1 VH及VL具有高同源性的源自cDNA的人類VH及VL胺基酸序列。最後,將CDR序列以及對於維持CDR結構而言重要的構架胺基酸殘基自TIG1 VH及VL移植至相應選擇的人類構架序列中。
所設計的人類化TIG1 VH (HuTIG1 VH)之胺基酸序列係MDSRLNLVFLVLILKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMVTVSS (SEQ ID NO: 34)。成熟HuTIG1 VH胺基酸序列,EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMVTVSS (SEQ ID NO:35),始於SEQ ID NO:34中之位置20。
所設計的人類化TIG1 VL (HuTIG1 VL)之胺基酸序列係MRFQVQVLGLLLLWISGAQCDIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIK (SEQ ID NO:36)。成熟HuTIG1 VL胺基酸序列,DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIK (SEQ ID NO:37),始於SEQ ID NO: 36中之位置21。
將編碼HuTIG1 VH之基因合成為外顯子,其包括在編碼區之3'端的剪接供體信號、在片段之5'端的SpeI位點及在片段之3'端的HindIII位點。在圖9A中,在所推斷的胺基酸序列(SEQ ID NO: 34)旁邊顯示藉由SpeI及HindIII位點側接的合成的HuTIG1 VH基因之核苷酸序列(SEQ ID NO: 38)。
將編碼HuTIG1 VL之基因合成為外顯子,其包括在編碼區之3'端的剪接供體信號、在片段之5'端的NheI位點及在片段之3'端的EcoRI位點。在圖9B中,在所推斷的胺基酸序列(SEQ ID NO: 36)旁邊顯示藉由NheI及EcoRI位點側接的合成的HuTIG1 VL基因之核苷酸序列(SEQ ID NO: 39)。
將用於產生小鼠抗人類TIGIT單株抗體TIG1 (HuTIG1-IgG1.AA)之人類化IgG1/κ形式的哺乳動物表現載體pHuTIG1.AA (圖10)構築成含有以下遺傳組分。自10圖中之SalI位點順時針前進,載體含有重鏈轉錄單元,從用於起始抗體重鏈基因之轉錄的人類巨細胞病毒(CMV)主要即刻早期啟動子及強化子(圖中之CMV-P)開始。CMV啟動子之後係編碼藉由SpeI及HindIII位點側接之TIG1的人類化形式的重鏈可變區(HuTIG1 VH)的外顯子;含有人類γ1重鏈恆定區的基因組序列,包括CH1、鉸鏈、CH2及CH3外顯子與介於中間的內含子;及人類γ1重鏈基因之聚腺苷酸化位點。在pHuTIG1.AA中編碼的CH2區將胺基酸取代攜帶至位置234及235 (Eu編號)處之丙胺酸殘基(L234A/L235A),以便消除效應功能(Hezareh等人,
J. Virol. 75:12161-12168, 2001)。在重鏈基因序列之後,輕鏈轉錄單元開始於CMV啟動子及強化子(CMV-P),繼之以編碼藉由NheI及EcoRI位點側接之TIG1的人類化形式之輕鏈可變區(HuTIG1 VL)的外顯子、含有人類κ鏈恆定區外顯子(Cκ)與在其之前的內含子之一部分的基因組序列、及在Cκ外顯子之後的人類κ鏈基因之聚腺苷酸化位點。輕鏈基因之後係SV40早期啟動子(SV40-P)、用於抵抗嘌呤黴素的嘌呤黴素N-乙醯基-轉移酶基因(puro)及含有SV40聚腺苷酸化位點(SV40-A)的區段。最後,pHuTIG1.AA含有質體pUC19之一部分,包含細菌複製起點(pUC ori)及β內醯胺酶基因(β內醯胺酶)。圖中之箭頭表示轉錄方向。
在pHuTIG1.AA中編碼的HuTIG1-IgG1.AA之成熟γ重鏈的胺基酸序列係EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:40)。
C端離胺酸可以存在或可以不存在。
在pHuTIG1.AA中編碼的HuTIG1-IgG1.AA之成熟κ輕鏈的胺基酸序列係DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:41)。
將表現載體pHuTIG1.AA引入中國倉鼠卵巢細胞株CHO-K1 (ATCC, Manassas, VA)之染色體中以獲得穩定地產生HuTIG1-IgG1.AA的細胞株。使CHO-K1細胞在37℃下在7.5% CO
2培育箱中的SFM4CHO培養基(GE Healthcare Life Sciences, Logan, UT)中生長。藉由電穿孔穩定轉染至CHO-K1中。在轉染之前,使用FspI使pHuTIG1.AA線性化。在典型實驗中,用20 μg經線性化之質體轉染約10
7個細胞,將其懸浮於SFM4CHO培養基中,且在適當稀釋細胞之後以100微升/孔塗鋪於若干96孔盤中。48小時後,以100微升/孔添加含有20 μg/ml嘌呤黴素之SFM4CHO培養基用於分離穩定轉染物。在開始選擇之後約十天,針對抗體產生分析轉染物之培養上清液。
藉由夾心ELISA量測HuTIG1-IgG1.AA之表現。在典型實驗中,用山羊抗人類IgG Fc特異性多株抗體塗佈ELISA培養盤,用洗滌緩衝劑(含有0.05% Tween 20之PBS)洗滌,且用ELISA緩衝劑(含有2%脫脂牛奶及0.05% Tween 20之PBS)阻斷。在用洗滌緩衝劑洗滌之後,向ELISA培養盤中施加在ELISA緩衝劑中恰當稀釋後的測試樣品。將適當人類化的IgG1/κ抗體用作標準。在室溫下培育ELISA培養盤1小時且用洗滌緩衝劑洗滌之後,使用HRP結合的山羊抗人類κ鏈多株抗體偵測結合抗體。在室溫下培育培養盤0.5小時且用洗滌緩衝劑洗滌之後,藉由添加100微升/孔之ABTS受質(Sigma-Aldrich)起始顯色且用100微升/孔之2%草酸停止。在405 nm下讀取吸光度。
使高度產生HuTIG1-IgG1.AA之CHO-K1穩定轉染物在SFM4CHO中擴增,直至細胞活力變得小於50%為止。在離心及過濾之後,將培養上清液加載至蛋白A管柱(HiTrap MABSelect SuRe, GE Healthcare, Piscataway, NJ)上。用PBS洗滌管柱,然後用0.1 M甘胺酸鹽酸鹽(pH 3.0)溶離抗體。用1 M Tris-HCl (pH 8)中和經溶離抗體之緩衝劑,且隨後藉由透析將緩衝劑改為PBS。藉由量測在280 nm下之吸光度(1 mg/ml = 1.4 OD)來測定抗體濃度。
實例 5 : HuTIG1-IgG1.AA 之表徵藉由ELISA檢查HuTIG1-IgG1.AA與人類TIGIT之結合。在4℃下用PBS中之5 μg/ml hTIGIT-Fc (100微升/孔)塗佈ELISA培養盤隔夜,用洗滌緩衝劑(含有0.05% Tween 20之PBS)洗滌,且用200微升/孔之SuperBlock阻斷緩衝液(Thermo Fisher Scientific)阻斷。在用洗滌緩衝劑洗滌各孔之後,添加HuTIG1-IgG1.AA,其以2.5 μg/ml開始且在SuperBlock阻斷緩衝劑中進行連續2倍稀釋,從而結合至培養盤結合的人類TIGIT。在室溫下培育ELISA培養盤1小時且用洗滌緩衝劑洗滌之後,用100微升/孔在ELISA緩衝劑中1/2,000稀釋的HRP結合的山羊抗人類κ鏈多株抗體(Southern Biotech)偵測結合抗體。在室溫下培育30分鐘且用洗滌緩衝劑洗滌之後,用100微升/孔之ABTS受質起始顯色且用100微升/孔之2%草酸停止。在405 nm下讀取吸光度。如圖11中所示,HuTIG1-IgG1.AA以劑量依賴性方式結合至人類TIGIT。HuTIG1-IgG1.AA結合至TIGIT的半數最大有效濃度(EC
50)係65 ng/ml。此顯示,HuTIG1-IgG1.AA係人類TIGIT之良好結合劑。
亦藉由流動式細胞測量術檢查HuTIG1-IgG1.AA與人類TIGIT之結合。在存在(或不存在)各種濃度之HuTIG1-IgG1.AA (以10 μg/ml開始且連續2倍稀釋)的情況下,將NS0-hTIGIT細胞(8×10
5個細胞)在4℃下在160 μl之FACS緩衝劑(含有0.5%牛血清白蛋白及0.05%疊氮化鈉的PBS)中培育20分鐘。在用FACS緩衝劑洗滌之後,用FACS緩衝劑中之經PE標記的山羊抗人類IgG抗體偵測結合在NS0-hTIGIT細胞上的HuTIG1-IgG1.AA。在培育20分鐘且用FACS緩衝劑洗滌之後,使用FACScan流式細胞儀(BD Biosciences, San Jose, CA)使細胞經歷流動式細胞測量術,獲得各抗體濃度下的平均通道螢光(MCF)。圖12顯示各抗體濃度(橫軸)下之MCF (縱軸)的曲線圖。EC
50值係60 ng/ml。此顯示,HuTIG1-IgG1.AA係在細胞表面上表現之人類TIGIT的良好結合劑。
藉由流動式細胞測量術,使用NS0-hTIGIT細胞分析HuTIG1-IgG1.AA阻斷人類TIGIT與人類CD155之間的相互作用的活性。將NS0-hTIGIT細胞(10
6個細胞)與亞飽和濃度(125 ng/ml)之經FITC標記的hCD155-Fc融合蛋白(hCD155-Fc-FITC)一起在200 μl之FACS緩衝劑中在存在(或不存在)各種濃度之HuTIG1-IgG1.AA (以10 μg/ml開始且連續2倍稀釋)的情況下在4℃下培育20分鐘。在用FACS緩衝劑洗滌之後,使用FACScan流式細胞儀(BD Biosciences, San Jose, CA),使NS0-hTIGIT細胞經歷流動式細胞測量術。為檢查hCD155-Fc-FITC在細胞上之結合,獲得各抗體濃度下之MCF。如圖13中所示,HuTIG1-IgG1.AA以劑量依賴性方式阻斷細胞表面上hCD155-Fc-FITC與TIGIT之間的相互作用。HuTIG1-IgG1.AA阻斷TIGIT-CD155相互作用之半數最大抑制濃度(IC
50)係67 ng/ml。此指示,HuTIG1-IgG1.AA係CD155與TIGIT之間的相互作用的有效阻斷劑。
實例 6 :人類化 TIG3 抗體之構築及表現根據實例4中所述之一般程序進行TIG3 VH及VL之人類化。所設計的人類化TIG3 VH (HuTIG3 VH)之胺基酸序列係MNFGLRLIFLVLTLKGVNCEVQLVESGGGLVQPGGSLRLSCAASGFAFSDYDMSWVRQAPGKGLEWVAYISDGGYNTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQILLRYYFDYWGQGTTVTVSS (SEQ ID NO: 42)。成熟HuTIG3 VH胺基酸序列,EVQLVESGGGLVQPGGSLRLSCAASGFAFSDYDMSWVRQAPGKGLEWVAYISDGGYNTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQILLRYYFDYWGQGTTVTVSS (SEQ ID NO:43),始於SEQ ID NO: 42中之位置20。
所設計的人類化TIG3 VL (HuTIG3 VL)之胺基酸序列係MDSQAQVLMLLLLWVSGTCGDIQMTQSPSSLSASVGDRVTITCKSSQSLLYSSNQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQYHSYPWTFGGGTKVEIK (SEQ ID NO:44)。成熟HuTIG3 VL胺基酸序列,DIQMTQSPSSLSASVGDRVTITCKSSQSLLYSSNQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQYHSYPWTFGGGTKVEIK (SEQ ID NO:45),始於SEQ ID NO: 44中之位置21。
將編碼HuTIG3 VH之基因合成為外顯子,其包括在編碼區之3'端的剪接供體信號、在片段之5'端的SpeI位點及在片段之3'端的HindIII位點。在圖14A中,在所推斷的胺基酸序列(SEQ ID NO: 42)旁邊顯示合成的HuTIG3 VH基因之核苷酸序列(SEQ ID NO: 46)。
將編碼人類化TIG3 VL (HuTIG3 VL)之基因合成為外顯子,其包括在編碼區之3'端的剪接供體信號、在片段之5'端的NheI位點及在片段之3'端的EcoRI位點。在圖14B中,在所推斷的胺基酸序列(SEQ ID NO: 44)旁邊顯示合成的HuTIG3 VL基因之核苷酸序列(SEQ ID NO: 47)。
用於產生抗人類TIGIT單株抗體TIG3 (HuTIG3-IgG1.AA)之人類化IgG1/κ形式的哺乳動物表現載體pHuTIG3.AA係藉由如下修飾pHuTIG1.AA來構築:(1)將SpeI與HindIII位點之間的HuTIG1 VH基因替換為HuTIG3 VH基因,及(2)將NheI與EcoRI位點之間的HuTIG1 VL基因替換為HuTIG3 VL基因。在pHuTIG3.AA中編碼的CH2區將胺基酸取代攜帶至位置234及235 (Eu編號)處之丙胺酸殘基(L234A/L235A)以消除效應功能。
在pHuTIG3.AA中編碼的HuTIG3-IgG1.AA之成熟γ重鏈的胺基酸序列係EVQLVESGGGLVQPGGSLRLSCAASGFAFSDYDMSWVRQAPGKGLEWVAYISDGGYNTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQILLRYYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:48)。
C端離胺酸可以存在或可以不存在。
在pHuTIG3.AA中編碼的HuTIG3-IgG1.AA之成熟κ輕鏈的胺基酸序列係DIQMTQSPSSLSASVGDRVTITCKSSQSLLYSSNQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQYHSYPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:49)。
根據供應商之方案,將pHuTIG3.AA短暫性轉染至100 ml指數生長的Expi293細胞(Thermo Fisher Scientific)中。高度產生HuTIG3-IgG1.AA之CHO-K1穩定轉染物亦藉由如上所述之pHuTIG3.AA之電穿孔產生且在SFM4CHO中擴增,直至細胞活力變得小於50%為止。藉由如上所述之蛋白A親和力管柱自短暫性轉染之Expi293細胞及穩定轉染之CHO-K1細胞中之每一者的培養上清液純化HuTIG3-IgG1.AA。
實例 7 : HuTIG3-IgG1.AA 之表徵如實例5中所述,藉由ELISA檢查HuTIG3-IgG1.AA與人類TIGIT之結合。如圖15中所示,HuTIG3-IgG1.AA以劑量依賴性方式結合至人類TIGIT。用於結合至TIGIT的HuTIG3-IgG1.AA之半數最大有效濃度(EC
50)係85 ng/ml。此顯示,HuTIG3-IgG1.AA係人類TIGIT之良好結合劑。
亦如實例5中所述,藉由流動式細胞測量術檢查HuTIG3-IgG1.AA與人類TIGIT之結合。如圖12中所示,HuTIG3-IgG1.AA以劑量依賴性方式結合至人類TIGIT。HuTIG3-IgG1.AA結合至TIGIT的半數最大有效濃度(EC
50)係370 ng/ml。此顯示,HuTIG3-IgG1.AA係人類TIGIT之良好結合劑。
