TWI605828B - 抗pd-l1抗體及其於增進t細胞功能之用途 - Google Patents
抗pd-l1抗體及其於增進t細胞功能之用途 Download PDFInfo
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Description
本發明大體而言係關於免疫功能及增進T細胞功能,包括調升細胞介導之免疫反應及治療T細胞功能障礙病症。
本申請案根據35 USC 119(e)主張2008年12月9日申請之美國臨時申請案第61/121092號之優先權,其揭示內容以全文引用的方式併入本文中。
用兩種不同信號協同刺激T細胞或向T細胞提供兩種不同信號為普遍接受之由抗原呈現細胞(APC)使靜息T淋巴細胞活化之淋巴細胞活化模型。Lafferty等人,Aust.J.Exp.Biol.Med.Sci. 53:27-42(1975)。此模型進一步提供區別自身與非自身之辨別力及免疫耐受性。Bretscher等人,Science 169:1042-1049(1970);Bretscher,P.A.,P.N.A.S.USA 96:185-190(1999);Jenkins等人,J.Exp.Med. 165:302-319(1987)。在識別在主要組織相容性複合物(MHC)之情形下存在之外來抗原肽之後,第一信號或抗原特異性信號經由T細胞受體(TCR)轉導。第二信號或協同刺激信號經由表現於抗原呈現細胞(APC)上之協同刺激分子傳遞至T細胞,且誘導T細胞促進純系擴增、細胞激素分泌及效應功能。Lenschow等人,Ann.Rev.Immunol. 14:233
(1996)。在無協同刺激存在下,T細胞會變得對抗原刺激無反應,不產生有效免疫反應且可能進一步導致外來抗原耗竭或耐受外來抗原。
簡單的雙信號模型可能過於簡化,此係因為TCR信號之強度實際上對T細胞活化及分化產生定量影響。Viola等人,Science 273:104-106(1996);Sloan-Lancaster,Nature 363:156-159(1993)。此外,若TCR信號強度較高,則即使在無協同刺激信號存在下,T細胞活化亦可發生。更重要地,T細胞接收正性與負性第二協同刺激信號。該等正性與負性信號之調控對最大化宿主之保護性免疫反應至關重要,同時維持免疫耐受性及防止產生自體免疫。
負性第二信號對誘導T細胞耐受性而言似乎必不可少,而正性信號促進T細胞活化。當簡單的雙信號模型仍能有效說明原初淋巴細胞時,宿主之免疫反應為動力學過程,且亦可向暴露於抗原中之T細胞提供協同刺激信號。
協同刺激之機制具有治療意義,此係因為協同刺激信號之處理已展示提供一種增進或終止基於細胞之免疫反應之方法。近來,已發現T細胞功能障礙或因應性缺失(anergy)與抑制受體(漸進式死亡多肽1(PD-1))之經誘導及維持表現同時出現。因此,對治療性靶向PD-1及經由與PD-1相互作用傳導信號之其他分子(諸如漸進式死亡配位體1(PD-L1)及漸進式死亡配位體2(PD-L2))極度關注。已提出抑制PD-L1信號傳導作為增進T細胞免疫以治療癌症(例如腫瘤免疫)及感染(包括急性與慢性(例如持續性)感染)之方法。然而,因為針對此路徑中之標靶之最佳治療法尚未商業化,所以存在明顯的未滿足之醫療需求。
本發明提供抗PD-L1抗體,包括編碼該等抗體之核酸及含有該等抗體之組合物;且提供該等抗體於增進T細胞功能以調升細胞介導之免疫反應及治療T細胞功能障礙病症之用途,該等T細胞功能障礙病
症包括感染(例如急性及慢性感染)及腫瘤免疫。
在一實施例中,本發明提供一種經分離重鏈可變區多肽,其包含HVR-H1、HVR-H2及HVR-H3序列,其中:(a)HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1);(b)HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);(c)HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);另外其中:X1為D或G;X2為S或L;X3為T或S。
在一特定態樣中,X1為D;X2為S且X3為T。在另一態樣中,多肽進一步包含根據下式並列於HVR之間的可變區重鏈構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,構架序列為VH III亞群共同構架。在另一態樣中,至少一個構架序列如下:HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4);HC-FR2為WVRQAPGKGLEWV(SEQ ID NO:5);HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6);HC-FR4為WGQGTLVTVSA(SEQ ID NO:7)。
在另一態樣中,重鏈多肽進一步與可變區輕鏈組合,該等可變區輕鏈包含HVR-L1、HVR-L2及HVR-L3,其中:(a)HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8);(b)HVR-L2序列為SASX9LX10S(SEQ ID NO:9);(c)HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10);另外其中:X4為D或V;X5為V或I;X6為S或N;X7為A或F;X8為V或L;X9為F或T;X10為Y或A;X11為Y、G、F或S;X12為L、Y、F或W;X13為Y、N、A、T、G、F或I;X14為H、V、P、T或I;X15為
A、W、R、P或T。
在另一態樣中,X4為D;X5為V;X6為S;X7為A;X8為V;X9為F;X10為Y;X11為Y;X12為L;X13為Y;X14為H;X15為A。在另一態樣中,輕鏈進一步包含根據下式並列於HVR之間的可變區輕鏈構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,構架序列為VL κ I共同構架。在另一態樣中,至少一個構架序列如下:LC-FR1為DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11);LC-FR2為WYQQKPGKAPKLLIY(SEQ ID NO:12);LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13);LC-FR4為FGQGTKVEIKR(SEQ ID NO:14)。
在另一實施例中,本發明提供一種經分離抗PD-L1抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中:(a)重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:(i)HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1)(ii)HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2)(iii)HVR-H3序列為RHWPGGFDY,且(SEQ ID NO:3)(b)輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中:(i)HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8)(ii)HVR-L2序列為SASX9LX10S;且(SEQ ID NO:9)(iii)HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10)另外其中:X1為D或G;X2為S或L;X3為T或S;X4為D或V;X5為V或I;X6為S或N;X7為A或F;X8為V或L;X9為F或T;X10為Y或A;X11為Y、G、F或S;X12為L、Y、F或W;X13為Y、N、A、T、
G、F或I;X14為H、V、P、T或I;X15為A、W、R、P或T。
在一特定態樣中,X1為D;X2為S且X3為T。在另一態樣中,X4為D;X5為V;X6為S;X7為A;X8為V;X9為F;X10為Y;X11為Y;X12為L;X13為Y;X14為H;X15為A。在另一態樣中,X1為D;X2為S且X3為T,X4為D;X5為V;X6為S;X7為A;X8為V;X9為F;X10為Y;X11為Y;X12為L;X13為Y;X14為H且X15為A。
在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4);HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5);HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6);HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11);LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12);
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13);LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由「無效應Fc突變(effector-less Fc mutation)」或非糖基化(aglycosylation)產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供一種抗PD-L1抗體,其包含重鏈及輕鏈可變區序列,其中:(a)重鏈進一步包含分別與GFTFSDSWIH(SEQ ID NO:15)、AWISPYGGSTYYADSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO:3)具有至少85%之序列一致性的HVR-H1、HVR-H2及HVR-H3序列,或(b)輕鏈進一步包含分別與RASQDVSTAVA(SEQ ID NO:17)、SASFLYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO:19)具有至少85%之序列一致性的HVR-L1、HVR-L2及HVR-L3序列。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-I3)-
(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4);HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5);HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6);HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11);LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12);LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13);LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供一種經分離抗PD-L1抗體,其包含
重鏈及輕鏈可變區序列,其中:(a)該重鏈序列與以下重鏈序列具有至少85%之序列一致性:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWIS PYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(SEQ ID NO:20),或(b)該輕鏈序列與以下輕鏈序列具有至少85%之序列一致性:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO:21)。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列係如下:HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4);HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5);HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6);HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11);LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12);LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13);LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由在原核細胞中產生而產生。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供組合物,其包含任何上述抗PD-L1抗體以及至少一種醫藥學上可接受之載劑。
在另一實施例中,本發明提供編碼抗PD-L1抗體之輕鏈或重鏈可變區序列之經分離核酸,其中:(a)重鏈進一步包含分別與GFTFSDSWIH(SEQ ID NO:15)、AWISPYGGSTYYADSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO:3)具有至少85%之序列一致性的HVR-H1、HVR-H2及HVR-H3序列,且(b)輕鏈進一步包含分別與RASQDVSTAVA(SEQ ID NO:17)、
SASFLYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO:19)具有至少85%之序列一致性的HVR-L1、HVR-L2及HVR-L3序列。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4);HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5);HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6);HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11);LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12);LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13);LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另
一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由在原核細胞中產生而產生。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一態樣中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一態樣中,核酸進一步包含適用於表現編碼任何前述抗PD-L1抗體之核酸之載體。在另一特定態樣中,載體進一步包含適用於表現核酸之宿主細胞。在另一特定態樣中,宿主細胞為真核細胞或原核細胞。在另一特定態樣中,真核細胞為哺乳動物細胞,諸如中國倉鼠卵巢細胞(Chinese Hamster Ovary,CHO)。
在另一實施例中,本發明提供一種製造抗PD-L1抗體或其抗原結合片段之方法,該方法包含在適於產生該抗體或片段之條件下培養含有編碼任何前述呈適於表現之形式的抗PD-L1抗體或抗原結合片段之核酸的宿主細胞,及回收該抗體或片段。
在另一實施例中,本發明提供一種組合物,其包含如本文所提供之抗PD-L1抗體或其抗原結合片段及至少一種醫藥學上可接受之載劑。
在另一實施例中,本發明提供一種製品,其包含密封治療有效量之本文所揭示之組合物的容器及指示治療T細胞功能障礙病症之使用的包裝插頁。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1組合物與至少一種BNCA分子組合。在一態樣中,BNCA分子為抗體、抗原結合抗體片段、BNCA寡肽、BNCA RNAi或BNCA小分子。
在另一態樣中,B7負性協同刺激分子係選自由以下組成之群:CTLA-4、PD-1、PD-L1、PD-L2、B7.1、B7-H3及B7-H4。
在另一實施例中,該製品包含任何上述抗PD-L1組合物與化學治療劑組合。在一態樣中,該化學治療劑為吉西他濱(gemcitabine)。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種針對正性協同刺激分子之促效劑組合。在一態樣中,正性協同刺激分子為B7家族協同刺激分子。在另一態樣中,正性協同刺激分子係選自由以下組成之群:CD28、CD80、CD86、ICOS/ICOSL。在另一態樣中,正性協同刺激分子為TNFR家族協同刺激分子。在另一態樣中,TNFR協同刺激分子係選自由以下組成之群:OX40/OX40L、4-1BB/4-1BBL、CD27/CD27L、CD30/CD30L及HVEM/LIGHT及其可溶性片段、構築體及促效抗體(agonist antibody)。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種抗生素組合。在一態樣中,該抗生素係選自由以下組成之群:抗病毒劑、抗細菌劑、抗真菌劑、抗原蟲劑。
在另一態樣中,抗病毒劑係選自由以下組成之群:逆轉錄酶抑制劑、蛋白酶抑制劑、整合酶抑制劑、進入或融合抑制劑、成熟抑制劑、病毒釋放抑制劑、免疫反應增強劑、抗病毒協同增強劑、疫苗、肝臟促效劑及草本治療劑。在另一態樣中,該組合包含一或多類抗病毒劑。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種疫苗組合。
在另一實施例中,本發明提供一種增進T細胞功能之方法,該方法包含投與有效量之任何上述抗PD-L1抗體或組合物。在一態樣中,該抗PD-L1抗體或組合物使功能障礙T細胞變得非功能障礙。
在另一實施例中,本發明提供一種治療T細胞功能障礙病症之方法,該方法包含投與治療有效量之任何上述抗PD-L1抗體或組合物。在一特定態樣中,T細胞功能障礙病症為感染或腫瘤免疫。在另一態樣中,感染為急性感染或慢性感染。在另一態樣中,慢性感染為持續性的、潛伏性的或緩慢的。在另一態樣中,慢性感染由選自由細菌、病毒、真菌及原蟲組成之群的病原體引起。在另一態樣中,宿主中之病原體含量降低。在另一態樣中,該方法進一步包含用疫苗治療。在另一態樣中,該方法進一步包含用抗生素治療。在另一態樣中,該病原體為細菌,且該方法進一步包含投與抗細菌劑。在另一態樣中,細菌係選自由以下組成之群:分枝桿菌屬(Mycobacterium spp.)、沙門氏桿菌屬(Salmonella spp.)、李氏菌屬(Listeria spp.)、鏈球菌屬(Streptococcus spp.)、嗜血桿菌屬(Haemophilus spp.)、奈瑟菌屬(Neisseria spp.)、克雷伯氏菌屬(Klebsiella spp.)、疏螺旋體屬(Borrelia spp.)、鬆脆桿菌(Bacterioides fragillis)、密螺旋體屬(Treponema spp.)及幽門螺旋桿菌(Helicobacter pylori)。在另一態樣中,該病原體為病毒,且該方法進一步包含投與抗病毒劑。在另一態樣中,該病毒係選自由以下組成之群:B型肝炎、C型肝炎、I型單純性疱疹病毒、II型單純性疱疹病毒、I型人類免疫缺乏病毒、II型人類免疫缺乏病毒、細胞巨大病毒、艾伯斯坦-巴爾病毒(Eppstein Barr virus)、人類乳頭狀瘤病毒、I型人類T淋巴細胞病毒、II型人類T淋巴細胞病毒、水痘帶狀疱疹病毒。在另一態樣中,該病原體為真菌,且該方法進一步包含投與抗真菌劑。在另一態樣中,該病症係選自由以下組成之群:麯黴病、芽生菌病、白色念珠菌病、粗球黴菌、組織漿菌病、副球黴菌病、微孢子蟲病。在另一態樣中,該病原體為原蟲,且該方法進一步包含投與抗原蟲劑。在另一態樣中,該病症係選自由以下組成之群:利什曼體病(leishmaniasis)、瘧原蟲病(亦即瘧疾)、隱
孢子蟲病、弓蟲病、錐蟲病及蠕蟲感染,包括由吸蟲(例如血吸蟲病)、絛蟲(例如包蟲病)及線蟲(例如旋毛蟲病、蛔蟲病、絲蟲病及糞類圓線蟲病)引起之蠕蟲感染。
在另一態樣中,T細胞功能障礙病症為腫瘤免疫。在另一態樣中,PD-L1抗體或組合物與治療方案組合,該治療方案進一步包含選自由以下組成之群的傳統療法:輻射療法、化學療法、靶向療法、免疫療法、激素療法、血管生成抑制及緩解性護理。在另一特定態樣中,化學療法治療係選自由以下組成之群:吉西他濱、環磷醯胺、小紅莓(doxorubicin)、紫杉醇(paclitaxel)、順鉑(cisplatin)。在另一特定態樣中,腫瘤免疫由選自由以下組成之群的癌症引起:乳癌、肺癌、結腸癌、卵巢癌、黑素瘤、膀胱癌、腎癌、肝癌、唾液腺癌、胃癌、神經膠質瘤、甲狀腺癌、胸腺癌、上皮癌、頭頸癌、胃癌及胰臟癌。
圖1為描繪由B7家族細胞表面分子協同刺激T細胞之圖解說明;圖2為展示PMEL/B16 T細胞刺激檢定之實驗設計之示意圖;圖3為經由應答黑素細胞肽gp100增進PMEL CD8+ T細胞中之IFN-γ產生展示抗PD-L1抗體對抗原特異性T細胞功能之作用的條形圖。在抗PD-L1抗體存在下在刺激期間,產生IFN-γ之CD8+ T細胞之百分比與其IFN-γ產生含量均增加;圖4為經由在經Ova脈衝之A20 B細胞/mPD-L1 APC二次刺激時抗PD-L1抗體YW243.55.S1增強Ova特異性CD4+ T細胞增殖展示抗PD-L1抗體對抗原特異性T細胞功能之作用的條形圖;圖5為一系列FACS圖,其展示在混合淋巴細胞反應中,抗PD-L1抗體YW243.55S1增進人類CD8 T細胞增殖。亦報導如由CFSE強度之稀釋倍數所量測之增殖細胞的百分比;圖6為用嵌合形式之抗PD-L1抗體YW243.55S70治療慢性LCMV之
實驗設計的示意圖。箭頭表示用2×106pfu純系13 LCMV感染後14天開始的抗PD-L1之6次劑量之計時;圖7A及圖7B為展示由抗PD-L1抗體YW243.55.S70活體內治療慢性LCMV感染後離體細胞中CD8效應功能增進之圖。由YW243.55.S70阻斷PD-L1增加CD8+ T細胞之去顆粒(如由表面CD107A之增加所量測)(圖7A)且應答LCMV肽gp33增加產生IFN-γ之細胞的百分比(圖7B)。用H2-Db gp33五聚物染色揭示gp33特異性細胞之出現率;圖8A及圖8B展示用抗PD-L1抗體活體內治療後,慢性LCMV感染中血液及組織LCMV效價之降低。在圖8A中,分別在抗體治療之後第21天及第28天、一週及兩週分析各種指定組織之病毒效價。在圖8B中,在第0天、第7天、第14天、第21天及第28天分析血清病毒效價,其中第0天進行LCMV接種且第14天開始治療;圖9A展示在治療性治療所建立之腫瘤(治療在第14天開始,此時腫瘤為250mm3)之後,MC38.Ova結腸癌腫瘤生長因施用抗PD-L1抗體而顯著減慢。圖9B為展示如流式細胞儀所量測之組織培養物中MC38.Ova細胞上之PD-L1表面表現含量的直方圖。MC38.Ova細胞不表現PD-L2;圖10為展示C57BL/6小鼠中PD-L1阻斷治療單獨及與抗VEGF或吉西他濱組合時對MC38.Ova腫瘤生長之作用的圖;及圖11A-圖11B分別為噬菌體呈現所鑑別之11種抗PD-L1抗體之重鏈及輕鏈可變區序列。陰影條展示具有各種定義之CDR,而方框區域展示HVR之範圍。
本文所提及之所有參考文獻特定地以全文引用的方式併入本文中。
通用技術
除非另外指出,否則本發明之實施將採用在此項技術範圍內之分子生物學(包括重組技術)、微生物學、細胞生物學、生物化學及免疫學之習知技術。該等技術透徹說明於以下文獻中:諸如Molecular Cloning:A LaboratoryManual,第2版(Sambrook等人,1989);Oligonucleotide Synthesis(M.J.Gait編,1984);Animal Cell Culture(R.I.Freshney編,1987);Methods in Enzymology(Academic Press,Inc.);Current Protocols in Molecular Biology(F.M.Ausubel等人編,1987且定期更新);PCR:The Polymerase Chain Reaction,(Mullis等人編,1994);A Practical Guide to Molecular Cloning(Perbal Bernard V.,1988);Phage Display:A Laboratory Manual(Barbas等人,2001)。
I.宿主免疫
A.淋巴細胞發育及活化
人類之兩種主要類型之淋巴細胞為T淋巴細胞(胸腺衍生)及B淋巴細胞(骨髓衍生)。此等細胞係衍生自已投入淋巴發育路徑中之骨髓及胎兒肝臟之造血幹細胞。此等幹細胞之子代遵循不同路徑以成熟為B或T淋巴細胞。人類B淋巴細胞發育完全在骨髓內進行。另一方面,T細胞由離開骨髓且穿過血液流到達胸腺之未成熟前驅體發育而來,在胸腺中該等未成熟前驅體增殖且分化為成熟T淋巴細胞。
自胸腺或骨髓中出現之成熟淋巴細胞處於靜止或「休眠」狀態,亦即其無有絲分裂活性。當分散至血液流中時,此等「初始」或「原始」淋巴細胞行進至諸如脾、淋巴結或扁桃體之各種次級或周邊淋巴器官中。大部分原始淋巴細胞具有固有較短的壽命且在離開骨髓或胸腺後幾天內即死亡。然而,若該類細胞接收指示抗原存在之信號,則其可活化且經歷連續幾輪細胞分裂。接著一些所得子代細胞恢復到休眠狀態變成記憶淋巴細胞(memory lymphocyte)B及T細胞,其基本上經預致敏以與刺激過敏原再次相遇。活化的原始淋巴細胞之其他
子代為效應細胞,雖然其僅存活幾天,但進行特異性防禦活動。
淋巴細胞活化係指當休眠淋巴細胞受到刺激分裂且產生子代時所經由的一系列有序事件,子代中之一些變為效應細胞。完全反應包括誘導細胞增殖(致有絲分裂)與表現免疫功能。當特異性配位體結合淋巴細胞表面上之受體時,該等淋巴細胞經活化。雖然針對T細胞及B細胞之配位體不同,但所得細胞內生理機制類似。
一些外來抗原本身可誘導淋巴細胞活化,交聯B細胞上之表面免疫球蛋白或T細胞上之其他醣蛋白之大聚合抗原尤其如此。然而,大部分抗原不為聚合的,且即使與大量B細胞直接結合,亦未能引起活化。當由鄰近經活化輔助T淋巴細胞協同刺激此等更常見抗原時,此等更常見抗原使B細胞活化。該刺激可自T細胞分泌之淋巴介質發生,但藉由使B細胞與T細胞表面蛋白質直接接觸最有效傳遞,該等T細胞表面蛋白質與某些B細胞表面受體相互作用產生第二信號。
B.T細胞
T淋巴細胞不表現免疫球蛋白,相反,經由稱為T細胞受體(TCR)之表面蛋白質偵測外來物質之存在。此等受體藉由直接接觸其他免疫細胞或經由影響其他免疫細胞之活性來識別抗原。T細胞以及巨噬細胞為涉及細胞介導之免疫的初級細胞類型。
不同於B細胞,T細胞僅在特定情形下可偵測外來物質。詳言之,僅當外來蛋白質首先裂解為小肽,接著顯示於稱為抗原呈現細胞(APC)之第二宿主細胞之表面上時,T淋巴細胞才會識別該外來蛋白質。許多類型之宿主細胞可在一些條件下呈現抗原,但某些類型(包括巨噬細胞及其他B細胞)更特定地適於此目的且在控制T細胞活性方面尤其重要。抗原呈現部分視呈現細胞表面上之稱為主要組織相容性複合物(MHC)蛋白之特定蛋白質而定。因此,為刺激細胞介導之免疫,外來肽必須呈現給T細胞與MHC肽之組合,且此組合必須由T細
胞受體識別。
存在兩個重要的T細胞子集:細胞毒性T淋巴細胞(Tc細胞或CTL)及輔助T細胞(TH),其可大致基於標記物CD8及CD4之細胞表面表現來鑑別。Tc細胞在病毒防禦方面很重要,且可直接藉由識別表現病毒肽之某些細胞表面來殺死病毒。TH細胞促進其他細胞類型之增殖、成熟及免疫功能,例如促進淋巴介質分泌以控制B細胞、巨噬細胞及細胞毒性T細胞之活性。原始與記憶T淋巴細胞通常保持處於休眠狀態,且在此狀態下,其不展現明顯的輔助或細胞毒活性。當活化時,此等細胞經歷若干輪有絲分裂產生子細胞。雖然一些此等子細胞回到休眠狀態成為記憶細胞,但其他變為積極表現輔助或細胞毒活性之效應細胞。此等子細胞類似其母體:CD4+細胞僅可產生CD4+子代,而CD8+細胞僅產生CD8+子代時。效應T細胞表現不表現於休眠T細胞上之細胞表面標記物,諸如CD25、CD28、CD29、CD40L、運鐵蛋白受體及II類MHC蛋白。當取出活化刺激物時,經若干天時間細胞毒性或輔助活性逐漸衰減,因為效應細胞已死亡或回到休眠狀態。
類似於B細胞活化,T淋巴細胞對大部分抗原之反應亦需要兩種類型之同步刺激物。首先為抗原,若該抗原由MHC蛋白適當顯示於抗原呈現細胞上,則其可由T細胞受體識別及結合。當此抗原-MHC複合物向細胞內部發送信號時,通常不足以引起T細胞活化。完全活化(諸如由輔助T細胞發生)需要用表現於抗原呈現細胞之表面上的稱為協同刺激劑之其他特異性配位體協同刺激。另一方面,活化細胞毒性T細胞一般需要IL-2,即由經活化輔助T細胞分泌之細胞激素。
C.免疫反應
使得哺乳動物免疫系統區別於其他身體防禦之三種主要功能性質包括:(1)特異性,個別地識別及應答或不應答許多標靶分子之一的能力,(2)辨別力,自非自身的中判定為自身的以便與所有數不清
的蛋白質及其他有機物質和平共存,但仍強烈應答引入身體之外來物質之能力,及(3)記憶力,由經驗形成以致後續與特定外來病原體相遇將引發比最初相遇使所發生之反應快速且強烈之反應的能力。當一或多個此等功能無效時,病理病狀產生。
原始淋巴細胞不斷自初級淋巴器官中釋放至周邊中,各帶有能夠抗原結合之表面受體。B細胞中之抗原結合係由表面結合之免疫球蛋白介導,而在T細胞中,由T細胞受體介導。當原始淋巴細胞活化時,其增殖,從而產生子細胞,該等子細胞接著可再經歷活化及增殖週期。對既定抗原之反應的速度及強度主要由純系選擇決定:對特定抗原具有特異性之子細胞或純系之數目越大,可識別且參與免疫反應之細胞的數目越大。每一免疫反應均是一系列複雜且雜亂調控之涉及若干細胞類型之事件。當免疫原進入身體且遇到稱為抗原呈現細胞(APC)之特定類細胞時,觸發免疫反應。此等APC捕捉極少量之免疫原,且將其顯示為可由抗原特異性輔助T淋巴細胞識別之形式。接著輔助T細胞經活化,且此又促進諸如B細胞或細胞毒性T細胞之其他類淋巴細胞活化。接著經活化淋巴細胞增殖且執行其特異性效應功能。在此方法之各階段,淋巴細胞及APC經由直接接觸或藉由分泌調控細胞激素彼此連通。
由APC捕捉之外源抗原經歷一系列稱為抗原加工(antigen processing)之變化。該加工(尤其蛋白質免疫原之該加工)包括變性及部分蛋白水解消化,以便使免疫原裂解為短肽。接著有限量之所得肽與II類MHC蛋白非共價締合且傳輸至APC表面,此為稱為抗原呈現(antigen presentation)之過程。雖然與APC直接接觸之CD4+輔助T淋巴細胞可經活化,但僅當該細胞表現可識別且結合由APC呈現之特定肽-MHCT複合物之T細胞受體蛋白時才會活化。
輔助T(TH)細胞為免疫反應之主要指揮者(orchestrators),因為其
為兩種其他淋巴效應細胞(細胞毒性T(Tc)細胞及抗體分泌漿細胞)活化所需。TH活化在免疫反應早期發生且需要至少兩個信號。一個信號係由T細胞抗原受體與APC表面上之抗原肽-MHC複合物結合提供,經由CD3蛋白複合物傳遞;而經由APC之第二協同刺激信號被認為由T細胞表面上之另一信號傳遞蛋白與APC上之特異性配位體結合產生。一種已知的該類相互作用為T細胞蛋白CD28與稱為B7之APC表面蛋白家族。其他表面蛋白對亦可介導協同刺激。協同刺激之過程更詳細地描述於下文中。相信本發明抗PD-L1抗體係經由PD-L1傳導信號所提供之負協同刺激信號的拮抗作用增進協同刺激。
兩個信號一起誘導輔助T細胞開始分泌細胞激素介白素-2(IL-2)以及開始表現特異性高親和力IL-2受體於其表面上。IL-2為T淋巴細胞之高度有效之有絲分裂因子且為活化T細胞之增殖反應所必需。IL-2對所分泌細胞的作用稱為自分泌作用(autocrine effect)之現象。已進一步顯示即使T細胞接收到兩個信號,若其自身表面IL-2受體經阻斷,則其亦不會增殖。IL-2亦可對緊鄰之細胞作用,即所謂的旁泌性作用(paracrine effect)。此作用對活化Tc細胞尤其重要,Tc細胞一般不產生足夠IL-2以刺激其自身之增殖。除IL-2以外,活化之TH細胞亦分泌其他細胞激素且促進B細胞、巨噬細胞及其他細胞類型之生長、分化及功能。
APC與抗原特異性TH細胞之間的接觸亦影響APC,一種最重要之影響為釋放IL-1。相信此細胞激素以自分泌方式作用來增加II類MHC蛋白及各種黏著性分子之表面表現,藉此強化TH細胞之結合且增進抗原呈現。同時,IL-1以旁泌性方式對TH細胞作用來促進IL-2分泌及IL-2受體表現。
在以前述方式活化TH細胞期間,一些B細胞亦可經由其抗原受體接合免疫原,該等抗原受體為薄膜結合形式之抗體,隨後將分泌。不
同於T細胞,B細胞識別呈游離、未加工形式之免疫原。特異性抗原結合提供一類可引起B細胞活化之信號。第二類係由活化之TH細胞提供,該等活化之TH細胞表現之蛋白質藉由與B細胞表面上之非免疫球蛋白受體結合來幫助活化B細胞。可不考慮B細胞抗原特異性對任何B細胞起作用的此等TH衍生信號稱為輔助因子。此等輔助因子包括IL-2,IL-4及IL-6。然而,輔助經由允許T細胞表面上之蛋白質與B細胞上之蛋白質直接接觸之細胞-細胞接觸實現更有效。當僅在TH細胞活化後表現於TH細胞上之稱為CD40配位體(CD40L)之蛋白質與B細胞上之稱為CD40之蛋白質結合時,發生最有效形式之接觸介導之輔助。在稱為鄰近活化(by-stander activation)之過程中,與經活化B細胞接觸甚至可足以活化休眠B細胞,即使B細胞之表面免疫球蛋白未與抗原接合。
Tc淋巴細胞之功能在於消除表現外來抗原於其表面上之細胞,諸如經病毒感染宿主細胞。大部分Tc細胞表現CD8而非CD4,且因此識別與I類而非II類MHC蛋白締合之抗原。當體細胞受病毒感染時,一些免疫原性病毒蛋白可在細胞內經受加工,且接著所得肽可作為與I類MHC分子之表面複合物出現。接著此等肽-MHC複合物可由抗原特異性純系之T細胞受體識別,從而提供Tc細胞活化所必需之兩個信號中之一個。此第一信號單獨在Tc細胞上誘導高親和力IL-2受體。第二信號由鄰近活化之TH淋巴細胞分泌之IL-2提供。在接收到該兩個信號後,經活化Tc細胞獲得細胞毒性活性,從而使其能夠殺死與其結合之細胞以及帶有相同肽-MHC I類複合物之任何其他細胞。在一些情況下,因為Tc釋放特異性毒素於標靶細胞上而發生殺死;在其他情況下,Tc誘導標靶細胞經細胞凋亡而自殺。經活化Tc細胞亦增殖,從而再產生具有相同抗原特異性之Tc細胞。
D.由免疫球蛋白超家族協同刺激:
1.B7.1/B7.2-CD28/CTLA-4
或許最明確之T細胞協同刺激路徑為經由B7.1(CD80)/B7.2(CD86)-CD28/CTLA-4(CD152)傳導信號之路徑。此信號傳導路徑對T細胞活化及耐受性而言至關重要。Karandikar等人,J.Neuroimmunol. 89:10-18(1998);Oosterwegal等人,Curr.Opin.Immunol. 11:294-300(1999);Salomon等人,Annu.Rev.Immunol. 19:225-252(2001);Sansom,D.M.,Immunol. 101:169-177(2000);Chambers等人,Annu.Rev.Immunol. 19:565-592(2001)。
B7.1[Freeman等人,J.Exp.Med. 174:625-631(1991);Freedman等人,J.Immunol. 137:3260-3267(1987);Yokochi等人,J.Immunol. 128:823-827(1982)]及B7.2[Freeman等人,Science 262:909-911(1993);Freeman等人,J.Exp.Med. 178:2185-2192(1993);Azuma等人,Nature 366:76-79(1993)]具有針對兩種刺激受體CD-28及CTLA-4之雙特異性。Aruffo等人,Proc.Natl.Acad.Sci.USA 84:8573-8577(1987);Gross等人,J.Immunol. 144:3201-3210(1990)。CD28組成性表現於T細胞之表面上[Gross等人,J.Immunol. 149:380-388(1992)],而較高親和力受體CTLA-4具有在T細胞活化後快速調升之表現。Peach等人,J.Exp.Med. 180:2049-2058(1994);Linsley等人,J.Exp.Med. 176:1595-1604(1992);Kinsley等人,Immunity 1:793-801(1994);Linsley等人,Immunity 4:535-543(1996)。大部分APC群體以低含量組成性表現B7.2,此表現可快速調升,而B7.1在活化後稍後誘導性表現。Freeman等人,Science 262:909-911(1993);Hathcock等人,J.Exp.Med. 180:631-640(1994)。B7.2之先前表現及小鼠基因剔除資料表明對引發免疫反應而言,B7.2為更重要之協同刺激分子,但另一方面,兩種分子之功能大部分重疊。McAdam等人,Immuno.Rev. 165:631-640(1994)。
CD28與B7.1及B7.2相互反應以傳遞與TCR信號系統協同促進T細胞活化之信號。Lenschow等人,Annu.Rev.Immunol. 165:233-258(1996);Lanzavecchia等人,Cell 96:1-4(1999)。在無TCR信號存在下,CD28信號傳導不具有生理學重要性。CD28信號傳導調控T細胞活化之臨限值且顯著降低T細胞活化所需之TCR接合的數目。Viola等人,Science 273:104-106(1996)。CD28活化藉由促進T細胞存活來維持T細胞反應,藉此使得細胞激素能夠引發T細胞純系擴充及分化。Thompson等人,Proc.Natl.Acad.Sci.USA 86:1333-1337(1989);Lucas等人,J.Immunol. 154:5757-5768(1995);Shahinian等人,Science 261:609-612(1993);Sperling等人,J.Immunol. 157:3909-3917(1996);Boise等人,Immunity 3:87-98(1995)。CD28亦最優化先前活化之T細胞的反應,從而促進介白素2(IL-2)產生及T細胞存活。雖然一些反應與CD28無關,但尚不清楚此為由強抗原刺激物引起之獨立的協同刺激抑或為依賴於其他未知的協同刺激路徑之結果。
CTLA-4活化引起負性信號,其抑制TCR及CD-28介導之信號轉導。CTLA-4接合使得IL-2合成及經由細胞週期進展受到抑制且T細胞反應終止。Walunas等人,Immunity 1:405-413(1994);Walunas等人,J.Exp.Med. 183:2541-2550(1996);Krummel等人,J.Exp.Med. 182:459-466(1995);Brunner等人,J.Immunol. 162:5813-5820(1999);Greenwald等人,Immunity 14:145-155(2001)。CTLA-4在調控包括周邊T細胞耐受性之T細胞反應中發揮重要作用。雖然尚不清楚信號傳導如何經由CTLA-4及CD28協調,但一些可能性包括藉由誘導免疫抑制細胞激素、CD28信號傳導及/或TCR介導之信號傳導之直接拮抗作用競爭過CD28以與B7結合。
因此,CTLA-4(例如拮抗劑抗CTLA抗體)之拮抗作用及/或促效B7.1/B7.2/CD28可適用於增強感染(例如急性及慢性感染)及腫瘤免疫
治療中之免疫反應。
2.ICOS/ICOSL信號傳導:APC與T細胞之間的相互作用之另一路徑經由ICOS(CD278)及ICOSL(B7-H2,CD275)發生。雖然ICOS/ICOSL信號傳導促進T輔助細胞分化及效應功能且對介白素-10(IL-10)產生而言尤其重要,但在調控T細胞擴充及IL-2產生(包括調控性T細胞、T細胞耐受性及自體免疫)中發揮的作用較適中。
與CD28形成對比,雖然ICOS不組成性表現於初始T細胞上,但在TCR接合之後在T細胞上快速經誘導。Hutloff等人,Nature 397:263-266(1999);Yoshinaga等人,Nature 402:827-832(1999);Beier等人,Eur.J.Immunol. 30:3707-3717(2000);Coyle等人,Immunity 13:95-105(2000);Mages等人,Eur.J.Immunol.30:1040-1047(2000);McAdam等人,J.Immunol. 165:5035-5040(2000)。此表明ICOS向經活化T細胞提供協同刺激信號。雖然由CD28協同刺激增強ICOS表現且在無B7.1及B7.2存在下ICOS表現降低,但ICOS不會完全依賴於CD28信號。McAdam等人,J.Immunol. 165:5035-5040(2000);Aicher等人,J.Immunol. 164:4689-4696(2000);Kopf等人,J.Exp.Med. 192:53-61(2000)。在最初分化階段期間,在1型及2型T輔助(TH1及TH2)細胞上ICOS調升,但在TH2細胞上含量仍較高且在TH1細胞上含量降低。ICOS在T細胞生發中心(germinal center)之表現模式(Beier等人,Eur.J.Immunol. 30:3707-3717(2000);Mages等人,Eur.J.Immunol. 30:1040-1047(2000))指示T細胞中之ICOS輔助B細胞之作用。功能研究已證實此作用,且甚至已對大鼠B細胞證實ICOS之表現,但未對其他物種證實)。Tezuka等人,Biochem.Biophys.Res.Commun. 276:335-345(2000);McAdam等人,Nature 409:102-105(2001);Dong等人,Nature 409:97-101(2001);Dong等人,J. Immunol. 166:3659-3662(2001);Tafuri等人,Nature 409:105-109(2001)。
ICOS/ICOSL信號傳導之一個作用似乎用於由最近經活化之T細胞以及效應T細胞調控細胞激素(例如IL-4、IL-13)產生。Hutloff等人,Nature 397:263-266(1999);Coyle等人,Immunity 13:95-105(2000);Dong等人,Nature 409:97-101(2001)。在過敏性氣管疾病之研究中,ICOS阻斷提供TH2效應功能而非TH2分化。Tesciuba等人,J.Immunol. 167:1996-2003(2001)。指示ICOS亦可調控TH1效應功能,TH1與TH2細胞激素之產生可由ICOS-Ig融合蛋白在活體外再活化後抑制。Kopf等人,J.Exp.Med. 192:53-61(2000)。
ICOS之另一潛在作用與維持TH1反應相關。在多發性硬化症之自體免疫性腦脊髓炎之實驗模型(EAE)中,由髓鞘特異性CD4+ T細胞介導之TH1疾病展示當依序在T細胞預致敏期間及EAE之效應階段期間阻斷協同刺激時,ICOS阻斷之結果可能不同。Dong等人,Nature 409:97-101(2001);Rottman等人,Nature Immunol. 2:605-611(2001);Sporici等人,Clin.Immunol. 100:277-288(2001)。在ICOS-/-基因剔除小鼠中,由髓鞘少樹突神經膠細胞醣蛋白(MOG)誘發之EAE極度惡化,同時與野生型相比IFN-γ之產生增加。類似地,EAE誘發期間,ICOS阻斷使疾病惡化,同時導致IFN-γ產生增加。因此,預致敏期間,ICOS阻斷導致反應向TH1極化。有趣的是,與活體內觀測到之ICOS-Ig阻斷之結果形成鮮明對比,在ICOS-Ig存在下活體外使髓鞘特異性TCR轉殖基因T細胞預致敏抑制其誘發EAE之能力。Sporici等人,同上。雖然造成活體外及活體內之相反結果之差異尚不清楚,但可反映在活體內ICOS阻斷期間,ICOS對產生IL-10之調控性T細胞以及效應T細胞之作用。經由IL-10協同刺激對增進IL-10產生極有效,且比經由CD28協同刺激有效。Hutloff等人,同上。IL-10、IL-12調控
性環在調控EAE中至關重要,此係因為IL-10-/-而非IL4-/-小鼠發展惡化的EAE。Segal等人,J.Exp.Med. 187:537-546(1998)。
ICOS之另一潛在作用為增進T細胞依賴性B細胞體液反應。ICOS-/-及ICOSL-/-小鼠已展示ICOS為T細胞依賴性B細胞反應所需。Hutloff等人,Nature 397:263-66(1999);Chapoval等人,Nat.Immunol. 2:269-74(2001);Coyle等人,Immunity 13:95-105(2000);McAdam等人,Nature 409:102-5(2001);Tafuri等人,Nature 409:105-9(2001);Suh等人,Nat.Immunol. 4:899-906(2003)。ICOS-/-小鼠亦展示應答初級免疫生發中心減小,應答二次攻擊生發中心形成存在嚴重缺陷,及IgG種類轉換中存在缺陷。ICOS在T:B細胞相互作用中之作用由在患有成人發作型普通變異型免疫缺陷病之患者之T細胞中鑑別到ICOS的同種接合子損失得到進一步驗證。Grimbacher等人,Nat.Immunol. 4:261-68(2003)。
因此,ICOS/ICOSL(例如促效劑抗ICOS抗體、可溶性ICOS/ICOSL配位體)之促效作用可適用於增強感染(例如急性及慢性感染)及/或腫瘤免疫治療中之免疫反應。
