CN112041336A - 针对mospd2和t细胞或nk细胞特异性分子的双特异性抗体 - Google Patents
针对mospd2和t细胞或nk细胞特异性分子的双特异性抗体 Download PDFInfo
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- CN112041336A CN112041336A CN201980028421.6A CN201980028421A CN112041336A CN 112041336 A CN112041336 A CN 112041336A CN 201980028421 A CN201980028421 A CN 201980028421A CN 112041336 A CN112041336 A CN 112041336A
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Abstract
本文公开了特异性结合含活动精子结构域的蛋白质2(MOSPD2)且特异性结合T细胞特异性或NK细胞特异性受体分子的双特异性抗体或其抗原结合片段、含有它们的药物组合物和试剂盒以及其制备和使用方法。
Description
电子提交的序列表的引用
随本申请一起提交的电子提交的序列表(名称:3182089PC01_SequenceListing_ST25.txt;大小:34,597字节;以及创建日期:2019年3月12日)的内容通过引用以其整体并入本文。
技术领域
本发明涉及双特异性抗体或其抗原结合片段、含有它们的药物组合物和试剂盒以及制备和使用它们的方法,该双特异性抗体或其抗原结合片段特异性结合含活动精子结构域的蛋白质2(MOSPD2)并且特异性结合T细胞特异性或NK细胞特异性受体分子。
背景技术
MOSPD2是长为518个氨基酸的高度保守的蛋白质,在人与小鼠之间具有90%的同源性。生物信息学分析表明,MOSPD2含有CRAL-TRIO区域,以细胞视黄醛结合蛋白(CRALBP)和TRIO蛋白命名。MOSPD2还含有线虫主要精子蛋白的结构相关区域和一个跨膜区域。
MOSPD2在渗透到发炎组织中的单核细胞和多种肿瘤类型上表达(国际公开号WO2017/021857)。它与癌细胞转移相关并且促进单核细胞迁移(国际公开号WO 2017/021857)。因此,抑制MOSPD2(例如,用抗MOSPD2抗体)已经被描述为炎性疾病和病症的治疗(国际公开号WO 2017/021855)以及癌症和癌症转移的治疗(国际公开号WO 2017/021857)。
抗体已被用来激活T细胞以识别和攻击肿瘤。例如,针对抗原特异性T细胞受体(TCR)/CD3复合物的抗体已被报道用于激活T细胞(Davis et al.,J.Immunol.137:3758-3767(1986))。此外,识别肿瘤细胞上抗原和TCR/CD3复合物的双特异性抗体已被报道用来激活T细胞并引起T细胞介导的肿瘤细胞裂解(Jung et al.,Proc.Natl.Acad.Sci.U.S.A.84:4611-4615(1987);Jung et al.,Immunol.Today 9:257-260(1988);Staerz et al.,Nature 314:628-631(1985);和Perez et al.,Nature 316:354-356(1985))。需要针对MOSPD2的双特异性抗体。
发明内容
在一些实施方式中,本发明涉及一种双特异性抗体或其抗原结合片段,包含:(i)针对含活动精子结构域的蛋白质2(MOSPD2)的一种或多种抗原结合结构域,和(ii)针对T细胞或NK细胞特异性受体分子的一种或多种抗原结合结构域。在一些实施方式中,T细胞或NK细胞特异性受体分子是CD3、T细胞受体(TCR)、CD28、CD16、NKG2D、Ox40、4-1BB、CD2、CD5或CD95。在一些实施方式中,针对MOSPD2的一种或多种抗原结合结构域是抗MOSPD2抗体或其抗原结合片段的Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、互补决定区(CDR)、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。在一些实施方式中,T细胞或NK细胞特异性受体分子是CD3,并且针对CD3的一种或多种抗原结合结构域是抗CD3抗体或其抗原结合片段的Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、CDR、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。
在一些实施方式中,双特异性抗体或其抗原结合片段包含下列抗原结合结构域中的一种或多种:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;和
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段包含下列抗原结合结构域中的一种或多种:
(i)抗CD3抗体或其抗原结合片段的重链可变区;和
(ii)抗CD3抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段包含以下抗原结合结构域:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区;
(iii)抗CD3抗体或其抗原结合片段的重链可变区;和
(iv)抗CD3抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段从N末端到C末端依次包含以下抗原结合结构域:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区;
(iii)抗CD3抗体或其抗原结合片段的重链可变区;和
(iv)抗CD3抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段的抗原结合结构域中的一种或多种通过肽接头接合。在一些实施方式中,双特异性抗体或其抗原结合片段的抗原结合结构域的一种或多种通过肽接头接合。在一些实施方式中,双特异性抗体或其抗原结合片段的所有抗原结合结构域通过肽接头接合。
在一些实施方式中,双特异性抗体或其抗原结合片段的至少一个抗原结合结构域是人类的或人源化的。
在一些实施方式中,双特异性抗体或其抗原结合片段是单链多肽。
在一些实施方式中,双特异性抗体或其抗原结合片段的分子量不超过约60,000道尔顿。
在一些实施方式中,双特异性抗体是纳米抗体、双抗体、CrossMab、Duobody、二价抗体、双特异性T细胞衔接子(BiTE)、双亲和重靶向体(DART)、三体、微型抗体、TriBi微型抗体、内体(胞内抗体,intrabody)或四价体(quadroma)。
在一些实施方式中,双特异性抗体或其抗原结合片段以约10-6M至约10-12M的平衡解离常数(KD)特异性结合MOSPD2和/或CD3。
在一些实施方式中,双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域特异性地结合MOSPD2的下列氨基酸区域中的一个或多个,根据SEQ ID NO:1编号:约505至约515,约500至约515,约230至约240,约510至约520,约210至约220,约15至约25,约505至约520,约505至约515,约90至约100,约505至约525,约230至约245,约505至约510,约130至约140,约220至约230,约15至约30,约80至约95,约40至约50,约460至约475,约340至约350,约500至约515,约460至约470,约325至约335,约20至约35,约215至约225,约510至约520,约175至约190,约500至约510,约505至约530,约60至约75,约500至约520,约145至约160,约502至约515,约85至约100,约205至约220,约175至约190,约500至约505,约500至约525,约495至约505,约495至约510,约190至约200,约190至约198,约502至约515,约1至约60,约80至约240,约90至约235,约330至约445,约330至约430,约495至约515,约145至约240,约145至约220,约145至约200,约160至约240,约160至约220,约160至约200,约175至约240,约175至约220,约175至约200,约170至约190,约178至约185,约85至约140,约85至约130,约90至约140,约90至约130,约95至约140,约95至约130,约100至约130,约100至约140,约110至约130,或约115至约127。
在一些实施方式中,双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域特异性地结合SEQ ID NO:1-4中的一个或多个或其功能变体、或特异性地结合由SEQ ID NO:5-8中的一个或多个或其功能变体编码的多肽。
在一些实施方式中,双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-6M至约10-12M的KD特异性结合MOSPD2。
在一些实施方式中,本发明涉及一种编码本文描述的双特异性抗体或其抗原结合片段的核酸。
在一些实施方式中,本发明涉及一种表达载体,其包含编码本文描述的双特异性抗体或其抗原结合片段的核酸。
在一些实施方式中,本发明涉及一种药物组合物,其包含本文描述的双特异性抗体或其抗原结合片段以及药学上可接受的载体。在一些实施方式中,该药物组合物适合全身或局部给药。在一些实施方式中,该药物组合物适合于经鼻、口服、腹膜内或肿瘤内给药。在一些实施方式中,该药物组合物适合于静脉内给药、肌内给药或皮下给药。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防癌症的方法,包括给予受试者有效量的本文所述的双特异性抗体或其抗原结合片段或者本文所述的药物组合物,以治疗或预防癌症。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防癌症转移的方法,包括给予受试者有效量的本文所述的双特异性抗体或其抗原结合片段或者本文所述的药物组合物,以治疗或预防癌症转移。
在一些实施方式中,该方法还包括给予受试者有效量的抗癌药。在一些实施方式中,抗癌药是醋酸阿比特龙、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(维布本妥昔单抗)、ADE、阿多曲妥珠单抗-美坦新、阿霉素(盐酸多柔比星)、Adrucil(氟尿嘧啶)、马来酸阿法替尼、飞尼妥(依维莫司)、Akynzeo(奈妥吡坦和帕洛诺司琼盐酸盐)、艾达乐(咪喹莫特)、阿地白介素、阿仑单抗、爱宁达(培美曲塞二钠)、阿乐喜(盐酸帕洛诺司琼)、Ambochlorin(苯丁酸氮芥)、Amboclorin(苯丁酸氮芥)、氨基乙酰丙酸、阿那曲唑、阿瑞匹坦、阿可达(帕米膦酸二钠)、安美达锭(阿那曲唑)、阿诺新(依西美坦)、Arranon(奈拉滨)、三氧化二砷、Arzerra(奥法木单抗)、天冬酰胺酶菊欧文氏菌、安维汀(贝伐单抗)、阿昔替尼、阿扎胞苷、BEACOPP、Becenum(卡莫司汀)、Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、贝伐单抗、贝沙罗汀、百克沙(托西莫单抗和I 131碘托西莫单抗)、比卡鲁胺、BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、维布本妥昔单抗、白消安、白舒非(白消安)、卡巴他赛、卡波替尼-S-苹果酸、CAF、坎帕斯(阿仑单抗)、开普拓(盐酸伊立替康)、卡培他滨、CAPOX、卡铂、卡铂-紫杉酚、卡非佐米、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀植入物、康士得(比卡鲁胺)、CeeNU(洛莫司汀)、色瑞替尼、Cerubidine(盐酸柔红霉素)、希瑞适(重组HPV二价疫苗)、西妥昔单抗、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂、Clafen(环磷酰胺)、氯法拉滨、CMF、Cometriq(卡波替尼-S-苹果酸)、COPP、COPP-ABV、Cosmegen(更生霉素)、克唑替尼、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗)、阿糖孢苷、阿糖孢苷、脂质体、Cytosar-U(阿糖孢苷)、Cytoxan(环磷酰胺)、达拉菲尼、达卡巴嗪、达克金(地西他滨)、更生霉素、达沙替尼、盐酸柔红霉素、地西他滨、地加瑞克、地尼白介素、狄诺塞麦、DepoCyt(脂质体阿糖孢苷)、DepoFoam(脂质体阿糖孢苷)、盐酸右雷佐生、地努图希单抗、多西他赛、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、Efudex(氟尿嘧啶)、埃立特(拉布立酶)、Ellence(盐酸表柔比星)、乐沙定(奥沙利铂)、艾曲波帕乙醇胺、Emend(阿瑞匹坦)、恩杂鲁胺、盐酸表柔比星、EPOCH、爱必妥(西妥昔单抗)、甲磺酸艾日布林、Erivedge(维莫德吉)、埃罗替尼盐酸盐、Erwinaze(天冬酰胺酶菊欧文氏菌)、Etopophos(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、易维特(盐酸雷洛昔芬)、依西美坦、法乐通(托瑞米芬)、Farydak(帕比司他)、芙仕得(氟维司群)、FEC、弗隆(来曲唑)、非格司亭、福达华(磷酸氟达拉滨)、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶)、氟尿嘧啶、Folex(甲氨蝶呤)、Folex PFS(甲氨蝶呤)、伊立替康、伊立替康-贝伐单抗、伊立替康-西妥昔单抗、Folfirinox、Folflox、Folotyn(普拉曲沙)、FU-LV、氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗)、Gazyva(奥比努珠单抗)、吉非替尼、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥单抗唑加米星、健择(盐酸吉西他滨)、Gilotrif(马来酸阿法替尼)、格列卫(甲磺酸伊马替尼)、格立得(卡莫司汀植入物)、格立得薄片(卡莫司汀植入物)、羧肽酶、醋酸戈舍瑞林、Halaven(甲磺酸艾日布林)、赫塞汀(曲妥珠单抗)、HPV二价疫苗重组体、HPV九价疫苗重组体、HPV四价疫苗重组体、美新(盐酸拓扑替康)、Hyper-CVAD、Ibrance(帕博西尼)、替伊莫单抗、依鲁替尼、ICE、Iclusig(盐酸波纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、甲磺酸伊马替尼、Imbruvica(依鲁替尼)、咪喹莫特、英立达(阿昔替尼)、Intron A(重组干扰素Alfa-2b)、碘131托西单抗和托西单抗、易普利姆玛、易瑞沙(吉非替尼)、盐酸伊立替康、Istodax(罗米地辛)、伊沙匹隆、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索替尼)、Jevtana(卡巴他赛)、Kadcyla(阿多曲妥珠单抗-美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明)、Keytruda(派姆单抗)、Kyprolis(卡非佐米)、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、来那度胺、甲磺酸乐伐替尼、Lenvima(甲磺酸乐伐替尼)、来曲唑、亚叶酸钙、瘤可宁(苯丁酸氮芥)、醋酸亮丙瑞林、Levulan(氨基乙酰丙酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、脂质体阿糖孢苷、洛莫司汀、Lupron(醋酸亮丙瑞林)、Lupron Depot(醋酸亮丙瑞林)、LupronDepot-Ped(醋酸亮丙瑞林)、Lupron Depot-3个月(醋酸亮丙瑞林)、Lupron Depot-4个月(醋酸亮丙瑞林)、Lynparza(奥拉帕尼)、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸丙卡巴嗪)、盐酸氮芥、梅格施(醋酸甲地孕酮)、醋酸甲地孕酮、Mekinist(曲美替尼)、巯基嘌呤、美司钠、Mesnex(美司钠)、Methazolastone(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福)、Mustargen(盐酸氮芥)、密吐霉素(丝裂霉素C)、马勒兰(白消安)、Mylosar(阿扎胞苷)、麦罗塔(吉妥单抗唑加米星)、纳米粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、诺维本(酒石酸长春瑞滨)、奈拉滨、Neosar(环磷酰胺)、奈妥吡坦和帕洛诺司琼盐酸盐、优保津(非格司亭)、蕾莎瓦(甲苯磺酸索拉非尼)、尼罗替尼、纳武单抗、诺瓦得士(枸橼酸他莫昔芬)、Nplate(罗米司亭)、奥比努珠单抗、OEPA、奥法木单抗、OFF、奥拉帕尼、高三尖杉酯碱、Oncaspar(培门冬酶)、Ontak(地尼白介素)、欧狄沃(纳武单抗)、OPPA、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、帕米膦酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、伯尔定(卡铂)、盐酸帕唑帕尼、培门冬酶、聚乙二醇干扰素Alfa-2b、PEG-Intron(聚乙二醇干扰素Alfa-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸波纳替尼、普拉曲沙、强的松、盐酸丙卡巴嗪、Proleukin(阿地白介素)、普罗利亚(狄诺塞麦)、Promacta(艾曲波帕乙醇胺)、普列威(Sipuleucel-T)、Purinethol(巯基嘌呤)、Purixan(巯基嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素Alfa-2b、瑞戈非尼、R-EPOCH、雷利米得(来那度胺)、Rheumatrex(甲氨蝶呤)、美罗华(利妥昔单抗)、利妥昔单抗、罗米地辛、罗米司亭、红比霉素(盐酸柔红霉素)、磷酸鲁索替尼、硬化性胸膜内气雾剂(滑石粉)、司妥昔单抗、Sipuleucel-T、索马杜林库(醋酸兰瑞肽)、甲苯磺酸索拉非尼、施达赛(达沙替尼)、STANFORD V、无菌滑石粉粉末(滑石粉)、无菌滑石粉(滑石粉)、Stivarga(瑞戈非尼)、苹果酸舒尼替尼、索坦(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素Alfa-2b)、Sylvant(司妥昔单抗)、昔诺韦(萨力多胺)、Synribo(高三尖杉酯碱)、TAC、Tafinlar(达拉菲尼)、滑石粉、枸橼酸他莫昔芬、Tarabine PFS(阿糖孢苷)、特罗凯(埃罗替尼盐酸盐)、Targretin(贝沙罗汀)、泰息安(尼罗替尼)、紫杉酚(紫杉醇)、泰索帝(多西他赛)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司、萨力多胺、Thalomid(萨力多胺)、噻替派、Toposar(依托泊苷)、盐酸拓扑替康、托瑞米芬、驮瑞塞尔(替西罗莫司)、托西莫单抗和I131碘托西莫单抗、Totect(盐酸右雷佐生)、TPF、曲美替尼、曲妥珠单抗、存达(盐酸苯达莫司汀)、Trisenox(三氧化二砷)、泰立沙(二甲苯磺酸拉帕替尼)、Unituxin(地努图希单抗)、凡德他尼、VAMP、Vectibix(帕尼单抗)、VeIP、Velban(硫酸长春碱)、万珂(硼替佐米)、Velsar(硫酸长春碱)、维莫非尼、凡毕士(依托泊苷)、Viadur(醋酸亮丙瑞林)、维达扎(阿扎胞苷)、硫酸长春碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉、Voraxaze(羧肽酶)、伏立诺他、Votrient(盐酸帕唑帕尼)、Wellcovorin(亚叶酸钙)、赛可瑞(克唑替尼)、希罗达(卡培他滨)、XELIRI、XELOX、Xgeva(狄诺塞麦)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(易普利姆玛)、Zaltrap(齐夫-阿柏西普)、泽波拉夫(维莫非尼)、泽娃灵(替伊莫单抗)、Zinecard(盐酸右雷佐生)、齐夫-阿柏西普、诺雷德(醋酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、择泰(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)、Zytiga(醋酸阿比特龙)或它们的组合。