如實例5中所述,藉由流動式細胞測量術,使用NS0-hTIGIT細胞及經FITC標記之hCD155-Fc分析HuTIG3-IgG1.AA阻斷TIGIT與CD155之相互作用的活性。如圖13中所示,HuTIG3-IgG1.AA以劑量依賴性方式阻斷TIGIT與CD155之間的相互作用。HuTIG3-IgG1.AA阻斷TIGIT-CD155相互作用之半數最大抑制濃度(IC
50)係279 ng/ml。此指示,HuTIG3-IgG1.AA係CD155與TIGIT之間的相互作用的有效阻斷劑。
實例 8 :藉由 TIGIT 阻斷增強人類 T 細胞中對破傷風類毒素的 IL-2 細胞介素反應使用對破傷風類毒素之活體外抗原特異性回憶分析檢查鼠類抗TIGIT抗體增強抗原特異性T細胞反應之能力(參見例如Piersma等人,
Vaccine. 2006年4月12日;24(16):3076-83;Zaunders等人,
J Immunol. 2009年8月15日;183(4):2827-36)。藉由增強注射達成對破傷風類毒素的足夠疫苗保護,增強注射允許免疫系統誘導CD4+及CD8+ T細胞記憶反應。作為有效性之替代量度(參見例如Plotkin等人,
Clin Vaccine Immunol. 2010年7月; 17(7): 1055-1065;Goulon等人 1972年11月
Presse Med. 1:3049-3050.),0.1 IU/mL之抗破傷風類毒素之血清含量指示維持性免疫反應。
自已接種破傷風類毒素疫苗的人類志願者獲得外周血液單核細胞(PBMC) (iQ Biosciences),其中藉由ELISA (Genway)證實志願者之破傷風血液效價高於1.0 IU/ml。在96孔圓底盤(Nunc)中含有10%胎牛血清(FBS)的RPMI 1640培養基(Invitrogen)中培養800,000個PBMC。在3.3 μg/ml或10 µg/ml的小鼠抗PD-1抗體(Biolegend,純系EH12.2H7)或抗TIGIT抗體(TIG1)存在下,向含有PBMC之孔中添加2 μg/ml之破傷風類毒素(List Biological Laboratories),在37℃下在5% CO
2培育箱中持續4天。作為對照,在無任何抗體的情況下,向PBMC中添加2 μg/ml之破傷風類毒素。自培養孔收集上清液且藉由細胞介素珠粒陣列(BD Pharmingen, CBA Th1/Th2細胞介素套組)藉由流動式細胞測量術(BD FACSCalibur)量測指示T細胞活化之細胞介素IL-2。如圖16中所示,單獨藉由破傷風類毒素刺激達成之IL-2產量係31 pg/ml。在3.3 μg/ml及10 μg/ml之小鼠抗TIGIT抗體TIG1存在下,IL-2產量分別進一步增強至70 pg/ml及86 pg/ml。在3.3 μg/ml及10 μg/ml之小鼠抗PD-1抗體EH12.2H7存在下,藉由破傷風類毒素刺激達成之IL-2產量亦分別增強至39 pg/ml及57 pg/ml。此等資料指示,TIG1具有增強抗原特異性T細胞細胞介素反應的功能能力。
實例 9 :藉由 TIGIT 阻斷增強對破傷風類毒素的人類 T 細胞增殖性反應使用對破傷風類毒素之活體外抗原特異性回憶分析檢查鼠類抗TIGIT抗體增強抗原特異性T細胞反應之能力(參見例如Piersma等人,
Vaccine. 2006年4月12日;24(16):3076-83;Zaunders等人,
J Immunol. 2009年8月15日;183(4):2827-36)。如實例8中所述,自已接種破傷風類毒素疫苗的人類志願者獲得PBMC (iQ Biosciences)。用羧基螢光素丁二醯亞胺酯(CFSE) (ThermoFisher)標記PBMC,其係用於活體外及活體內標記細胞以便使用染料稀釋液藉由流動式細胞測量術追蹤多代的試劑。在96孔圓底盤(Nunc)中之AIM-V培養基(Invitrogen)中培養250,000個經CFSE標記之PBMC。在各孔中2.5 μg/ml、5 μg/ml或10 μg/ml之小鼠抗PD-1抗體(Biolegend純系EH12.2H7)或TIG1存在下,向各孔中添加2 μg/ml破傷風類毒素(Astarte Biologics, LLC)。將細胞在5% CO
2培育箱中在37℃下培育4天。在第4天向培養物中添加IL-2 [50個單位/毫升] (Peprotech)且在第6天收集PBMC,以便藉由流動式細胞測量術(BD FACSCalibur)針對CD4+ T細胞或CD8+ T細胞上之CFSE稀釋液進行增殖性量測。
如圖17 (上圖)中所示,破傷風類毒素分別誘導源自供體1及2之人類CD4+ T細胞增殖4.5%及6.5%。在所測試之所有抗體濃度(2.5 μg/ml、5 μg/ml及10 μg/ml)下,TIG1之添加進一步增強CD4+ T細胞增殖,且在彼等劑量範圍下,用抗PD-1抗體觀察到類似的增殖作用。
如圖17 (下圖)中所示,破傷風類毒素分別誘導源自供體1及2之人類CD8+ T細胞增殖15%及15.5%。在所測試之所有抗體濃度(2.5 μg/ml、5 μg/ml及10 μg/ml)下,TIG1之添加進一步增強CD8+ T細胞增殖,且在彼等劑量範圍下,用抗PD-1抗體EH12.2H7觀察到類似的增殖作用。此等結果表明,TIG1具有增強抗原特異性T細胞增殖反應的能力。
實例 10 :藉由 TIGIT 阻斷增加人類初級效應細胞及 K562 目標細胞之 NK 細胞介導的細胞毒性人類NK細胞能夠對缺乏MHC I之目標細胞(諸如慢性骨髓性白血病(CML)細胞株K562)誘出天然細胞毒性(參見例如Nagel等人,
Cancer Res1981;41:2284-2288;Andersson等人,
Int J Cancer. 1979年2月;23(2):143-7;Lozzio等人,
Leuk Res. 1979;3(6):363-70)。使用商業抗體(Biolegend抗CD155純系SKII.4)證實CD155 (PVR)在K562細胞(ATCC)上之表現。如圖18 (上圖)中所示,發現98%之K562細胞表現高含量之CD155 (黑色直方圖)。亦使用商業抗體(eBiosciences抗TIGIT純系MBSA43及Biolegend抗CD56純系HCD56),證實在3個代表性人類供體上,TIGIT在PBMC (iQ Biosciences)中之人類CD56陽性NK細胞上之表現(圖18,下圖)。
在存在及不存在TIG1之情況下,量測由NK細胞介導之K562細胞的溶解。將PBMC在AIM-V培養基(Invitrogen)中在介白素-2 (IL-2) [200個單位/毫升] (Peprotech)存在下在37℃下在5% CO
2培育箱中培養隔夜。第二天,將K562細胞經CFSE標記且與PBMC一起在37℃下在5% CO
2培育箱中在10 μg/ml TIG1存在下1:100 (目標:PBMC;一個K562細胞:一百個含有約5% NK細胞的PBMC)共培養4小時。在培育期之後,收集細胞且用5 nM Sytox紅(ThermoFisher)染色以藉由(CFSE+ Sytox Red+)區分死的目標細胞。藉由流動式細胞測量術(FACSCalibur;FlowJo分析)測定由NK細胞溶解之K562目標細胞的百分比。如圖19中所示,在無TIG1的情況下,2% K562細胞溶解。當添加TIG1時,4.4% K562細胞溶解。TIG1之添加使K562細胞的由NK細胞介導之天然細胞毒性增強兩倍,表明TIG1具有提高人類效應細胞之亞群殺死目標細胞之水準的能力。
實例 11 :藉由 TIGIT 阻斷增強 SEB 誘導的人類 T 細胞細胞介素產生諸如SEB (葡萄球菌腸毒素B)之超抗原藉由將抗原呈現細胞上之MHC II類分子連接至TCR之νβ元件,引起細胞介素之產生而活化T細胞,細胞介素包括介白素-2 (IL-2)、介白素-6 (IL-6)、腫瘤壞死因子α (TNFα)及干擾素γ (IFNγ) (參見例如Krakauer等人,
Toxins(Basel). 2010年8月; 2(8): 1963-1983)。相較於可以活化0.1-0.001% T細胞的典型回憶抗原誘導的T細胞反應,SEB能夠視攜帶各特定血液供體中所存在的νβ3、νβ12、νβ14及νβ17之T細胞的分率而定活化人類血液中多達10-20%之T細胞。因此,SEB可用於基於T細胞之細胞介素分泌分析來測定藉由用人類全血細胞(WBC)進行TIGIT阻斷所達成的目標調整水準。
使用肝素鈉在抽血4小時內在看不見溶血跡象的情況下獲得新鮮分離的WBC樣品(史丹福血液中心(Stanford Blood Center))。將250 μl等分至96孔圓底盤(Nunc)中之各孔中且在10 μg/ml人類化抗PD-1單株抗體或10 μg/ml HuTIG1-IgG1.AA存在下在37℃下在5% CO
2培育箱中用最終濃度1 μg/ml之SEB (Toxin Technology)刺激24小時。24小時後,簡單地離心96孔盤,分離血漿層以便收集。在血漿樣品收集之後,藉由細胞介素珠粒陣列(Biolegend, LEGENDplex™人類CD8/NK Panel)藉由流動式細胞測量術(BD FACSCalibur)量測IL-2、IL-6、TNFα及IFNγ之表現量且用Biolegend軟體分析以便定量量測。
為確定IL-2、IL-6、TNFα及IFNγ中之每一者之表現量的改變,將在存在測試抗體(加SEB)情況下的細胞介素含量除以在不存在各供體之抗體情況下的細胞介素含量。因此,2倍改變(例如在存在抗TIGIT情況下所偵測的)意謂在實驗中量測到之細胞介素之絕對濃度係在SEB刺激之對照情況下發現的量的兩倍。如圖20中所示,在10 μg/ml人類化抗PD-1或10 μg/ml之HuTIG1-IgG1.AA存在下,健康的供體血細胞的SEB刺激的IL-2、IL-6、TNFα或IFNγ產量增強。在此等條件下,WBC之SEB誘導的細胞介素產生及其藉由HuTIG1-IgG1.AA達成之調整係細胞介素效應反應之增強作用的讀出。HuTIG1-IgG1.AA能夠增強免疫反應,如藉由此處所示之分析中IL-2、IL-6、TNFα及IFNγ之產生的刺激所證明。
實例 12 : HuTIG1-IgG1.AA 及 HuTIG3-IgG1.AA 介導之補體依賴性細胞毒性的表徵補體依賴性細胞毒性(CDC)係指在補體存在下表現其目標分子之細胞的溶解(參見例如Gazzano-Santoro等人, J
. Immunol. Methods, 202:163)。傳統補體路徑之活化係藉由補體系統之第一組分(C1q)與(適當子類別之)抗體的結合起始,該等抗體結合至其在細胞表面上之同源抗原。為評定補體活化,使人類T細胞Jurkat雙重報導親本細胞株(雙重Jurkat;Invivogen)經工程改造以在表面上穩定表現人類TIGIT (Jurkat-TIGIT)。如圖21中所示,藉由流動式細胞測量術用商業上的經PE標記之抗TIGIT抗體(eBiosciences純系MSBA43)證實TIGIT在Jurkat-TIGIT細胞之表面上之表現。因此,Jurkat-TIGIT用作組成性表現膜結合TIGIT之目標細胞且因此可以在補體存在下經歷抗體結合CDC活性。
在至多50 µg/ml之遞增濃度的HuTIG1-IgG1.AA、HuTIG3-IgG1.AA或兔抗胸腺細胞球蛋白(ATG) (Fresenius Biotech GmbH)存在下,用Jurkat-TIGIT細胞及人類補體進行CDC分析。ATG用作陽性對照,此係因為其與Jurkat細胞之反應性且與Jurkat細胞一起展現出補體依賴性細胞毒性活性(參見例如Eiermann等人,
J Hematother Stem Cell Res. 2001年6月;10(3):385-90;Ayuk等人,
AntiCancer Research29: 1355-1360 (2009))。將含有10%胎牛血清(FBS)之RPMI 1640培養基(Invitrogen)中的50,000個Jurkat-TIGIT細胞接種至96孔圓底盤(Nunc)中。治療抗體以50 μg/ml之最高濃度開始添加,繼之以三倍稀釋系列,且使其與細胞一起在37℃下在5% CO
2培育箱中培育1小時。此1小時培育之後,添加人類補體且使其在37℃下在5% CO
2培育箱中再培育3小時。在完成此3小時培育之後,添加5 μg/ml碘化丙錠(ThermoFisher)且藉由流動式細胞測量術(BD FACSCalibur)分析樣品以測定碘化丙錠陽性之百分比作為細胞死亡之讀出。
為確定標準化改變,藉由流動式細胞測量術量測活力百分比且以死細胞評估碘化丙錠陽性細胞之百分比。將未經處理之樣品值標準化為100%。將樣品在抗體存在下之活力百分比除以未經處理之標準化值,得到活力改變倍數。如圖22中所示,高達50 μg/ml之HuTIG1-IgG1.AA及HuTIG3-IgG1.AA均未誘導出CDC活性。此等資料表明,HuTIG1-IgG1.AA及HuTIG3-IgG1.AA均不結合至TIGIT,導致T細胞之補體介導性細胞死亡。
實例 13 : HuTIG1-IgG1.AA 及 HuTIG3-IgG1.AA 之 Jurkat 雙重報導細胞株表徵使用在染色體中攜帶分泌型螢光素酶報導基因的Jurkat-TIGIT報導細胞株分析阻斷人類TIGIT受體之功能結果,該分泌型螢光素酶報導基因係藉由與NF-κB共同轉錄反應元件之五個複本及c-Rel結合位點之三個複本融合的IFNβ最小啟動子驅動。Jurkat-TIGIT細胞亦在ISG54最小啟動子以及五個IFN刺激之反應元件的控制下表現分泌型胚胎鹼性磷酸酶(SEAP)報導基因。
分析包括兩個細胞株,其代表T效應細胞(Jurkat-TIGIT)及抗原呈現細胞。T效應細胞穩定地表現在T細胞受體(TCR)之下游活化的螢光素酶報導子。抗原呈現細胞(人工抗原呈現細胞或「aAPC」)穩定地表現T細胞活化蛋白,其以抗原獨立方式結合且活化T效應細胞,諸如Jurkat-TIGIT (Promega)。將aAPC細胞進一步工程改造以表現CD155。當T效應細胞與其相應aAPC細胞一起共培養時,TIGIT與CD155之相互作用抑制T效應細胞之活化且降低螢光素酶之表現。阻斷抗體之抗TIGIT的添加釋放了抑制信號,允許螢光素酶活性之表現。
在此分析中,將16,000個表現人類CD155及T細胞活化蛋白之aAPC (TCR活化劑CD155 CHO-K1) (Promega)塗鋪至96孔盤之一半區域上且在37℃下在5% CO
2培育箱中培育24小時。次日,將50,000個人類Jurkat-TIGIT細胞與TCR活化劑CD155 CHO-K1細胞一起在不存在或存在以10 µg/ml開始且兩倍稀釋系列的HuTIG1-IgG1.AA或HuTIG3-IgG1.AA的情況下再共培養24小時。收集上清液且使用QUANTI-Luc (Invivogen)及多模式讀板儀(Perkin Elmer EnSpire)按相對光單位量測所分泌的螢光素酶。為確定相對光單位的倍數改變,將存在各種濃度之抗TIGIT抗體的情況下與TCR活化劑CD155 CHO-K1一起共培養的Jurkat-TIGIT之相對光單位除以在不存在抗體的情況下的相對光單位。因此舉例而言,2倍增加(例如在抗TIGIT存在下所偵測到的)由此意謂在實驗中量測到的相對光單位係在僅TCR活化劑刺激之對照情況下發現的量的兩倍。
如圖23中所示,如藉由在0.6 μg/ml至10 μg/ml之各阻斷性TIGIT抗體存在下所誘導的約1.5至2.5倍增加的遞增相對光單位增加所測定,HuTIG1-IgG1.AA及HuTIG3-IgG1.AA均能夠增加固有T細胞活化信號傳導。此等資料表明,抗TIGIT抗體藉由阻斷TIGIT之功能而具有拮抗活性且增加固有T細胞活性。