3.PD-1路徑:調控T細胞活化之重要負性協同刺激信號由漸進式死亡-1受體(PD-1)(CD279)及其配位體結合搭配物PD-L1(B7-H1、CD274)及PD-L2(B7-DC、CD273)提供。PD-1之負性調控作用由易具有自體免疫之PD-1基因剔除物種(Pdcd1 -/- )揭示。Nishimura等人,Immunity 11:141-51(1999);Nishimura等人,Science 291:319-22(2001)。雖然PD-1與CD28及CTLA-4有關,但缺乏允許均二聚之近膜半胱胺酸。PD-1之細胞質域含有基於免疫受體酪胺酸之抑制基元(ITIM,V/IxYxxL/V)。PD-1僅與PD-L1及PD-L2結合。Freeman等人,J.Exp.Med. 192:1-9(2000);Dong等人,NatureMed. 5:1365-1369(1999);Latchman等
人,Nature Immunol. 2:261-268(2001);Tseng等人,J.Exp.Med. 193:839-846(2001)。
PD-1可表現於T細胞、B細胞、天然殺傷T細胞、經活化單核細胞及樹突狀細胞(DC)上。PD-1由經活化人類CD4+及CD8+ T細胞、B細胞及骨髓細胞表現,但不由未刺激之該等細胞表現。此與CD28及CTLA-4之更受限制之表現形成對比。Nishimura等人,Int.Immunol. 8:773-80(1996);Boettler等人,J.Virol. 80:3532-40(2006)。存在至少4種自經活化人類T細胞選殖之PD-1變異體,包括缺乏(i)外顯子2、(ii)外顯子3、(iii)外顯子2及3或(iv)外顯子2至4之轉錄物。Nielsen等人,Cell.Immunol. 235:109-16(2005)。除PD-1Δex3以外,所有變異體均以類似於全長PD-1之含量表現於休眠周邊血液單核細胞(PBMC)中。所有變異體之表現在人類T細胞經抗CD3及抗CD28活化後均顯著誘導。PD-1Δex3變異體缺乏跨膜域且類似於在自體免疫中發揮重要作用之可溶性CTLA-4。Ueda等人,Nature 423:506-11(2003)。此變異體富集於患類風濕性關節炎之患者的滑液及血清中。Wan等人,J.Immunol. 177:8844-50(2006)。兩種PD-1配位體在其表現模式上有差異。PD-L1組成性表現於小鼠T及B細胞、CD、巨噬細胞、間葉幹細胞及骨髓衍生肥大細胞上。Yamazaki等人,J.Immunol. 169:5538-45(2002)。PD-L1表現於各種非造血細胞(例如角膜、肺、血管上皮細胞、肝臟非實質細胞、間葉幹細胞、胰島、胎盤合體滋養層細胞、角質細胞等)上〔Keir等人,Annu.Rev.Immunol.26:677-704(2008)〕,且在許多細胞類型上經活化後調升。I型與II型干擾素(IFN)調升PD-L1。Eppihimer等人,Microcirculation 9:133-45(2002);Schreiner等人,J.Neuroimmunol. 155:172-82(2004)。當MyD88、TRAF6及MEK受到抑制時,細胞株中PD-L1之表現降低。Liu等人,Blood 110:296-304(2007)。JAK2亦涉及PD-L1誘導。Lee等人,FEBS Lett. 580:755-
62(2006);Liu等人,Blood 110:296-304(2007)。磷酸酶及張力蛋白同系物(PTEN)、修飾磷脂醯肌醇3-激酶(PI3K)之細胞磷酸酶及Akt信號傳導之損失或抑制增加癌症中轉錄後PD-L1之表現。Parsa等人,Nat.Med. 13:84-88(2007)。
與PD-L1相比,PD-L2表現更受限制。PD-L2誘導性表現於DC、巨噬細胞及骨髓衍生肥大細胞上。PD-L2亦表現於約二分之一至三分之二之休眠腹膜B1細胞上,但不表現於習知B2B細胞上。Zhong等人,Eur.J.Immunol. 37:2405-10(2007)。PD-L2+B1細胞結合磷脂醯膽鹼,且對針對細菌性抗原之先天免疫反應而言可能很重要。由IFN-γ誘導PD-L2部分依賴於NF-κB。Liang等人,Eur.J.Immunol. 33:2706-16(2003)。PD-L2亦可在單核細胞及巨噬細胞上由GM-CF、IL-4及IFN-γ誘導。Yamazaki等人,J.Immunol. 169:5538-45(2002);Loke等人,PNAS 100:5336-41(2003)。
PD-1信號傳導對細胞激素產生之作用通常大於對細胞增殖之作用,且對IFN-γ、TNF-α及IL-2產生具有明顯作用。PD-1介導之抑制性信號傳導亦視TCR信號傳導之強度而定,在低含量TCR刺激下傳遞較大的抑制作用。該降低可藉由經由CD28協同刺激[Freeman等人,J.Exp.Med. 192:1027-34(2000)]或存在IL-2[Carter等人,Eur.J.Immunol. 32:634-43(2002)]來克服。
有證據證明經由PD-L1及PD-L2之信號傳導可為雙向的。亦即除改變TCR或BCR信號傳導以外,信號傳導亦可經傳遞回到表現PD-L1及PD-L2之細胞。雖然用自患有瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia)之患者分離之天然人類抗PD-L2抗體處理樹突狀細胞未發現調升MHC II或B7協同刺激分子,但該等細胞產生較大量之促炎細胞激素,尤其TNF-α及IL-6,且刺激T細胞增殖。Nguyen等人,J.Exp.Med. 196:1393-98(2002)。用此抗體處理小
鼠亦(1)增進針對移殖之b16黑素瘤之抗性且快速誘導腫瘤特異性CTL,Radhakrishnan等人,J.Immunol. 170:1830-38(2003);Radhakrishnan等人,Cancer Res. 64:4965-72(2004);Heckman等人,Eur.J.Immunol. 37:1827-35(2007);(2)阻斷過敏性哮喘小鼠模型中氣管炎性疾病的發展,Radhakrishnan等人,J.Immunol. 173:1360-65(2004);Radhakrishnan等人,J.Allergy Clin.Immunol. 116:668-74(2005)。
反向信號傳導至樹突狀細胞(「DC」)之另一證據由關於與可溶性PD-1(與Ig恆定區融合之PD-1EC域,「s-PD-1」)培養之骨髓衍生DC之研究得出。Kuipers等人,Eur.J.Immunol. 36:2472-82(2006)。此sPD-1經由投與抗PD-1以可逆方式抑制DC活化且增加IL-10產生。
另外,若干研究展示與PD-1無關之PD-L1或PD-L2之受體。B7.1已鑑別為PD-L1之結合搭配物。Butte等人,Immunity 27:111-22(2007)。化學交聯研究表明PD-L1與B7.1可經由其IgV樣域相互作用。B7.1:PD-L1相互作用可誘導向T細胞傳導抑制性信號。由B7.1連接CD4+ T細胞上之PD-L1或由PD-L1連接CD4+ T細胞上之B7.1傳遞抑制性信號。缺乏CD28及CTLA-4之T細胞當受抗CD3加B7.1塗布之珠粒刺激時,展示增殖及細胞激素產生降低。在缺乏B7.1之所有受體(亦即CD28、CTLA-4及PD-L1)之T細胞中,T細胞增殖及細胞激素產生不再受抗CD3加B7.1塗布之珠粒抑制。此指示在無CD28及CTLA-4存在下,B7.1經由PD-L1特異性對T細胞起作用。類似地,當在抗CD3加PD-L1塗布之珠粒存在下受刺激時,缺乏PD-1之T細胞展示增殖及細胞激素產生降低,從而說明PD-L1連接對T細胞上之B7.1的抑制作用。當T細胞缺乏PD-L1之所有已知受體(亦即無PD-1及B7.1)時,T細胞增殖不再經抗CD3加PD-L1塗布之珠粒減弱。因此,PD-L1可經由B7.1或PD-1發揮對T細胞之抑制性作用。
B7.1與PD-L1之間的直接相互作用表明目前對協同刺激之理解不完全,且強調此等分子於T細胞上表現之重要性。PD-L1-/- T細胞之研究指示T細胞上之PD-L1可調降T細胞細胞激素產生。Latchman等人,Proc.Natl.Acad.Sci.USA 101:10691-96(2004)。因為PD-L1與B7.1均表現於T細胞、B細胞、DC及巨噬細胞上,所以此等細胞類型上之B7.1與PD-L1之間可能存在定向的相互作用。另外,非造血細胞上之PD-L1可與T細胞上之B7.1以及PD-1相互作用,從而產生PD-L1是否涉及其調控的問題。B7.1:PD-1相互作用之抑制性作用之一種可能的解釋為T細胞PD-L1可攔截或隔斷APC B7.1與CD28之相互作用。
因此,經由PD-L1之信號傳導之拮抗作用(包括阻斷PD-L1與PD-1、B7.1或兩者之相互作用,藉此阻止PD-L1向T細胞及其他抗原呈現細胞發送負性協同刺激信號)很可能增強應答感染(例如急性及慢性感染)及腫瘤免疫之免疫。此外,本發明抗PD-L1抗體可與PD-1:PD-L1信號傳導之其他組分之拮抗劑(例如拮抗劑抗PD-1及抗PD-L2抗體)組合。
4.B7-H3
協同刺激信號亦經由廣泛表現於淋巴及非淋巴組織中之B7-H3(B7RP-2、CD276、PRO352)提供。Chapoval等人,Nat.Immunol. 2:269-74(2001)。在人類中,B7-H3具有4Ig與2Ig變異體,其中4Ig形式佔優勢,而在小鼠中2Ig變異體佔優勢。Sun等人,J.Immunol. 168:6294-97(2002);Steinberger等人,J.Immunol. 172:2352-59(2004);Ling等人,Genomics 82:365-77(2003)。
最近研究展示B7-H3為T細胞反應之刺激劑與抑制劑。刺激性活化之證據由以下提供:(1)與抗CD3組合,B7-H3/Ig融合體協同刺激CD4+及CD8+ T細胞增殖,且刺激IFN-γ及CD8溶解活性,Chapoval等人,Nat.Immunol. 2:269-74(2001);及(2)將B7-H3表現質體注射至
EL-4淋巴瘤模型之腫瘤中引起50%之腫瘤完全退化,此舉依賴於CD8+ T細胞及NK細胞。然而,若干最近研究已展示此分子之抑制性作用。B7-H3-/- APC基因剔除物種展示在MLR反應中同種異體反應性T細胞增殖增加兩倍。在經任一形式之B7-H3轉染之HLA-DR2中,由抗CD3及抗CD28活化CD4 T細胞受到抑制。Ling等人,Genomics 82:365-77(2003)。結果,IFN-γ、TNF-α、IL-10及GM-CSF之增殖及產生均降低。類似於CD28及CTLA-4如何經由B7.1及B7.2調控信號傳導,此等研究之一致之處在於存在兩種具有相反功能之B7-H3受體。
因此,當與本發明抗PD-L1抗體組合時,阻斷B7-H3信號傳導可有助於增強對感染及腫瘤免疫之免疫反應。
5.B7-H4
最近添加至B7家族中的是B7-H4(B7x、B7-S1、B7-H.5、VTCN1、PRO1291),其為T細胞反應之負性調控劑。Zang等人,Proc.Natl.Acad.Sci.U.S.A.100(18),10388-10392(2003);Watanabe等人,Nat.Immunol. 4(7),670-679(2003;Prasad等人,Immunity 18(6),863-873(2003);Sica等人,Immunity 18(6),849-861(2003)。人類與小鼠B7-H4廣泛表現於淋巴器官(脾臟及胸腺)及非淋巴器官(包括肺、肝臟、睾丸、卵巢、胎盤、骨骼肌、胰腺及小腸)中。在正常人組織中B7-H4不會藉由IHC或轉譯含量之B7-H4之調節偵測到。IHC展示B7-H4高度表現於肺及卵巢腫瘤中,且即時聚合酶鏈反應(PCR)分析指示小鼠B7-H4亦高度表現於前列腺、肺及結腸癌瘤細胞株中。B7-H4結合經活化而非初始之T細胞上之尚未知的受體,該受體不同於CTLA-4、ICOS、PD-1及B7-H3之受體。儘管最初報導BTLA為B7-H4之配位體,但所報導之B7-H4/Ig融合體與野生型而非BTLA-/-細胞之結合得出如下結論:HVEM而非BTLA為B7-H4之獨特配位體。Sedy等人,Nat.Immunol. 6:90-98(2004)。
關於B7-H4轉染物及固定之B7-H4/Ig融合體之研究說明B7-H4傳遞抑制TCR介導之CD4+及CD8+ T細胞增殖、G0/G1期中之細胞週期進展及IL-2產生之信號。Sica等人,Immunity 18:849-61(2003);Zang等人,PNAS 100:10388-92(2003);Prasad等人,Immunity 18:863-73(2003)。B7.1協同刺激不能克服B7-H4/Ig誘導之抑制。阻斷抗B7-H4抗體活體外增加T細胞增殖及IL-2產生。與投與於傅氏完全佐劑(complete Freund's adjuvant,CFA)中之匙孔螺血氰蛋白(KLH)相稱活體內投與抗B7-H4抗體在活體外經KLH再刺激後引起抗KLH抗體IgM產生適度增加及T細胞增殖及IL-2產生增加兩至三倍,從而表明在抗B7-H4存在下活體內T細胞預致敏較大。在抗B7-H4處理之自體免疫小鼠模型之腦中,抗B7-H4阻斷抗體顯著加速EAE之發作及嚴重性且CD4+及CD8+ T細胞及CD11b+巨噬細胞增加。關於B7-H4獲得之組合實驗資料表明其可調降周邊組織中之免疫反應且在調控T細胞耐受性中發揮作用。B7-H4之表現亦可在逃避腫瘤免疫之宿主免疫反應中發揮作用。Choi等人,J.Immunol. 171:4650-54(2003)。因此,當與本發明抗PD-L1抗體組合時,B7-H4之拮抗作用可適用於增強對感染及腫瘤免疫之免疫反應。
6.BTLA:B7家族成員BTLA(CD272,BTLA-1)在功能上類似於PD-1及CTLA。最初鑑別為Th1細胞之選擇性標記物之BTLA僅表現於淋巴細胞上。類似於CTLA-4、ICOS及PD-1,在活化期間在T細胞上誘導BTLA。然而,與在Th2細胞上仍較高但在Th1細胞中調降之ICOS形成對比,BTLA仍表現於Th1細胞上,但不表現於Th2細胞上。類似於PD-1,BTLA亦表現於B細胞上。Gavrieli等人,Biochem.Biophys.Res.Commun. 312:1236-43(2003)。然而,BTLA表現於休眠與經活化B細胞上,而在經活化B細胞上,調升PD-1。BTLA具有兩個ITIM基
元。
BTLA對B與T淋巴細胞均具有抑制性作用。Watanabe等人,Nat.Immunol. 4:670-79(2003)。BLTA-/- B細胞活體外展示對抗IgM之反應適度,但對抗CD3之反應增加。經極化BTLA-/- Th1細胞活體外展示應答抗原暴露之增殖增加約兩倍。BTLA-/-小鼠活體內展示半抗原特異性抗體反應增加三倍且EAE感染性增加。BTLA-/-小鼠之表型類似於PD-1-/-小鼠之表型,展現自體免疫敏感性增加,但為比CTLA-4-/-小鼠更精細的表型。然而,倘若BTLA之作用為負性調控劑,則當與本發明抗PD-L1抗體組合時,BTLA之阻斷可證明適用於增強感染及抗腫瘤免疫中之免疫反應。
有趣的是,最近已展示Ig超家族成員BTLA亦與TNFR家族成員HVEM相互作用。Sedy等人,Nat.Immunol. 6:90-98(2005);Gonzalez等人,Proc.Natl.Acad.Sci.USA 102:1116-1121(2005)。HVEM綜述於下文TNFR家族協同刺激劑中。
E.TNFR家族協同刺激劑
1.OX40/OX40L(CD134)
缺乏OX40(CD134,TXPG1L,TNFRSF4)及OX40L(CD134L,CD252,GP34,TNFSF4,TXGP1)之小鼠對病毒及常見蛋白質抗原與在接觸敏感性反應中之初級CD4+ T細胞反應降低。Chen等人,Immunity 11:689-698(1999);Kopf等人,Immunity 11:699-708(1999);Murata等人,J.Exp.Med. 191:365-374(2000);Gramaglia等人,J.Immunol. 165:3043-3050(2000)。初級反應後期抗原特異性效應T細胞之出現率較低,且較少記憶T細胞發育。Gramaglia等人,同上。與缺乏CD27之T細胞形成對比,在缺乏OX40之初始CD4+ T細胞群體中早期增殖未減弱。然而,活化之後4-5天,增殖降低且細胞凋亡式細胞死亡顯著,結果是幾乎無T細胞長期存活。Rogers等人,
Immunity 15:445-455(2001)。對於缺乏OX40之CD8+ T細胞而言,雖然初始細胞分裂不受影響,但與抗原相遇之後3-6天,初級效應細胞之積聚顯著減少。Croft等人,Nat.Immunol. 3:609-620(2003)。
由樹突狀細胞或T細胞轉殖基因表現OX40L增加抗原應答CD4+ T細胞的數目且產生與異常T細胞活化相關之自體免疫樣症狀。Brocker等人,Eur.J.Immunol. 29:1610-1616(1999);Murata等人,J.Immunol. 169:4628-4636(2002)。免疫之後,注射促效抗OX40抗體引起更大量之抗原反應性CD4+ T細胞在初級反應峰值時積聚,且引起所產生之記憶T細胞的數目相伴增加。Gramaglia等人,同上;Bansai-Pakala等人,Nature Med. 7:907-912(2001);Maxwell等人,J.Immunol. 164:107-112(2000);Weatherill等人,Cell.Immunol. 209:63-75(2001)。當用對OX40具有特異性之促效抗體處理經抗原預致敏之小鼠時,初級效應CTL之積聚增加。De Smedt等人,J.Immunol. 168:661-670(2002)。
咸信OX40提供允許新近產生之效應細胞在初級免疫反應峰值時存活之後期作用信號。亦存在有力的證據證明除由CD28信號介導之OX40的表現增加以外,OX40在CD28之下游起作用,CD28缺乏對OX40缺乏之功能分析已展示在無CD28信號存在下早期初級T細胞反應顯著減弱,但在無OX40信號存在下僅後期反應減弱。Rogers等人,Immunity 15:445-455(2001);Bertram等人,J.Immunol. 168:3777-3785(2002)。
因此,當與本發明抗PD-L1抗體組合時,活化OX40/OX40L(諸如經由施用促效抗體)很可能可適用於治療T細胞功能障礙病症。
2.4-1BB(CD137)/4-1BBL
類似於OX40/OX40L,當4-1BBL不存在且較少記憶T細胞發育時,缺乏4-1BB(CD137,TNFRSF9)及4-1BBL(TNFSF9)之T細胞展示
在初級反應中抗原反應性CD8+ T細胞積聚較少。DeBenedette等人,J.Immunol. 163:4833-4841(1999);Tan等人,J.Immunol. 163:4859-4868(1999);Tan等人,J.Immunol. 164:2320-2325(2000)。此外,阻斷4-1BBL不會改變CD8+ T細胞之最初增殖反應,但會在3-6天之後抑制初級反應峰值時效應CTL之積聚,此係由於已分裂若干次之細胞凋亡。Cooper等人,Eur.J.Immunol. 32:521-529(2002)。促效抗4-1BB抗體及抗4-1BBL轉染之APC亦已產生類似的結果:活體內CTL及CD4+ T細胞反應明顯增加。Melero等人,NatureMed. 3:682-685(1997);Melero等人,Eur.J.Immunol. 28:1116-1121(1998);Takahashi等人,J.Immunol. 162:5037-5040(1999);Guinn等人,J.Immunol.162:5003-5010(1999);Halstead等人,Nature Immunol. 3:536-541(2002);Takahashi等人,Immunol.Lett. 76:183-191(2001);Bansal-Pakala等人,J.Immunol. 169:5005-5009(2002)。4-1BB特異性抗體不會改變最初增殖反應,從而支持由4-1BBL阻斷實驗得出之結論且指出4-1BB在提供細胞存活信號中之後期活性。
如同OX40,咸信4-1BB提供允許新近產生之效應細胞在初級免疫反應峰值時存活之後期作用信號。亦存在有力的證據證明除由CD28信號介導之OX40及4-1BB的表現增加以外,4-1BB在CD28之後起作用,CD28缺乏對4-1BB缺乏之功能分析已展示在無CD28信號存在下早期初級T細胞反應顯著減弱,但在無OX40信號存在下僅後期反應減弱。Rogers等人,Immunity 15:445-455(2001);Bertram等人,J.Immunol. 168:3777-3785(2002)。
在CD8+CTL起重要作用之癌症中促效抗CD137抗體可誘導腫瘤退化。Melero等人,Nat.Med. 3:682-5(1997);Hirano等人,Cancer Res. 65(3):1089-96(2005)。PD-L1之組成性及誘導性表現使該等腫瘤具有抗性,此表現當PD-L1阻斷後可逆。Hirano等人。
因此,活化4-1BB/4-BBL(諸如經由施用促效抗體,尤其與PD-L1拮抗劑(例如抗PD-L1抗體)組合)很可能可適用於治療T細胞功能障礙病症。
3.CD27/CD27L(CD70)
在CD27/CD70相互作用已破壞之活體外阻斷研究中已說明T細胞反應之最初階段中CD27(TNFRSF7,S152)及CD27L(CD70,TNFSF7)信號傳導之重要性。Oshima等人,Int.Immunol. 10:517-526(1998);Agematsu等人,J.Immunol. 153:1421-1429(1994);Hintzen等人,J.Immunol. 154:2612-2623(1995)。雖然缺乏CD27之T細胞最初正常分裂,但接著在活化之後3天或3天以上不佳地增殖。Hendriks等人,Nature Immunol. 1:433-440(2000)。此指示CD27藉由早期抑制T細胞死亡或藉由在活化之後2-3天對細胞週期起作用以允許持續分裂來參與促進初始T細胞群體之最初擴充。此進一步得到缺乏CD27之小鼠的活體內研究支持,在該研究中經3週或3週以上出現較少數目之抗原特異性反應(第4-8天)且較少記憶T細胞發育。Hendriks等人,同上。在T細胞活化之後早期調升CD27之表現,表明其主要傳遞在效應反應峰值之前維持早期增殖之信號。
因此,活化CD27/CD27L(包括經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)很可能可適用於治療T細胞功能障礙病症。
4.CD30/CD30L(CD153)
CD30(TNFRSF8,Ki-1)及CD30L(CD153,TNFSF8)信號傳導活體外協同刺激若干T細胞功能。Del Prete等人,J.Exp.Med. 182:1655-1661(1995);Bowen等人,J.Immunol. 156:442-449(1995)。CD30L之阻斷試劑活體外抑制Th2細胞發育且增進Th1細胞發育。此活性與展示CD30由Th2細胞及2型細胞毒性Tc2細胞優先表現之資料一致。Del Prete等人,同上;Nakamura等人,J.Immunol. 158:2090-2098
(1996)。在未極化初級反應中活化初始T細胞之後3-4天表現CD30。Nakamura等人,同上指示其作用不限於2型細胞激素支配之反應。
雖然CD30/CD30L信號傳導之確切機制尚不清楚,但已表明可能類似於OX40及4-1BB。當將過繼轉移之抗原特異性CD8+ T細胞轉移至缺乏CD30L之小鼠中時,其不會在初級反應峰值時大量積聚,且較少記憶T細胞發育。因此,CD30亦可提供增殖及/或存活信號以允許在初級反應峰值時產生大量抗原特異性T細胞。
因此,活化CD27/CD27L(包括經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)很可能可適用於治療T細胞功能障礙病症。
5.HVEM/LIGHT
HVEM(HVEA,ATAR,LIGHTR,TNFRSF14,PRO509)及LIGHT(CD258,HVEML,TR2,TNFSF14,PRO726)對T細胞協同刺激之作用因以下而變得複雜:1)LIGHT亦能夠結合淋巴毒素-β受體(LTβR),及2)HVEM結合可溶性LTα3。因此,關於HVEM/LIGHT之作用的任何研究亦應考慮此信號傳導系統之其他結合搭配物的作用。阻斷LIGHT可早期抑制同種異體混合淋巴細胞反應(MLR)中之T細胞增殖及細胞激素分泌。Tamada等人,J.Immunol. 164:4105-4110(2000);Kwon等人,J.Biol.Chem. 272:14272-14276(1997);Harrop等人,J.Immunol. 161:1786-1794(1998);Tamada等人,NatureMed. 6:283-289(2000)。當阻斷MHC錯配心臟同種異體移植物中之LIGHT時,促炎性細胞激素之產生受到抑制。Ye等人,J.Exp.Med. 195:795-800(2002)。此外,在缺乏LIGHT與CD28之接受者中,同種異體皮膚移植物因延遲之動力學而被排斥。Scheu等人,J.Exp.Med. 195:1613-1624(2002)。有證據表明延遲之移植物排斥可能指示T細胞純系擴充或細胞激素產生早期受到抑制。此結論由以下來支持:(i)活體外研究展示應答同種異體抗原之缺乏LIGHT之脾細胞的TH1與TH2細胞
激素之產生降低且產生弱細胞毒性T淋巴細胞活性(CTL活性)[Sheu等人,同上]及(ii)活體內研究展示阻斷LIGHT降低同種異體反應性CTL之產生的。Tamada等人,Nature Med. 6:283-289(2000)。
因此,HVEM/LIGHT(諸如經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)可適用於治療T細胞功能障礙病症。
II.定義
「過敏原」或「免疫原」為可觸發免疫反應之任何分子。如本文所用之術語涵蓋抗原分子本身或其來源,諸如花粉粒、動物皮屑、昆蟲毒液或食品。此與術語抗原形成對比,抗原係指可由免疫球蛋白或T細胞受體特異性識別之分子。能夠誘導免疫反應之任何外來物質均為潛在過敏原。已知許多天然與合成起源之不同化學物質具過敏原性。複合天然有機化學物質、尤其蛋白質很可能引起抗體介導之過敏反應,而簡單有機化合物、無機化學物質及金屬更優先引起T細胞介導之過敏反應。在一些情況下,同一過敏原可負責一種以上類型之過敏反應。可經由吸入、注射、注射或皮膚接觸暴露於過敏原。
「功能障礙」在免疫功能障礙情形下係指對抗原刺激之免疫應答降低之狀態。該術語包括可能發生抗原識別但後續免疫反應對控制感染或腫瘤生長無效之耗竭及/或無反應之共同要素。
「耐受性」或「免疫耐受性」係指免疫系統未能對特定抗原產生防禦性免疫反應。耐受性可為天然的或自身的,其中身體不攻擊其自身蛋白質及抗原,或其可因免疫系統經操縱而誘導。中樞耐受性在淋巴細胞發育期間出現且作用於胸腺及骨髓中。在此過程中,識別自身抗原之T及B淋巴細胞在其發育成全免疫活性細胞之前被除去。雖然此過程在胎兒發育期間最活躍,但持續整個生命過程,因為有未成熟淋巴細胞產生。周邊T細胞耐受性係指功能上不應答周邊組織中存在之自身抗原,且在T及B細胞成熟且進入周邊之後出現。此等過程
包括由「調控性」T細胞抑制自身反應性細胞且在無伴隨發炎之協同刺激信號存在下遇到抗原的淋巴細胞中產生低應答(無反應)。「獲得」或「誘導耐受性」係指免疫系統對以淋巴組織對既定抗原之特異性無反應為特徵的外部抗原的適應,該既定抗原在其他情況下很可能將誘導細胞介導或體液免疫。在成人中,耐受性可藉由重複投與極大劑量之抗原或低於刺激免疫反應所需之臨限值的小劑量之可溶性抗原(諸如經由靜脈內或舌下投與)臨床誘導。免疫抑制亦有助於誘導耐受性。破環自身耐受性可產生自體免疫。
「增進T細胞功能」意謂誘導、引起或刺激T細胞具有持續或擴增之生物功能,或更新或再活化已耗竭或失活T細胞。增進T細胞功能之實例包括:相對於介入之前的程度,增加自CD8+ T細胞之γ-干擾素分泌、增加增殖、增加抗原應答(例如病毒或病原體清除)。在一實施例中,增進之程度為至少50%、或者60%、70%、80%、90%、100%、120%、150%、200%。一般熟習此項技術者已知量測此增進之方法。
「T細胞功能障礙病症」為以對抗原刺激之應答降低為特徵之T細胞病症或病狀。在一特定實施例中,T細胞功能障礙病症為與經由PD-1之信號傳導不當增加特定相關之病症。在另一實施例中,T細胞功能障礙病症為T細胞無反應性或分泌細胞激素、增殖或實行細胞溶解活性之能力降低的病症。在一特定態樣中,應答降低導致對表現免疫原之病原體或腫瘤之控制無效。以T細胞功能障礙為特徵之T細胞功能障礙病症之實例包括未消除之急性感染、慢性感染及腫瘤免疫。
「慢性感染」係指在急性感染期間感染因子(例如病原體,諸如病毒、細菌、原蟲寄生蟲、真菌或其類似物)在受感染宿主中誘導免疫反應但尚未自該宿主中清除或消除之感染。慢性感染可為持續性、潛伏性或緩慢的。雖然急性感染通常在幾日或幾週內由免疫系統消除
(例如流行性感冒),但持續性感染可以相對較低之程度持續幾個月、幾年、幾十年或一生(例如B型肝炎)。相反,潛伏性感染之特徵在於長期無症狀活性不時由一段快速增加之高度感染及病原體含量升高之時期打斷(例如單純性疱疹)。最後,緩慢感染為以疾病症狀逐漸且持續增加為特徵之感染,諸如長期潛伏,之後在臨床症狀發作後,開始拖延性且進行性之臨床過程。不同於潛伏性及持續性感染,緩慢感染可能不會以急性病毒增殖期開始(例如小核糖核酸病毒感染,綿羊髓鞘脫落病毒、綿羊癢病、庫茲德-賈克氏病(Creutzfeldt-Jakob disease))。能夠誘發慢性感染之例示性感染因子包括病毒(例如細胞巨大病毒、艾伯斯坦-巴爾病毒(Epstein Barr virus)、B型肝炎病毒、C型肝炎病毒、I型單純性疱疹病毒及II型單純性疱疹病毒、1型人類免疫缺乏病毒及2型人類免疫缺乏病毒、人類乳頭狀瘤病毒、1型人類T淋巴細胞病毒及2型人類T淋巴細胞病毒、水痘帶狀疱疹病毒及其類似病毒)、細菌(例如結核分枝桿菌(Mycobacterium tuberculosis)、李氏菌屬、肺炎克雷伯氏桿菌(Klebsiella pneumoniae)、肺炎鏈球菌(Streptococcus pneumoniae)、金黃色葡萄球菌(Staphylococcus aureus)、疏螺旋體屬、幽門螺旋桿菌及其類似細菌)、原蟲寄生蟲(例如利什曼蟲屬(Leishmania spp.)、惡性瘧原蟲(Plasmodium falciparum)、血吸蟲屬(Schistosoma spp.)、弓形蟲屬(Toxoplasma spp.)、錐蟲屬(Trypanosoma spp.)、肥頭帶絛蟲(Taenia carssiceps)及其類似原蟲寄生蟲)及真菌(例如麯黴屬(Aspergillus spp.)、白色念珠菌(Candida albicans)、粗球黴菌(Coccidioides immitis)、莢膜組織漿菌(Histoplasma capsulatum)、肺炎肺囊蟲(Pneumocystis carinii)及其類似真菌)。其他感染因子包括藉由進一步在此等組織中產生錯誤摺疊之蛋白質,從而導致形成致使細胞死亡、組織損傷且最終死亡之澱粉樣斑塊而影響腦或神經元結構的朊病毒或錯誤摺疊蛋白質。由朊病毒感
染引起之疾病之實例包括庫茲德-賈克氏病及其變種、格-施-沙症候群(Gerstmann-Sträussler-Scheinker syndrome,GSS)、致死性家族失眠(sFI)、庫魯症(kuru)、綿羊癢病、牛中之牛腦海綿狀病(Bovine spongiform encephalopathy,BSE)(亦稱為「瘋牛」病)及腦病之各種其他動物形式〔例如傳染性貂腦病(TME);白尾鹿、麋鹿及長耳鹿中之慢性消耗性疾病(CWD);貓海綿狀腦病;林羚(nyala)、羚羊及較大撚角羚中之外來有蹄類腦病(EUE)、鴕為之海綿狀腦病〕。
「腫瘤免疫」係指腫瘤逃避免疫識別及清除之過程。因此,作為治療性概念,當該逃避減弱時,腫瘤免疫得以「治療」,且腫瘤由免疫系統識別及攻擊。腫瘤識別之實例包括腫瘤結合、腫瘤收縮及腫瘤清除。
「B7負性協同刺激拮抗劑」(「BNCA」)為降低、阻斷、抑制、消除或干擾由或經由於由B7家族成員介導表現於T淋巴細胞上之細胞表面蛋白所介導之負性協同刺激信號之藥劑。在一態樣中,BNCA可單獨或與本發明抗PD-1抗體組合使功能障礙T細胞變得非功能障礙。在另一態樣中,BNCA可為抑制B7負性協同刺激分子之核酸或蛋白質合成、表現、信號傳導及/或表現後加工之藥劑。在另一態樣中,BNCA為由B7負性協同刺激分子降低、阻斷、抑制、消除或干擾信號轉導之抗體、抗原結合抗體片段、BNCA寡肽、BNCA RNAi或BNCA小分子。B7負性協同刺激分子之實例包括:CTLA-4、PD-L1、PD-1、B7.1(表現於T細胞上)、PD-L2、B7-H3及B7-H4。
正性協同刺激促效劑為增加、增進、強化或促進由或經由表現於T淋巴細胞上之細胞表面蛋白介導之協同刺激信號之分子。在一態樣中,正性協同刺激分子可為活化正性協同刺激路徑之細胞外域、可溶性構築體或促效抗體。正性協同刺激分子之實例包括B7超家族分子,例如B7.1、B7.2、CD28及ICOS/ICOSL。其他實例包括TNFR家族
協同刺激分子,例如OX40/OX40L、41-BB/41-BBL、CD27/CD27L、CD30/CD30L及HVEM/LIGHT。
「小分子」或「小有機分子」為分子量低於約500道爾頓之分子。
「干擾RNA」、「RNAi」為長度為10至50個核苷酸且降低標靶基因之表現的RNA,其中鏈之數部分充分互補(例如與標靶基因之一致性為至少80%)。RNA干涉之方法係指以轉錄後含量(例如轉譯)出現之基因表現之標靶特異性抑制(亦即「基因沉默」),且包括RNA介導之基因表現抑制之所有轉錄後機制及轉錄機制,諸如以下中所述之機制:P.D.Zamore,Science 296:1265(2002);及Hannan及Rossi,Nature 431:371-378(2004)。如本文所用之RNAi可呈小干擾RNA(siRNA)、短髮夾RNA(shRNA)及/或微RNA(miRNA)形式。該等RNAi分子通常為可以獨立互補或部分互補RNA鏈形式表現之雙鏈RNA複合物。此項技術中熟知設計雙鏈RNA複合物之方法。舉例而言,適合之shRNA及siRNA之設計及合成可見於Sandy等人,BioTechniques 39:215-224(2005)中。
「小干擾RNA」或siRNA為長度為10至50個核苷酸且降低標靶基因之表現的雙鏈RNA(dsRNA)雙鏈體,其中第一鏈之數部分充分互補(例如與標靶基因之一致性為至少80%)。siRNA經特異性設計以避免抗病毒反應,該抗病毒反應之特徵在於干擾素合成增加、非特異性蛋白合成受抑制及RNA降解,該RNA降解通常導致與在哺乳動物細胞中使用RNAi相關之細胞自殺或死亡。Paddison等人,Proc Natl Acad Sci USA 99(3):1443-8.(2002)。
術語「髮夾」係指具有7-20個核苷酸之環狀RNA結構。「短髮夾RNA」或shRNA為長度為10至50個核苷酸且以降低標靶基因表現之急轉彎(hairpin turn)為特徵之單鏈RNA,其中RNA鏈之數部分充分互補
(例如與標靶基因之一致性為至少80%)。術語「莖環(stem-loop)」係指同一分子鹼基對之兩個區之間配對形成在未配對短環中結束,從而得到棒棒糖形結構之雙螺旋。
「微RNA」或「miRNA」(先前稱為stRNA)為長度為約10至70個核苷酸且最初轉錄為以「莖環」結構為特徵之miRNA前體(pre-miRNA),隨後在經由RNA誘導之沉默複合物(RISC)進一步加工之後加工成成熟miRNA之單鏈RNA。
「BNCA干擾RNA」或「BNCA RNAi」較佳特異性結合BNCA核酸且降低其表現。此意謂與不存在BNCA RNAi之對照組中之B7負性協同刺激分子之表現相比,在BNCA RNAi存在下B7負性協同刺激分子之表現較低。BNCA RNAi可使用已知方法鑑別且合成(Shi Y.,Trends in Genetics 19(1):9-12(2003);WO2003056012;WO2003064621;WO2001/075164;WO2002/044321)。
「BNCA寡肽」為較佳特異性結合包括分別如本文所述之受體、配位體或信號傳導組分之B7負性協同刺激多肽之寡肽。該等寡肽可使用已知寡肽合成方法化學合成或可使用重組技術製備及純化。該等寡肽長度通常為至少約5個胺基酸,或者長度為至少約6、7、8、9、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、36、37、38、39、40、41、42、43、44、45、46、47、48、49、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100個或100個以上胺基酸。該等寡肽可在無過度實驗下使用熟知技術鑑別。就此點而言,應注意此項技術中熟知篩檢能夠特異性結合多肽標靶之寡肽之寡肽文庫的技術(參見例如美國專利第5,556,762號、第
5,750,373號、第4,708,871號、第4,833,092號、第5,223,409號、第5,403,484號、第5,571,689號、第5,663,143號;PCT公開案第WO84/03506號及第WO84/03564號;Geysen等人,Proc.Natl.Acad.Sci.U.S.A.,81:3998-4002(1984);Geysen等人,Proc.Natl.Acad.Sci.U.S.A.,82:178-182(1985);Geysen等人,Synthetic Peptides as Antigens,130-149(1986);Geysen等人,J.Immunol.Meth.,102:259-274(1987);Schoofs等人,J.Immunol.,140:611-616(1988);Cwirla,S.E.等人,Proc.Natl.Acad.Sci.USA,87:6378(1990);Lowman,H.B.等人,Biochemistry,30:10832(1991);Clackson,T.等人,Nature,352:624(1991);Marks,J.D.等人,J.Mol.Biol.,222:581(1991);Kang,A.S.等人,Proc.Natl.Acad.Sci.USA,88:8363(1991);及Smith,G.P.,CurrentOpin.Biotechnol.,2:668(1991)。
「BNCA小分子拮抗劑」或「BNCA小分子」為較佳特異性抑制B7負性協同刺激多肽之除本文所定義之寡肽或抗體以外的有機分子。該B7負性協同刺激信號傳導抑制較佳使功能障礙T細胞能應答抗原刺激。BNCA小分子之實例可使用已知方法鑑別及化學合成(參見例如PCT公開案第WO2000/00823號及第WO2000/39585號)。該等BNCA小分子之大小通常小於約2000道爾頓,或者大小小於約1500、750、500、250或200道爾頓,能夠較佳特異性結合如本文所述之B7負性刺激多肽且可在無過度實驗下使用熟知技術鑑別。就此點而言,應注意此項技術中熟知篩檢能夠結合多肽標靶之分子之有機分子文庫的技術(參見例如PCT公開案第WO00/00823號及第WO00/39585號)。
術語「抗生素」包括特異性抑制或消除諸如病毒、細菌、真菌或原蟲之微生物生長但在投藥濃度及給藥間隔下不會致使宿主死亡之任何分子。如本文所用之術語抗生素包括抗菌劑、抗病毒劑、抗真菌劑及抗原蟲劑。在一特定態樣中,抗生素在投藥濃度及給藥間隔下對
宿主無毒。抗細菌抗生素或抗細菌劑可大致分類為殺細菌型(亦即直接殺死)或抑細菌型(亦即阻止分裂)。殺細菌型抗生素可進一步分為以下亞類:窄譜類(亦即僅影響一小類細菌子集,例如革蘭氏陰性菌(gram-negative)等)或廣譜類(亦即影響一大類)。抗生素之實例包括:(i)胺基糖苷類,例如阿米卡星(amikacin)、慶大黴素(gentamicin)、康黴素(kanamycin)、新黴素(neomycin)、奈替米星(netilmicin)、鏈黴素(streptomycin)、托普黴素(tobramycin)、嘌呤黴素(paromycin),(ii)袢黴素類(ansamycins),例如,格爾德黴素(geldanamycin)、除莠黴素(herbimycin);(iii)碳頭孢烯類(carbacephems),例如氯碳頭孢(loracarbef);(iv)碳青黴烯類(carbapenems),例如厄他培南(ertapenum)、多尼培南(doripenem)、亞胺培南(imipenem)/西司他汀(cilastatin)、美羅培南(meropenem);(v)頭孢菌素類(cephaolsporins)(第一代),例如頭孢羥胺苄(cefadroxil)、頭孢唑啉(cefazolin)、頭孢噻吩(cefalotin)、頭孢胺苄(cefalexin);(vi)頭孢菌素類(第二代),例如頭孢克洛(ceflaclor)、頭孢孟多(cefamandole)、頭孢西丁(cefoxitin)、頭孢丙烯(cefprozil)、頭孢呋辛(cefuroxime);(vi)頭孢菌素類(第三代),例如頭孢克肟(cefixime)、頭孢地尼(cefdinir)、頭孢托侖(cefditoren),頭孢哌酮(cefoperazone)、頭孢噻肟(cefotaxime)、頭孢泊肟(cefpodoxime)、頭孢他啶(ceftazidime)、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、頭孢曲松(ceftriaxone);(vii)頭孢菌素類(第四代)、例如頭孢吡肟(cefepime);(viii)頭孢菌素類(第五代),例如頭孢吡普(ceftobiprole);(ix)醣肽類(glycopeptides),例如替考拉寧(teicoplanin)、萬古黴素(vancomycin);(x)巨環內酯類,例如阿齊黴素(axithromycin)、克拉黴素(clarithromycin)、地紅黴素(dirithromycine)、紅黴素(erythromycin)、羅紅黴素(roxithromycin)、醋竹桃黴素(troleandomycin)、泰利黴素(telithromycin)、觀黴素
(spectinomycin);(xi)單醯胺菌素類(monobactams),例如安曲南(axtreonam);(xii)青黴素類(penicilins),例如安莫西林(amoxicillin)、安比西林(ampicillin)、阿洛西林(axlocillin)、卡本西林(carbenicillin)、氯唑西林(cloxacillin),雙氯噁唑西林(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、甲氧西林(meticillin)、夫西林(nafcilin)、苯唑青黴素(oxacillin)、青黴素(penicillin)、哌拉西林(peperacillin)、替卡西林(ticarcillin);(xiii)抗生素多肽,例如桿菌肽(bacitracin)、黏菌素(colistin)、多黏菌素B(polymyxin B);(xiv)喹諾酮類(quinolones),例如環丙沙星(ciprofloxacin)、依諾沙星(enoxacin)、加替沙星(gatifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lemefloxacin)、莫西沙星(moxifloxacin)、諾氟沙星(norfloxacin)、氧氟沙星(orfloxacin)、曲伐沙星(trovafloxacin);(xv)磺醯胺類,例如磺胺米隆(mafenide)、百浪多息(prontosil)、磺胺醋醯胺(sulfacetamide)、磺胺甲二唑(sulfamethizole)、磺胺(sulfanilamide)、柳氮磺啶(sulfasalazine)、磺胺異噁唑(sulfisoxazole)、甲氧苄啶(trimethoprim)、甲氧苄啶-磺胺甲異噁唑(TMP-SMX);(xvi)四環素類(tetracyclines),例如地美環素(demeclocycline)、多西環素(doxycycline)、米諾環素(minocycline)、土黴素(oxytetracycline)、四環素;及(xvii)其他,諸如阿斯凡納明(arspenamine)、氯黴素(chloramphenicol)、克林黴素(clindamycin)、林可黴素(lincomycin)、乙胺丁醇(ethambutol)、磷黴素(fosfomycin)、梭鏈孢酸(fusidic acid)、呋喃唑酮(furazolidone)、異菸肼(isoniazid)、利奈唑胺(linezolid)、甲硝唑(metronidazole)、莫匹羅星(mupirocin)、硝基呋喃妥因(nitrofurantoin)、平板黴素(platensimycin)、吡嗪醯胺(pyrazinamide)、奎努普丁(quinupristin)/達福普丁(dalfopristin)、利福平(rifampin)/利福黴素(rifampicin)或替硝唑(tinidazole)。
術語「抗病毒劑」包括抑制或消除病毒生長、致病性及/或存活之任何分子。其包括抗反轉錄病毒藥物,諸如(1)逆轉錄酶抑制劑,包括例如:(a)核苷類似物逆轉錄酶抑制劑(NRTI),例如阿昔洛韋(aciclovir/acyclovir)(ZOVIRAX®,ZOVIR®)、西多福韋(cidofovir)、疊氮胸苷(azidothymidine)/齊多夫定(zidovudine)(AZT,RETROVIR®)、去羥肌苷(didanosine)(ddI、VIDEX®);紮西他濱(zalcitabine)(ddC,HIVID®);司他夫定(stavudine)(d4T,ZERIT®);拉米夫定(lamivudine)(3TC,EPIVIR®);阿巴卡韋(abacavir)(ZIAGEN®);恩曲他濱(emtricitabine)(EMTRIVA®);溴夫定(brivudine)(HELPIN®);因提弗(entecavir)(BARACLUDE®);碘苷(idoxuridine);偉拉咪定(viramidine)(Valeant Pharmacueticals之他立韋林(taribavirin))、Pharmasset/Roche之胞嘧啶核苷類似物聚合酶抑制劑PCI-6130及前藥變異體(例如R7128);Merck/Isis Pharmaceuticals之核苷類似物抑制劑MK-0608;(b)核苷酸類似物逆轉錄酶抑制劑(NtRTI),例如泰諾福韋(tenofovir)(VIREAD®);阿德福韋(adefovir)(PREVEON®,HEPSERA®);福米韋生(fomivirsen)(VITRAVENE®);(c)非核苷逆轉錄酶抑制劑(NNRTI),依發韋侖(efavirenz)(SUSTIVA®,STOCRIN®);奈韋拉平(nevirapine)(VIRAMUNE®)、地拉韋啶(delavirdine)(RESCRIPTOR®)、依曲韋林(etravirine)(INTELENCE®)、洛韋胺(loviride);ViroChem Pharma之HCV RNA依賴性核糖核酸聚合酶之非核苷抑制劑VCH-759,Pfizer之HCV聚合酶抑制劑之非核苷抑制劑PF-868554;及(d)聚合酶抑制劑,包括:Boehringer Ingelheim之C型肝炎病毒之RNA依賴性核糖核酸聚合酶BILB-1941、Roche之核糖核酸聚合酶抑制劑R1626;Achillion Pharmaceuticals之複製酶抑制劑ACH-0137171、Roche/Pharmasset之聚合酶抑制劑R7128、Abbott之聚合酶抑制劑ABT-333及ABT-072、Boehringer Ingelheim之聚合酶抑制劑BI