在一些实施方式中,本发明涉及一种用于在受试者中抑制或减少肿瘤细胞的方法,包括给予受试者本文所述的双特异性抗体或抗原结合片段或本文所述的药物组合物。在该方法的一些实施方式中,与对照或参考值相比,肿瘤细胞的数量减少至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或至少约100%。
在一些实施方式中,本发明涉及一种用于在受试者中增加表达CD3的细胞产生细胞因子的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种增加T细胞中IL-2、CD69和/或IFN-γ产生或浓度的方法,包括使T细胞与本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物接触。在一些实施方式中,与对照或参考值相比,IFN-γ生产增加了至少约100%、至少约200%、至少约300%、至少约400%、至少约500%、至少约600%、至少约700%、至少约800%、至少约900%或至少约1000%。在一些实施方式中,与对照或参考值相比,IFN-γ浓度增加了至少约1000pg/ml、至少约2000pg/ml、至少约3000pg/ml、至少约4000pg/ml、至少约5000pg/ml、至少约6000pg/ml、至少约7000pg/ml、至少约8000pg/ml、至少约9000pg/ml或至少约10000pg/ml。在一些实施方式中,与对照或参考值相比,CD69生产增加了至少约1%、至少约2%、至少约3%、至少约4%、至少约5%、至少约6%、至少约7%、至少约8%、至少约9%、至少约10%、至少约15%、至少约20%、至少约25%或至少约30%。
在一些实施方式中,本发明涉及一种刺激受试者中免疫应答的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种在受试者中刺激针对癌细胞的T细胞介导的细胞毒性免疫应答的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种增加T细胞增殖的方法,包括使T细胞与本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物接触。
在一些实施方式中,本发明涉及一种减少或耗尽受试者肿瘤中T调节细胞数量的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种用于预测、诊断或预后受试者中癌症或癌症转移的方法,包括使用本文所述的双特异性抗体或其抗原结合片段确定受试者样品中的MOSPD2表达水平。在一些实施方式中,该方法包括:(i)使用本文所述的双特异性抗体或其抗原结合片段确定或量化受试者样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于对照或参考值,增加的MOSPD2表达水平指示了癌症、患癌症的风险增加或癌症预后不良。
在一些实施方式中,本发明涉及一种用于预测、诊断或预后受试者中肿瘤进展或肿瘤侵袭性的方法,包括使用本文所述的双特异性抗体或其抗原结合片段确定受试者样品中的MOSPD2表达水平。在一些实施方式中,该方法包括:(i)使用本文所述的双特异性抗体或其抗原结合片段确定或量化受试者样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于对照或参考值,增加的MOSPD2表达水平指示了肿瘤进展或肿瘤侵袭性预后不良。
在一些实施方式中,用于预测、诊断或预后的方法进一步包含下列步骤中的一个或多个:
指示实验室量化样品中的MOSPD2表达水平;
从实验室获得样品中MOSPD2表达水平的报告;和/或
给予受试者治疗有效量的MOSPD2抑制剂(例如,抗MOSPD2抗体)。
在一些实施方式中,用于预测、诊断或预后的方法中的样品是来自受试者的组织活检、肿瘤活检或血液样品。
在一些实施方式中,用于预测、诊断或预后的方法中的对照或参考值是正常组织或正常相邻组织(NAT)中的MOSPD2表达水平。在一些实施方式中,用于预测、诊断或预后的方法中的对照或参考值为无可检测的MOSPD2表达或无明显的MOSPD2表达。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防MOSPD2表达肿瘤的方法,包括给予受试者有效量的本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防MOSPD2表达肿瘤。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防具有MOSPD2表达肿瘤相关的巨噬细胞的肿瘤的方法,包括给予受试者有效量的本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防具有MOSPD2表达肿瘤相关的巨噬细胞的肿瘤。
在一些实施方式中,本发明涉及一种用于生产本文所述的双特异性抗体或其抗原结合片段的方法,包括:(i)培养使用本文所述的核酸或本文所述的表达载体转化的宿主细胞,和(ii)采集并纯化所表达的双特异性抗体或其抗原结合片段。
在一些实施方式中,本发明涉及一种试剂盒,包含(i)本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,和(ii)使用说明。
附图说明
本文仅通过示例的方式,参考附图描述了本发明的一些实施方式。现在具体地参考详细附图,需要强调的是,所示出的细节仅作为示例并且出于说明性讨论本发明实施方式的目的。
图1显示MOSPD2促进转移性乳腺癌和黑色素瘤细胞的迁移。通过用sh-MOSPD2慢病毒颗粒转导细胞而将MDA-231乳腺癌和A2058黑色素瘤细胞中的MOSPD2表达沉默。图1中的蛋白质印迹显示,用sh-MOSPD2转导的细胞的MOSPD2蛋白表达降低。图1还显示了在跨孔迁移测定中,用sh-对照或sh-MOSPD2慢病毒颗粒转导的细胞向10%胎牛血清(FCS)和EGF(200ng/ml)迁移的测试结果。
图2显示MOSPD2的沉默不会影响MDA-231细胞的细胞活力或增殖。接种用sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231细胞、采集并且连续三天每24小时进行计数。测量细胞增殖速率,并在图2中表示为一式三份的平均值±标准偏差。
图3A-3C显示在有或没有MOSPD2沉默情况下MDA-231细胞转移的体内测试结果。在图3A中,将用sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231细胞注射(106)在SCID小鼠的尾静脉中(n=10/组)。在第28天处死小鼠,收获其肺以进行H&E染色,并确定肿瘤面积。图3A所示的结果表示为测量的转移大小的平均值±标准误差(*p<0.05)。
在图3B和3C中,将用sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231细胞(分别为n=13和n=8)注射(5x106)在SCID小鼠的乳腺脂肪垫中。在第56天处死小鼠。切离同侧腹股沟淋巴结(图3B),收获其肺部进行H&E染色,并确定肿瘤面积(图3C)。图3C中显示的结果表示为测量的转移大小的平均值±标准误差。相比于sh-MOSPD2转导细胞为550.0±326.2(n=8),Sh-对照转导细胞的肿瘤面积为1376.9±752.6(n=13),。
图3A-3C显示MOSPD2促进MDA-231乳腺癌细胞在体内的转移。
图4A-4E显示了各种人类癌症组织中MOSPD2表达水平与其相应的正常组织对应物之间的比较。用对照或抗-MOSPD2抗体对含有各种正常和癌性人类组织的载玻片进行染色。显示了MOSPD2染色呈阳性的癌症组织。图4A-4E显示在各种人类癌症组织中表达了MOSPD2。
图5A和5B示出了在跨孔迁移测定中测试的用对照或MOSPD2CRISPR-CAS9慢病毒颗粒转导的癌细胞的结果。使用补充有10%FCS和EGF(200ng/ml)的培养基将细胞接种到上层隔室并吸引到下层隔室。图5A中所示的图是通过荧光激活的细胞分选(FACS)确定的,结果表示为一式三份的平均值±标准偏差。图5B中显示的图像来自视觉记录。在图5A和5B中,用带有质粒(含有对照或MOSPD2 CRISPR-CAS9体系)的慢病毒颗粒转导MDA-231细胞。蛋白质印迹显示用MOSPD2 CRISPR-CAS9体系转导的细胞中MOSPD2蛋白表达降低(插图)。图5A和5B显示,CRISPR-CAS9驱动的MOSPD2基因编辑抑制乳腺癌细胞迁移。
图5C显示了MOSPD2沉默对与细胞迁移相关的磷酸化事件的影响。使用10%FCS和EGF(400ng/ml)将用对照或MOSPD2 CRISPR-CAS9慢病毒颗粒转导的MDA-231温育10分钟。使用蛋白质印迹确定ERK、AKT和FAK的磷酸化。将HSP90用作加载对照。图5C显示CRISPR-CAS9驱动的基因编辑使MOSPD2沉默抑制了与细胞迁移相关的磷酸化事件。
图5D显示了用对照或MOSPD2 CRISPR-CAS9慢病毒颗粒转导的MDA-231乳腺癌细胞的转移的体内测试结果。在图5D中,将106个对照或MOSPD2 CRISPR-CAS9慢病毒转导的MDA-231细胞注射到8周龄雌性SCID小鼠(C.B-17/IcrHsd-Prkdcscid,Harlan Israel)的尾静脉。3周后处死小鼠,切下它们的肺以进行组织病理学检查。图5D显示,通过CRISPR-CAS9系统使MOSPD2沉默显著抑制肺中转移性乳腺癌细胞的存在,抑制超过95%(转移面积)。P=0.002。
图6A-6B显示抗-MOSPD2 F(ab')2mAb与A2058黑色素瘤和HepG2肝癌细胞系上的MOSPD2结合。
图7显示抗-MOSPD2 F(ab')2mAb显著抑制了EGF诱导的MDA-231细胞的跨孔迁移。
图8A-8F显示了来自不同病理阶段或来自与肿瘤相邻的正常组织(正常相邻组织;NAT)的人类乳腺癌样品的组织学图像。将样品固定在载玻片上,并用抗-MOSPD2抗体染色。图8A-8F显示,MOSPD2表达与乳腺癌细胞从局限性肿瘤向侵袭性和转移性肿瘤的转变有关。
图9显示了来自不同阶段乳腺癌或正常相邻组织(NAT)的样品中MOSPD2表达强度的评分(在0-3级范围内,其中0为无表达而3为非常高的表达)(*p<0.001)。
图10A-10D显示的图像比较了从结肠(图10A-10B)或肝脏(图10C-10D)中采集的各种正常和癌性人体组织中的MOSPD2表达水平。MOSPD2在67%的结肠腺癌和45%的肝细胞癌样品中表达,而在正常结肠和肝组织中未检测到表达。
图11A-11E显示了从人类肝脏采集的正常组织、NAT和不同级别的癌组织中MOSPD2表达水平的比较。将样品固定在载玻片上,并用抗-MOSPD2抗体染色。图11C-11E显示,MOSPD2染色强度随肝细胞癌的肿瘤级别的增加而增加。
图12A-12B显示了从肝细胞癌采集的样品中的MOSPD2表达强度。将样品固定在载玻片上,并用抗-MOSPD2抗体染色。图12A显示,与正常和NAT样品相比,从恶性肝细胞癌采集的样品中MOSPD2表达显著增加(p≤0.001)。图12B显示,MOSPD2染色强度显著增加,与肝细胞癌的进展相关。
图13A显示,施用增加浓度的抗-MOSPD2/抗-CD3双特异性抗体(BiTE)导致实体瘤源性细胞系存活的剂量依赖性下降和T细胞活化的增加。*=P<0.01。图13B和13C显示,施用增加浓度的BiTE还导致分别添加到HELA和A2058培养物中的CD8效应T细胞的IFN-γ释放的剂量依赖性增加。N.D=未检出。
图14A显示抗-MOSPD2/抗-CD3双特异性抗体(BiTE)的施用导致单核细胞系存活降低和T细胞活化增加。**=P<0.001。图14B显示了添加到THP-1和U937培养物中的T细胞的CD3和CD69染色。图14C显示,BiTE的施用还导致添加到THP-1和U937培养物中的T细胞的IFN-γ释放增加。N.D=未检出。
图15显示抗-MOSPD2/抗-CD3双特异性抗体的施用导致MDA-231乳腺癌细胞的存活显著降低。将预激活的CD8+T细胞分别以5:1的比例与MDA-231细胞和对照抗体(IgG)或抗-MOSPD2/抗-CD3双特异性抗体(双特异性Ab1-双特异性Ab4)共温育。温育24小时后,收集细胞并使用FACS流式细胞仪计数。显示的结果是每种处理三个平行孔的平均细胞计数±标准误差。**p<0.005;***p<0.001。
具体实施方式
在详细解释本发明的实施方式之前,应当理解的是,本发明在应用中不限于以下描述中阐述的或由实施例举例说明的细节。本发明可以具有其它实施方式或能够以其它方式来实践或执行。另外,应当理解的是,本文采用的措词和术语是出于描述的目的且不应被认为是限制性的。
一般定义
术语“包含(comprises)”、“包含(comprising)”、“包括(includes)”、“含有(including)”、“具有(having)”及其词形变化表示“包括但不限于”。
术语“由……组成”是指“包括且限于”。
术语“基本上由……组成”是指组合物的指定材料或方法的指定步骤,以及不会实质性影响该材料或方法的基本特性的那些其它材料或步骤。
词语“示例性”在本文中用来表示“用作示例、实例或说明”。被描述为“示例性”的任何实施方式不一定被解释为比其它实施方式优选或有利和/或从其它实施方式中排除特征的并入。
词语“可选地”在本文中用来表示“在一些实施方式中提供而在其它实施例中不提供”。本发明的任何特定实施方式可以包括多个“可选的”特征,除非这些特征冲突。
如本文所使用的,单数形式“一个(a)”、“一种(an)”和“该/(the)”包括复数引用,除非上下文另有明确规定。例如,术语“一种化合物”或“至少一种化合物”可以包括多种化合物,包括它们的混合物。
如本文所用,修饰与本发明有关的量的术语“约”是指数值量的变化,这种变化可能例如通过常规测试和处理;通过这种测试和处理中的无意错误;通过本发明所用成分的制造、来源或纯度上的差异等而发生。不论是否被术语“约”修饰,权利要求均包括所列举量的等同形式。在一个实施方式中,术语“约”是指所报告数值的10%以内。在另一实施方式中,术语“约”是指所报告数值的5%以内。
在整个本申请中,本发明的各实施方式可以以范围格式表示。应当理解的是,范围格式的描述仅是为了方便和简洁,而不应被解释为对本发明范围的硬性限制。因此,范围的描述应视为已明确公开了该范围内的所有可能子范围以及个体数值。例如,对诸如范围1至6的描述应被视为已经明确公开了该范围内的子范围,诸如1至3、1至4、1至5、2至4、2至6、3至6等,以及个体数字,例如1、2、3、4、5和6。无论范围的广度,这都适用。
如本文所用,术语“方法”是指用于完成给定任务的方式、手段、技术和程序,包括但不限于化学、药理、生物学、生化和医学领域的从业人员已知的那些方式、手段、技术和程序,或从已知的方式、手段、技术和程序容易开发的那些方式、手段、技术和程序。
如本文所用,术语“治疗”包括消除、基本上抑制、减缓或逆转病情的进展,基本上可以改善病情的临床或审美症状,或基本上预防出现某种病情的临床或审美症状。
如本文所用,“MOSPD2”是指归类为含活动精子结构域的蛋白质2或具有等同功能的任何多肽。MOSPD2的示例包括但不限于SEQ ID NO:1-4中任一个的多肽或其功能变体(例如具有与SEQ ID NO:1-4中任一个具有至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的序列)。MOSPD2的其它示例包括但不限于SEQ ID NO:5-8中任一个的多核苷酸或其功能变体(例如与SEQ ID NO:5-8中任一个具有至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的多核苷酸)编码的多肽。MOSPD2的其它例子包括美国申请公开No.2004/0171009中公开的脂质相关分子("LIPAM"),通过引用将其全部内容并入本文。LIPAM-5与SEQ ID NOL:1具有100%的同一性,不同之处在于氨基酸残基482是丝氨酸而不是精氨酸。如本领域技术人员所公知的,可以通过搜索公共数据库(例如BLAST)来识别MOSPD2的其它示例。
在本文所述的任何实施方式中,MOSPD2可以是癌细胞例如人类癌细胞表达的MOSPD2。另外,在本文描述的任何实施方式中,MOSPD2可以是哺乳动物MOSPD2或人类MOSPD2。
“抗体”或抗体的“抗原结合片段”包括但不限于多克隆、单克隆、鼠、人类、人源化或嵌合抗体,单链抗体,表位结合片段,例如Fab、Fab'和F(ab')2、Fd、Fvs、单链Fvs(scFv),单链抗体,二硫键连接的Fvs(sdFv),轻链可变区(VL)或重链可变区(VH)结构域,包含VL或VH结构域的片段,和由Fab表达文库产生的片段。抗体或抗体的抗原结合片段可以是任何类型免疫球蛋白分子(例如IgG、IgE、IgM、IgD、IgA和IgY)、任何类别的免疫球蛋白分子(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或免疫球蛋白分子的任何子类。用于制备抗体的抗原结合片段的方法是已知的,并且包括例如抗体的化学或蛋白酶消化。
如本文所用,“抗原结合结构域”是特异性结合抗原的抗体或其片段的多肽区域。抗原结合结构域的示例包括但不限于Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、互补决定区(CDR)、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。
如本文所用,“T细胞或NK细胞特异性受体分子”是指特异性地结合到或者引导另一分子、化合物或肽特异性地结合到T细胞特异性受体或NK细胞特异性受体的任何分子、化合物或肽。示例包括但不限于CD3、T细胞受体(TCR)、CD28、CD16、NKG2D、Ox40、4-1BB、CD2、CD5和CD95。
“特异性结合”通常是指抗体或其片段、变体或衍生物通过其抗原结合结构域与表位结合,并且该结合需要抗原结合结构域与表位之间具有一定的互补性。根据该定义,当抗体或其片段、变体或衍生物通过其抗原结合结构域与表位结合时比与随机、无关的表位结合时更容易,则说该抗体或其片段、变体或衍生物“特异性结合”表位。
如本文所用,“表位”是指抗体可以特异性结合的抗原的局部区域。表位可以是例如多肽的连续氨基酸(线性或连续表位),或者表位可以例如一起来自一个或多个多肽的两个或更多个非连续区域(构象、非线性、不连续或非连续表位)。在某些实施方式中,可以通过文献和本文中描述的方法,例如NMR光谱、X射线衍射晶体学研究、ELISA测定、氢/氘交换与质谱联用(例如MALDI质谱)、基于阵列的寡肽扫描测定和/或诱变作图(例如定点诱变作图),来确定抗体结合的表位。
如本领域已知的,术语“同一性百分比”是通过比较序列确定的两个或更多个多肽序列或两个或更多个多核苷酸序列之间的关系。在本领域中,“同一性”和“序列同一性”还指视情况而定通过这种序列字符串之间的匹配确定的多肽或多核苷酸序列之间的序列相关性程度。“同一性”和“相似性”可以通过已知方法和公开可用的资源轻松计算,包括但不限于下列中描述的那些:(1)Computational Molecular Biology(Lesk,A.M.,Ed.)OxfordUniversity:NY(1988);(2)Biocomputing:Informatics and Genome Projects(Smith,D.W.,Ed.)Academic:NY(1993);(3)Computer Analysis of Sequence Data,Part I(Griffin,A.M.,and Griffin,H.G.,Eds.)Humania:NJ(1994);(4)Sequence Analysis inMolecular Biology(von Heinje,G.,Ed.)Academic(1987);和(5)Sequence AnalysisPrimer(Gribskov,M.and Devereux,J.,Eds.)Stockton:NY(1991)。