實例 14 :與 TIGIT 之競爭性結合使用流動式細胞測量術鑑別與TIG1競爭結合至人類TIGIT之抗體。使用Pierce FITC抗體標記套組(Thermo Fisher Scientific),根據製造商之方案,用螢光染料FITC標記TIG1。使用NS0-hTIGIT細胞,藉由流動式細胞測量術檢查所得經FITC標記之TIG1與人類TIGIT之結合。將十萬個NS0-hTIGIT細胞與以10 μg/ml開始且兩倍連續稀釋的各種濃度之經FITC標記之TIG1一起在200 μl之FACS緩衝劑(含有0.5%牛血清白蛋白及0.05%疊氮化鈉之PBS)中在4℃下培育30分鐘。在用2 ml之FACS緩衝劑洗滌之後,將NS0-hTIGIT細胞懸浮於0.2 ml之FACS緩衝劑中且使用FACScan流式細胞儀(BD Biosciences, San Jose, CA),使其經歷流動式細胞測量術分析,且獲得各抗體濃度下之平均通道螢光(MCF)。確定經FITC標記之TIG1的亞飽和濃度,其中達成90%之最大螢光含量。
將亞飽和濃度之經FITC標記之TIG1與十萬個NS0-hTIGIT細胞一起在存在(或不存在)高出200倍的濃度的測試抗體的情況下在200 μl之FACS緩衝劑中在4℃下培育30分鐘。舉例而言,當使用0.1 μg/ml之經FITC標記之TIG1結合至NS0-hTIGIT細胞時,向細胞懸浮液中添加20 μg/ml之測試抗體。作為背景對照,在無任何抗體的情況下培育十萬個NS0-hTIGIT細胞。在用2 ml之FACS緩衝劑洗滌之後,將NS0-hTIGIT細胞懸浮於0.2 ml之FACS緩衝劑中且經歷流動式細胞測量術分析。
將與經FITC標記之TIG1一起培育的NS0-hTIGIT細胞的MCF [MCF A]標準化為100%,且將不與抗體一起培育之NS0-hTIGIT細胞的MCF [MCF B]標準化為0%。與經FITC標記之TIG1及測試抗體一起培育的NS0-hTIGIT細胞的MCF [MCF C]係藉由下式標準化:100 × ([MCF C] - [MCF B]) / ([MCF A] - [MCF B])。當與經FITC標記之TIG1及測試抗體一起培育的NS0-hTIGIT細胞之標準化MCF小於20%時,判定測試抗體與TIG1競爭結合至人類TIGIT。
可以使用相同的分析鑑別與TIG2或TIG3競爭的抗體。
實例 15 :親和力量測單株抗體之抗原結合親和力可以藉由不含標籤的光學表面電漿子共振(SPR)生物感測器量測,諸如Biacore T100 (GE Healthcare Life Sciences, Marlborough, MA)、ProteOn XPR36 (BioRad, Hercules, CA)、Octet RED384 (ForteBio, Menlo Park, CA)及IBIS MX96 (Wasatch Microfluidics, Salt Lake City, UT) (Yang等人,
Anal. Biochem. 508:78-96, 2016)。TIG1、TIG2及TIG3中之每一者的抗原結合親和力係使用Biacore T100量測,如Yang等人(同前文獻)所述。使用標準偶聯方案,將蛋白A/G (Thermo Fisher Scientific)固定至CM5感測器晶片(GE Healthcare Life Sciences)上的流槽。藉由蛋白A/G在CM5感測器晶片上捕捉測試抗體(TIG1、TIG2或TIG3)。在流槽中使用各種濃度之重組性人類TIGIT蛋白質,諸如經His標記的重組性人類TIGIT (Creative BioMart, Shirley, NY),用於結合至感測器晶片上之測試抗體。使用BIA評估軟體(GE Healthcare Life Sciences)獲得測試抗體與人類TIGIT之間的相互作用的結合速率(ka)及解離速率(kd)。關於TIG1、TIG2及TIG3中之每一者,藉由結合速率(ka)除以解離速率(kd)計算結合常數(Ka)。藉由解離速率(kd)除以結合速率(ka)計算解離常數(Kd)。
在BioRad ProteOn XPR36系統上,在10 mM HEPES、150 mM NaCl pH 7.4、0.005% Tween-20及0.2 mg/ml BSA中在25℃下對HuTIG1-IgG1.AA進行生物感測器研究。將HuTIG1-IgG1.AA稀釋至3.7、1.2及0.4 nM,且歷經5分鐘捕捉至塗有約10,000 RU之GE抗人類IgG抗體的GLM感測器晶片上。在最高濃度100 nM下在降至1.2 nM之3倍稀釋系列中測試經His標記之可溶性重組性人類TIGIT (目錄號TIT-H52H3;Acro Biosystems, Newark, DE)。使用局部Rmax將來自三個不同密度抗體表面之資料與1:1相互作用模型全面擬合。所獲得的結合速率(ka)及解離速率(kd)分別係(4.42 ± 0.02) × 10
5M
-1s
-1及(4.09 ± 0.02) × 10
-4s
-1。所計算的解離常數(Kd)係925 ± 7 pM。
實例 16 :抗原決定基定位為在TIGIT分子中定位由TIG1、TIG2及TIG3中之每一者識別的抗原決定基,在TIGIT (SEQ ID NO: 3)之胞外區中藉由使用重疊延伸PCR法定點突變誘發產生單一胺基酸取代突變體(Higuchi, R., 1989, 「
PCR Technology: Principles and Applications for DNA Amplification」, Erlich, H. A.編, Stockton Press, New York, NY, 第61-70頁)。使用TIGIT之胞外區中的以下六個突變體進行分析:Q35A (SEQ ID NO:50)、N37A (SEQ ID NO:51)、Q39A (SEQ ID NO:52)、N49A (SEQ ID NO:53)、D51A (SEQ ID NO:54)及F86A (SEQ ID NO:55)。各突變體名稱中左側之字母、中間之數字及右側之字母分別表示野生型TIGIT中之胺基酸殘基、自TIGIT (SEQ ID NO: 3)之胞外區中之N端甲硫胺酸殘基計數的位置及突變體中之胺基酸。胺基酸殘基用單字母代碼表示。該六個突變體各自將胺基酸取代攜帶至TIGIT-CD155複合物之界面附近(Stengel,
Proc. Natl. Acad. Sci. USA,109:5399-5404, 2012)。
哺乳動物表現載體pFCm179具有與pFCm404相同的結構(圖1),但以下除外:(i)嘌呤黴素N-乙醯基-轉移酶基因替換為大腸桿菌(
E. coli)黃嘌呤鳥嘌呤磷酸核糖轉移酶基因,且(ii)人類TIGIT之胞外區替換為人類IL-15。將編碼人類TIGIT之胞外區的六個丙胺酸取代突變體的DNA片段個別地引入pFCm179中以替換IL-15編碼區。所得表現載體pFCm179-Q35A、pFCm179-N37A、pFCm179-Q39A、pFCm179-N49A、pFCm179-D51A及pFCm179-F86A在TIGIT編碼區中分別攜帶Q35A、N37A、Q39A、N49A、D51A及F86A突變體,且除了對各突變體具有特異性的單一胺基酸取代以外,表現與pFCm404中編碼之TIGIT-Fc融合蛋白相同的序列。
野生型及突變型TIGIT-Fc融合蛋白在人類胎腎細胞株HEK293中暫時表現。使HEK293細胞在含有10% FCS之DMEM中在37℃下在7.5% CO
2培育箱中生長。使用聚乙烯亞胺法,將野生型及突變型TIGIT-Fc融合蛋白之表現載體(pFCm404、pFCm179-Q35A、pFCm179-N37A、pFCm179-Q39A、pFCm179-N49A、pFCm179-D51A及pFCm179-F86A)個別地轉染至HEK293細胞中(Durocher等人
Nucl. Acids Res. 30: e9, 2002)。藉由ELISA量測培養上清液中TIGIT-Fc融合蛋白之產量。簡言之,用100微升/孔之在4℃下在PBS中1/2,000稀釋隔夜的山羊抗人類IgG Fc特異性多株抗體(Sigma-Aldrich)塗佈ELISA培養盤,用洗滌緩衝劑洗滌,且用200微升/孔之ELISA緩衝劑在室溫下阻斷20分鐘。在用洗滌緩衝劑洗滌之後,向ELISA培養盤施用在ELISA緩衝劑(100微升/孔)中經過恰當稀釋的短暫性轉染之HEK293細胞的培養上清液。經純化之hTIGIT-Fc係用作標準。在室溫下培育ELISA培養盤30分鐘且用洗滌緩衝劑洗滌之後,使用100微升/孔在ELISA緩衝劑中1,2000稀釋的HRP結合的山羊抗人類IgG多株抗體(SouthernBiotech)偵測結合的Fc融合蛋白。在室溫下培育培養盤30分鐘且用洗滌緩衝劑洗滌之後,藉由添加100微升/孔之ABTS受質(Sigma-Aldrich)起始顯色且用100微升/孔之2%草酸停止。在405 nm下讀取吸光度。
藉由ELISA檢查小鼠TIG1、TIG2及TIG3抗體中之每一者與TIGIT突變體的結合。用100微升/孔之在4℃下在PBS中1/2,000稀釋隔夜的山羊抗人類IgG Fc特異性多株抗體(Sigma-Aldrich)塗佈ELISA培養盤,用洗滌緩衝劑洗滌,且用200微升/孔之ELISA緩衝劑在室溫下阻斷20分鐘。在用洗滌緩衝劑洗滌之後,向ELISA培養盤一式兩份地施用於ELISA緩衝劑(100微升/孔)中之0.5 μg/ml之暫時表現的TIGIT-Fc融合蛋白,其攜帶野生型TIGIT或六種TIGIT突變體中之一者,將其在室溫下培育30分鐘。關於陰性對照,使用未經轉染之HEK293細胞的培養上清液。在用洗滌緩衝劑洗滌之後,施用100微升/孔於ELISA緩衝劑(100微升/孔)中之200 ng/ml的測試抗體(TIG1、TIG2或TIG3)。在室溫下培育ELISA培養盤30分鐘且用洗滌緩衝劑洗滌之後,使用100微升/孔於ELISA緩衝劑中1/2,000稀釋的HRP結合的山羊抗小鼠κ鏈多株抗體(Bethyl Laboratories, Montgomery, TX)偵測結合抗體。在室溫下培育培養盤0.5小時且用洗滌緩衝劑洗滌之後,藉由添加100微升/孔之ABTS受質(Sigma-Aldrich)起始顯色且用100微升/孔之2%草酸停止。在405 nm下讀取吸光度。
表1:TIG1、TIG2及TIG3與TIGIT突變體之結合
關於TIG1、TIG2及TIG3中之每一者,在下式中計算與各TIGIT突變體之相對結合。將野生型TIGIT-Fc融合蛋白之平均吸光度[Abs A]標準化為100%,且將未經轉染之HEK293細胞之培養上清液的平均吸光度[Abs B]標準化為0%。藉由下式標準化突變型TIGIT-Fc融合蛋白之平均吸光度[Abs C]:100 × ([Abs C] - [Abs B]) / ([Abs A] - [Abs B])。結果概述於表1中。當在位置35、37、49或51處之胺基酸殘基經丙胺酸取代時,TIG1之相對結合小於5%,表明在此四個位置處之胺基酸殘基對於TIG1與TIGIT之結合係關鍵的。此分析中所用的TIGIT突變體均未消除TIG2及TIG3與TIGIT之結合。
實例 17 :在添加 HuTIG1-IgG1.AA 、抗 PD-L1 抗體及 HuTIG1-IgG1.AA 與抗 PD-L1 抗體之組合之後, IFNɣ 之分泌增強首先藉由使血液在密度梯度培養基(Lymphoprep;STEMCELL;07801)上分層且在離心之後自界面收集PBMC而自白血球層分離人類PBMC。在下一步中,藉由CD14陽性選擇(EasySep人類CD14陽性選擇套組;STEMCELL;目錄號18058),根據製造商之方案自PBMC分離人類單核球且將其在補充有5% FBS及0.1 µg/ml GM-CSF (R&D;目錄號215-GM-050/CF)及0.1 µg/ml IL-4 (R&D;目錄號204-IL-050/CF)的RPMI培養基中培養六天。收集分化的單核球源性樹突狀細胞(moDC)且藉由流動式細胞測量術檢查CD155、CD112及PD-L1之表現(圖24)。
藉由負消耗法(negative depletion) (RosetteSep人類CD4 T細胞富集混合物;STEMCELL;#15062)自4個不同供體的白血球層分離人類CD4+細胞且使用流動式細胞測量術測定純度。
將moDC及CD4+細胞以1:4比率(25,000個moDC;100,000個CD4+細胞)組合,且在不含血清之培養基(X-Vivo-20;LONZA;目錄號04-448Q)中在HuTIG1-IgG1.AA (5 µg/ml或15 µg/ml)或抗PD-L1抗體(10 µg/ml;純系243.55.S1;SEQ ID NO: 56及57)或HuTIG1-IgG1.AA (15 µg/ml)及抗PD-L1抗體(10 µg/ml)兩者存在下培養4天,然後使用細胞學珠粒陣列(CBA;人類IFN-ɣ Flex Set;BD;目錄號560111)進行IFNγ定量。人類IgG1 Fc (25 µg/ml;BioXcell;目錄號BE0096)用作對照。
如圖25中所示,相較於適當同型對照抗體,HuTIG1-IgG1.AA及抗PD-L1抗體阻斷獨立地增加IFNγ之產量。相較於單獨的任一單一療法,HuTIG1-IgG1.AA與抗PD-L1抗體之組合顯著地且協同地增強IFNγ之產生。
實例 18 : HuTIG1-IgG1.AA 及 HuTIG3-IgG1.AA 偵測在人類淋巴及骨髓細胞上表現之 TIGIT用描繪T細胞、B細胞、NK細胞及骨髓系亞群的直接結合的抗體共染色自十個供體分離的總的人類PBMC。使用Live/dead Aqua可固定死細胞染色套組排除死細胞。使用與Alexa647染料結合之HuTIG1-IgG1.AA及HuTIG3-IgG1.AA抗體測定TIGIT之表現。使用市售抗CD96抗體(純系NK92.39)測定CD96之表現。在圖26A中,加號(+)符號表示超過背景之表現,其中(+++)表示所觀察到的最高表現。加號/減號(+/-)符號表示,在指定群體內僅一小類細胞超過背景表現TIGIT或CD96,且減號(-)符號表示缺乏超過背景之表現。在所有情況下,使用改良的螢光減一(FMO)法測定背景,其中添加染色組中所用的所有螢光染料,但目標抗體(亦即HuTIG1-IgG1.AA、HuTIG3-IgG1.AA、抗CD96抗體)除外。確切而言,用相同結合之IgG特異性同型對照抗體替換目標抗體。圖26B顯示在各種表現量下PBMC中之抗TIGIT抗體染色的代表性直方圖,其用於分配圖26A中之CD96之表現量。淺色直方圖表示改良的FMO。深色直方圖表示HuTIG1-IgG1.AA或HuTIG3-IgG1.AA染色。
自商業來源購買來自黑素瘤、結腸直腸癌、非小細胞肺癌及腎透明細胞癌的離散腫瘤細胞且用描繪T細胞及抗原呈現細胞亞群的直接結合的抗體染色。使用泛同功異型物抗CD45抗體(純系HI30)鑑別白血球。使用Live/dead Aqua可固定死細胞染色套組排除死細胞。使用與Alexa647染料結合之HuTIG1-IgG1.AA抗體測定TIGIT之表現。在所有情況下,使用改良的螢光減一(FMO)法測定背景,其中添加染色組中所用的所有螢光染料,但目標抗體(亦即HuTIG1-IgG1.AA)除外。確切而言,用相同結合之IgG特異性同型對照抗體替換目標抗體。圖32B顯示在圖32A中所示之各種表現量下腫瘤浸潤性淋巴細胞(TIL)上之抗TIGIT染色的代表性直方圖。淺色直方圖表示改良的FMO。深色直方圖表示HuTIG1-IgG1.AA染色。