207127、Pharmasset之聚合酶抑制劑PSI-7851、Anadys Pharmaceuticals之聚合酶抑制劑ANA598、Merck之聚合酶抑制劑MK-3281、Idenix之聚合酶抑制劑IDX184、Glaxo Smith Kline之聚合酶抑制劑GSK 625433、Inhibitex之聚合酶抑制劑INX-189、Idenix之聚合酶抑制劑NM283、Wyeth之聚合酶抑制劑HCV796、Gilead之聚合酶抑制劑GL60667及GS9190、Pfizer之聚合酶抑制劑PF-00868554、Virochem之聚合酶抑制劑VCH759、VCH916、VX222及VX759、Idenix之聚合酶抑制劑IDX184及IDX375、Bristol Myers Squibb之聚合酶抑制劑BMS650032;(2)蛋白酶抑制劑,包括例如:沙奎那韋(saquinavir)(FOROVASE®/INVIRASE®)、利托那韋(ritonavir)(NORVIR®)、茚地那韋(indinavir)(CRIXIVAN®)、奈非那韋(nelfinavir)(VIRACEPT®)、安普那韋(amprenavir)(AGENERASE®)、洛匹那韋(lopinavir)(KALETRA®)、阿紮那韋(atazanavir)(REYATAZ®)、夫沙那韋(fosamprenavir)(LEXIVA®)、替拉那韋(tipranavir)(APTIVUS®)、地瑞那韋(darunavir)(PREZISTA®)、特拉匹韋(telapravir)(VX-950);Vertex Pharmaceuticals之第二代HCV蛋白酶抑制劑VX-500及VX-813;Intermune/Roche之NS3/4A蛋白酶抑制劑ITMN-191/R-7227、波沙匹韋(boceprevir)、Schering-Plough之蛋白酶抑制劑SCH 503034、Medivir/Tibotec之HCV NS3/4A蛋白酶抑制劑TMC435/TMC435350、Achillion Pharmaceuticals之蛋白酶抑制劑ACH-1625、Achillion/Gilead之蛋白酶抑制劑ACH-806、Boehringer Ingelheim之蛋白酶抑制劑BI201335及BILN 2061、Schering-Plough之蛋白酶抑制劑SCH 900518/SP900518(那拉匹韋(narlaprevir))、Merck之蛋白酶抑制劑MK-7009、Bristol Myeres Squibb之蛋白酶抑制劑BMS-650032、BMS-790052及BMS-791325、Roche之蛋白酶抑制劑R7227、Phenomix之蛋白酶抑制劑PHX1766、Avila Therapeutics之蛋白酶抑制
劑AVL-181、膽綠素(biliverdin)、Roche Biosciences之蛋白酶抑制劑CTS-1027、Vertex之蛋白酶抑制劑VX985、Virochem/Vertex之蛋白酶抑制劑VCH-759及VCH-917、Idenix之蛋白酶抑制劑IDX-136及316、Abbott之蛋白酶抑制劑ABT-450、Virobay之蛋白酶抑制劑VBY 376;(3)整合酶抑制劑,包括例如:雷特格韋(raltegravir)ISENTRESS®)、依維拉韋(elvitegravir);(4)核苷類似物/核苷酸類似物抑制劑之組合療法,阿曲普(atripla)(泰諾福韋+恩曲他濱+依發韋侖)、卡貝滋(combivir)(拉米夫定+齊多夫定);(5)進入或融合抑制劑,包括例如:馬拉韋羅(maraviroc)、恩夫韋地(enfuvirtide)、多可沙諾(docosanol)、抗CD4抗體、抗gp120抗體、抗CCR5抗體、HCV NS5a拮抗劑:(a)Arrow Therapeutics之A-831、A-689及AZD 2836,(b)Bristol Myers Squibb之BMS-790052及BMS-824393,(c)Glaxo Smith Kline之GSK-625433,(d)NS4a拮抗劑ACH-1095;(5)成熟抑制劑,包括例如:貝韋立馬(bevirimat)及維韋克(vivecon);(6)病毒釋放抑制劑,包括例如:紮那米韋(zanamivir)(RELENZA®)、奧司他韋(oseltamivir)(TAMIFLU®)、阿比朵爾(arbidol);(7)免疫反應增強劑,包括例如干擾素-α,例如Biolex Therapeutics之BLX-883及BLX 883 CR,Nautilus Biotech之貝洛芬(belerofon),LG Life Sciences之長效IFN-α、IFN-αSR,Flamel Technologies之長效IFN-α2b CR及IFN-α2b XL,聚乙二醇化IFN-α(例如PEG-IFN-α-2a,PEGASYS®;PEG-IFN-α-2b,PEGINTRON®),IFN-a2b-人血清白蛋白融合蛋白(ALBUFERON®);干擾素-β(包括IFN-β-1b(BETASERON®))、干擾素-γ、干擾素-λ、聚乙二醇化干擾素-λ(例如ZymoGenetics/Novo Nordisk之PEG-rIL-29)、干擾素-ω/白血球II干擾素(例如Intarcia Therapeutics)、鐘樣受體7促效劑(包括Anadys Pharmaceuticals之咪喹莫特(imiquimod)、艾沙托立濱(isatoribine)及其前藥變異體(例如ANA-
975及ANA-971))、Implicit Bioscience之奧穀凡尼(oglufanide)(IM862、L-Glu-L-Trp-OH)及其脂質或醣基結合變異體、NOV-205(例如Molixan®,NovelosTherapeutics,Inc.之一種抗病毒肽)、Enzo Biochem之抗病毒EHC18、γ-D-麩胺醯基-L-色胺酸(例如SCV-07,SciClone Pharmaceuticals/Verta)、阿洛夫隆(aloferon)(例如阿洛夫隆-1-HGVSGHGQHGVHG、阿洛夫隆-2-GVSGHGQHGVHG)、Coley Pharmaceuticals/Actilon之TLR-9促效劑CPG 10101;(8)抗病毒協同增強劑,亦即雖然單獨時具有極小抗病毒性質或無抗病毒性質,但增進其他抗病毒劑之作用,例如氯奎寧(choroquine)、葡萄柚汁(grapefruit juice)、羥基尿素(hydroxyurea),來氟米特(leflunomide)、黴酚酸(mycophenolic acid)、白藜蘆醇(resveratrol)、利托那韋(ritonavi);以及其他抗病毒藥物,諸如三環癸胺(amantadine)、依度尿苷(edoxudine)、泛昔洛韋(famciclovir)(FAMVIR®)、噴昔洛韋(penciclovir)、膦甲酸鈉(fascarnet)、膦乙酸(fosfonet)、更昔洛韋(ganciclovir)(CYTOVENE®、CYMEVENE®、VITRASERT®)、嘉喜(gardasil)、伊巴他濱(ibacitabine)、異丙肌苷(imunovir)、嗎啉胍(moroxydine)、多吉美(nexavir)、帕拉米韋(peramivir)、普來可那利(pleconaril)、足葉草毒素(podophyllotoxin)、病毒唑(ribavirin)、金剛乙胺(rimantadine)、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)、阿糖腺苷(vidarabine)及干擾素增強劑,諸如Transition Therapeutics之EMZ702、組胺二鹽酸鹽(例如Ceplene®+IFN-α);及(9)雜項或未分類抗病毒劑,諸如:Kemin Pharmaceuticals之KPE-02003002(雙氫青蒿素(Artenimol))、Antipodean Pharmaceuticals之輔酶Q10抗氧化促效劑米托喹酮(mitoquinone)、I型α-葡萄糖苷酶抑制劑(例如Migenix Pharmaceuticals之塞而高斯
(celgosivir)MX-3253、栗樹精胺(castanospermine))、糖皮質激素拮抗劑(例如HCV IRES抑制劑、米非司酮(mifepristone)、VGX Pharmaceuticals之VGX-410C)、肝臟促效劑(例如Phynova Pharmaceuticals之PYN17)、衍生自傳統草本療法之抗病毒劑(例如Phynova Pharmaceuticals之PYN18)、卡斯蛋白酶抑制劑(caspase inhibitor)(例如LG Life Sciences之LB-84451、Pfizer之依莫瑞生(emricasan)PF-03491390/IDN-6556)、藉由阻止與親環蛋白A(cyclophilin A)結合來抑制病毒複製之環孢素類似物(例如Novartis之SDZ NIM 911、Debiopharm之Debio-025)。
術語「抗真菌劑」包括抑制或消除真菌生長、致病性及/或存活之任何分子。其包括例如(1)多烯抗真菌劑,諸如納他黴素(natamyin)、龜裂殺菌素(rimocidin)、菲律賓菌素(filipin)、製真菌素(nystatin)、兩性黴素B(Amphotericin B)、坎底辛(candicin);(2)咪唑類,諸如咪康唑(miconazole)、酮康唑(ketoconazole)(LOTRIMIN®)、益康唑(econazole)、聯苯苄唑(bifonazole)、布康唑(butoconazole)、芬替康唑(fenticonazole)、異康唑(isoconazole)、奧昔康唑(oxiconazole)、舍他康唑(sertaconazole)(ERTACZO®)、硫康唑(sulconazole)、噻康唑(tioconazole);(3)三唑類,諸如氟康唑(fluconazole)、伊曲康唑(itraconazole)、艾沙康唑(isavuconazole)、拉夫康唑(ravuconazole)、泊沙康唑(posaconazole)、伏立康唑(voriconazole)、特康唑(terconazole);(4)烯丙胺類,諸如特比萘芬(terbinafine)(LAMISIL®)、阿莫羅芬(amorolfine)、萘替芬(naftifine)(Naftin®)、布替萘芬(butenafine)(LOTRIMIN ULTRA®);(5)棘白菌素類(Echinocandins),諸如阿尼芬淨(anidulafungin)、卡泊芬淨(caspofungin)、米卡芬淨(micafungin)及具有抗真菌性質之其他物質,諸如苯甲酸、環吡酮(cicclopix)、氟胞嘧啶(flucytosine)、灰黃黴素
(griseofulvin)、甲基紫(gentian violet)、鹵普羅近(haloprogin)、托萘酯(tolnaftate)(TINACTIN®、DESENEX®、AFTATE®)、十一烯酸、茶樹油ISO 4730(茶樹精油,萜品烯-4-醇型)、香茅油、檸檬草、橙油、玫瑰草油、天竺薄荷油、檸檬桃金娘油、苦楝油、椰子油。
術語「抗原蟲劑」包括抑制或消除原蟲生物體之生長、致病性及/或存活之任何分子。抗原蟲劑之實例包括(1)抗瘧疾劑,例如奎寧(quinine)、奎寧麥克斯(quinimax)、奎尼丁(quinidine)、奎寧麥克斯、氯奎寧(ARALEN®)、脛氯奎寧(Hydroxycloroquine)(PLAQUENIL®)、阿莫地奎寧、乙胺嘧啶(pyrimethamine)(DARAPRIM®)、磺胺多辛(sulphadoxine)、氯胍(proguanil)、美爾奎寧(mefloquine)(LARIAM®)、鹵泛群(halofantrine)、伯胺奎(primaquine)、青蒿素(artemesinin)及其衍生物(例如蒿甲醚(artemether)、青蒿琥酯(artensunate)、雙氫青蒿素(dihydroartemisinin)、蒿乙醚(arteether))、克林黴素(clindamycin)及其組合;(2)蛋白酶抑制劑及藥物,苄硝唑(benznidaole)、布帕伐醌(buparvaquone)、卡巴胂(carbarsone)、氯碘羥喹(clioquinol)、雙硫侖(disulfiram)、依氟鳥胺酸(eflornithine)、依米丁(emetine)、呋喃唑酮(furazolidone)、葡甲胺銻酸鹽(meglumine antimoniate)、美拉胂醇(melarsoprol)、甲硝唑(metronidazole)(FLAGYL®)、米替福新(miltefosine)、硝呋替莫(nifurtimox)、硝唑尼特(nitazoxanide)、奧硝唑(ornidazole)、硫酸巴龍黴素(paromomycin sulfate)、噴他脒(pentamidine)、乙胺嘧啶(pyrimethamine)(DARAPRIM®)、塞克硝唑(secnidazole)、替硝唑(tinidazole)。
如本文所用之術語「疫苗」包括當接種至宿主中時誘導針對特異性病原體之保護性免疫的任何非病原性免疫原。疫苗可採用許多形式。疫苗可為與病原體共享重要抗原但本身不具病原性之完整生物體
(例如牛痘)。疫苗亦可藉由殺死(例如沙克小兒麻痹疫苗(Salk polio vaccine))或減毒(損失產生疾病之能力,例如沙賓小兒麻痹疫苗(Sabin polio vaccine))來製備。疫苗亦可由自病原生物體分離之經純化大分子製備。舉例而言,含有失活形式之可溶性細菌毒素之類毒素疫苗(例如破傷風及白喉症),其引起產生抗毒素抗體,但對完整細菌不具有免疫力。次單位疫苗(例如B型肝炎)僅含有自相關病原體分離之單一免疫原性蛋白質。半抗原結合疫苗使自相關病原體分離之某些碳水化合物或多肽抗原決定基附著於免疫原運載體(諸如破傷風類毒素)。此等策略基本上使用抗原決定基作為半抗原來誘導抗體產生,該等抗體接著識別天然病原體中之相同抗原決定基。然而,為使效果最佳,該等疫苗必須合併有B與T細胞抗原決定基,且T細胞抗原決定基必須經選擇以確保其可由宿主個體之免疫系統識別、由該免疫系統呈現且應答該免疫系統。
DNA疫苗利用宿主細胞溶解及表現肌內注射之編碼病原性蛋白質之DNA的能力。
可與抗PD-L1抗體組合用於本文所述之方法中的抗病毒疫苗之實例包括:Pevion Biotech.之HCV疫苗(病毒顆粒)、經設計以增進細胞(細胞毒性T淋巴細胞CD4+及CD8+)針對NS3、NS4及NS5B之免疫反應的Transgene viron之TG4040(MVA-HCV)、Inovio Biomedical之密碼子經優化之NS3/4a DNA疫苗CHRONVAC®、Novartis之HCV/CpG疫苗、Globeimmune之HCV疫苗GI-5005、Intercell之具有HCV CD4及CD8 T抗原決定基之合成肽與聚L-精胺酸組合之混合物IC41。
若以與佐劑之混合物形式投與,則可增強宿主對免疫原之反應。免疫佐劑以一或多種以下方式起作用:(1)延長免疫原留存時間,(2)增加免疫原之有效大小(且因此促進對巨噬細胞之吞噬及呈現),(3)刺激巨噬細胞或其他免疫細胞流入注射部位,或(4)促進局部
細胞激素產生及其他免疫活性。佐劑之實例包括:傅氏完全佐劑(CFA)、鋁鹽及分支桿菌衍生蛋白(諸如胞壁醯二肽或胞壁醯三肽)。
術語「抗體」包括單株抗體(包括具有免疫球蛋白Fc區之全長抗體)、具有多抗原決定基特異性之抗體組合物、多特異性抗體(例如雙特異性抗體、雙功能抗體及單鏈分子)以及抗體片段(例如Fab、F(ab')2及Fv)。本文中術語「免疫球蛋白」(Ig)可與「抗體」互換使用。
基本四鏈抗體單位為雜四聚醣蛋白,其由兩條相同之輕(L)鏈及兩條相同之重(H)鏈構成。IgM抗體由5個基本雜四聚體單位以及稱為J鏈之另一多肽組成,且含有10個抗原結合位點,而IgA抗體包含2-5個可與J鏈組合聚合形成多價裝配體(assemblage)之基本四鏈單位。在IgG之情況下,四鏈單位一般為約150,000道爾頓。各L鏈經由一個共價雙硫鍵與H鏈鍵聯,而視H鏈同型而定,兩條H鏈經由一或多個雙硫鍵彼此鍵聯。各H及L鏈亦具有規則間隔之鏈內雙硫橋。各H鏈在N末端具有可變域(VH),繼之以各α及γ鏈之三個恆定域(CH)及μ及ε同型之四個CH域。各L鏈在N末端具有可變域(VL),繼之以位於其另一端之恆定域。VL對準VH且CL對準重鏈之第一恆定域(CH1)。咸信特定胺基酸殘基在輕鏈與重鏈可變域之間形成界面。VH與VL一起配對形成單一抗原結合位點。關於不同種類抗體之結構及性質,參見例如Basic and Clinical Immunology,第8版,Daniel P.Stites,Abba I.Terr及Tristram G.Parslow(編),Appleton & Lange,Norwalk,Conn.,1994,第71頁及第6章。基於恆定域之胺基酸序列,任何脊椎動物物種之L鏈均可歸為稱為κ及λ之兩個明顯不同之類型中的一者中。視重鏈之恆定域(CH)之胺基酸序列而定,免疫球蛋白可歸為不同類別或同型中。免疫球蛋白有五種類別:IgA、IgD、IgE、IgG及IgM,其分別具有以α、δ、ε、γ及μ表示之重鏈。基於CH序列及功能之相對較小之差異,γ及α類別進一步細分成亞類,例如人類表現以下亞類:IgG1、IgG2A、
IgG2B、IgG3、IgG4、IgA1及IgA2。
「經分離」抗體為已自其產生環境(例如天然或重組)之組分中鑑別、分離及/或回收之抗體。較佳地,經分離多肽不與其產生環境之所有其他組分締合。其產生環境之污染組分(諸如由重組轉染細胞產生之污染組分)為通常將干擾抗體之研究、診斷或治療性用途之物質,且可包括酶、激素及其他蛋白質或非蛋白質溶質。在較佳實施例中,將多肽(1)純化至如藉由例如勞立(Lowry)方法所測定,95重量%以上之抗體,且在某些實施例中,純化至99重量%以上;(1)純化至藉由使用旋杯式序列分析儀足以獲得N末端或內部胺基酸序列之至少15個殘基的程度,或(3)純化至使用考馬斯藍(Coomassie blue)或較佳銀染在非還原或還原條件下由SDS-PAGE鑑定為均質(homogeneity)。由於抗體天然環境之至少一種組分將不存在,故經分離抗體包括原位(in situ)處於重組細胞內之抗體。然而,經分離多肽或抗體通常將由至少一個純化步驟來製備。
抗體之「可變區」或「可變域」係指抗體之重鏈或輕鏈之胺基末端域。重鏈及輕鏈之可變域可分別稱為「VH」及「VL」。此等域一般為抗體之最可變部分(相對於同一類別之其他抗體)且含有抗原結合位點。
術語「可變」係指抗體中可變域之某些區段在序列上廣泛不同。V域介導抗原結合且定義特定抗體對其特定抗原之特異性。然而,可變性並非均勻分布於整個可變域中。相反,其集中於輕鏈可變域與重鏈可變域中稱為高變區(HVR)之三個區段中。可變域之更高保守部分稱作構架區(FR)。天然重鏈及輕鏈之可變域各包含四個主要採用β-摺疊構型之FR區,該等FR區由三個HVR連接,該等HVR形成連接β-摺疊結構之環,且在一些情況下形成β-摺疊結構之一部分。各鏈中之HVR與另一鏈中之HVR藉由FR區緊密結合在一起,促使形成抗
體之抗原結合位點(參見Kabat等人,Sequences of Immunological Interest,第五版,National Institute of Health,Bethesda,MD(1991))。雖然恆定域並不直接參與抗體與抗原之結合,但展現各種效應功能,諸如使抗體參與抗體依賴性細胞毒性。
如本文所用之術語「單株抗體」係指自實質上均質之抗體群體所獲得之抗體,亦即,構成該群體之個別抗體除可微量存在之可能的天然存在之突變及/或轉譯後修飾(例如異構化、醯胺化)外相同。單株抗體針對單一抗原位點具有高特異性。與通常包括針對不同決定子(抗原決定基)之不同抗體的多株抗體製劑相反,各單株抗體針對抗原上之單一決定子。除其特異性以外,單株抗體之有利之處在於其藉由融合瘤培養合成,不受其他免疫球蛋白污染。修飾語「單株」指示如同獲自實質上均質之抗體群體之抗體特徵,且不應理解為需要由任何特定方法產生抗體。舉例而言,根據本發明欲使用之單株抗體可由多種技術製備,該等技術包括例如融合瘤方法(例如,Kohler及Milstein.,Nature,256:495-97(1975);Hongo等人,Hybridoma,14(3):253-260(1995);Harlow等人,Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,第2版,1988);Hammerling等人,Monoclonal Antibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981))、重組DNA方法(參見例如美國專利第4,816,567號)、噬菌體呈現技術(參見例如Clackson等人,Nature,352:624-628(1991);Marks等人,J.Mol.Biol.222:581-597(1992);Sidhu等人,J.Mol.Biol.338(2):299-310(2004);Lee等人,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);及Lee等人,J.Immunol.Methods 284(1-2):119-132(2004))及在動物中產生具有部分或所有編碼人類免疫球蛋白序列之人類免疫球蛋白基因座或基因之人類或人類樣抗體的技術(參見例如WO
1998/24893;WO 1996/34096;WO 1996/33735;WO 1991/10741;Jakobovits等人,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits等人,Nature 362:255-258(1993);Bruggemann等人,Year in Immunol.7:33(1993);美國專利第5,545,807號;第5,545,806號;第5,569,825號;第5,625,126號;第5,633,425號及第5,661,016號;Marks等人,Bio/Technology 10:779-783(1992);Lonberg等人,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild等人,Nature Biotechnol.14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996);及Lonberg及Huszar,Intern.Rev.Immunol.13:65-93(1995)。
術語「裸抗體」係指未與細胞毒性部分或放射性標記結合之抗體。
術語「全長抗體」、「完整抗體」及「全抗體」可互換使用,指與如抗體片段相對之大體上為完整形式的抗體。特定言之,全抗體包括具有包括Fc區之重鏈及輕鏈之抗體。恆定域可為天然序列恆定域(例如人類天然序列恆定域)或其胺基酸序列變異體。在一些情況下,完整抗體可具有一或多種效應功能。
「抗體片段」包含完整抗體之一部分,較佳為完整抗體之抗原結合區及/或可變區。抗體片段之實例包括Fab、Fab'、F(ab')2及Fv片段;雙功能抗體;線性抗體(參見美國專利5,641,870,實例2;Zapata等人,Protein Eng. 8(10):1057-1062[1995]);單鏈抗體分子及由抗體片段形成之多特異性抗體。木瓜蛋白酶消化抗體產生稱為「Fab」片段之兩個相同之抗原結合片段及殘餘「Fc」片段,該名稱反映容易地結晶之能力。Fab片段由整個L鏈以及H鏈之可變區之域(VH)及一條重鏈之第一恆定域(CH1)組成。各Fab片段對抗原結合而言為單價的,亦即其具有單一抗原結合位點。用胃蛋白酶處理抗體產生單一大F(ab')2
片段,其大致對應於具有不同抗原結合活性之兩個雙硫鍵鍵聯之Fab片段且仍能夠交聯抗原。Fab'片段與Fab片段之不同之處在於在包括一或多個來自抗體鉸鏈區之半胱胺酸的CH1域之羧基末端具有少量其他殘基。Fab'-SH在本文中為恆定域之半胱胺酸殘基帶有游離硫醇基之Fab'的名稱。最初F(ab')2抗體片段以其間具有鉸鏈半胱胺酸之Fab'片段對形式產生。亦已知抗體片段之其他化學偶合。
Fc片段包含經由雙硫鍵結合在一起之兩條H鏈之羧基末端部分。抗體之效應功能由Fc區中之序列決定,該區亦由某些類型細胞上所發現之Fc受體(FcR)識別。
「Fv」為含有完全抗原識別及結合位點之最小抗體片段。此片段由緊密非共價締合之一重鏈可變區之域與一輕鏈可變區之域之二聚體組成。此兩個域之摺疊產生6個高變環(H及L鏈各3個環),該等環提供胺基酸殘基供抗原結合且賦予抗原結合抗體之特異性。然而,甚至單一可變域(或僅包含三個對抗原具有特異性之HVR的Fv的一半)亦具有識別及結合抗原之能力,但親和力比整個結合位點低。
「單鏈Fv」亦縮寫為「sFv」或「scFv」,其為包含連接於單一多肽鏈中之VH及VL抗體域之抗體片段。較佳地,sFv多肽進一步包含VH與VL域之間使sFv能夠形成抗原結合所要之結構的多肽連接子。關於sFv之綜述,參見Pluckthun,The Pharmacology of Monoclonal Antibodies,第113卷,Rosenburg及Moore編,Springer-Verlag,New York,第269-315頁(1994)。
本發明抗體之「功能片段」包含完整抗體之一部分,一般包括完整抗體之抗原結合區或可變區或保留FcR結合能力或具有改良之FcR結合能力之抗體的Fc區。抗體片段之實例包括線性抗體、單鏈抗體分子及由抗體片段形成之多特異性抗體。
術語「雙功能抗體」係指藉由在VH與VL域之間用短連接子(約5-
10個殘基)構築sFv片段(參見先前段落)以致實現V域之鏈間配對而非鏈內配對,藉此產生二價片段(亦即具有兩個抗原結合位點之片段)所製備之小抗體片段。雙特異性雙功能抗體為具有兩個「交叉」sFv片段之雜二聚體,其中兩個抗體之VH及VL域存在於不同多肽鏈上。雙功能抗體更詳細描述於例如EP 404,097;WO 93/11161;Hollinger等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)中。
本文之單株抗體特定包括「嵌合」抗體(免疫球蛋白),其中重鏈及/或輕鏈的一部分與衍生自特定物種或屬於特定抗體類別或亞類之抗體中的相應序列相同或同源,而該(該等)鏈之其餘部分與衍生自另一物種或屬於另一抗體類別或亞類之抗體中的相應序列相同或同源;以及該等抗體之片段,只要其展現出所要的生物活性即可(美國專利第4,816,567號;Morrison等人,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。本文之相關嵌合抗體包括PRIMATIZED®抗體,其中抗體之抗原結合區係衍生自藉由例如用相關抗原使獼猴免疫所產生之抗體。如本文所用之「人類化抗體」為「嵌合抗體」之子集。
非人類(例如鼠類)抗體之「人類化」形式為含有衍生自非人類免疫球蛋白之最小序列的嵌合抗體。在一實施例中,人類化抗體為人類免疫球蛋白(接受者抗體),其中來自接受者之HVR(下文定義)的殘基經來自具有所要特異性、親和力及/或能力之非人類物種(供體抗體)(諸如小鼠、大鼠、兔或非人類靈長類動物)之HVR的殘基置換。在一些情況下,人類免疫球蛋白之構架(「FR」)殘基經相應非人類殘基置換。此外,人類化抗體可包含接受者抗體或供體抗體中未發現之殘基。可進行此等修飾以進一步改進抗體效能,諸如結合親和力。一般而言,人類化抗體將包含實質上所有至少一個且通常兩個可變域,其中所有或實質上所有高變環對應於非人類免疫球蛋白序列之高變環,且所有或實質上所有FR區為人類免疫球蛋白序列之FR區,但FR區可
包括一或多種改良抗體效能(諸如結合親和力、異構化作用、免疫原性等)之個別FR殘基取代。FR之H鏈中之此等胺基酸取代的數目通常不超過6,且在L鏈中不超過3。人類化抗體視情況亦將包含至少一部分免疫球蛋白恆定區(Fc),通常為人類免疫球蛋白之恆定區。關於更多詳情,參見例如Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-329(1988);及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。亦參見例如Vaswani及Hamilton,Ann.Allergy,Asthma & Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle及Gross,Curr.Op.Biotech.5:428-433(1994);及美國專利第6,982,321號及第7,087,409號。
「人類抗體」為具有對應於人類所產生之抗體之胺基酸序列的胺基酸序列的抗體及/或已使用如本文所揭示之用於製造人類抗體之技術中之任一種製成的抗體。人類抗體之此定義特定排除包含非人類抗原結合殘基之人類化抗體。可使用此項技術中已知之各種技術(包括噬菌體呈現文庫)產生人類抗體。Hoogenboom及Winter,J.Mol.Biol.,227:381(1991);Marks等人,J.Mol.Biol.,222:581(1991)。亦可用於製備人類單株抗體之方法為Cole等人,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,第77頁(1985);Boerner等人,J.Immunol.,147(1):86-95(1991)中所述之方法。亦參見van Dijk及van de Winkel,Curr.Opin.Pharmacol., 5:368-74(2001)。人類抗體可藉由向已經修飾以應答抗原攻擊產生該等抗體但內源性基因座已喪失能力之轉殖基因動物(例如經免疫異種小鼠)投與抗原來製備(關於XENOMOUSETM技術,參見例如美國專利第6,075,181號及第6,150,584號)。關於經由人類B細胞融合瘤技術產生之人類抗體,亦參見例如Li等人,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)。
術語「高變區」、「HVR」或「HV」在本文中使用時係指序列高
變且/或形成結構確定之環之抗體可變域的區。一般而言,抗體包含6個HVR;三個位於VH中(H1,H2、H3),且三個位於VL中(L1、L2,L3)。在天然抗體中,H3及L3在六個HVR中顯示最具多樣性,且咸信尤其H3在賦予抗體精細特異性方面發揮獨特作用。參見例如Xu等人,Immunity 13:37-45(2000);Johnson及Wu,Methods in Molecular Biology 248:1-25(Lo編,Human Press,Totowa,NJ,2003)。實際上,僅由重鏈組成之天然存在之駱駝抗體無輕鏈存在下亦具功能性且穩定。參見例如Hamers-Casterman等人,Nature 363:446-448(1993);Sheriff等人,Nature Struct.Biol. 3:733-736(1996)。
有許多HVR描繪在使用且其為本文中所涵蓋。Kabat互補決定區(CDR)係基於序列可變性且最常使用(Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。Chothia另外指出結構環之位置(Chothia及Lesk J.Mol.Biol. 196:901-917(1987))。AbM HVR表示Kabat HVR與Chothia結構環之間的折衷,且藉由Oxford Molecular之AbM抗體模型化軟體使用。「contact」HVR係基於對可用複雜晶體結構之分析。此等HVR中之每一者之殘基如下所說明。
HVR可包含如下「延長HVR」:VL中之24-36或24-34(L1)、46-56或50-56(L2)及89-97或89-96(L3);及VH中之26-35(H1)、50-65或49-65(H2)及93-102、94-102或95-102(H3)。可變域殘基係根據Kabat等人,同上關於此等定義中之每一者所述編號。
表述「如Kabat中編號之可變域殘基」或「如Kabat中編號之胺基酸位置」及其變化形式係指Kabat等人,同上中用於抗體彙編之重鏈可變域或輕鏈可變域的編號系統。使用此編號系統,實際的線性胺基酸序列可含有更少或額外的胺基酸,相當於縮短可變域之FR或HVR或在其中進行插入。舉例而言,重鏈可變域可包括H2之殘基52之後的單一胺基酸插入(根據Kabat之殘基52a)及重鏈FR殘基82之後的插入殘基(例如,根據Kabat之殘基82a、82b及82c等)。可藉由將既定抗體之序列同源區與「標準」Kabat編號序列比對來確定該抗體殘基的Kabat編號。
「構架」或「FR」殘基為除如本文所定義之HVR殘基以外的彼等可變域殘基。
「人類共同構架」或「受體人類構架」為在選擇人類免疫球蛋白VL或VH構架序列時表示最通常存在之胺基酸殘基的構架。一般而言,人類免疫球蛋白VL或VH序列係選自可變域序列之亞群。一般而言,序列之亞群為如Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中之亞群。對於VL,實例包括該亞群可為如Kabat等人,同上中之亞群κI、κII、κIII或κIV。另外,對於VH,亞群可為如Kabat等人,同上中之亞群I、亞群II或亞群
III。或者,人類共同構架可衍生自諸如當人類構架殘基係基於與供體構架之同源性藉由比對供體構架序列與許多各種人類構架序列而選擇時具有特定殘基之以上亞群。「衍生自」人類免疫球蛋白構架或人類共同構架之受體人類構架可包含其相同胺基酸序列或其可含有預先存在之胺基酸序列變化。在一些實施例中,預先存在之胺基酸變化之數目為10個或更少、9個或更少、8個或更少、7個或更少、6個或更少、5個或更少、4個或更少、3個或更少或2個或更少。
「VH亞群III共同構架」包含獲自Kabat等人,同上之可變重鏈亞群III之胺基酸序列中的共同序列。在一實施例中,VH亞群III共同構架胺基酸序列包含以下每一序列之至少一部分或全部:EVQLVESGGGLVQPGGSLRLSCAAS(HC-FR1)(SEQ ID NO:4)、WVRQAPGKGLEWV(HC-FR2)(SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(HC-FR3,SEQ ID NO:6)、WGQGTLVTVSA(HC-FR4)(SEQ ID NO:7)。
「VL κI共同構架」包含獲自Kabat等人,同上之可變輕鏈κ亞群I之胺基酸序列中的共同序列。在一實施例中,VH亞群I共同構架胺基酸序列包含以下每一序列之至少一部分或全部:DIQMTQSPSSLSASVGDRVTITC(LC-FR1)(SEQ ID NO:11)、WYQQKPGKAPKLLIY(LC-FR2)(SEQ ID NO:12)、GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(LC-FR3)(SEQ ID NO:13)、FGQGTKVEIKR(LC-FR4)(SEQ ID NO:14)。
指定位置(例如,Fc區域之指定位置)之「胺基酸修飾」係指指定殘基之取代或缺失或至少一個胺基酸殘基鄰接指定殘基插入。「鄰接」指定殘基插入意謂在其一至兩個殘基範圍內插入。插入可在指定殘基之N末端或C末端。本文中之較佳胺基酸修飾為取代。
「親和力成熟」抗體為在其一或多個HVR中具有一或多處可使
得抗體對抗原之親和力改良之變化的抗體(與不具有彼等變化之親本抗體相比)。在一實施例中,親和力成熟抗體對標靶抗原具有奈莫耳(nanomolar)或甚至皮莫耳(picomolar)親和力。親和力成熟抗體由此項技術中已知之程序產生。舉例而言,Marks等人,Bio/Technology 10:779-783(1992)描述藉由VH及VL域改組(shuffling)達成之親和力成熟。HVR及/或構架殘基之隨機突變誘發例如描述於Barbas等人,Proc Nat.Acad.Sci.USA 91:3809-3813(1994);Schier等人,Gene 169:147-155(1995);Yelton等人,J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-9(1995);及Hawkins等人,J.Mol.Biol.226:889-896(1992)。
如本文所用之術語「特異性結合」或「具有特異性」係指諸如標靶與抗體之間的結合之可量測且可重現之相互作用,其在包括生物分子之分子之異質群體存在下確定標靶之存在。舉例而言,特異性結合標靶(可為抗原決定基)之抗體為與結合其他標靶相比以較大親和力(affinity、avidity)、更容易及/或以更長持續時間結合此標靶之抗體。在一實施例中,如例如放射性免疫檢定(RIA)所量測,抗體與無關標靶結合之程度為抗體與該標靶之結合之約10%以下。在某些實施例中,特異性結合標靶之抗體的解離常數(Kd)1μM、100nM、10nM、1nM或0.1nM。在某些實施例中,抗體特異性結合在來自不同物種之蛋白質中為保守的蛋白質上之抗原決定基。在另一實施例中,特異性結合可包括(但不必需)排他性結合。
「阻斷」抗體或「拮抗」抗體為抑制或降低所結合之抗原之生物活性的抗體。在某些實施例中,阻斷抗體或拮抗抗體實質上或完全抑制抗原之生物活性。本發明抗PD-L1抗體阻斷經由PD-1之信號傳導以便使T細胞之功能反應自功能障礙狀態恢復至抗原刺激。
「促效」或活化抗體為增強或引發所結合之抗原之信號傳導的
抗體。在一些實施例中,在無天然配位體存在下,促效抗體引起或活化信號傳導。
術語「固相」描述本發明抗體可黏著之非水性基質。本文中所涵蓋之固相之實例包括部分或完全由玻璃(例如受控微孔玻璃)、多醣(例如瓊脂糖)、聚丙烯醯胺、聚苯乙烯、聚乙烯醇及聚矽氧形成之固相。在某些實施例中,視上下文而定,固相可包含檢定板之孔;在其他實施例中,其為純化管柱(例如親和層析管柱)。此術語亦包括離散粒子之不連續固相,諸如美國專利第4,275,149號中所述之固相。
「抗體效應功能」係指彼等可歸功於抗體之Fc區(天然序列Fc區或胺基酸序列變異Fc區)之生物活性,且隨抗體同型而變化。抗體效應功能之實例包括:C1q結合及補體依賴性細胞毒性、Fc受體結合、抗體依賴性細胞介導之細胞毒性(ADCC)、吞噬作用、細胞表面受體(例如B細胞受體)調降及B細胞活化。「降低或最小化」抗體效應功能意謂比野生型或未經修飾之抗體減少至少50%(或者60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)。抗體效應功能之測定可由一般熟習此項技術者容易地測定及量測。在一較佳實施例中,補體結合、補體依賴性細胞毒性及抗體依賴性細胞毒性之抗體效應功能受到影響。在本發明之某些實施例中,經由消除糖基化之恆定區中之突變(例如「無效應突變(effector-less mutation)」)消除效應功能。在一態樣中,無效應突變為CH2區中之N297A或DANA突變(D265A+N297A)。Shields等人,J.Biol.Chem. 276(9):6591-6604(2001)。或者,導致效應功能降低或消除之其他突變包括:K322A及L234A/L235A(LALA)。或者,可經由諸如表現於不糖基化或產生對促進效應功能無效或效果較差之改變之糖基化模式之宿主細胞(例如大腸桿菌)中的產生技術來降低或消除效應功能(例如Shinkawa等人,J.Biol.Chem. 278(5):3466-3473(2003))。
「抗體依賴性細胞介導之細胞毒性」或ADCC係指一種細胞毒性形式,其中所分泌之結合於存在於某些細胞毒性細胞(例如天然殺傷(NK)細胞、嗜中性白血球及巨噬細胞)上之Fc受體(FcR)的Ig使得此等細胞毒效應細胞能夠與帶有抗原之標靶細胞特異性結合且隨後以細胞毒素殺傷該標靶細胞。該等抗體「武裝」細胞毒性細胞且為利用此機制殺死標靶細胞所需。介導ADCC之初級細胞NK細胞僅表現FcγRIII,而單核細胞表現FcγRI、FcγRII及FcγRIII。Fc在造血細胞上之表現概述於Ravetch及Kinet,Annu.Rev.Immunol. 9:457-92(1991)之第464頁之表3中。為評估相關分子之ADCC活性,可執行活體外ADCC檢定,諸如美國專利第5,500,362號或第5,821,337號中所述之檢定。適用於該等檢定之效應細胞包括周邊血液單核細胞(PBMC)及自然殺傷(NK)細胞。或者或另外,可例如在諸如Clynes等人,PNAS USA 95:652-656(1998)中所揭示之動物模型中活體內評估相關分子之ADCC活性。
除非本文另有指示,否則免疫球蛋白重鏈中之殘基編號為如Kabat等人,同上中之EU索引編號。「如Kabat中之EU索引」係指人類IgG1 EU抗體之殘基編號。
本文中之術語「Fc區」用以定義免疫球蛋白重鏈之C末端區,包括天然序列Fc區及變異Fc區。儘管免疫球蛋白重鏈之Fc區之邊界可變化,但人類IgG重鏈Fc區通常定義為自位置Cys226處之胺基酸殘基或自Pro230至其羧基末端的一段。可例如在抗體產生或純化期間或藉由重組工程改造編碼抗體重鏈之核酸來移除Fc區之C末端離胺酸(根據EU編號系統為殘基447)。因此,完整抗體之組合物可包含已移除所有K447殘基之抗體群體、未移除任何K447殘基之抗體群體及具有有及無K447殘基之抗體之混合物的抗體群體。適用於本發明抗體之天然序列Fc區包括人類IgG1、IgG2(IgG2A、IgG2B)、IgG3及IgG4。
「Fc受體」或「FcR」描述結合抗體Fc區之受體。較佳FcR為天然序列人類FcR。此外,較佳FcR為結合IgG抗體(γ受體)且包括FcγRI、FcγRII及FcγRIII亞類之受體(包括此等受體之對偶基因變異體及替代性剪接形式)的FcR,FcγRII受體包括FcγRIIA(「活化受體」)及FcγRIIB(「抑制受體」),其具有主要其細胞質域不同之類似胺基酸序列。活化受體FcγRIIA在其細胞質域中含有基於免疫受體酪胺酸之活化基元(ITAM)。抑制受體FcγRIIB在其細胞質域中含有基於免疫受體酪胺酸之抑制基元(ITIM)。(參見M.Daëron,Annu.Rev.Immunol. 15:203-234(1997))。FcR綜述於Ravetch及Kinet,Annu.Rev.Immunol. 9:457-92(1991);Capel等人,Immunomethods 4:25-34(1994);及de Haas等人,J.Lab.Clin.Med. 126:330-41(1995)中。本文之術語「FcR」涵蓋其他FcR,包括有待將來鑑別之FcR。
術語「Fc受體」或「FcR」亦包括新生兒受體FcRn,其負責將母體IgG轉移至胎兒。Guyer等人,J.Immunol. 117:587(1976)及Kim等人,J.Immunol. 24:249(1994)。已知量測與FcRn之結合之方法(參見例如Ghetie及Ward,Immunol.Today 18:(12):592-8(1997);Ghetie等人,Nature Biotechnology 15(7):637-40(1997);Hinton等人,J.Biol.Chem. 279(8):6213-6(2004);WO 2004/92219(Hinton等人))。可例如在表現人類FcRn之轉殖基因小鼠或經轉染人類細胞株中,或在投與具有變異Fc區之多肽的靈長類動物中,檢定活體內與FcRn之結合及人類FcRn高親和力結合多肽之血清半衰期。WO 2004/42072(Presta)描述與FcR之結合提高或降低之抗體變異體。亦參見例如Shields等人,J.Biol.Chem. 9(2):6591-6604(2001)。
「效應細胞」為表現一或多個FcR且執行效應功能之白血球。在一態樣中,效應細胞至少表現FcγRIII且執行ADCC效應功能。介導ADCC之人類白血球之實例包括周圍血液單核細胞(PBMC)、天然殺傷
(NK)細胞、單核細胞、細胞毒性T細胞及嗜中性白血球。效應細胞可自例如血液之天然來源分離。效應細胞一般為與效應期相關之淋巴細胞,且用以產生細胞激素(輔助T細胞)、殺死受病原體感染之細胞(細胞毒性T細胞)或分泌抗體(分化B細胞)。
「補體依賴性細胞毒性」或「CDC」係指在補體存在下標靶細胞之溶解。藉由使補體系統之第一組分(C1q)結合至與其同源抗原結合之抗體(屬於適當亞類)引發典型補體路徑之活化。為評估補體活化,可執行CDC檢定,例如如Gazzano-Santoro等人,J.Immunol.Methods 202:163(1996)中所述。具有改變之Fc區胺基酸序列及增強或降低之C1q結合能力的抗體變異體描述於美國專利第6,194,551B1號及WO99/51642中。彼等專利公開案之內容特別地以引用的方式併入本文中。亦參見Idusogie等人,J.Immunol.164:4178-4184(2000)。
IgG中之N糖基化位點位於CH2域中之Asn297處。本發明亦提供具有效應功能降低或無效應功能之Fc區的結合抗原之人類化抗體之組合物。可實現此舉之一種方式為A297N取代,先前已展示其消除抗CD20抗體中之補體結合及效應功能(「無效應Fc突變」)。Idusgie等人,同上。由於此突變,在諸如CHO之哺乳動物細胞中產生含有此Fc突變之本發明抗PD-L1抗體無任何糖基化,且此又產生降低的或最小效應功能。或者,可在無CH2取代下藉由表現於諸如大腸桿菌之非哺乳動物細胞中消除抗體效應功能。
