CN117715654A - 包含抗-cd205抗体和免疫检查点抑制剂的药物组合 - Google Patents
包含抗-cd205抗体和免疫检查点抑制剂的药物组合 Download PDFInfo
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Abstract
本发明涉及增加患有癌症的患者中的抗肿瘤免疫反应的方法,治疗或预防癌症的方法,和增强PD1/PD‑L1相互作用的抑制剂的有效性的方法。还提供了药物组合,其包括(a)针对CD205的抗体或其抗原结合部分,和(b)PD1/PD‑L1检查点抑制剂。
Description
技术领域
本公开总体涉及免疫学和分子生物学领域。更具体地,本文提供了增加患有癌症的患者中的抗肿瘤免疫反应的方法,更具体地,增加T细胞介导的肿瘤特异性反应或T细胞数量的方法,用于治疗或预防癌症的方法,以及增强PD1/PD-L1相互作用抑制剂的有效性的方法。还提供了药物组合,其包括(a)针对CD205的抗体或其抗原结合部分,和(b)PD1/PD-L1检查点抑制剂。
背景技术
树突细胞(DC)在起始针对外源和内源抗原的免疫反应中发挥重要作用。有两种类型DC,其具有不同起源和功能:髓样树突细胞(mDC)和浆细胞样树突细胞(pDC)。mDC和pDC都能够高效诱导针对病原体的CD4+和CD8+T细胞反应,并且都能够与自然杀伤(NK)细胞相互作用。CD4+、CD8+和NK细胞在免疫介导的抗癌反应中发挥重要作用。然而,pDC和mDC也可以通过诱导调节性T细胞(Treg)诱导对癌症的耐受性(Ito等JEM,[2007]),进而阻止T细胞增殖和T细胞激活。
Liu,X等(Journal of Cancer,[2019],第10卷,第6711-6715页)公开了Treg和pDC是胃癌肿瘤微环境中的主要免疫抑制细胞。他们表明,在各个区室中,与具有低pDC量的患者相比,胃癌组织和外周血中pDC数量都偏高的患者具有更短的总生存期。由于DC在癌症组织中的存在,在乳腺癌、卵巢癌和肾癌中也描述了类似的对癌症患者生存的负面影响。
CD205(也称为DEC205和淋巴细胞抗原75)被DC用作自身和外源抗原呈递的内吞受体以诱导免疫反应或免疫耐受。CD205在CD8+mDC和CD8+pDC上都表达(Shrimpton等,2009)CD205区分两种主要类型的DC。CD8+/CD205+DC驻留在淋巴器官的T细胞区,CD8-/33D1+DC驻留在红髓中和边缘区(Dudziak等Science第315期第107-111页[2007]。据报道,CD8+
CD205+DC选择性诱导免疫抑制性Treg(Yamazaki等,2008;Okeke和Uzonna,2019;Simon和Bromberg,2016;Kushwah和Hu,2011)以及Treg细胞在血液中的形成与所有CD11c+DC中CD8+CD205+DC的比例相关(Simon和Bromberg,2016)。已知Treg抑制肿瘤CD8+或特异性细胞毒性T细胞(Chen等2005;Li等2020)。
WO2009/061996公开了基于与人CD205结合的分离的单克隆抗体和相关抗体的组合物和分子。还公开了包含该抗体的药物组合物,以及使用该抗体的治疗和诊断方法。
WO2008/104806公开了能够结合CD205的亲和试剂用于癌症的治疗或预防。
WO2015/052537公开了能够结合CD205的特异性分离的抗体及其在治疗多种癌症中的用途。
程序性细胞死亡1(PD1)和程序性细胞死亡配体1(PD-L1)是免疫检查点蛋白,其相互作用在限制T细胞活性中发挥重要作用,它们提供了主要免疫抵抗机制,肿瘤细胞通过这种机制逃避免疫监视。
多种针对PD-1/PD-L1通路的试剂已经被开发出来,并已被证明可有效治疗多种癌症类型。
近年来,开展了大量涉及PD-1/PD-L1检查点抑制剂与大范围其他试剂的组合的临床试验。其中大多数是PD1与CTLA4、血管生成抑制剂或化疗剂的组合。这些试验的结果显示出了多种结果(Schmidt,E.V.,Semin Immunopathol;41(1),21-30[2019])。
胃癌是消化系统最常见的恶性肿瘤之一,是发病率和死亡率位居前5的恶性肿瘤之一。晚期胃癌目前的治疗选择有限,一线治疗是化疗。曲妥珠单抗和雷莫芦单抗已经分别被批准用于一线治疗失败的HER-2和VEGF阳性肿瘤。全球胃癌的总生存率仅为~20%。单药免疫检查点抑制剂已经被证明对胃癌有一定效力,但效率较差(Song,X.,等Oncologyletters,20(4),[2020])。
子宫内膜癌是美国最常见的妇科癌症,每年约50,000名女性被诊断出。目前使用放疗、化疗或激素疗法治疗晚期子宫内膜癌。然而,需要开发新的靶向疗法以治疗难治性或复发性疾病。
发明内容
本发明是基于发明人令人惊喜的发现,即在特定群体的CD205+免疫调节细胞被耗竭的癌症患者中,观察到外周血中CD4+和CD8+T细胞的数量都显著增加。发明人还发现,随着此种T细胞数量增加,还观察到表达PD1的CD4+和CD8+T细胞的数量都显著增加。
发明人还观察到,患者血样中存在pDC的绝对数量在用CD205-DM4抗体药物偶联物(ADC)治疗后最初迅速下降,随后在治疗后第21天补充并翻倍。在CD205+pDC细胞中观察到相同的模式。在CD205+mDC细胞中也观察到类似的模式,在用CD205-DM4 ADC治疗后,下降到第8天,但随后在第21天时变成四倍。
发明人相信,CD205+免疫调节细胞的耗竭和随后的CD4+和CD8+T细胞的增加增强了患者对肿瘤的免疫反应。他们进一步假设,随着CD4+和CD8+T细胞数量增加,在CD205+免疫调节细胞耗竭后,T细胞被激活。发明人还假设观察到的CD205+pDC群的耗竭逆转了经CD205-DM4 ADC治疗的患者中的免疫抑制。如上所述,Liu等人的公开支持了这一点,这表明pDC是胃癌肿瘤微环境中主要的免疫抑制细胞,与更短的总生存期相关。由于PD1/PD-L1表达显著增加,可以通过给予防止免疫抑制的免疫检查点抑制剂延长增强的免疫反应。
根据本发明的第一方面,提供了用于治疗或预防癌症的方法,其包括向有需要的患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及治疗有效量的包含检查点抑制剂的组合物。
对于本领域技术人员显而易见的是,调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及包含检查点抑制剂的组合物可以同时、分开或依次给予,优选依次给予。
在一个实施方式中,检查点抑制剂是针对选自下组的检查点蛋白:PD1、PD-L1、PD-L2、CTLA-4、ICOS、TIGIT、CD28、TMIGD2、CD137、CD137L、CD27、OX40、OX40L、LAG3、VISTA、GITR、DNAM-1、CD96、2B4、TIM-3、CEACAM、CRTAM、SLAMF6、半乳凝素-9、CD48、CD155、GITRL、CD40、CD40L、CD70、HVEM、B7-H7、B7-H3、B7-H4、ICOSL、CD80、CD86、BTLA、CD160、LIGHT、腺苷A2a受体、SIRPα、DC-SIGN、CD200R、DR3、TL1A、CD200、BTN2A1、CD47、IDO、TDO。
在一个实施方式中,检查点抑制剂是PD1或PD-Ll的,优选PD1的。
根据本发明的第二方面,提供了增强PD1/PD-L1抑制剂在被鉴定为有需要的患者中的有效性的方法,所述方法包括向所述患者给予(a)治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及(b)包含PD1/PD-L1相互作用抑制剂的组合物。
对于本领域技术人员显而易见的是,调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及包含PD1/PD-L1相互作用抑制剂的组合物可以同时、分开或依次给予,优选依次给予。
对于本领域技术人员显而易见的是,本文所用术语增强意指免疫检查点抑制剂的有效性水平增加,使得在CD205+免疫调节细胞群的调节之后观察到比耗竭之前更高的细胞毒性水平,或增加免疫检查点抑制剂有效的时间段。可以认为,给予调节CD205+免疫调节细胞群体的抗体或其抗原结合片段起到引发免疫系统表达免疫检查点蛋白的作用。因此,免疫检查点抑制剂的给予将产生更高和/或延长的细胞毒性。
根据本发明的第三方面,提供了一种用于增加患癌患者中抗肿瘤免疫反应的方法,其包括向所述患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
如第三方面的上下文中所使用的,术语‘增加抗肿瘤免疫反应’是指在CD205+免疫调节细胞耗竭后观察到患者中存在的免疫细胞数量比耗竭前增加所衡量的对癌症的免疫反应更强。
在一个实施方式中,抗肿瘤免疫反应是免疫细胞介导的肿瘤特异性反应。在一个优选的实施方式中,免疫反应是T细胞介导的肿瘤特异性反应。
在进一步的实施方式中,抗肿瘤免疫反应是NK细胞介导的肿瘤特异性反应。
根据本发明的第四方面,提供了一种用于增加患癌患者中T细胞数量的方法,其包括向所述患者给予调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
在一个实施方式中T细胞是CD8+T细胞。
在另一个实施方式中T细胞是CD4+T细胞。
在进一步的实施方式中T细胞是肿瘤特异性T细胞。
根据另一方面,提供了一种用于减少患癌患者中的肿瘤大小的方法,包括向所述患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
在一个实施方式中,肿瘤是转移性肿瘤。在进一步的实施方式中,转移性肿瘤位于肺或肝中。
为了避免疑问,下面描述本发明的任何实施方式在适当的情况下参考本发明的所有先前方面。
在本发明的一个实施方式中,CD205+免疫调节细胞是CD8+。优选地,CD205+CD8+免疫调节细胞被耗竭。