實例 19 :藉由流動式細胞測量術對抗人類 TIGIT 抗體 HuTIG1-IgG1.AA 進行抗原決定基定位將人類TIGIT cDNA選殖至pcDNA 3.1 (+)中,其中9殘基血球凝集素(HA)肽標籤及10殘基肽連接子相繼插入21殘基天然信號肽之後及成熟TIGIT蛋白質(SEQ ID NO: 58)之N端之前。使人類TIGIT之胞外區之相關胺基酸殘基(T34、Q35、N37、E39、L44、I47、N49、D51、L52、H55、F86、I88、H90、Y92及T96)突變成丙胺酸,一次一個胺基酸。純化質體,且使用Fugene 6 (Promega)轉染試劑,根據製造商之建議將其短暫性轉染至CHO-K1細胞中。藉由抗HA抗體偵測證實HA標記之人類TIGIT突變體表現。
關於結合抗原決定基之抗hTIGIT抗體之流動式細胞測量術分析,將含或不含單一胺基酸突變之HA標記的人類TIGIT蛋白質短暫性轉染至CHO-K1細胞中。24小時後,將經轉染的細胞懸浮於HBSS緩衝劑(Thermo Fisher Scientific,目錄號14175095)中,且與不同濃度之HuTIG1-IgG1.AA抗體一起在50 µL體積中培育。在4℃下培育1小時後,洗滌細胞且與50 µL Alexa488結合的抗人類IgG (H+L)二級抗體(Thermo Fisher Scientific,目錄號A-11013)一起進行第二次培育,從而偵測由抗體結合之細胞。將細胞與作為陽性對照的抗HA抗體(Sigma,目錄號H7411)一起培育,且將未經轉染之CHO-K1細胞用作陰性對照。在Attune NxT細胞計數器(Thermo Fisher Scientific)上分析細胞且使用FlowJo軟體處理資料。關於各突變體,將飽和抗體結合MFI (平均螢光強度)標準化為100% POC (對照之百分比),且將無初級抗體結合對照MFI標準化為0% POC。隨後使用GraphPad Prism 7曲線擬合,使用下式將資料與四參數非線性S形曲線擬合:Y = 下限(Bottom) + (上限(Top)-下限)/(1+
10
((LogEC 50 -X)* 希爾斜率 (HillSlope)))。
在此分析中,HuTIG1-IgG1.AA以EC
50= 1.28 nM結合至野生型人類TIGIT。十五個單點丙胺酸TIGIT突變體中之五個以結合親和力減小超過10倍結合HuTIG1-IgG1.AA。含突變N49A、D51A、H90A、N37A或Q35A之人類TIGIT (SEQ ID NO: 3)分別以在EC
50= 17.7至176 nM範圍內之遞減效能結合HuTIG1-IgG1.AA (圖27)。此等殘基全部共定位於TIGIT IgV細胞外域之前部β片結構上的一個離散區(圖28)。
實例 20 :來自給予 HuTIG1-IgG1.AA 之非人類靈長類動物之全血的 T 細胞亞群的離體免疫表型分型由Charles River Laboratories (Reno, NV)進行藥物動力學研究。此研究之目的係離體檢查經以10 mg/kg單一劑量之抗TIGIT (HuTIG1-IgG1.AA)抗體處理之食蟹獼猴的全血樣品以便間接評定TIGIT之受體佔有率。
向三隻在實驗上未經處理之雌性食蟹獼猴(#67、#68及#69)投與10 mg/kg單一靜脈內劑量之HuTIG1-IgG1.AA抗體。在最後一個採樣時間點24小時內(對應於給藥前)、給藥後第1天、第2天、第7天、第14天、第21天及第28天時間點收集置入肝素鈉之全血樣品。關於全血流動式細胞測量術研究,使用來自BioLegend (純系MBSA43)之經螢光標記之抗人類TIGIT測定TIGIT在食蟹獼猴血液淋巴細胞細胞亞群上之表現量,因為其已顯示與非人類靈長類動物交叉反應(
PLoS Pathog.2016年1月; 12(1);BioLegend)。藉由FACSCalibur獲得活細胞且藉由FlowJo軟體分析。
當對給藥前全血樣品染色時,抗TIGIT (MBSA43)能夠結合CD4+及CD8+ T細胞亞群。在給藥後,視所檢查的不同動物而定,視截至第21天或第28天含量回到給藥前偵測含量的所檢查的不同猴而定,在第14天或第21天之前,抗TIGIT (MBSA43)都不能偵測TIGIT在此等T細胞亞群上之表現(圖29B及圖30B)。不能偵測TIGIT表現係因為CD4+或CD8+ T細胞頻率(分別係圖29A及圖30A)顯著改變,表明表面TIGIT由治療抗體(HuTIG1-IgG1.AA)佔據,且並非係因為T細胞亞群耗竭。
此等資料支持,抗TIGIT抗體HuTIG1-IgG1.AA與食蟹獼猴交叉反應,且使用來自BioLegend (純系MBSA43)之抗人類TIGIT評定TIGIT受體佔有率。
實例 21 :藉由 HuTIG1-IgG1.AA 及 HuTIG3-IgG1.AA 增強 K562 目標細胞上 NK 細胞介導之細胞毒性使用經純化之NK細胞代替PBMC重複
實例 10中所述之NK細胞介導之細胞毒性分析。為獲得用於此等實驗之足夠的且適當的經純化之NK細胞,篩選具有高NK細胞頻率、足夠的TIGIT表面表現及足夠的CD226表現的供體PBMC係重要的。獲得外周血LeukoPak (由100億或更多的細胞組成)且使用Miltenyi autoMACS Pro分離器根據製造商之說明書(Miltenyi Biotec,目錄號130-092-657)進行NK細胞分離。將經純化之NK細胞再懸浮於6孔盤中含有介白素-2 (IL-2) [200個單位/毫升]的培養基中。將6孔盤於37℃下5% CO
2培育箱中置放24小時,隨後用自各孔收集之細胞進行天然細胞毒性研究。
在存在及不存在抗TIGIT抗體(TIG1)之情況下,量測由經純化之NK細胞介導之K562細胞的溶解。將NK細胞在RPMI 1640培養基(Invitrogen)中在介白素-2 (IL-2) [200個單位/毫升] (Peprotech)存在下,在37℃下在5% CO
2培育箱中培養隔夜。第二天,將K562細胞用CFSE標記,且在10 μg/ml美羅華(Rituxan)或人類化抗TIGIT抗體(HuTIG1-IgG1.AA或HuTIG3-IgG1.AA)存在下,與NK細胞以1:20比例(目標:NK;一個K562細胞:二十個NK細胞)在37℃下於5% CO
2培育箱中共培養4小時。美羅華係用作陰性對照,因為K562細胞不表現CD20。在培育期之後,收集細胞且用5 nM Sytox紅(ThermoFisher)染色以藉由(CFSE+ Sytox Red+)區分出死亡的目標細胞。藉由流動式細胞測量術(FACSCalibur;FlowJo分析)測定由NK細胞溶解之K562目標細胞的百分比。
如圖31中所示,當使用經純化之NK細胞時,添加抗TIGIT抗體增強了K562細胞之NK細胞介導的天然細胞毒性,表明抗TIGIT抗體(HuTIG1-IgG1.AA或HuTIG3-IgG1.AA)具有增加人類效應細胞之亞群殺死目標細胞之量的能力(相對於『無抗體』或美羅華標準化百分比,分別增加28%或19%)。
環 | Kabat | AbM | Chothia | Contact |
L1 | L-24--L34 | L24--34 | L24--L34 | L30--L36 |
L2 | L50--L56 | L50--l56 | L50---L56 | L46--L55 |
L3 | L89--L97 | L89--97 | L89--L97 | L89--L96 |
H1 | H31--H35B (Kabat編號) | H26--H35b | H26--H32..34 | H30--H35B |
H1 | H31-H35 (Chothia編號) | H26--H35 | H26--H32 | H30--H35 |
H2 | H50--H65 | H50--H58 | H52--H56 | H47--H58 |
H3 | H95--H102 | H95--H102 | H95--H102 | H93--H10 |
與TIGIT之相對結合(%) | |||
TIGIT突變體 | TIG1 | TIG2 | TIG3 |
Q35A (SEQ ID NO: 50) | -0.1 | 29.1 | 57.8 |
N37A (SEQ ID NO: 51) | 0.8 | 75.1 | 83.5 |
E39A (SEQ ID NO: 52) | 71.1 | 69.1 | 94.2 |
N49A (SEQ ID NO: 53) | 0.5 | 42.6 | 37.2 |
D51A (SEQ ID NO: 54) | 1.8 | 61.0 | 41.1 |
F86A (SEQ ID NO: 55) | 49.5 | 40.5 | 43.2 |
圖1係重組性TIGIT及CD155蛋白質之表現載體的示意性結構。
圖2描繪藉由抗TIGIT抗體達成的TIGIT-CD155相互作用之抑制。
圖3描繪TIG1 VH之胺基酸序列。
圖4描繪TIG1 VL之胺基酸序列。
圖5描繪TIG2 VH之胺基酸序列。
圖6描繪TIG2 VL之胺基酸序列。
圖7描繪TIG3 VH之胺基酸序列。
圖8描繪TIG3 VL之胺基酸序列。
圖9A描繪HuTIG1 VH基因之核苷酸序列及所編碼之胺基酸序列,而圖9B描繪HuTIG1 VL基因之核苷酸序列及所編碼之胺基酸序列。
圖10顯示表現載體pHuTIG1.AA之示意性結構。
圖11顯示關於HuTIG1-IgG1.AA與人類TIGIT之結合的ELISA分析的結果。
圖12:關於HuTIG1-IgG1.AA及HuTIG3-IgG1.AA與人類TIGIT之結合的FACS分析。
圖13係顯示藉由HuTIG1-IgG1.AA及HuTIG3-IgG1.AA阻斷人類TIGIT與人類CD155之間的相互作用的圖。
圖14A描繪HuTIG3 VH基因之核苷酸序列及所編碼之胺基酸序列,而圖14B描繪HuTIG3 VL基因之核苷酸序列及所編碼之胺基酸序列。
圖15描繪關於HuTIG3-IgG1.AA與人類TIGIT之結合的ELISA分析。
圖16顯示在抗原特異性回憶刺激中藉由TIG1增加的IL-2產生。
圖17描繪在抗原特異性回憶刺激中藉由TIG1增加的CD4+及CD8+ T細胞增殖。
圖18描繪CD155在K562細胞上 (上圖)及TIGIT在NK細胞上(下圖)的表現。
圖19描繪藉由TIG1達成的對K562目標細胞的增強的NK細胞介導的細胞毒性。
圖20指示,HuTIG1-IgG1.AA增強細胞介素效應反應。
圖21描繪人類TIGIT在其細胞表面上之Jurkat-TIGIT細胞株表現。
圖22指示,HuTIG1-IgG1.AA及HuTIG3-IgG1.AA未誘出CDC活性。
圖23顯示,HuTIG1-IgG1.AA及HuTIG3-IgG1.AA增加了抗人類TIGIT抗體之活體外T細胞拮抗活性分析中的固有T細胞活化。
圖24描繪GM-CSF/IL-4區分表現CD112、CD155及PD-L1之單核球源性樹突狀細胞(moDC)。
圖25描繪在添加HuTIG1-IgG1.AA、抗PD-L1抗體及HuTIG1-IgG1.AA與抗PD-L1抗體之組合之後,IFNɣ之分泌增強。
圖26A描繪TIGIT及CD96在人類淋巴及骨髓細胞上之表現。圖26B描繪在各種表現量下之抗TIGIT染色的代表性直方圖。
圖27描繪藉由流動式細胞測量術達成之HuTIG1-IgG1.AA抗原決定基定位。
圖28描繪人類TIGIT之細胞外IgV域的帶狀表示,其中帶編號的抗原決定基殘基側鏈用桿狀表示呈現。
圖29A及圖29B描繪CD4+ T細胞亞群關於TIGIT表現的分析結果。
圖30A及圖30B描繪CD8+ T細胞亞群關於TIGIT表現的分析結果。
圖31描繪藉由HuTIG1-IgG1.AA及HuTIG3-IgG1.AA達成的對K562目標細胞的增強的NK細胞介導的細胞毒性。
圖32A描繪TIGIT在來自離散腫瘤樣品之腫瘤浸潤性淋巴細胞上的表現。圖32B描繪在各種表現量下抗TIGIT染色之代表性直方圖。
<![CDATA[<110> 美商JN生物科學有限責任公司(JN Biosciences, LLC)]]> 美商安伯諾治療有限責任公司(Abmuno Therapeutics LLC) <![CDATA[<120> 針對TIGIT之抗體]]> <![CDATA[<130> ]]> <![CDATA[<140> ]]> <![CDATA[<141> ]]> <![CDATA[<150> US62/304,045]]> <![CDATA[<151> 2016-03-04]]> <![CDATA[<150> US62/413,025]]> <![CDATA[<151> 2016-10-26]]> <![CDATA[<160> 65 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 223]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Leu Leu Gly Ala Met Ala Ala Thr 115 120 125 Leu Val Val Ile Cys Thr Ala Val Ile Val Val Val Ala Leu Thr Arg 130 135 140 Lys Lys Lys Ala Leu Arg Ile His Ser Val Glu Gly Asp Leu Arg Arg 145 150 155 160 Lys Ser Ala Gly Gln Glu Glu Trp Ser Pro Ser Ala Pro Ser Pro Pro 165 170 175 Gly Ser Cys Val Gln Ala Glu Ala Ala Pro Ala Gly Leu Cys Gly Glu 180 185 190 Gln Arg Gly Glu Asp Cys Ala Glu Leu His Asp Tyr Phe Asn Val Leu 195 200 205 Ser Tyr Arg Ser Leu Gly Asn Cys Ser Phe Phe Thr Glu Thr Gly 210 215 220 <![CDATA[<210> 2]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Met Gly Trp Ser Trp Ile Phe Phe Phe Leu Leu Ser Gly Thr Ala Ser 1 5 10 15 Val Leu Ser <![CDATA[<210> 3]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 4]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 4]]> Thr Gly Gly Gly 1 <![CDATA[<210> 5]]> <![CDATA[<211> 232]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 165 170 175 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <![CDATA[<210> 6]]> <![CDATA[<211> 317]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Asp Val Val Val Gln Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp 1 5 10 15 Ser Val Thr Leu Pro Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr 20 25 30 His Val Ser Gln Leu Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met 35 40 45 Ala Val Phe His Gln Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg 50 55 60 Leu Glu Phe Val Ala Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser 65 70 75 80 Leu Arg Met Phe Gly Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys 85 90 95 Leu Phe Val Thr Phe Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu 100 105 110 Arg Val Leu Ala Lys Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln 115 120 125 Leu Thr Gly Glu Pro Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly 130 135 140 Arg Pro Pro Ala Gln Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro 145 150 155 160 Asn Thr Ser Gln Val Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr 165 170 175 Ser Leu Trp Ile Leu Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val 180 185 190 Thr Cys Lys Val Glu His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr 195 200 205 Val Asn Leu Thr Val Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr 210 215 220 Asp Asn Asn Trp Tyr Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp 225 230 235 240 Ala Arg Ser Asn Pro Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met 245 250 255 Gly Pro Leu Pro Pro Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile 260 265 270 Arg Pro Val Asp Lys Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr 275 280 285 Asn Ala Leu Gly Ala Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu 290 295 300 Gly Pro Pro Ser Glu His Ser Gly Met Ser Arg Asn Ala 305 310 315 <![CDATA[<210> 7]]> <![CDATA[<211> 553]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> Asp Val Val Val Gln Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp 1 5 10 15 Ser Val Thr Leu Pro Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr 20 25 30 His Val Ser Gln Leu Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met 35 40 45 Ala Val Phe His Gln Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg 50 55 60 Leu Glu Phe Val Ala Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser 65 70 75 80 Leu Arg Met Phe Gly Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys 85 90 95 Leu Phe Val Thr Phe Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu 100 105 110 Arg Val Leu Ala Lys Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln 115 120 125 Leu Thr Gly Glu Pro Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly 130 135 140 Arg Pro Pro Ala Gln Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro 145 150 155 160 Asn Thr Ser Gln Val Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr 165 170 175 Ser Leu Trp Ile Leu Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val 180 185 190 Thr Cys Lys Val Glu His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr 195 200 205 Val Asn Leu Thr Val Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr 210 215 220 Asp Asn Asn Trp Tyr Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp 225 230 235 240 Ala Arg Ser Asn Pro Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met 245 250 255 Gly Pro Leu Pro Pro Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile 260 265 270 Arg Pro Val Asp Lys Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr 275 280 285 Asn Ala Leu Gly Ala Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu 290 295 300 Gly Pro Pro Ser Glu His Ser Gly Met Ser Arg Asn Ala Thr Gly Gly 305 310 315 320 Gly Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 325 330 335 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 340 345 350 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 355 360 365 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 370 375 380 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 385 390 395 400 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 405 410 415 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 420 425 430 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 435 440 445 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 450 455 460 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 465 470 475 480 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 485 490 495 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 500 505 510 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 515 520 525 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 530 535 540 Lys Ser Leu Ser Leu Ser Pro Gly Lys 545 550 <![CDATA[<210> 8]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 8]]> Asp Tyr Lys Asp Asp Asp Asp Lys 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 37]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 9]]> Pro Asn Lys Gly Ser Gly Thr Thr Ser Gly Thr Thr Arg Leu Leu Ser 1 5 10 15 Gly His Thr Cys Phe Thr Leu Thr Gly Leu Leu Gly Thr Leu Val Thr 20 25 30 Met Gly Leu Leu Thr 35 <![CDATA[<210> 10]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 10]]> Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <![CDATA[<210> 11]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 11]]> Asn Phe Gly Met His 1 5 <![CDATA[<21]]>0> 12]]> <br/><![CDATA[<211> 17]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成構築體]]> <br/> <br/><![CDATA[<400> 12]]> <br/> <br/><![CDATA[Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val Lys 1 5 10 15 Gly <![CDATA[<210> 13]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 13]]> Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 14]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 14]]> Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly 1 5 10 15 Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr 20 25 30 Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 15]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序]]>列 <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 15]]> Arg Ala Ser Lys Ser Ile Ser Lys Tyr Leu Ala 1 5 10 <![CDATA[<210> 16]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 16]]> Ser Gly Ser Thr Leu Gln Ser 1 5 <![CDATA[<210> 17]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 17]]> Gln Gln His Asn Glu Tyr Pro Trp Thr 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 18]]> Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Met His Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Gly Trp Tyr Asn Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <![CDATA[<210> 19]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 19]]> Glu Tyr Thr Met His 1 5 <![CDATA[<210> 20]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 20]]> Gly Ile Asn Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 21]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 21]]> Pro Gly Trp Tyr Asn Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 