「結合親和力」一般係指分子(例如抗體)之單一結合位點與其結合搭配物(例如抗原)間之非共價相互作用的總強度。除非另作指示,否則如本文所用之「結合親和力」係指反映結合對(例如抗體與抗原)成員之間1:1相互作用之固有結合親和力。分子X對其搭配物Y之親和力一般可由解離常數(Kd)表示。親和力可由此項技術中已知之常用方法(包括本文所述之彼等方法)量測。低親和力抗體一般緩慢地結合抗
原且傾向於容易地解離,而高親和力抗體一般較快地結合抗原且傾向於長時間保持結合。此項技術中已知多種量測結合親和力之方法,該等方法中之任一者皆可用於達成本發明之目的。量測結合親和力之具體說明性及例示性實施例描述於下文中。
在一實施例中,由放射性標記抗原結合檢定(RIA)量測本發明之「Kd」或「Kd值」,該檢定用抗體之Fab形式與抗原分子如以下檢定所述執行:藉由在一系列用於滴定之未標記抗原存在下以最低濃度之經(125I)標記抗原平衡Fab、接著以塗有抗Fab抗體之板捕捉結合抗原來量測Fab對抗原之溶液結合親和力(Chen等人,(1999)J.Mol Biol 293:865-881)。為建立檢定條件,將微量滴定板(Dynex)以50mM碳酸鈉(pH 9.6)中之5μg/ml之捕捉抗Fab抗體(Cappel Labs)塗布隔夜,且隨後在室溫下(約23℃)以2%(w/v)牛血清白蛋白之PBS溶液阻斷2至5小時。在非吸附性板(Nunc #269620)中,將100pM或26pM[125I]抗原與相關Fab之連續稀釋液混合(與抗VEGF抗體Fab-12之評估一致,Presta等人,(1997)Cancer Res.57:4593-4599)。接著培育相關Fab隔夜;然而,培育可持續一段較長之時間(例如65小時)以確保達到平衡。此後,將混合物轉移至捕捉板中,在室溫下培育1小時。接著移除溶液且用0.1% Tween-20之PBS溶液洗滌板8次。當乾燥板時,每孔添加150μl閃爍體(MicroScint-20;Packard),且在Topcount γ計數器(Packard)上對板計數10分鐘。選擇提供小於或等於20%最大結合之各Fab濃度用於競爭性結合檢定。
根據另一實施例,使用表面電漿共振檢定,使用BIACORE®-2000或BIACORE®-3000儀器(BIAcore,Inc.,Piscataway,NJ),在25℃下,以約10個反應單位(RU)之固定抗原CM5晶片量測Kd。簡言之,根據供應商之說明書用N-乙基-N'-(3-二甲基胺基丙基)-碳化二亞胺鹽酸鹽(EDC)及N-羥基丁二醯亞胺(NHS)使羧甲基化葡聚糖生物感測器
晶片(CM5,BIAcore Inc.)活化。用10mM乙酸鈉(pH 4.8)稀釋抗原至5微克/毫升(約0.2μM),之後以5微升/分鐘之流速注射,以獲得約10個反應單位(RU)之偶合蛋白。注射抗原後,注射1M乙醇胺以阻斷未反應基團。為進行動力學量測,在25℃下以約25μL/min之流速注射Fab於有0.05% TWEEN 20TM界面活性劑(PBST)之PBS中之兩倍連續稀釋液(0.78nM至500nM)。使用簡單的一對一朗繆爾結合模型(BIAcore®評估軟體3.2版)藉由同時擬合締合及解離感測器圖譜計算締合速率(kon)及解離速率(Koff)。以比率koff/kon計算平衡解離常數(kd)。參見例如Chen等人,J.Mol.Biol.293:865-881(1999)。若藉由以上表面電漿共振檢定測定時,締合速率超過106 M-1 S-1,則締合速率可使用螢光淬滅技術量測,該技術係如分光計(諸如具有攪拌式光析管之止流裝備型分光光度計(Aviv Instruments)或8000-系列SLM-AMINCOTM分光光度計(ThermoSpectronic))中所量測,在遞增濃度之抗原存在下,在25℃下量測PBS(pH 7.2)中之20nM抗抗原抗體(Fab形式)之螢光發射強度(激發=295nm;發射=340nm,16nm帶通)之增或減。
本發明之「締合速率」或「kon」亦可如上所述在25℃下,使用BIACORE®-2000或BIACORE®-3000系統(BIAcore,Inc.,Piscataway,NJ),以約10個反應單位(RU)之固定抗原CM5晶片測定。簡言之,根據供應商之說明書用N-乙基-N'-(3-二甲胺基丙基)-碳化二亞胺鹽酸鹽(ECD)及N-羥基丁二醯亞胺(NHS)使羧甲基化葡聚糖生物感測器晶片(CM5,BIAcore Inc.)活化。用10mM乙酸鈉(pH 4.8)稀釋抗原至5mg/m1(約0.2mM),之後以5ml/min之流速注射以獲得約10個反應單位(RU)之偶合蛋白。注射抗原後,添加1M乙醇胺以阻斷未反應基團。為進行動力學量測,在25℃下以約25ul/min之流速注射Fab於有0.05% Tween 20(PBST)之PBS中之兩倍連續稀釋液(0.78nM至500nM)。使用簡單的一對一朗繆爾結合模型(BIAcore評估軟體3.2版)藉
由同時擬合締合及解離感測器圖譜計算締合速率(kon)及離解速率(koff)。以比率koff/kon計算平衡解離常數(kd)。參見例如Chen,Y.,等人,(1999)J.Mol Biol 293:865-881。然而,若由上述表面電漿共振檢定測定時,締合速率超過106 M-1 S-1,則締合速率較佳使用螢光淬滅技術測定,該技術係如分光計(諸如具有攪拌式光析管之止流裝備型分光光度計(Aviv Instruments)或8000-系列SLM-Aminco分光光度計(ThermoSpectronic))中所量測,在遞增濃度之抗原存在下,在25℃下量測PBS(pH 7.2)中之20nM抗抗原抗體(Fab形式)之螢光發射強度(激發=295nm;發射=340nm,16nm帶通)之增或減。
如本文中所用之短語「實質上減少」或「實質上不同」表示兩個數值之間的差異足夠大(通常,一數值與一分子相關而另一數值與參考/對比分子相關),以致熟習該項技術者認為兩個值之間的差異在該等值(例如Kd值)所量度之生物學特徵之範圍內具有統計顯著性。該兩個數值之間的差異作為參考/對比分子之值的函數例如大於約10%、大於約20%、大於約30%、大於約40%及/或大於約50%。
如本文所用之術語「實質上類似」或「實質上相同」表示兩個數值之間具有足夠高之類似性(例如,一數值與本發明抗體相關而另一數值與參考/對比抗體相關),以致熟習此項技術者認為兩個值之間的差異在該等值(例如Kd值)所量度之生物學特徵之範圍內具有極小或不具有生物及/或統計顯著性。該兩個數值之間的差異作為參考/比較值的函數例如小於約50%、小於約40%、小於約30%、小於約20%及/或小於約10%。
肽、多肽或抗體序列之「胺基酸序列一致性百分比(%)」及「同源性」係定義為:在比對序列及(若需要)引入缺口以獲得最大序列一致性百分比,且不將任何保守性取代視為序列一致性之一部分之後,候選序列中與特定肽或多肽序列中胺基酸殘基相同之胺基酸殘基的百
分比。為測定胺基酸序列一致性百分比而進行之比對可以此項技術中熟知之多種方式實現,例如使用公用電腦軟體,諸如BLAST、BLAST-2、ALIGN或MEGALIGNTM(DNASTAR)軟體。熟習此項技術者可確定用於量測比對之適當參數,包括為獲得與所比較序列全長範圍內之最大比對所需的任何算法。然而,出於本文之目的,使用Genentech,Inc.設計之序列比較電腦程式ALIGN-2產生胺基酸序列一致性百分比值。ALIGN-2之源代碼已以使用者文件(user documentation)於美國版權局(U.S.Copyright Office,Washington D.C.,20559)中申請,其中其以美國版權註冊號TXU510087註冊。ALIGN-2程式可自Genentech,Inc.,South San Francisco,California公開獲得。ALIGN-2程式應編譯以用於UNIX操作系統,較佳數位UNIX V4.0D中。所有序列比較參數由ALIGN-2程式設定且不改變。
在使用ALIGN-2進行胺基酸序列比較之情況下,既定胺基酸序列A與既定胺基酸序列B之胺基酸序列一致性百分比(或者其可表述成與既定胺基酸序列B具有或包含某胺基酸序列一致性百分比之既定胺基酸序列A)如下計算:100乘以分數X/Y
其中X為由序列比對程式ALIGN-2在該程式之A及B比對中評分為一致匹配的胺基酸殘基之數目,且其中Y為B中胺基酸殘基之總數。應瞭解,若胺基酸序列A之長度不同於胺基酸序列B之長度,則A對B之胺基酸序列一致性百分比將不等於B對A之胺基酸序列一致性百分比。
除非另外明確規定,否則本文所用之所有胺基酸序列一致性百分比值係如先前段落使用ALIGN-2電腦程式所述獲得。
編碼本文之抗體之「經分離」核酸分子為經鑑別且與在該核酸之產生環境中通常與其締合之至少一種污染核酸分子分離的核酸分
子。較佳地,經分離核酸不與與產生環境相關之所有組分締合。編碼本文之多肽及抗體之經分離核酸分子呈除自然界中所發現之形式或設定以外之形式。因此,經分離核酸分子不同於編碼天然存在於細胞中之本文之多肽及抗體的核酸。
術語「控制序列」係指在特定宿主生物體內表現可操作連接之編碼序列所需的DNA序列。適用於原核生物之控制序列例如包括啟動子、視情況存在之操縱子序列(operator sequence)及核糖體結合位點。已知真核細胞利用啟動子、聚腺苷酸化信號及強化子。
當核酸置於與另一核酸序列之功能關係中時,其係經「可操作連接」。舉例而言,若前序列或分泌性前導序列之DNA表現為參與多肽分泌之前體蛋白,則其與該多肽之DNA可操作連接;若啟動子或強化子影響編碼序列之轉錄,則其與該序列可操作連接;或若核糖體結合位點經定位以有利於轉譯,則其與編碼序列可操作連接。一般而言,「可操作連接」意謂所連接之DNA序列相鄰且在分泌性前導序列之情況下為相鄰的且在閱讀相(reading phase)中。然而,強化子不必為相鄰的。連接係藉由在適宜限制性位點處連接來實現。若該等位點不存在,則根據習知實踐使用合成寡核苷酸接附子或連接子。
術語「經抗原決定基標記」在本文中使用時係指包含與「標籤多肽」融合之本文所述之多肽或抗體的嵌合多肽。標籤多肽具有足夠的殘基來提供產生抗體時可針對之抗原決定基,而其足夠短使得其不干擾其所融合之多肽的活性。標籤多肽較佳亦相當獨特以便使抗體實質上不與其他抗原決定基交叉反應。適合之標籤多肽一般具有至少6個胺基酸殘基,且通常介於約8個與50個胺基酸殘基之間(較佳介於約10個與20個胺基酸殘基之間)。
如本文所用之術語「免疫黏附素」表示將異源蛋白(「黏附素」)之結合特異性與免疫球蛋白恆定域之效應功能組合的抗體樣分子。在
結構上,免疫黏附素包含具有所要結合特異性(其不為抗體之抗原識別及結合位點,亦即「異源」)之胺基酸序列與免疫球蛋白恆定域序列的融合體。免疫黏附素分子之黏附素部分通常為至少包含受體或配位體之結合位點之相鄰胺基酸序列。免疫黏附素中之免疫球蛋白恆定域序列可自任何免疫球蛋白獲得,諸如IgG-1、IgG-2(包括IgG2A及IgG2B)、IgG-3或IgG-4亞型、IgA(包括IgA-1及IgA-2)、IgE、IgD或IgM。Ig融合體較佳包括用本文所述之多肽或抗體域替代Ig分子內之至少一個可變區。在一尤佳實施例中,免疫球蛋白融合體包括IgG1分子之鉸鏈區、CH2區及CH3區,或鉸鏈區、CHI區、CH2區及CH3區。關於免疫球蛋白融合體之產生,亦參見1995年6月27日頒布之美國專利第5,428,130號。舉例而言,適用作適用於本文之組合療法之第二藥劑之免疫黏附素包括包含PD-L1或PD-L2之細胞外或PD-1結合部分或反之與免疫球蛋白序列之恆定域融合之多肽。
「融合蛋白」及「融合多肽」係指具有共價連接在一起之兩部分的多肽,其中每一部分為具有不同性質之多肽。該性質可為生物性質,諸如活體外或活體內活性。該性質亦可為簡單的化學或物理性質,諸如與標靶分子結合、催化反應等。兩部分可經由單一肽鍵直接鍵聯或經由肽連接子(將位於閱讀框架中)相互鍵聯。
「穩定」調配物為儲存後蛋白質基本上保持其物理及化學穩定性及完整性之調配物。此項技術中可利用各種量測蛋白質穩定性之分析技術且該等技術綜述於Peptide and Protein Drug Delivery,247-301,Vincent Lee編,Marcel Dekker,Inc.,New York,New York,Pubs.(1991)及Jones,A.Adv.Drug Delivery Rev. 10:29-90(1993)中。可在選定溫度下量測一段選定時期的穩定性。對於快速篩檢,可將調配物保持在40℃下2週至1個月,此時量測穩定性。在將調配物儲存於2-8℃下之情況下,調配物一般在30℃或40℃下應穩定至少1個月及/或在2-
8℃下應穩定至少2年。在調配物儲存於30℃之情況下,調配物一般在30℃下應穩定至少2年及/或在40℃下應穩定至少6個月。舉例而言,儲存期間之聚集程度可用作蛋白質穩定性之指示。因此,「穩定」調配物可為在調配物中約10%以下且較佳約5%以下之蛋白質呈現聚集體者。在其他實施例中,可測定調配物儲存期間聚集體形成之任何增加。
「復原」調配物為已藉由將冷凍乾燥蛋白質或抗體調配物溶解於稀釋劑中以致蛋白質完全分散所製備之調配物。復水調配物適用於投與(例如皮下投與)經相關蛋白質治療之患者,且在本發明之某些實施例中,可為適用於非經腸或靜脈內投與之調配物。
「等張」調配物為與人類血液具有基本相同之滲透壓的調配物。等張調配物一般具有約250至350mOsm之滲透壓。術語「低張」描述滲透壓低於人體血液之滲透壓的調配物。相應地,術語「高張」係用於描述滲透壓高於人體血液之滲透壓的調配物。等張性可使用例如蒸氣壓或冰凍型滲壓計來量測。由於本發明調配物中添加鹽及/或緩衝液,故其為高張的。
如本文所用之「載劑」包括在所採用之劑量及濃度下,對暴露於其中之細胞或哺乳動物無毒之醫藥學上可接受之載劑、賦形劑或穩定劑。生理學上可接受之載劑一般為pH緩衝水溶液。生理學上可接受之載劑之實例包括:緩衝液,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸;低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖醇,諸如甘露糖醇或山梨糖醇;成鹽相對離子,諸如鈉;及/或非離子型界面活性劑,諸如TWEENTM、聚乙
二醇(PEG)及PLURONICSTM。
「包裝插頁」係指通常包括於藥劑之商業包裝中之說明書,其含有關於使用該等藥劑之適應症、用法、劑量、投藥、禁忌、與所包裝產品組合之其他藥劑及/或注意事項等資訊。
「醫藥學上可接受之酸」包括無機酸及有機酸,該等酸在其調配濃度及方式下無毒。舉例而言,適合之無機酸包括鹽酸、過氯酸、氫溴酸、氫碘酸、硝酸、硫酸、磺酸、亞磺酸,對胺基苯磺酸、磷酸、碳酸等。適合之有機酸包括直鏈及分支鏈烷基、芳族、環狀、環脂族、芳基脂族、雜環、飽和、不飽和的單羧酸、二羧酸及三羧酸,包括例如甲酸、乙酸、2-羥基乙酸、三氟乙酸、苯乙酸、三甲基乙酸、第三丁基乙酸、鄰胺基苯甲酸、丙酸、2-羥基丙酸、2-側氧基丙酸、丙二酸(propandioic)、環戊烷丙酸、環戊烷丙酸、3-苯基丙酸、丁酸、丁二酸(butandioic)、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、2-乙醯氧基-苯甲酸、抗壞血酸、肉桂酸、月桂基硫酸、硬脂酸、黏康酸、杏仁酸、丁二酸、亞甲基雙羥萘酸(embonic)、反丁烯二酸、蘋果酸、順丁烯二酸、羥基順丁烯二酸、丙二酸(malonic)、乳酸、檸檬酸、酒石酸、乙醇酸、甘醇酸、葡萄糖酸、丙酮酸、乙醛酸、草酸、甲磺酸、丁二酸、水楊酸、鄰苯二甲酸、雙羥萘酸(palmoic)、棕櫚酸(palmeic)、硫氰酸、甲烷磺酸、乙烷磺酸、1,2-乙烷二磺酸、2-羥基乙烷磺酸、苯磺酸、4-氯苯磺酸、萘-2-磺酸、對甲苯磺酸、樟腦磺酸、4-甲基二環[2.2.2]-辛-2-烯-1-甲酸、葡糖庚酸、4,4'-亞甲基雙-3-(羥基-2-烯-1-甲酸)、羥基萘甲酸。
「醫藥學上可接受之鹼」包括無機鹼及有機鹼,該等鹼在其調配濃度及方式下無毒。舉例而言,適合之鹼包括彼等由以下形成之鹼:無機鹼形成金屬,諸如鋰、鈉、鉀、鎂、鈣、銨、鐵、鋅、銅、錳、鋁;N-甲基葡萄胺;嗎啉;哌啶及有機無毒鹼,包括一級胺、二
級胺及三級胺、經取代之胺、環胺及鹼離子交換樹脂〔例如N(R')4 +(其中R'獨立地為H或C1-4烷基,例如銨、Tris)〕,例如異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺,2-二乙胺基乙醇、緩血酸胺、二環己胺、離胺酸、精胺酸、組胺酸、咖啡鹼、普魯卡因(procaine)、海卓胺(hydrabamine)、膽鹼、甜菜鹼、乙二胺、葡糖胺、甲基葡萄胺、可可豆鹼、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺樹脂及其類似鹼。尤佳有機無毒鹼為異丙胺、二乙胺、乙醇胺、緩血酸胺、二環己胺、膽鹼及咖啡鹼。本發明可使用之其他醫藥學上可接受之酸及鹼包括彼等衍生自例如組胺酸、甘胺酸、苯丙胺酸、天冬胺酸、麩胺酸、離胺酸及天冬醯胺之胺基酸之酸及鹼。
「醫藥學上可接受」之緩衝液及鹽包括彼等衍生自上述酸及鹼之酸加成鹽與鹼加成鹽之緩衝液及鹽。特定緩衝液及/或鹽包括組胺酸、丁二酸鹽及乙酸鹽。
「醫藥學上可接受之糖」為當與相關蛋白質組合時儲存後顯著阻止或降低蛋白質之化學及/或物理不穩定性之分子。當意欲將調配物冷凍乾燥且接著復原時,「醫藥學上可接受之糖」亦可稱為「冷凍乾燥保護劑」。例示性糖及其相應糖醇包括:胺基酸,諸如麩胺酸一鈉或組胺酸;甲基胺,諸如甜菜鹼;感膠離子鹽,諸如硫酸鎂;多元醇,諸如三元或更高分子量糖醇,例如丙三醇、葡聚糖、赤藻糖醇、甘油、阿糖醇、木糖醇、山梨糖醇及甘露糖醇;丙二醇;聚乙二醇;PLURONICS®;及其組合。其他例示性冷凍乾燥保護劑包括丙三醇;及明膠;及糖類,蜜二糖、松三糖、棉子糖、甘露三糖及水蘇糖。還原糖之實例包括葡萄糖、麥芽糖、乳糖、麥芽酮糖、異麥芽酮糖及乳果糖。非還原糖之實例包括選自糖醇及其他直鏈多元醇之多羥基化合物之非還原糖苷。較佳糖醇為單糖苷、尤其彼等藉由還原諸如乳糖、麥芽糖、乳果糖及麥芽酮糖之雙醣獲得之化合物。糖苷側基可為葡萄
糖苷或半乳糖苷。糖醇之其他實例為葡糖醇、麥芽糖醇、乳糖醇及異麥芽酮糖。較佳醫藥學上可接受之糖為非還原糖海藻糖或蔗糖。將醫藥學上可接受之糖以「保護量」添加至調配物中(例如預先冷凍乾燥),保護量意謂在儲存期間(例如復原及儲存後)蛋白質基本上保持其物理及化學穩定性及完整性。
本文相關之「稀釋劑」為醫藥學上可接受(對投與人類而言為安全且無毒的)且適用於液體調配物(諸如在冷凍乾燥後之復原之調配物)之製備的稀釋劑。例示性稀釋劑包括無菌水、抑菌注射用水(BWFI)、pH緩衝溶液(例如磷酸鹽緩衝生理食鹽水)、無菌生理食鹽水溶液、林格氏溶液(Ringer's solution)或右旋糖溶液。在一替代實施例中,稀釋劑可包括鹽及/或緩衝液之水溶液。
「防腐劑」為可添加至本文之調配物中以降低細菌活性之化合物。添加防腐劑可例如有助於多次使用(多次劑量)之調配物的生產。潛在防腐劑之實例包括十八烷基二甲基苄基氯化銨、氯化六羥季銨、氯化苯甲烴銨(烷基為長鏈化合物之氯化烷基苯甲基二甲基銨之混合物)及苄索氯銨。其他類型之防腐劑包括芳醇,諸如苯酚、丁醇及苯甲醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯、兒茶酚、間苯二酚、環己醇、3-戊醇及間甲酚。本文之最佳防腐劑為苯甲醇。
「治療」係指經設計以改變所治療之個體或細胞之自然過程的臨床介入,且可出於預防之目的或在臨床病理學過程中進行。所需治療作用包括阻止疾病發生或復發、阻止轉移、降低疾病進展速率、改善或緩解疾病狀態及減輕或改良預後。在某些實施例中,使用本發明抗體延遲疾病或病症之發展。若減輕與T細胞功能障礙病症相關之一或多種症狀,則例如使用本發明細胞凋亡型抗PD-L1抗體成功「治療」個體。
「有效量」係指在一定劑量下且經歷一段必要時間有效達成所要或指示作用(包括治療性或預防性結果)之至少量。舉例而言,本發明抗PD-L1抗體之有效量至少為抑制經由T細胞上之PD-1或其他APC上之B7.1或兩者自PD-L1信號傳導的最小濃度。
「治療有效量」至少為實現特定病症之可量測改良或預防所需之最小濃度。本文之治療有效量可隨以下因素而變化,諸如患者之疾病狀態、年齡、性別及體重以及抗體在個體中引發所要反應之能力。治療有效量亦為抗體之治療上有益作用勝過任何有毒或有害作用之量。舉例而言,本發明抗PD-L1抗體之治療有效量至少為抑制T細胞功能障礙病症之至少一種症狀之最小濃度。
「預防有效量」係指在一定劑量下且經歷一段必要時間有效達成所要預防性結果之量。舉例而言,本發明抗PD-L1抗體之預防有效量至少為阻止或減弱T細胞功能障礙病症之至少一種症狀發展之最小濃度。
「慢性」投藥係指以與急性模式相反之連續藥劑投與,以使最初治療作用(活性)維持一段較長之時間。「間歇」投藥為不中斷而是實際上循環之不連續進行的治療。
用於治療之「哺乳動物」係指歸類為哺乳動物的任何動物,包括人類、家畜及農畜,及動物園、運動或玩賞動物,諸如犬、馬、兔、牛、豬、倉鼠、沙鼠、小鼠、雪貂、大鼠、貓等。哺乳動物較佳為人類。
術語「醫藥調配物」係指呈使活性成份之生物活性有效之形式且不含有對將投與該調配物的個體具有不可接受之毒性之其他組分的製劑。該等調配物為無菌的。
「無菌」調配物為滅菌的或不含所有活微生物及其孢子。
如本文所用之術語「約」係指容易地為熟習此技術領域者所知
之各別值之常見誤差範圍。
「自體免疫病症」為由個體自身組織或器官或其共分離體或表現形式或由其所引起之病狀產生且針對個體自身組織或器官或其共分離體或表現形式或由其所引起之病狀的疾病或病症。自體免疫病可為器官特異性疾病(亦即,免疫反應特異性針對某一器官系統,諸如內分泌系統、造血系統、皮膚、心肺系統、胃腸與肝系統、腎系統、甲狀腺、耳、神經肌肉系統、中樞神經系統等)或可影響多個器官系統之全身性疾病(例如全身性紅斑性狼瘡(SLE)、類風濕性關節炎(RA)、多發性肌炎等)。較佳之該等疾病包括自體免疫性風濕病症(諸如RA、修格連氏症候群(Sjögren's syndrome)、硬皮病、狼瘡(諸如SLE)及狼瘡腎炎、多發性肌炎-皮膚肌炎、冷球蛋白血症、抗磷脂抗體症候群及牛皮癬性關節炎)、自體免疫性胃腸及肝病症(諸如發炎性腸病(例如潰瘍性結腸炎及克羅恩氏病(Crohn's disease))、自體免疫性胃炎及惡性貧血、自體免疫性肝炎、原發性膽汁性肝硬化症、原發性硬化性膽管炎及乳糜瀉)、血管炎(諸如ANCA陰性血管炎及ANCA相關血管炎,包括丘-施氏血管炎(Churg-Strauss vasculitis)、韋格納氏肉芽腫病(Wegener's granulomatosis)及顯微鏡下多血管炎)、自體免疫性神經性病症(諸如多發性硬化症、眼陣攣肌陣攣症候群、重症肌無力、視神經脊髓炎、帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)及自體免疫性多發性神經病)、腎病症(諸如絲球體腎炎、古德帕斯氏症候群(Goodpasture's syndrome)及貝爾氏病(Berger's disease))、自體免疫性皮膚病症(諸如牛皮癬、風疹、蕁麻疹、尋常型天疱瘡、大皰性類天疱瘡及皮膚紅斑狼瘡)、血液病症(諸如血小板減少性紫癜、血栓性血小板減少性紫癜、輸血後紫癜及自體免疫性溶血性貧血)、動脈粥樣硬化、葡萄膜炎、自體免疫性聽覺疾病(諸如內耳病及聽力喪失)、貝西氏病(Behcet's disease)、雷諾氏症候
群(Raynaud's syndrome)、器官移植及自體免疫性內分泌病症(諸如糖尿病相關自體免疫疾病,諸如胰島素依賴性糖尿病(IDDM)、阿狄森氏病(Addison's disease)及自體免疫性甲狀腺疾病(例如葛瑞夫茲氏病(Graves'disease)及甲狀腺炎))。更佳之該等疾病包括例如RA、潰瘍性結腸炎、ANCA相關血管炎、狼瘡、多發性硬化症、修格連氏症候群、葛瑞夫茲氏病、IDDM、惡性貧血、甲狀腺炎及絲球體腎炎。
如本文所用之術語「細胞毒性劑」係指抑制或阻止細胞功能及/或導致細胞破壞之物質。該術語包括放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32及Lu之放射性同位素);及毒素,諸如小分子毒素或細菌、真菌、植物或動物來源之酶促活性毒素,或其片段。
「化學治療劑」為適用於癌症治療之化合物。化學治療劑之實例包括:烷基化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXAN®);烷基磺酸酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,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)、三伸乙基蜜胺(triethylenemelamine)、三伸乙基磷醯胺(trietylenephosphoramide)、三伸乙基硫代磷醯胺(triethylenethiophosphoramide)及三甲密胺(trimethylolomelamine);多聚乙醯(acetogenin)(尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));δ-9-四氫大麻酚(delta-9-tetrahydrocannabinol)(屈大麻酚(dronabinol),MARINOL®);β-拉帕醌(beta-lapachone);拉帕醇(lapachol);秋水仙鹼(colchicine);樺木酸(betulinic acid);喜樹鹼(camptothecin)(包括合成類似物拓朴替康(topotecan)(HYCAMTIN®)、CPT-11(伊立替康(irinotecan),CAMPTOSAR®)、乙醯基喜樹鹼
(acetylcamptothecin)、斯考普萊汀(scopolectin)及9-胺基喜樹鹼);苔蘚抑素(bryostatin);培美曲唑(pemetrexed);卡利他汀(callystatin);CC-1065(包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物);足葉草毒素(podophyllotoxin);足葉草酸(podophyllinic acid);替尼泊苷(teniposide);自念珠藻環肽(cryptophycin)(尤其自念珠藻環肽1及自念珠藻環肽8);海兔毒素(dolastatin);多卡米新(duocarmycin)(包括合成類似物KW-2189及CB1-TM1);艾榴塞洛素(eleutherobin);盤克斯坦汀(pancratistatin);TLK-286;CDP323,一種口服α-4整合素抑制劑;沙考地汀(sarcodictyin);海綿抑素(spongistatin);氮芥,諸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、環磷醯胺、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、氮芥(mechlorethamine)、鹽酸氧化氮芥、美法侖(melphalan)、新恩比興(novembichin)、膽固醇苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、烏拉莫司汀(uracil mustard);亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及拉甯司汀(ranimnustine);抗生素,諸如烯二炔抗生素(例如卡奇黴素(calicheamicin),尤其卡奇黴素γ1I及卡奇黴素ωI1(參見例如Nicolaou等人,Angew.Chem Intl.Ed.Engl.,33:183-186(1994));達米辛(dynemicin),包括達米辛A;埃斯培拉黴素(esperamicin);以及新製癌菌素(neocarzinostatin)發色團及相關色蛋白烯二炔抗生素發色團)、克拉斯米辛(aclacinomysin)、放線菌素(actinomycin)、奧斯拉菌素(authramycin)、偶氮絲胺酸(azaserine)、博萊黴素(bleomycin)、放線菌素C(cactinomycin)、卡拉比星(carabicin)、洋紅黴素(carminomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycinis)、放線菌素D(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(包括ADRIAMYCIN®、N-嗎啉基-小紅莓(morpholino-doxorubicin)、氰基(N-嗎啉基)小紅莓、2-吡咯啉并小紅莓、鹽酸小紅莓脂質體注射劑(DOXIL®)及去氧小紅莓(deoxydoxorubicin))、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(諸如絲裂黴素C)、黴酚酸、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(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、吉西他濱(gemcitabine)(GEMZAR®)、喃氟啶(tegafur)(UFTORAL®)、卡西他濱(capecitabine)(XELODA®)、埃博黴素(epothilone)及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、喋羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、噻咪嘌呤(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(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)及伊馬替尼(imatinib)(2-苯基胺基嘧啶衍生物),以及其他c-Kit抑制劑;抗腎上腺藥劑,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如夫羅林酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);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);艾弗利散(elfornithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);羅尼達寧(lonidainine);美登醇(maytansinoid),諸如美登素(maytansine)及安絲菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidanmol);硝拉維林(nitraerine);噴司他丁(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙醯肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK®多醣複合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根瘤菌素(rhizoxin);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;單端孢黴烯族毒素(trichothecene)(尤其T-2毒素、弗納庫林A(verracurin A)、桿孢菌素A(roridin A)及胺癸叮(anguidine));烏拉坦(urethan);長春地辛(vindesine)(ELDISINE®、FILDESIN®);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);雙溴丙基哌嗪(pipobroman);甲托辛(gacytosine);阿糖胞苷(arabinoside)(「Ara-C」);噻替哌;紫杉醇,例如太平洋紫杉醇(TAXOL®)、白蛋白工程改造之太平洋紫杉醇奈米粒子調配物(ABRAXANETM)及多西紫杉醇(TAXOTERE®);苯丁酸氮芥(chloranbucil);6-硫鳥嘌呤;巰基嘌呤(mercaptopurine);甲胺喋呤;鉑類似物,諸如順鉑(cisplatin)及卡鉑(carboplatin);長春鹼(vinblastine)(VELBAN®);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺;米托蒽醌;長春新鹼(ONCOVIN®);奧賽力鉑(oxaliplatin);盧考弗文(leucovovin);長春瑞濱(NAVEIBINE®);諾凡特龍
(novantrone);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基喋呤(aminopterin);伊班膦酸鹽(ibandronate);拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(difluoromethylornithine)(DMFO);類視色素,諸如視黃酸(retinoic acid);上述化學治療劑中之任一者之醫藥學上可接受之鹽、酸或衍生物;以及上述化學治療劑中之兩者或兩者以上之組合,諸如CHOP(環磷醯胺、小紅莓、長春新鹼及潑尼松龍(prednisolone)之組合療法之縮寫)及FOLFOX(奧賽力鉑(ELOXATINTM)與5-FU及盧考弗文組合之治療方案之縮寫)。尤其在腫瘤免疫治療中與本發明抗PD-L1抗體組合使用之尤佳化學治療劑為吉西他濱。
該定義中亦包括起調控、降低、阻斷或抑制可促進癌症生長之激素之效應的作用且通常為全身性治療之形式的抗激素劑。其本身可為激素。實例包括抗雌激素藥及選擇性雌激素受體調節劑(SERM),包括例如他莫昔芬(tamoxifen)(包括NOLVADEX®他莫昔芬)、雷諾昔芬(raloxifene)(EVISTA®)、曲洛昔芬(droloxifene)、4-羥基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷諾昔芬鹽酸鹽(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(FARESTON®);抗孕酮;雌激素受體調降劑(ERD);雌激素受體拮抗劑,諸如氟維司群(FASLODEX®);用以抑制或制止卵巢功能之藥劑,例如黃體生成激素釋放激素(LHRH)促效劑,諸如乙酸亮丙瑞林(leuprolide acetate)(LUPRON®及ELIGARD®)、乙酸戈舍瑞林(goserelin acetate)、乙酸布舍瑞林(buserelin acetate)及曲特瑞林(tripterelin);抗雄激素藥,諸如氟他胺(flutamide)、尼魯米特(nilutamide)及比卡魯胺(bicalutamide);及抑制芳香酶(其調控腎上腺中雌激素之產生)之芳香酶抑制劑,諸如4(5)-咪唑、胺魯米特(aminoglutethimide)、乙酸甲地孕酮(megestrol acetate)(MEGASE®)、依西美坦(exemestane)(AROMASIN®)、福美斯坦(formestanie)、法屈
唑(fadrozole)、伏羅唑(vorozole)(RIVISOR®)、來曲唑(letrozole)(FEMARA®)及安美達錠(anastrozole)(ARIMIDEX®)。此外,該化學治療劑之定義包括:雙膦酸鹽,諸如氯屈膦酸鹽(clodronate)(例如,BONEFOS®或OSTAC®)、依替膦酸鹽(etidronate)(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(zoledronic acid/zoledronate)(ZOMETA®)、阿侖膦酸鹽(alendronate)(FOSAMAX®)、帕米膦酸鹽(pamidronate)(AREDIA®)、替魯膦酸鹽(tiludronate)(SKELID®)或利塞膦酸鹽(risedronate)(ACTONEL®);以及曲沙他濱(troxacitabine)(1,3-二氧戊環核苷胞嘧啶類似物);反義寡核苷酸,尤其抑制異常細胞增殖所牽涉之信號傳導路徑中基因之表現的彼等反義寡核苷酸,諸如PKC-α、Raf、H-Ras及表皮生長因子受體(EGF-R);疫苗,諸如THERATOPE®疫苗及基因治療疫苗,例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗及VAXID®疫苗;拓撲異構酶1抑制劑(例如LURTOTECAN®);抗雌激素藥,諸如氟維司群(fulvestrant);Kit抑制劑,諸如伊馬替尼(imatinib)或EXEL-0862(酪胺酸激酶抑制劑);EGFR抑制劑,諸如埃羅替尼(erlotinib)或西妥昔單抗(cetuximab);抗VEGF抑制劑,諸如貝伐單抗(bevacizumab);瑞諾替康(arinotecan);rmRH(例如ABARELIX®);拉帕替尼(lapatinib)及拉帕替尼對甲苯磺酸鹽(lapatinib ditosylate)(ErbB-2與EGFR雙重酪胺酸激酶小分子抑制劑,亦稱為GW572016);17AAG(作為熱休克蛋白(Hsp)90毒劑之格爾德黴素(geldanamycin)衍生物);及上述化學治療劑中之任一者之醫藥學上可接受之鹽、酸或衍生物。
「生長抑制劑」係指抑制細胞生長之化合物或組合物,該生長視活體外或活體內受體活化而定。因此,生長抑制劑包括顯著降低S期中受體依賴性細胞之百分比的生長抑制劑。生長抑制劑之實例包括
阻斷細胞週期進程(在不同於S期之其他時期)之藥劑,諸如誘導G1停滯及M期停滯之藥劑。經典M期阻斷劑包括長春鹼類及長春生物鹼(長春新鹼及長春鹼)、紫杉烷及拓撲異構酶II抑制劑(諸如小紅莓、表柔比星、道諾黴素、依託泊苷及博萊黴素)。使G1停滯之彼等藥劑亦使S期停滯,例如DNA烷基化劑,諸如他莫昔芬、潑尼松(prednisone)、達卡巴嗪、氮芥、順鉑、甲胺喋呤、5-氟尿啶及ara-C。其他資訊可見於The Molecular Basis of Cancer,Mendelsohn及Israel編,第1章,標題為「Cell cycle regulation,oncogenes,and antineoplastic drugs」Murakami等人,(WB Saunders:Philadelphia,1995),尤其第13頁中。紫杉烷(太平洋紫杉醇及多烯紫杉醇)皆為源自紫杉之抗癌藥。衍生自歐洲紫杉之多烯紫杉醇(TAXOTERE®,Rhone-Poulenc Rorer)為太平洋紫杉醇(TAXOL®,Bristol-Myers Squibb)之半合成類似物。
術語「細胞激素」為有關由一個細胞群體所釋放並作為細胞間介體對另一細胞起作用之蛋白質的通用術語。該等細胞激素之實例為淋巴介質、單核球激素;介白素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-11、IL-12、IL-13、IL-15、IL-35,包括PROLEUKIN® rIL-2;腫瘤壞死因子,諸如TNF-α或TNF-β;及其他多肽因子,包括LIF及套組配位體(KL),而目前術語「介白素」基本上為細胞激素之同義詞。如本文所用之術語細胞激素包括來自天然來源或來自重組細胞培養物之蛋白質及天然序列細胞激素之生物活性等效物,包括合成產生之小分子實體及其醫藥學上可接受之衍生物及鹽。細胞激素可根據預定標靶之近端位置進行分類,其中自分泌係指對分泌細胞激素之同一細胞之作用,旁分泌係指侷限於分泌有細胞激素之鄰近區域的作用,且內分泌係指對身體之遠區域的作用。免疫細胞激素亦可藉由其增進有利於細胞免疫之I型反應與否(例如IFN-γ、TGF-β等)或有利於抗體或體液免疫之II型反應與否(IL-
4、IL-10、IL-13等)進行分類。免疫細胞激素在各種免疫細胞之協同刺激、成熟、增殖、活化、發炎、生長、分化、細胞激素產生及分泌、存活中發揮作用。
術語「激素」係指一般由具有管道之腺器官分泌之多肽激素。激素包括例如生長激素,諸如人生長激素、N-甲硫胺醯基人生長激素及牛生長激素;甲狀旁腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;雌二醇;激素替代治療;雄激素,諸如卡普睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)或睾內酯(testolactone);鬆弛素原(prorelaxin);醣蛋白激素,諸如促濾泡激素(FSH)、促甲狀腺激素(TSH)及促黃體生成激素(LH);促乳素、胎盤生乳素、小鼠促性腺激素相關肽、促性腺激素釋放激素;抑制素;活化素;苗勒氏管抑制物質(mullerian-inhibiting substance);及血小板生成素。如本文所用之術語激素包括來自天然來源或來自重組細胞培養物之蛋白質,及天然序列激素之生物活性等效物,其包括合成產生之小分子實體及其醫藥學上可接受之衍生物及鹽。
III.本發明之實施方式
A.使用噬菌體呈現進行人類化
由編碼人類受體序列之核酸的孔克突變誘發(Kunkel mutagenesis)使用各高變區之獨立的寡核苷酸產生本文所述之高變區移植變異體。Kunkel等人,Methods Enzymol. 154:367-382(1987)。可使用常規技術在構架及/或高變區內引入適當變化,以校正及重建適當的高變區-抗原相互作用。
可使用噬菌體(噬菌粒)呈現(本文亦稱作噬菌體呈現)作為產生及篩檢由序列隨機化所產生之文庫中之許多不同的潛在變異抗體之方便且快速的方法。然而,熟習此項技術者可利用製造及篩檢已改變之抗
體之其他方法。
可使用噬菌體(噬菌粒)呈現(在一些情形下,本文亦稱作噬菌體呈現)作為產生及篩檢由序列隨機化所產生之文庫中之許多不同的潛在變異抗體之方便且快速的方法。然而,熟習此項技術者可利用製造及篩檢已改變之抗體之其他方法。
噬菌體(噬菌粒)呈現技術已提供產生及選擇結合配位體(諸如抗原)之新穎蛋白質的強有力工具。使用噬菌體(噬菌粒)呈現技術允許產生可迅速分選出彼等以高親和力與標靶分子結合之序列的大型蛋白質變異體文庫。一般使編碼變異多肽之核酸與編碼病毒鞘蛋白(諸如基因III蛋白或基因VIII蛋白)之核酸序列融合。已開發出使編碼蛋白質或多肽之核酸序列與編碼一部分基因III蛋白之核酸序列融合之單價噬菌粒呈現系統。(Bass,S.,Proteins,8:309(1990);Lowman及Wells,Methods:A Companion to Methods in Enzymology,3:205(1991))。在單價噬菌粒呈現系統中,以低含量表現基因融合體,且亦表現野生型基因III蛋白以使粒子之感染力得以保持。許多專利(例如美國專利第5,723,286號、美國專利第5,432,018號、美國專利第5,580,717號、美國專利第5,427,908號及美國專利第5,498,530號)中已揭示產生肽文庫及篩檢彼等文庫之方法。
已以多種方法製備抗體或抗原結合多肽之文庫,該等方法包括藉由插入隨機DNA序列改變單個基因或藉由選殖相關基因家族。使用噬菌體(噬菌粒)呈現來呈現抗體或抗原結合片段之方法已描述於美國專利第5,750,373號、美國專利第5,733,743號、美國專利第5,837,242號、美國專利第5,969,108號、美國專利第6,172,197號、美國專利第5,580,717號及美國專利第5,658,727號中。接著針對具有所要特徵之抗體或抗原結合蛋白之表現篩檢文庫。
此項技術中已完善建立將所選胺基酸代入模板核酸中之方法,
本文描述其中一些方法。舉例而言,可使用孔克方法取代高變區殘基。參見例如Kunkel等人,Methods Enzymol.154:367-382(1987)。
寡核苷酸之序列包括一或多個用於待改變之高變區殘基之經設計密碼子組。密碼子組為一組用以編碼所要變異胺基酸之不同核苷酸三聯體序列。根據以下IUB代碼所示,密碼子組可使用符號表示來指定特定核苷酸或核苷酸之等莫耳混合物。
可使用標準方法合成寡核苷酸或引子組。一組寡核苷酸可例如由固相合成來合成,其含有代表由密碼子組提供之核苷酸三聯體之所有可能的組合且將編碼所要胺基酸群組的序列。此項技術中熟知在某些位置具有所選核苷酸「簡併性」之寡核苷酸的合成。該等具有某些密碼子組之核苷酸組可使用商業核酸合成器(可自例如Applied Biosystems,Foster City,CA獲得)合成或可購得(例如自Life Technologies,Rockville,MD購得)。因此,所合成之一組具有特定密碼子組之寡核苷酸通常將包括複數個具有不同序列之寡核苷酸,該等
差異由整個序列內之密碼子組產生。根據本發明使用之寡核苷酸具有允許與可變域核酸模板雜交且亦可包括用於選殖目的之限制酶位點的序列。
在一方法中,編碼變異胺基酸之核酸序列可由寡核苷酸介導之突變誘發產生。如Zoller等人,Nucleic Acids Res.10:6487-6504(1987)所述,在此項技術中熟知此技術。簡言之,藉由使編碼所要密碼子組之寡核苷酸組與DNA模板雜交產生編碼變異胺基酸之核酸序列,其中該模板為含有可變區核酸模板序列之質體之單鏈形式。雜交後,使用DNA聚合酶合成模板之整個第二條互補鏈,因此該鏈將合併寡核苷酸引子且將含有由寡核苷酸組所提供之密碼子組。
一般而言,使用長度為至少25個核苷酸之寡核苷酸。最佳寡核苷酸將具有在編碼突變之核苷酸之任一側與模板完全互補之12至15個核苷酸。此確保寡核苷酸將與單鏈DNA模板分子適當雜交。寡核苷酸易於使用此項技術中已知之諸如Crea等人,Proc.Nat'l.Acad.Sci.USA,75:5765(1978)所述之技術合成。
由彼等衍生自噬菌體M13載體(適合的為市售M13mp18及M13mp19載體)之載體或彼等如Viera等人,Meth.Enzymol.,153:3(1987)所述含有單鏈噬菌體複製起點之載體產生DNA模板。因此,可將待突變之DNA插入一種該等載體中以產生單鏈模板。單鏈模板之產生描述於上述Sambrook等人之4.21-4.41章節中。
為改變天然DNA序列,在適合之雜交條件下使寡核苷酸與單鏈模板雜交。接著添加DNA聚合酶(通常T7 DNA聚合酶或DNA聚合酶I之Klenow片段)以使用寡核苷酸作為合成引子來合成該模板之互補鏈。由此形成異源雙鏈分子從而使得一條DNA鏈編碼突變形式之基因1,且另一條鏈(原始模板)編碼基因1之天然的未改變序列。接著將此異源雙鏈分子轉形於適合之宿主細胞中,該宿主細胞通常為原核生
物,諸如大腸桿菌JM101。使細胞生長後,將其塗鋪於瓊脂糖板上且使用以32-磷酸鹽作放射性標記之寡核苷酸引子篩檢以鑑別含有突變DNA之菌落。