应当理解的是,为清楚起见而在单独实施方式的背景下描述的本发明的某些特征也可以在单个实施方式中组合提供。相反,为简洁起见而在单个实施方式的背景下描述的本发明的各种特征,也可以单独地提供或以任何合适的子组合提供或者在本发明的任何其它的实施方式中合适地提供。在各种实施方式的背景下描述的某些特征不应被认为是那些实施方式的必要特征,除非该实施方式在没有那些要素的情况下不起作用。
双特异性抗体及其抗原结合片段
在一些实施方式中,本发明涉及双特异性抗体或其抗原结合片段,其特异性地结合MOSPD2和T细胞或NK细胞特异性受体分子。在一些实施方式中,双特异性抗体或其抗原结合片段包含(i)针对MOSPD2的一种或多种抗原结合结构域,和(ii)针对T细胞或NK细胞特异性受体分子的一种或多种抗原结合结构域。
在一些实施方式中,MOSPD2是SEQ ID NO:1-4中任一个的多肽或其功能变体(例如具有与SEQ ID NO:1-4中任一个具有至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的序列)。在其它实施方式中,MOSPD2是由SEQ ID NO:5-8中任一个的多核苷酸或其功能变体(例如具有与SEQ ID NO:5-8中任一个具有至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的序列的多核苷酸)编码的多肽。在其它实施方式中,MOSPD2是美国申请公开No.2004/0171009中公开的脂质相关分子(“LIPAM”),通过引用将其全部内容并入本文。LIPAM-5与SEQ ID NOL:1具有100%的同一性,不同之处在于氨基酸残基482是丝氨酸而不是精氨酸。如本领域技术人员所公知的,可以通过搜索公共数据库(例如BLAST)来识别其它示例性MOSPD2。
在一些实施方式中,T细胞或NK细胞特异性受体分子是CD3、T细胞受体(TCR)、CD28、CD16、NKG2D、Ox40、4-1BB、CD2、CD5或CD95。如本领域技术人员所公知的,可以通过搜索公共数据库(例如BLAST)来识别其它示例性T细胞或NK细胞特异性受体分子。
在一些实施方式中,针对MOSPD2和/或T细胞或NK细胞特异性受体分子的抗原结合结构域是抗体的Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、互补决定区(CDR)、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。
在一些实施方式中,双特异性抗体或其抗原结合片段包含下列抗原结合结构域中的一种或多种:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;和
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段包含下列抗原结合结构域中的一种或多种:
(i)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的重链可变区;和
(ii)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的轻链可变区。
在一些实施方式中,双特异性抗体或其抗原结合片段包含以下抗原结合结构域:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区;
(iii)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的重链可变区;和
(iv)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的轻链可变区。
在一些实施方式中,双特异性抗体或抗原结合片段从N末端到C末端依次包含以下抗原结合结构域:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区;
(iii)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的重链可变区;和
(iv)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的轻链可变区。
在一些实施方式中,双特异性抗体或抗原结合片段从N末端到C末端依次包含以下抗原结合结构域:
(i)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的重链可变区;
(ii)特异性结合T细胞或NK细胞特异性受体分子的抗体或其抗原结合片段(例如抗CD3抗体或其抗原结合片段)的轻链可变区;
(iii)抗MOSPD2抗体或其抗原结合片段的重链可变区;和
(iv)抗MOSPD2抗体或其抗原结合片段的轻链可变区。
在一些实施方式中,通过肽接头连接双特异性抗体或其抗原结合片段的抗原结合结构域的一种或多种。在一些实施方式中,通过肽接头连接双特异性抗体或其抗原结合片段的抗原结合结构域的全部。在一些实施方式中,肽接头的长度为约5个氨基酸至约50个氨基酸(例如长度为约5个氨基酸至约40个氨基酸、约5个氨基酸至约30个氨基酸、约5个氨基酸至约20个氨基酸、约5个氨基酸至约10个氨基酸、约10个氨基酸至约50个氨基酸、约10个氨基酸至约40个氨基酸、约10个氨基酸至约30个氨基酸、约10个氨基酸至约20个氨基酸、约20个氨基酸至约50个氨基酸、约20个氨基酸至约40个氨基酸、约20个氨基酸至约30个氨基酸、约30个氨基酸至约50个氨基酸、约30个氨基酸至约40个氨基酸、或约40个氨基酸至约50个氨基酸)。在一些实施方式中,肽接头的长度为约5个氨基酸、约10个氨基酸、约20个氨基酸、约30个氨基酸、约40个氨基酸或约50个氨基酸。在一些实施方式中,肽接头由丝氨酸(S)和甘氨酸(G)残基或者丙氨酸(A)和甘氨酸残基组成。在一些实施方式中,肽接头为(GGGGS)n、(SGGGG)n或(GGGGGGGG)n,其中n是约1至约10的整数。
在一些实施方式中,双特异性抗体或抗原结合片段的至少一个抗原结合结构域是人类的或人源化的。
在一些实施方式中,双特异性抗体或其抗原结合片段是单链多肽。
在一些实施方式中,双特异性抗体或其抗原结合片段的分子量不超过约60,000道尔顿。
在一些实施方式中,双特异性抗体是纳米抗体、双抗体、CrossMab、Duobody、二价抗体、双特异性T细胞衔接子(BiTE)、双亲和重靶向体(DART)、三体、微型抗体、TriBi微型抗体、内体或四价体。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域特异性地结合SEQ ID NO:1-4中的一个或多个或其功能变体,或者特异性地结合由SEQ ID NO:5-8中的一个或多个或其功能变体编码的多肽。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-6M至约10-12M的平衡解离常数(KD)特异性地结合MOSPD2。在一些实施方式中,双特异性抗体或其抗原结合片段以约10-6M至约10-12M的KD特异性地结合T细胞或NK细胞特异性受体分子(例如CD3)和/或CD3。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-6M至约10-12M或其任何取值范围(例如约10-7M至约10-12M、约10-8M至约10-12M、约10-9M至约10-12M、约10-10M至约10-12M、约10-11M至约10-12M、约10-6M至约10-11M、约10-7M至约10-11M、约10-8M至约10-11M、约10-9M至约10-11M、约10-10M至约10-11M、约10-6M至约10-10M、约10-7M至约10-10M、约10-8M至约10-10M、约10-9M至约10-10M、约10-6M至约10-9M、约10-7M至约10-9M、约10-8M至约10-9M、约10-6M至约10-8M、或约10-7M至约10-8)的KD特异性结合MOSPD2。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-6M、约10-7M、约10-8M、约10-9M、约10-10M、约10-11M或约10-12M的KD特异性结合MOSPD2。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域与MOSPD2上的一个或多个表位特异性结合。在一些实施方式中,通过Scatchard分析、表面等离子体共振(在一些实施方式中在37℃下)确定KD。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约1031/Ms至约1061/Ms或其任何取值范围(例如,约1031/Ms至约1051/Ms、约1041/Ms至约1051/Ms、约1041/Ms至约1061/Ms、约1051/Ms至约1061/Ms、或约1031/Ms至约1041/Ms)的Kon特异性结合MOSPD2。在其它实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域的Kon为约1031/Ms、约1041/Ms、约1051/Ms或约1061/Ms。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-31/s至约10-61/s或其任何取值范围(例如,约10-31/s至约10-51/s、约10-41/s至约10-51/s、约10-41/s至约10-61/s、约10-51/s至约10-61/s、或约10-31/s至约10-41/s)的Koff特异性结合MOSPD2。在其它实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域的Koff为约10-31/s、约10-41/s、约10-51/s或约10- 61/s。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域与MOSPD2的以下氨基酸区域的一个或多个特异性结合,根据SEQ ID NO:1编号:约505至约515,约500至约515,约230至约240,约510至约520,约210至约220,约15至约25,约505至约520,约505至约515,约90至约100,约505至约525,约230至约245,约505至约510,约130至约140,约220至约230,约15至约30,约80至约95,约40至约50,约460至约475,约340至约350,约500至约515,约460至约470,约325至约335,约20至约35,约215至约225,约510至约520,约175至约190,约500至约510,约505至约530,约60至约75,约500至约520,约145至约160,约502至约515,约85至约100,约205至约220,约175至约190,约500至约505,约500至约525,约495至约505,约495至约510,约190至约200,约190至约198,约502至约515,约1至约60,约80至约240,约90至约235,约330至约445,约330至约430,约495至约515,约145至约240,约145至约220,约145至约200,约160至约240,约160至约220,约160至约200,约175至约240,约175至约220,约175至约200,约170至约190,约178至约185,约85至约140,约85至约130,约90至约140,约90至约130,约95至约140,约95至约130,约100至约130,约100至约140,约110至约130,或约115至约127。
在一些实施方式中,双特异性抗体或其抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域与MOSPD2的以下氨基酸区域的一个或多个特异性结合,根据SEQ ID NO:1编号:约508至约517,约501至约514,约233至约241,约509至约517,约212至约221,约13至约24,约505至约517,约505至约514,约89至约100,约506至约517,约233至约245,约504至约514,约128至约136,约218至约226,约15至约24,约83至约96,约42至约50,约462至约474,约340至约351,约504至约517,约462至约470,约327至约337,约21至约32,约217至约226,约510至约517,约178至约190,约497至约509,约504至约516,约64至约77,约504至约515,约147至约159,约503至约515,约88至约97,约208至约218,约178至约191,约502至约515,约503至约516,约497至约505,约500至约509,约189至约202,约189至约197,约505至约516,约1至约63,约82至约239,约93至约234,约327至约445,约327至约431,和约497至约517。
文献中已经描述了可以在本发明的双特异性抗体中使用的特异性结合MOSPD2的抗体,例如国际公开No.WO 2017/021855和国际公开No.WO 2017/021857,通过引用将其全部内容并入本文。
文献中已经描述了可以在本发明的双特异性抗体中使用的特异性结合T细胞或NK细胞特异性受体分子(例如CD3)的抗体,例如美国专利No.7,112,324;7,262,276;7,635,472;9,249,217;和9,676,858,通过引用将其全部内容并入本文。
此外,文献中也已经描述了使用特异性结合MOSPD2的抗体和抗原结合结构域以及特异性结合T细胞或NK细胞特异性受体分子的抗体和抗原结合结构域获得本发明的双特异性抗体或其抗原结合片段的方法,例如美国专利No.7,112,324;7,262,276;7,635,472;9,249,217;和9,676,858,通过引用将其全部内容并入本文。
在一些实施方式中,本发明涉及一种编码本文描述的双特异性抗体或其抗原结合片段的核酸。
在一些实施方式中,本发明涉及一种表达载体,包含编码本文描述的双特异性抗体或其抗原结合片段的核酸。
药物组合物和试剂盒
本发明的其它实施方式涉及一种药物组合物,包含特异性结合MOSPD2并且特异性结合T细胞或NK细胞特异性受体分子的双特异性抗体或其抗原结合片段。
在一些实施方式中,药物组合物包含本文所述的双特异性抗体或其抗原结合片段以及药学上可接受的载体。术语“药学上可接受的载体”包括但不限于赋形剂、润滑剂、缓冲剂、抗菌剂、填充剂(例如甘露醇)、抗氧化剂(例如抗坏血酸或亚硫酸氢钠)、稀释剂、佐剂、赋形药等。
在一些实施方式中,药物组合物适用于全身、局部、经鼻、口服、腹膜内、肿瘤内、肠胃外、经粘膜、直肠、颊、吸入、静脉内、肌内或皮下给药。
在一些实施方式中,药物组合物含有治疗有效量的特异性结合MOSPD2且特异性结合T细胞或NK细胞特异性受体分子的双特异性抗体或其抗原结合片段,例如约1μg/ml至约10μg/ml或其任何取值范围(例如约2μg/ml至约10μg/ml、约3μg/ml至约10μg/ml、约4μg/ml至约10μg/ml、约5μg/ml至约10μg/ml、约6μg/ml至约10μg/ml、约7μg/ml至约10μg/ml、约8μg/ml至约10μg/ml、约9μg/ml至约10μg/ml、约1μg/ml至约9μg/ml、约2μg/ml至约9μg/ml、约3μg/ml至约9μg/ml、约4μg/ml至约9μg/ml、约5μg/ml至约9μg/ml、约6μg/ml至约9μg/ml、约7μg/ml至约9μg/ml、约8μg/ml至约9μg/ml、约1μg/ml至约8μg/ml、约2μg/ml至约8μg/ml、约3μg/ml至约8μg/ml、约4μg/ml至约8μg/ml、约5μg/ml至约8μg/ml、约6μg/ml至约8μg/ml、约7μg/ml至约8μg/ml、约1μg/ml至约7μg/ml、约2μg/ml至约7μg/ml、约3μg/ml至约7μg/ml、约4μg/ml至约7μg/ml、约5μg/ml至约7μg/ml、约6μg/ml至约7μg/ml、约1μg/ml至约6μg/ml、约2μg/ml至约6μg/ml、约3μg/ml至约6μg/ml、约4μg/ml至约6μg/ml、约5μg/ml至约6μg/ml、约1μg/ml至约5μg/ml、约2μg/ml至约5μg/ml、约3μg/ml至约5μg/ml、约4μg/ml至约5μg/ml、约1μg/ml至约4μg/ml、约2μg/ml至约4μg/ml、约3μg/ml至约4μg/ml、约1μg/ml至约3μg/ml、约2μg/ml至约3μg/ml、或约1μg/ml至约2μg/ml)。
在一些实施方式中,治疗有效量为约1μg/ml、约2μg/ml、约3μg/ml、约4μg/ml、约5μg/ml、约6μg/ml、约7μg/ml、约8μg/ml、约9μg/ml或约10μg/ml。
在一些实施方式中,治疗有效量为约10mg/kg至约40mg/kg或其任何取值范围(例如约15mg/kg至约40mg/kg、约20mg/kg至约40mg/kg、约25mg/kg至约40mg/kg、约30mg/kg至约40mg/kg、约35mg/kg至约40mg/kg、约10mg/kg至约35mg/kg、约15mg/kg至约35mg/kg、约20mg/kg至约35mg/kg、约25mg/kg至约35mg/kg、约30mg/kg至约35mg/kg、约10mg/kg至约30mg/kg、约15mg/kg至约30mg/kg、约20mg/kg至约30mg/kg、约25mg/kg至约30mg/kg、约10mg/kg至约25mg/kg、约15mg/kg至约25mg/kg、约20mg/kg至约25mg/kg、约10mg/kg至约20mg/kg、约15mg/kg至约20mg/kg、或约10mg/kg至约15mg/kg)。
在一些实施方式中,治疗有效量为约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg或约40mg/kg。
在一些实施方式中,本发明涉及一种试剂盒,包含(i)本文所述的双特异性抗体或抗原结合片段或本文所述的药物组合物,和(ii)使用说明。在一些实施方式中,说明中的使用是本文所述的一种或多种使用方法。
使用方法和生产方法
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防癌症的方法,包括以有效量给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防癌症。本文其它地方描述了双特异性抗体或其抗原结合片段的有效量。
在一些实施方式中,本发明涉及一种在受试者中治疗或预防癌症转移的方法,包含以有效量给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防癌症转移。
在一些实施方式中,本文所述的任何方法的癌症为膀胱癌、脑癌、乳腺癌、结肠癌、直肠癌、肾癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌、皮肤癌、造血系统癌、舌癌、间充质起源的癌症、中枢或周围神经系统的癌症、子宫内膜癌、头颈癌、胶质母细胞瘤或恶性腹水。
在一些实施方式中,肺癌是小细胞肺癌或非小细胞肺癌。
在一些实施方式中,皮肤癌是鳞状细胞癌、基底细胞癌、黑色素瘤、隆突性皮肤纤维肉瘤、梅克尔细胞癌、卡波西氏肉瘤、角化棘皮瘤、梭形细胞瘤、皮脂腺癌、微囊性附件癌、乳房佩吉特氏病、非典型纤维黄瘤、平滑肌肉瘤或血管肉瘤。
在一些实施方式中,造血系统癌是淋巴谱系的造血系统癌。在一些实施方式中,淋巴谱系的造血系统癌是白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯基特淋巴瘤。在一些实施方式中,造血系统癌是骨髓谱系的造血系统癌。在一些实施方式中,骨髓谱系的造血系统癌是急性髓细胞性白血病、慢性髓细胞性白血病、骨髓增生异常综合症或早幼粒细胞白血病。