22]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 22]]> Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Gly Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr His Cys Gln Gln His Tyr Ile Thr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 23]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 23]]> Lys Ala Ser Gln Gly Val Ser Thr Ala Val Ala 1 5 10 <![CDATA[<210> 24]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 24]]> Ser Ala Ser Tyr Arg Tyr Thr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 25]]> Gln Gln His Tyr Ile Thr Pro Trp Thr 1 5 <![CDATA[<210> 26]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 26]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asp Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <![CDATA[<210> 27]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 27]]> Asp Tyr Asp Met Ser 1 5 <![CDATA[<210> 28]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 28]]> Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val Lys 1 5 10 15 Gly <![CDATA[<210> 29]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220]]>>]]> <br/><![CDATA[<223> 合成構築體]]> <br/> <br/><![CDATA[<400> 29]]> <br/> <br/><![CDATA[Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 30]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 30]]> Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys <![CDATA[<210> 31]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 31]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <![CDATA[<210> 32]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 32]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 33]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<21]]>3> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成構築體]]> <br/> <br/><![CDATA[<400> 33]]> <br/> <br/><![CDATA[Gln Gln Tyr His Ser Tyr Pro Trp Thr 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 138]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 34]]> Met Asp Ser Arg Leu Asn Leu Val Phe Leu Val Leu Ile Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asn Phe Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala 65 70 75 80 Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Met Val Thr Val Ser Ser 130 135 <![CDATA[<210> 35]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 35]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <![CDATA[<210> 36]]> <![CDATA[<211> 127]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 36]]> Met Arg Phe Gln Val Gln Val Leu Gly Leu Leu Leu Leu Trp Ile Ser 1 5 10 15 Gly Ala Gln Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser 35 40 45 Ile Ser Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn 100 105 110 Glu Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 115 120 125 <![CDATA[<210> 37]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 37]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 38]]> <![CDATA[<211> 448]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 38]]> actagtacca ccatggactc caggctcaat ctggttttcc ttgtccttat tctgaaaggc 60 gtccagtgtg aagtgcagct ggtggagtct gggggaggcc tggtgcagcc tggagggtcc 120 ctgagactct cctgtgcagc ctctggattc actttcagta actttggaat gcactgggtt 180 cgacaggctc cagggaaggg gctggagtgg gtcgcattca ttagtagtgg cagtagttcc 240 atctactatg cagacacagt gaagggccga ttcaccatct ccagagacaa tgccaagaac 300 agcctgtacc tgcaaatgaa cagtctgagg gctgaggaca ctgccgtgta ttactgtgca 360 agaatgagac tggattacta tgctatggac tactggggtc aaggaaccat ggtcaccgtc 420 tcctcaggta agtatggcct ctaagctt 448 <![CDATA[<210> 39]]> <![CDATA[<211> 416]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 39]]> gctagcacca ccatgaggtt ccaggttcag gttctggggc tccttctgct ctggatctca 60 ggagcccagt gtgatatcca gatgacccag tctccatctt ctctttctgc atctgttgga 120 gatagagtca ctattacttg cagggcaagt aagagcatta gcaaatatct ggcctggtat 180 caacagaaac ctgggaaagc tcctaagctg cttatctact ctgggtccac tttgcaatct 240 ggagttccat caagattcag tggcagtgga tctggtacag atttcactct caccatcagt 300 agcctgcagc ctgaagattt tgcaacctat tactgtcaac agcataatga atacccctgg 360 accttcggcg gaggcaccaa agtcgaaatc aaacgtaagt agaatccaaa gaattc 416 <![CDATA[<210> 40]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 40]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile 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 Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 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 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln 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 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 41]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 41]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 42]]> <![CDATA[<211> 138]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 42]]> Met Asn Phe Gly Leu Arg Leu Ile Phe Leu Val Leu Thr Leu Lys Gly 1 5 10 15 Val Asn Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe 35 40 45 Ser Asp Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro 65 70 75 80 Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 130 135 <![CDATA[<210> 43]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 43]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asp Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 44]]> <![CDATA[<211> 133]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 44]]> Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Trp Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln 50 55 60 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg 65 70 75 80 Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr 100 105 110 Tyr Cys Gln Gln Tyr His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr 115 120 125 Lys Val Glu Ile Lys 130 <![CDATA[<210> 45]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 45]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Leu Leu Ile 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 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys <![CDATA[<210> 46]]> <![CDATA[<211> 448]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 46]]> actagtacca ccatgaactt tgggctcaga ttgattttcc ttgtccttac tctgaaaggc 60 gtgaactgtg aagtccagct cgtggagtct gggggaggcc ttgtgcagcc tggagggtcc 120 ctgagactct cctgtgcagc ctctggattc gctttcagtg actatgacat gtcttgggtt 180 cgccaggctc ctggcaaggg gctggagtgg gtcgcataca ttagtgatgg cggttataac 240 acctactatc cagacactgt gaagggccga ttcaccatct ccagagacaa tgccaagaac 300 tccctgtacc tgcaaatgaa cagtctgagg gctgaggaca cagccgtcta ttactgtgca 360 agacaaattc tgctgcggta ctactttgac tactggggcc aaggcaccac tgtcacagtc 420 tcctcaggtg agtccttaaa acaagctt 448 <![CDATA[<210> 47]]> <![CDATA[<211> 434]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 47]]> gctagcacca ccatggattc acaggcccag gttcttatgc tgctgctgct ctgggtttct 60 ggaacctgtg gggacattca gatgacacag tctccatcct ccctgtctgc