可對上文剛描述之方法進行修改以便產生質體之兩條鏈均含有突變之同源雙鏈分子。修改如下:使單鏈寡核苷酸與上述單鏈模板黏接。將三種去氧核糖核苷酸(去氧核糖腺苷(dATP)、去氧核糖鳥苷(dGTP)及去氧核糖胸苷(dTT))之混合物與稱作dCTP-(aS)之經修飾硫代去氧核糖胞嘧啶(其可自Amersham獲得)組合。將此混合物添加至模板-寡核苷酸複合物中。向此混合物中添加DNA聚合酶後,產生除突變鹼基以外皆與模板相同之DNA鏈。另外,此新DNA鏈將含有dCTP-(aS)而非dCTP,該dCTP-(aS)用以保護該DNA鏈以免由限制核酸內切酶消化。在雙鏈異源雙鏈體(heteroduplex)之模板鏈經適當限制酶形成缺口後,可用ExoIII核酸酶或另一在不為含待突變誘發位點之區處切斷之適當核酸酶消化模板鏈。接著終止反應留下僅為部分單鏈之分子。接著在所有四種三磷酸去氧核糖核苷酸、ATP及DNA連接酶存在下使用DNA聚合酶形成完整雙鏈DNA同源雙鏈體。接著可使此同源雙鏈分子轉形於適合之宿主細胞中。
如先前所指示,寡核苷酸組之序列具有足以與模板核酸雜交的長度且亦可(但不必)含有限制位點。可由彼等衍生自噬菌體M13載體之載體或彼等如Viera等人,Meth.Enzymol.,153:3(1987)所述之含有單鏈噬菌體複製起點之載體產生DNA模板。因此,必須將待突變之DNA插入一種該等載體中以產生單鏈模板。單鏈模板之產生描述於Sambrook等人,同上之4.21-4.41章節中。
根據另一方法,可藉由提供上游及下游寡核苷酸組來產生文庫,各組具有複數個具有不同序列之寡核苷酸,該等不同序列係由寡核苷酸之序列內所提供之密碼子組產生。上游及下游寡核苷酸組以及
可變域模板核酸序列可用於聚合酶鏈反應中以產生PCR產物之「文庫」。該等PCR產物可稱作「核酸卡匣(nucleic acid cassette)」,此係由於可使用已建立之分子生物技術使其與其他相關或不相關核酸序列(例如病毒鞘蛋白及二聚合域)融合。
PCR引子之序列包括一或多個針對高變區中之溶劑可接近且高度不同的位置之經設計密碼子組。如上所述,密碼子組為一組用於編碼所要變異胺基酸之不同核苷酸三聯體序列。可使用標準重組技術分離及選殖如經適當篩檢/選擇步驟選擇之符合所要標準之抗體選擇物。
B.重組製備
本發明亦提供一種編碼抗PD-L1抗體之經分離核酸、包含該等核酸之載體及宿主細胞及產生該抗體之重組技術。
對於重組產生抗體,分離編碼該抗體之核酸且插入可複製載體中以便進一步選殖(DNA擴增)或表現。使用習知程序(例如藉由使用能夠特異性結合編碼抗體之重鏈及輕鏈之基因之寡核苷酸探針)容易地分離編碼單株抗體之DNA並測序。可利用許多載體。載體之選擇部分視待使用之宿主細胞而定。一般而言,較佳宿主細胞起源於原核生物或真核生物(一般哺乳動物)。
1.在原核細胞中產生抗體
a)載體構築
可使用標準重組技術獲得編碼本發明抗體之多肽組分的聚核苷酸序列。可自產生抗體之細胞(諸如融合瘤細胞)中分離所要聚核苷酸序列並測序。或者,可使用核苷酸合成器或PCR技術合成聚核苷酸。一旦獲得編碼多肽之序列,即將其插入能夠在原核宿主中複製且表現異源聚核苷酸之重組載體中。出於本發明之目的,可使用許多可利用且為此項技術中所知之載體。適當載體之選擇將主要視待插入載體中之核酸的大小及待經載體轉形之特定宿主細胞而定。各載體視其功能
(異源聚核苷酸之擴增或表現或兩者)及其與其所駐留之特定宿主細胞之相容性而定含有多種組分。載體組分一般包括(但不限於):複製起點、選擇標記基因、啟動子、核糖體結合位點(RBS)、信號序列、異源核酸插入物及轉錄終止序列。
含有衍生自與宿主細胞相容之物種之複製子及控制序列的質體載體一般聯合此等宿主使用。載體通常帶有複製位點以及能夠在轉形細胞中提供表型選擇之標記序列。舉例而言,通常使用衍生自大腸桿菌物種之質體pBR322使大腸桿菌轉形。pBR322含有編碼安比西林(Amp)及四環素(Tet)抗性之基因,且因此提供鑑別經轉形細胞之容易方式。pBR322、其衍生物或其他微生物質體或噬菌體亦可含有或經修飾含有可由微生物使用以供表現內源蛋白質之啟動子。Carter等人之美國專利第5,648,237號中詳細描述用於表現特定抗體之pBR322衍生物之實例。
此外,含有與宿主微生物相容之複製子及控制序列的噬菌體載體可聯合此等宿主用作轉形載體。舉例而言,可利用諸如GEM.TM.-11之噬菌體製備可用以使諸如大腸桿菌LE392之易感宿主細胞轉形的重組載體。
本發明之表現載體可包含兩種或兩種以上編碼各多肽組分之啟動子-順反子(cistron)對。啟動子為位於調節其表現之順反子上游(5')的未經轉譯之調控序列。原核啟動子通常分為兩類:誘導型及組成型。誘導型啟動子為一種啟動子,在該啟動子控制下應答培養條件之改變(例如在有或無營養物存在下或溫度改變)開始順反子之增加含量之轉錄。
熟知由多種潛在宿主細胞所識別之大量啟動子。可藉由經限制酶消化自來源DNA移出所選擇之啟動子且將所分離之啟動子序列插入本發明載體中而使該啟動子可操作連接至編碼輕鏈或重鏈之順反子
DNA。可使用天然啟動子序列與許多異源啟動子來引導標靶基因之擴增及/或表現。在一些實施例中,利用異源啟動子,此係因為一般而言,與天然標靶多肽啟動子相比,異源啟動子所允許之經表現之標靶基因的轉錄較大且產率較高。
適於原核宿主使用之啟動子包括PhoA啟動子、β-半乳糖苷酶及乳糖啟動子系統、色胺酸(trp)啟動子系統及雜交啟動子(諸如tac或trc啟動子)。然而,在細菌中起作用之其他啟動子(諸如其他已知細菌或噬菌體啟動子)亦適合。已公開其核苷酸序列,藉此使得熟練技術者能夠使用連接子或接附子(adaptor)提供任何所需限制位點使該等序列與編碼標靶輕鏈及重鏈之順反子可操作連接(Siebenlist等人,(1980)Cell 20:269)。
在一態樣中,重組載體中之各順反子包含引導所表現多肽跨膜移位之分泌信號序列組分。一般而言,信號序列可為載體之組分,或其可為插入載體中之標靶多肽DNA之一部分。出於本發明之目的所選擇之信號序列應為由宿主細胞識別及加工(亦即由信號肽酶裂解)之信號序列。對於不識別及加工異源多肽之天然信號序列的原核宿主細胞而言,使信號序列經例如選自由以下組成之群的原核信號序列取代:鹼性磷酸酶、青黴素酶、Ipp或熱穩定腸毒素II(STII)前導序列、LamB、PhoE、PelB、OmpA及MBP。在本發明之一實施例中,用於表現系統之該兩種順反子中之信號序列為STII信號序列或其變異體。
在另一態樣中,本發明之免疫球蛋白的產生可發生在宿主細胞之細胞質中,且因此無需各順反子內均存在分泌信號序列。就此而言,免疫球蛋白輕鏈及重鏈皆在細胞質內表現、摺疊及裝配以形成功能性免疫球蛋白。某些宿主菌株(例如大腸桿菌trxB-菌株)提供有利於雙硫鍵形成之細胞質條件,藉此允許適當摺疊及裝配經表現之蛋白質次單元。Proba及Pluckthun Gene,159:203(1995)。
本發明提供一種表現系統,其中可調節所表現多肽組分之定量比例以最大化所分泌及適當裝配之本發明抗體之產率。該調節可至少部分藉由同時調節多肽組分之轉譯強度來完成。
調節轉譯強度之一種技術揭示於Simmons等人,美國專利第5,840,523號中。其利用順反子內之轉譯起始區(TIR)之變異體。對於既定TIR,可在一定範圍之轉譯強度下產生一系列胺基酸或核酸序列變異體,藉此提供針對特定鏈之所要表現含量調節此因子的方便方式。TIR變異體可由引起可改變胺基酸序列之密碼子改變的習知突變誘發技術產生,但在核苷酸序列中靜默改變較佳。TIR改變可包括例如Shine-Dalgarno序列之編號或間隔改變以及信號序列改變。一種產生突變信號序列之方法為在不改變信號序列之胺基酸序列的編碼序列起始處產生「密碼子庫」(亦即,改變為靜默型)。此可藉由改變各密碼子之第三核苷酸位置來實現;另外,諸如白胺酸、絲胺酸及精胺酸之一些胺基酸具有多個可增加製庫複雜性的第一及第二位置。此突變誘發方法詳細描述於Yansura等人,(1992)METHODS:A Companion to Methods in Enzymol.4:151-158中。
較佳地,產生一組載體,其內部各順反子具有一系列TIR強度。
此有限的組提供各鏈之表現含量的比較以及各種TIR強度組合下所要抗體產物的產率。如Simmons等人,美國專利第5,840,523中詳細描述,TIR強度可藉由定量報導基因之表現含量來確定。基於轉譯強度比較,可選擇所要的個別TIR以組合於本發明之表現載體構築體中。
b)原核宿主細胞
適於表現本發明抗體之原核宿主細胞包括古細菌(Archaebacteria)及真細菌(Eubacteria),諸如革蘭氏陰性(Gram-negative)或革蘭氏陽性生物體。適用細菌之實例包括埃希氏桿菌屬(例如大腸桿菌)、芽孢桿菌屬(Bacilli)(例如枯草芽孢桿菌(B.subtilis))(例如枯草芽孢桿菌(B. subtilis))、腸細菌(Enterobacteria)、假單胞菌屬(Pseudomonas)物種(例如銅綠假單胞菌(P.aeruginosa))、鼠傷寒沙門氏桿菌(Salmonella typhimurium)、黏質沙雷菌(Serratia marcescans)、克雷伯氏菌屬、變形菌屬、志賀氏菌屬(Shigella)、根瘤菌屬(Rhizobia)、透明顫菌(Vitreoscilla)或副球菌屬(Paracoccus)。在一實施例中,使用革蘭氏陰性細胞。在一實施例中,使用大腸桿菌細胞作為本發明宿主。大腸桿菌菌株之實例包括菌株W3110(Bachmann,Cellular and Molecular Biology,第2卷(Washington,D.C.:American Society for Microbiology,1987),第1190-1219頁;ATCC寄存編號27,325)及其衍生物,包括具有基因型W3110 ÿfhuA(ÿtonA)ptr3 lac Iq lacL8 ÿompTÿ(nmpc-fepE)degP41 kan R 之菌株33D3(美國專利第5,639,635號)。其他菌株及其衍生物(諸如大腸桿菌294(ATCC 31,446)、大腸桿菌B、大腸桿菌1776(ATCC 31,537)及大腸桿菌RV308(ATCC 31,608))亦適合。此等實例為說明性的而非限制性的。構築具有確定的基因型之任何以上提及之細菌的衍生物的方法在此項技術中為已知的且描述於例如Bass等人,Proteins,8:309-314(1990)中。一般需要考慮複製子在細菌細胞中之可複製性來選擇適當細菌。舉例而言,當使用熟知質體(諸如pBR322、pBR325、pACYC177或pKN410)提供複製子時,適合地可使用大腸桿菌、沙雷氏菌或沙門氏菌物種作為宿主。
宿主細胞通常應分泌最少量之蛋白水解酶,且理想地,可將額外蛋白酶抑制劑併入細胞培養物中。
c)抗體產生
用上述表現載體使宿主細胞轉形,且在適當時經修飾之習知培養基中培養以誘導啟動子、選擇轉形體或擴增編碼所要序列之基因。轉形意謂將DNA引入原核宿主中,以便DNA可作為染色體外要素或由染色體成分複製。視所使用之宿主細胞而定,使用適於該等細胞之
標準技術進行轉形。對含有實質細胞壁障壁之細菌細胞而言,一般使用採用氯化鈣之鈣處理。另一轉形方法採用聚乙二醇/DMSO。所使用之另一技術為電穿孔法。
使用以產生本發明抗體的原核細胞在此項技術中已知且適於培養所選宿主細胞之培養基中生長。適合之培養基之實例包括溶菌培養液(luria broth,LB)加必需營養補充劑。在一些實施例中,培養基亦含有基於表現載體之構築而選擇之選擇劑,以選擇性允許含有表現載體之原核細胞生長。舉例而言,向培養基中添加安比西林以使表現安比西林抗性基因之細胞生長。
亦可包括除碳、氮及無機磷酸鹽來源以外之任何必需補充劑,其單獨或以與另一補充劑或培養基(諸如複合氮源)之混合物的形式以適當濃度引入。視情況,培養基可含有一或多種選自由以下組成之群的還原劑:麩胱甘肽、半胱胺酸、胱胺、巰基乙酸酯、二硫赤蘚糖醇及二硫蘇糖醇。
在適合之溫度下培養原核宿主細胞。對大腸桿菌生長而言,例如,較佳溫度係在約20℃至約39℃、更佳約25℃至約37℃之範圍內,甚至更佳在約30℃下。培養基之pH值主要視宿主生物體而定,可為約5至約9範圍內之任何pH值。對於大腸桿菌而言,pH值較佳為約6.8至約7.4,且更佳為約7.0。
若本發明之表現載體中使用誘導型啟動子,則在適於活化該啟動子之條件下誘導蛋白質表現。在本發明之一態樣中,使用PhoA啟動子控制多肽轉錄。因此,在磷酸鹽限制培養基中培養經轉形之宿主細胞以誘導。較佳地,磷酸鹽限制培養基為C.R.A.P培養基(參見例如Simmons等人,J.Immunol.Methods(2002),263:133-147)。如此項技術中所知,可根據所用載體構築體使用多種其他誘導劑。
本發明之經表現抗體蛋白質分泌至宿主細胞之周質中且自其中
回收。蛋白質回收通常涉及一般由諸如滲透壓衝擊、音波處理或溶解之方式使微生物碎裂。一旦細胞碎裂,即可藉由離心或過濾來移除細胞碎片或完整細胞。蛋白質可例如由親和樹脂層析進一步純化。或者,可將蛋白質傳輸至培養基中且在其中進行分離。可自培養物中移除細胞,且過濾培養物上清液且濃縮以進一步純化所產生之蛋白質。可使用諸如聚丙烯醯胺凝膠電泳(PAGE)及西方墨點檢定之通常已知的方法進一步分離經表現之多肽且加以鑑別。
或者,藉由醱酵過程實現抗體大批量產生。可利用多種大規模分批饋料醱酵程序來產生重組蛋白質。大規模醱酵具有至少1000公升之容量,較佳約1,000至100,000公升之容量。此等醱酵器使用攪拌葉輪來分配氧氣及養分,尤其葡萄糖(較佳碳/能量來源)。小規模醱酵一般係指在體積容量不超過約100公升且可在約1公升至約100公升範圍內之醱酵器中進行的醱酵。
在醱酵過程中,通常在已使細胞在適合條件下生長至所需密度(例如OD550為約180-220,在此階段細胞處於穩定期早期)後開始誘導蛋白質表現。如此項技術中已知且如上文所述,可根據所用載體構築體使用多種誘導劑。可在誘導細胞之前使細胞生長較短時間。誘導細胞之時間通常為約12-50小時,但可使用更長或更短之誘導時間。
為改良本發明抗體的產率及品質,可改變各種醱酵條件。舉例而言,為改良所分泌之抗體多肽之適當裝配及摺疊,可使用過度表現伴侶蛋白(chaperone protein)之其他載體使宿主原核細胞共轉形,該等伴侶蛋白諸如Dsb蛋白(DsbA、DsbB、DsbC、DsbD及/或DsbG)或FkpA(具有伴侶活性之肽基脯胺醯基順式/反式異構酶)。已說明伴侶蛋白有助於所產生之異源蛋白質在細菌宿主細胞中之適當摺疊及溶解。Chen等人,(1999)J Bio Chem 274:19601-19605;Georgiou等人,美國專利第6,083,715號;Georgiou等人,美國專利第6,027,888號;
Bothmann及Pluckthun(2000)J.Biol.Chem.275:17100-17105;Ramm及Pluckthun(2000)J.Biol.Chem.275:17106-17113;Arie等人,(2001)Mol.Microbiol.39:199-210。
為使所表現之異源蛋白質(尤其彼等對易蛋白水解之蛋白質)之蛋白水解降至最低,本發明可使用某些缺乏蛋白水解酶之宿主菌株。舉例而言,宿主細胞菌株可經修飾以在編碼已知細菌蛋白酶(諸如蛋白酶III、OmpT、DegP、Tsp、蛋白酶I、蛋白酶Mi、蛋白酶V、蛋白酶VI及其組合)之基因中實現基因突變。可利用一些缺乏大腸桿菌蛋白酶之菌株且其描述於例如Joly等人,(1998),同上;Georgiou等人,美國專利第5,264,365號;Georgiou等人,美國專利第5,508,192號;Hara等人,Microbial Drug Resistance,2:63-72(1996)中。
可使用缺乏蛋白水解酶且經過度表現一或多種伴侶蛋白之質體轉形的大腸桿菌菌株作為編碼本發明抗體之表現系統中之宿主細胞。
d)抗體純化
本文中所產生之抗體蛋白質可進一步經純化以獲得實質上均質的製劑來進行其他檢定及使用。可利用此項技術中已知之標準蛋白質純化方法。以下程序為適合之純化程序的例示性實例:免疫親和管柱或離子交換管柱分級分離、乙醇沈澱、逆相HPLC、二氧化矽或陽離子交換樹脂(諸如DEAE)層析、層析聚焦、SDS-PAGE、硫酸銨沈澱及使用例如Sephadex G-75之凝膠過濾。
在一態樣中,使用固定於固相上之蛋白質A進行本發明全長抗體產物的免疫親和純化。蛋白質A為來自金黃色葡萄球菌(Staphylococcus aureas)之41kD細胞壁蛋白,其以高親和力結合抗體之Fc區。Lindmark等人(1983)J.Immunol.Meth.62:1-13。蛋白質A所固定之固相較佳為包含玻璃或二氧化矽表面之管柱,更佳為受控微孔玻璃管柱或矽酸管柱。在一些應用中,管柱已塗布有諸如甘油之試劑
以力圖防止污染物之非特異性黏附。接著洗滌固相以移除與固相非特異性結合之污染物。最後,藉由溶離自固相回收相關抗體。
2.在真核細胞中產生抗體
對於真核表現,載體組分一般包括(但不限於)以下之一或多者:信號序列、複製起點、一或多個標記基因及強化子元件(enhancer element)、啟動子及轉錄終止序列。
a)信號序列組分
用於真核宿主中之載體亦可為編碼信號序列之插入物或在成熟蛋白質或多肽之N末端具有特異性裂解位點之其他多肽。所選擇之異源信號序列較佳為由宿主細胞識別及加工(亦即由信號肽酶裂解)之信號序列。在哺乳動物細胞表現中,可利用哺乳動物信號序列以及病毒分泌前導序列(例如單純性疱疹gD信號)。
該前驅區之DNA在閱讀框架中與編碼本發明抗體之DNA連接。
b)複製起點
一般而言,哺乳動物表現載體無需複製起點組分(因SV40起點含有早期啟動子,故通常可僅使用該起點)。
c)選擇基因組分
表現及選殖載體可含有亦稱為可選擇標記物之選擇基因。典型選擇基因編碼具有下列作用之蛋白質:(a)賦予針對抗生素或其他毒素(例如安比西林、新黴素、甲胺喋呤或四環素)之抗性;(b)補充營養缺陷型不足;或(c)供應不可自複合培養基獲得之關鍵養分,例如對芽孢桿菌而言,為編碼D-丙胺酸消旋酶之基因。
選擇方案之一個實例利用藥物來阻滯宿主細胞生長。彼等經異源基因成功轉形之細胞產生賦予耐藥性之蛋白質,且因此在經歷選擇方案之後存活。該類顯性選擇之實例使用藥物新黴素、黴酚酸及潮黴素(hygromycin)。
哺乳動物細胞之適合之可選擇標記物的另一實例為彼等能夠鑑別能吸收編碼本發明抗體之核酸之細胞的標記物,諸如DHFR、胸苷激酶、金屬硫蛋白-I及金屬硫蛋白-II(較佳為靈長類動物金屬硫蛋白基因)、腺苷去胺酶、鳥胺酸脫羧酶等。
舉例而言,首先藉由在含有甲胺喋呤(Mtx)(DHFR之競爭性拮抗劑)之培養基中培養所有轉形體來鑑別經DHFR選擇基因轉形之細胞。當採用野生型DHFR時,適當之宿主細胞為缺乏DHFR活性之中國倉鼠卵巢(CHO)細胞株(例如ATCC CRL-9096)。
或者,可藉由使細胞在含有可選擇標記物之選擇劑(諸如胺基糖苷抗生素,例如康黴素(kanamycin)、新黴素或G418)的培養基中生長來選擇經編碼抗體之DNA序列、野生型DHFR蛋白及另一可選擇標記物(諸如,胺基糖苷3'-磷酸轉移酶(APH))轉形或共轉形之宿主細胞(尤其含有內源DHFR之野生型宿主)。參見美國專利第4,965,199號。
d)啟動子組分
表現及選殖載體通常含有由宿主生物體所識別且可操作連接至編碼所要抗體序列之核酸的啟動子。實際上所有真核基因均具有位於轉錄起始位點上游約25至30個鹼基處之富集AT之區。在許多基因轉錄起始處上游70至80個鹼基處發現的另一序列為CNCAAT區,其中N可為任何核苷酸。大部分真核基因之3'端為AATAAA序列,該序列可為用於將聚腺苷酸尾(poly A tail)添加至編碼序列之3'端的信號。所有此等序列均可插入真核表現載體中。
適於原核宿主使用之其他啟動子包括phoA啟動子、β-內醯胺酶及乳糖啟動子系統、鹼性磷酸酶啟動子、色胺酸(trp)啟動子系統及雜交啟動子,諸如tac啟動子。然而,其他已知細菌啟動子亦適合。用於細菌系統中之啟動子亦將含有可操作連接至編碼抗體多肽之DNA的夏因-達爾加諾(Shine-Dalgarno,S.D.)序列。
抗體多肽自哺乳動物宿主細胞中之載體之轉錄例如受以下啟動子控制:自病毒(諸如多瘤病毒、禽痘病毒、腺病毒(諸如腺病毒2)、牛乳頭狀瘤病毒、禽肉瘤病毒、細胞巨大病毒、反轉錄病毒、B型肝炎病毒且最佳猿病毒40(Simian Virus 40,SV40))之基因組獲得的啟動子、異源哺乳動物啟動子(例如肌動蛋白啟動子或免疫球蛋白啟動子)、熱休克啟動子,其限制條件為該等啟動子與宿主細胞系統相容。
SV40病毒之早期及晚期啟動子宜作為亦含有SV40病毒複製起點之SV40限制片段獲得。人巨細胞病毒之即刻早期啟動子宜作為HindIII E限制片段獲得。美國專利第4,419,446號中揭示在哺乳動物宿主中使用牛乳頭狀瘤病毒作為載體來表現DNA之系統。美國專利第4,601,978號中描述此系統之修改。關於小鼠細胞中之人類-干擾素cDNA在單純性疱疹病毒之胸苷激酶啟動子控制下之表現,亦參見Reyes等人,Nature 297:598-601(1982)。或者,可使用勞氏肉瘤病毒(Rous Sarcoma Virus)長末端重複單元作為啟動子。
e)強化子元件組分
由高級真核細胞轉錄編碼本發明抗體之DNA通常藉由將強化子序列插入載體中來增強。目前已知許多強化子序列來自哺乳動物基因(血球蛋白、彈性蛋白酶、白蛋白、α-胎蛋白及胰島素)。然而,通常將使用來自真核細胞病毒之強化子。實例包括位於複製起點晚期側之SV40強化子(bp 100-270)、細胞巨大病毒早期啟動子強化子、複製起點晚期側的多瘤病毒強化子及腺病毒強化子。關於活化真核啟動子之強化元件,亦參見Yaniv,Nature 297:17-18(1982)。雖然可在抗體編碼序列之位置5'或3'處將強化子剪接至載體中,但較佳定位於啟動子之5'位點處。
f)轉錄終止組分
用於真核宿主細胞(酵母菌、真菌、昆蟲、植物、動物、人類或來自其他多細胞生物體之有核細胞)之表現載體亦將含有終止轉錄及穩定mRNA所必需之序列。該等序列通常可自真核或病毒DNA或cDNA之5'及偶爾3'之未經轉譯區獲得。此等區含有在編碼抗體之mRNA之未經轉譯部分中轉錄為聚腺苷酸化片段的核苷酸區段。一種適用之轉錄終止組分為牛生長激素聚腺苷酸化區。參見WO94/11026及其中所揭示之表現載體。
g)宿主細胞之選擇及轉形
適於選殖或表現DNA於本文載體中之宿主細胞包括本文所述之高級真核細胞,包括脊椎動物宿主細胞。使脊椎動物細胞於培養物(組織培養物)中繁殖已成為常規程序。適用之哺乳動物宿主細胞株之實例為由SV40轉形之猴腎CV1細胞株(COS-7,ATCC CRL 1651);人胚腎細胞株(經次選殖在懸浮培養物中生長之293或293細胞,Graham等人,J.Gen Virol.36:59(1977));幼倉鼠腎細胞(BHK,ATCC CCL 10);中國倉鼠卵巢細胞/-DHFR(CHO,Urlaub等人,Proc.Natl.Acad.Sci.USA 77:4216(1980));小鼠足細胞(TM4,Mather,Biol.Reprod.23:243-251(1980));猴腎細胞(CV1 ATCC CCL 70);非洲綠猴腎細胞(VERO-76,ATCC CRL-1587);人宮頸癌細胞(HELA,ATCC CCL 2);犬腎細胞(MDCK,ATCC CCL 34);布法羅大鼠肝細胞(buffalo rat liver cell)(BRL 3A,ATCC CRL 1442);人肺細胞(W138,ATCC CCL 75);人肝細胞(Hep G2,HB 8065);小鼠乳腺腫瘤(MMT 060562,ATCC CCL51);TRI細胞(Mather等人,Annals N.Y.Acad.Sci.383:44-68(1982));MRC 5細胞;FS4細胞;及人肝癌細胞株(Hep G2)。
用產生抗體之上述表現載體或選殖載體使宿主細胞轉形,且在適當時經修飾之習知培養基中培養以誘導啟動子、選擇轉形體或擴增編碼所要序列之基因。
h)培養宿主細胞
可在多種培養基中培養用以產生本發明抗體之宿主細胞。諸如漢姆氏F10(Ham's F10)(Sigma)、最低必需培養基((MEM),Sigma)、RPMI-1640(Sigma)及達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle's Medium)((DMEM),Sigma)之市售培養基適於培養宿主細胞。此外,Ham等人,Meth.Enz.58:44(1979);Barnes等人,Anal.Biochem.102:255(1980);美國專利第4,767,704號、第4,657,866號、第4,927,762號、第4,560,655號或第5,122,469號;WO 90/03430;WO 87/00195;或美國專利Re.30,985中所述之任何培養基均可用作宿主細胞之培養基。任何此等培養基均可視需要補充激素及/或其他生長因子(諸如胰島素、運鐵蛋白或表皮生長因子)、鹽(諸如氯化鈉、鈣鹽、鎂鹽及磷酸鹽)、緩衝液(諸如HEPES)、核苷酸(諸如腺苷及胸苷)、抗生素(諸如GENTAMYCINTM藥物)、微量元素(定義為通常以在微莫耳濃度範圍內之最終濃度存在的無機化合物)及葡萄糖或等效能源。亦可包括熟習此項技術者已知之適當濃度之任何其他必要補充劑。諸如溫度、pH值及其類似條件之培養條件為彼等先前供選擇用於表現之宿主細胞使用之條件且對一般熟習此項技術者而言將顯而易見。
i)純化抗體
當使用重組技術時,抗體可在細胞內產生於周質間隙中或直接分泌至培養基中。若抗體在細胞內產生,則作為第一步,藉由例如離心或超濾移除微粒碎片(宿主細胞或溶解片段)。Carter等人,Bio/Technology 10:163-167(1992)描述分離分泌至大腸桿菌之周質間隙中之抗體的程序。簡言之,在乙酸鈉(pH 3.5)、EDTA及苯基甲基磺醯氟(PMSF)存在下經約30分鐘使細胞糊狀物解凍。可藉由離心移除細胞碎片。當抗體分泌至培養基中時,一般首先使用市售蛋白質濃縮
過濾器(例如Amicon或Millipore Pellicon超濾單元)濃縮該等表現系統之上清液。在任何先前步驟中均可包括諸如PMSF之蛋白酶抑制劑以抑制蛋白水解,且可包括抗生素以阻止外來污染物生長。
可使用例如羥磷灰石層析法、凝膠電泳法、透析及親和層析法純化自細胞製備之抗體組合物,其中親和層析法為較佳純化技術。蛋白質A作為親和配位體之適宜性視存在於抗體中之任何免疫球蛋白Fc域的種類及同型而定。可使用蛋白質A純化基於含有1、2或4條重鏈之人類免疫球蛋白之抗體(Lindmark等人,J.Immunol.Meth.62:1-13(1983))。對所有小鼠同型及人類3型而言,推薦蛋白質G(Guss等人,EMBO J.5:15671575(1986))。雖然親和配位體所附著之基質最常為瓊脂糖,但可利用其他基質。機械穩定基質(諸如受控微孔玻璃或聚(苯乙烯-二乙烯基)苯)所允許之流動速率比瓊脂糖可達成的快,且所允許之處理時間比瓊脂糖可達成的短。當抗體包含CH3域時,Bakerbond ABXTM樹脂(J.T.Baker,Phillipsburg,NJ)適用於純化。視待回收之抗體而定,亦可利用其他蛋白質純化技術,諸如離子交換管柱分級分離、乙醇沈澱、逆相HPLC、二氧化矽層析、肝素SEPHAROSETM層析、陰離子或陽離子交換樹脂(諸如聚天冬胺酸管柱)層析、層析聚焦、SDS-PAGE及硫酸銨沈澱。
在任何初步純化步驟後,可使包含相關抗體及污染物之混合物經受使用pH值介於約2.5-4.5之間的溶離緩衝液之低pH值疏水相互作用層析,較佳在低鹽濃度(例如約0-0.25M鹽)下進行該層析。
C.抗體製備
1)多株抗體
一般藉由多次皮下(sc)或腹膜內(ip)注射相關抗原及佐劑在動物中產生多株抗體。可能適用於使用雙功能或衍生化藥劑(例如順丁烯二醯亞胺苯甲醯磺基丁二醯亞胺酯(經由半胱胺酸殘基結合)、N-羥基
丁二醯亞胺(經由離胺酸殘基)、戊二醛、丁二酸酐、SOCl2或R1N=C=NR,其中R及R1獨立地為低碳烷基)使相關抗原結合與在待免疫之物種中具免疫原性之蛋白質結合,該等蛋白質例如匙孔螺血氰蛋白(KLH)、血清白蛋白、牛甲狀腺球蛋白或大豆胰蛋白酶抑制劑。可使用之佐劑之實例包括傅氏完全佐劑(Freund's complete adjuvant)及MPL-TDM佐劑(單磷醯基脂質A、合成繭蜜糖二黴菌酸酯(trehalose dicorynomycolate))。熟習此項技術者可在無過度實驗之情況下選擇免疫方案。
藉由使例如100μg或5μg蛋白質或結合物(分別用於兔或小鼠)與3體積傅氏完全佐劑組合且在多個部位皮內注射該溶液使動物對抗原、免疫原結合物或衍生物免疫。1個月後,在多個部位以1/5至1/10初始量之於傅氏完全佐劑中之肽或結合物皮下注射來加強動物。7至14天後,對動物進行抽血且檢定血清之抗體效價。加強動物直至達到效價平線區。結合物亦可在重組細胞培養物中作為蛋白融合體製得。諸如明礬之凝集劑亦適於增強免疫反應。
2)單株抗體
單株抗體係自一群實質上均質之抗體獲得,亦即構成此群體之個別抗體除可少量存在之可能的天然存在之突變及/或轉譯後修飾(例如異構化、醯胺化)外均相同。因此,修飾語「單株」指示抗體不為離散抗體之混合物的特徵。
舉例而言,可使用由Kohler等人,Nature, 256:495(1975)首次描述之融合瘤方法製備單株抗體,或可由重組DNA方法(美國專利第4,816,567號)製備單株抗體。
在融合瘤方法中,如上文所述使小鼠或諸如倉鼠之其他適當宿主動物免疫以激發產生或能夠產生將與用於免疫之蛋白質特異性結合的抗體的淋巴細胞。或者,可活體外使淋巴細胞免疫。接著使用諸如
聚乙二醇之適合融合劑使淋巴細胞與骨髓瘤細胞融合以形成融合瘤細胞(Goding,Monoclonal Antibodies:Principles and Practice,第59-103頁(Academic Press,1986))。
免疫劑通常將包括抗原蛋白質或其融合變異體。一般而言,若需要具有人類起源之細胞,則使用周邊血淋巴細胞(「PBL」);或若需要非人類哺乳動物來源,則使用脾臟細胞或淋巴結細胞。接著,使用諸如聚乙二醇之適合融合劑使淋巴細胞與永生化細胞株融合以形成融合瘤細胞。Goding,Monoclonal Antibodies:Principles and Practice,Academic Press(1986),第59-103頁。
永生化細胞株通常為經轉形之哺乳動物細胞,尤其齧齒動物、牛及人類起源之骨髓瘤細胞。通常使用大鼠或小鼠骨髓瘤細胞株。接種由此製備之融合瘤細胞且使之在較佳含有一或多種抑制未融合之親本骨髓瘤細胞生長或存活之物質的適合之培養基中生長。舉例而言,若親本骨髓瘤細胞缺乏酶次黃嘌呤鳥嘌呤磷酸核糖基轉移酶(HGPRT或HPRT),則用於融合瘤之培養基通常將包括次黃嘌呤、胺基喋呤及胸苷(HAT培養基),該等物質為阻止缺乏HGPRT之細胞生長的物質。
較佳永生化骨髓瘤細胞為高效融合、支持由所選擇之抗體產生細胞穩定高含量產生抗體的骨髓瘤細胞,且其對諸如HAT培養基之培養基敏感。其中,較佳為鼠類骨髓瘤細胞株,諸如可自Salk Institute Cell Distribution Center,San Diego,California USA獲得之源自MOPC-21及MPC-11小鼠腫瘤之細胞株及可自American Type Culture Collection,Manassas,Virginia USA獲得之SP-2細胞(及其衍生物,例如X63-Ag8-653)。亦已描述人類骨髓瘤及小鼠-人類雜骨髓瘤細胞株用於產生人類單株抗體(Kozbor,J.Immunol.,133:3001(1984);Brodeur等人,Monoclonal Antibody Production Techniques and Applications,第51-63頁(Marcel Dekker,Inc.,New York,1987))。
檢定融合瘤細胞生長之培養基的針對抗原之單株抗體之產生。
由融合瘤細胞產生之單株抗體之結合特異性較佳由免疫沈澱或由諸如放射免疫檢定(RIA)或酶聯免疫吸附檢定(ELISA)之活體外結合檢定來測定。
可檢定培養融合瘤細胞之培養基中針對所要抗原之單株抗體的存在。較佳地,可藉由免疫沈澱或藉由活體外結合檢定(諸如放射免疫檢定(RIA)或酶聯免疫吸附檢定(ELISA))來測定單株抗體之結合親和力及特異性。此項技術中已知該等技術及檢定。舉例而言,可由Munson等人,Anal.Biochem.,107:220(1980)之斯卡查德分析(Scatchard analysis)測定結合親和力。
鑑別產生具有所要特異性、親和力及/或活性之抗體的融合瘤細胞之後,可由限制稀釋程序次選殖純系且經由標準方法使其生長(Goding,同上)。出於此目的,適合之培養基包括例如D-MEM或RPMI-1640培養基。另外,融合瘤細胞可在哺乳動物中活體內生長為腫瘤。
由諸如蛋白質A-瓊脂糖、羥基磷灰石層析、凝膠電泳、透析或親和層析之習知免疫球蛋白純化程序適合地使由次純系分泌之單株抗體與培養基、腹水流體或血清分離。
亦可由諸如美國專利第4,816,567號中所述之彼等方法之重組DNA方法來製備單株抗體。使用習知程序(例如,藉由使用能夠與編碼鼠類抗體之重鏈及輕鏈之基因特異性結合之寡核苷酸探針)容易地分離編碼單株抗體之DNA並測序。融合瘤細胞充當該DNA之較佳來源。一旦分離後,即可將DNA置放於表現載體中,接著將該等表現載體轉染於不另外產生免疫球蛋白之諸如大腸桿菌細胞、猿猴COS細胞、中國倉鼠卵巢(CHO)細胞或骨髓瘤細胞之宿主細胞中,以在該類重組宿主細胞中合成單株抗體。關於編碼抗體之DNA之細菌中的重組
表現的綜述文章包括Skerra等人,Curr.Opinion in Immunol.,5:256-262(1993)及Plückthun,Immunol.Revs.,130:151-188(1992)。
在另一實施例中,可使用McCafferty等人,Nature,348:552-554(1990)中所述之技術自所產生之抗體噬菌體文庫中分離抗體。Clackson等人,Nature,352:624-628(1991)及Marks等人,J.Mol.Biol.,222:581-597(1991)分別描述使用噬菌體文庫分離鼠類及人類抗體。後續公開案描述藉由鏈改組(Marks等人,Bio/Technology,10:779-783(1992)),以及作為構築極大噬菌體文庫之策略的組合感染及活體內重組(Waterhouse等人,Nuc.Acids.Res.,21:2265-2266(1993))產生高親和力(奈莫耳濃度(nM)範圍)人類抗體。因此,該等技術為分離單株抗體之傳統單株抗體融合瘤技術之可行替代方案。
亦可例如藉由用人類重鏈及輕鏈恆定域之編碼序列取代同源鼠類序列(美國專利第4,816,567號;Morrison,等人,Proc.NatlAcad.Sci.USA,81:6851(1984))或藉由使整個或部分非免疫球蛋白多肽之編碼序列共價連接於免疫球蛋白編碼序列來修飾DNA。通常,該等非免疫球蛋白多肽取代抗體之恆定域,或其取代抗體之一個抗原組合位點之可變域以產生包含一個對抗原具有特異性之抗原組合位點及另一個對不同抗原具有特異性之抗原組合位點的嵌合二價抗體。
本文所述之單株抗體可為單價的,其製備在此項技術中為熟知的。舉例而言,一種方法包括重組表現免疫球蛋白輕鏈及經修飾重鏈。一般在Fc區之任一點截斷重鏈以阻止重鏈交聯。或者,相關半胱胺酸殘基可經另一胺基酸殘基取代或經缺失以阻止交聯。活體外方法亦適於製備單價抗體。消化抗體以產生其片段(尤其Fab片段)可使用此項技術中已知之常規技術來實現。
亦可使用合成蛋白質化學中之已知方法(包括彼等涉及交聯劑之方法)活體外製備嵌合或雜交抗體。舉例而言,可使用雙硫鍵交換反
應或藉由形成硫醚鍵來構築免疫毒素。適於此目的之試劑之實例包括亞胺基硫醇酯(iminothiolate)及甲基-4-巰基丁醯亞胺酯(methyl-4-mercaptobutyrimidate)。
3)人類化抗體
本發明抗體可進一步包含人類化或人類抗體。非人類(例如鼠類)抗體之人類化形式為含有衍生自非人類免疫球蛋白之最小序列之嵌合免疫球蛋白、其免疫球蛋白鏈或片段(諸如Fv、Fab、Fab'、F(ab')2或抗體之其他抗原結合子序列)。人類化抗體包括來自接受者之互補決定區(CDR)(如本文使用之HVR)之殘基經來自非人類物種(供體抗體)(諸如具有所要特異性、親和力及能力之小鼠、大鼠或兔)之CDR之殘基置換的人類免疫球蛋白(接受者抗體)。在一些情況下,人類免疫球蛋白之Fv構架殘基經相應非人類殘基置換。人類化抗體亦可包含既不可見於接受者抗體中亦不可見於輸入CDR或構架序列中之殘基。一般而言,人類化抗體將包含實質上全部至少一個及通常兩個可變域,其中全部或實質上全部CDR區對應於非人類免疫球蛋白之彼等區,且全部或實質上全部FR區為人類免疫球蛋白共同序列之彼等區。人類化抗體最佳亦包含至少一部分免疫球蛋白恆定區(Fc),通常為人類免疫球蛋白之恆定區。Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-329(1988)及Presta,Curr.Opin.Struct.Biol. 2:593-596(1992)。
此項技術中熟知使非人類抗體人類化之方法。人類化抗體一般具有一或多個自非人類來源引入之胺基酸殘基。該等非人類胺基酸殘基通常稱為「輸入」殘基,其通常取自「輸入」可變域。人類化大體上可根據Winter及合作者之方法(Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature 332:323-327(1988);Verhoeyen等人,Science 239:1534-1536(1988)),或藉由用齧齒動物CDR序列取代
人類抗體之對應序列來進行。因此,該等「人類化」抗體為嵌合抗體(美國專利第4,816,567號),其中實質上近似完整之人類可變域已經來自非人類物種之對應序列取代。實際上,人類化抗體通常為一些CDR殘基及可能一些FR殘基經齧齒動物抗體類似位點之殘基取代的人類抗體。
待用於製備人類化抗體之人類輕鏈及重鏈可變域之選擇對降低抗原性而言極重要。根據所謂的「最佳匹配」方法,針對整個已知人類可變域序列文庫篩檢齧齒動物抗體之可變域序列。接著將最接近齧齒動物序列之人類序列接受為人類化抗體之人類構架(FR)。Sims等人,J.Immunol., 151:2296(1993);Chothia等人,J.Mol.Biol.,196:901(1987)。另一方法使用衍生自具有輕鏈或重鏈之特定亞群之所有人類抗體的共同序列的特定構架區。若干不同人類化抗體可使用同一構架。Carter等人,Proc.Natl.Acad.Sci.USA,89:4285(1992);Presta等人,J.Immunol.,151:2623(1993)。
另外,經人類化抗體保留對抗原之高親和力及其他有利生物性質係重要的。為達成此目標,根據一較佳方法,藉由使用親本序列及人類化序列之三維模型來分析親本序列及各種概念性人類化產物的方法製備人類化抗體。三維免疫球蛋白模型普遍可得且為熟習此項技術者所熟知。可獲得說明及呈現所選擇之候選免疫球蛋白序列之可能三維構型結構的電腦程式。該等呈現之檢驗准許分析殘基在候選免疫球蛋白序列之功能中之可能作用,亦即,分析影響候選免疫球蛋白結合其抗原之能力的殘基。以此方式,可自接受者序列及輸入序列選擇FR殘基且將其加以組合,以便達成所要抗體特徵,諸如對標靶抗原之親和力增加。CDR殘基通常直接且大部分實質上涉及對抗原結合之影響。
涵蓋各種形式之人類化抗體。舉例而言,人類化抗體可為諸如
Fab之抗體片段,其視情況與一或多種細胞毒性劑結合以產生免疫結合物。或者,人類化抗體可為完整抗體,諸如完整IgG1抗體。
4)人類抗體
作為人類化之替代,可產生人類抗體。舉例而言,現有可能產生在免疫後在不存在產生內源免疫球蛋白之情況下能夠產生全譜系人類抗體之轉殖基因動物(例如,小鼠)。舉例而言,已描述嵌合及生殖系突變小鼠中抗體重鏈連接區(JH)基因之同型純合子缺失導致內源抗體產生之完全抑制。將人類生殖系免疫球蛋白基因陣列轉移至該等生殖系突變小鼠中將會在抗原攻擊後產生人類抗體。參見例如Jakobovits等人,Proc.Natl.Acad.Sci.USA,90:2551(1993);Jakobovits等人,Nature,362:255-258(1993);Bruggermann等人,Year in Immuno.,7:33(1993);美國專利第5,591,669號及WO 97/17852。
或者,可使用噬菌體呈現技術由未免疫供體之免疫球蛋白可變(V)域基因譜系活體外產生人類抗體及抗體片段。McCafferty等人,Nature 348:552-553(1990);Hoogenboom及Winter,J.Mol.Biol. 227:381(1991)。根據該技術,將抗體V域基因同框(in-frame)選殖於絲狀噬菌體之主要或次要鞘蛋白基因(諸如M13或fd)中且呈現為噬菌體顆粒之表面上之功能抗體片段。因為絲狀顆粒含有噬菌體基因組之單鏈DNA複本,所以基於抗體之功能性質進行選擇亦促使選擇編碼展示彼等性質之抗體之基因。因此,噬菌體模擬B-細胞之一些性質。可以多種格式進行噬菌體呈現;綜述於例如Johnson,Kevin S.及Chiswell,David J.,Curr.Opin Struct.Biol. 3:564-571(1993)中。噬菌體呈現可使用若干V基因區段來源。Clackson等人,Nature 352:624-628(1991)自衍生自免疫小鼠之脾之V基因之小隨機組合文庫分離抗噁唑酮抗體之多樣性陣列。可構築未免疫人類供體之V基因譜系且可大體上根據
Marks等人,J.Mol.Biol.222:581-597(1991)或Griffith等人,EMBO J.12:725-734(1993)所述之技術分離多樣性抗原(包括自體抗原)陣列之抗體。亦參見美國專利第5,565,332號及第5,573,905號。
亦可利用Cole等人及Boerner等人之技術製備人類單株抗體(Cole等人,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,第77頁(1985)及Boerner等人,J.Immunol. 147(1):86-95(1991)。類似地,亦可藉由將人類免疫球蛋白基因座引入轉殖基因動物中來製備人類抗體,該轉殖基因動物例如內源性免疫球蛋白基因已部分或完全失活之小鼠。攻擊後,觀察人類抗體產生,其在各方面均與人類中所見極其類似,包括基因重排、裝配及抗體譜系。此方法描述於例如美國專利第5,545,807號;第5,545,806號;第5,569,825號;第5,625,126號;第5,633,425號;第5,661,016號及以下科學出版物中:Marks等人,Bio/Technology 10:779-783(1992);Lonberg等人,Nature 368:856-859(1994);Morrison,Nature 368:812-13(1994);Fishwild等人,Nature Biotechnology 14:845-51(1996);Neuberger,Nature Biotechnology 14:826(1996)及Lonberg及Huszar,Intern.Rev.Immunol. 13:65-93(1995)。
最後,亦可由經活化B細胞活體外產生人類抗體(參見美國專利第5,567,610號及第5,229,275號)。
5)抗體片段
在某些情形下,使用抗體片段而非全抗體具有優勢。較小片段尺寸可允許快速清除且可產生改進之通向實體腫瘤之通道。
已開發多種產生抗體片段之技術。該等片段傳統上經由完整抗體之蛋白水解消化獲得(參見例如Morimoto等人,J Biochem Biophys.Method. 24:107-117(1992);及Brennan等人,Science,229:81(1985))。然而,現可由重組宿主細胞直接產生該等片段。Fab、Fv及
ScFv抗體片段所有皆可表現於大腸桿菌中且自大腸桿菌分泌,因此容易地產生大量此等片段。可自以上所討論之抗體噬菌體文庫分離抗體片段。或者,可直接自大腸桿菌回收Fab'-SH片段且使其化學偶合以形成F(ab')2片段(Carter等人,Bio/Technology 10:163-167(1992))。根據另一方法,可自重組宿主細胞培養物直接分離F(ab')2片段。活體內半衰期增加之Fab及F(ab')2描述於美國專利第5,869,046號中。在其他實施例中,所選擇之抗體為單鏈Fv片段(scFv)。參見WO 93/16185;美國專利第5,571,894號及美國專利第5,587,458號。抗體片段亦可為「線性抗體」,例如如美國專利5,641,870中所述。該等線性抗體片段可為單特異性或雙特異性抗體。
6)抗體依賴性酶介導之前藥療法(ADEPT)
本發明抗體亦可藉由使抗體與前藥活化酶結合而用於ADEPT中,該前藥活化酶使前藥(例如肽基化學治療劑,參見WO 81/01145)轉化為活性抗癌藥。參見例如WO 88/07378及美國專利第4,975,278號。
適用於ADEPT之免疫結合物之酶組分包括能夠對前藥起作用以便使其轉化為其更具活性之細胞毒性形式之任何酶。
適用於本發明方法之酶包括(但不限於)糖苷酶、葡萄糖氧化酶、人類溶菌酶、人類葡糖醛酸酶、適用於使含磷酸酯前藥轉化為游離藥物之鹼性磷酸酶;適用於使含硫酸酯前藥轉化為游離藥物之芳基硫酸酯酶;適用於使無毒5-氟胞嘧啶轉化為抗癌藥物5-氟尿嘧啶之胞嘧啶去胺酶;適用於使含肽前藥轉化為游離藥物之蛋白酶,諸如沙雷氏菌蛋白酶(serratia protease)、嗜熱菌蛋白酶、枯草桿菌蛋白酶、羧肽酶(例如羧肽酶G2及羧基肽酶A)及組織蛋白酶(諸如組織蛋白酶B及L);適用於轉化含有D-胺基酸取代基之前藥的D-丙胺醯基羧肽酶;適用於使糖基化前藥轉化為游離藥物之碳水化合物裂解酶,諸如β-半乳糖苷
酶及神經胺糖酸苷酶;適用於使經β-內醯胺衍生之藥物轉化為游離藥物之β-內醯胺酶;及適用於使分別在胺氮處經苯氧基乙醯基或苯乙醯基衍生之藥物轉化為游離藥物之青黴素醯胺酶,諸如青黴素V醯胺酶或青黴素G醯胺酶。或者,可使用在此項技術中亦稱為「抗體酶」之具有酶促活性之抗體使本發明前藥轉化為游離活性藥物(參見例如Massey,Nature 328:457-458(1987))。可如本文所述製備抗體-抗體酶結合物以將抗體酶傳遞至腫瘤細胞群體中。
上述酶可由此項技術中熟知之技術(諸如使用以上所討論之異雙功能交聯劑)與本文所述之多肽或抗體共價結合。或者,可使用此項技術中熟知之重組DNA技術構築包含與本發明酶之至少一個功能活性部分連接之本發明抗體之至少一個抗原結合區的融合蛋白(參見例如Neuberger等人,Nature 312:604-608(1984))。
7)雙特異性及多特異性抗體