在一个实施方式中,免疫调节细胞是T-Reg细胞。
在本发明的一个实施方式中,CD205+免疫调节细胞是pDC和/或mDC。优选地,增加pDC和/或mDC的数量。
在本发明的一个实施方式中,CD205+免疫调节细胞是CD4+。优选地,CD205+CD4+免疫调节细胞被耗竭。
在一个实施方式中,免疫调节细胞是T-Reg细胞。
在本发明的一个实施方式中,免疫调节细胞是免疫抑制细胞。
在一些实施方式中,免疫调节细胞是树突细胞。
在本发明的一个实施方式中,将癌症疫苗同时地、分开地、依次地或随后地给予患者。
在本发明的另一个实施方式中,将双特异性抗体同时地、分开地、依次地或相继地给予患者。优选地,双特异性抗体是T细胞接合器(BiTE)。更优选地,双特异性抗体包含与CD3结合的第一结合结构域。
优选地,双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
在一个实施方式中,患者是对至少一种化疗难治性的患者,或其癌症已在至少一种化疗后进展。
在另一个实施方式中,患者对检查点调节剂疗法是难治性的。
在另一个实施方式中,患者对检查点调节剂疗法不适格。
本领域技术人员将理解,对检查点调节剂疗法不适格的患者是满足针对特定适应症的治疗标准的患者。
在一个实施方式中,检查点调节剂疗法是PD1疗法。
在另一个实施方式中,患者患有PDL1阴性或低水平的癌症。
本领域技术人员将理解,术语PDL1低表达是指癌症具有低于50%、低于40%、低于30%、低于20%、低于10%、低于5%、低于4%、低于3%、低于2%或低于1%的PD-L1表达。
如本文所用,术语PDL1阴性意指使用IHC未检测到PDL1表达的癌症。
在另一实施方式中,癌症是MSI稳定的。
在一个实施方式中,在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD8+细胞是CD205+。
在另一个实施方式中,在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD4+细胞是CD205+。
在另一个实施方式中,在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的pDC和/或mDC是CD205+。
在一个实施方式中,抗体或其抗原结合部分结合CD205。
在一个优选的实施方式中,用于本发明的方法的与CD205结合的抗体或其抗原结合部分包含:
重链可变区,包括:
i)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;和
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
i)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;和
iii)第三vlCDR,包含SEQ ID NO:10
任选地,其中上述SEQ ID NO的任一个或多个独立地包含一个、两个、三个、四个或五个氨基酸取代、添加或缺失。
在一个实施方案中,抗体被内化。
在进一步的实施方式中,用于本发明方法的抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区与SEQ ID NO:1具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链可变区与SEQ ID NO:2具有至少80%、85%、90%、95%或99%氨基酸序列相同性。
本公开还意在涵盖上述值之间的范围,例如,与任何上述序列具有至少80-85%、85-90%、90-95%或95-100%序列相同性的重链和轻链可变区。
在一个实施方式中,用于本发明方法的抗-CD205抗体或其抗原结合部分包含抗-CD205抗体的重链可变(VH)区的CDR1、CDR2和CDR3结构域,其具有如SEQ ID NO:1所示的序列,和/或抗-CD205抗体的轻链可变(VL)区的CDR1、CDR2和CDR3结构域,其具有如SEQ IDNO:2所示的序列。
在优选的实施方式中,CDR由Kabat或Chothia系统定义。
在另一个实施方式中,用于本发明方法的抗体或其抗原结合部分包含重链可变区,其包含:包含SEQ ID NO:5的第一vhCDR;包含SEQ ID NO:6的第二vhCDR;和包含SEQ IDNO:7的第三vhCDR;以及轻链可变区,其包含:包含SEQ ID NO:8的第一vlCDR;包含SEQ IDNO:9的第二vlCDR;以及包含SEQ ID NO:10的第三vlCDR。
在另一个实施方式中,用于本发明方法的抗CD205抗体或其抗原结合部分与人CD205结合并且包括含有SEQ ID NO:1和/或其保守序列修饰的重链可变区。抗体还可包括包含SEQ ID NO:2和/或其保守序列修饰的轻链可变区。
在另一个实施方式中,用于本发明方法的抗CD205抗体或其抗原结合部分包含重链框架区,该重链框架区包含与SEQ ID NO:12、13、14和15所示的SEQ ID NO:1的重链可变区的框架区至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的氨基酸序列。在另一个实施方式中,用于本发明方法的抗CD205抗体或其抗原结合部分包含轻链框架区,该轻链框架区包含与SEQ ID NO:16、17、18和19所示的SEQ ID NO:2的轻链可变区的框架区至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的氨基酸序列。
在一个实施方式中,用于本发明方法的抗CD205抗体或其抗原结合部分包含重链可变区和轻链可变区,所述重链可变区和轻链可变区分别由包含SEQ ID NO:3和4的核酸序列编码,或由与前述核酸序列具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同性的核酸序列编码,或由于遗传密码的简并性而不同于SEQ ID NO:3和4的序列编码。
在一个实施方式中,用于本发明的方法的抗体或其抗原结合部分进一步包含共价连接部分。优选地,所述部分是药物。更优选地,所述药物选自下组:美登木素(maytansinoid)、多拉司他汀、哈米特林(hemiasterlin)、奥瑞他汀、单端孢菌素(trichothecene)、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉(pyranoindoizinoquinoline)、喜树碱、蒽环类、安曲霉素(antheamycin)、噻吩并吲哚(thienoindole)、鹅膏毒素、CC1065或紫杉醇及其衍生物。
在一个优选的实施方式中,所述药物是美登木素,选自DM4和DM1,优选DM4。
在一个实施方式中,所述癌症是CD205阳性癌症。
在一个优选的实施方式中,用于本发明方法的调节CD205+免疫调节细胞群体的组合物包含抗体,所述抗体与CD205结合,其包含:
重链可变区,包括:
i)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;和
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
i)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;和
iii)第三vlCDR,包含SEQ ID NO:10;
其中所述抗体偶联至细胞毒性部分,所述细胞毒性部分包含美登木素DM4。
在一个实施方式中,PD1/PD-L1抑制剂是抗体。
本领域技术人员将理解PD1/PD-L1抗体可以是任何合适的抗体。
在优选的实施方式中,用于本发明方法的抗-PD-1抗体选自:纳武单抗(Nivolumab)(MDX-1 106,Opdivo;百时美施贵宝公司(Bristol-Myers Squibb))、派姆单抗(Pembrolizumab)(MK-3475,Keytruda、兰姆单抗(lambrolizumab),BMS-936558;默克公司(Merck))、多塔利单抗(Dostarlimab)(TSR-042Tesaro,Inc.)、西米普利单抗(Cemiplimab)(REGN2810,Libtayo,再生元制药公司(Regeneron Pharmaceuticals))、EH12.2H7(白乐津公司(BioLegend),目录号329902)、巴替利单抗(Balstilimab)(Agenus Inc)。
在其他优选的实施方式中,用于本发明方法的抗-PD-L1抗体选自下组:阿维鲁单抗(Avelumab)(Bavencio;默克雪兰诺公司(EMD Serono),辉瑞公司(Pfizer))、德瓦鲁单抗(Durvalumab)(Imfinzi,阿斯利康(AstraZeneca))、BMS-936559、阿特珠单抗(Atezolizumab)(Tecentriq,基因泰克(Genentech))。
在本发明的一个实施方式中,在给予结合至CD205的抗体或其抗原结合部分之后7天-12周给予检查点抑制剂,优选7天-10周,或7天-8周,或7天-6周,或7天-4周,或7-21天,或10-19天,12-16天,14-16天,或19-28天,更优选20-25天,最优选21天-24天。
在本发明的一个实施方式中,在给予抗体后1周、2周、3周、4周、5周或6周给予检查点抑制剂。
技术人员将理解,随着表达PD1的T细胞的数量或百分比增加,免疫反应将被抑制。这可能是通过PD1/PD-L1免疫检查点的相互作用实现的。如果可以通过给予检查点抑制剂等方法来预防这些相互作用,那么患者针对肿瘤的免疫反应就可以持续,从而导致T细胞对肿瘤产生更强的细胞毒性。
在一个实施方式中,向患者给予调节CD205+免疫调节细胞群体的抗体或其抗原结合片段至少1个周期、至少2个周期、至少3个周期、至少4个周期或至少5个周期之后给予检查点调节剂。