ctcagttgga 120 gacagggtta ctatcacctg caagtccagt cagagtcttc tgtatagtag caatcaaaag 180 aactacttgg cctggtacca gcagaaacca gggaaggctc ctaaactgct gatttactgg 240 gcatccacta gggaatctgg ggtccctagt cgcttctcag gcagtggatc tgggacagat 300 ttcactctca ccatcagcag tctgcagcct gaagacttcg cagtttatta ctgtcagcaa 360 tatcatagct atccctggac cttcggcgga ggcaccaagg tggaaatcaa acgtaagtag 420 aatccaaaga attc 434 <![CDATA[<210> 48]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 48]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asp Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile 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 Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 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 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln 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 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 49]]> <![CDATA[<211> 22]]>0 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 49]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Leu Leu Ile 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 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln 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 Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 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 Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[<210> 50]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 50]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Ala Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 51]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 51]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Ala Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 52]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 52]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Ala Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 53]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 53]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Ala Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 54]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 54]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Ala Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 55]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 55]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Ala Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly 115 120 <![CDATA[<210> 56]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 56]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 57]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 57]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Phe Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 58]]> <![CDATA[<211> 263]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 58]]> Met Arg Trp Cys Leu Leu Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala 1 5 10 15 Pro Leu Ala Ser Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Gly Gly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser Met Met Thr Gly Thr Ile Glu Thr 35 40 45 Thr Gly Asn Ile Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys 50 55 60 His Leu Ser Ser Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln 65 70 75 80 Gln Asp Gln Leu Leu Ala Ile Cys Asn Ala Asp Leu Gly Trp His Ile 85 90 95 Ser Pro Ser Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu 100 105 110 Thr Leu Gln Ser Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile 115 120 125 Tyr His Thr Tyr Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu 130 135 140 Val Leu Glu Ser Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro 145 150 155 160 Leu Leu Gly Ala Met Ala Ala Thr Leu Val Val Ile Cys Thr Ala Val 165 170 175 Ile Val Val Val Ala Leu Thr Arg Lys Lys Lys Ala Leu Arg Ile His 180 185 190 Ser Val Glu Gly Asp Leu Arg Arg Lys Ser Ala Gly Gln Glu Glu Trp 195 200 205 Ser Pro Ser Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala 210 215 220 Ala Pro Ala Gly Leu Cys Gly Glu Gln Arg Gly Glu Asp Cys Ala Glu 225 230 235 240 Leu His Asp Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Asn Cys 245 250 255 Ser Phe Phe Thr Glu Thr Gly 260 <![CDATA[<210> 59]]> <![CDATA[<211> 358]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 59]]> Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Thr Gly Thr Gly Gly Gly Glu Pro 115 120 125 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 130 135 140 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 145 150 155 160 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 165 170 175 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 180 185 190 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 195 200 205 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 210 215 220 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 225 230 235 240 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 245 250 255 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 260 265 270 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 275 280 285 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 290 295 300 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 305 310 315 320 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 325 330 335 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 340 345 350 Ser Leu Ser Pro Gly Lys 355 <![CDATA[<210> 60]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 60]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile 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 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 Ile 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 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln 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 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 61]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 61]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Ser Ser Gly Ser Ser Ser Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Arg Leu Asp Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 62]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 62]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asp Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile 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 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 Ile 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 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln 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 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 63]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 63]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asp Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Asp Gly Gly Tyr Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Ile Leu Leu Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 64]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 64]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 65]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 65]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Leu Leu Ile 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 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln 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 Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 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 Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220