雙特異性抗體(BsAb)為對至少兩個不同抗原決定基(包括同一或另一蛋白質上之抗原決定基)具有結合特異性之抗體。或者,一個臂可與標靶抗原結合,且另一臂可與結合白血球上之觸發分子(諸如T細胞受體分子(例如CD3)或IgG之Fc受體(FcγR),諸如FcγR1(CD64)、FcγRII(CD32)及FcγRIII(CD16))之臂組合,以便將細胞防禦機制聚焦且定位於標靶抗原表現細胞。該等抗體可衍生自全長抗體或抗體片段(例如F(ab')2雙特異性抗體)。
雙特異性抗體亦可用於將細胞毒性劑定位於表現標靶抗原之細胞。該等抗體具有一個結合所要抗原之臂及另一結合細胞毒性劑(例如沙泊寧(saporin)、抗干擾素-α、長春生物鹼、篦麻毒素A鏈(ricin A chain)、甲胺喋呤或放射性同位素半抗原)之臂。已知雙特異性抗體之實例包括抗ErbB2/抗FcgRIII(WO 96/16673)、抗ErbB2/抗FcgRI(U.S.P.5,837,234)、抗ErbB2/抗CD3(U.S.P.5,821,337)。
此項技術中已知製造雙特異性抗體之方法。全長雙特異性抗體之傳統產生係基於兩個免疫球蛋白重鏈/輕鏈對之共表現,其中兩個鏈具有不同特異性。Millstein等人,Nature,305:537-539(1983)。由於免疫球蛋白重鏈及輕鏈之隨機分配,因此該等融合瘤(四融合瘤(quadromas))產生10種不同抗體分子之潛在混合物,其中僅一個具有正確的雙特異性結構。通常由親和層析步驟進行之正確分子之純化相當繁瑣且產物產率低。類似程序揭示於WO 93/08829中及Traunecker等人,EMBO J.,10:3655-3659(1991)中。
根據一種不同方法,使具有所要結合特異性(抗體-抗原組合位點)之抗體可變域與免疫球蛋白恆定域序列融合。較佳與包含鉸鏈區、CH2及CH3區中之至少部分之免疫球蛋白重鏈恆定域融合。較佳具有第一重鏈恆定區(CH1),該恆定區含有輕鏈結合所必需之位點(存在於融合中之至少一者中)。將編碼免疫球蛋白重鏈融合及必要時編碼免疫球蛋白輕鏈之DNA插入獨立表現載體中且共轉染於適合之宿主生物體中。在構築中所使用之3個多肽鏈之不相等比率提供最佳產率之實施例中,此舉提供調節3個多肽片段之相互比例之高靈活性。然而,當等比率之至少兩個多肽鏈之表現產生高產率時或當比率不具有特殊顯著性時,有可能將兩個或所有三個多肽鏈之編碼序列插入一個表現載體中。
在該方法之一較佳實施例中,雙特異性抗體包含一臂中之具有第一結合特異性之雜交免疫球蛋白重鏈及另一臂中之雜交免疫球蛋白重鏈-輕鏈對(提供第二結合特異性)。已發現該不對稱結構有利於分離所要雙特異性化合物與非所要免疫球蛋白鏈組合,因為雙特異性分子之僅一半中存在免疫球蛋白輕鏈提供容易的分離方法。該方法揭示於WO 94/04690中。關於產生雙特異性抗體之其他詳情,參見例如Suresh等人,Methods in Enzymology,121:210(1986)。
根據WO 96/27011或美國專利5,731,168中所述之另一方法,可使一對抗體分子之間的界面工程化以最大化自重組細胞培養物回收之雜二聚體的百分率。較佳界面包含抗體恆定域之CH3區之至少一部分。在該方法中,用較大側鏈(例如酪胺酸或色胺酸)置換一或多個來自第一抗體分子界面之小胺基酸側鏈。藉由用較小側鏈(例如丙胺酸或蘇胺酸)置換大胺基酸側鏈在第二抗體分子界面上產生具有與大側鏈相同或相似大小之補償「空穴」。此舉提供使雜二聚體之產率增加超過諸如均二聚體之非所要最終產物之機制。
文獻中已描述由抗體片段產生雙特異性抗體之技術。舉例而言,可使用化學鍵聯製備雙特異性抗體。Brennan等人,Science 229:81(1985)描述使完整抗體蛋白水解裂解以產生F(ab')2片段之程序。在二硫醇錯合劑亞砷酸鈉存在下,該等片段被還原以使鄰二硫醇穩定且阻止形成分子間二硫化物。接著使所產生之Fab'片段轉化為硫基硝基苯甲酸酯(TNB)衍生物。接著使Fab'-TNB衍生物中之一者再轉化為Fab'-TNB衍生物以形成雙特異性抗體。所產生之雙特異性抗體可用作酶選擇性固定化之試劑。
可自大腸桿菌中直接回收Fab'片段且使該等片段化學偶合形成雙特異性抗體。Shalaby等人,J.Exp.Med.,175:217-225(1992)描述完全人類化雙特異性抗體F(ab')2分子之產生。各Fab'片段係獨立地自大腸桿菌分泌且使其活體外經受直接化學偶合以形成雙特異性抗體。所形成之雙特異性抗體能夠與過度表現ErbB2受體之細胞及正常人類T細胞結合,以及觸發人類細胞毒性淋巴細胞對人類乳房腫瘤標靶之溶解活性。
亦已描述多種直接自重組細胞培養物製備及分離二價抗體片段之技術。舉例而言,已使用白胺酸拉鏈產生二價雜二聚體。Kostelny等人,J.Immunol.,148(5):1547-1553(1992)。藉由基因融合使來自
Fos蛋白質及Jun蛋白質之白胺酸拉鏈肽與兩個不同抗體之Fab'部分連接。使抗體均二聚體在鉸鏈區處還原以形成單體且接著再氧化以形成抗體雜二聚體。Hollinger等人,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)所述之「雙功能抗體」技術已提供製備雙特異性/二價抗體片段之替代機制。該等片段包含經由過短而無法使同一鏈上之兩個域配對之連接子與輕鏈可變域(VL)連接之重鏈可變域(VH)。因此,一個片段之VH域及VL域被迫與另一片段之互補VL域及VH配對,從而形成兩個抗原結合位點。亦已報導利用單鏈Fv(sFv)二聚體製備雙特異性/二價抗體片段之另一策略。參見Gruber等人,J.Immunol.,152:5368(1994)。
涵蓋具有超過兩個價數之抗體。舉例而言,可製備三特異性抗體。Tutt等人,J.Immunol. 147:60(1991)。
例示性雙特異性抗體可與既定分子上之兩個不同抗原決定基結合。或者,抗蛋白質臂可與結合白血球上之觸發分子(諸如T細胞受體分子(例如CD2、CD3、CD28或B7);或IgG之Fc受體(FcγR),諸如FcγRI(CD64)、FcγRII(CD32)及FcγRIII(CD16))的臂組合以便將細胞防禦機制聚焦於表現特定蛋白質之細胞。雙特異性抗體亦可用於將細胞毒性劑定位於表現特定蛋白質之細胞。該等抗體具有蛋白結合臂及結合細胞毒性劑或放射性核素螯合劑(諸如EOTUBE、DPTA、DOTA或TETA)之臂。另一相關雙特異性抗體結合相關蛋白質且進一步結合組織因子(TF)。
8)多價抗體
與二價抗體相比,表現抗體所結合之抗原的細胞可能更快地內化(及/或異化(catabolized))多價抗體。本發明抗體可為具有三個或三個以上抗原結合位點之多價抗體(其為除IgM類別以外之抗體)(例如四價抗體),其可容易地藉由重組表現編碼抗體多肽鏈之核酸產生。多
價抗體可包含一個二聚化域及三個或三個以上抗原結合位點。較佳二聚化域包含一Fc區或一鉸鏈區(或由其組成)。在此情況下,抗體將包含一Fc區及在Fc區胺基末端之三個或三個以上抗原結合位點。本文之較佳多價抗體包含3至約8個、但較佳4個抗原結合位點(或由其組成)。多價抗體包含至少一條多肽鏈(且較佳兩條多肽鏈),其中該(等)多肽鏈包含兩個或兩個以上可變域。舉例而言,多肽鏈可包含VD1-(X1)n-VD2-(X2)n-Fc,其中VD1為第一可變域,VD2為第二可變域,Fc為Fc區之一條多肽鏈,X1及X2表示胺基酸或多肽,且n為0或1。舉例而言,多肽鏈可包含VH-CH1-可撓性連接子-VH-CH1-Fc區鏈或VH-CH1-VH-CH1-Fc區鏈。本文之多價抗體較佳進一步包含至少2個(且較佳4個)輕鏈可變域多肽。本文之多價抗體可例如包含約2至約8個輕鏈可變域多肽。此處涵蓋之輕鏈可變域多肽包含輕鏈可變域且視情況進一步包含CL域。
9)雜結合抗體
雜結合抗體亦在本發明之範疇內。雜結合抗體由兩個共價連接之抗體構成。舉例而言,雜結合物中之一個抗體可與抗生物素蛋白偶合,另一抗體與生物素偶合。舉例而言,提出該等抗體使免疫系統細胞靶向不合需要之細胞(U.S.P.4,676,980)且治療HIV感染。WO 91/00360、WO 92/200373及EP 0308936。預期可使用合成蛋白質化學中已知之方法(包括涉及交聯劑之方法)活體外製備抗體。舉例而言,可使用雙硫鍵交換反應或藉由形成硫醚鍵來構築免疫毒素。適於此目之試劑之實例包括亞胺硫醇酯及甲基-4-巰基丁亞胺酯及例如美國專利第4,676,980號中所揭示之試劑。可使用任何方便之交聯方法製備雜結合抗體。適合之交聯劑以及許多交聯技術在此項技術中為熟知的且揭示於美國專利第4,676,980號中。
10)效應功能工程改造
可能需要在Fc效應功能方面對本發明抗體進行修飾,例如以便改良(例如增進或消除)抗體之抗原依賴性細胞介導細胞毒性(antigen-dependent cell-mediated cyotoxicity,ADCC)及/或補體依賴性細胞毒性(complement dependent cytotoxicity,CDC))。在一較佳實施例中,降低或消除抗PD-L1抗體之Fc效應功能。此舉可藉由將一或多個胺基酸取代引入抗體之Fc區中來達成。或者或另外,可將半胱胺酸殘基引入Fc區中,藉此允許在此區中形成鏈間雙硫鍵。由此產生之均二聚抗體可具有改良之內化能力及/或增加之補體介導細胞殺死及抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity,ADCC)。參見Caron等人,J.Exp Med.176:1191-1195(1992)及Shopes,B.J.Immunol.148:2918-2922(1992)。亦可使用如Wolff等人,Cancer Research 53:2560-2565(1993)中所述之異雙功能交聯劑來製備抗腫瘤活性增強之均二聚抗體。或者,抗體可經工程改造,具有雙Fc區且藉此可具有增強之補體溶解及ADCC能力。參見Stevenson等人,Anti-Cancer Drug_Design 3:219-230(1989)。
舉例而言,如美國專利第5,739,277號中所述,為增加抗體之血清半衰期,可將救助受體結合抗原決定基併入抗體(尤其抗體片段)中。如本文所用之術語「救助受體結合抗原決定基」係指IgG分子(例如IgG1、IgG2、IgG3或IgG4)之Fc區之抗原決定基,其負責增加IgG分子之活體內血清半衰期。
11)其他胺基酸序列修飾
涵蓋本文所述之抗體之胺基酸序列修飾。舉例而言,可能需要改良抗體之結合親和力及/或其他生物性質。抗體之胺基酸序列變異體係藉由將適當核苷酸變化引入抗體核酸中製備或由肽合成製備。該等修飾包括例如使抗體之胺基酸序列內的殘基缺失及/或在該等殘基中插入其他殘基及/或使該等殘基被取代。可進行缺失、插入及取代
之任何組合以獲得最終構築體,其限制條件為最終構築體具有所要特徵。胺基酸變化在抗體之轉譯過程後亦可能改變,諸如糖基化位點之編號或位置變化。
鑑別抗體之某些為突變誘發之較佳位置的殘基或區的適用方法如Cunningham及Wells,Science,244:1081-1085(1989)所述稱為「丙胺酸掃描突變誘發」。此處,鑑別殘基或標靶殘基組(例如,帶電殘基,諸如arg、asp、his、lys及glu)且用中性或帶負電胺基酸(最佳為丙胺酸或聚丙胺酸)將其置換以影響胺基酸與抗原之相互作用。隨後藉由在取代位點處或針對取代位點引入其他變異體來改進彼等對取代證實功能敏感性之胺基酸位置。因此,雖然預先確定引入胺基酸序列變化之位點,但不必預先確定突變之性質本身。舉例而言,為分析給定位點處之突變效能,在標靶密碼子或區處進行ala掃描或隨機突變誘發,且就所要活性篩檢所表現之抗體變異體。
胺基酸序列插入包括長度在1個殘基至含有一百個或以上之殘基之多肽範圍內的胺基及/或羧基末端融合,以及單一或多個胺基酸殘基之序列內插入。末端插入之實例包括具有N末端甲硫胺醯基殘基之抗體或與細胞毒性多肽融合之抗體。抗體分子之其他插入變異體包括抗體之N末端或C末端與酶(例如,對於ADEPT而言)或多肽的融合體,其增加抗體之血清半衰期。
另一類變異體為胺基酸取代變異體。該等變異體在抗體分子中具有至少一個經不同殘基置換之胺基酸殘基。雖然最受關注之取代性突變誘發之位點包括高變區,但亦涵蓋FR變化。保守取代展示於下表A中之「較佳取代」之標題下。若該等取代導致生物活性變化,則可引入表A中稱為「例示性取代」或如以下關於胺基酸類別之進一步所描述之更實質性變化且篩檢產物。
抗體之生物性質之實質性修飾係藉由選擇對維持以下之作用顯著不同的取代來實現:(a)取代區域中之多肽主鏈之結構,例如呈摺疊片或螺旋構型;(b)標靶位點處分子之電荷或疏水性;或(c)側鏈大小。基於常見側鏈性質將天然存在之殘基分為以下群組:(1)疏水性:正白胺酸、met、ala、val、leu、ile;(2)中性親水性:cys、ser、thr;(3)酸性:asp、glu;(4)鹼性:asn、gln、his、lys、arg;(5)影響鏈取向之殘基:gly、pro;及(6)芳族:trp、tyr、phe。
非保守取代將必然使該等類別中之一者之成員換成另一類別。
通常亦可用絲胺酸取代任何不涉及維持抗體之適當構型之半胱胺酸殘基以改良分子之氧化穩定性且阻止異常交聯。相反地,可將半胱胺酸鍵添加至抗體中以改良其穩定性(尤其當抗體為諸如Fv片段之抗體片段時)。
一類尤其較佳取代性變異體涉及取代親本抗體(例如,人類化抗體或人類抗體)之一或多個高變區殘基。相對於產生該等變異體之親本抗體,選擇用於進一步研發之所得變異體通常將具有改良之生物性質。產生該等取代性變異體之方便方法涉及使用噬菌體呈現之親和力成熟。簡言之,使若干高變區位點(例如,6-7個位點)突變以在各位點處產生所有可能的胺基酸取代。使如此產生之抗體變異體與封裝於各絲狀噬菌體顆粒內之M13之基因III產物融合而由絲狀噬菌體顆粒以單價形式呈現。隨後,如本文所揭示,就生物活性(例如,結合親和力)篩檢噬菌體呈現變異體。為鑑別用於修飾之候選高變區位點,可進行丙胺酸掃描突變誘發以鑑別顯著有助於抗原結合之高變區殘基。或者或另外,分析抗原-抗體複合物之晶體結構可有益於鑑別抗體與其標靶(例如PD-L1、B7.1)之間的接觸點。根據本文詳述之技術,該等接觸殘基及相鄰殘基為取代候選物。一旦產生該等變異體,則如本文所述使一系列變異體經受篩檢,且可選擇在一或多個相關檢定中具有優良性質之抗體以用於進一步研發。
另一類抗體胺基酸變異體改變抗體之原始糖基化模式。改變意謂使抗體中發現之一或多個碳水化合物部分缺失及/或添加抗體中不存在之一或多個糖基化位點。
抗體之糖基化通常為N-連接型或O-連接型。N-連接型係指碳水化合物部分與天冬醯胺酸殘基之側鏈的連接。三肽序列天冬醯胺酸-X-絲胺酸及天冬醯胺酸-X-蘇胺酸(其中X為除脯胺酸以外之任何胺基酸)為碳水化合物部分與天冬醯胺酸側鏈之酶促連接的識別序列。因
此,在多肽中存在該等三肽序列中之任一者產生潛在糖基化位點。雖然O-連接型糖基化係指糖N-乙醯基半乳胺糖、半乳糖或木糖中之一者與羥基胺基酸(最常見為絲胺酸或蘇胺酸)的連接,但亦可使用5-羥基脯胺酸或5-羥基離胺酸。
宜藉由改變胺基酸序列將糖基化位點添加至抗體中從而使其含有上述三肽序列中之一或多者來實現(就N-連接型糖基化位點而言)。該改變亦可藉由向原始抗體之序列添加一或多個絲胺酸或蘇胺酸殘基或用一或多個絲胺酸或蘇胺酸殘基取代來實現(就O-連接型糖基化位點而言)。
編碼本發明抗體胺基酸序列變異體之核酸分子由此項技術中已知之多種方法製備。此等方法包括(但不限於)自天然來源分離(在天然存在之胺基酸序列變異體之情況下),或藉由早期製備之變異體或非變異體形式發生寡核苷酸介導(或定點特異性)之突變誘發、PCR突變誘發及卡匣突變誘發來製備。
12)其他抗體修飾
本發明抗體可經進一步修飾以含有此項技術中已知且易於利用之其他非蛋白質部分。較佳地,適於衍生抗體之部分為水可溶聚合物。水可溶聚合物之非限制性實例包括(但不限於)聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纖維素、葡聚糖、聚乙烯醇、聚乙烯吡咯啶酮、聚-1,3-二氧戊環、聚-1,3,6-三噁烷、乙烯/順丁烯二酸酐共聚物、聚胺基酸(均聚物或無規共聚物)及葡聚糖或聚(N-乙烯吡咯啶酮)聚乙二醇、聚丙二醇均聚物、聚氧化丙烯/氧化乙烯共聚物、聚乙氧基化多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛因其於水中之穩定性而可在製造中具有優勢。聚合物可具有任何分子量,且可為分支或未分支聚合物。與抗體連接之聚合物的數目可變化,且若連接一個以上聚合物,則聚合物可為相同或不同分子。一般而言,
用於衍生化之聚合物之數目及/或類型可基於以下考慮因素來確定,該等考慮因素包括(但不限於)待改良之抗體之特定性質或功能、抗體衍生物是否將在規定條件下用於療法中等。該等技術及其他適合之調配物揭示於Remington:The Science and Practice of Pharmacy,第20版,Alfonso Gennaro編,Philadelphia College of Pharmacy and Science(2000)中。
D.醫藥調配物
藉由混合具有所要純度之活性成份與視情況選用之醫藥學上可接受之載劑、賦形劑或穩定劑來製備治療調配物以儲存(Remington:The Science and Practice of Pharmacy,第20版,Lippincott Williams & Wiklins,Pub.,Gennaro編,Philadelphia,PA 2000)。可接受之載劑、賦形劑或穩定劑在所用劑量及濃度下對接受者而言無毒,且包括緩衝液、抗氧化劑(包括抗壞血酸、甲硫胺酸、維生素E、偏亞硫酸氫鈉)、防腐劑、等張劑、穩定劑、金屬錯合物(例如Zn-蛋白質錯合物)、螯合劑(諸如EDTA)及/或非離子型界面活性劑。
當治療劑為抗體片段時,特異性結合標靶蛋白質之結合域之最小抑制性片段較佳。舉例而言,可基於抗體之可變區序列設計保留結合標靶蛋白質序列之能力的抗體片段或甚至肽分子。該等肽可藉由化學上合成及/或利用DNA重組技術產生(參見例如Marasco等人,Proc.Natl.Acad.Sci.USA 90:7889-7893[1993])。
使用緩衝液將pH值控制在使療效最佳之範圍內,當穩定性具有pH依賴性時尤其如此。緩衝液之濃度較佳在約50mM至約250mM範圍內。適用於本發明之緩衝劑包括有機酸與無機酸及其鹽。舉例而言,檸檬酸鹽、磷酸鹽、丁二酸鹽、酒石酸鹽、反丁烯二酸鹽、葡糖酸鹽、草酸鹽、乳酸鹽、乙酸鹽。另外,緩衝液可包含組胺酸及三甲胺鹽(諸如Tris)。
添加防腐劑以延遲微生物生長,且添加量通常在0.2%-1.0%(w/v)範圍內。適用於本發明之防腐劑包括氯化十八基二甲基苯甲基銨;氯化六烴季銨;鹵化苯甲烴銨(例如氯化苯甲烴銨、溴化苯甲烴銨,碘化苯甲烴銨)、苄索氯銨(benzethonium chloride);硫柳汞、苯酚、丁醇或苯甲醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇、3-戊醇及間甲酚。
存在張力劑(有時稱為「穩定劑」)以調整或維持組合物中液體之張力。當與大帶電生物分子(諸如蛋白質及抗體)使用時,其通常稱為「穩定劑」,此係因為其可與胺基酸側鏈之帶電基團相互作用,藉此減小分子間及分子內相互作用之潛能。考慮到其他成份之相對量,張力劑可以0.1重量%至25重量%、較佳地1重量%至5重量%之間的任何量存在。較佳張力劑包括多元糖醇,較佳三元或三元以上糖醇(higher sugar alcohol),諸如甘油、赤藻糖醇、阿糖醇、木糖醇、山梨糖醇及甘露糖醇。
其他賦形劑包括可充當一或多種以下之試劑:(1)增積劑,(2)溶解增強劑,(3)穩定劑,及(4)阻止變性或黏著於容器壁之試劑。該等賦形劑包括:多元糖醇(以上所列舉);胺基酸,諸如丙胺酸、甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸、離胺酸、鳥胺酸、白胺酸、2-苯丙胺酸、麩胺酸、蘇胺酸等;有機糖或糖醇,諸如蔗糖、乳糖、乳糖醇、海藻糖、水蘇糖、甘露糖、山梨糖、木糖、核糖、核糖醇、肌糖(myoinisitose)、肌糖醇(myoinisitol)、半乳糖、半乳糖醇、甘油、環多醇(例如肌醇)、聚乙二醇;含硫還原劑,諸如尿素、麩胱甘肽、硫辛酸、硫代羥乙酸鈉、硫代甘油、α-單硫代甘油及硫代硫酸鈉;低分子量蛋白質,諸如人血清白蛋白、牛血清白蛋白、明膠或其他免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;單醣(例如木糖、甘露糖、果糖、葡萄糖);雙醣(例如乳糖、麥芽糖、蔗糖);三
醣,諸如棉子糖;及多醣,諸如糊精或葡聚糖。
存在非離子型界面活性劑或清潔劑(亦稱為「濕潤劑」)以有助於使治療劑增溶以及保護治療蛋白質以免發生攪動誘導之聚集,其亦允許調配物暴露於剪切表面應力而不引起活性治療蛋白質或抗體變性。非離子型界面活性劑之存在量在約0.05mg/ml至約1.0mg/ml、較佳約0.07mg/ml至約0.2mg/ml範圍內。
適合之非離子型界面活性劑包括聚山梨醇酯(20、40、60、65、80等)、泊洛沙姆(polyoxamer)(184、188等)、PLURONIC®多元醇、TRITON®、聚氧化乙烯脫水山梨糖醇單醚(TWEEN®-20、TWEEN®-80等)、聚桂醇400、硬脂酸聚乙二醇40、聚氧化乙烯氫化蓖麻油10、50及60、單硬脂酸甘油酯、蔗糖脂肪酸酯、甲基纖維素及羧甲基纖維素。可使用之陰離子清潔劑包括月桂基硫酸鈉、丁二酸二辛酯磺酸鈉及二辛基磺酸鈉。陽離子清潔劑包括氯化苯甲烴銨或苄索氯銨。
為使調配物用於活體內投藥,其必須為無菌的。可藉由經無菌過濾膜過濾使調配物無菌。一般將本文之治療組合物置放於具有無菌接取口之容器中,例如具有可由皮下注射針刺穿之塞子的靜脈內溶液袋或小瓶。
投藥途徑與已知且公認之方法一致,諸如藉由在一段長時間內以適合之方式單次或多次快速注射或輸注(例如藉由皮下、靜脈內、腹膜內、肌肉內、動脈內、病灶內或關節內途徑注射或輸注)、表面投藥、吸入或藉由持續釋放或延長釋放方式。
本文之調配物亦可含有所治療之特定適應症所必需的一種以上活性化合物,較佳具有彼此並無不利影響之互補活性之活性化合物。或者或另外,組合物可包含細胞毒性劑、細胞激素或生長抑制劑。該等分子適當以對預定目的有效之量組合存在。
亦可例如藉由凝聚技術或藉由界面聚合將活性成份截留在所製
備之微囊(例如分別為羥甲基纖維素或明膠微囊及聚(甲基丙烯酸甲酯)微囊)中、截留在膠狀藥物傳遞系統(例如脂質體、白蛋白微球體、微乳液、奈米粒子及奈米膠囊)中或截留在巨乳液中。該等技術揭示於Remington's Pharmaceutical Sciences第18版,同上中。
可經由使用無毒「水可溶多價金屬鹽」增進本文所述蛋白質及抗體之穩定性。鹽之實例包括Ca2+、Mg2+、Zn2+、Fe2+、Fe3+、Cu2+、Sn2+、Sn4+、Al2+及Al3+。可與上述多價金屬陽離子形成水可溶鹽之陰離子的實例包括彼等由無機酸及/或有機酸形成之陰離子。該等水可溶鹽於水中之溶解度(在20℃下)為至少約20mg/ml,或者至少約100mg/ml,或者至少約200mg/ml。
可用於形成「水可溶多價金屬鹽」之適合之無機酸包括鹽酸、乙酸、硫酸、硝酸、硫氰酸及磷酸。可使用之適合有機酸包括脂族羧酸及芳族酸。此定義中之脂族酸可定義為飽和或不飽和C2-9羧酸(例如脂族單羧酸、脂族二羧酸及脂族三羧酸)。舉例而言,此定義中之例示性單羧酸包括飽和C2-9單羧酸(乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸及癸酸)及不飽和C2-9單羧酸(丙烯酸、丙炔酸、甲基丙烯酸、丁烯酸及異巴豆酸)。例示性二羧酸包括飽和C2-9二羧酸(丙二酸、丁二酸、戊二酸、己二酸及庚二酸),而不飽和C2-9二羧酸包括順丁烯二酸、反丁烯二酸的、甲基順丁烯二酸及甲基反丁烯二酸。例示性三羧酸包括飽和C2-9三羧酸(丙三羧酸及1,2,3-丁烷三羧酸)。另外,此定義之羧酸亦可含有一或兩個羥基以形成羥基羧酸。例示性羥基羧酸包括乙醇酸、乳酸、甘油酸、羥丙二酸、蘋果酸、酒石酸及檸檬酸。此定義中之芳族酸包括苯甲酸及水楊酸。
通常使用之可用於幫助使經囊封本發明多肽穩定的水可溶多價金屬鹽包括例如:(1)無機酸金屬鹽:鹵化物(例如氯化鋅、氯化鈣)、硫酸鹽、硝酸鹽、磷酸鹽及硫氰酸鹽;(2)脂族羧酸金屬鹽(例如乙酸
鈣、乙酸鋅、丙酸鈣、羥乙酸鋅、乳酸鈣、乳酸鋅及酒石酸鋅);及(3)芳族羧酸金屬鹽:苯甲酸鹽(例如苯甲酸鋅)及水楊酸鹽。
E.治療方法:對於疾病之預防或治療,活性劑之適當劑量將視以下而定:如上所定義之待治療疾病之類型、疾病嚴重程度及過程、投與藥劑用於預防性目的還是治療性目的、先前療法、患者臨床病史及對藥劑之反應及主治醫師之判斷。適合地,將藥劑一次性或經一系列治療投與患者。
在一特定實施例中,本發明係關於藉由減弱經由PD-1之信號傳導引起協同刺激,尤其藉由施用阻止結合PD-1及/或B7.1之PD-L1抗體來減弱,以及關於T細胞功能障礙病症之治療性治療。
1.感染
PD-1及其配位體(「PD-1:PD-L」)在調控針對引起急性及慢性感染之病原體之免疫防禦中發揮重要作用。PD-1:PD-L信號傳導在調控有效抗微生物免疫防禦與免疫介導之組織損傷之間的平衡中發揮關鍵作用。舉例而言,雖然PD-1基因剔除小鼠清除腺病毒感染比其野生型對應小鼠快,但其發展更嚴重之肝細胞損傷。Iwai等人,J.Exp.Med. 198:39-50(2003)。在疱疹基質性角膜炎小鼠模型中,阻斷抗PD-L1抗體使角膜炎惡化,從而增強HSV-1特異性效應CD4 T細胞之擴充及IFN-γ之產生及存活。Jun等人,FEBS Lett. 579:6259-64(2005)。
引起慢性感染之微生物利用PD-1:PD-L信號傳導路徑逃避宿主免疫反應,此導致慢性感染。引起慢性感染之病毒可使病毒特異性T細胞變成非功能性細胞,且藉此使抗病毒T細胞反應沉默。Barber等人,Nature 439:682-87(2006);Wherry等人,J.Virol. 78:5535-45(2004)。CD8+ T細胞之T細胞耗竭或無反應為慢性感染期間病毒控制無效之重要原因,且為小鼠慢性LCMV感染以及人類HIV、HBV、
HCV及HTLV感染及靈長類動物SIV感染的特徵。在病毒特異性CD8+ T細胞已耗竭之表型內似乎存在階層式進行性功能損失,其中首先細胞毒性及IL-2產生損失,接著效應細胞激素產生損失。
PD-1在活化後調升,且在患有LCMV慢性感染之小鼠中,表現因CD8+ T細胞耗竭而維持在高含量下。Barber等人,同上。投與阻斷PD-1:PD-L1結合之抗體引起T細胞反應增強且病毒負荷實質性減少。在CD4+ TH反應無效之持續性感染小鼠中,阻斷PD-1:PD-L1使CD8+ T細胞自導致增殖、細胞激素分泌、殺死受感染細胞之功能障礙狀態中恢復,且降低病毒負荷,從而強有力地提出一種治療慢性病毒感染之治療方法。
由於PD-1:PD-L在LCMV中之作用,因此對將此路徑靶向人類慢性感染治療展示強烈關注。在HIV特異性T細胞[Petrovas等人,J.Exp.Med. 203:2281-92(2006);Day等人,Nature 443:350-54(2006);Traumann等人,Nat.Med. 12:1198-202(2006)]、HBV特異性T細胞[Boettler等人,J.Virol. 80:3532-40(2006);Boni等人,J.Virol. 81:4215-25(2007)]及HCV特異性T細胞[Urbani等人,J.Virol. 80:11398-403(2006)]上,PD-L1高度表現。在患有慢性HBV感染之患者的周邊血液CD14+單核細胞及骨髓DC[Chen等人,J.Immunol. 178:6634-41(2007);Geng等人,J.Viral Hepat. 13:725-33(2006)]HIV患者之CD14+細胞及T細胞[Trabattoni等人,Blood 101:2514-20(2003)]上,PD-L1亦調升。活體外阻斷PD-1:PD-L1相互作用逆轉HIV特異性、HBV特異性、HCV特異性及SIV特異性CD8+及CD4+ T細胞之耗竭,且恢復增殖及細胞激素之產生。Petrovas等人,J.Exp.Med.203:2281-92(2006);Day等人,同上;Trautmann等人,同上;Boni等人,同上;Urbani等人,同上;Velu等人,J.Virol. 81:5819-28(2007)。
PD-1表現含量亦可為病毒特異性CD8+ T細胞之指示T細胞耗竭及疾病嚴重程度的有效診斷指標。HIV特異性CD8+ T細胞上之PD-1表現含量與病毒負荷、CD4+計數減少及CD8+ T細胞活體外應答HIV抗原增殖之能力降低有關。對應於活體內觀察結果,HIV特異性CD4+ T細胞上之PD-1表現與病毒負荷之間直接相關。D'Souza等人,J.Immunol. 179:1979-87(2007)。與表現顯著調升之PD-1之典型進展者(progressor)相反,長期非進展者(nonprogressor)具有PD-1表現明顯降低之功能性HIV特異性記憶CD8+ T細胞,調升之PD-1與CD4+ T細胞數目減少、CD4+ T細胞數目減少、HIV特異性效應記憶CD8+ T細胞功能降低及血漿病毒負荷增加相關。Zhang等人,Blood 109:4671-78(2007)。
PD-1:PD-L路徑亦涉及慢性細菌感染。幽門螺旋桿菌引起慢性胃炎及胃十二指腸潰瘍,且為發展胃癌之風險因素。在幽門螺旋桿菌感染期間,T細胞反應不足以清除感染,從而引起持續性感染。活體外或活體內暴露於幽門螺旋桿菌之後,調升胃上皮細胞上之PD-L1。胃上皮細胞表現MHC II類分子,且認為在幽門螺旋桿菌感染期間,發揮重要的APC作用。阻斷PD-1與PD-L1相互作用之抗PD-L1抗體增強暴露於幽門螺旋桿菌之胃上皮細胞及CD4 T細胞之培養物中的T細胞增殖及IL-2產生。用抗體或siRNA阻斷PD-L1阻止調控性T細胞產生,從而表明在幽門螺旋桿菌感染期間,PD-L1可藉由控制調控性T細胞與效應T細胞之間的動力學來促進T細胞抑制及持續性感染。Beswick等人,Infect.Immun. 75:4334-41(2007)。
寄生蠕蟲亦利用PD-1:PD-L1路徑誘導抑制免疫反應之巨噬細胞。在小鼠肥頭絛蟲(Taenia crassiceps)(亦即絛蟲)感染期間,調升經活化巨噬細胞上之PD-1及PD-L2,且CD4+ T細胞表現PD-1。阻斷PD-1、PD-L1或PD-L2顯著降低由感染絛蟲之小鼠的巨噬細胞所致的活體
外T細胞增殖抑制。Terrazas等人,Int.J.Parasitol. 35:1349-58(2005)。在小鼠曼氏血吸蟲(Shistosoma mansoni)感染期間,巨噬細胞表現高含量之PD-L1及較適中含量之PD-L2。抗PD-L1移除此等巨噬細胞活體外抑制T細胞增殖之能力,然而抗PD-L2無作用。在感染12週後,受感染小鼠巨噬細胞上之PD-L1表現下降,此與T細胞無反應受破壞有關。Smith等人,J.Immunol. 173:1240-48(2004)。
2.腫瘤免疫
腫瘤免疫之經驗證據包括(i)觀察到自發緩解;(ii)存在可偵測但無效之對腫瘤的宿主免疫反應;(iii)增加免疫缺陷患者之原發性及繼發性惡性腫瘤之發病率;(iv)偵測到腫瘤患者之抗體及T淋巴細胞之含量增加;及(v)觀察到測試動物可對各種類型腫瘤具有免疫力。
研究已顯示大部分人類腫瘤表現可由T細胞識別且因此潛在能夠誘導免疫反應之腫瘤相關抗原(TAA)。Boon等人,Immunol.Today 16:334-336(1995)。已藉由用TAA或經TAA脈衝之專業抗原呈現細胞為癌症患者接種疫苗開始早期臨床試驗。Dudley等人,Science 298:850-854(2002);Gajewski等人,Clin.Cancer Res. 7:895s-901s(2001);Marincola等人,Adv.Immunol. 74:181-273(2000);Peterson等人,J.Clin.Oncol. 21:2342-2348(2003)。在許多此等試驗中已實現誘導腫瘤抗原特異性CD8+ T細胞。Mackensen等人,Eur.Cytokine Netw 10:329-336(1999);Peterson等人,同上。亦已繼續研究將腫瘤抗原特異性T細胞接受性轉移至患者中,且已揭示使所擴充細胞毒性T淋巴細胞(CTL)回到腫瘤位點。Meidenbauer等人,J.Immunol. 170:2161-2169(2003)。然而,儘管腫瘤經免疫效應細胞浸潤,但腫瘤生長顯少得到控制。
充分確定,腫瘤微環境可保護腫瘤細胞免受免疫破壞。Ganss等人,Cancer Res. 58:4673-4681(1998);Singh等人,J.Exp.Med. 175:
139-146(1992)。已發現,腫瘤表現可溶性因子以及膜結合分子,包括轉化生長因子β(TGF-β)、介白素(IL)-10、前列腺素E2、FASL、CTLA-4配位體、誘導腫瘤壞死因子相關細胞凋亡之配位體(TRAIL)及漸進式死亡受體配位體1(PD-L1,亦稱為B7-H1),且咸信因子介導免疫逃避。因此,阻斷腫瘤細胞上之此負性免疫調控信號為增進活體內腫瘤特異性CD8+ T細胞免疫之有前景的方法。
許多腫瘤上之PD-L1表現為此抑制之組成部分且可與其他免疫抑制信號協同起作用。PD-L1負性調控T細胞受體信號傳導。已展示PD-L1原位表現於各種實體腫瘤上,該等實體腫瘤包括乳癌、肺癌、結腸癌、卵巢癌、黑素瘤、膀胱癌、肝癌、唾液腺癌、胃癌、神經膠質瘤、甲狀腺癌、胸腺癌、上皮癌、頭頸癌。Brown等人,J.Immunol. 170:1257-66(2003);Dong等人,Nat.Med. 8:793-800(2002);Hamanishi等人,PNAS 104:3360-65(2007);Strome等人,Cancer Res. 63:6501-5(2003);Inman等人,Cancer 109:1499-505(2007);Konishi等人,Clin.Cancer Res. 10:5094-100(2004);Nakanishi等人,Cancer Immunol.Immunother. 56:1173-82(2007);Nomi等人,Clin.Cancer Res. 13:2151-57(2004);Thompson等人,PNAS 101:17174-79(2004);Wu等人,Acta Histochem. 108:19-24(2006)。
免疫染色亦揭示PD-1:PD-L表現於各種癌症上之表現。
有趣的是,癌症亦視為慢性發炎疾病。Coussens等人,Nature 420:860-867(2002)。雖然全世界多達15%之癌症具有直接感染性起源[Kuper等人,J.Intern.Med. 248:171-183(2000)],但許多人類腫瘤與慢性刺激及發炎有關。Zou等人,Ntu.Rev.Cancer 5:263-274(2005)。
雖然使腫瘤上PD-L1表現與疾病結果相關之研究顯示PD-L1表現與腎癌、卵巢癌、膀胱癌、乳癌、胃癌及胰臟癌之不利預後密切相
關,但可能不與小細胞肺癌之不利預後相關。Hamanishi等人,Proc.Natl.Acad.Sci.USA 104:3360-65(2007);Inman等人,Cancer 109:1499-505(2007);Konishi等人,Clin.Cancer Res. 10:5094-100(2004);Nakanishi等人,Cancer Immunol.Immunother. 56:1173-82(2007);Nomi等人,Clin.Cancer Res. 13:2151-57(2007);Thompson等人,Proc.Natl.Acad.Sci.USA 101:17174-79(2004);Wu等人,Acta Histochem. 108:19-24(2006)。此外,此等研究表明腫瘤上之較高含量之PD-L1表現可能有助於推進腫瘤期別且侵入更深組織結構中。
PD-1:PD-L路徑亦可能在血液惡性腫瘤中發揮作用。雖然PD-1或PD-L1很少表現於B細胞惡性腫瘤中,但PD-L2過度表現於套細胞惡性腫瘤中。Brown等人,同上;Rosenwald等人,J.Exp.Med. 198:851-62(2003)。雖然PD-L1表現於多發性骨髓瘤細胞上,但不表現於正常漿細胞上。PD-L1阻斷活體外增加應答骨髓瘤細胞之T細胞擴充。Liu等人,Blood 110:296-304(2007)。PD-L1表現於一些原發性T細胞淋巴瘤上,尤其多形性大T細胞淋巴瘤上,且PD-L1表現於相關濾泡性樹突狀細胞網狀結構上。Dorfman等人,Am.J.Surg.Pathol. 30:802-10(2006)。微陣列分析進一步表明在霍奇金淋巴瘤(Hodgkin lymphoma)中腫瘤相關T細胞原位應答PD-1信號。Chemnitz等人,Blood 110:3226-33(2007)。PD-1及PD-L1表現於HTLV-1介導之成人T細胞白血病及淋巴瘤中之CD4+ T細胞上。Shimauchi等人,Int.J.Cancer 121:2585-90(2007)。此等腫瘤細胞對TCR信號之反應不足,且PD-1阻斷增加其TNF-α之表現,但不增加IFN-γ之表現。動物模型之研究說明腫瘤上之PD-L1表現抑制T細胞活化及腫瘤細胞溶解,且在一些情況下,使得腫瘤特異性T細胞死亡增加。Dong等人,Nat.Med. 8:793-800(2006);Hirano等人,Cancer Res. 65:1089-96
(2005)。
因此,用本發明抗PD-L1抗體抑制經由PD-L1之信號傳導以便增進T細胞功能展示有希望減弱腫瘤免疫,且因此,可有效治療癌症。
F.組合療法
本發明方法可與治療慢性感染或癌症之已知方法組合作為經組合或額外治療步驟或作為治療性調配物之額外組分。
1.癌症:增進宿主之免疫功能以對抗腫瘤為日益受到關注之主題。習知方法包括(i)APC增進,諸如(a)向腫瘤中注射編碼外來MHC同種異體抗原之DNA,或(b)用增加腫瘤之免疫抗原識別(例如免疫刺激細胞激素、GM-CSF、協同刺激分子B7.1、B7.2)可能性的基因轉染活組織檢查腫瘤細胞,(iii)授受性細胞免疫療法或用經活化腫瘤特異性T細胞治療。授受性細胞免疫療法包括分離腫瘤浸潤性宿主T淋巴細胞,諸如藉由用IL-2或腫瘤或兩者刺激活體外擴充該群體。另外,亦可藉由活體外施用本發明抗PD-L1抗體活化功能障礙性經分離T細胞。接著可將由此活化之T細胞再投與宿主。
癌症之傳統療法包括以下:(i)輻射療法(例如放射線療法、X射線療法、照射)或使用電離輻射殺死癌細胞及使腫瘤縮小。輻射療法可經由外粒子束放射線療法(EBRT)外部投與或經由近接治療(brachytherapy)內部投與;(ii)化學療法,或施用一般影響快速分裂之細胞之細胞毒性藥物;(iii)靶向療法,或特異性影響癌細胞之不受調控之蛋白質的藥劑(例如酪胺酸激酶抑制劑伊馬替尼(imatinib)、吉非替尼(gefitinib);單株抗體;光動力療法);(iv)免疫療法,或增強宿主之免疫反應(例如疫苗);(v)激素療法,或阻斷激素(例如當腫瘤對激素敏感時);(vi)血管生成抑制劑,或阻斷血管形成及生長;及(vii)緩解性護理,或針對改良護理品質以降低疼痛、噁心、嘔吐、腹瀉及出
血之治療。諸如嗎啡鹼(morphine)及羥可待酮(oxycodone)之疼痛藥物、諸如昂丹司瓊(ondansetron)及阿瑞匹坦(aprepitant)之抗嘔吐藥可允許更具侵襲性之治療方案。
在癌症治療中,可在投與本發明抗PD-L1抗體之前、之後或同時進行癌症免疫治療之任何前述習知治療。另外,本發明抗PD-L1抗體可在習知癌症治療(諸如投與腫瘤結合抗體(例如單株抗體、毒素結合單株抗體)及/或投與化學治療劑)之前、之後或同時投與。
2.感染:在感染(例如急性感染及/或慢性感染)治療中,除刺激對感染之天然宿主免疫防禦以外或代代該刺激,可將本發明抗PD-L1抗體投藥與習知治療相組合。對感染之天然宿主免疫防禦包括(但不限於)發炎、發熱、抗體介導之宿主防禦、T淋巴細胞介導之宿主防禦(包括淋巴介質分泌及細胞毒性T細胞(尤其在病毒感染期間))、補體介導之溶解及助噬作用(促進吞噬)及吞噬作用。本發明抗PD-L1抗體使功能障礙性T細胞再活化之能力將特別適用於治療慢性感染、尤其細胞介導之免疫對完全康復而言至關重要之感染。
a.細菌
對於由細菌性感染引起之感染,本發明抗PD-L1抗體可與治療細菌性感染之標準療法同時、在其之前或之後投與來組合。雖然現今細菌性感染最通常用抗細菌性抗生素治療,但來自經免疫宿主之含病原體特異性抗體之血清亦會有效。
因分泌毒素(產毒素細菌)、用失活毒素接種及/或投與阻斷毒素之毒性的治療劑而具有病原性之細菌通常有效(例如多株血清、抗體、抗生素等)。此等生物體包括梭菌屬(Clostridium spp.)、芽孢桿菌屬(bacillus spp.)、棒狀桿菌屬(Corynebacterium spp.)、霍亂弧菌(Vibrio chloerae)、百日咳桿菌(Bordetella pertussis)、葡萄球菌屬
(Staphylococcus spp.)、鏈球菌屬。通常亦應答該等傳統療法之革蘭氏陰性細菌包括腸細菌(Enterobacteria)(例如埃希氏桿菌、克雷伯氏菌、變形菌屬、耶氏桿菌(Yersinia)、伊文氏桿菌(Erwina))、沙門氏桿菌(Salmonella)及綠膿假單胞桿菌(Pseudomonas aeruginosa)。對吞噬作用及助噬作用有抗性且因此通常阻止對免疫清除之更顯著攻擊的有莢膜細菌包括:鏈球菌屬、嗜血桿菌屬、奈瑟菌屬、克雷伯氏菌屬及鬆脆桿菌。
藉由侵入細胞中而逃避宿主防禦以逃避血清抗體及補體之細菌顯示特定攻擊。清除此等感染幾乎完全依賴於T淋巴細胞介導之免疫,且尤其易變為慢性感染。特定實例包括沙門氏桿菌(傷寒沙門氏桿菌(S.typhi)、豬霍亂沙門氏桿菌(S.choleraesuis)、腸炎沙門氏桿菌(S.enteritidis))、退伍軍人菌桿屬(Legionella spp.)、李氏菌屬、布魯菌屬(Brucella spp.)及分枝桿菌(結核分枝桿菌(M.tuberculosis)、鳥分枝桿菌(M.avium)及麻瘋分枝桿菌(M.leprae))。
包括密螺旋體屬、疏螺旋體屬及鉤端螺旋體屬(Leptospira spp.)之螺旋體為引起持續性及潛伏性感染之細菌。引起梅毒疾病之病原體梅毒螺旋體(Treponema palladium)為若不加以治療,則可產生嚴重病理性後果的性傳播疾病。該疾病經由不同階段進行。最初臨床階段為螺旋體接種部位之潰瘍或下疳。此後為螺旋體血症及微生物轉移性分布時期,該時期持續進行,包括重複病狀感染週期及消除週期,此稱為二期梅毒。在消除二期梅毒之後,疾病進入無症狀潛伏期,該潛伏期在三期梅毒時結束,三期梅毒為嚴重且通常致死之病狀。三期梅毒可表現於以下中:(i)心臟,如主動脈炎及動脈瘤形成及二級主動脈瓣不足,(ii)中樞神經系統(脊髓癆、麻痹性癡呆),(iii)眼睛(間質性角膜炎),或(iv)耳(神經性耳聾)。非性交形式類似於性交形式之臨床表現形式,但主要經由直接接觸及不良衛生傳播。其包括莓疹病(yaws)(梅
毒密螺旋體細弱亞種(T.pallidum subp.pertenue))、品他病(pinta)(品他密螺旋體(T.carateum))及貝耶病(bejel)(梅毒密螺旋體地方亞種(T.pallidum subsp.endemicum))。
梅毒之治療包括青黴素(例如青黴素G)、四環素、多西環素、頭孢曲松及阿奇黴素(azithromycin)。最宜投與本發明抗PD-L1抗體來治療潛伏性感染時期。
由伯氏疏螺旋菌(Borrelia burgdorferi)引起之萊姆病(Lyme disease)經由壁虱叮咬傳播給人類。該疾病最初表現為局部皮疹,之後為流行性感冒樣症狀,包括不適、發熱、頭痛、頸強直及關節痛。隨後的表現表式可包括遷移性或多關節性關節炎、神經及心臟受累伴有腦神經麻痹及神經根病變、心肌炎及心律不齊。萊姆病之一些病例變成持續性的,產生類似於三期梅毒之不可逆損害。
萊姆病之當前療法主要包括投與抗生素。可用羥氯奎或甲胺喋呤(methotrexate)治療抗生素抗性菌株。可用加巴噴丁(gabapentin)治療患有神經痛之抗生素不應患者。米諾環素對具有神經學或其他發炎性表現形式之晚期/慢性萊姆病有幫助。最宜投與抗PD-L1抗體來治療潛伏性感染時期。
除非血液效價達到導致肝內阻塞之濃度,否則其他形式之疏螺旋體病(諸如由回歸熱疏螺旋體(B.recurentis)、赫姆斯疏螺旋體(B.hermsii)、北美回歸熱包柔氏疏螺旋體(B.turicatae)、派可瑞疏螺旋體(B.parikeri)、西班牙疏螺旋體(B.hispanica)、杜通疏螺旋體(B.duttonii)及波斯疏螺旋體(B.persica)引起之疏螺旋體病)以及鉤端螺旋體病(例如問號狀鉤端螺旋體(L.interrogans))通常自發消除。
b.病毒
對於由病毒原因引起之感染,本發明抗PD-L1抗體可藉由與施用治療病毒感染之標準療法同時、在其之前或之後施用來組合。該等標
準療法視病毒類型而變化,但在幾乎所有的情況下,投與含對病毒具特異性之抗體(例如IgA、IgG)之人類血清均會有效。
1)流行性感冒
流行性感冒感染引起發熱、咳嗽、肌痛、頭痛及不適,其通常出現在季節性流行病中。流行性感冒亦與許多感染後病症相關,諸如腦炎、心肌心包炎、古德巴斯德症候群(Goodpasture's syndrome)及雷爾氏症候群(Reye's syndrome)。流行性感冒感染亦抑制正常肺部抗細菌防禦,以致患者自流行性感冒康復時發展細菌性肺炎的風險增加。
流行性感冒病毒表面蛋白展示由突變及重組產生之顯著抗原變異。因此,細胞溶解T淋巴細胞為宿主在感染後消除病毒之主要媒介物。流行性感冒主要分為三類:A、B及C。A型流行性感冒之獨特之處在於其感染人類與許多其他動物(例如豬、馬、鳥及海豹)且為泛流行性感冒之主要原因。此外,當細胞由兩種不同A型流行性感冒病毒株感染時,在複製期間兩種親代病毒類型之區段RNA基因組混合產生雜交複製體,從而產生新流行性病毒株。B型流行性感冒不在動物中複製且因此具有較小的遺傳變異,且C型流行性感冒僅具有單一血清型。
最習知之療法為緩解由感染引起之症狀,而宿主之免疫反應實際上清除該疾病。然而,某些病毒株(例如A型流行性感冒)可引起更嚴重的疾病及死亡。A型流行性感冒可藉由投與抑制病毒複製之環胺抑制劑三環癸胺及金剛乙胺臨床上與預防性處理。然而,由於有害反應發生率相對較高、抗病毒譜較窄(僅A型流行性感冒)且病毒有耐藥傾向,因此該等藥物之臨床效用有限。向主要流行性感冒表面蛋白、血球凝集素及神經胺糖酸苷酶投與血清IgG抗體可預防肺部感染,然而需要黏膜IgA以預防上呼吸道及氣管感染。當前最有效之流行性感冒之治療為藉由投與經福馬林(formalin)或β-丙內酯失活之病毒接種。
2)麻疹病毒