在另一个实施方式中,向患者给予调节CD205+免疫调节细胞群体的抗体或其抗原结合片段1-5个周期、2-4个周期或2-3个周期之后给予检查点调节剂。
在一些实施方式中,癌症选自下组:胰腺癌、卵巢癌、乳腺癌、结直肠癌、子宫内膜癌、食道癌、胃食管连接部癌、皮肤癌、甲状腺癌、肺癌、肾癌、肝癌、头颈癌、膀胱癌、胃癌、白血病,优选急性髓系白血病或慢性淋巴细胞白血病、骨髓瘤,优选多发性骨髓瘤和淋巴瘤,优选弥漫性大B细胞淋巴瘤(DLBCL)、B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、粘膜相关淋巴组织(MALT)淋巴瘤、富含T细胞/组织细胞的B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、小淋巴细胞淋巴瘤、边缘区淋巴瘤、T细胞淋巴瘤、外周T细胞淋巴瘤、间变性大细胞淋巴瘤和血管免疫母细胞性T细胞淋巴瘤。
优选地,所述癌症选自下组:胃癌、子宫内膜癌、胃食管连接部癌、食管癌、卵巢癌、肺癌、乳腺癌、肾癌和膀胱癌。最优选地,胃癌。
在一个实施方式中,乳腺癌是三阴性乳腺癌(TNBC)。在另一个实施方式中,乳腺癌是Her2-ve乳腺癌。
在一个实施方式中,抗CD205抗体或其抗原结合部分的给予导致患者中CD8+T细胞数量增加,导致针对肿瘤的T细胞细胞毒性增加。
在优选的实施方式中,根据任一前述方面的患者是人。
在本发明的一些实施方式中,调节CD205+免疫调节细胞群体的抗体或其抗原结合片段是抗-CD205-DM4 ADC。
在一个实施方式中,以约0.8至10mg/kg宿主体重的剂量范围向患者给予抗-CD205-DM4 ADC,例如1.0mg/kg至8.0mg/kg、1.2mg/kg至7.5mg/kg、1.4mg/kg至7.0mg/kg、1.6至6.0mg/kg、1.6至5mg/kg、2.0至4mg/kg、2.5至3.6mg/kg宿主体重。例如,剂量可以是0.8mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg体重、2.0mg/kg体重、2.5mg/kg体重、3.5mg/kg体重、4mg/kg体重或5mg/kg体重。最优选地,3.5mg/kg。示例性治疗方案需要每周一次、每两周一次、每三周一次、每四周一次、每月一次、每六周一次、每3个月一次或每三至6个月一次给予。
用于本发明方法的抗-CD205-DM4 ADC的优选剂量方案包括2.0mg/kg体重、2.5mg/kg体重、3.0mg/kg体重、3.5mg/kg体重或5mg/kg体重,通过静脉内给予,并使用以下给药方案之一给予抗体药物偶联物:(i)每3周一次,共六剂;(ii)每三周一次;(iii)2.5mg/kg体重一次,随后每三周2mg/kg体重。
用于本发明方法的抗-CD205抗体药物偶联物的进一步优选剂量方案包括通过静脉内给予0.8mg/kg体重、1.0mg/kg体重、1.2mg/kg体重或1.4mg/kg体重,使用以下给药方案之一给予抗体药物偶联物:(i)每周一次;(ii)每周一次,共4剂;(iii)每周一次,共3剂;(iv)每周三次,每三周一次。
在一个实施方式中,以200mg至480mg的剂量范围,例如200mg、240mg、400mg或480mg,向患者给予PD1抗体。示例性治疗方案需要每两周一次、每三周一次、每四周一次、每五周一次或每六周一次给予。
在另一个实施方式中,对于给予PD-L1抗体,剂量范围为800mg至1500mg,例如800mg、1200mg或1500mg。示例性治疗方案需要每两周一次、每三周一次或每四周一次给予。
根据本发明的另一方面,提供了药物组合,其包含:
a)抗CD205抗体或其抗原结合部分,所述抗体包含:
重链可变区,包括:
i)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;和
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
i)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;和
iii)第三vlCDR,包含SEQ ID NO:10;和
b)检查点抑制剂。
在一个实施方式中,药物组合是用于同时、分开或依次使用的组合制剂的形式。
在进一步的实施方式中,检查点抑制剂是PD1/PD-L1检查点抑制剂,优选地PD1/PD-L1检查点抑制剂是抗体。
优选地,药物组合用于治疗癌症。
在一个实施方式中,PD1/PD-L1检查点抑制剂是抗体。
本领域技术人员将理解PD1/PD-L1抗体可以是任何合适的抗体。
在优选的实施方式中,抗-PD-1抗体选自:纳武单抗(Nivolumab)(MDX-1106,Opdivo;百时美施贵宝公司(Bristol-Myers Squibb))、派姆单抗(Pembrolizumab)(MK-3475,Keytruda、兰姆单抗(lambrolizumab),BMS-936558;默克公司(Merck))、多塔利单抗(Dostarlimab)(TSR-042Tesaro,Inc.)、西米普利单抗(Cemiplimab)(REGN-2810,Libtayo,再生元(Regeneron))、EH12.2H7(白乐津公司(BioLegend),目录号329902)。
在其他优选的实施方式中,抗-PD-L1抗体选自下组:阿维鲁单抗(Avelumab)(Bavencio;默克雪兰诺公司(EMD Serono),辉瑞公司(Pfizer))、德瓦鲁单抗(Durvalumab)(Imfinzi,阿斯利康(AstraZeneca))、BMS-936559、阿特珠单抗(Atezolizumab)(Tecentriq,基因泰克(Genentech))。
在进一步的实施方式中,抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区与SEQ ID NO:1具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链可变区与SEQ ID NO:2具有至少80%、85%、90%、95%或99%氨基酸序列相同性。在一个优选的实施方式中,抗体或其抗原结合片段包含重链可变区和轻链可变区,所述重链可变区具有SEQ ID NO:1的序列,所述轻链可变区具有SEQ ID NO:2的序列。
在进一步的实施方式中,抗体包含重链和轻链,其中所述重链与SEQ ID NO:100具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链与SEQ ID NO:101具有至少80%、85%、90%、95%或99%氨基酸序列相同性。在一个优选的实施方式中,抗体包含重链和轻链,所述重链具有SEQ ID NO:100的序列,所述轻链具有SEQ ID NO:101的序列。
本文公开的所有抗体可以是全长的,例如任何以下同种型:IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgD和IgE。或者,抗体可以是片段,例如抗原结合部分或单链抗体(例如,Fab、F(ab')2、Fv、单链Fv片段、分离的互补决定区(CDR)或两个或更多个分离的CDR的组合)。抗体可以是任何种类的抗体,包括但不限于人抗体、人源化抗体和嵌合抗体。
在一个实施方式中,抗-CD205抗体或其抗原结合部分进一步包含共价连接部分。优选地,所述部分是药物。更优选地,所述药物选自下组:美登木素(maytansinoid)、多拉司他汀、哈米特林(hemiasterlin)、奥瑞他汀、单端孢菌素(trichothecene)、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉(pyranoindoizinoquinoline)、喜树碱、蒽环类、安曲霉素(antheamycin)、噻吩并吲哚(thienoindole)、鹅膏毒素、CC1065或紫杉醇及其衍生物。
在一个优选的实施方式中,所述药物是美登木素,选自DM4和DM1,优选DM4。
在进一步的实施方式中,药物组合包含至少一种药学上可接受的稀释剂、赋形剂或运载体。
在本发明的另一方面,提供了用于治疗癌症的本发明的组合物或药物组合。
还提供了如上所定义的组分(a)和(b)在制备用于分开、依次使用来治疗癌症的药物组合中的用途。
根据本发明的另一方面,提供了选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:
鉴定其中先前从患者分离的血液样品中至少20%的CD8+细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
根据本发明的另一方面,提供了选择患者接受用结合CD205的抗体或其抗原结合片段治疗的体外方法,包括:
a.确定先前从所述患者分离的血液样品中CD8+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD8+细胞CD205+,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
在一个实施方式中,选择患者的方法还包括向所述患者给予治疗有效量的与CD205结合的所述抗体或其抗原结合片段的步骤。
根据本发明的另一个方面,提供了一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
从所述对象获得血液样品,
鉴定血液样品中是否至少20%的CD8+细胞是CD205+的。
在一个实施方式中,如果血液样品中至少20%的CD8+细胞是CD205+的,则确定功效的方法进一步包括向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
在进一步的实施方式中,至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+细胞是CD205+的。