Claims (75)
- 一種抗TIGIT抗體,其結合至一或多個包含D51之胺基酸殘基上的TIGIT多肽,其中該TIGIT多肽具有對應於SEQ ID NO: 1之胺基酸序列。
- 如請求項1之抗TIGIT抗體,其中該抗體係單株抗體。
- 如請求項1或2之抗TIGIT抗體,其中該抗體係嵌合的、人類化的或經鑲飾的(veneered)。
- 如請求項1之抗TIGIT抗體,其中該抗體係人類抗體。
- 如請求項1至4中任一項之抗TIGIT抗體,其中該抗體不會結合至一或多個包含L44、I47或H55之胺基酸殘基。
- 如請求項1至5中任一項之抗TIGIT抗體,其中該抗體包含SEQ ID NO: 14之成熟輕鏈可變區及SEQ ID NO: 10之成熟重鏈可變區。
- 如請求項1至6中任一項之抗TIGIT抗體,其中該抗體與TIG1結合至對應於SEQ ID NO: 1之胺基酸序列上的同一抗原決定基。
- 如請求項1至7中任一項之抗TIGIT抗體,其包含三個包含SEQ ID NO: 15-17之輕鏈CDR及三個包含SEQ ID NO: 11-13之重鏈CDR。
- 如請求項1至7中任一項之抗TIGIT抗體,其包含與SEQ ID NO: 35具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 37具有至少90%序列一致性的成熟輕鏈可變區。
- 如請求項9之抗TIGIT抗體,其中該成熟重鏈可變區包含SEQ ID NO: 35之胺基酸序列且該成熟輕鏈可變區包含SEQ ID NO: 37之胺基酸序列。
- 如請求項9或10之抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於包含SEQ ID NO: 40之重鏈恆定區,且該成熟輕鏈可變區係連接於包含SEQ ID NO: 41之輕鏈恆定區。
- 一種單株抗體,其與TIG1、TIG2或TIG3中之任一者競爭結合至人類TIGIT,其中抗體TIG1之特徵在於SEQ ID NO: 14之成熟輕鏈可變區及SEQ ID NO: 10之成熟重鏈可變區,抗體TIG2之特徵在於SEQ ID NO: 22之成熟輕鏈可變區及SEQ ID NO: 18之成熟重鏈可變區,且抗體TIG3之特徵在於SEQ ID NO: 30之成熟輕鏈可變區及SEQ ID NO: 26之成熟重鏈可變區,用於特異性結合至CD155。
- 如請求項12之單株抗體,其與TIG1、TIG2或TIG3中之任一者結合至人類TIGIT上的同一抗原決定基。
- 如請求項1至13中任一項之抗體,其抑制CD155與人類TIGIT之結合。
- 如請求項12之單株抗體,其包含三個輕鏈CDR及三個重鏈CDR,其對應於TIG1、TIG2或TIG3中之任一者的三個輕鏈及三個重鏈CDR。
- 如請求項12之單株抗體,其包含TIG1、TIG2或TIG3中之任一者的三個重鏈CDR及三個輕鏈CDR。
- 如請求項12之單株抗體,其包含TIG1 (SEQ ID NO: 15-17輕鏈及11-13重鏈)、TIG2 (SEQ ID NO: 23-25輕鏈,19-21重鏈)或TIG3 (SEQ ID NO: 31-33輕鏈及27-29重鏈)中之任一者的如由Kabat所定義的三個重鏈CDR及如由Kabat所定義的三個輕鏈CDR。
- 如請求項12至17中任一項之單株抗體,其係嵌合的、人類化的或經鑲飾的。
- 如請求項12之單株抗體,其係人類抗體。
- 如請求項12至19中任一項之單株抗體,其具有人類IgG1κ同型。
- 如請求項12至20中任一項之單株抗體,其係完整抗體。
- 如請求項12至20中任一項之單株抗體,其係單鏈抗體、Fab或F(ab') 2片段。
- 如請求項12至21中任一項之單株抗體,其包含與SEQ ID NO: 35具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 37具有至少90%序列一致性的成熟輕鏈可變區。
- 如請求項23之單株抗體,其中該成熟重鏈可變區與SEQ ID NO: 35具有至少95%序列一致性且該成熟輕鏈可變區與SEQ ID NO: 37具有至少95%序列一致性。
- 如請求項24之單株抗體,其中該成熟重鏈可變區具有SEQ ID NO: 35之胺基酸序列且該成熟輕鏈可變區具有SEQ ID NO: 37之胺基酸序列。
- 如請求項25之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於包含SEQ ID NO: 40之重鏈恆定區,且該成熟輕鏈可變區係連接於包含SEQ ID NO: 41之輕鏈恆定區。
- 如請求項25之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於包含SEQ ID NO: 60之重鏈恆定區,且該成熟輕鏈可變區係連接於包含SEQ ID NO: 64之輕鏈恆定區。
- 如請求項25之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於包含SEQ ID NO: 61之重鏈恆定區,且該成熟輕鏈可變區係連接於包含SEQ ID NO: 64之輕鏈恆定區。
- 如請求項12至21中任一項之單株抗體,其包含與SEQ ID NO: 43具有至少90%序列一致性的成熟重鏈可變區及與SEQ ID NO: 45具有至少90%序列一致性的成熟輕鏈可變區。
- 如請求項29之單株抗體,其中該成熟重鏈可變區與SEQ ID NO: 43具有至少95%序列一致性且該成熟輕鏈可變區與SEQ ID NO: 45具有至少95%序列一致性。
- 如請求項30之單株抗體,其中該成熟重鏈可變區具有SEQ ID NO: 43之胺基酸序列且該成熟輕鏈可變區具有SEQ ID NO: 45之胺基酸序列。
- 如請求項31之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於重鏈恆定區,獲致包含SEQ ID NO: 48之重鏈,且該成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 49之輕鏈。
- 如請求項31之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於重鏈恆定區,獲致包含SEQ ID NO: 62之重鏈,且該成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 65之輕鏈。
- 如請求項31之單株抗體,其中該成熟重鏈可變區在C端離胺酸存在或不存在的條件下係連接於重鏈恆定區,獲致包含SEQ ID NO: 63之重鏈,且該成熟輕鏈可變區係連接於輕鏈恆定區,獲致包含SEQ ID NO: 65之輕鏈。
- 一種單株抗體,其結合至包含SEQ ID NO: 1之殘基35及37及/或SEQ ID NO: 1之殘基49及51的抗原決定基。
- 如請求項35之單株抗體,其結合至包含SEQ ID NO: 1之殘基35、37、49及51的抗原決定基。
- 如請求項35之單株抗體,其結合至由以下組成之肽:SEQ ID NO: 1之殘基35-51及任一側上不超過五個來自SEQ ID NO: 1之側接胺基酸。
- 如請求項37之單株抗體,其結合至由SEQ ID NO: 1之殘基35-51組成的肽。
- 如請求項35之單株抗體,其中該抗原決定基由SEQ ID NO: 1之3至20個相鄰殘基組成。
- 如前述請求項中任一項之單株抗體,其具有以下性質中之一或多者:(a) 視情況以15-100 ng/ml之IC 50抑制TIGIT與CD155之結合;(b)在表現CD155之抗原呈現細胞存在下,視情況以1.5-3倍量增加如藉由IL-2產生所量測的固有T細胞活化;(c)視情況以1.5-3倍量增加如藉由IL-12產生所量測的抗原特異性T細胞活化;(d)視情況以1.5-3倍量增加如藉由IL-2、IL-6、TNFα或IFNγ中之任一者的產生所量測的自然殺手細胞活化;(e)視情況以1.5-3倍量增加至少一種促炎性細胞介素之T細胞產生;及(f) 視情況以1.5-3倍量減少至少一種抗炎性細胞介素之T細胞產生。
- 一種醫藥組合物,其包含如前述請求項中任一項之抗體及醫藥學上可接受之載劑。
- 一種治療癌症或實現癌症預防的方法,其包含向患有癌症或具有患癌症風險之個體投與有效養生法或治療有效量的如前述請求項中任一項之抗體。
- 如請求項42之方法,其中該癌症係急性骨髓性白血病或成人T細胞白血病。
- 如請求項42或43之方法,其中向該個體投與由該抗體活化的腫瘤浸潤性T細胞。
- 如請求項42至44中任一項之方法,其中向該個體投與誘導針對該癌症之免疫反應的疫苗,該免疫反應係藉由該抗體增強。
- 如請求項45之方法,其中該疫苗包含在癌細胞表面上表現的抗原或其片段。
- 如請求項42至46中任一項之方法,其中向該個體投與自然殺手細胞,其針對該癌症之細胞毒性係藉由該抗體增強。
- 如請求項42至47中任一項之方法,其中向該個體進一步投與針對在癌細胞表面上表現的抗原的第二抗體,藉此該第二抗體針對該癌症之效應子介導細胞毒性係藉由該抗體增強。
- 如請求項42至47中任一項之方法,其中向該個體進一步投與針對在免疫細胞表面上表現的抗原之第二抗體。
- 如請求項49之方法,其中該免疫細胞係T細胞或自然殺手細胞。
- 如請求項49或50之方法,其中該抗原係CTLA-4、PD-1或PD-L1。
- 如請求項42至51中任一項之方法,其中向該個體進一步投與一或多種選自由化學療法、輻射、基於細胞之療法及外科手術組成之群的療法。
- 如請求項42至52中任一項之方法,其中向該個體進一步投與一或多個免疫檢查點受體或配體的抑制劑。
- 如請求項53之方法,其中該抑制劑係選自由伊匹單抗(ipilimumab)、納武單抗(nivolumab)、派姆單抗(pembrolizumab) (蘭利珠單抗(lambrolizumab))及阿特珠單抗(atezolizumab)組成之群。
- 一種治療經病原體感染之個體的方法,其包含向該個體投與有效方案或治療有效量的如前述請求項中任一項之抗體。
- 如請求項55之方法,其中該病原體係病毒、細菌、真菌或原蟲。
- 如請求項56之方法,其中該病原體係HIV、SIV、肝炎、疱疹病毒、腺病毒、流感病毒、黃病毒、埃可病毒(echovirus)、鼻病毒、科沙奇病毒(coxsackie virus)、冠狀病毒、呼吸道融合性病毒、腮腺炎病毒、輪狀病毒、麻疹病毒、風疹病毒、小病毒、痘瘡病毒、HTLV病毒、登革熱病毒(dengue virus)、乳突狀瘤病毒、軟疣病毒、脊髓灰白質炎病毒、狂犬病病毒、JC病毒、蟲媒腦炎病毒、衣原體、立克次體細菌(rickettsial bacteria)、分枝桿菌、葡萄球菌、鏈球菌、肺炎球菌、腦膜炎球菌、淋球菌(conococci)、克雷伯氏菌(klebsiella)、變形桿菌、沙雷氏菌(serratia)、假單胞菌、軍團桿菌(legionella)、白喉、沙門氏菌(salmonella)、桿菌、霍亂(cholera)、破傷風、肉毒中毒、炭疽、瘟疫、鉤端螺旋體病及萊姆病(Lyme disease)細菌。
- 如請求項55至57中任一項之方法,其中該個體係用誘導針對該病原體之免疫反應的疫苗治療,該免疫反應係藉由該抗體增強。
- 如請求項58之方法,其中該疫苗包含該病原體之蛋白質或其片段。
- 如請求項55至59中任一項之方法,其中向該個體進一步投與針對該病原體之第二抗體,其中該第二抗體之針對該病原體之效應子介導細胞毒性係藉由該抗體增強。
- 如請求項55至60中任一項之方法,其中向該個體進一步投與抗病毒劑、抗寄生蟲劑、抗細菌劑或抗真菌劑中之一或多者。
- 一種幫助治療癌症之方法,其包含向患有癌症之個體投與治療有效量的如前述請求項中任一項之抗體。
- 如請求項62之方法,其中該癌症係急性骨髓性白血病或成人T細胞白血病。
- 如請求項62或63之方法,其中向該個體投與由該抗體活化的腫瘤浸潤性T細胞。
- 如請求項62至64中任一項之方法,其中向該個體投與誘導針對該癌症之免疫反應的疫苗,該免疫反應係藉由該抗體增強。
- 如請求項65之方法,其中該疫苗包含在癌細胞表面上表現的抗原或其片段。
- 如請求項62至66中任一項之方法,其中向該個體投與自然殺手細胞,其針對該癌症之細胞毒性係藉由該抗體增強。
- 如請求項62至67中任一項之方法,其中向該個體進一步投與針對在癌細胞表面上表現的抗原的第二抗體,藉此該第二抗體之針對該癌症之效應子介導細胞毒性係藉由該抗體增強。
- 如請求項62至67中任一項之方法,其中向該個體進一步投與針對在免疫細胞表面上表現的抗原的第二抗體。
- 如請求項69之方法,其中該免疫細胞係T細胞或自然殺手細胞。
- 如請求項69或70之方法,其中該抗原係CTLA-4、PD-1或PD-L1。
- 如請求項62至71中任一項之方法,其中向該個體進一步投與一或多種選自由化學療法、輻射、基於細胞之療法及外科手術組成之群的療法。
- 如請求項62至72中任一項之方法,其中向該個體進一步投與一或多個免疫檢查點受體或配體的抑制劑。
- 如請求項73之方法,其中該一或多個免疫檢查點受體或配體係選自由以下組成之群:CTLA-4、PD-1、PD-L1、TIM-3、LAG-3、BTLA、VISTA、CD96、A2aR、A2bR、精胺酸酶、CD39、CD73、IDO及TDO。
- 如請求項74之方法,其中該抑制劑係選自由伊匹單抗、納武單抗、派姆單抗 (蘭利珠單抗)及阿特珠單抗組成之群。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US62/304,045 | 2016-03-04 | ||
US62/413,025 | 2016-10-26 |
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TW202409084A true TW202409084A (zh) | 2024-03-01 |
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