在一些实施方式中,间充质起源的癌症是纤维肉瘤、横纹肌肉瘤、软组织肉瘤或骨肉瘤。
在一些实施方式中,中枢或周围神经系统的癌症是星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
在一些实施方式中,癌症是肛门癌、骨癌、胃肠道间质癌、妊娠滋养细胞疾病、霍奇金淋巴瘤、卡波西肉瘤、角化棘皮瘤、恶性间皮瘤、多中心卡斯特莱曼病、多发性骨髓瘤和其它浆细胞瘤、骨髓增生性肿瘤、神经母细胞瘤、非霍奇金淋巴瘤、骨肉瘤、卵巢癌、输卵管、或原发性腹膜癌、阴茎癌、视网膜母细胞瘤、横纹肌肉瘤、精原细胞瘤、软组织肉瘤、胃(胃)癌、睾丸癌、畸胎癌、甲状腺滤泡癌、阴道癌、外阴癌、威尔姆斯瘤和其它儿童期肾癌、或着色性干皮病。
在一些实施方式中,治疗或预防癌症或癌症转移的方法进一步包括给予受试者有效量的抗癌药。在一些实施方式中,抗癌药是醋酸阿比特龙、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(维布本妥昔单抗)、ADE、阿多曲妥珠单抗-美坦新、阿霉素(盐酸多柔比星)、Adrucil(氟尿嘧啶)、马来酸阿法替尼、飞尼妥(依维莫司)、Akynzeo(奈妥吡坦和帕洛诺司琼盐酸盐)、艾达乐(咪喹莫特)、阿地白介素、阿仑单抗、爱宁达(培美曲塞二钠)、阿乐喜(盐酸帕洛诺司琼)、Ambochlorin(苯丁酸氮芥)、Amboclorin(苯丁酸氮芥)、氨基乙酰丙酸、阿那曲唑、阿瑞匹坦、阿可达(帕米膦酸二钠)、安美达锭(阿那曲唑)、阿诺新(依西美坦)、Arranon(奈拉滨)、三氧化二砷、Arzerra(奥法木单抗)、天冬酰胺酶菊欧文氏菌、安维汀(贝伐单抗)、阿昔替尼、阿扎胞苷、BEACOPP、Becenum(卡莫司汀)、Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、贝伐单抗、贝沙罗汀、百克沙(托西莫单抗和I 131碘托西莫单抗)、比卡鲁胺、BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、维布本妥昔单抗、白消安、白舒非(白消安)、卡巴他赛、卡波替尼-S-苹果酸、CAF、坎帕斯(阿仑单抗)、开普拓(盐酸伊立替康)、卡培他滨、CAPOX、卡铂、卡铂-紫杉酚、卡非佐米、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀植入物、康士得(比卡鲁胺)、CeeNU(洛莫司汀)、色瑞替尼、Cerubidine(盐酸柔红霉素)、希瑞适(重组HPV二价疫苗)、西妥昔单抗、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂、Clafen(环磷酰胺)、氯法拉滨、CMF、Cometriq(卡波替尼-S-苹果酸)、COPP、COPP-ABV、Cosmegen(更生霉素)、克唑替尼、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗)、阿糖孢苷、阿糖孢苷、脂质体、Cytosar-U(阿糖孢苷)、Cytoxan(环磷酰胺)、达拉菲尼、达卡巴嗪、达克金(地西他滨)、更生霉素、达沙替尼、盐酸柔红霉素、地西他滨、地加瑞克、地尼白介素、狄诺塞麦、DepoCyt(脂质体阿糖孢苷)、DepoFoam(脂质体阿糖孢苷)、盐酸右雷佐生、地努图希单抗、多西他赛、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、Efudex(氟尿嘧啶)、埃立特(拉布立酶)、Ellence(盐酸表柔比星)、乐沙定(奥沙利铂)、艾曲波帕乙醇胺、Emend(阿瑞匹坦)、恩杂鲁胺、盐酸表柔比星、EPOCH、爱必妥(西妥昔单抗)、甲磺酸艾日布林、Erivedge(维莫德吉)、埃罗替尼盐酸盐、Erwinaze(天冬酰胺酶菊欧文氏菌)、Etopophos(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、易维特(盐酸雷洛昔芬)、依西美坦、法乐通(托瑞米芬)、Farydak(帕比司他)、芙仕得(氟维司群)、FEC、弗隆(来曲唑)、非格司亭、福达华(磷酸氟达拉滨)、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶)、氟尿嘧啶、Folex(甲氨蝶呤)、FolexPFS(甲氨蝶呤)、伊立替康、伊立替康-贝伐单抗、伊立替康-西妥昔单抗、Folfirinox、Folflox、Folotyn(普拉曲沙)、FU-LV、氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗)、Gazyva(奥比努珠单抗)、吉非替尼、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥单抗唑加米星、健择(盐酸吉西他滨)、Gilotrif(马来酸阿法替尼)、格列卫(甲磺酸伊马替尼)、格立得(卡莫司汀植入物)、格立得薄片(卡莫司汀植入物)、羧肽酶、醋酸戈舍瑞林、Halaven(甲磺酸艾日布林)、赫塞汀(曲妥珠单抗)、HPV二价疫苗重组体、HPV九价疫苗重组体、HPV四价疫苗重组体、美新(盐酸拓扑替康)、Hyper-CVAD、Ibrance(帕博西尼)、替伊莫单抗、依鲁替尼、ICE、Iclusig(盐酸波纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、甲磺酸伊马替尼、Imbruvica(依鲁替尼)、咪喹莫特、英立达(阿昔替尼)、Intron A(重组干扰素Alfa-2b)、碘131托西单抗和托西单抗、易普利姆玛、易瑞沙(吉非替尼)、盐酸伊立替康、Istodax(罗米地辛)、伊沙匹隆、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索替尼)、Jevtana(卡巴他赛)、Kadcyla(阿多曲妥珠单抗-美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明)、Keytruda(派姆单抗)、Kyprolis(卡非佐米)、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、来那度胺、甲磺酸乐伐替尼、Lenvima(甲磺酸乐伐替尼)、来曲唑、亚叶酸钙、瘤可宁(苯丁酸氮芥)、醋酸亮丙瑞林、Levulan(氨基乙酰丙酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、脂质体阿糖孢苷、洛莫司汀、Lupron(醋酸亮丙瑞林)、Lupron Depot(醋酸亮丙瑞林)、Lupron Depot-Ped(醋酸亮丙瑞林)、Lupron Depot-3个月(醋酸亮丙瑞林)、Lupron Depot-4个月(醋酸亮丙瑞林)、Lynparza(奥拉帕尼)、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸丙卡巴嗪)、盐酸氮芥、梅格施(醋酸甲地孕酮)、醋酸甲地孕酮、Mekinist(曲美替尼)、巯基嘌呤、美司钠、Mesnex(美司钠)、Methazolastone(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福)、Mustargen(盐酸氮芥)、密吐霉素(丝裂霉素C)、马勒兰(白消安)、Mylosar(阿扎胞苷)、麦罗塔(吉妥单抗唑加米星)、纳米粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、诺维本(酒石酸长春瑞滨)、奈拉滨、Neosar(环磷酰胺)、奈妥吡坦和帕洛诺司琼盐酸盐、优保津(非格司亭)、蕾莎瓦(甲苯磺酸索拉非尼)、尼罗替尼、纳武单抗、诺瓦得士(枸橼酸他莫昔芬)、Nplate(罗米司亭)、奥比努珠单抗、OEPA、奥法木单抗、OFF、奥拉帕尼、高三尖杉酯碱、Oncaspar(培门冬酶)、Ontak(地尼白介素)、欧狄沃(纳武单抗)、OPPA、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、帕米膦酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、伯尔定(卡铂)、盐酸帕唑帕尼、培门冬酶、聚乙二醇干扰素Alfa-2b、PEG-Intron(聚乙二醇干扰素Alfa-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸波纳替尼、普拉曲沙、强的松、盐酸丙卡巴嗪、Proleukin(阿地白介素)、普罗利亚(狄诺塞麦)、Promacta(艾曲波帕乙醇胺)、普列威(Sipuleucel-T)、Purinethol(巯基嘌呤)、Purixan(巯基嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素Alfa-2b、瑞戈非尼、R-EPOCH、雷利米得(来那度胺)、Rheumatrex(甲氨蝶呤)、美罗华(利妥昔单抗)、利妥昔单抗、罗米地辛、罗米司亭、红比霉素(盐酸柔红霉素)、磷酸鲁索替尼、硬化性胸膜内气雾剂(滑石粉)、司妥昔单抗、Sipuleucel-T、索马杜林Depot(醋酸兰瑞肽)、甲苯磺酸索拉非尼、施达赛(达沙替尼)、STANFORD V、无菌滑石粉粉末(滑石粉)、无菌滑石粉(滑石粉)、Stivarga(瑞戈非尼)、苹果酸舒尼替尼、索坦(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素Alfa-2b)、Sylvant(司妥昔单抗)、昔诺韦(萨力多胺)、Synribo(高三尖杉酯碱)、TAC、Tafinlar(达拉菲尼)、滑石粉、枸橼酸他莫昔芬、Tarabine PFS(阿糖孢苷)、特罗凯(埃罗替尼盐酸盐)、Targretin(贝沙罗汀)、泰息安(尼罗替尼)、紫杉酚(紫杉醇)、泰索帝(多西他赛)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司、萨力多胺、Thalomid(萨力多胺)、噻替派、Toposar(依托泊苷)、盐酸拓扑替康、托瑞米芬、驮瑞塞尔(替西罗莫司)、托西莫单抗和I 131碘托西莫单抗、Totect(盐酸右雷佐生)、TPF、曲美替尼、曲妥珠单抗、存达(盐酸苯达莫司汀)、Trisenox(三氧化二砷)、泰立沙(二甲苯磺酸拉帕替尼)、Unituxin(地努图希单抗)、凡德他尼、VAMP、Vectibix(帕尼单抗)、VeIP、Velban(硫酸长春碱)、万珂(硼替佐米)、Velsar(硫酸长春碱)、维莫非尼、凡毕士(依托泊苷)、Viadur(醋酸亮丙瑞林)、维达扎(阿扎胞苷)、硫酸长春碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉、Voraxaze(羧肽酶)、伏立诺他、Votrient(盐酸帕唑帕尼)、Wellcovorin(亚叶酸钙)、赛可瑞(克唑替尼)、希罗达(卡培他滨)、XELIRI、XELOX、Xgeva(狄诺塞麦)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(易普利姆玛)、Zaltrap(齐夫-阿柏西普)、泽波拉夫(维莫非尼)、泽娃灵(替伊莫单抗)、Zinecard(盐酸右雷佐生)、齐夫-阿柏西普、诺雷德(醋酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、择泰(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)、Zytiga(醋酸阿比特龙)或它们的组合。
在一些实施方式中,本发明涉及一种用于在受试者中抑制或减少肿瘤细胞的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。在一些实施方式中,与对照或参考值相比,肿瘤细胞的数量减少了至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或至少约100%。
在一些实施方式中,本发明涉及一种在受试者中增加表达CD3的细胞产生细胞因子的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种增加T细胞中IL-2、CD69和/或IFN-γ产生或浓度的方法,包括使T细胞接触本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。在一些实施方式中,与对照或参考值相比,IFN-γ生产增加了至少约100%、至少约200%、至少约300%、至少约400%、至少约500%、至少约600%、至少约700%、至少约800%、至少约900%或至少约1000%。在一些实施方式中,与对照或参考值相比,IFN-γ浓度增加了至少约1000pg/ml、至少约2000pg/ml、至少约3000pg/ml、至少约4000pg/ml、至少约5000pg/ml、至少约6000pg/ml、至少约7000pg/ml、至少约8000pg/ml、至少约9000pg/ml或至少约10000pg/ml。在一些实施方式中,与对照或参考值相比,CD69生产增加了至少约1%、至少约2%、至少约3%、至少约4%、至少约5%、至少约6%、至少约7%、至少约8%、至少约9%、至少约10%、至少约15%、至少约20%、至少约25%或至少约30%。
在一些实施方式中,本发明涉及一种刺激受试者中免疫应答的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种在受试者中刺激针对癌细胞的T细胞介导的细胞毒性免疫应答的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种增加T细胞增殖的方法,包括使T细胞接触本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种减少或耗尽受试者肿瘤中T调节细胞数量的方法,包括给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物。
在一些实施方式中,本发明涉及一种用于预测、诊断或预后受试者中癌症或癌症转移的方法,包括使用本文所述的双特异性抗体或其抗原结合片段确定受试者样品中的MOSPD2表达水平。在一些实施方式中,该方法包括(i)使用本文所述的双特异性抗体或其抗原结合片段确定或量化受试者样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于对照或参考值,增加的MOSPD2表达水平指示了癌症、患癌症的风险增加或癌症预后不良。
在一些实施方式中,本发明涉及一种用于预测、诊断或预后受试者中肿瘤进展或肿瘤侵袭性的方法,包括使用本文所述的双特异性抗体或其抗原结合片段确定受试者样品中的MOSPD2表达水平。在一些实施方式中,该方法包括(i)使用本文所述的双特异性抗体或其抗原结合片段确定或量化受试者样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于对照或参考值,增加的MOSPD2表达水平指示了肿瘤进展或肿瘤侵袭性预后不良。
在一些实施方式中,用于预测、诊断或预后的方法还包括以下步骤的一个或多个:
指示实验室量化样品中的MOSPD2表达水平;
从实验室获得样品中MOSPD2表达水平的报告;和/或
给予受试者治疗有效量的MOSPD2的抑制剂。
在用于预测、诊断或预后的方法的一些实施方式中,样品是来自受试者的组织活检、肿瘤活检或血液样品。
在用于预测、诊断或预后的方法的一些实施方式中,对照或参考值是正常组织或正常相邻组织(NAT)中的MOSPD2表达水平。
在用于预测、诊断或预后的方法的一些实施方式中,对照或参考值是没有可检测的MOSPD2表达或没有显著的MOSPD2表达。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防MOSPD2表达肿瘤的方法,包括以有效量给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防MOSPD2表达肿瘤。
在一些实施方式中,本发明涉及一种用于在受试者中治疗或预防具有MOSPD2表达肿瘤相关巨噬细胞的肿瘤的方法,包括以有效量给予受试者本文所述的双特异性抗体或其抗原结合片段或本文所述的药物组合物,以治疗或预防具有MOSPD2表达肿瘤相关巨噬细胞的肿瘤。
在一些实施方式中,本文所述的任何方法的受试者是哺乳动物。在一些实施方式中,本文所述的任何方法的受试者是人类。在一些实施方式中,本文所述的任何方法的受试者是兽类动物(兽医动物,veterinary animal)(例如狗、猫、马、绵羊、牛或山羊)。
在一些实施方式中,本发明涉及一种用于生产本文所述的双特异性抗体或其抗原结合片段的方法,包括培养用本文所述的核酸或表达载体转化的宿主细胞,和收集并纯化所表达的双特异性抗体或其抗原结合片段。
实施例
现在参考以下实施例,其与以上描述一起以非限制性方式示出了本发明的一些实施方式。
材料与方法
MOSPD2沉默
人乳腺癌细胞系MDA-MB-231(下文称为MDA-231)(HTB-26)和人恶性黑色素瘤细胞系A2058(CRL-11147)购自美国典型培养物保藏(ATCC)。将细胞(2ml中2x106)置于15ml管中。将表达对照短发夹RNA(sh-RNA)的慢病毒颗粒(2x105病毒颗粒)或表达人类MOSPD2 sh-RNA的慢病毒颗粒(2x106病毒颗粒)施加到细胞,然后在8μg/ml聚凝胺(Sigma,Israel)存在下于室温以2000rpm旋转60分钟。然后将细胞接种到6孔板中。72小时后,加入含有嘌呤霉素(4μg/ml Sigma,Israel)的新鲜培养基以选择转导细胞。对于CRISPR-CAS9介导的沉默,如上所述,用CRISPR-CAS9非靶对照或CRISPR-CAS9人MOSPD2慢病毒颗粒转导MDA-231细胞。对转导的细胞进行单细胞克隆以分离具有沉默的MOSPD2蛋白表达和迁移受损的细胞。
蛋白质印迹
洗涤sh-对照或sh-MOSPD2慢病毒转导的A2058或MDA-231细胞、或对照或MOSPD2CRISPR-CAS9慢病毒颗粒转导的MDA-231细胞(106),并且重悬于含有1:100二硫苏糖醇(DTT)、磷酸酶和蛋白酶抑制剂的裂解缓冲液(Thermo Scientific)中。将样品加载到预制的Criterion TGX凝胶上(Bio-Rad,Hemel Hempstead,UK)并且转移到硝酸纤维素膜上。在Tris缓冲盐水和吐温20(TBST)中用5%牛奶或牛血清白蛋白(BSA)封闭印迹1小时,然后与一级抗体和二级抗体一起温育。用ECL试剂盒(Thermo Scientific)将膜显影。使用下列抗体进行免疫印迹:
一级抗体:由Vascular Biogenics Ltd.产生的兔抗-MOSPD2(1:5000)。磷酸化细胞外调节激酶(p-ERK1/2)(Thr 183和Tyr 185,1:4000)购自Sigma(Israel)。磷酸化-AKT(Ser 473,1:1000)购自Cell Signaling。磷酸化-FAK(1:2000)购自Abcam(Cambridge,UK)。热激蛋白(HSP)90(1:1000)购自Santa Cruz Biotechnology(Dallas,TX)。
二级抗体:辣根过氧化物酶(HRP)驴抗-兔(1:5000)和HRP山羊抗-小鼠(1:5000)抗体购自Jackson ImmunoResearch(West Grove,PA)。
Q-PCR
为了确定沉默效果,使用Rneasy迷你试剂盒(Qiagen,ValenVBa,CA)从sh-对照和sh-MOSPD2慢病毒转导的MDA-231细胞提取RNA。对于cDNA制备,将2μg的RNA与qScript反应混合物和qScript逆转录酶(Quanta Bioscience,Gaithersburg,MD)合并。将反应置于热循环仪(BioRad,Hercules,CA)中并且根据制造商的说明设置运行程序。在AppliedBiosystems 7300实时PCR系统(Grand Island,NY)上,使用人类MOSPD2,28S引物组标准化RNA水平(BIOSEARCH TECHNOLOGIES,Petaluma,CA)和SYBR Green PCR Master混合物(Applied Biosystems,Warrington,UK),进行实时PRC反应。