根据本发明的另一方面,提供了选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:
鉴定其中先前从患者分离的血液样品中至少20%的CD4+细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
根据本发明的再另一方面,提供了选择患者接受用结合CD205的抗体或其抗原结合片段治疗的体外方法,包括:
a.确定先前从所述患者分离的血液样品中CD4+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD4+细胞CD205+,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
在一个实施方式中,选择患者的方法还包括用与CD205结合的所述抗体或其抗原结合片段治疗所述患者的步骤。
根据本发明的另一个方面,提供了一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
a.从所述对象获得血液样品,
b.鉴定血液样品中是否至少20%的CD4+细胞是CD205+的。
在一个实施方式中,如果血液样品中至少20%的CD4+细胞是CD205+的,则确定功效的方法进一步包括向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
在进一步的实施方式中,至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD4+细胞是CD205+的。
根据本发明的另一方面,提供了选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:鉴定其中先前从患者分离的血液样品中至少20%的CD8+和CD4+的细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
根据本发明的再另一方面,提供了选择患者接受用结合CD205的抗体或其抗原结合片段治疗的体外方法,包括:
a.确定从所述患者分离的血液样品中CD8+和CD4+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD8+和CD4+细胞CD205+,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
在一个实施方式中,选择患者的方法还包括用与CD205结合的所述抗体或其抗原结合片段治疗所述患者的步骤。
根据本发明的另一个方面,提供了一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
从所述对象获得血液样品,
鉴定血液样品中是否至少20%的CD8+和CD4+细胞是CD205+的。
在一个实施方式中,如果血液样品中至少20%的CD8+和CD4+细胞是CD205+的,则确定功效的方法进一步包括向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
在进一步的实施方式中,至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+和CD4+细胞是CD205+的。
根据本发明的另一方面,提供了治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少20%的CD8+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
优选地,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+细胞是CD205+的。
根据本发明的另一方面,提供了治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少20%的CD4+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
优选地,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD4+细胞是CD205+的。
根据本发明的另一方面,提供了治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少200%的CD8+细胞和CD4+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
优选地,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+和CD4+细胞是CD205+的。
根据另一方面,提供了一种治疗方法,包括:
(a)计算先前从诊断患有癌症的患者分离的血液样品中CD4+和/或CD8+细胞为CD205+的百分比,以鉴定该患者具有应答者(responder)表型;和
(b)向具有应答者表型的患者给予治疗有效量的结合CD205的抗体或其抗原结合片段。
如本文所用,术语应答者表型定义为在患者中先前从所述患者分离的血液样品中至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的CD4+和/或CD8+细胞是CD205+阳性的。
在一个实施方式中,所述结合CD205的抗体或其抗原结合片段还包含共价连接的部分。优选地,所述部分是药物。优选地,所述药物选自下组:美登木素(maytansinoid)、多拉司他汀、哈米特林(hemiasterlin)、奥瑞他汀、单端孢菌素(trichothecene)、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉(pyranoindoizinoquinoline)、喜树碱、蒽环类、安曲霉素(antheamycin)、噻吩并吲哚(thienoindole)、鹅膏毒素、CC1065或紫杉醇及其衍生物。
在一个优选的实施方式中,所述药物是美登木素,选自DM4和DM1,优选DM4。
在一些实施方式中,该方法还包括随后向所述患者给予检查点抑制剂的步骤。
在某些实施方式中,检查点抑制剂是针对选自下组的检查点蛋白:PD1、PD-L1、PD-L2、CTLA-4、ICOS、TIGIT、CD28、TMIGD2、CD137、CD137L、CD27、OX40、OX40L、LAG3、VISTA、GITR、DNAM-1、CD96、2B4、TIM-3、CEACAM、CRTAM、SLAMF6、半乳凝素-9、CD48、CD155、GITRL、CD40、CD40L、CD70、HVEM、B7-H7、B7-H3、B7-H4、ICOSL、CD80、CD86、BTLA、CD160、LIGHT、腺苷A2a受体、SIRPα、DC-SIGN、CD200R、DR3、TL1A、CD200、BTN2A1、CD47、IDO、TDO。
优选地,检查点抑制剂是PD1或PD-Ll,更优选PD1。
在一个实施方式中,PD1/PD-L1抑制剂是抗体。
在一些实施方式中,所述抗-PD-1抗体是:纳武单抗(Nivolumab)(MDX-1106,Opdivo;百时美施贵宝公司(Bristol-Myers Squibb)),派姆单抗(Pembrolizumab)(MK-3475,Keytruda,兰姆单抗(lambrolizumab),BMS-936558;默克公司(Merck)),西米普利单抗(Cemiplimab)(REGN-2810,Libtayo;再生元),多塔利单抗(Dostarlimab)(TSR-042,Tesaro,Inc.),EH12.2H7(ENUM-388D4,白乐津公司(BioLegend),目录号329902),巴替利单抗(Balstilimab)(Agenus Inc.)。
在其他实施方式中,所述抗-PD-L1抗体是:阿维鲁单抗(Avelumab)(Bavencio;默克雪兰诺公司(EMD Serono),辉瑞公司(Pfizer)),德瓦鲁单抗(Durvalumab)(Imfinzi,阿斯利康(AstraZeneca)),BMS-936559,阿特珠单抗(Atezolizumab)(Tecentriq,基因泰克(Genentech))。
在多个实施方式中,在给予结合至CD205的抗体或其抗原结合部分之后7天-12周给予检查点抑制剂,优选7天-10周,或7天-8周,或7天-6周,或7天-4周,或7-21天,或10-19天,或12-16天,或14-16天,或19-28天,更优选20-25天,最优选21天-24天。
优选地,所述患者先前不能用检查点抑制剂治疗。
在本发明的另一方面,提供了用于治疗或预防癌症的方法,其包括向有需要的患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及治疗有效量的包含癌症疫苗的组合物。
在本发明的另一方面,提供了用于增强癌症疫苗在患者中的有效性的方法,所述方法包括向所述患者给予(a)治疗有效量的抗体或其抗原结合片段,其调节CD205+免疫调节细胞群和(b)包含癌症疫苗的组合物。
对于本领域技术人员显而易见的是,调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及包含癌症疫苗的组合物可以同时、分开或依次给予。
技术人员将理解,如本文所述,给予调节CD205+免疫调节细胞群体的抗体或其抗原结合片段可以导致患者血液中存在的pDC和mDC数量的增加以及T细胞数量的增加。他们将进一步理解,这种增加可以改善对癌症疫苗的反应,因为呈递癌症疫苗编码的抗原的树突状细胞数量增加,并且可被呈递的抗原激活的T细胞数量增加。
在本发明的另一方面,提供了用于治疗或预防癌症的方法,其包括向有需要的患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及治疗有效量的包含双特异性抗体的组合物。