培育9-11天後,感染麻疹病毒之宿主會發展發熱、咳嗽,鼻炎及結膜炎。在1-2天內,發展紅斑斑丘疹,其快速遍布全身。因為感染亦抑制細胞免疫,所以宿主有較大風險發展細菌重複感染(bacterial superinfection),包括中耳炎、肺炎及感染後腦脊髓炎。急性感染與高發病率及死亡率有關,在營養不良青少年中尤其如此。
麻疹之治療包括被動投與混合人類IgG,其即使在暴露之後長達一週才給予,亦可在非免疫個體中預防感染。然而,預先用活的減毒病毒免疫為最有效的治療且在95%以上之經免疫個體中預防疾病。因為存在一種此病毒之血清型,所以單一免疫或感染通常產生終身保護免受後續感染。
在小部分受感染宿主中,麻疹可發展成SSPE,SSPE為由中樞神經系統之持續性感染引起之慢性進行性神經病症。SSPE由具有干擾病毒粒子裝配及出芽之缺陷的麻疹病毒純系變異體引起。對於此等患者,將需要用本發明抗PD-L1抗體使T細胞再活化以有助於病毒清除。
3)B型肝炎病毒
B型肝炎病毒(HB-V)為最具傳染性之已知血源性病原體。其為急性及慢性肝炎及肝癌以及終身慢性感染之主要原因。感染後,病毒在肝細胞中複製,其接著亦排出表面抗原HBsAg。偵測血清中之過量HBsAg為用於診斷B型肝炎感染之標準方法。急性感染可消除或其可發展成慢性持續性感染。
慢性HBV之當前治療包括α-干擾素,其增加I類人類白血球抗原(HLA)在肝細胞表面上之表現,藉此有助於細胞毒性T淋巴細胞對其之識別。另外,在臨床試驗中核苷類似物更昔洛韋、泛昔洛韋及拉米夫定亦展示一定的治療HBV感染之功效。HBV之其他治療包括聚乙二
醇化α-干擾素、阿德福韋(adenfovir)、因提弗及喜必福(telbivudine)。雖然可經由非經腸投與抗HBsAg血清抗體賦予被動免疫,但用失活或重組HBsAg接種亦賦予抗感染性。可使本發明抗PD-L1抗體與B型肝炎感染之習知治療組合來達成治療優勢。
4)C型肝炎病毒
C型肝炎病毒(HC-V)感染可導致慢性形式之肝炎,從而導致肝硬化。雖然症狀類似於由B型肝炎引起之感染,但與HB-V明顯不同,受感染宿主可能10-20年均無症狀。HC-V感染之治療包括投與α-干擾素及病毒唑之組合。HC-V感染之有前景之潛在療法為蛋白酶抑制劑替普瑞韋(telapravir)(VX-960)。其他治療包括:抗PD-1抗體(MDX-1106,Medarex),巴維昔單抗(bavituximab)(一種以B2-醣蛋白I依賴性方式結合陰離子磷脂磷脂醯絲胺酸之抗體,Peregrine Pharmaceuticals)、抗HPV病毒鞘蛋白E2抗體(例如ATL 6865-Ab68+Ab65,XTL Pharmaceuticals)及Civacir®多株抗HCV人免疫球蛋白)。可使本發明抗PD-L1抗體與C型肝炎感染之一或多種此等治療組合來達成治療優勢。
5)人類免疫缺乏病毒(HIV)
HIV攻擊CD4+細胞,包括T淋巴細胞、單核細胞-巨噬細胞、濾泡性樹突狀細胞及蘭氏細胞(Langerhan's cells),且耗盡CD4+輔助/誘導細胞。因此,宿主獲得嚴重的細胞介導之免疫缺陷。HIV感染在至少50%的個體中導致AIDS,且經由性接觸、投與受感染血液或血液製品、用受感染精液人工授精、暴露於含有血液之針或注射器及分娩期間由受感染母親傳播給嬰兒而傳播。
感染HIV之宿主可能無症狀或可能發展類似於單核細胞增多症之急性疾病:發熱、頭痛、喉嚨痛、不適及皮疹。症狀可發展成進行性免疫功能障礙,包括持續性發熱、盜汗、體重下降、不明原因腹瀉、
濕疹、牛皮癬、脂溢性皮炎、帶狀疱疹、口腔念珠菌病及口腔毛狀白斑。感染發展成AIDS之患者中常見由許多寄生蟲引起之機會性感染。
HIV之治療包括抗病毒療法,包括核苷類似物,單獨或與去羥肌苷或紮西他濱組合之齊多夫定(AST)、雙去氧肌苷(dideoxyinosine)、雙去氧胞苷(dideoxycytidine)、拉脈優錠(lamidvudine)、司他夫定;逆轉錄抑制劑,諸如地拉韋啶、奈韋拉平、洛韋胺;及蛋白酶抑制因子,諸如沙奎那韋、利托那韋、茚地那韋及奈非那韋。可使本發明抗PD-L1抗體與HIV感染之習知治療組合來達成治療優勢。
6)細胞巨大病毒
細胞巨大病毒(CMV)感染通常與持續性、潛伏性及復發性感染相關。CMV感染單核細胞及粒細胞-單核細胞祖細胞且潛伏其中。CMV之臨床症狀包括單核細胞增多症樣症狀(亦即發熱、腺腫脹、不適)及易於發展針對抗生素之過敏性皮疹。病毒經由直接接觸擴散。病毒於尿、唾液、精液中排出及較小程度上於其他體液中排出。亦可自受感染母體傳播至其胎兒或新生兒及經由輸血及器官移植傳播。CMV感染引起一般細胞免疫受損,其特徵為對非特異性有絲分裂原及特異性CMV抗原之胚芽生殖反應減弱、細胞毒性能力減弱及CD4+淋巴細胞之CD8淋巴細胞數目增加。
CMV感染之治療包括抗病毒劑更昔洛韋、膦甲酸(foscarnet)及西多韋(cidovir),但此等藥物通常僅開立於免疫受之患者的處方中。可使本發明抗PD-L1抗體與細胞巨大病毒感染之習知治療組合來達成治療優勢。
7)艾伯斯坦-巴爾病毒
艾伯斯坦-巴爾病毒(EBV)可產生持續性及潛伏性感染且主要攻擊B細胞。EBV感染引起傳染性單核細胞增多症之臨床病狀,包括發
熱、喉嚨痛、通常有分泌物、全身性淋巴腺病及脾腫大。亦出現肝炎,其可發展成黃疸。
雖然EBV感染之典型治療緩解症狀,但EBV與某些癌症(諸如伯基特淋巴瘤(Burkitt's lymphoma)及鼻咽癌)之發展相關。因此,在此等併發症產生之前清除病毒感染具有重大益處。可使本發明抗PD-L1抗體與艾伯斯坦-巴爾病毒感染之習知治療組合來達成治療優勢。
8)疱疹病毒
單純性疱疹病毒(HSV)經由與受感染宿主直接接觸而傳播。雖然直接感染可能無症狀,但通常產生含傳染性粒子之水皰。該疾病表現為疾病活動期之循環,其中病變隨病毒潛伏性感染神經節後續爆發而出現及消失。病變可位於臉、生殖器,眼睛及/或手上。在一些情況下,感染亦可引起腦炎。
疱疹感染之治療主要針對消除症狀爆發,且包括全身抗病毒藥,諸如:阿昔洛韋(例如Zovirax®)、伐昔洛韋、泛昔洛韋、噴昔洛韋及表面藥物,諸如多可沙諾(Abreva®)、曲金剛胺及吉拉克定(zilactin)。清除疱疹之潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與疱疹病毒感染之習知治療組合來達成治療優勢。
9)HTLV
人類T淋巴細胞病毒(HTLV-1、HTLV-2)經由性接觸、母乳餵養或暴露於受污染血液來傳播。病毒活化使稱為Th1細胞之TH細胞子集活化,從而導致其過度增殖及過度產生Th1相關細胞激素(例如IFN-γ及TNF-α)。此舉又導致抑制Th2淋巴細胞及降低Th2細胞激素產生(例如IL-4、IL-5、IL-10及IL-13),從而引起受感染宿主對清除時需要Th2依賴性反應之侵入生物體(例如寄生蟲感染、黏膜及體液抗體產生)產生適當免疫反應之能力下降。
HTLV感染引起機會性感染,引發支氣管擴張症、皮炎及由葡萄
球菌屬(Staphylococcus spp.)及圓線蟲屬(Strongyloides spp.)重複感染,從而導致因多微生物性敗血症而死亡。HTLV感染亦可直接引發成人T細胞白血病/淋巴瘤及進行性脫髓鞘上運動神經原疾病(稱為HAM/TSP)。清除HTLV潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與HTLV感染之習知治療組合來達成治療優勢。
10)HPV
人類乳頭狀瘤病毒(HPV)主要影響角質細胞且以兩種形式存在:皮膚形式及生殖器形式。咸信經由直接接觸及/或性行為傳播。皮膚與生殖器HPV感染可引起疣及潛伏性感染及有時引起復發感染,其雖然受控制症狀且阻斷疣出現之宿主免疫控制,但宿主仍能夠將感染傳播給其他人。
HPV感染亦可引發某些癌症,諸如子宮頸癌、肛門癌、外陰癌、陰莖癌及口咽癌。尚無已知之HPV感染治療,但當前治療為表面施用咪喹莫特,其刺激免疫系統攻擊受感染區域。清除HPV潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與HPV感染之習知治療組合來達成治療優勢。
c. 真菌
真菌感染或黴菌病可因免疫系統受內源性菌叢損害之宿主的初次感染或機會性移生而引起。對黴菌病之免疫主要為細胞免疫,包括嗜中性白細胞、巨噬細胞、淋巴細胞及可能自然殺傷(NK)之細胞。黴菌病通常不易由抗體及補體直接殺死。由初次感染引起之全身侵襲性黴菌病包括芽生菌病、球黴菌病、組織漿菌病及副球黴菌病。對於由真菌感染引起之慢性感染,本發明抗PD-L1可在此等黴菌病之任何習知治療之前、與其同時或在其之後投與。
由皮炎芽生菌(Blastomyces dermatitis)所引起之芽生菌病經由吸入獲得且產生原發性肺部感染或血原性傳播疾病(主要包括皮膚、骨
及男性泌尿生殖道)。最初暴露可能無症狀,或其可產生流行性感冒樣症候群。此疾病可以慢性無痛形式表現。該疾病亦與諸如患AIDS之患者之受損免疫相關。皮炎芽生菌感染之習知療法包括伊曲康唑、酮康唑或靜脈內注射雙性黴素B。
由粗球黴菌引起之球黴菌病經由吸入獲得且可引起原發性肺部感染、進行性肺病或血原性傳播疾病(主要包括皮膚、皮下組織、骨、關節及腦膜)。最初暴露可能無症狀(60%)或與流行性感冒樣症候群相關。可能出現肺炎、胸膜炎及肺空洞形成。轉移性表現形式包括皮膚損害,包括節結、潰瘍、深處及疣狀肉芽瘤之竇道、骨、關節、腱鞘及腦膜(包括腦膜炎)。該疾病亦與諸如患AIDS之患者之受損免疫相關。球黴菌病之治療包括酮康唑、伊曲康唑及氟康唑,尤其用於非腦膜病之長期維持療法。腦膜形式通常由鞘內投與雙性黴素B來治療。
由莢膜組織漿菌引起之組織漿菌病為網狀內皮系統之經由吸入獲得之疾病,其中極少酵母菌駐留於巨噬細胞中。此可產生原發性肺部感染、進行性肺病或血原性傳播疾病(主要包括網狀內皮系統、黏膜表面及腎上腺)。潛伏性感染之再活化通常出現在諸如患AIDS之患者的免疫受損患者中。最初暴露可能無症狀或與流行性感冒樣症候群相關,包括肺炎、胸膜炎、肺空洞形成及縱隔腺病。轉移性部位包括網狀內皮系統(肝脾腫大、淋巴腺病、貧血、白血球減少症及血小板減少症)、黏膜(鼻咽旁潰瘍)、胃腸道(吸收障礙)及腎上腺機能不全。雖然大部分初次感染自發消除,但當與諸如患AIDS之患者之受損免疫相關時,不停復發且通常與血原性肺炎、ARDS、散播性血管內凝血(DIC)、血原性分布丘疹膿皰及腦膜炎相關。組織漿菌病用雙性黴素B(尤其患急性血原性播散病之免疫受損患者)、伊曲康唑及酮康唑治療。
由巴西副球黴菌(Paracoccidioides brasiliensis)引起之副球黴菌病為可產生原發性肺部感染或血原性傳播疾病(主要包括皮膚、黏膜、網狀內皮系統及腎上腺)之經由吸入獲得之黴菌病。感染最初可能無症狀,但休眠,且接著復活。此感染之治療使用酮康唑、伊曲康唑及磺醯胺。
出現於免疫受損宿主中之由機會性病原體引起之全身侵襲性黴菌病包括念珠菌病、隱球菌病、麯黴病、白黴菌病及肺囊蟲病。因本發明抗PD-L1抗體增強受損免疫系統之免疫反應,故其在此等病狀之治療中亦可具有治療性價值,尤其當與習知療法組合時。
念珠菌病(由白色念珠菌、熱帶念珠菌(C.tropicalis)、光滑念珠菌(C.glabrata)引起)、隱球菌病(由新型隱球酵母(Cryptococcus neoformans)引起)、麯黴病(由黃麴黴(Aspergillus flavus)、菸麯黴(A.fumigatus)、土麯黴(A.tereus)及黑麯黴(A.niger)引起)及白黴菌病(由少根根黴(Rhizopus arrhizus)、根毛黴屬(Rhizomuco)、犁頭黴屬(Absidia)、小克銀漢黴屬(Cunninghamella)、被孢黴屬(Mortierella)、瓶黴屬(Saksenaea spp.)引起)之治療可在用或不用氟胞嘧啶下用一或多種以下咪唑來治療:酮康唑、伊曲康唑、氟康唑、雙性黴素B。最近自原蟲重新分類為真菌之肺囊蟲病(由肺炎肺囊蟲(penumocystis carnii)引起)係用甲氧苄啶-磺胺甲異噁唑(TMP-SMZ)及靜脈內噴他脒羥乙磺酸鹽以及胺苯碸、TMP-胺苯碸、三甲曲沙(trimetrexate)、克林黴素-伯胺奎(clindamycin-primaquine)及阿維尼農(atovagnone)治療。
由微孢子寄生蟲引起之微孢子蟲病最近自原蟲重新分類為真菌。其為具有殘留紡錘體而非線粒體之單細胞生物體。可在人類中引起疾病之生物體包括:比氏腸微孢子蟲(Enterocytozoon bieneusi)、海倫腦炎微孢子蟲(Encephalitozoon hellem)、小腸腦炎微孢子蟲(Encephalitozoon intestinalis)、兔子腦炎微孢子蟲(Encephalitozoon cuniculi)、孢蟲屬(Pleistophora spp)、人微孢子蟲(Trachipleistophora hominis)、吸血微孢子蟲(Trachipleistophora anthropophthera)、人小孢子蟲(Nosema connori)、眼小孢子蟲(Nosema ocularum)、泡狀小孢子蟲(Brachiola vesicularum)、角膜小孢子蟲(Vittaforma corneae)、錫蘭微孢子蟲(Microsporidium ceylonensis)、非洲微孢子蟲(Microsporidium africanum)、小孢子蟲屬真菌(Brachiola algerae)。
咸信感染因與動物、受污染水或另一感染宿主直接接觸而傳播給人類。感染宿主細胞之後,孢原質生長,分裂或形成可具有複雜生命週期(包括無性與有性繁殖)之多核變形體。繼代自體感染及慢性衰弱性疾病通常為微孢子感染之特徵。
疾病之臨床表現形式可視物種及宿主之免疫狀態而變化,且包括結膜炎(例如角膜小孢子蟲)、慢性腹瀉、吸收障礙及消耗病(例如比氏腸微孢子蟲、小腸腦炎微孢子蟲)。
眼、腸及傳播性微孢子菌病之治療包括投與阿苯達唑(albendazole)。表面施用菸黴素(fumagillin)亦可有效用於治療微孢子性角膜結膜炎。其他藥物包括驅蠕蟲劑(例如阿苯達唑)、抗生素(例如菸黴素)、免疫調節劑(例如沙立度胺(thalidomide))、抗原蟲藥(例如甲硝唑)。
d.原蟲
在發展中國家,由寄生蟲病症(諸如瘧疾、血吸蟲病及利什曼體病)引起之疾病為最普遍且重要之健康問題之一。此等疾病構成特別挑戰,此係因為其可經由各種方式逃避宿主免疫,該等方式包括1)生存在宿主細胞內部(例如利什曼蟲),2)快速改變表面抗原(例如錐蟲),及3)藉由顯示宿主抗原將其自身「偽裝」成宿主細胞(例如肝血吸蟲病)。癌症治療中免疫抑制藥物的使用及器官移植以及AID之全球流行會使瘧原蟲屬(Plasmodium spp.)、弓形蟲屬、利什曼蟲屬、隱胞
子蟲屬、錐蟲屬及蠕蟲屬之潛伏性或亞臨床感染再活化。
對於由原蟲寄生蟲感染引起之慢性感染,本發明抗PD-L1抗體可藉由與標準抗原蟲療法組合、在其之前或之後投與來組合。
由瘧原蟲屬寄生蟲(例如蛋形瘧原蟲(P.ovale)、三日瘧原蟲(P.malariae)、惡性瘧原蟲(P.falciparum)、間日瘧原蟲(P.vivax))引起之瘧疾以在雌性按蚊之腸中發育之孢子體開始感染週期。當傳播給人類後,此等孢子體侵入肝細胞內且在其中繁殖,但不誘導發炎反應。此等生物體之子代(稱為裂殖子)接著侵入紅血球細胞中且開始通常以發熱及發寒為特徵之疾病之臨床期。在感染為地方病之世界的某些區域,幾乎所有居民均隱藏低至中等病原性之連續低程度之慢性感染,其中遞增含量之IgG抗體阻止裂殖子進入紅血球中。
目前可用於臨床疾病治療與預防之抗瘧疾藥物包括:蒿甲醚-苯芴醇(Artemether-lumefantrine)(治療,例如Coartem®及Riamet®)、青蒿琥酯-阿莫地奎寧(artesunate-amodiaquine)(治療)、青蒿琥酯-美爾奎寧(artesunate-mefloquine)(治療)、青蒿琥酯-磺胺多辛/乙胺嘧啶(artesunate-Sulfadoxine/pyrimethamine)(治療)、阿托伐醌-氯胍(atovaquone-proguanil)(治療及預防,例如Malarone®),奎寧(治療)、氯奎寧(治療及預防)、可曲齊特(cotrifazid)(治療及預防)、多西環素(治療及預防)、美爾奎寧(治療及預防,例如Lariam®)、伯胺奎(僅治療間日瘧原蟲及蛋形瘧原蟲;不用於預防)、氯胍(預防)、磺胺多辛-乙胺嘧啶(sulfadoxine-pyrimethamine)(治療及預防)、羥氯奎(治療及預防,例如Plaquenil®)。
因為本發明抗PD-L1抗體使無反應性T細胞再活化,所以其尤其可在輔助瘧原蟲清除中具有治療性。
雖然由弓形蟲(Toxoplasma)屬寄生蟲引起之弓蟲病(Toxoplasmosis)通常無症狀,但小部分可發展臨床疾病,該臨床疾病
可在急性良性淋巴腺病至中樞神經系統之致死感染變動。感染源包括生的或部分烹熟的豬肉或羊肉中之包囊及受感染貓之糞便中傳播之卵母細胞。感染通常經由胃腸道發生於人類中,且原蟲可鑽入身體之幾乎每個細胞中並在其中增殖(作為速殖子)。此等速殖子可產生充滿可長時間保持生活力之微小緩慢生長之感染體(緩殖子)之包囊,從而引起潛伏性慢性感染。免疫系統受損之宿主(諸如服用免疫抑制藥物或患HIV之宿主)尤其易患弓蟲病。
用於治療原發性弓蟲病之藥物包括以下:有與無伴隨抗生素(例如磺胺嘧啶、克林黴素、螺旋黴素(spiramycin)及米諾環素)之乙胺嘧啶。潛伏性弓蟲病可在用與不用克林黴素下用抗生素阿托伐醌治療。
由利什曼蟲屬寄生蟲引起之利什曼體病感染皮膚及內臟之巨噬細胞且經由白蛉(sandfly)傳播給人類。因為存在少量或不存在特異性血清抗體,所以經由活化T細胞之細胞介導之免疫似乎為清除感染之關鍵途徑。亦稱為熱帶瘡之舊大陸型利什曼體病(Old World Leishmaniasis)係由若干利什曼蟲物種引起:熱帶利什曼原蟲(L.tropica)、碩大利什曼原蟲(L.major)及埃塞俄比亞利什曼原蟲(L.aethiopica)。新大陸型利什曼病(New World Leishmaniasis)係由墨西哥利什曼原蟲(L.Mexicana)及巴西利什曼原蟲(L.braziliensis)之各種亞種引起。雖然此等寄生蟲誘導強細胞介導之免疫反應,但臨床疾病之結果亦部分引起宿主反應。若宿主出現經抑制或不適當之細胞介導之反應,則引發自愈希望渺茫之彌漫性慢性皮膚利什曼病(例如埃塞俄比亞利什曼原蟲、墨西哥利什曼原蟲)。若宿主出現過度細胞介導之反應,則反應為類狼瘡或瑞什地伐(recidiva)利什曼原蟲病,在主要病變邊緣(例如熱帶利什曼原蟲)出現持續性非潰瘍性淋巴節結。瑞什地伐利什曼原蟲病可在最初病變之後1至10年出現。有兩種形式之疾病,即皮膚疾病及內臟疾病,其中表現形式為具有細胞介導之免疫之
皮膚病變之皮膚形式對清除而言至關重要。在內臟形式中,細胞介導之免疫不充分或不存在,且該疾病臨床表現為多株B細胞高γ-球蛋白血症、白血球減少症、脾腫大及TNF-α產生增加。
米替福新(例如Impavido®)及副肌凝蛋白(paramyocin)為皮膚與內臟利什曼病之現用治療。
由隱孢子蟲屬(Crytosporidia)原蟲感染所引起之隱孢子蟲病係因人類與受感染宿主之糞便排泄物直接接觸引起。腸黏膜組織之感染可引起腹瀉。該疾病通常表現為急性感染,但其可變成慢性的,尤其在免疫受損之個體中。雖然治療(尤其水療)通常為舒減性的,但巴龍黴素、阿奇黴素及血清Ig(例如Lactobin-R®)已成功清除感染。
由錐蟲屬寄生蟲(例如布氏錐蟲甘比亞亞種(T.Brucei,subsp.gambiense)、布氏錐蟲羅得西亞亞種(T.Brucei,subsp.rodesiense))引起之錐蟲病經由采采蠅(Tsetse-fly)叮咬感染人類及牛。此病原體引起之攻擊係由顯示不同表面抗原之群體的繼代引起。感染之特徵在於非特異性及非保護性血清免疫球蛋白之含量升高。
錐蟲病之治療包括下列靜脈內投與:噴他脒(用於布氏甘比亞錐蟲),靜脈內蘇拉明(用於布氏羅得西亞錐蟲),依氟鳥胺酸、美拉胂醇,兩者與及不與硝呋替莫。
由吸蟲(例如血吸蟲屬(Schistomsoma spp.))、絛蟲及線蟲引起之蠕蟲感染共有嗜酸性球增多症及反應抗體(reaginic antibody)之常見免疫反應,該等反應為T細胞依賴性的。
由曼氏血吸蟲(Shistosoma mansoni)、日本血吸蟲(S.japonicum)、埃及血吸蟲(S.haematobium)及湄公血吸蟲(S.mekongi)引起之血吸蟲病(亦稱為住血裂體蛭病)於水中以卵開始其生命週期,接著孵化成纖毛幼蟲(miracidia),鑽入蝸牛中且產生多代孢子囊。此等孢子囊又產生叉尾尾動幼蟲(cercariae),該等尾動幼蟲可以幼蟲
(schistosomula)形式感染人類宿主之血流,幼蟲最初遷移至肺,接著遷移至肝臟。此等吸蟲最終在腸系膜小靜脈中配對、交配且產卵。雖然許多此等卵行進至腸中並被排泄出,但一些截留在黏膜下層、肝臟之門小靜脈及身體之其他器官中。與所截留之卵相關之肉芽腫發炎為慢性血吸蟲病之明確症狀。
血吸蟲病之治療包括投與Praziquantel®、銻、奧沙尼喹(曼氏血吸蟲(S.mansoni))及Mirazid®。
絛蟲感染可分為兩類,一類為腸居住型成年絛蟲,諸如廣節裂頭絛蟲(Diphyllobothrium latum)及無鉤絛蟲(Taenia saginata),其具有限制的非體液免疫作用。第二類描述遷移型組織包囊幼期絛蟲,諸如包膜絛蟲(Hymenolepis nana)、犬絛蟲(Echinococcus granulosus)及有鉤絛蟲(Taenia solium),其誘導強非經腸宿主反應及保護性血清抗體。人類之最嚴重絛蟲感染為包蟲病,當其植入肝臟、肺、腦、腎臟或身體其他部分時,可導致形成包蟲囊腫。
包蟲病之治療包括投與甲硝唑、阿苯達唑及外科介入,諸如移除、抽吸、袋形縫術或網膜固定術。
線蟲為最常見的形式多樣且分布廣泛之感染人類之蠕蟲,其引發諸如旋毛蟲病、蛔蟲病、絲蟲病及類圓線蟲病之病症。由旋毛蟲(Trichinella spiralis)引起之旋毛蟲病可因攝入生肉或部分烹熟之肉(諸如豬肉)中之旋毛蟲幼蟲而引起。在人類中,感染引起IgM升高,之後產生IgG,之後由T淋巴細胞快速排出經抗體破壞之蠕蟲的強體液反應。
唯一已知之殺死腸中之成年蠕蟲的治療為腐絕(thiabendazole),然而尚無殺死幼蟲之已知治療。
亦稱為巨大蛔蟲(人蛔蟲(Ascaris lumbricoides))之蛔蟲為因攝入經糞便污染之物質產生之常見人類寄生蟲。雖然患者可在很長時間內
保持無症狀,但當幼蟲期穿行於身體中時,其可引起內臟損害、腹膜炎及發炎、肝臟或脾臟腫大、毒性及肺炎。
蛔蟲病之治療包括在投與或不投與哌嗪、己雷瑣辛(hexylresorcinol)、山道年(santonin)及香藜油(oil of Chenopodium)下投與甲苯達唑(mebendazole)(例如Vermox®)、哌嗪、雙羥萘酸喹嘧啶(pyrantel pamoate)(例如Antiminth®、Pin-Rid®、Pin-X®)、阿苯達唑、腐絕。本發明抗PD-L1抗體可與投與治療蛔蟲病之此等療法組合、在其之前或之後投與。
由絲蟲類線蟲引起之絲蟲病由昆蟲載體引入人類中。引起盤尾絲蟲病(onchoceriasis)或河盲症(river blindness)之旋盤尾絲蟲(Onchocerca volvulus)經由黑蠅(blackfly)叮咬傳播。感染性幼蟲將其自身寄生在皮下且發育成成蟲,誘導致纖維化宿主反應,且排出大量微絲蟲,該等微絲蟲在皮下分散且遍及眼睛,進一步誘發角膜炎或視網膜炎,接著導致角膜不透明。淋巴絲蟲病由血絲蟲屬(Brugia spp.)及吳策絲蟲屬(Wuchereria spp.)感染引起。隨著時間推移,尤其腹股溝中之淋巴組織結疤可阻止引流,從而引發外貌損傷病狀象皮病。
絲蟲病之初步治療為在投與或不投與伊維菌素(ivermectin)或阿苯達唑下投與抗生素伊維菌素、阿本達唑(abendazole)及枸櫞酸乙胺嗪(diethylcarbamazine citrate)(DEC,Hetrazan®)。其他治療預期藥物(prospect)包括多西環素,其殺死共生細菌沃爾巴克氏體(wolbochia)。
由圓線蟲屬寄生蟲(例如糞類圓線蟲(S.stercoralis)、福氏類圓線蟲(S.fülleborni))引起之類圓線蟲病為經由糞便污染之土壤傳播給人類之疾病。其可存在於獨立生存週期(桿狀幼蟲成熟為成年蠕蟲)以及寄生週期(絲狀幼蟲成熟為成年蠕蟲)中,其鑽入皮膚中,進入肺中,接著進入咽中,且最終駐留在腸中。亦已知發生圓線蟲自體感染,此基本上為絲狀幼蟲繼代之重複感染。
感染可能無症狀,或特徵可為胃腸道疼痛及腹瀉、肺之呂佛勒症候群(Löffler's syndrome)(亦即嗜酸性球增多症)及風疹。亦可存在血液嗜酸性球增多症。因為圓線蟲持續性感染可酷似消化性潰瘍、膽囊疾病及克羅恩氏病,所以常會誤診。其為免疫受損宿主之特別問題。
類圓線蟲病之已知治療為伊維菌素、阿苯達唑或腐絕,但因為此介導作用僅殺死成年蠕蟲,所以必需重複投藥。
e.接種
通常使用接種或投與抗原物質以誘導對疾病之免疫來預防或改善病原體之感染作用。增進宿主免疫可用於不僅在感染性病原體上發現而且在已患病(例如患癌症)之宿主組織上亦發現之不想要抗原。雖然疫苗傳統上衍生自已衰弱或死亡之完整病原體,但其亦可為呈現完整病原體上之人類I類或II類主要組織相容性複合物(MHC)分子特異性識別之抗原決定基的肽。特別相關之肽抗原為T細胞特異性識別之肽抗原。
最近,已展示使治療性接種與投與PD-L1阻斷於耗竭之CD8+ T細胞上相組合會增強慢性感染小鼠模型之功能及病毒控制。Ha等人,J.Exp.Med.205(3):543-555(2008)。因此,本文所述之抗PD-L1抗體亦可與抗原接種組合(例如在抗原接種之前、與其同時或在其之後投與)來治療由病毒、細菌、真菌或原蟲侵入引起之感染(例如急性感染及慢性感染)以及腫瘤免疫。
G.醫藥劑量:本發明醫藥組合物之劑量及所要藥物濃度可視預想之特定用途而變化。適當劑量或投藥途徑之確定完全在一般技術者之技術範圍內。動物實驗為人類療法提供確定有效劑量之可靠指導。有效劑量之種間縮放可遵循Mordenti,J.及Chappell,W.「The Use of Interspecies
Scaling in Toxicokinetics」,Toxicokinetics and New Drug Development,Yacobi等人編,Pergamon Press,New York 1989,第42-46頁所規定之原則進行。
當使用活體內投與本文所述之多肽或抗體時,正常劑量可能視投藥途徑而自每天每公斤哺乳動物體重約10ng至約100mg或100mg以上、較佳每天每公斤約1mg至10mg變化。文獻中提供關於特定劑量及傳遞方法之指導;參見例如美國專利第4,657,760號;第5,206,344號或第5,225,212號。在本發明之範疇內,不同調配物將對不同治療及不同病症有效,且意欲治療特定器官或組織之投藥可能必需以不同於另一器官或組織之方式傳遞。此外,劑量可藉由一或多次獨立投藥或藉由連續輸注來投與。對於經數天或更長時間重複投藥,視病狀而定,持續治療直至實現對疾病症狀之所要抑制。然而,其他給藥方案亦可適用。此療法之進程由習知技術及檢定容易地監測。
H.投與調配物
根據已知方法,諸如在一段時間內以快速注射或藉由連續輸注靜脈內投與、經由肌肉內、腹膜內、腦脊髓內、皮下、關節內、滑膜內、鞘內、經口、表面或吸入途徑,將本發明調配物(包括但不限於復原調配物及液體調配物)投與需要用抗PD-L1抗體治療之哺乳動物(較佳人類)。
在較佳實施例中,調配物藉由皮下(亦即在皮膚之下)投藥投與哺乳動物。為達成該等目的,可使用注射器注射調配物。然而,亦可利用其他投與調配物之裝置,諸如注射裝置(例如INJECT-EASETM及GENJECTTM裝置);注射筆(injector pen)(諸如GENPENTM);自動注射裝置、無針裝置(例如MEDIJECTORTM及BIOJECTORTM);及皮下貼片傳遞系統。
在一特定實施例中,本發明係針對產生單次劑量投藥單位之套
組。該等套組包含治療蛋白質或抗體之水性調配物之容器,包括單室或多室預填充注射器。例示性預填充注射器可自Vetter GmbH,Ravensburg,Germany獲得。
蛋白質之適當劑量(「治療有效量」)將視以下而定,例如待治療之病狀、病狀嚴重程度及進程、投與蛋白質用於預防性目的還是治療性目的、先前療法、患者臨床病史及對抗PD-L1抗體之反應、所用調配物之形式及主治醫師之判斷。適合地,將抗PD-L1抗體一次性或經一系列治療投與患者,且可自診斷起在任何時候投與患者。可將抗PD-L1抗體作為唯一治療投與或聯合適用於治療所討論之病狀之其他藥物或療法投與。
對於抗PD-L1抗體,投與患者之最初候選劑量可在約0.1-20mg/kg之範圍內,其可採用一或多次獨立投藥之形式。然而,其他給藥方案亦可適用。該療法之進程由習知技術容易地監測。
I.製品
在本發明之另一實施例中,提供一種含有調配物且較佳提供其使用說明書之製品。該製品包含容器。適合之容器包括例如瓶子、小瓶(例如雙室小瓶)、注射器(諸如單室或雙室注射器)及試管。該容器可由多種材料(諸如玻璃或塑膠)形成。該容器容納調配物。容器上或與容器有關之標籤可指示復原及/或使用說明。該標籤可進一步指示調配物適用於或意欲用於皮下投與及/或治療T細胞功能障礙病症。容納調配物之容器可為允許重複投與(例如,2-6次投與)復原調配物之多次使用的小瓶。該製品可進一步包含含適合之稀釋劑(例如BWFI)之第二容器。當混合稀釋劑與冷凍乾燥調配物後,復原調配物中之最終蛋白質濃度一般應為至少50mg/ml。該製品可進一步包括自商業性及使用者觀點需要之其他材料,包括其他緩衝液、稀釋劑、過濾器、針、注射器及附帶使用說明書之包裝插頁。
參考以下實例將更充分瞭解本發明。然而,不應將其視為限制本發明之範疇。因此,本案之所有引用明確地以引用的方式併入本文中。
在另一實施例中,本發明提供一種於自動注射裝置中投與之包含本文所述之調配物的製品。自動注射器可描述為激活後無需患者或投藥人的其他必需的動作即會傳遞內含物之注射裝置。當傳遞速率必須為常數且傳遞時間大於一定時間時,其尤其適用於治療性調配物之自我藥療。
進行文庫分選及篩檢以鑑別抗PD-L1抗體
使用人類(R&D Systems,目錄號156-B7)及鼠類(R&D Systems,目錄號1019-B7)PD-L1-Fc融合體作為交替文庫分選之抗原。詳言之,首先針對人類抗原分選噬菌體文庫,接著在後續三輪中針對鼠類、人類及鼠類抗原分選噬菌體文庫。在4℃下將Nunc 96孔Maxisorp®免疫板用標靶抗原(10μg/ml)塗布隔夜且在室溫下用噬菌體阻斷緩衝液PBST(磷酸鹽緩衝生理食鹽水(PBS)及1%(w/v)牛血清白蛋白(BSA)及0.05%(v/v)tween-20)阻斷1小時。將抗體噬菌體文庫VH(參見例如Lee等人,J.Immunol.Meth. 284:119-132,2004)及VH/VL(參見Liang等人,J.Mol.Biol. 366:815-829,2007)分別添加至抗原板中且在室溫下培育隔夜。第二天,將塗布抗原之板用PBT(具有0.05% Tween-20之PBS)洗滌十次,且用50mM HCl及500mM NaCl溶離結合之噬菌體30分鐘且用等體積之1M Tris鹼(pH 7.5)中和。在大腸桿菌XL-1 Blue細胞中擴增回收之噬菌體。在後續幾輪選擇期間,將用塗布抗原之板培育抗體噬菌體縮短至2-3小時,且逐漸增加板洗滌之嚴格性。
4輪淘選後,觀測到明顯的富集。自VH及VH/VL文庫分選中各揀
選96種純系來確定其是否與人類與鼠類PD-L1-Fc特異性結合。對此等純系之可變區進行PCR測序以鑑別獨特的序列純系。
藉由將個別純系之VL及VH區分別選殖至LPG3及LPG4載體中(Lee等人,同上)、短暫表現於哺乳動物CHO細胞中且用蛋白質A管柱純化將相關親本純系重組成IgG。評價13種噬菌體抗體之阻斷可溶性PD-1-Fc融合蛋白與表現於293細胞中之人類或小鼠PD-L1之間的相互作用之能力(IC50值表示於表1的上半部分中)。按後續親和力成熟選擇阻斷人類PD-L1與PD-1之結合的IC50最小之抗體YW243.55來改良其對於人類與小鼠PD-L1之親和力。(表1)。針對靈長類與鼠類物種具有可比的交叉反應性(而且保持對人類之親和力)之抗體將提供具有高價值之療法,因為實驗模型中已充分表徵之相同抗體可用於人類臨床試驗中。此舉避免由使用模型特定代用品引起之不確定性。
用於衍生自V
H
文庫之純系的親和力改良之構築體文庫
噬菌粒pW0703(衍生自噬菌粒pV0350-2b(Lee等人,J.Mol.Biol 340:1073-1093(2004)),在所有CDR-L3位置均含有終止密碼子(TAA)且在M13噬菌體之表面上顯示單價Fab)充當自VH文庫移植相關純系之重鏈可變域(VH)以達成親和力成熟之文庫模板。使用硬與軟隨機突變策略進行親和力成熟。對於硬隨機突變,使用經設計以模擬天然人類抗體之胺基酸使一個具有三個輕鏈CDR之所選位置之輕鏈文庫隨機突變,且所設計之DNA簡併係如Lee等人(J.Mol.Biol 340,1073-1093(2004))中所述。對於軟隨機突變,靶向CDR-L3之位置91-94及96、CDR-H1之位置28-31及34-35、CDR-H2之位置50、52及53-58、CDR-H3之位置95-99及100A之殘基;且選擇CDR環之兩種不同組合L3/H1/H2及L3/H3進行隨機突變。為達成在所選位置處引入約50%之突變率的軟隨機突變條件,用有利於野生型核苷酸之鹼基之70-10-10-10混合物合成突變誘發DNA(Gallop等人,Journal of Medicinal Chemistry 37:1233-1251(1994))。
分選噬菌體以產生親和力改良
使先前所鑑別之噬菌體純系經受第一輪板分選,接著經受5或6輪溶液分選。分別針對人類及鼠類PD-L1-Fc(R&D Systems,分別為目錄號156-B7,目錄號1019-B7)分選文庫。對於人類PD-L1-Fc標靶,在第一輪板分選下,在室溫下於1% BSA及0.05% Tween 20中用約3O.D./ml之噬菌體輸入分別針對標靶塗布板(NUNC Maxisorp®板)分選三個文庫2小時。在第一輪板分選後,執行溶液分選以增加選擇之嚴格性。對於溶液分選,在室溫下於100μL含有1% Superblock(Pierce Biotechnology)及0.05% Tween-20之緩衝液中與20nM經生物素標記標靶蛋白(濃度係以親本純系噬菌體IC50值計)一起培育自第一輪板分選繁殖之1O.D./ml噬菌體30分鐘。進一步用1% Superblock稀釋混合物10倍,且在室溫下在輕輕震盪下向中性鏈親和素塗布之各孔(5μg/ml)中每孔施加100微升歷時15分鐘,以致經生物素標記標靶結合噬菌體。用PBS-0.05% Tween-20洗滌各孔10次。為測定本底結合,於中性鏈親和素塗布之板上對含有噬菌體及未經生物素標記之標靶的對照孔進行捕捉。用0.1N HCl溶離結合之噬菌體20分鐘,用1/10體積之1M Tris pH-11中和,測定效價且繁殖以用於下一輪。接著,連同兩種增加選擇嚴格性之方法一起再進行5輪溶液分選。第一輪係藉由使經生物素標記標靶蛋白濃度自4nM降至0.5nM進行締合速率選擇,且第二輪係藉由在室溫下或在37℃下添加過量非生物素標記標靶蛋白(100至2000倍以上)以競爭除去較弱結合物進行解離速率選擇。同時,降低噬菌體輸入(0.1至0.5O.D/ml)以降低本底噬菌體結合。對於鼠類PD-L1-Fc標靶而言,噬菌體分選方法類似於以上關於人類PD-L1 Fc抗原所述之噬菌體分選方法,其中稍有一些改動。詳言之,在第一輪板淘選之後即刻使用100nM經生物素標記鼠類PD-L1-Fc進行溶液淘選。
在後續4輪溶液淘選中,經生物素標記標靶自10nM降至1nM,且在室溫下添加200-500倍過量之非生物素標記標靶。
隨後進一步用以下實例中所述之高通量親和力篩檢ELISA程序篩檢親和力成熟純系。
高通量親和力篩檢ELISA(單點競爭)
分別自人類及鼠類PD-L1標靶之第7輪及第6輪篩檢中揀選菌落。使菌落在96孔板(Falcon)中在37℃下於每孔150微升含50μg/ml卡本西林(carbenicillin)及1E10/ml KO7之2YT培養基中生長隔夜。自同一板揀選經XL-1感染之親本噬菌體之菌落作為對照組。將96孔Nunc Maxisorp®板分別每孔用100微升於PBS中之人類及鼠類PD-L1-Fc蛋白(2μg/ml)在4℃下塗布隔夜或在室溫下塗布2小時。用65μL 1% BSA阻斷板30分鐘且用40μL 1% Tween 20再阻斷30分鐘。
用有或無10nM標靶蛋白之ELISA(酶聯免疫吸附檢定)緩衝液(含0.5% BSA、0.05% Tween-20之PBS)按1:10稀釋噬菌體上清液,總體積為100μL,且在室溫下於F板(NUNC)中培育至少1小時。將有或無標靶蛋白之75μL混合物並排轉移至標靶蛋白塗布之板中。將板輕輕震盪15分鐘以允許未經結合之噬菌體被捕捉至標靶蛋白塗布之板上。用PBS-0.05% Tween-20洗滌板至少5次。藉由添加與辣根過氧化酶(HRP)結合之抗M13抗體於ELISA緩衝液中之溶液(1:5000)來定量結合,且在室溫下培育30分鐘。用PBS-0.05% Tween 20洗滌板至少5次。接著,按每孔100μL向孔中添加1:1比例之3,3',5,5'-四甲基聯苯胺(TMB)過氧化酶受質及Peroxidase SolutionB(H2O2)(Kirkegaard-Perry Laboratories(Gaithersburg,MD)),且在室溫下培育5分鐘。藉由向各孔中添加將100μL 1M磷酸(H3PO4)使反應終止,且在室溫下培育5分鐘。在450nm下使用標準ELISA板讀取器測定各孔中黃顏色之OD(光密度)。利用以下等式計算OD減少率(%)。
OD450nm減少率(%)=[(有競爭者之孔的OD450nm)/(無競爭者之孔的OD450nm)]×100
揀選人類與鼠類標靶之與親本噬菌體之孔的OD450nm減少率(%)(100%)相比具有低於50%之OD450nm減少率(%)的純系用於序列分析。選擇獨特純系進行噬菌體製備以藉由與親本純系相比確定針對人類與鼠類PD-L-Fc之結合親和力(噬菌體IC50)。
材料
自R&D Systems購得hPD-1-Fc、hPD-L1-Fc、hB7.1-Fc、mPD-1-Fc、mPD-L1-Fc及mB7.1。在Genentech使用習知技術產生表現293細胞之hPD-L1。自Jackson ImmunoResearch Laboratories購得F(ab')2山羊抗人類IgG Fc。
蛋白質之結合
如製造商所述,在室溫下用EZ-Link N-羥基硫代琥珀醯亞胺-LC-LC-生物素(sulfo-NHS-LC-LC-biotin)(Pierce)對PD-1-Fc及B7.1-Fc蛋白作生物素標記30分鐘。如製造商所述,用Quick Spin高容量管柱G50-Sephadex(Roche)移除過量未反應生物素。
如製造商所述,用MSD Sulfo-Tag N-羥基琥珀醯亞胺酯(NHS-Ester)(Meso Scale Discovery)對F(ab')2山羊抗人類IgG Fc作釕標記,且用Quick Spin高容量管柱G50-Sephadex移除過量未反應Sulfo-Tag。
測試噬菌體抗體之ECL細胞結合檢定
利用電化學發光(ECL)細胞結合檢定量測引起hPD-1-Fc與表現hPD-L1之293細胞之結合受50%抑制之抗體濃度(IC50)。用磷酸鹽緩衝生理食鹽水(PBS)洗滌hPD-L1表現293細胞且在96孔高度結合板(Meso Scale Discovery)上按每孔25,000個細胞接種於25μL PBS中。在室溫下培育板以使細胞附著於板之碳表面上。向各孔中添加25μL 30% FBS且在輕微攪拌下培育板30分鐘以阻斷非特異性結合位點。在輕輕
分配及抽吸條件下在ELISA微量板洗滌機(ELx405 Select,Bio-Tek Instruments)用PBS洗滌板三次。藉由用紙巾吸乾板移除孔中之過量PBS。向含3% FBS之PBS溶液(檢定緩衝液)之各孔中添加12.5μL 2倍濃度之抗體,接著添加12.5μL 4μg/mL(2倍濃度)hPD-1-生物素之檢定緩衝液溶液,且在輕微攪拌下培育板1小時。在微量板洗滌機上用PBS洗滌板3次且用紙巾吸乾板。添加25μL 2μg/mL抗生蛋白鏈菌素-釕(Meso Scale Discovery)且在室溫下在輕輕攪拌下於檢定緩衝液中培育30分鐘。在微量板洗滌機上用PBS洗滌3次且用紙巾吸乾板。添加150μL 1倍無界面活性劑之MSD讀取緩衝液(Meso Scale Discovery)。
在Sector Imager 6000讀取器(Meso Scale Discovery)上在620nm下讀取所發射之發光。用檢定中所用之測試抗體的濃度使用四參數非線性最小二乘法擬合分析ECL值,獲得檢定中各競爭者之IC50值。
結果及討論:選擇15種結合人類與鼠類PD-L1之衍生自YW243.55之獨特噬菌體抗體且重組為全長IgG1抗體以用於進一步評估。此等抗體之輕鏈及重鏈可變區序列報導於圖11A及圖11B中。
經由電化學發光(ECL)細胞結合檢定測試該15種重組抗體阻斷PD-1與表現人類或小鼠PD-L1之293細胞結合之能力。表1的下半部分:在表1中「格式1」描述可溶性人類PD-1-Fc與人類PD-L1-轉染之293細胞的結合;「格式2」描述鼠類PD-1-Fc與鼠類的PD-L1轉染之293細胞的結合,且「格式3」描述人類PD-1與鼠類PD-L1轉染之293細胞的結合。雖然所有15種親和力改良之抗體均已獲得明顯的與小鼠PD-L1之交叉反應性,但仍基於YW243.55S70阻斷人類與小鼠PD-L1結合PD-1之能力(表1:IC50值分別為49pM及22pM)選擇其作為第一候選物繼續研究。
使用BIAcoreTM-3000儀器由表面電漿共振(SRP)量測抗PD-L1噬菌體抗體YW243.55及YW243.55S70針對重組人類及小鼠PD-L1之結合親和力。將重組人類PD-L1-Fc(R&D Systems,目錄號156-B7)及重組小鼠PD-L1-Fc(R&D Systems,目錄號1019-B7)直接塗布於CM5生物感測器晶片上以達到約500個應答單位(RU)。對於動力學量測,在25℃下
將兩倍連續稀釋液(3.9nm至500nm)以30μL/min之流動速率注射至PBT緩衝液(含0.05% Tween-20之PBS)中。使用簡單的一對一朗繆耳結合模型(Languir binding model)(BIAcore Evaluation Software 3.2版)計算締合速率(k on )及解離速率(k off )。以比率koff/kon計算平衡解離常數(kD)。
所量測之抗PD-L1噬菌體抗體純系YW243.55及YW243.55.S70之結合親和力報導於下表2中。
此實例展示本發明之抗PD-L1抗體對人類、恆河猴及小鼠PD-L1之特異性。此外,其展示該抗體對293轉染細胞之細胞膜上所表現之小鼠及人類PD-L1之親和力。
將人類及小鼠PD-L1穩定轉染至293細胞中。收集細胞且按每孔150,000個細胞塗鋪於96孔板中以進行結合研究。
自美國生物醫學研究西南基金會(Southwest Foundation for Biomedical Research)(San Antonio,Texas)獲得恆河猴血液。用等體積PBS稀釋血液且塗覆在96% Ficoll-Paque(GE Healthcare)上以分離單核細胞。使用紅血球溶解緩衝液(Qiagen)溶解紅血球得到單核細胞,且
以每毫升1.5×106個細胞與5ng/ml PMA加1μM依諾黴素(ionomycin)一起在6孔板中培養隔夜。培養基為含10%胎牛血清、20μM HEPES及來自Gibco之以下補充劑之1:100稀釋液的RPMI 1640:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。第二天收集細胞,且等分至96孔板中以進行結合研究(每孔約120,000個細胞)。
由三倍連續稀釋液以10μg/ml起始滴定PD-L1抗體YW243.55.S70或Herceptin®抗體對照組,且在冰上於50μl體積中與細胞結合25分鐘。洗滌細胞,且接著在冰上與20μg/ml抗人類IgG PE(Caltag)結合25分鐘。亦用CD3 FITC及CD4 APC(BD Biosciences)使恆河猴細胞共同染色以區別CD4+ T細胞。
所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用Tree Star,Inc.FlowJo®軟體分析隨抗PD-L1抗體濃度變化之PD-L1結合資料之平均螢光強度;使用Kaleidagraph計算EC50值(與半最大結合相關的抗體濃度)。此外,執行平衡結合研究以確定YW24355S70與293細胞上表現之人類及小鼠PD-L1之結合的精確親和力(Kd)(實例3B)。此等值概述於以下表3中:
在37℃下於5% CO2中,在生長培養基中培養經人類或小鼠PD-L1轉染之293細胞,該生長培養基係由補充有10%胎牛血清(FBS)、2mM L-麩胺醯胺、1×青黴素-鏈黴素之RPMI 1640培養基組成。用結合緩衝液(含2% FBS及50mM Hepes(pH 7.2)之50:50 DMEM/F12)洗滌細胞,且將約230,000個細胞於0.2mL結合緩衝液中置放於96孔板中。使用四氯二苯基苷脲(Iodogen)法碘化抗PD-L1抗體YW243.55.S70.hIgG。
藉由凝膠過濾使用NAP-5管柱自游離125I-NA純化經放射性標記之抗PD-L1抗體;經純化之抗體之比活性為17.41μCi/μg。將體積為50μL之含固定濃度之碘化抗體及遞減濃度之連續稀釋未標記抗體的競爭反應混合物置放於96孔板中。在37℃下在5% CO2中,在生長培養基中培養表現人類PD-L1及鼠類PD-L1之293穩定轉染細胞株,該生長培養基係由補充有10%胎牛血清(FBS)、2mM L-麩胺醯胺、1×青黴素-鏈黴素之50:50 DMEM/F12培養基組成。用結合緩衝液(含2% FBS、50mM HEPES(pH 7.2)及2mM疊氮化鈉之50:50 DMEM/F12)洗滌細胞,且於0.2mL結合緩衝液中以約200,000個細胞之密度添加至50μL競爭反應混合物中。各含細胞之競爭反應物中碘化抗體之最終濃度為約150pM(約120,000cpms/0.25mL),且含細胞之競爭反應物中未經標記之抗體的最終濃度不等,以500nM起始,隨後按2倍遞減,獲得10個濃度。在室溫下培育含細胞之競爭反應物2小時。一式三份檢定含細胞之競爭反應物的未經標記之抗體的各濃度。培育2小時後,將競爭反應物轉移至Millipore Multiscreen過濾板中,且用結合緩衝液洗滌4次以分離游離碘化抗體與結合碘化抗體。在Wallac Wizard 1470γ計數器(PerkinElmer Life and Analytical Sciences Inc.Wellesley,MA)上計數過濾器。使用NewLigand軟體(Genentech)評估結合資料,該軟體使用莫森(Munson)及羅巴德(Robard)擬合算法確定抗體之結合親和力。