免疫组织化学染色
为了评估MOSPD2在癌症组织中的表达水平,使用兔抗-MOSPD2抗体或对照兔IgG(R&D Systems Cat#AB-105-C)对乳腺癌(T088B和BR2028a)、肝癌(BC03116a)和多器官肿瘤(MC6163)的Biomax阵列(US Biomax Rockville,MD)进行染色,随后使用抗-兔HRP(Cat#0399DAKO,Denmark)温育。
实施例1
MOSPD2和转移细胞系的迁移
为了评估MOSPD2在癌细胞迁移中的作用,如国际公开No.2017/021857中所描述的,使用sh-对照或sh-MOSPD2慢病毒颗粒将两个转移性细胞系A2058黑色素瘤和MDA-231乳腺癌中的MOSPD2表达沉默。
特别地,将先前在0.5%FBS/RPMI-1640中饥饿3小时的sh-对照或sh-MOSPD2转导的A2058或MDA-231细胞(3x105)接种在QCM 24孔5μm孔隙迁移分析板(Corning-Costar,Corning,NY)的上室中,随后在下室中存在10%FBS/RPMI-1640和EGF(200ng/ml,PeprotechIsrael)的情况下温育24小时。随后,将迁移到下部隔室的细胞用结晶紫染色,随后拍摄图像。
图1表明,sh-MOSPD2慢病毒颗粒在体外显著降低了蛋白质表达并抑制了癌细胞迁移。
实施例2
MOSPD2和细胞增殖
为了确定MOSPD2沉默后的细胞迁移的抑制作用是否是基本细胞功能(如增殖)的继发作用,如国际公开No.2017/021857中所描述的,在3天时间段内测试sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231乳腺癌细胞的增殖。
具体地,将sh-对照或sh-MOSPD2慢病毒转导的MDA-231细胞接种在6孔板中(104/孔)。通过FACS每24小时计数细胞一式三份,连续3天。
图2中显示的数据表明,MOSPD2对于这些细胞的增殖不是必不可少的,这表明MOSPD2特别是在迁移中的调节作用。
实施例3
MOSPD2和细胞转移
为了评估MOSPD2在将癌细胞扩散到原始癌症部位以外的器官中的作用,如国际公开No.2017/021857中所描述的,将sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231乳腺癌细胞中的肺转移程度过继转移到免疫缺陷小鼠中。在起始部位发生在乳腺中的另一模型中,在乳脂垫用sh-对照或sh-MOSPD2慢病毒颗粒转导的MDA-231乳腺癌细胞温育免疫缺陷小鼠。
病理检查:用苏木精/曙红(H&E)将组织学载玻片染色。将福尔马林固定的组织脱水,包埋在石蜡中,并切成4μm的厚度。H&E染色在Leica染色模块上校准。将载玻片加热至90℃,持续7分钟,然后根据全自动协议进行处理。将切片脱蜡并重新水化后,将载玻片在Gill的苏木精3号(Surgipath)中染色7分钟,洗涤,浸入酸性醇中,然后洗涤。短暂浸入70%乙醇和96%乙醇后,将载玻片在曙红(Sigma)中染色4分钟,然后在96%乙醇中脱水,然后在100%乙醇中脱水两次,每次1分钟。在自动染色机上运行完后,将切片在二甲苯中清洗10秒,并用Entellan安装。平均肿瘤面积包括对每只小鼠测得的最大肺肿瘤面积。
全身性:将106个sh-对照或sh-MOSPD2慢病毒转导的MDA-231细胞注射入8周龄雌性SCID小鼠(C.B-17/IcrHsd-Prkdcscid,Harlan Israel)的尾静脉。4周后处死小鼠。切下肺以进行组织病理学检查。图3A的结果显示,沉默MOSPD2表达显著地(p=0.023)抑制肺中转移性乳腺癌细胞的存在,抑制超过50%(转移面积)。
原位:将5x106个sh-对照或sh-MOSPD2慢病毒转导的MDA-231细胞注射到8周龄雌性SCID小鼠(C.B-17/IcrHsd-Prkdcscid,Harlan Israel)的乳腺脂肪垫中。10周后处死小鼠。切下同侧腹股沟淋巴结和肺进行检查。宏观检验显示,从sh-对照细胞转移的小鼠切下的绝大多数淋巴结比从sh-MOSPD2处理细胞转移的小鼠切下的淋巴结要更大的多(图3B)。另外,与对照组相比,在用sh-MOSPD2处理的细胞转移的小鼠肺中测得的平均转移面积减少了超过50%(图3C)。
如材料和方法中所描述的,通过Q-PCR确定的sh-MOSPD2注射细胞中MOSPD2 mRNA沉默的比例为~80%。
这些结果表明,MOSPD2在乳腺癌转移中起主要作用。
实施例4
各种类型癌症中的MOSPD2表达
为了确定MOSPD2表达是否与细胞从正常向癌变的转化有关,如在材料和方法章节中以及国际公开No.2017/021857中所描述的,使用抗-MOSPD2抗体筛选载有正常和癌组织的载玻片。
图4A显示了正常和癌性乳腺组织的代表性染色。虽然正常和癌性乳腺组织用对照IgG抗体染色均呈阴性,但抗-MOSPD2抗体仅对癌性组织显著染色。类似地,MOSPD2在正常的膀胱、脑、结肠、食道、舌头、肾和肝组织中不表达,但是当这些组织变成癌性时会上调(图4B-4E)。这些结果表明,在各种组织中,MOSPD2表达与正常组织向癌性组织的转化有关。
实施例5
MOSPD2基因敲低和癌细胞迁移
体外:为了实现MOSPD2的可持续敲低,如材料和方法章节以及国际公开No.2017/021857中所描述的,用含有CRISPR-CAS9基因编辑系统的慢病毒颗粒转导MDA-231乳腺癌细胞。通过上述方法测试对照或MOSPD2 CRISPR-CAS9慢病毒颗粒转导的MDA-231细胞的迁移。将对照或MOSPD2 CRISPR-CAS9慢病毒颗粒转导的MDA-231细胞(3x105)接种在上室,随后温育2-4小时。随后,通过FACS确定迁移至下部隔室的细胞数量。
图5A和5B显示,在MDA-231癌细胞中引入用于MOSPD2的CRISPR-CAS9系统消除蛋白质表达,从而在跨孔测定中显著抑制细胞迁移。
为了测试由CRISPR-CAS9沉默的MOSPD2对趋化因子受体驱动的信号转导事件的影响,如材料和方法中所描述的,研究了ERK、AKT和FAK的磷酸化水平。根据迁移测定结果,与对照相比,通过CRISPR-CAS9系统使MOSPD2沉默完全防止了暴露于EGF的细胞中AKT的磷酸化,并明显抑制了ERK和FAK的磷酸化(参见图5C中的蛋白印迹)。
体内:将106个CRISPR-对照或CRISPR-MOSPD2慢病毒转导的MDA-231细胞注射到8周龄雌性SCID小鼠(C.B-17/IcrHsd-Prkdcscid,Harlan Israel)的尾静脉。3周后将小鼠处死。切下肺以进行组织病理学检查。图5D显示,通过CRISPR-CAS9系统沉默MOSPD2显著地抑制了肺中转移性乳腺癌细胞的存在,抑制超过95%(转移面积)。
实施例6
抗-MOSPD2 F(ab')2mAb特异性结合人乳腺癌细胞上的内源性MOSPD2
如国际公开No.2017/021857中所描述的,生成了抗-MOSPD2 F(ab')2mAb并且测试了与A2058黑色素瘤和HepG2肝癌细胞系表面表达的内源性MOSPD2的结合。用抗-MOSPD2 F(ab')2mAb将细胞染色并且测试与MOSPD2的结合。图6A-6B显示,抗-MOSPD2 F(ab')2mAb与黑色素瘤和肝癌细胞上的内源性MOSPD2特异性结合。
实施例7
抗-MOSPD2 F(ab')2mAb抑制EGF诱导的MDA-231癌细胞迁移
使用国际公开No.2017/021857中解释的跨孔迁移分析了抗-MOSPD2F(ab')2mAb对EGF诱导的MDA-231癌细胞迁移的影响。在含有0.5%FCS的RPMI培养基中将MDA-231乳腺癌细胞(3x105)饥饿4-5小时,然后用抗-MOSPD2 F(ab')2mAb温育1小时。将EGF溶解并且放置于含有具有10%FCS的RPMI培养基的QCM 24-孔迁移分析板(8μm孔)(Corning-Costar,Corning,NY)的下室中(400ng/ml)。将细胞接种到上室中,然后过夜温育,然后通过FACS确定迁移到下层隔室的细胞数。
如图7所示,抗-MOSPD2 F(ab')2mAb显著地抑制了EGF诱导的MDA-231乳腺癌细胞的跨孔迁移。
实施例8
抗-MOSPD2抗体的表位作图
为了确定抗-MOSPD2抗体可以特异性结合在人MOSPD2上的表位,如本文所述,通过在SA芯片上预先固定的链霉亲和素(SA)捕获N端生物素化的MOSPD2片段,并测量滴定在MOSPD2表面的抗-MOSPD2抗体的结合动力学(3000TM表面等离子体共振(SPR)系统,Biacore,Inc.,Piscataway NJ),测量与各种人类MOSPD2片段的结合亲和力。在HBS-EP运行缓冲液(10mM HEPES pH 7.4,150mM NaCl,3mM EDTA,0.005%v/v聚山梨酸酯P20)中进行BIAcore测定。通过将N-生物素化的MOSPD2稀释到HBS-EP缓冲液中至小于0.001mg/mL的浓度,并使用可变的接触时间将其注入整个SA传感器芯片中来制备MOSPD2表面。将对应于捕获水平<50响应单位(RU)的低容量表面用于高分辨率动力学研究,而将高容量表面(约800RU捕获的MOSPD2)用于浓度研究、筛选和溶液亲和力确定。
通过以两倍或三倍的增量将抗体G1 Fab稀释到1μM-0.1nM的浓度范围(目的在于0.1-10倍估计的KD)来获得动力学数据。典型地以100μL/min注射样品1分钟,且解离时间至少为10分钟。每个结合循环后,在25%v/v乙醇中用25mM NaOH再生表面,这可耐受数百个循环。使用BIAevaluation程序,将整个滴定系列(通常生成一式两份)全局拟合为1:1Langmuir结合模型。这为每个结合相互作用返回了一对独特的缔合和解离动力学速率常数(分别为Kon和Koff),其比率为平衡解离常数(KD=Koff/Kon)。
抗-MOSPD2抗体可特异性结合人类MOSPD2的以下氨基酸区域的一个或多个,根据SEQ ID NO:1编号(氨基酸残基1-518):508-517,501-514,233-241,509-517,212-221,13-24,505-517,505-514,89-100,506-517,233-245,504-514,128-136,218-226,15-24,83-96,42-50,462-474,340-351,504-517,462-470,327-337,21-32,217-226,510-517,178-190,497-509,504-516,64-77,504-515,147-159,503-315,88-97,208-218,178-191,502-515,503-516,497-505,500-509,189-202,189-197,505-516,1-63,82-239,93-234,327-445,327-431,497-517,145-240,145-220,145-200,160-240,160-220,160-200,175-240,175-220,175-200,170-190,178-185,85-140,85-130,90-140,90-130,95-140,95-130,100-130,100-140,110-130,或115-127。
实施例9
另外的抗-MOSPD2抗体
按照本文或国际公开No.2017/021857中描述的方法,生成了识别一个或多个MOSPD2表位的附加抗-MOSPD2抗体。
简而言之,将本文或国际公开No.2017/021857中确定为MOSPD2表位的MOSPD2部分与人类Fc融合并固定在固体载体上。将噬菌体颗粒上存在的文库(HuCAL平台;Bio-Rad AbD Serotec,GmnH)与固定的抗原一起温育。通过广泛洗涤除去非特异性抗体,并通过添加还原剂洗脱特异性抗体噬菌体。将抗体DNA分离为库(池,pool)并且亚克隆到大肠杆菌表达载体中以产生二价F(ab')2mAb。收集种群并且在微量滴定板中生长。裂解培养物以释放抗体分子,并通过ELISA和FACS筛选特异性抗原结合。表达独特的抗体并使用一步亲和色谱法纯化,然后通过ELISA和FACS再次测试特异性。
实施例10
在各种类型的癌症中,与肿瘤等级相关增加MOSPD2表达
为了确定MOSPD2表达是否与肿瘤进展相关,如国际公开No.2017/021857中所描述的,使用抗-MOSPD2抗体筛选载有正常和不同肿瘤等级癌性组织的载玻片。以0至3的等级根据染色强度对MOSPD2丰度进行评分。如果观察到单个核心内的内异质性染色,则分配覆盖率最高的区域的分数。
图8A-8F显示了乳腺癌和对照组织中的代表性MOSPD2染色。将正常相邻组织(NAT)用作阴性对照,并且不断升级的肿瘤分期包括小叶原位癌(LCIS)、导管内原位癌(IDIS)、侵袭性导管癌(IDC)、侵袭性小叶癌(ILC)和转移性侵袭性导管癌(MIDC)。尽管代表性NAT、LCIS和IDIS染色对MOSPD2染色均呈阴性,但IDC、ILC和MIDC代表性染色显示强烈的MOSPD2阳性染色。
图9显示了侵袭性和转移性乳腺癌中MOSPD2染色强度增加。在NAT内,只有18%(2/11)的样品显示出1的染色强度,而21%(4/19)的原位癌样品(IDIS+LCIS)评分为1或2。然而,与NAT和原位癌(IDIS+LCIS)相比,侵袭性和转移性组织的分析显示,评分为2的频率更高且将染色强度提高至多达评分3。因此,ILC、IDC和MIDC的结合评分2和3的百分比分别为63%(12/19)、77%(50/65)和81%(25/31)。
MOSPD2表达还与结肠和肝组织中正常细胞向癌性细胞的转化有关。图10A-10D表明,在67%测试的结肠癌样品和45%测试的肝细胞癌样品中,存在MOSPD2阳性染色。在测试的正常结肠或肝组织中未检测到MOSPD2染色(0%)。
MOSPD2表达也与恶性肿瘤相关。图11A-11E示出了在肝细胞癌中的强MOSPD2染色,其随肿瘤级别增加,而正常和NAT样品对MOSPD2染色均呈阴性。
图12A-12B汇总了恶性肝组织或对照中MOSPD2染色的强度。与正常和NAT相比,恶性样品中的MOSPD2染色强度分别显著增加了3.2倍或4倍(p≤0.001)。图12B显示了不同阶段的肝细胞癌中MOSPD2染色强度的增加。
实施例11
抗-MOSPD2/抗-CD3双特异性抗体杀死实体瘤源性细胞并激活T细胞
将黑色素瘤(A2058)和宫颈(Hela)癌细胞系接种在48-孔板(4x104个细胞/孔)中含有10%胎牛血清(FCS)、青霉素和链霉素的RPMI-1640培养基中过夜。一天后,在存在或不存在图13A中所示浓度的抗-MOSPD2/抗-CD3双特异性抗体(BiTE)的情况下,以10:1的比率(效应细胞:T细胞)向板中加入用人T细胞激活/扩增试剂盒(Miltenyi Biotec,GmbHCat.No.130-091-441)引发的CD8效应T细胞,持续72小时。然后,收集上清液和细胞,以1,500rpm旋转5分钟,并保持冷冻直至测试。
通过酶联免疫吸附测定(ELISA)使用Duoset人类IFN-γELISA试剂盒(R&DSystems Cat.No.DY-285)测试上清液中的IFN-γ分泌。使用胰蛋白酶-EDTA(0.25%)将癌症细胞分开,使用含有10%FCS的PBS洗涤并且重悬于FACS缓冲液(PBS+2%FCS+0.02%叠氮化钠)中。每个样品通过FACS运行2分钟以评估活细胞的数量。样品运行一式三份。
图13A显示,施用增加浓度的抗-MOSPD2/抗-CD3双特异性抗体(BiTE)导致实体瘤源性细胞系存活率呈剂量依赖性降低。结果示出为平均值±标准偏差(SD)。*=P<0.01。
还分析了上清液中由T细胞分泌的IFN-γ。样品运行一式两份。
图13B和13C显示,施用增加浓度的BiTE还分别导致添加到HELA和A2058培养物中CD8效应T细胞的IFN-γ释放呈剂量依赖性增加。N.D=未检出。结果显示为三个样品的平均值±SD。
因此,在BiTE的存在下,由IFN-γ的分泌证明了T细胞被激活,并且以剂量依赖性方式介导了肿瘤细胞死亡。
实施例12
抗-MOSPD2/抗-CD3双特异性抗体杀死骨髓源性癌细胞并激活T细胞
将THP-1和U937骨髓源性癌细胞系接种在48-孔板(4x104个细胞/孔)中含有10%胎牛血清(FCS)、青霉素和链霉素的RPMI-1640培养基中过夜。使用人类全T细胞分离试剂盒(Miltenyi Biotec,GmbH Cat.No.130-096-535)从新鲜抽取的血液样品中分离T细胞。在存在或不存在10μg/ml抗-MOSPD2/抗-CD3双特异性抗体(BiTE)的情况下,以10:1的比率(效应细胞:T细胞)将T细胞添加到板中,持续48小时。然后收集上清液和细胞,以1,500rpm旋转5分钟,并且保持冷冻直到测试。
通过ELISA使用Duoset人类IFN-γELISA试剂盒(R&D Systems Cat.No.DY-285)测试上清液中的IFN-γ分泌。在FACS缓冲液中使用抗人CD3-PE(Thermo Fisher Cat.No.12-0038)和抗人CD69-APC(Thermo Fisher Cat.No.17-0699)将细胞染色30分钟。每个样品通过FACS运行2分钟,以评估活癌细胞的数量和活化的T细胞的比率。
通过酶联免疫吸附测定(ELISA)使用Duoset人类IFN-γELISA试剂盒(R&DSystems Cat.No.DY-285)测试上清液中的IFN-γ分泌。使用胰蛋白酶-EDTA(0.25%)将癌症细胞分开,使用含有10%FCS的PBS洗涤并且重悬于FACS缓冲液(PBS+2%FCS+0.02%叠氮化钠)中。在FACS缓冲液中使用抗人CD3-PE(Thermo fisher cat#12-0038)和抗人CD69-APC(Thermo fisher cat#17-0699)将细胞染色30分钟。每个样品细胞通过FACS运行两分钟,以评估活癌细胞的数量和活化的T细胞的比率。每个样品通过FACS运行2分钟以评估活细胞的数量。样品运行一式两份。
图14A显示,施用抗-MOSPD2/抗-CD3双特异性抗体(BiTE)导致单核细胞系存活降低。**=P<0.001。图14B显示了添加到THP-1和U937培养物中的T细胞的CD3和CD69染色。图14C显示,施用BiTE还导致添加到THP-1和U937培养物中的T细胞的IFN-γ释放增加。N.D=未检出。
因此,在BiTE存在下,通过CD3和CD69染色以及IFN-γ的分泌证明了T细胞被激活,并且介导了肿瘤细胞死亡。
实施例13
抗-MOSPD2/抗-CD3双特异性抗体杀死MDA-231乳腺癌细胞
以2x105个细胞/孔的浓度将预先激活的CD8+T细胞接种在48-孔板中并且在1μg/ml对照IgG抗体或抗-MOSPD2/抗CD3双特异性抗体存在下,与浓度为4x104个细胞/孔的MDA-231乳腺癌细胞一起共温育。温育24小时后,洗涤细胞并用胰蛋白酶处理。然后收集细胞并使用FAC流式细胞仪计数。图15中将所得的细胞计数示出为三个复孔的平均细胞计数±标准误差。**p<0.005;***p<0.001。图15显示,施用抗-MOSPD2/抗-CD3双特异性抗体导致乳腺癌细胞的存活显著下降。
本申请中提及的所有出版物、专利和专利申请在此都通过引用以其整体并入本说明书,其程度如同每个单独的出版物、专利或专利申请被具体且单独地指示通过引用并入本文一样。此外,本申请中对任何参考文献的引用或标识均不应解释为承认该参考文献可作为本发明的现有技术使用。就使用章节标题而言,不应将其解释为必然的限制。
序列表
<110> 脉管生物生长有限公司(VASCULAR BIOGENICS LTD.)
<120> 针对MOSPD2和T细胞或NK细胞特异性分子的双特异性抗体
<130> 3182.089PC01/GLL/LMB
<150> 62/642,339
<151> 2018-03-13
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Ile Ala Phe Trp Leu Glu Arg Tyr Ala Lys Arg Glu Asn Gly Lys Pro
130 135 140
Val Thr Val Met Phe Asp Leu Ser Glu Thr Gly Ile Asn Ser Ile Asp