在一个实施方式中,双特异性抗体是双特异性T细胞接合器(BiTE)。优选地,双特异性抗体包含与CD3结合的第一结合结构域。更优选地,双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
对于本领域技术人员显而易见的是,调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及包含双特异性抗体的组合物可以同时、分开或依次给予。
另一方面,提供了增强双特异性(优选BiTE)抗体在被鉴定为有需要的患者中的有效性的方法,所述方法包括向所述患者给予(a)治疗有效量的调节CD205+免疫调节细胞群体的抗体或抗原其结合片段,以及(b)包含双特异性抗体的组合物。
技术人员将理解,由于给予调节CD205+免疫调节细胞群的抗体或其抗原结合片段后T细胞数量增加,这种可被激活的细胞数量增加,并通过双特异性抗体(优选BiTE)使之与靶细胞紧密接近,从而提高其治疗癌症的有效性。
本领域技术人员将理解双特异性抗体可以是任何合适的双特异性抗体,优选BiTE。例如但不限于,结合CD19和CD3、Epcam和CD3、DLL3和CD3或B7H6和CD3的双特异性抗体。
本发明还提供了治疗对象的癌症的方法,所述方法包括:
a.从所述对象获得肿瘤样品,
b.对所述肿瘤样品进行免疫组织化学染色,以鉴定肿瘤样品中是否至少50%的肿瘤细胞以至少2+的水平表达DCE205,以及
c.如果肿瘤样品中至少50%的肿瘤细胞确实以至少2+的水平表达DCE205,则向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段。
在进一步的方面,本发明提供了用于治疗人类患者中的癌症的方法,所述方法包括:鉴定患有肿瘤的患者,其中通过免疫组织化学(IHC)测量,至少50%的肿瘤细胞以2+的水平表达CD205;以及向所述患者给予治疗有效量的结合CD205的抗体或其抗原结合片段。
根据另一方面,提供了选择适合接受抗-CD205抗体疗法的患者的方法,所述方法包括:鉴定患有肿瘤的患者,通过免疫组织化学测量,所述肿瘤具有至少50%的2+水平的CD205表达;以及指导医疗保健提供者向所述患者给予抗CD205抗体或其抗原结合片段。
根据本发明的另一方面,提供了选择癌症患者接受用结合CD205的抗体或其抗原结合片段的治疗的体外方法,所述方法包括:
测定分离自所述患者的肿瘤样品中CD205的表达水平;以及
如果通过IHC测定肿瘤样品在至少50%的肿瘤细胞中显示2+的表达水平,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
在一个实施方式中,体外方法还包括用结合CD205的所述抗体或其抗原结合片段治疗所述患者的步骤。
在本发明的另一方面,提供了一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
从所述对象获得肿瘤样品,
对所述肿瘤样品进行免疫组织化学染色,以鉴定肿瘤样品中是否至少50%的肿瘤细胞以至少2+的水平表达DCE205。
在一个实施方式中,如果肿瘤样品中至少50%的肿瘤细胞确实以至少2+的水平表达CD205,则该方法还包括向所述对象给予治疗有效量的与CD205结合的抗体或其抗原结合片段的步骤。
在进一步的实施方式中,当通过IHC测量时,至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%肿瘤样品中的肿瘤细胞以至少2+的水平表达DEC 205。
显而易见的是,可以使用任何合适的方案和特异性结合肿瘤样品上的CD205的任何合适的抗体来进行IHC。在一个实施方式中,抗体是来自Leica的抗-CD205抗体(目录号:NCL-L-CD205)。
在一种实施方式中,肿瘤样品是福尔马林固定石蜡包埋的形式(FFPE样品。在替代性实施方式中,样品是新鲜冷冻的肿瘤样品。包含本发明的药物组合和任选的使用说明书的试剂盒也在本发明的范围内。试剂盒还可含有至少一种附加试剂或一种或多种附加抗体。
从下文的详述和所附权利要求中能够很容易地了解本发明的其它特征和优点。
附图简要说明
图1描述了CD205_A1抗体重链可变区的序列(SEQ ID NO:1)。CD205_A1抗体重链的CDR区有下划线。
图2描述了CD205_A1抗体轻链可变区的序列(SEQ ID NO:2)。CD205_A1抗体轻链的CDR区有下划线。
图3在左分图中显示了在用2.5mg/kg的抗-CD205-DM4 ADC治疗后第1、8、15和21天取自胃癌患者的血液样品中CD8+T-细胞数量的变化。右分图显示CD4+T-细胞数量随时间的变化。
图4中左分图显示了用2.5mg/kg的抗-CD205-DM4 ADC治疗后21天的时间过程中,由CD4+(上图)和CD8+(下图)T细胞组成的总T细胞群百分比的变化。右分图显示在21天的时间过程中,PD1+的CD4+和CD8+T细胞百分比的变化。
图5中左分图显示了患者血液中存在的CD8+同时也是PD1+的T细胞数量随时间过程的变化。右分图显示患者血液中存在的CD4+同时也是PD1+的T细胞数量随时间过程的变化。
图6显示了用2.5mg/kg的抗-CD205-DM4 ADC治疗后21天时间过程中CD8+CD205+细胞数量的变化。
图7显示了用2.5mg/kg的抗-CD205-DM4 ADC治疗后21天时间过程中CD4+CD205+细胞数量的变化。
图8在左分图中显示了在用2.5mg/kg的抗-CD205-DM4 ADC治疗后第1、8、15和21天取自胃癌患者的血液样品中mDC和pDC的数量。右分图显示了21天时间过程中患者血液中CD205+mDC和pDC数量的变化。
具体实施方式
本公开涉及用于增强患有癌症的患者的免疫反应和用于增强免疫检查点抑制剂的功效的方法。还公开了包含抗-CD205抗体和免疫检查点抑制剂的药物组合,其中所述药物组合是用于分开或依次使用的组合制剂的形式。
CD205蛋白
CD205作为内吞受体,将捕获的抗原从细胞外空间引导至专门的抗原加工室,并被认为会导致B淋巴细胞增殖减少。
根据UNIPROT,CD205在脾脏、胸腺、结肠和外周血淋巴细胞中表达。已在骨髓细胞和B淋巴细胞系中检测到它。同种型OGTA076b和OGTA076c在称为霍奇金和里-斯氏(HRS)细胞的恶性霍奇金淋巴瘤细胞中表达。CD205作为内吞受体,将捕获的抗原从细胞外空间引导至专门的抗原加工室。它会导致B淋巴细胞增殖减少。
CD205的表达已在胃癌、胰腺癌、膀胱癌、卵巢癌、乳腺癌(包括Her2-ve和三阴性)、结直肠癌、肾癌、子宫内膜癌、胃食管交界处癌、食管癌、皮肤癌、甲状腺癌和肺癌(非小细胞)以及多发性骨髓瘤和许多不同亚型的淋巴瘤(包括DLBCL)和白血病中观察到。
在某些情况下,用于本发明的方法或组合的抗CD205抗体或其抗原结合部分可以与来自除人之外的物种的CD205交叉反应。例如,为了促进临床测试,抗CD205抗体可以与鼠类或灵长类动物CD205分子交叉反应。或者,在某些实施方式中,该抗体可能对人CD205具有完全特异性并且可能不表现出物种或其他类型的非人交叉反应性。
PD-L1蛋白
根据UNIPROT,PD-L1是一种I型膜蛋白。该蛋白由以下组成:氨基酸19-238的胞外结构域,该结构域由1个Ig样V型(免疫球蛋白样)结构域,1个Ig样C2型(免疫球蛋白样)结构域组成;其进一步由一个跨膜区和一个胞质区组成。
在一些实施方式中,用于本发明的方法或组合的抗体结合人PD-L1。
在某些情况下,用于如本发明的实施方式用途的抗体可以与来自非人物种的PD-L1蛋白交叉反应。例如,为了促进临床前和毒理学测试,本发明的抗体可以与鼠或灵长类PD-L1蛋白交叉反应。或者,在某些实施方式中,用于本发明方法的抗体可以对人PD-L1蛋白具有特异性,并且可以不表现出物种或其他类型的非人交叉反应性。
PD1蛋白
根据UNIPROT,PD1是抗原激活T细胞上的一种抑制性受体,在诱导和维持自身免疫耐受方面发挥着关键作用。PD1在与配体CD274/PDL1和CD273/PDLG2结合后传递抑制信号。
肿瘤利用PD1介导的抑制途径来减弱抗肿瘤免疫力并逃避免疫系统的破坏,从而促进肿瘤存活。与CD274/PDL1的相互作用会抑制细胞毒性T淋巴细胞(CTL)效应功能。PD1介导的通路的阻断导致耗尽的T细胞表型的逆转和抗肿瘤反应的正常化,为癌症免疫治疗提供了理论基础。
在一些实施方式中,用于本发明的方法或组合的抗体结合人PD1。
在某些情况下,用于如本发明的实施方式用途的抗体可以与来自非人物种的PD1蛋白交叉反应。例如,为了促进临床前和毒理学测试,本发明的抗体可以与鼠或灵长类PD1蛋白交叉反应。或者,在某些实施方式中,用于本发明方法的抗体可以对人PD1蛋白具有特异性,并且可以不表现出物种或其他类型的非人交叉反应性。
抗体
可用于本发明方法的抗体可以采用本文所述的多种形式,包括传统抗体以及抗体衍生物、片段和模拟物。在一个实施方式中,本发明提供了包含本文定义的一组6个CDR(包括如下所述的少量氨基酸变化)的抗体结构。
如本领域技术人员应理解的,本文使用的“抗体”包括多种结构,在一些实施方式中,其最少包含至少一组6个本文定义的CDR;包括但不限于传统抗体(包括单克隆和多克隆抗体)、人源化和/或嵌合抗体、抗体片段、工程改造抗体(例如具有如下所述的氨基酸修饰)、多特异性抗体(包括双特异性抗体)和其他本领域已知的类似物。
传统的抗体结构单元通常包含四聚体。各四聚体通常包含相同的两对多肽链,每对具有一条“轻”链(通常具有约25kDa的分子量)和一条“重”链(通常具有约50-70kDa的分子量)。各链的氨基末端部分包含约100-110或更多个氨基酸的可变区,主要负责抗原识别。在可变区,重链和轻链的各V域聚集三个环,形成一个抗原结合位点。每个环被称为互补决定区(以下简称“CDR”),其中氨基酸序列的变异最为显著。“可变”是指可变区的某些片段在抗体之间的序列差异很大。可变区内的可变性不是均匀分布的。相反,V区由以下组成:称之为框架区(FR)的约15-30个氨基酸的较少可变的区段,以及分隔这些FR的称之为“高变区”的极具可变性的、长度各为9-15个氨基酸或更长的较短区域。