Musson等人,Anal.Biochem. 107:220-39(1980)。
由斯卡查德分析所測定之Kd值證實表3中所示之抗PD-L1抗體與人類及小鼠PD-L1之結合的EC50值。
此實例展示用於評估本發明之全長抗PD-L1抗體阻斷PD-L1結合PD-1與B7.1之能力的結合選擇性及親和力(IC50)檢定。
方法: hB7.1-Fc-生物素及hPD-1-Fc-生物素與hPD-L1-Fc ELISA之結合(格式4):將Nunc Maxisorp 384孔板用25μL 250ng/mL hPD-L1-Fc之PBS溶液塗布隔夜。在微量板洗滌機上用0.05% Tween之PBS溶液(洗滌緩衝液)洗滌各孔三次且用0.5% BSA之PBS溶液阻斷各孔。向含0.05% Tween、0.5% BSA之PBS溶液(檢定稀釋液)之各孔中添加12.5μL 2倍濃度之抗體,接著添加12.5μL 250ng/mL(2倍濃度)hB7.1-Fc-生物素之檢定稀釋液溶液,且在攪拌下培育板一個半小時。用洗滌緩衝液洗滌各孔6次且添加25μL抗生蛋白鏈菌素-HRP(1:40,000檢定稀釋液溶液,GE Healthcare)。在攪拌下培育板30分鐘且用洗滌緩衝液洗滌各孔6次。添加25μL TMB受質(Kirkegaard and Perry Laboratories)歷時1小時且用25μL 1M磷酸終止反應。如實例1在ECL細胞結合檢定中所述,在450nm下讀取吸光度且分析IC50值。
格式5、6、7:對於hPD-1-Fc-生物素與hPD-L1-Fc之結合(格式5),該格式類似於以上檢定,其中例外為使用hPD-1-Fc-生物素代替hB7.1-Fc-生物素進行結合。TMB受質反應時間為17分鐘。
對於mB7.1-Fc-生物素與mPD-L1-Fc之結合(格式6),該格式類似於格式5,其中例外為使用mPD-L1-Fc代替hPD-L1-Fc塗布板,且使用
mB7.1-Fc-生物素代替hB7.1-Fc-生物素進行結合。TMB受質反應時間為7分鐘。
對於mPD-1-Fc-生物素與mPD-L1-Fc之結合(格式7),該格式類似於以上所提及之小鼠ELISA,其中例外為使用mPD-1-Fc-生物素代替mB7.1-Fc-生物素進行結合。TMB受質反應時間為5分鐘。
結果:親和力成熟噬菌體抗PD-L1抗體YW243.55.S70阻斷指定結合對之間的相互作用的IC50之評定報導於表3中。YW243.55S70能夠在38pM之半最大抑制濃度下阻斷人類PD-L1與hB7.1 Fc之結合,該濃度相對而言可比於阻斷PD-L1/PD-1相互作用之IC50值(42pM)。量測YW243.55S70阻斷PD-L1與PD-1及B7.1之相互作用之能力的Biacore研究與此等ELISA結果(資料未展示)一致。
此實例展示如應答黑素細胞肽gp100之γ-IFN產生的增強所量測,本發明抗PD-L1抗體對PMEL T細胞受體轉殖基因CD8+ T細胞活化之作用。在此程序中,自CD8+ T細胞表現對gp100肽具有特異性之TCR的PMEL TCR轉殖基因小鼠獲得CD8+ T細胞。純化CD8+ T細胞之後,執行多輪刺激以產生且擴充活化之CD8+ T細胞,而CD8+ T細胞接著又將調升PD-1表現。同時,用IFN-γ處理B16黑素瘤細胞以調升
其PD-L1表現。接著,在抗PD-L1抗體存在下共培養該等細胞,且評估對IFN-γ產生之作用。針對三次刺激選擇B16細胞,因為其內源性表現低含量之gp100肽(與肽之外源應用相反)。此外,因為此等細胞亦不表現PD-L2、B7.1或B7.2,所以與PD-L1無關之其他信號傳導(例如經由CD28或CTLA-4之信號傳導,或經由PD-1之PD-L2誘導之信號傳導)之作用降至最低。
PMEL檢定:如圖3所示,抗PD-L1抗體增加產生IFN-γ之PMEL CD8+ T細胞之百分比與應答指定量之gp100肽所產生之IFN-γ的平均含量。
D.011.10活體外檢定:利用Ova特異性TCR Tg CD4+ T細胞之類似檢定展示,在抗PD-L1抗體存在下在先前用Ova肽刺激以誘導PD-1之表現之後,T細胞增殖增強(圖4)。在最終刺激中,使用表現PD-L1之經照射A20 B細胞向DO.11.10 T細胞提供指定濃度之Ova肽。值得注意的是,在較低程度的抗原受體刺激下,PD-1/PD-L1軸之貢獻更明顯,含量更密切地反映刺激之生理學相關量值。
材料及方法:PMEL檢定
初次刺激(第0-4天)
自PMEL轉殖基因T細胞受體小鼠收集脾臟及腸系膜淋巴結。將器官粉碎成單細胞懸浮液且溶解紅血球。使用CD8+ T細胞分離套組及AutoMACS細胞分離器(Miltenyi Biotec)根據製造商之說明書分離CD8+ T細胞。
自非轉殖基因性別匹配之小鼠分離脾臟且粉碎成單細胞懸浮液,且溶解紅血球。在37℃下用0.1μg/ml gp100脈衝細胞2小時且洗滌。
在96孔平底板中與200,000個PMEL CD8+ T細胞及75,000個經gp100脈衝之脾細胞一起共培養細胞4天。培養基為伊思考夫氏改良之達爾伯克氏培養基(Iscove's Modified Dulbecco's medium)+10%胎牛血清+20μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。
二次刺激(第4-7天)
離心PMEL培養物,且使用多通道吸管吸出培養基。添加新鮮培養基並混合以洗滌細胞,之後再次離心。移除大部分培養基,且添加抗體(Herceptin®、YW243.55.S70或無)至最終濃度為10μg/ml。一式兩份在孔中設立條件以致可在終點時評定平均IFN-γ產生。
在37℃下用0.1μg/ml gp100肽脈衝DC-1細胞2小時且洗滌。按每孔40,000個細胞向已洗滌之PMEL培養物中添加經Gp100脈衝之DC-1細胞。將PMEL及DC-1+抗體共培養3天。
三次刺激(第7-8天)
在三次刺激的前一天,即第6天,與20ng/ml小鼠IFN-γ(R&D Systems)一起培育B16黑素瘤細胞隔夜以調升其PD-L1表現。
第7天,離心PMEL培養物且使用多通道吸管吸出培養基。添加新鮮培養基並混合,之後再離心。移除大部分培養基,且添加抗體至最終濃度為10μg/ml。
用IFN-γ刺激隔夜後,洗滌B16細胞且分成三組,在無gp100、1ng/ml gp100(低gp100)及10ng/ml gp100(高gp100)下培育兩小時。洗滌細胞,且接著按每孔40,000個細胞添加至已洗滌之PMEL+抗體培養物中且一起培育隔夜。
第8天IFN-γ細胞內染色
根據製造商之說明書,添加Golgi-Plug(BD Biosciences)供培養的最後5小時使用。根使用BD Biosciences Cytofix/Cytoperm
Fixation/Permeabilization Solution套組據製造商之說明書進行IFN-γ細胞內染色,且所有染色抗體亦來自BD Biosciences。用CD8a PE及Thy1.1 FITC使細胞表面染色,且用飽和濃度之IFN-γ APC使細胞細胞內染色。
所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用TreeStar,Inc.FLOWJOTM軟體分析資料。
D011.10活體外檢定
收集DO11.10轉殖基因小鼠之脾臟及腸系膜淋巴結,粉碎成單細胞懸浮液且溶解紅血球。按每毫升1×106個細胞之密度在含0.3μM之Ova肽之6孔板中培養細胞72小時。培養基為RPMI 1640+10%胎牛血清+20μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。
初次刺激之後,收集細胞且使用小鼠CD4 T細胞純化套組根據製造商之說明書(Miltenyi Biotec)純化CD4+ T細胞。接著使經純化之CD4+ T細胞靜置隔夜。
次日,收集細胞,洗滌且與經照射(10,000拉德(rad))A20細胞共培養。在96孔U形底板中一式三份在孔中設立與50,000個CD4+ T細胞至40,000個A20細胞及最終濃度為20μg/ml之經滴定Ova肽及抗體的共培養。48小時後,每孔用1μCi 3H-胸苷脈衝培養物隔夜且次日冷凍。隨後將板解凍,在細胞收集器上收集,且在β計數器上讀數。
圖5說明抗PD-L1(例如YW243.55.S1)能夠應答來自MHC錯配供體之細胞增進人類CD8 T細胞之增殖。藉由首先使用CD8+ T細胞RosetteSep®(StemCell Technologies)根據製造商之說明書自供體A之全血富集應答之CD8+ T細胞。接著用等體積磷酸鹽緩衝生理食鹽水
(PBS)稀釋細胞,且藉由塗覆於Ficoll-Paque Plus(GE Healthcare)上經梯度離心分離。分離後,用CD8 APC(BD Biosciences)使細胞染色且結果為78% CD8+ T細胞染色。用2.5μM CFSE示蹤染料(Molecular Probes)對細胞作螢光標記。
為充當同種異體抗原呈現細胞(APC),首先自供體B之全血分離單核細胞,且接著耗盡CD3+T細胞。用等體積PBS稀釋血液,且在經Ficoll梯度離心之後分離單核細胞。用CD3 FITC(BD Biosciences)使細胞染色,洗滌且接著與抗FITC微珠(Miltenyi Biotec)一起培育。接著在AutoMACS細胞分離器(Miltenyi Biotec)上耗盡CD3 FITC陽性細胞。接著在銫照射器中以2500拉德照射細胞。
在含150,000個CD8+ T細胞及150,000個APC之96孔平底板中與10μg/ml抗體一起共培養細胞5天。培養基為RPMI 1640+10%胎牛血清+20μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。
在第5天,收集細胞,洗滌且依序用CD8-生物素及抗生蛋白鏈菌素-PerCp(BD Biosciences)使之染色。所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用Tree Star,Inc.FlowJo軟體分析資料。
在抗PD-L1存在下觀察到應答MHC錯配供體之細胞的CD8 T細胞之增殖增強約45%。
已展示T細胞在慢性刺激條件下調升且維持抑制性受體PD-1之表現。PD-1與其兩種配位體PD-L1及PD-L2中之任一者的連接造成慢性活化T細胞之不應狀態(refractory state),從而減弱其對其同源抗原之反應。在持續經淋巴細胞性脈絡叢腦膜炎病毒(lymphocytic
choriomeningitis virus,LCMV)感染之小鼠中,阻斷PD-1或其配位體PD-L1足以使慢性不應T細胞恢復,從而增加抗病毒T細胞反應之量值及功能品質。類似地,經HIV或HCV慢性感染之人類展現T細胞對模擬無反應,其活性可藉由阻斷PD-1或PD-L1活體外增強。因此,LCMV模型中PD-L1阻斷之活性表明具有增強抗病毒及抗腫瘤免疫之治療潛能。
對於小鼠之LCMV活體內實驗,吾人已藉由將噬菌體衍生之重鏈及輕鏈可變區序列選殖於小鼠IgG2a重鏈及小鼠κ輕鏈恆定域之上游來重組人類化抗PD-L1抗體(YW243.55S70)。為阻止PD-L1表現細胞之抗體介導之細胞毒性,藉由抑制Fcγ受體結合,將位置265(天冬胺酸)及297(天冬醯胺)改為丙胺酸(DANA)。Shields,RL等人,J.Biol Chem 2001 276(9):6591-6604。為測試抗PD-L1抗體在慢性感染中增強抗病毒免疫之能力,在第0天,用2×106個空斑形成單位(plaque forming unit,pfu)之純系13 LCMV或LCMV之Armstrong病毒株感染小鼠作為參考對照組。實驗設計之示意圖顯示於圖6中。用純系13感染導致慢性感染,其特徵在於T細胞擴充但不能有效清除病毒;而Armstrong LCMV在感染8-10天內即被清除。在第14天,小鼠開始受以10mg/kg劑量傳遞之抗PD-L1或對照mIgG處理,每週3次。在第21天及第28天,執行血液及組織的CD8 T細胞功能及病毒效價之分析。
與Barber等人,Nature 439:682-7(2006)公開之資料一致,此實例展示在慢性LCMV感染中,在2週處理方案後,抗PD-L1抗體能夠增強細胞毒性淋巴細胞對LCMV之反應。圖7A展示應答gp33 LCMV特異性肽表現CD107a於細胞表面上之CD8 T細胞的百分比。通常於細胞內表現之CD107a之質膜表現伴隨去顆粒過程,且因此充當去顆粒之代用指標。相對於來自急性Armstrong LCMV感染之細胞之反應,來自受慢性病毒株純系13感染之動物之細胞的去顆粒減弱(對照Ig組),而
PD-L1阻斷能夠使CD8+之去顆粒恢復至可比於Armstrong感染中所觀測到之去顆粒的程度。類似地,7B說明在抗PD-L1處理組中應答LCMV gp33之產生IFN-γ之CD8 T細胞相對於對照Ig的增加百分比。
接著,測試抗PD-L1抗體對降低或消除血液及組織中之LCMV病毒的影響。在圖8A中,圖展示在用純系13 LCMV感染之後第21天及第28天,經對照Ig及PD-L1處理之動物之指定組織中的對數病毒效價。在感染後第14天,開始抗體處理。阻斷PD-L1引起血液、肝臟、腦、肺及腎臟中之病毒效價極顯著地降低。印象深刻的是,在5隻小鼠中之3隻中,α-PD-L1抗體使血液LCMV效價降低至偵測限值以下之含量(<1×10-5)。在可比設計之後續實驗中,在所有5隻用劑量為10mg/kg或2mg/kg之抗PD-L1處理2週(每週3次)之小鼠中均觀測到血液及肝臟中之病毒根除(資料未圖示)。下圖展示血液中病毒效價降低之動力學,且說明在第28天抗PD-L1處理組相對於對照組平均降低96.8%。此等資料證明PD-1/PD-L1路徑在慢性感染中在抑制T細胞反應方面之重要性且與活體外PD-L1阻斷對自患有慢性感染(諸如C型肝炎及HIV)人類獲得之T細胞之作用一致。
材料及方法:測定CD8 T細胞應答LCMV gp33肽產生之IFN-γ的百分比
自經感染小鼠中分離脾臟,且藉由在完全培養基中粉碎器官產生單細胞懸浮液,該完全培養基為含10%熱失活胎牛血清、2mM L-麩胺醯胺、100U/ml青黴素/鏈黴素及10mM 2-巰基乙醇之IMDM(Invitrogen Inc.,Carlsbad,CA)。使用ACK溶解緩衝液(0.15M NH4Cl、10mM KHCO3、0.1mM EDTA)溶解紅血球。為量測抗原特異性CD8 T細胞反應,用完全培養基洗滌脾細胞,且用LCMV肽GP33(KAVYNFATC,ProImmune Inc.,Bradenton,FL)活體外再刺激4小時。在96孔平底板中在100單位/毫升人類介白素-2(Sigma-Aldrich,St.
Louis,MO)、1微升/毫升布雷菲德菌素A(brefeldin A)及1微升/毫升莫能星(monensin)(BD pharmingen)(1:1000稀釋液)及抗CD107a FITC(純系ID4B,BD Biosciences,San Jose,CA)存在下與100奈克/毫升GP33肽一起培養1×106個脾細胞。培育後,用含2%胎牛血清之PBS洗滌細胞一次,且使用螢光染料結合抗體使細胞表面標記物染色,該等螢光染料結合抗體為抗CD8 APC(純系53.67,BD Biosciences,San Jose,CA)、抗CD4 PerCp-Cy5.5(純系RM4-5,BD Biosciences,San Jose,CA)及抗PD-1 PE(純系J43,BD Biosciences,SanJose,CA)。使用Cytofix Cytoperm Plus套組(BD Biosciences,San Jose,CA)根據製造商之說明書使用抗IFN-γ PE-Cy7(純系XMG1.2,eBioscience Inc.San Diego,CA)進行細胞內IFN-γ染色。為偵測GP33特異性CD8 T細胞之數目,用GP33五聚物(與APC連接之H2-Db,ProImmune Inc.,Bradenton,FL)根據製造商之說明書使新鮮脾細胞染色。使用BD FACSAria(BD Biosciences,San Jose,CA)收集資料,且用FlowJo軟體(Tree Star Inc.Ashland OR)分析。
測定LCMV病毒效價: 用於完全IMDM中之含LCMV之血液或組織勻漿的10倍連續稀釋液感染MC57纖維肉瘤細胞。接著在組織培養恆溫箱中在37℃下培育反應物2-6小時,接著用含1%甲基纖維素之DMEM塗覆。此後培育3-5天,接著藉由抽吸移除甲基纖維素層。用PBS/4%三聚甲醛固定細胞,接著用0.5%曲拉通-x(Triton-x)增加通透性歷時20分鐘,用PBS洗滌,接著在輕微搖動下於10% FCS中阻斷1小時。用VL4抗體對LCMV進行染色(1小時),洗滌2次,接著用於阻斷緩衝液中之抗大鼠HRP(1:400)顯色。此後洗滌3次,接著向各孔中添加鄰苯二胺受質(SIGMA P8806-50TAB 3毫克/錠劑)以顯色。
目前顯而易見,許多腫瘤利用PD-1配位體之表現作為減弱抗腫瘤T細胞反應之方法。若干人類癌症之特徵在於在腫瘤與腫瘤浸潤性白血球上表現高含量之PD-L1且此高PD-L1表現通常與較差預後相關。小鼠腫瘤模型說明腫瘤內PD-L1表現類似地增加且說明PD-1/PD-L1路徑在抑制腫瘤免疫中之作用。
此處吾人提供說明阻斷PD-L1對同基因C57B6小鼠中MC38.Ova鼠類結腸直腸癌細胞之正位腫瘤生長之影響的實驗(圖9A)。如流式細胞儀所評定,此等細胞經由逆轉錄病毒轉導表現卵清蛋白且表現PD-L1(但不表現PD-L2)於其細胞表面上(直方圖-圖10A)。在第0天,用50萬個MC38.Ova細胞經皮下給小鼠接種。在第1天或第14天,用10mg/kg抗PD-L1(YW243.55S70-小鼠IgG2a-DANA)、對照Ig或阻斷抗CTLA4抗體(UC10-4F10-11)處理小鼠(當腫瘤平均大小達到250mm3時)(每組10隻小鼠),每週3次,歷時研究持續時間。早期或在後期介入中阻斷PD-L1均極有效作為單一藥劑療法阻止腫瘤生長。相反,阻斷CTLA4(T細胞上表現之另一抑制性分子)展示無抑制腫瘤生長之跡象。此等結果說明PD-1/PD-L1軸優於CTLA4/B7之抑制抗腫瘤免疫反應之獨特作用,且證明用阻斷PD-L1與PD-1及B7.1相互作用之抗體具有治療人類癌症之潛能。
MC38.Ova同基因腫瘤模型:方法。在第0天,用於100微升HBSS+基質膠(matrigel)中之50萬個MC38.Ova細胞經皮下給70隻動物接種。第1天開始,將20隻小鼠招募至2個處理組(參見下文:第1組或第2組)中之一個中。使其餘40隻小鼠生長腫瘤直至第14天。在此等40隻小鼠中,將30隻具有類似大小之腫瘤的小鼠招募至3個處理組(第3組至第5組)中之一個中。每週2次量測腫瘤且稱重小鼠。對因腫瘤體積不相似而未招募至以下處理組中之小鼠實行安樂死。
第1組:抗gp120抗體,10mg/kg(腹膜內),100μL,第1天,每週3次
第2組:抗PD-L1抗體,10mg/kg(腹膜內),100μL,第1天,每週3次
第3組:抗gp120抗體,10mg/kg(腹膜內),100μL,第14天,每週3次
第4組:抗PD-L1抗體,10mg/kg(腹膜內),100μL,第14天,每週3次
第5組:抗CTLA-4抗體,10mg/kg(腹膜內),100μL,第14天,每週3次
***第1組及第2組在第1天開始給藥;第3組、第4組及第5組在第14天開始給藥。
在第0天,用於100微升HBSS+基質膠中之50萬個MC38.Ova細胞經皮下給150隻動物接種。使小鼠生長腫瘤。每週2次稱重小鼠且量測直至第11天(當腫瘤體積介於100mm3與200mm3之間時)。在第11天,腫瘤量測之後,將小鼠招募至以下12個處理組中之一個中。對因腫瘤體積不相似而未招募至以下處理組中之小鼠實行安樂死。吉西他濱(第4組)處理在第12天開始,而其餘抗體組之處理在第14天開始。所有體積均為100μl(於惰性媒劑中),其他詳情如下所報導:第1組:抗gp120抗體,10mg/kg(腹膜內),100μL,每週3次共5次,n=10
第2組:抗PD-L1抗體,10mg/kg(腹膜內),100μL,每週3次共5次,n=10
第3組:抗VEGF抗體,5mg/kg(腹膜內),100μL,每週2次共5次,n=10
第4組:吉西他濱,40mg/kg(腹膜內),100μl,第12、16、20天投與,n=10
第5組:抗PD-L1抗體+抗gp120抗體,n=10
第6組:抗PD-L1抗體+抗VEGF抗體,n=10
第7組:抗PD-L1抗體+吉西他濱,n=10
第8組:抗gp120抗體+吉西他濱,n=10
第9組:抗gp120抗體+抗VEGF,n=10
第12天:在麻醉下自第1組之小鼠眼後抽血(100微升)用於CBC分析。
第14天及第22天:在麻醉下自第4組之小鼠眼後抽血(100微升)用於CBC分析。
第19天:在麻醉下自除第4組以外之所有小鼠眼後抽血(100微升)用於CBC分析。
第26天:在麻醉下自除第4組以外之所有小鼠眼後抽血(100微升)用於PK分析。
每週2次量測腫瘤且稱重小鼠。每天將稱重展現體重減輕>15%之動物,且若其體重減輕>20%,則實行安樂死。當腫瘤體積超過3,000mm3時或3個月之後尚未形成腫瘤時,將對小鼠實行安樂死。
此研究展示(圖10),與單獨的α-VEGF及吉西他濱誘導性方案相比,PD-L1阻斷更有效。
此實例說明藉由於哺乳動物細胞中重組表現製備潛在糖基化之形式之抗PD-L1抗體。
使用載體pRK5(參見1989年3月15日公開之EP 307,247)作為表現載體。視情況,使編碼抗體輕鏈及/或重鏈之DNA連接於含所選限制酶之pRK5中以允許使用諸如Sambrook等人,同上中所述之連接方法插入該DNA。
在一實施例中,所選宿主細胞可為293細胞。在組織培養板中使人類293細胞(ATCCCCL 1573)在諸如補充有胎牛血清及視情況選用之營養組分及/或抗生素之DMEM的培養基中生長至匯合。混合約10μg編碼pRK5抗體之DNA與約1μg編碼VA RNA基因之DNA[Thimmappaya等人,Cell,31:543(1982)],且溶解於500μL 1mM Tris-HCl、0.1mM EDTA、0.227M CaCl2中。向此混合物中逐滴添加500μL 50mM HEPES(pH 7.35)、280mM NaCl、1.5mM NaPO4,且在25℃下形成沈澱歷時10分鐘。將沈澱懸浮且添加至293細胞中且在37℃下沈降約4小時。吸出培養基且添加2ml 20%甘油之PBS溶液歷時30秒。接著用無血清培養基洗滌293細胞,添加新鮮培養基且培育細胞約5天。
轉染後約24小時,移除培養基且用培養基(單獨)或含200μCi/ml 35S-半胱胺酸及200μCi/ml 35S-甲硫胺酸之培養基更換。培育12小時後,收集改良之培養基,在旋轉過濾器上濃縮且裝載於15% SDS凝膠上。可乾燥經加工凝膠且暴露於薄膜一段所選時間來揭示抗體之存在性。含經轉染細胞之培養物可經受進一步培育(於無血清培養基中),且在所選生物檢定中測試培養基。
在替代技術中,可使用Somparyrac等人,Proc.Natl.Acad.Sci.,12:7575(1981)所述之硫酸葡聚糖法(dextran sulfate method)將抗體短暫引入293細胞中。使293細胞在旋轉燒瓶中生長至最大密度,且添加700μg編碼pRK5抗體之DNA。首先藉由離心自旋轉燒瓶中濃縮細胞且用PBS洗滌。在細胞離心塊上培育DNA-葡聚糖沈澱4小時。用20%甘油處理細胞90秒,用組織培養基洗滌且再引入含有組織培養基、5
μg/ml牛胰島素及0.1μg/ml牛運鐵蛋白之旋轉燒瓶中。約4天後,離心改良之培養基並過濾以移除細胞及碎片。接著可濃縮含經表現抗體之樣品且利用諸如透析及/或管柱層析法之任何所選方法進行純化。
在另一實施例中,可表現抗體於CHO細胞中。可使用諸如CaPO4或DEAE-葡聚糖之已知試劑將編碼連接於pRK5中之抗體的DNA轉染至CHO細胞中。如上所述,可培育細胞培養物,且用培養基(單獨)或含有諸如35S-甲硫胺酸之放射性標記之培養基更換培養基。確定抗體之存在性後,可用無血清培養基更換培養基。較佳培育培養物約6天,且接著收集改良之培養基。接著可濃縮含經表現抗體之培養基且利用任何所選方法純化。
亦可表現抗體之標記抗原決定基之變異體於宿主CHO細胞中。可將編碼連接於pRK5中之抗體的DNA次選殖於pRK5載體外部。次選殖插入物可經受PCR以與諸如poly-his標籤之所選抗原決定基標籤同框融合於桿狀病毒表現載體中。接著可將編碼抗體插入物之標記poly-his之DNA次選殖於含有用於選擇穩定純系之諸如DHFR之選擇標記物的SV40驅動載體中。最終,可用SV40驅動載體轉染(如上所述)CHO細胞。可如上所述作標記來驗證表現。接著可濃縮含經表現之標記poly-His之抗體的培養基且利用任何所選方法(諸如利用Ni2+-螯合親和層析法)純化。
亦可利用短暫表現程序表現抗體於CHO及/或COS細胞中,或利用另一穩定表現程序表現抗體於CHO細胞中。
使用以下程序進行於CHO細胞中之穩定表現。該等蛋白質表現為IgG構築體(免疫黏附素),其中各別蛋白質之可溶性形式(例如細胞外域)之編碼序列與含鉸鏈、CH2及CH2域之IgG1恆定區序列融合,及/或該等蛋白質為標記poly-His之形式。
PCR擴增後,使用如Ausubel等人,Current Protocols of Molecular Biology,Unit 3.16,John Wiley and Sons(1997)中所述之標準技術將各別DNA次選殖於CHO表現載體中。CHO表現載體經構築具有相關DNA之相容性限制位點5=及3=以允許cDNA=s方便穿梭(shuttling)。用於在CHO細胞中表現之載體係如Lucas等人,Nucl.Acids Res. 24:9(1774-1779)(1996)中所述,且使用SV40早期啟動子/強化子驅動相關cDNA及二氫葉酸還原酶(DHFR)之表現。DHFR表現允許選擇轉染後穩定維持之質體。
使用市售轉染試劑SUPERFECT®(Quiagen)、DOSPER®或FUGENE®(Boehringer Mannheim),將12微克所要質體DNA引入約1000萬個CHO細胞中。如Lucas等人,同上所述使細胞生長。於安瓿中冷凍約3×10-7個細胞以如下所述進行進一步生長及生產。
藉由置放於水浴中將含質體DNA之安瓿解凍,且藉由渦旋混合。將內含物吸移至含10mL培養基之離心管中,且在1000rpm下離心5分鐘。吸出上清液,且將細胞再懸浮於10mL選擇性培養基(含5%經0.2μm滲濾之胎牛血清的經0.2μm過濾之PS20)中。接著將細胞等分至含90mL選擇性培養基之100mL旋轉器中。1-2天後,將細胞轉移至填充有150mL選擇性生長培養基之250mL旋轉器中,且在37℃下培育。再過2-3天後,按每毫升3×105個細胞給250mL,500mL及2000mL旋轉器接種。藉由離心及再懸浮於生產培養基中,用新鮮培養基更換細胞培養基。儘管可使用任何適合之CHO培養基,但實際上可使用1992年6月16日頒布之美國專利第5,122,469號中所述之生產培養基。按每毫升1.2×106個細胞給3L生產旋轉器接種。在第0天,測定細胞數量及pH值。在第1天,獲取旋轉器樣品且開始用經過濾空氣噴氣。在第2天,獲取旋轉器樣品,溫度變至33℃,且取30mL 500g/L葡萄糖及0.6mL 10%消泡劑(例如35%聚二甲基矽氧烷乳液,Dow Corning 365 Medical Grade Emulsion)。在整個生產過程中,必要時,
調節pH值以使其維持在約7.2。10天後或直至生活力降至70%以下,藉由離心且經由0.22μm過濾器過濾收集細胞培養物。將濾液儲存在4℃下或立即裝載於管柱上進行純化。
對於標記poly-His之構築體,使用Ni-NTA管柱(Qiagen)純化蛋白質。純化之前,向改良之培養基中添加咪唑直至濃度為5mM。將改良之培養基以4-5ml/min之流動速率泵送至在4℃下於含0.3M NaCl及5mM咪唑之20mM Hepes(pH 7.4)緩衝液中平衡之6ml Ni-NTA管柱上。裝載後,再用平衡緩衝液洗滌管柱,且用含0.25M咪唑之平衡緩衝液溶離蛋白質。隨後將高度純化之蛋白質脫鹽於含10mM Hepes,0.14M NaCl及4%甘露糖醇之儲存緩衝液(pH 6.8)中及25ml G25超細(Pharmacia)管柱中,且儲存於-80℃下。
如下自改良之培養基中純化免疫黏附素(含Fc)構築體。將改良之培養基泵送至已於20mM磷酸鈉緩衝液(pH 6.8)中平衡之5ml蛋白質A管柱(Pharmacia)上。裝載後,用平衡緩衝液澈底洗滌管柱,之後用100mM檸檬酸(pH 3.5)溶離。立即藉由收集1ml溶離份於含275μL 1M Tris緩衝液(pH 9)之管中來中和經溶離蛋白質。隨後將高度純化之蛋白質脫鹽於以上關於標記poly-His之蛋白質所述之儲存緩衝液中。利用SDS聚丙烯醯胺凝膠及利用埃德曼降解(Edman degradation)測定N末端胺基酸序列來評定均質性。
此實例說明藉由於大腸桿菌中重組表現製備未糖基化之形式之抗PD-L1抗體。
最初使用所選PCR引子擴增編碼抗PD-L1抗體之DNA序列。引子應含有對應於所選表現載體之限制酶位點的限制酶位點。可利用多種表現載體。適合之載體之實例為pBR322(衍生自大腸桿菌;參見
Bolivar等人,Gene,2:95(1977)),其含有安比西林(ampicillin)及四環素(tetracycline)抗性基因。用限制酶消化載體,且脫去磷酸。接著使PCR擴增序列連接於載體中。載體較佳應包括編碼抗生素抗性基因、trp啟動子、polyhis前導序列(包括頭6個STII密碼子、polyhis序列及腸激酶裂解位點)、NPOR編碼區、λ轉錄終止子及argU基因的序列。
接著使用Sambrook等人,同上中所述之方法使用連接混合物使所選大腸桿菌菌株轉形。根據於LB板上生長之能力鑑別轉形體,且接著選擇抗生素抗性菌落。可分離質體DNA且藉由限制分析及DNA測序證實。
可使所選純系在諸如補充有抗生素之LB培養液之液體培養基中生長隔夜。隨後可使用隔夜培養物接種較大規模培養物。接著使細胞生長至所要光學密度,在此期間開啟表現啟動子。
再培養細胞若干小時後,可藉由離心收集細胞。可使用此項技術中已知之各種試劑溶解由離心獲得之細胞離心塊,且接著使用金屬螯合管柱在允許緊密結合抗體之條件下純化經溶解抗體。
亦可使用以下程序將抗PD-L1抗體以標記poly-His之形式表現於大腸桿菌中。最初使用所選PCR引子擴增DNA編碼抗體。引子含有對應於所選表現載體上之限制酶位點之限制酶位點,及提供有效且可靠之轉譯起始、在金屬螯合管柱上快速純化及用腸激酶蛋白水解移除的其他適用序列。接著使經PCR擴增之標記poly-His的序列連接於表現載體中,基於菌株52(W3110 fuhA(tonA)lon galE rpoHts(htpRts)clpP(lacIq))使用該表現載體使大腸桿菌宿主轉形。首先在30℃下在震盪下使轉形體在含有50mg/ml卡本西林之LB中生長直至O.D.600達到3-5。接著在CRAP培養基(藉由混合3.57g(NH4)2SO4、0.71g二水合檸檬酸鈉、1.07g KCl、5.36g Difco酵母提取物、於500mL水中之5.36g Sheffield hycase SF以及110mM MPOS(pH 7.3)、0.55%(w/v)葡萄糖
及7mM MgSO4製備)中稀釋培養物50-100倍,且使之在震盪下在30℃下生長約20-30小時。移除樣品以藉由SDS-PAGE分析驗證表現,且離心大量培養物使細胞形成離心塊。冷凍細胞離心塊直至純化及再摺疊(refolding)。
將來自0.5至1L醱酵物之大腸桿菌糊狀物(6-10g離心塊)再懸浮於10倍體積(w/v)之7M胍、20mM Tris(pH 8)緩衝液中。分別添加固體亞硫酸鈉及四硫磺酸鈉以使得最終濃度為0.1M及0.02M,且在4℃下攪拌溶液隔夜。此步驟產生所有半胱胺酸殘基均經亞硫酸鹽化(sulfitolization)阻斷之變性蛋白質。在40,000rpm下於Beckman Ultracentifuge中離心溶液30分鐘。用3-5倍體積之金屬螯合管柱緩衝液(6M胍、20mM Tris,pH 7.4)稀釋上清液,且經由0.22微米過濾器過濾使之澄清。視條件而定,將經澄清萃取物裝載於以金屬螯合管柱緩衝液平衡之5ml Qiagen Ni-NTA金屬螯合管柱上。再用含50mM咪唑緩衝液(Calbiochem,Utrol grade)(pH 7.4)洗滌管柱。用含250mM咪唑緩衝液溶離蛋白質。彙集含所要蛋白質之溶離份且儲存於4℃下。
基於蛋白質之胺基酸序列使用所計算之消光係數由其280nm下之吸光度估算蛋白質濃度。
藉由於新近製備之再摺疊緩衝液中緩慢稀釋樣品使蛋白質再摺疊,該再摺疊緩衝液由20mM Tris(pH 8.6)、0.3M NaCl、2.5M尿素、5mM半胱胺酸、20mM甘胺酸及1mM EDTA組成。選擇再摺疊體積以便最終蛋白質濃度介於50至100微克/毫升之間。在4℃下輕輕攪拌再摺疊溶液12-36小時。藉由添加TFA至最終濃度為0.4%(pH值為約3)中止再摺疊反應。在進一步純化蛋白質之前,經由0.22微米過濾器過濾溶液,且添加乙腈至最終濃度為2-10%。在Poros R1/H逆相管柱上使用0.1% TFA之移動緩衝液以10%至80%之乙腈梯度溶離,層析分離再摺疊蛋白質。在SDS聚丙烯醯胺凝膠上分析具有A280吸光度之
溶離份等分試樣,且彙集含均質再摺疊蛋白質之溶離份。一般而言,在最小濃度之乙腈下溶離大部分蛋白質之適當再摺疊物質,因為彼等物質之疏水性內部最緊實受到保護而不與逆相樹脂相互作用。通常在較高乙腈濃度下溶離聚集之物質。除自所要形式消除錯誤摺疊形式之蛋白質以外,逆相步驟亦自樣品中移除內毒素。
彙集含所要摺疊抗PD-L1抗體之溶離份,且使用對準溶液之輕柔氮氣流移除乙腈。藉由透析或藉由使用於調配緩衝液中平衡之G25超細(Pharmacia)樹脂之凝膠過濾將蛋白質調配於20mM Hepes(pH 6.8)及0.14M氯化鈉及4%甘露糖醇中且無菌過濾。
<110> 美商建南德克公司
<120> 抗PD-L1抗體及其於增進T細胞功能之用途
<130> P4192R1 WO
<140> 098141907
<141> 2009-12-08
<150> 61/121,092
<151> 2008-12-09
<160> 40
<210> 1
<211>10
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<220>
<221> variable residue
<222> 6
<223> 合成序列
<400> 1
<210> 2
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<220>
<221> variable residues
<222> 4
<223> 合成序列
<220>
<221> variable residue
<222> 10
<223> 合成序列
<400> 2
<210> 3
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 3
<210> 4
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 4
<210> 5
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 5
<210> 6
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 6
<210> 7
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 7
<210> 8
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<220>
<221> variable residue
<222> 5
<223> 殘基為D或V
<220>
<221> variable residue
<222> 6
<223> 殘基為V或I
<220>
<221> variable residue
<222> 7
<223> 殘基為S或N
<220>
<221> variable residue
<222> 9
<223> 殘基為A或F
<220>
<221> variable residue
<222> 10
<223> 殘基為V或L
<400> 8
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<220>
<221> variable residue
<222> 4
<223> 殘基為F或T
<220>
<221> variable residue
<222> 6
<223> 殘基為Y或A
<400> 9
<210> 10
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<220>
<221> variable residue
<222> 3
<223> 殘基為Y、G、F或S
<220>
<221> variable residue
<222> 4
<223> 殘基為L、Y、F或W
<220>
<221> variable residue
<222> 5
<223> 殘基為Y、N、A、T、G、F或I
<220>
<221> variable residue
<222> 6
<223> 殘基為H、V、P、T或I
<220>
<221> variable residue
<222> 8
<223> 殘基為A、W、R、P或T
<400> 10
<210> 11
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 11
<210> 12
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 12
<210> 13
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 13
<210> 14
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 14
<210> 15
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 15
<210> 16
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 16
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 17
<210> 18
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 18
<210> 19
<211> 9
<212>PRT
<213> 人工序列
<220>
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Claims (4)
- 一種組合物的用途,其用於製造供治療T細胞功能障礙病症之藥劑,其中該組合物包含經分離之抗PD-L1抗體或抗原結合片段及至少一種醫藥學上可接受之載劑,其中該經分離之抗PD-L1抗體或抗原結合片段包含重鏈及輕鏈可變區序列,其中:(a)該重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:(i)該HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1);(ii)該HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);(iii)該HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);及(b)該輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中:(iv)該HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8);(v)該HVR-L2序列為SASX9LX10S(SEQ ID NO:9);(vi)該HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10);其中:X1為D或G;X2為S或L;X3為T或S;X4可為D或V;X5可為V或I;X6可為S或N;X7可為A或F;X8可為V或L;X9可為F或T;X10可為Y或A;X11可為Y、G、F或S;X12可為L、Y、F或W;X13可為Y、N、A、T、G、F或I;X14可為H、V、P、T或I;X15可為A、W、R、P或T,其中該T細胞功能障礙病症係慢性感染,及其中該慢性感染為持續性的,潛伏性的或緩慢的(slow)。
- 一種組合物的用途,其用於製造供治療T細胞功能障礙病症之藥劑,其中該組合物包含經分離之抗PD-L1抗體或抗原結合片段及 至少一種醫藥學上可接受之載劑,其中該經分離之抗PD-L1抗體或抗原結合片段包含重鏈及輕鏈可變區序列,其中:(a)該重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:(i)該HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1);(ii)該HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);(iii)該HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);及(b)該輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中:(iv)該HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8);(v)該HVR-L2序列為SASX9LX10S(SEQ ID NO:9);(vi)該HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10);其中:X1為D或G;X2為S或L;X3為T或S;X4可為D或V;X5可為V或I;X6可為S或N;X7可為A或F;X8可為V或L;X9可為F或T;X10可為Y或A;X11可為Y、G、F或S;X12可為L、Y、F或W;X13可為Y、N、A、T、G、F或I;X14可為H、V、P、T或I;X15可為A、W、R、P或T,其中該T細胞功能障礙病症係感染,及其中該感染由病毒引起且該藥劑與抗病毒劑組合使用。
- 一種組合物的用途,其用於製造供治療T細胞功能障礙病症之藥劑,其中該組合物包含經分離之抗PD-L1抗體或抗原結合片段及至少一種醫藥學上可接受之載劑,其中該經分離之抗PD-L1抗體或抗原結合片段包含重鏈及輕鏈可變區序列,其中:(a)該重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:(i)該HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1); (ii)該HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);(iii)該HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);及(b)該輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中:(iv)該HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8);(v)該HVR-L2序列為SASX9LX10S(SEQ ID NO:9),(vi)該HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10);其中:X1為D或G;X2為S或L;X3為T或S;X4可為D或V;X5可為V或I;X6可為S或N;X7可為A或F;X8可為V或L;X9可為F或T;X10可為Y或A;X11可為Y、G、F或S;X12可為L、Y、F或W;X13可為Y、N、A、T、G、F或I;X14可為H、V、P、T或I;X15可為A、W、R、P或T,其中該T細胞功能障礙病症係感染,及其中該感染由真菌引起且該藥劑與抗真菌劑組合使用。
- 一種組合物的用途,其用於製造供治療T細胞功能障礙病症之藥劑,其中該組合物包含經分離之抗PD-L1抗體或抗原結合片段及至少一種醫藥學上可接受之載劑,其中該經分離之抗PD-L1抗體或抗原結合片段包含重鏈及輕鏈可變區序列,其中:(a)該重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:(i)該HVR-H1序列為GFTFSX1SWIH(SEQ ID NO:1);(ii)該HVR-H2序列為AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);(iii)該HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);及(b)該輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中: (iv)該HVR-L1序列為RASQX4X5X6TX7X8A(SEQ ID NO:8);(v)該HVR-L2序列為SASX9LX10S(SEQ ID NO:9);(vi)該HVR-L3序列為QQX11X12X13X14PX15T(SEQ ID NO:10);其中:X1為D或G;X2為S或L;X3為T或S;X4可為D或V;X5可為V或I;X6可為S或N;X7可為A或F;X8可為V或L;X9可為F或T;X10可為Y或A;X11可為Y、G、F或S;X12可為L、Y、F或W;X13可為Y、N、A、T、G、F或I;X14可為H、V、P、T或I;X15可為A、W、R、P或T,其中該T細胞功能障礙病症係感染,及其中該感染由原蟲引起且該藥劑與抗原蟲劑組合使用。
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