145 150 155 160
Met Asp Phe Val Arg Phe Ile Ile Asn Cys Phe Lys Val Tyr Tyr Pro
165 170 175
Lys Tyr Leu Ser Lys Ile Val Ile Phe Asp Met Pro Trp Leu Met Asn
180 185 190
Ala Ala Phe Lys Ile Val Lys Thr Trp Leu Gly Pro Glu Ala Val Ser
195 200 205
Leu Leu Lys Phe Thr Ser Lys Asn Glu Val Gln Asp Tyr Val Ser Val
210 215 220
Glu Tyr Leu Pro Pro His Met Gly Gly Thr Asp Pro Phe Lys Tyr Ser
225 230 235 240
Tyr Pro Pro Leu Val Asp Asp Asp Phe Gln Thr Pro Leu Cys Glu Asn
245 250 255
Gly Pro Ile Thr Ser Glu Asp Glu Thr Ser Ser Lys Glu Asp Ile Glu
260 265 270
Ser Asp Gly Lys Glu Thr Leu Glu Thr Ile Ser Asn Glu Glu Gln Thr
275 280 285
Pro Leu Leu Lys Lys Ile Asn Pro Thr Glu Ser Thr Ser Lys Ala Glu
290 295 300
Glu Asn Glu Lys Val Asp Ser Lys Val Lys Ala Phe Lys Lys Pro Leu
305 310 315 320
Ser Val Phe Lys Gly Pro Leu Leu His Ile Ser Pro Ala Glu Glu Leu
325 330 335
Tyr Phe Gly Ser Thr Glu Ser Gly Glu Lys Lys Thr Leu Ile Val Leu
340 345 350
Thr Asn Val Thr Lys Asn Ile Val Ala Phe Lys Val Arg Thr Thr Ala
355 360 365
Pro Glu Lys Tyr Arg Val Lys Pro Ser Asn Ser Ser Cys Asp Pro Gly
370 375 380
Ala Ser Val Asp Ile Val Val Ser Pro His Gly Gly Leu Thr Val Ser
385 390 395 400
Ala Gln Asp Arg Phe Leu Ile Met Ala Ala Glu Met Glu Gln Ser Ser
405 410 415
Gly Thr Gly Pro Ala Glu Leu Thr Gln Phe Trp Lys Glu Val Pro Arg
420 425 430
Asn Lys Val Met Glu His Arg Leu Arg Cys His Thr Val Glu Ser Ser
435 440 445
Lys Pro Asn Thr Leu Thr Leu Lys Asp Asn Ala Phe Asn Met Ser Asp
450 455 460
Lys Thr Ser Glu Asp Ile Cys Leu Gln Tyr Ser
465 470 475
<210> 5
<211> 3219
<212> DNA
<213> 智人
<220>
<223> 含活动精子结构域的2, 转录变体 1, mRNA, 编码区域 125-1678
<400> 5
accgcctccc cctcccaccc ttctctgtct acctctgggc gggactgccg ggtgatgaga 60
tactcggtcg gcgacggtag aacgggcgac ggcgacaacc gcaatcacat ccacgacggt 120
gatcatggca gagaatcacg cccagaataa agccaagctc atctctgaga cccggaggag 180
gttcgaagct gagtatgtga cagataagtc agataaatat gatgcacgtg atgttgaaag 240
gctacaacaa gatgataact gggttgaaag ttacttatct tggagacata atattgtaga 300
tgaaacactg aagatgctcg atgagagttt tcagtggagg aaagaaattt ctgtcaatga 360
ccttaatgaa tcctccattc ccagatggtt attggaaatt ggtgttattt atctccatgg 420
ttatgacaaa gaaggtaaca aattgttctg gatcagggtg aagtatcatg taaaagacca 480
gaaaaccata ttggacaaaa agaagctcat agcattctgg ttggaacgtt atgctaagag 540
ggaaaatggg aaacctgtaa cagtgatgtt tgacctgtca gaaactggaa taaatagcat 600
tgacatggac tttgtacgct ttatcatcaa ctgctttaag gtttattacc ctaaatacct 660
ctcaaaaata gtgatctttg atatgccttg gttaatgaat gctgctttca aaattgtgaa 720
aacctggctt ggtccagaag cagtgagctt gttgaagttt acaagcaaaa atgaagtcca 780
ggactatgtc agtgtagaat acctgcctcc ccacatgggt ggaactgatc ctttcaagta 840
tagctatcca ccactagtag atgatgactt ccagacccca ctgtgtgaga atgggcctat 900
taccagtgag gatgaaactt caagtaaaga agacatagaa agtgatggca aagaaacatt 960
ggaaacaatt tctaatgaag aacaaacacc tcttcttaaa aagattaacc caaccgaatc 1020
tacttccaaa gcagaagaaa atgaaaaagt tgattcaaaa gtgaaagctt tcaagaaacc 1080
attgagtgta tttaaaggcc ccttactaca catcagccca gcagaagaac tgtactttgg 1140
aagtacagaa tccggagaga agaaaacctt aatagtgttg acaaatgtaa ctaaaaatat 1200
agtggcattt aaggtgagaa caacagctcc agaaaaatac agagtcaagc caagcaatag 1260
cagctgtgac ccgggtgcat cagtggatat agttgtgtct ccccatgggg gtttaacagt 1320
ctctgcccaa gaccgttttc tgataatggc tgcagaaatg gaacagtcat ctggcacagg 1380
cccagcagaa ttaactcagt tttggaaaga agttcccaga aacaaagtga tggaacatag 1440
gttaagatgc catactgttg aaagcagtaa accaaacact cttacgttaa aagacaatgc 1500
tttcaatatg tcagataaaa ccagtgaaga tatatgtcta caactcagtc gtttactaga 1560
aagcaatagg aagcttgaag accaagttca gcgttgtatc tggttccagc agctgctgct 1620
ttccttaaca atgctcttgc ttgcttttgt cacctctttc ttctatttat tgtacagtta 1680
aagaagtggt gccgggtagg aaccacggtt ccttcgtcca ttagttggaa aaagtaacag 1740
acctaaaact ctaccaagct actaaaaaca ttgcacatct gtgcttccta aaaggaaata 1800
tgcagcacgt ggaggggaac acatacatgt cttgaaaata aactgctaga ataaagaaat 1860
gctggagaaa ttgattataa gagactatag ctatttagta aagtaagtaa aggcatatcc 1920
attgtgtaaa ttaatagttt aaatataatt tattttttcc ttttgatctg aatactttta 1980
aagcttaagt tttatcgtgt aaatacatta gctaaactga aaagtataag taacatgctt 2040
tgttgcagcc aaaaaatgta atctgctttt ttatgacaga attattatag ctgagctgac 2100
ttactagctt ttctatacta tgtatataga agaacatgta tattgagaaa gaaaacatac 2160
ttatatagag gaatttatgt aaccatgact ttgtaatttt gagaattcct cccagtgatg 2220
gtcagtattc ttttggaatg taaaccgatt taatgccaaa ccaccttaac ctttgtttct 2280
cagtgttcct taacagcctg ccttttatta atctcaggct tttttatgaa cactctcatt 2340
tcagtagaat ttggaaaact aagcgtggtt ggaatttctt tgaattctgt tagtaatgcc 2400
caaaagaaaa gtctcaagca gtccccctat ccagtcattt ttatggagtt tcatgttgtc 2460
cactatagct ggacactgaa ccttttgcct aatttattat aaaggcctga ccctctattg 2520
tcccatcttc acccccattc cagagcagag gagtctctgt ggaccatgaa ttgcactgtc 2580
tccctcctca tttctaaatg aaaggtatta gatataaatt tttttgaaag gttagttgtt 2640
tgagatgcta agcaggataa taaatttaga ttttaaaatg ttccctgtaa aagtcagccc 2700
atgacaagga aatttacaaa atactagagt atctagaagg gtgaaaacaa aaaaaaataa 2760
aaagaaacac agacgcccag gtgtcagctc tccgtttaaa gaatgaaaaa tgtaactcat 2820
gatgatctgt gaaaccttca aactaggacc aattgactta cttgatattc tgcctttgat 2880
atggtagtac ccacccggta ttcctaaaat cctaaaaaga tacaccttgc agtagcagag 2940
gcaatgacat gagtttgttt tctcattaat atgaccagtt tgggtctatg ttggttcaca 3000
tgtacatcta ctttatatga aagaaaaaac agttgtctgc ctgtaaaatg ttgagtttcg 3060
attgagccat gtttggagat tttattacta ttctgaaggg tagtgttgtt ggttttcatc 3120
ttcaagaagt tgattccaaa actgagttat gaagaatgat ataacagttc cttcaaaatt 3180
ggcctaggaa ataaaacctt aaaaggacaa aaaaaaaaa 3219
<210> 6
<211> 3183
<212> DNA
<213> 智人
<220>
<223> 含活动精子结构域的2, 转录变体 2, mRNA, 编码区域 278-1642
<400> 6
agtcacaata ataggtactt aaaaacatgt catatgatag gaaactagaa taacacacct 60
ctaaataatc catggattac caacttctca gcaatggtgt aaattcttct gctaaataac 120
ccgtgggtta aagaggacat cacattggaa attccagagt acttaaaata agtcagataa 180
atatgatgca cgtgatgttg aaaggctaca acaagatgat aactgggttg aaagttactt 240
atcttggaga cataatattg tagatgaaac actgaagatg ctcgatgaga gttttcagtg 300
gaggaaagaa atttctgtca atgaccttaa tgaatcctcc attcccagat ggttattgga 360
aattggtgtt atttatctcc atggttatga caaagaaggt aacaaattgt tctggatcag 420
ggtgaagtat catgtaaaag accagaaaac catattggac aaaaagaagc tcatagcatt 480
ctggttggaa cgttatgcta agagggaaaa tgggaaacct gtaacagtga tgtttgacct 540
gtcagaaact ggaataaata gcattgacat ggactttgta cgctttatca tcaactgctt 600
taaggtttat taccctaaat acctctcaaa aatagtgatc tttgatatgc cttggttaat 660
gaatgctgct ttcaaaattg tgaaaacctg gcttggtcca gaagcagtga gcttgttgaa 720
gtttacaagc aaaaatgaag tccaggacta tgtcagtgta gaatacctgc ctccccacat 780
gggtggaact gatcctttca agtatagcta tccaccacta gtagatgatg acttccagac 840
cccactgtgt gagaatgggc ctattaccag tgaggatgaa acttcaagta aagaagacat 900
agaaagtgat ggcaaagaaa cattggaaac aatttctaat gaagaacaaa cacctcttct 960
taaaaagatt aacccaaccg aatctacttc caaagcagaa gaaaatgaaa aagttgattc 1020
aaaagtgaaa gctttcaaga aaccattgag tgtatttaaa ggccccttac tacacatcag 1080
cccagcagaa gaactgtact ttggaagtac agaatccgga gagaagaaaa ccttaatagt 1140
gttgacaaat gtaactaaaa atatagtggc atttaaggtg agaacaacag ctccagaaaa 1200
atacagagtc aagccaagca atagcagctg tgacccgggt gcatcagtgg atatagttgt 1260
gtctccccat gggggtttaa cagtctctgc ccaagaccgt tttctgataa tggctgcaga 1320
aatggaacag tcatctggca caggcccagc agaattaact cagttttgga aagaagttcc 1380
cagaaacaaa gtgatggaac ataggttaag atgccatact gttgaaagca gtaaaccaaa 1440
cactcttacg ttaaaagaca atgctttcaa tatgtcagat aaaaccagtg aagatatatg 1500
tctacaactc agtcgtttac tagaaagcaa taggaagctt gaagaccaag ttcagcgttg 1560
tatctggttc cagcagctgc tgctttcctt aacaatgctc ttgcttgctt ttgtcacctc 1620
tttcttctat ttattgtaca gttaaagaag tggtgccggg taggaaccac ggttccttcg 1680
tccattagtt ggaaaaagta acagacctaa aactctacca agctactaaa aacattgcac 1740
atctgtgctt cctaaaagga aatatgcagc acgtggaggg gaacacatac atgtcttgaa 1800
aataaactgc tagaataaag aaatgctgga gaaattgatt ataagagact atagctattt 1860
agtaaagtaa gtaaaggcat atccattgtg taaattaata gtttaaatat aatttatttt 1920
ttccttttga tctgaatact tttaaagctt aagttttatc gtgtaaatac attagctaaa 1980
ctgaaaagta taagtaacat gctttgttgc agccaaaaaa tgtaatctgc ttttttatga 2040
cagaattatt atagctgagc tgacttacta gcttttctat actatgtata tagaagaaca 2100
tgtatattga gaaagaaaac atacttatat agaggaattt atgtaaccat gactttgtaa 2160
ttttgagaat tcctcccagt gatggtcagt attcttttgg aatgtaaacc gatttaatgc 2220
caaaccacct taacctttgt ttctcagtgt tccttaacag cctgcctttt attaatctca 2280
ggctttttta tgaacactct catttcagta gaatttggaa aactaagcgt ggttggaatt 2340
tctttgaatt ctgttagtaa tgcccaaaag aaaagtctca agcagtcccc ctatccagtc 2400
atttttatgg agtttcatgt tgtccactat agctggacac tgaacctttt gcctaattta 2460
ttataaaggc ctgaccctct attgtcccat cttcaccccc attccagagc agaggagtct 2520
ctgtggacca tgaattgcac tgtctccctc ctcatttcta aatgaaaggt attagatata 2580
aatttttttg aaaggttagt tgtttgagat gctaagcagg ataataaatt tagattttaa 2640
aatgttccct gtaaaagtca gcccatgaca aggaaattta caaaatacta gagtatctag 2700
aagggtgaaa acaaaaaaaa ataaaaagaa acacagacgc ccaggtgtca gctctccgtt 2760