每个VH和VL由三个高变区(“互补决定区”,“CDR”)和四个FR组成,从氨基端到羧基端按以下顺序排列:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
高变区通常包括来自轻链可变区中的约氨基酸残基24-34(LCDR1;“L”表示轻链),50-56(LCDR2)和89-97(LCDR3),和重链可变区中的约31-35B(HCDR1;“H”表示重链),50-65(HCDR2)和95-102(HCDR3)的氨基酸残基;Kabat等,免疫学热门蛋白质序列(SEQUENCES OFPROTEINS OF IMMUNOLOGICAL INTEREST),第5版,公共健康服务(Public HealthService),国立卫生研究院(National Institutes of Health),马里兰州贝塞斯达(1991)和/或形成高变环的那些残基(例如,轻链可变区中的残基26-32(LCDR1)、50-52(LCDR2)和91-96(LCDR3)和重链可变区中的残基26-32(HCDR1)、53-55(HCDR2)和96-101(HCDR3);Chothia和Lesk(1987)J.Mol.Biol.196:901-917。本发明的特定CDR如下所述。
在本说明书中,Kabat编号系统通常用于指可变结构域中的残基(约为轻链可变区的残基1-107和重链可变区的残基1-113)(例如,Kabat等,同上(1991))。
CDR有助于抗原结合位点的形成,或更具体地,抗体的表位结合位点的形成。术语“表位”或“抗原决定簇”是指抗原上免疫球蛋白或抗体特异性结合的位点。表位既可以由连续氨基酸形成,也可以由蛋白质三级折叠并列的非连续氨基酸形成。
在一些实施方式中,用于本发明方法的抗体是全长的。“全长抗体”是指构成抗体的天然生物学形式的结构,包括可变区和恒定区,包括本文概述的一种或多种修饰。
或者,用于本发明方法的抗体可以是多种结构,包括但不限于抗体片段、单克隆抗体、双特异性抗体、微型抗体、域抗体、合成抗体(有时在本文中称为“抗体模拟物”)、嵌合抗体、人源化抗体、抗体融合物(有时称为“抗体偶联物”)、嵌合抗原受体(CAR)以及各自的片段。依赖于使用一组CDR的结构包含在“抗体”的定义中。
在一个实施方式中,用于本发明方法的抗体是抗体片段。特定的合抗体片段包括但不限于,(i)由VL,VH,CL和CH1结构域组成的Fab片段,(ii)由VH和CH1结构域组成的Fd片段,(iii)由单个抗体的VL和VH结构域组成的Fv片段;(iv)dAb片段(Ward等,1989,Nature341:544-546,通过引用其全文纳入本文),其由单个可变区组成,(v)分离的CDR区,(vi)F(ab')2片段,包含两个连接的Fab片段的二价片段,(vii)单链Fv分子(scFv),其中VH结构域和VL结构域通过肽接头连接,所述肽接头允许两个结构域联合以形成抗原结合位点(Bird等,1988,Science 242:423-426,Huston等,1988,Proc.Natl.Acad.Sci.U.S.A.85:5879-5883,通过引用其全文纳入本文)),(viii)双特异性单链Fv(WO 03/11161,通过引用纳入本文)和(ix)"双抗体"或“三抗体”,通过基因融合构建的多价或多特异性片段(Tomlinson等,2000,Methods Enzymol.326:461-479;WO94/13804;Holliger等,1993,Proc.Natl.Acad.Sci.U.S.A.90:6444-6448,均通过引用纳入本文)。
嵌合和人源化抗体
在一些实施方式中,抗体可以是来自不同物种的混合体,例如嵌合抗体和/或人源化抗体。即,在本发明中,CDR组可以与除本文序列具体描述的那些之外的构架区和恒定区一起使用。
在一个实施方式中,用于本发明方法的抗体可以是多特异性抗体,特别是双特异性抗体,有时也称为“双抗体”。这些是能结合至两种(或多种)不同抗原或同一抗原上的不同表位的抗体。双抗体可以本领域已知的多种方式制造(Holliger和Winter,1993,CurrentOpinion Biotechnol.4:446-449,均以引用方式纳入本文),例如,化学制备或从杂交杂交瘤制备。
在一个实施方式中,用于本发明方法的抗体是微型抗体(minibody)。微型抗体是最小化的抗体样蛋白,包含连接到CH3结构域的scFv。Hu等,1996,Cancer Res.56:3055-3061,通过引用其全文方式纳入本文。在某些情况下,scFv可以接合到Fc区,并且可以包括一些或整个铰链区。应注意,尽管微型抗体没有完整的CDR组,但它仍包含在“抗体”的定义中。
公开的用于本文所述方法的抗体可以是分离的或重组的。“分离的”当用于描述本文公开的各种多肽时,意指已从表达其的细胞或细胞培养物中鉴定并分离和/或回收的多肽。因此,分离的抗体旨在指基本上不含具有不同抗原特异性的其他抗体的抗体(例如,特异性结合CD205的分离的抗体基本上不含特异性结合除CD205之外的抗原的抗体)。因此,“分离的”抗体是以自然界中通常不存在的形式(例如非天然存在的)发现的抗体。在一个实施方式中,本文定义的分离的抗体可以包含至少一种在“天然”存在的抗体中不存在的氨基酸。该氨基酸可以通过添加或取代的方式引入。应理解,引入的氨基酸可以是天然存在的或非天然存在的氨基酸。在一些实施方式中,本发明的抗体是重组蛋白,分离的蛋白质或基本上纯的蛋白质。“分离的”蛋白质不伴有至少一些在其自然状态下通常与之相关的材料,例如构成给定样品中总蛋白质重量的至少约5%或至少约50%的那些。应理解,根据不同情况,分离的蛋白质可以占总蛋白质含量的5至99.9重量%。例如,可以通过使用诱导型启动子或高表达启动子以显著更高的浓度制备蛋白质,从而制备浓度水平增加的蛋白质。在重组蛋白的情况下,该定义包括在本领域已知的多种生物体和/或宿主细胞中产生抗体,其中在抗体在所述生物体和/或宿主细胞中不是天然产生的。通常,分离的多肽将通过至少一个纯化步骤来制备。“分离的抗体”是指基本上不含具有不同抗原特异性的其它抗体的抗体。例如,特异性结合CD205的分离的抗体基本上不含特异性结合除CD205以外的其它抗原的抗体。
具有不同特异性的分离的单克隆抗体可以组合成组分明确(well-defined)的组合物。因此,例如,本发明的抗体可以任选地和单独地包括或排除在制剂中,如下文进一步讨论。
用于本发明的抗-CD205抗体特异性结合CD205(例如,SEQ ID NO:11)。“特异性结合”或“特异性结合至”或“特异于”特定抗原或表位是指与非特异性相互作用可测量地不同的结合。例如,特异性结合可通过测定某分子的结合并与对照分子的结合进行比较来测量,对照分子通常是结构上相似但没有结合活性的分子。例如,可通过与靶标相似的对照分子的竞争来确定特异性结合。
对特定抗原或表位的特异性结合可以通过例如以下特征显示:抗体对于某一抗原或表位的KD是至少约10-4M,至少约10-5M,至少约10-6M,至少约10-7M,至少约10-8M,至少约10-9M,或者至少约10-10M,至少约10-11M,至少约10-12M,或更高,其中KD指的是特定抗体-抗原相互作用的解离率。通常,特异性结合至抗原的抗体对于所述抗原或表位的KD相对于对照分子高20倍,50倍,100倍,500倍,1000倍,5,000倍,10,000倍或更多倍。然而,在本发明中,当给予本发明的CD205抗体的ADC时,重要的是KD足以允许内化并因此细胞死亡而没有显著的副作用。
同样,对于特定抗原或表位的特异性结合可以例如通过如下方式显示:抗体对于抗原或表位的KA或Ka相对于对照对于该表位的情形大至少20倍,50倍,100倍,500倍,1000倍,5,000倍,10,000倍或更多倍,其中KA或Ka指的是特定抗体-抗原相互作用的结合率。
评估抗体对CD205的结合能力的标准试验可在蛋白质或细胞水平上进行并且是本领域已知的,包括例如ELISA,Western印迹,RIA,试验和流式细胞术分析。合适的试验在实施例中详细描述。抗体的结合动力学(例如结合亲和性)也可以通过本领域中已知的标准试验法,如通过/>系统分析评估。为了评估与Raji或Daudi B细胞肿瘤细胞的结合,Raji(ATCC保藏号CCL-86)或Daudi(ATCC保藏号CCL-213)细胞可以从公开来源获得,例如美国典型培养物保藏中心(American Type Culture Collection),并用于标准测定,例如流式细胞术分析。
CD205抗体
当与在细胞表面上表达CD205的细胞接触时,用于本发明方法中的与CD205(SEQID NO:11)结合的CD205抗体可以被内化。这些抗体在本文中被称为“抗-CD205”抗体,或者为了便于描述,被称为“CD205抗体”。这两个术语在本文中可互换使用。
用于本发明方法的CD205抗体在与表面表达CD205的细胞、特别是肿瘤细胞接触后被内化。也就是说,还包含药物偶联物的本文定义的CD205抗体被肿瘤细胞内化,导致药物释放和随后的细胞死亡,从而允许治疗表现出CD205表达的癌症。在这种情况下,内化可以通过多种方式来衡量。在一个实施方式中,使用标准测定法例如MAbZap,将CD205抗体与细胞接触,例如本文概述的细胞系。技术人员清楚MabZap测定代表了使用抗体-药物偶联物(ADC)预期观察到的效果。在后一种情况下,ADC将被内化,从而将药物带入细胞中。有毒的药物会具有杀死细胞的能力,即杀死靶向的癌细胞的能力。来自MabZap测定的数据很容易被本领域技术人员接受为ADC测定的代表(Kohls,M和Lappi,D.,[2000]Biotechniques,第28卷,第1期,162-165)。
在一个实施方式中,用于本发明方法的抗CD205抗体包含本文描述的特定抗体(例如,本文称为“CD205_A1”)的重链和轻链互补决定区(CDR)或可变区(VR)。因此,在一个实施方式中,用于本发明方法的抗体包含具有SEQ ID NO:1所示序列的抗体CD205_A1的重链可变(VH)区的CDR1、CDR2和CDR3结构域,并且具有SEQ ID NO:2所示序列的抗体CD205_A1的轻链可变(VL)区的CDR1、CDR2和CDR3结构域。
在另一个实施方式中,用于本发明方法的抗-CD205抗体包含重链可变区,其包含:包含SEQ ID NO:5的第一vhCDR;包含SEQ ID NO:6的第二vhCDR;和包含SEQ ID NO:7的第三vhCDR;以及轻链可变区,其包含:包含SEQ ID NO:8的第一vlCDR;包含SEQ ID NO:9的第二vlCDR;以及包含SEQ ID NO:10的第三vlCDR。
在另一个实施方式中,用于本发明方法的抗-CD205抗体与人CD205结合并且包括重链可变区,该重链可变区包含含有SEQ ID NO:1的氨基酸序列,及其保守序列修饰。用于本发明方法的抗体还可以包括轻链可变区,该轻链可变区包含含有SEQ ID NO:2的氨基酸序列,及其保守序列修饰。
在进一步的实施方式中,用于本发明方法的抗-CD205抗体结合人CD205并且包括重链可变区和轻链可变区,所述重链可变区和轻链可变区包含下表1中列出的序列组合之一:
表1
在进一步的实施方式中,用于本发明方法的抗-CD205抗体结合人CD205并且包括重链可变区和轻链可变区,该重链可变区和轻链可变区分别包含SEQID NO:1和/或2中列出的氨基酸序列,及其保守序列修饰。如本文所用,术语保守序列修饰是指,例如,用具有相似特征的氨基酸取代氨基酸。本领域技术人员熟知哪些取代可被认为是保守的。可以被认为是保守序列修饰的其他修饰包括例如糖基化。
任选地,SEQ ID NO:5-10中的一个或多个独立地包含一、二、三、四或五个保守氨基酸取代;任选地,SEQ ID NO:5-10中的一个或多个独立地包含一或两个保守氨基酸取代。
优选地,术语“保守序列修饰”旨在包括不显著影响或改变含有氨基酸序列的抗体的结合特征的氨基酸修饰。这种保守修饰包括氨基酸取代,添加和缺失。可以通过本领域所知的标准技术例如定点诱变和PCR介导的诱变将修饰引入本发明的抗体。保守氨基酸取代是其中一个氨基酸残基被具有相似侧链的另一个氨基酸残基替代的情况。本领域已定义具有带相似侧链的氨基酸残基家族。这些家族包括:具有碱性侧链的氨基酸(如赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(如天冬氨酸、谷氨酸)、具有不带电极性侧链的氨基酸(如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、具有非极性侧链的氨基酸(如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、具有β-分支侧链的氨基酸(如苏氨酸、缬氨酸、异亮氨酸)和具有芳族侧链的氨基酸(如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,本发明抗体的CDR区内的一个或多个氨基酸残基可以用来自相同侧链家族的其他氨基酸残基替换,并且可以使用本文描述的功能测定来测试改变的抗体的保留功能。
在一个实施方式中,用于本发明方法的抗CD205抗体包含重链可变区,该重链可变区包含SEQ ID NO:1或与SEQ ID NO:1至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的序列。在另一个实施方式中,用于本发明方法的抗CD205抗体包含轻链可变区,该轻链可变区包含SEQ ID NO:2或与SEQ IDNO:2至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的序列。在另一个实施方式中,用于本发明方法的抗CD205抗体包含重链框架区,该重链框架区包含与包含SEQ ID NO:12、13、14和15的SEQ ID NO:1的重链可变区的框架区至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的氨基酸序列。在另一个实施方式中,用于本发明方法的抗CD205抗体包含轻链框架区,该轻链框架区包含与包含SEQ ID NO:16、17、18和19的SEQID NO:2的轻链可变区的框架区至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同的氨基酸序列。
在一个实施方式中,用于本发明方法的抗CD205抗体在本文中被称为“CD205_A1抗体”,其包含以下CDR,以及含有有限数量的氨基酸变体的变体:
表2
A1 | SEQ ID NO |
可变重链CDR1 | 5 |
可变重链CDR2 | 6 |
可变重链CDR3 | 7 |
可变轻链CDR1 | 8 |
可变轻链CDR2 | 9 |
可变轻链CDR3 | 10 |
本文还公开了包含本发明的CDR组的可变重链和轻链,以及全长重链和轻链(例如,也包含恒定区)。如本领域技术人员所理解的,抗-CD205抗体的CDR组可并入鼠、人源化或人恒定区(包括框架区)。因此,本公开提供了与本文公开的SEQ ID至少约90%-99%相同的可变重链和轻链,其中90%、91%、92%、93%、94%、95%、96%、97%、98%和99%相同的所有这些都可用于本发明。
在一个实施方式中,用于本发明方法的抗体特异性结合包含SEQ ID NO:11的人CD205。优选地,用于本发明方法的抗CD205抗体以高亲和力结合人CD205。
抗体修饰
本发明还提供了用于本发明方法的变体抗体,有时称为“抗体衍生物”或“抗体类似物”。也就是说,可以对本发明的抗体进行许多修饰,包括但不限于CDR中的氨基酸修饰(亲和成熟)、框架区中的氨基酸修饰、Fc区中的氨基酸修饰、糖基化变体、其他类型的共价修饰(例如,用于药物偶联物的连接等)。
本文中“变体”是指由于至少一个氨基酸修饰而与亲本多肽的序列不同的多肽序列。在这种情况下,亲本多肽是分别在SEQ ID NO:1或2中列出的全长可变重链或轻链,或者是在SEQ ID NO:5-10和12-19中列出的重链和轻链的CDR区或框架区。氨基酸修饰可以包括取代、插入和缺失,在许多情况下前者是优选的。应理解,氨基酸取代可以是保守性或非保守性取代,其中保守性取代是优选的。此外,所述取代可以是用天然或非天然存在的氨基酸取代。
本文中的“氨基酸取代”或“取代”是指用可以是天然或非天然存在的另一氨基酸的替换亲本多肽序列中特定位置处的氨基酸。例如,取代S100A是指其中100位的丝氨酸被丙氨酸取代的变体多肽。如本文所用,“氨基酸插入”或“插入”是指在亲本多肽序列的特定位置添加氨基酸。如本文所用,“氨基酸缺失”或“缺失”是指去除亲本多肽序列中特定位置处的氨基酸。
如本文所用,“亲本多肽”,“亲本蛋白质”,“前体多肽”或“前体蛋白质”是指随后被修饰以产生变体的未修饰多肽。一般而言,本文的亲本多肽是LY75_A1。因此,本文所用的“亲本抗体”是指经修饰以产生变体抗体的抗体。
“野生型”或“WT”或“天然”在本文中是指在自然界中存在的氨基酸序列或核苷酸序列,包括等位基因变异。WT蛋白,多肽,抗体,免疫球蛋白,IgG等具有未经有意修饰的氨基酸序列或核苷酸序列。
“变体Fc区”在本文中是指由于至少一个氨基酸修饰而与野生型Fc序列的Fc序列不同的Fc序列。Fc变体可以指Fc多肽本身,包含Fc变体多肽的组合物或氨基酸序列。
在一些情况下,CDR中的氨基酸修饰被称为“亲和成熟”。“亲和成熟的”抗体是在一个或多个CDR上具有一个或多个改变的多肽,与不具有这些一个或多个改变的亲本抗体相比,这导致抗体对其抗原的亲和力改进。在某些情况下,虽然很少见,但可能需要降低抗体与其抗原的亲和力,但这通常不是优选的。
或者,可以在本发明抗体的一个或多个“沉默”的CDR中进行氨基酸修饰,例如,不会显著改变抗体对抗原的亲和力。可以出于多种原因进行这些,包括优化表达(如可以对编码本发明的抗体的核酸进行的那样)。
因此,本发明的CDR和抗体的定义内包括变体CDR和抗体;也就是说,本发明的抗体可以在LY75_A1的一个或多个CDR中包含氨基酸修饰。此外,如下所述,氨基酸修饰也可以独立地且任选地在CDR之外的任何区域中进行,包括本文所述的框架区和恒定区。
在一些实施方式中,抗LY75抗体由变体Fc结构域构成。正如本领域已知的,抗体的Fc区与许多Fc受体和配体相互作用,提供一系列重要的功能能力,称为效应子功能。此外,半胱氨酸的修饰在抗体-药物偶联物(ADC)应用中特别有用,下文将进一步描述。在一些实施方式中,可以将抗体的恒定区工程改造成含有一种或多种特别具有“巯基反应性”的半胱氨酸,从而允许药物部分的更特异性和受控定位。参见例如美国专利号7,521,541,其通过引用全文方式纳入本文。
抗体-药物偶联物
在一些实施方式中,用于本文公开的本发明方法的抗CD205抗体或其抗原结合部分与药物偶联以形成抗体-药物偶联物(ADC)。一般而言,ADC用于肿瘤学应用,其中使用抗体-药物偶联物用于局部递送细胞毒性剂或细胞抑制剂,其能够将药物部分靶向递送至肿瘤,从而实现更高的功效、更低的毒性等。Ducry等,Bioconjugate Chem.,21:5-13(2010),Carter等,Cancer J.14(3):154(2008)和Senter,Current Opin.Chem.Biol.13:235-244(2009)中提供了该技术的概述,所有这些均通过引用整体纳入本文。
因此,本发明提供了药物组合,其尤其包含与药物偶联的抗CD205抗体。一般而言,偶联是通过与抗体共价连接来完成的,如下文进一步描述的,并且通常依赖于接头,通常是肽键(如下文所述,其可以被设计为对靶位点处的蛋白酶切割敏感,或者不是)。另外,如上所述,接头-药物单元(LU-D)的连接可以通过连接至抗体内的半胱氨酸来完成。如本领域技术人员应理解的,每个抗体的药物部分的数量可以根据反应条件而改变,并且可以在1:1至10:1的药物:抗体之间变化。如本领域技术人员将理解的,实际数量是平均值。