taaagaatga aaaatgtaac tcatgatgat ctgtgaaacc ttcaaactag gaccaattga 2820
cttacttgat attctgcctt tgatatggta gtacccaccc ggtattccta aaatcctaaa 2880
aagatacacc ttgcagtagc agaggcaatg acatgagttt gttttctcat taatatgacc 2940
agtttgggtc tatgttggtt cacatgtaca tctactttat atgaaagaaa aaacagttgt 3000
ctgcctgtaa aatgttgagt ttcgattgag ccatgtttgg agattttatt actattctga 3060
agggtagtgt tgttggtttt catcttcaag aagttgattc caaaactgag ttatgaagaa 3120
tgatataaca gttccttcaa aattggccta ggaaataaaa ccttaaaagg acaaaaaaaa 3180
aaa 3183
<210> 7
<211> 2330
<212> DNA
<213> 智人
<220>
<223> 含活动精子结构域的2, 转录变体 X1, mRNA, 编码区域 125-1582
<400> 7
accgcctccc cctcccaccc ttctctgtct acctctgggc gggactgccg ggtgatgaga 60
tactcggtcg gcgacggtag aacgggcgac ggcgacaacc gcaatcacat ccacgacggt 120
gatcatggca gagaatcacg cccagaataa agccaagctc atctctgaga cccggaggag 180
gttcgaagct gagtatgtga cagataagtc agataaatat gatgcacgtg atgttgaaag 240
gctacaacaa gatgataact gggttgaaag ttacttatct tggagacata atattgtaga 300
tgaaacactg aagatgctcg atgagagttt tcagtggagg aaagaaattt ctgtcaatga 360
ccttaatgaa tcctccattc ccagatggtt attggaaatt ggtgttattt atctccatgg 420
ttatgacaaa gaaggtaaca aattgttctg gatcagggtg aagtatcatg taaaagacca 480
gaaaaccata ttggacaaaa agaagctcat agcattctgg ttggaacgtt atgctaagag 540
ggaaaatggg aaacctgtaa cagtgatgtt tgacctgtca gaaactggaa taaatagcat 600
tgacatggac tttgtacgct ttatcatcaa ctgctttaag gtttattacc ctaaatacct 660
ctcaaaaata gtgatctttg atatgccttg gttaatgaat gctgctttca aaattgtgaa 720
aacctggctt ggtccagaag cagtgagctt gttgaagttt acaagcaaaa atgaagtcca 780
ggactatgtc agtgtagaat acctgcctcc ccacatgggt ggaactgatc ctttcaagta 840
tagctatcca ccactagtag atgatgactt ccagacccca ctgtgtgaga atgggcctat 900
taccagtgag gatgaaactt caagtaaaga agacatagaa agtgatggca aagaaacatt 960
ggaaacaatt tctaatgaag aacaaacacc tcttcttaaa aagattaacc caaccgaatc 1020
tacttccaaa gcagaagaaa atgaaaaagt tgattcaaaa gtgaaagctt tcaagaaacc 1080
attgagtgta tttaaaggcc ccttactaca catcagccca gcagaagaac tgtactttgg 1140
aagtacagaa tccggagaga agaaaacctt aatagtgttg acaaatgtaa ctaaaaatat 1200
agtggcattt aaggtgagaa caacagctcc agaaaaatac agagtcaagc caagcaatag 1260
cagctgtgac ccgggtgcat cagtggatat agttgtgtct ccccatgggg gtttaacagt 1320
ctctgcccaa gaccgttttc tgataatggc tgcagaaatg gaacagtcat ctggcacagg 1380
cccagcagaa ttaactcagt tttggaaaga agttcccaga aacaaagtga tggaacatag 1440
gttaagatgc catactgttg aaagcagtaa accaaacact cttacgttaa aagacaatgc 1500
tttcaatatg tcagataaaa ccagtgaaga tatatgtcta caatttgcca cctccagctg 1560
tgaaatggac tgcagtccac cctaagtact gtgcacagta tctccctgtg tgtgtgcaca 1620
gtggcttccc cttacatggt agatttttgg ccttaatata atctaatccc aaagtagttg 1680
tgtatgtttt ctgttccttg gcaaataaat gaagaaataa ttagccaaga ttgaaaatgt 1740
attgtcctaa cggtgtccct ttaatgtttc atatgaaaaa ttatgttgac ccactaaaat 1800
atccttgctc aatgtctggt cagttgaatt taataacata tcttgttaat gtttgtgtgt 1860
ctattaaatg tgactaagca ggattactga aaattcacta taaaatcaaa ggcatctaaa 1920
cgtttgtact tgtcttgatt aatcatatat ttacacttga tttttttctg tcttcatttg 1980
tttttattta atcataattg catgattttt ttggtactct aatcagtaat tttattttta 2040
atcatgtcat tacctattca tgaccaaatt accaaggaac caacatttag atttagatat 2100
ttgttttcac ttaggaatgg aaattaatag attttccatg aaagcattag tgaaatatca 2160
ttaccttgat ctgcaagtag cctaaaaatg cgattgctgg taaacctggc ctcaaatttc 2220
atactaccat aactgttttt atatattgcc actaattttg actggattta atagcacttt 2280
attgtacaac tacaaaaaaa aatatattcc tagaattgtt gccagtgtaa 2330
<210> 8
<211> 3909
<212> DNA
<213> 智人
<220>
<223> 含活动精子结构域的2, 转录变体 X2, mRNA, 编码区域 125-1549
<400> 8
accgcctccc cctcccaccc ttctctgtct acctctgggc gggactgccg ggtgatgaga 60
tactcggtcg gcgacggtag aacgggcgac ggcgacaacc gcaatcacat ccacgacggt 120
gatcatggca gagaatcacg cccagaataa agccaagctc atctctgaga cccggaggag 180
gttcgaagct gagtatgtga cagataagtc agataaatat gatgcacgtg atgttgaaag 240
gctacaacaa gatgataact gggttgaaag ttacttatct tggagacata atattgtaga 300
tgaaacactg aagatgctcg atgagagttt tcagtggagg aaagaaattt ctgtcaatga 360
ccttaatgaa tcctccattc ccagatggtt attggaaatt ggtgttattt atctccatgg 420
ttatgacaaa gaaggtaaca aattgttctg gatcagggtg aagtatcatg taaaagacca 480
gaaaaccata ttggacaaaa agaagctcat agcattctgg ttggaacgtt atgctaagag 540
ggaaaatggg aaacctgtaa cagtgatgtt tgacctgtca gaaactggaa taaatagcat 600
tgacatggac tttgtacgct ttatcatcaa ctgctttaag gtttattacc ctaaatacct 660
ctcaaaaata gtgatctttg atatgccttg gttaatgaat gctgctttca aaattgtgaa 720
aacctggctt ggtccagaag cagtgagctt gttgaagttt acaagcaaaa atgaagtcca 780
ggactatgtc agtgtagaat acctgcctcc ccacatgggt ggaactgatc ctttcaagta 840
tagctatcca ccactagtag atgatgactt ccagacccca ctgtgtgaga atgggcctat 900
taccagtgag gatgaaactt caagtaaaga agacatagaa agtgatggca aagaaacatt 960
ggaaacaatt tctaatgaag aacaaacacc tcttcttaaa aagattaacc caaccgaatc 1020
tacttccaaa gcagaagaaa atgaaaaagt tgattcaaaa gtgaaagctt tcaagaaacc 1080
attgagtgta tttaaaggcc ccttactaca catcagccca gcagaagaac tgtactttgg 1140
aagtacagaa tccggagaga agaaaacctt aatagtgttg acaaatgtaa ctaaaaatat 1200
agtggcattt aaggtgagaa caacagctcc agaaaaatac agagtcaagc caagcaatag 1260
cagctgtgac ccgggtgcat cagtggatat agttgtgtct ccccatgggg gtttaacagt 1320
ctctgcccaa gaccgttttc tgataatggc tgcagaaatg gaacagtcat ctggcacagg 1380
cccagcagaa ttaactcagt tttggaaaga agttcccaga aacaaagtga tggaacatag 1440
gttaagatgc catactgttg aaagcagtaa accaaacact cttacgttaa aagacaatgc 1500
tttcaatatg tcagataaaa ccagtgaaga tatatgtcta caatacagtt aaagaagtgg 1560
tgccgggtag gaaccacggt tccttcgtcc attagttgga aaaagtaaca gacctaaaac 1620
tctaccaagc tactaaaaac attgcacatc tgtgcttcct aaaaggaaat atgcagcacg 1680
tggaggggaa cacatacatg tcttgaaaat aaactgctag aataaagaaa tgctggagaa 1740
attgattata agagactata gctatttagt aaagtaagta aaggcatatc cattgtgtaa 1800
attaatagtt taaatataat ttattttttc cttttgatct gaatactttt aaagcttaag 1860
ttttatcgtg taaatacatt agctaaactg aaaagtataa gtaacatgct ttgttgcagc 1920
caaaaaatgt aatctgcttt tttatgacag aattattata gctgagctga cttactagct 1980
tttctatact atgtatatag aagaacatgt atattgagaa agaaaacata cttatataga 2040
ggaatttatg taaccatgac tttgtaattt tgagaattcc tcccagtgat ggtcagtatt 2100
cttttggaat gtaaaccgat ttaatgccaa accaccttaa cctttgtttc tcagtgttcc 2160
ttaacagcct gccttttatt aatctcaggc ttttttatga acactctcat ttcagtagaa 2220
tttggaaaac taagcgtggt tggaatttct ttgaattctg ttagtaatgc ccaaaagaaa 2280
agtctcaagc agtcccccta tccagtcatt tttatggagt ttcatgttgt ccactatagc 2340
tggacactga accttttgcc taatttatta taaaggcctg accctctatt gtcccatctt 2400
cacccccatt ccagagcaga ggagtctctg tggaccatga attgcactgt ctccctcctc 2460
atttctaaat gaaaggtatt agatataaat ttttttgaaa ggttagttgt ttgagatgct 2520
aagcaggata ataaatttag attttaaaat gttccctgta aaagtcagcc catgacaagg 2580
aaatttacaa aatactagag tatctagaag ggtgaaaaca aaaaaaaata aaaagaaaca 2640
cagacgccca ggtgtcagct ctccgtttaa agaatgaaaa atgtaactca tgatgatctg 2700
tgaaaccttc aaactaggac caattgactt acttgatatt ctgcctttga tatggtagta 2760
cccacccggt attcctaaaa tcctaaaaag atacaccttg cagtagcaga ggcaatgaca 2820
tgagtttgtt ttctcattaa tatgaccagt ttgggtctat gttggttcac atgtacatct 2880
actttatatg aaagaaaaaa cagttgtctg cctgtaaaat gttgagtttc gattgagcca 2940
tgtttggaga ttttattact attctgaagg gtagtgttgt tggttttcat cttcaagaag 3000
ttgattccaa aactgagtta tgaagaatga tataacagtt ccttcaaaat tggcctagga 3060
aataaaacct taaaaggaca ctggtgtgct actttgtctt aatttgggct tttctgtttc 3120
agtttgccac ctccagctgt gaaatggact gcagtccacc ctaagtactg tgcacagtat 3180
ctccctgtgt gtgtgcacag tggcttcccc ttacatggta gatttttggc cttaatataa 3240
tctaatccca aagtagttgt gtatgttttc tgttccttgg caaataaatg aagaaataat 3300
tagccaagat tgaaaatgta ttgtcctaac ggtgtccctt taatgtttca tatgaaaaat 3360
tatgttgacc cactaaaata tccttgctca atgtctggtc agttgaattt aataacatat 3420
cttgttaatg tttgtgtgtc tattaaatgt gactaagcag gattactgaa aattcactat 3480
aaaatcaaag gcatctaaac gtttgtactt gtcttgatta atcatatatt tacacttgat 3540
ttttttctgt cttcatttgt ttttatttaa tcataattgc atgatttttt tggtactcta 3600
atcagtaatt ttatttttaa tcatgtcatt acctattcat gaccaaatta ccaaggaacc 3660
aacatttaga tttagatatt tgttttcact taggaatgga aattaataga ttttccatga 3720
aagcattagt gaaatatcat taccttgatc tgcaagtagc ctaaaaatgc gattgctggt 3780
aaacctggcc tcaaatttca tactaccata actgttttta tatattgcca ctaattttga 3840
ctggatttaa tagcacttta ttgtacaact acaaaaaaaa atatattcct agaattgttg 3900
ccagtgtaa 3909
Claims (53)
1.一种双特异性抗体或其抗原结合片段,包含(i)针对MOSPD2的一种或多种抗原结合结构域,和(ii)针对T细胞或NK细胞特异性受体分子的一种或多种抗原结合结构域。
2.根据权利要求1所述的双特异性抗体或其抗原结合片段,其中所述T细胞或NK细胞特异性受体分子是CD3、T细胞受体(TCR)、CD28、CD16、NKG2D、Ox40、4-1BB、CD2、CD5或CD95。
3.根据权利要求1或2所述的双特异性抗体或其抗原结合片段,其中所述针对MOSPD2的一种或多种抗原结合结构域是抗MOSPD2抗体或其抗原结合片段的Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、互补决定区(CDR)、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。
4.根据权利要求1至3中任一项所述的双特异性抗体或其抗原结合片段,其中所述T细胞或NK细胞特异性受体分子是CD3并且针对CD3的一种或多种抗原结合结构域是抗CD3抗体或其抗原结合片段的Fab、Fab'、F(ab')2、Fv、scFv、sdFv片段、重链可变区、轻链可变区、CDR、重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2或轻链CDR3。
5.根据权利要求1至4中任一项所述的双特异性抗体或其抗原结合片段,包含下列抗原结合结构域中的一种或多种:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;和
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区。
6.根据权利要求1至5中任一项所述的双特异性抗体或其抗原结合片段,包含下列抗原结合结构域中的一种或多种:
(i)抗CD3抗体或其抗原结合片段的重链可变区;和
(ii)抗CD3抗体或其抗原结合片段的轻链可变区。
7.根据权利要求1至6中任一项所述的双特异性抗体或其抗原结合片段,包含以下抗原结合结构域:
(i)抗MOSPD2抗体或其抗原结合片段的重链可变区;
(ii)抗MOSPD2抗体或其抗原结合片段的轻链可变区;
(iii)抗CD3抗体或其抗原结合片段的重链可变区;和
(iv)抗CD3抗体或其抗原结合片段的轻链可变区。
8.根据权利要求1至7中任一项所述的双特异性抗体或其抗原结合片段,其中所述抗原结合结构域中的一种或多种由肽接头连接。
9.根据权利要求1至8中任一项所述的双特异性抗体或其抗原结合片段,其中至少一种抗原结合结构域是人类的。
10.根据权利要求1至8中任一项所述的双特异性抗体或其抗原结合片段,其中至少一种抗原结合结构域是人源化的。
11.根据权利要求1至10中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或其抗原结合片段是单链多肽。
12.根据权利要求1至11中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或其抗原结合片段的分子量不超过约60,000道尔顿。
13.根据权利要求1至12中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体是纳米抗体、双抗体、Duobody、CrossMab、二价抗体、双特异性T细胞衔接子(BiTE)、双亲和重靶向体(DART)、三体、微型抗体、TriBi微型抗体、内体或四价体。
14.根据权利要求1至13中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或其抗原结合片段以约10-6M至约10-12M的平衡解离常数(KD)特异性结合MOSPD2和/或CD3。
15.根据权利要求1至14中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域特异性结合SEQID NO:1-4中的一个或多个或其功能变体。
16.根据权利要求1至15中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域特异性结合由SEQ ID NO:5-8中一个或多个或其功能变体编码的多肽。
17.根据权利要求1至16中任一项所述的双特异性抗体或其抗原结合片段,其中所述双特异性抗体或抗原结合片段、或针对MOSPD2的一种或多种抗原结合结构域以约10-6M至约10-12M的KD特异性结合MOSPD2。
18.一种药物组合物,包含权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段以及药学上可接受的载体。
19.根据权利要求18所述的药物组合物,适用于全身给药。
20.根据权利要求18所述的药物组合物,适用于局部给药。
21.根据权利要求18所述的药物组合物,适用于口服给药。
22.根据权利要求18所述的药物组合物,适用于鼻腔给药。
23.根据权利要求18所述的药物组合物,适用于腹膜内给药。
24.根据权利要求18所述的药物组合物,适用于肿瘤内给药。
25.根据权利要求18所述的药物组合物,适用于静脉内给药。
26.根据权利要求18所述的药物组合物,适用于肌内给药。
27.根据权利要求18所述的药物组合物,适用于皮下给药。
28.一种在受试者中治疗或预防癌症的方法,包括以有效量给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物,以治疗或预防癌症。
29.一种在受试者中治疗或预防癌症转移的方法,包括以有效量给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物,以治疗或预防癌症转移。
30.根据权利要求28或29所述的方法,进一步包括给予所述受试者有效量的抗癌药。
31.根据权利要求30所述的方法,其中所述抗癌药是醋酸阿比特龙、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(维布本妥昔单抗)、ADE、阿多曲妥珠单抗-美坦新、阿霉素(盐酸多柔比星)、Adrucil(氟尿嘧啶)、马来酸阿法替尼、飞尼妥(依维莫司)、Akynzeo(奈妥吡坦和帕洛诺司琼盐酸盐)、艾达乐(咪喹莫特)、阿地白介素、阿仑单抗、爱宁达(培美曲塞二钠)、阿乐喜(盐酸帕洛诺司琼)、Ambochlorin(苯丁酸氮芥)、Amboclorin(苯丁酸氮芥)、氨基乙酰丙酸、阿那曲唑、阿瑞匹坦、阿可达(帕米膦酸二钠)、安美达锭(阿那曲唑)、阿诺新(依西美坦)、Arranon(奈拉滨)、三氧化二砷、Arzerra(奥法木单抗)、天冬酰胺酶菊欧文氏菌、安维汀(贝伐单抗)、阿昔替尼、阿扎胞苷、BEACOPP、Becenum(卡莫司汀)、Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、贝伐单抗、贝沙罗汀、百克沙(托西莫单抗和I 131碘托西莫单抗)、比卡鲁胺、BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、维布本妥昔单抗、白消安、白舒非(白消安)、卡巴他赛、卡波替尼-S-苹果酸、CAF、坎帕斯(阿仑单抗)、开普拓(盐酸伊立替康)、卡培他滨、CAPOX、卡铂、卡铂-紫杉酚、卡非佐米、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀植入物、康士得(比卡鲁胺)、CeeNU(洛莫司汀)、色瑞替尼、Cerubidine(盐酸柔红霉素)、希瑞适(重组HPV二价疫苗)、西妥昔单抗、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂、Clafen(环磷酰胺)、氯法拉滨、CMF、Cometriq(卡波替尼-S-苹果酸)、COPP、COPP-ABV、Cosmegen(更生霉素)、克唑替尼、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗)、阿糖孢苷、阿糖孢苷、脂质体、Cytosar-U(阿糖孢苷)、Cytoxan(环磷酰胺)、达拉菲尼、达卡巴嗪、达克金(地西他滨)、更生霉素、达沙替尼、盐酸柔红霉素、地西他滨、地加瑞克、地尼白介素、狄诺塞麦、DepoCyt(脂质体阿糖孢苷)、DepoFoam(脂质体阿糖孢苷)、盐酸右雷佐生、地努图希单抗、多西他赛、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、Efudex(氟尿嘧啶)、埃立特(拉布立酶)、Ellence(盐酸表柔比星)、乐沙定(奥沙利铂)、艾曲波帕乙醇胺、Emend(阿瑞匹坦)、恩杂鲁胺、盐酸表柔比星、EPOCH、爱必妥(西妥昔单抗)、甲磺酸艾日布林、Erivedge(维莫德吉)、埃罗替尼盐酸盐、Erwinaze(天冬酰胺酶菊欧文氏菌)、Etopophos(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、易维特(盐酸雷洛昔芬)、依西美坦、法乐通(托瑞米芬)、Farydak(帕比司他)、芙仕得(氟维司群)、FEC、弗隆(来曲唑)、非格司亭、福达华(磷酸氟达拉滨)、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶)、氟尿嘧啶、Folex(甲氨蝶呤)、FolexPFS(甲氨蝶呤)、伊立替康、伊立替康-贝伐单抗、伊立替康-西妥昔单抗、Folfirinox、Folflox、Folotyn(普拉曲沙)、FU-LV、氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗)、Gazyva(奥比努珠单抗)、吉非替尼、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥单抗唑加米星、健择(盐酸吉西他滨)、Gilotrif(马来酸阿法替尼)、格列卫(甲磺酸伊马替尼)、格立得(卡莫司汀植入物)、格立得薄片(卡莫司汀植入物)、羧肽酶、醋酸戈舍瑞林、Halaven(甲磺酸艾日布林)、赫塞汀(曲妥珠单抗)、HPV二价疫苗重组体、HPV九价疫苗重组体、HPV四价疫苗重组体、美新(盐酸拓扑替康)、Hyper-CVAD、Ibrance(帕博西尼)、替伊莫单抗、依鲁替尼、ICE、Iclusig(盐酸波纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、甲磺酸伊马替尼、Imbruvica(依鲁替尼)、咪喹莫特、英立达(阿昔替尼)、Intron A(重组干扰素Alfa-2b)、碘131托西单抗和托西单抗、易普利姆玛、易瑞沙(吉非替尼)、盐酸伊立替康、Istodax(罗米地辛)、伊沙匹隆、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索替尼)、Jevtana(卡巴他赛)、Kadcyla(阿多曲妥珠单抗-美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明)、Keytruda(派姆单抗)、Kyprolis(卡非佐米)、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、来那度胺、甲磺酸乐伐替尼、Lenvima(甲磺酸乐伐替尼)、来曲唑、亚叶酸钙、瘤可宁(苯丁酸氮芥)、醋酸亮丙瑞林、Levulan(氨基乙酰丙酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、脂质体阿糖孢苷、洛莫司汀、Lupron(醋酸亮丙瑞林)、Lupron Depot(醋酸亮丙瑞林)、Lupron Depot-Ped(醋酸亮丙瑞林)、Lupron Depot-3个月(醋酸亮丙瑞林)、Lupron Depot-4个月(醋酸亮丙瑞林)、Lynparza(奥拉帕尼)、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸丙卡巴嗪)、盐酸氮芥、梅格施(醋酸甲地孕酮)、醋酸甲地孕酮、Mekinist(曲美替尼)、巯基嘌呤、美司钠、Mesnex(美司钠)、Methazolastone(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福)、Mustargen(盐酸氮芥)、密吐霉素(丝裂霉素C)、马勒兰(白消安)、Mylosar(阿扎胞苷)、麦罗塔(吉妥单抗唑加米星)、纳米粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、诺维本(酒石酸长春瑞滨)、奈拉滨、Neosar(环磷酰胺)、奈妥吡坦和帕洛诺司琼盐酸盐、优保津(非格司亭)、蕾莎瓦(甲苯磺酸索拉非尼)、尼罗替尼、纳武单抗、诺瓦得士(枸橼酸他莫昔芬)、Nplate(罗米司亭)、奥比努珠单抗、OEPA、奥法木单抗、OFF、奥拉帕尼、高三尖杉酯碱、Oncaspar(培门冬酶)、Ontak(地尼白介素)、欧狄沃(纳武单抗)、OPPA、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、帕米膦酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、伯尔定(卡铂)、盐酸帕唑帕尼、培门冬酶、聚乙二醇干扰素Alfa-2b、PEG-Intron(聚乙二醇干扰素Alfa-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸波纳替尼、普拉曲沙、强的松、盐酸丙卡巴嗪、Proleukin(阿地白介素)、普罗利亚(狄诺塞麦)、Promacta(艾曲波帕乙醇胺)、普列威(Sipuleucel-T)、Purinethol(巯基嘌呤)、Purixan(巯基嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素Alfa-2b、瑞戈非尼、R-EPOCH、雷利米得(来那度胺)、Rheumatrex(甲氨蝶呤)、美罗华(利妥昔单抗)、利妥昔单抗、罗米地辛、罗米司亭、红比霉素(盐酸柔红霉素)、磷酸鲁索替尼、硬化性胸膜内气雾剂(滑石粉)、司妥昔单抗、Sipuleucel-T、索马杜林Depot(醋酸兰瑞肽)、甲苯磺酸索拉非尼、施达赛(达沙替尼)、STANFORD V、无菌滑石粉粉末(滑石粉)、无菌滑石粉(滑石粉)、Stivarga(瑞戈非尼)、苹果酸舒尼替尼、索坦(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素Alfa-2b)、Sylvant(司妥昔单抗)、昔诺韦(萨力多胺)、Synribo(高三尖杉酯碱)、TAC、Tafinlar(达拉菲尼)、滑石粉、枸橼酸他莫昔芬、Tarabine PFS(阿糖孢苷)、特罗凯(埃罗替尼盐酸盐)、Targretin(贝沙罗汀)、泰息安(尼罗替尼)、紫杉酚(紫杉醇)、泰索帝(多西他赛)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司、萨力多胺、Thalomid(萨力多胺)、噻替派、Toposar(依托泊苷)、盐酸拓扑替康、托瑞米芬、驮瑞塞尔(替西罗莫司)、托西莫单抗和I 131碘托西莫单抗、Totect(盐酸右雷佐生)、TPF、曲美替尼、曲妥珠单抗、存达(盐酸苯达莫司汀)、Trisenox(三氧化二砷)、泰立沙(二甲苯磺酸拉帕替尼)、Unituxin(地努图希单抗)、凡德他尼、VAMP、Vectibix(帕尼单抗)、VeIP、Velban(硫酸长春碱)、万珂(硼替佐米)、Velsar(硫酸长春碱)、维莫非尼、凡毕士(依托泊苷)、Viadur(醋酸亮丙瑞林)、维达扎(阿扎胞苷)、硫酸长春碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉、Voraxaze(羧肽酶)、伏立诺他、Votrient(盐酸帕唑帕尼)、Wellcovorin(亚叶酸钙)、赛可瑞(克唑替尼)、希罗达(卡培他滨)、XELIRI、XELOX、Xgeva(狄诺塞麦)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(易普利姆玛)、Zaltrap(齐夫-阿柏西普)、泽波拉夫(维莫非尼)、泽娃灵(替伊莫单抗)、Zinecard(盐酸右雷佐生)、齐夫-阿柏西普、诺雷德(醋酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、择泰(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)或Zytiga(醋酸阿比特龙)。
32.一种用于在受试者中抑制或减少肿瘤细胞的方法,包括给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
33.根据权利要求32所述的方法,其中与对照或参考值相比,所述肿瘤细胞的数量减少至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或至少约100%。
34.一种在受试者中增加表达CD3的细胞产生细胞因子的方法,包括给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
35.一种增加T细胞中IL-2、CD69和/或IFN-γ产生或浓度的方法,包括使所述T细胞接触权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
36.根据权利要求35所述的方法,其中与对照或参考值相比,IFN-γ产生增加至少约100%、至少约200%、至少约300%、至少约400%、至少约500%、至少约600%、至少约700%、至少约800%、至少约900%或至少约1000%。
37.根据权利要求35所述的方法,其中与对照或参考值相比,IFN-γ浓度增加至少约1000pg/ml、至少约2000pg/ml、至少约3000pg/ml、至少约4000pg/ml、至少约5000pg/ml、至少约6000pg/ml、至少约7000pg/ml、至少约8000pg/ml、至少约9000pg/ml或至少约10000pg/ml。
38.根据权利要求35所述的方法,其中与对照或参考值相比,CD69产生增加至少约1%、至少约2%、至少约3%、至少约4%、至少约5%、至少约6%、至少约7%、至少约8%、至少约9%、至少约10%、至少约15%、至少约20%、至少约25%或至少约30%。
39.一种刺激受试者中免疫应答的方法,包括给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
40.一种在受试者中刺激针对癌细胞的T细胞介导的细胞毒性免疫应答的方法,包括给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
41.一种增加T细胞增殖的方法,包括使T细胞接触权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
42.一种减少或耗尽受试者肿瘤中T调节细胞数量的方法,包括给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物。
43.一种用于预测、诊断或预后受试者中癌症或癌症转移的方法,包括使用权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段确定所述受试者的样品中的MOSPD2表达水平。
44.根据权利要求43所述的方法,包括(i)使用权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段确定或量化所述受试者的样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于所述对照或参考值,增加的MOSPD2表达水平指示癌症、患癌症的风险增加或癌症预后不良。
45.一种用于预测、诊断或预后受试者中肿瘤进展或肿瘤侵袭性的方法,包括使用权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段确定所述受试者的样品中的MOSPD2表达水平。
46.根据权利要求45所述的方法,包括(i)使用权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段确定或量化所述受试者的样品中的MOSPD2表达水平,和(ii)将步骤(i)中获得的表达水平与对照或参考值进行比较,其中相对于所述对照或参考值,增加的MOSPD2表达水平指示肿瘤进展或肿瘤侵袭性预后不良。
47.根据权利要求43至46中任一项所述的方法,进一步包括下列步骤中的一个或多个:
指示实验室量化样品中的MOSPD2表达水平;
从实验室获得样品中MOSPD2表达水平的报告;和/或
给予所述受试者治疗有效量的MOSPD2的抑制剂。
48.根据权利要求43至47中任一项所述的方法,其中所述样品是来自所述受试者的组织活检、肿瘤活检或血液样品。
49.根据权利要求43至48中任一项所述的方法,其中对照或参考值是正常组织或正常相邻组织(NAT)中的MOSPD2表达水平。
50.根据权利要求43至48中任一项所述的方法,其中对照或参考值是没有可检测的MOSPD2表达或没有显著的MOSPD2表达。
51.一种用于在受试者中治疗或预防MOSPD2表达肿瘤的方法,包括以有效量给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物,以治疗或预防MOSPD2表达肿瘤。
52.一种用于在受试者中治疗或预防具有MOSPD2表达肿瘤相关巨噬细胞的肿瘤的方法,包括以有效量给予所述受试者权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物,以治疗或预防具有MOSPD2表达肿瘤相关巨噬细胞的肿瘤。
53.一种试剂盒,包含(i)权利要求1至17中任一项所述的双特异性抗体或其抗原结合片段或权利要求18至27中任一项所述的药物组合物,和(ii)使用说明。
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