因此,抗CD205抗体可以与药物偶联。如下所述,所提供的ADC的药物可以是任意数量的试剂,包括但不限于细胞毒性剂,例如化疗剂、生长抑制剂、毒素(例如,细菌、真菌、植物或动物来源的酶活性毒素或其片段)或放射性同位素(即放射性偶联物)。在其他实施方式中,本发明进一步提供使用ADC的方法。
本发明可用的药物包括细胞毒性药物,尤其癌症治疗中所用的那些。此类药物一般包括DNA损伤剂、抗代谢物、天然产物及其类似物。细胞毒性剂的示例性类别包括酶抑制剂例如二氢叶酸还原酶抑制剂和胸苷酸合酶抑制剂、DNA嵌入剂、DNA切割剂、拓扑异构酶抑制剂、蒽环家族药物、长春花药物、丝裂霉素、博来霉素、细胞毒性核苷、蝶啶家族药物、二炔类(diynenes)、鬼臼毒素、尾海兔素(dolastatins)、美登木素类、分化诱导剂和紫杉醇。
这些类别的成员包括,例如,紫杉醇,氨甲蝶呤,甲氨喋呤,二氯氨甲蝶呤,5-氟尿嘧啶,6-巯基嘌呤,阿糖胞苷,美法仑,环氧长春碱,异长春碱(leurosideine),放线菌素,柔红霉素,多柔比星,丝裂霉素C,丝裂霉素A,洋红霉素,氨基蝶呤,他利霉素,鬼臼毒素和鬼臼毒素衍生物例如依托泊苷或磷酸依托泊苷,长春花碱,长春新碱,长春地辛,紫杉烷类包括紫杉醇,视黄酸紫杉醇酯(taxotere retinoic acid),丁酸,N8-乙酰基亚精胺,喜树碱,卡奇霉素,埃斯培拉霉素,烯-二炔,多卡霉素A,多卡霉素SA,卡奇霉素,喜树碱,哈米特林类,美登木素类(包括DM1)和单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)和美登木素类(DM4)及其类似物。
毒素可以用作抗体-毒素偶联物并且包括细菌毒素例如白喉毒素、植物毒素例如蓖麻毒素,小分子毒素例如格尔德霉素(Mandler等(2000)J.Nat.Cancer Inst.92(19):1573-1581;Mandler等(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler等(2002)Bioconjugate Chem.13:786-791),美登木素类(EP 1391213;Liu等.,(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623),以及卡奇霉素(calicheamicin)(Lode等(1998)Cancer Res.58:2928;Hinman等(1993)Cancer Res.53:3336-3342),哈米特林类(hemiasterlins)(WO2004/026293;Zask等.,(2004)J.Med.Chem,47:4774-4786)。毒素可能通过微管蛋白结合、DNA结合或拓扑异构酶抑制等机制发挥细胞毒性和细胞抑制作用。
也可以使用抗CD205抗体和一种或多种小分子毒素的偶联物,例如美登木素类、尾海兔素、奥瑞他汀、单端孢霉烯、卡奇霉素和CC1065,以及具有毒素活性的这些毒素的衍生物。
优选地,抗-CD205抗体被偶联至DM1或DM4,最优选偶联至DM4。
接头单元
通常,抗体-药物偶联物化合物包含药物单元和抗体单元之间的接头单元。在一些实施方式中,接头在胞内或胞外条件下是可裂解的,从而接头裂解在合适的环境中由抗体释放药物单元。例如,分泌某些蛋白酶的实体瘤可以作为可裂解接头的靶标;在其他实施方案中,利用的是胞内蛋白酶。在另外的其他实施方式中,接头单元是不可裂解的,并且例如,药物通过溶酶体中抗体降解而释放。
在一些实施方式中,接头可以通过存在于胞内环境中(例如,在溶酶体或内体或小窝(caveolea))的裂解剂进行裂解。接头可以是,例如,这样的肽基接头,其被胞内肽酶或蛋白酶裂解,包括但不限于溶酶体或内体蛋白酶。在一些实施方式中,肽基接头的长度为至少两个氨基酸或至少三个氨基酸或更长。
裂解剂可以包括,但不限于,组织蛋白酶B和D以及纤溶酶,已知所有这些都可以水解二肽药物衍生物,导致活性药物在靶细胞内释放(参见例如,Dubowchik和Walker,1999,Pharm.Therapeutics 83:67-123)。可被表达CD205的细胞中存在的酶裂解的肽基接头。例如,可以使用将被癌组织中高度表达的硫醇依赖性蛋白酶组织蛋白酶B裂解的肽基接头(例如,Phe-Leu或Gly-Phe-Leu-Gly接头)。这类接头的其它示例述于例如美国专利号6,214,345,通过引用其全部内容将其纳入本文用于所有目的。
在一些实施方式中,可被胞内蛋白酶裂解的肽基接头是Val-Cit接头或Phe-Lys接头(参见,例如,美国专利号6,214,345,其描述了合成带Val-Cit接头的多柔比星)。
在其它实施方式中,可裂解接头具有pH敏感性,即某些pH值下对水解敏感。通常,pH敏感性接头在酸性条件下水解。
在其它实施方式中,该接头在还原条件下可裂解(如二硫化物接头)。
在其它实施方式中,接头是丙二酸接头(Johnson等,1995,Anticancer Res.15:1387-93)、马来酰亚胺苯甲酰接头(Lau等,1995,Bioorg-Med-Chem.3(10):1299-1304)或3’-N-酰胺类似物(Lau等,1995,Bioorg-Med-Chem.3(10):1305-12)。
在其他实施方式中,接头单元不可裂解的,并且药物通过抗体降解而释放。(参见美国公开号2005/0238649,通过引用其全部内容纳入本文用于所有目的)。
在许多实施方式中,接头是自毁型的。如本文所用,术语“自毁型间隔物”指能够将两个间隔开的化学部分共价连接在一起形成稳定的三方分子的双功能化学部分。如果它与第一个部分的键断裂,它将自发地与第二个化学部分分离。参见例如,WO 2007/059404A2,WO06/110476A2,WO05/112919A2,WO2010/062171,WO09/017394,WO07/089149,WO 07/018431,WO04/043493和WO02/083180。
通常,接头基本上对胞外环境不敏感。如本文所用,在接头的上下文中,“对胞外环境基本上不敏感”指当抗体药物偶联物化合物存在于胞外环境中(例如,在血浆中)时,抗体药物偶联物化合物的样品中不超过约20%,15%,10%,5%,3%或不超过约1%的接头被裂解。
在其他非互斥的实施方式中,接头促进细胞内化。在某些实施方式中,在与治疗剂偶联时(即在如本文所述的抗体药物偶联物化合物的接头治疗剂部分的环境中)促进细胞内化。在其他实施方式中,当与奥瑞他汀化合物和本发明的抗-CD205抗体二者偶联时,接头促进细胞内化。
可用于本发明组合物和方法的多种示例性接头描述于WO2004/010957、美国公开号2006/0074008、美国公开号20050238649和美国公开号2006/0024317(其各自通过引用其全部内容纳入本文)。
优选地,接头是SPDB(N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯)。
药物组合物
组合
本发明的药物组合是用于分开或依次使用的组合制剂的形式。类似地,在本发明的方法中,药物组合的组分(a)和(b)可以分开或依次给予患者。
本文所用的术语“药物组合”是指在单一制剂中或作为单独组分包含至少两种活性成分的药物产品。
本文所用的术语“组合制剂”是指包含组分a)和b)作为单独组分或在单一制剂中的制剂。
当依次给予时,给予第二组分的延迟应当使得由使用组合产生的效果的益处最大化。因此,在一个实施方式中,相继治疗涉及在84天的时间段内给予组合的每一组分。在另一个实施方式中,该时间段是77天。在另一个实施方式中,该时间段是70天。在另一个实施方式中,该时间段是63天。在另一个实施方式中,该时间段是56天。在另一个实施方式中,该时间段是49天。在另一个实施方式中,该时间段是42天。在另一个实施方式中,该时间段是35天。在另一个实施方式中,该时间段是28天。在另一个实施方式中,该时间段是24天。在另一个实施方式中,该时间段是21天。在另一个实施方式中,该时间段是18天。在另一个实施方式中,该时间段是15天。在另一个实施方式中,该时间段是13天。在另一个实施方式中,该时间段是11天。在另一个实施方式中,该时间段是9天内。在另一个实施方式中,该时间段是7天内。在另一个实施方式中,该时间段是5天内。在另一个实施方式中,该时间段是3天内。在另一个实施方式中,该时间段是1天内。在一个优选的实施方式中,相继治疗涉及在14-16天的时间段内给予组合的每种组分。
应首先给予组分(a),然后给予组分(b)。
组合制剂中待给予的组分(a)与组分(b)的总量的比例可以变化,例如为了满足待治疗的患者亚群的需要或单个患者的需要,不同的需要可能由于患者的年龄、性别、体重等而导致。
组分(a)和(b),无论存在于单一组合物中还是存在于分开的组合物中,都可以独立地与一种或多种药学上可接受的运载体一起配制。本发明的药物组合还可以包括至少一种其他抗肿瘤剂、或抗炎剂或免疫抑制剂。如本文所用,“药学上可接受的运载体”包括生理上相容的任何和所有溶剂,分散介质,包被,抗细菌剂和抗真菌剂,等渗剂和吸收延迟剂,等等。优选地,运载体适于静脉内、肌肉内、皮下、肠胃外、脊柱或表皮给予(例如,通过注射或输注)。根据给药途径,活性化合物,即抗体、免疫偶联物或双特异性分子,可以包被在材料中以保护化合物免受酸和其它可能使化合物失活的自然条件的作用。
可用于本文所述药物组合中的合适的水性和非水性运载体的例子包括水,乙醇,多元醇(例如甘油,丙二醇,聚乙二醇等)及其合适的混合物,植物油,例如橄榄油和可注射的有机酯,例如油酸乙酯。例如,通过使用包衣材料(例如卵磷脂),通过在分散系的情况保持所需的粒度,以及通过使用表面活性剂可以保持适当的流动性。
这些组合或其部分还可包含佐剂,例如防腐剂、湿润剂、乳化剂和分散剂。可通过灭菌步骤(见上)和加入各种抗细菌和抗真菌剂,例如对羟基苯甲酸酯类、氯代丁醇、苯酚、山梨酸等确保防止微生物的出现。组合物中也可能需要包含等渗剂,如糖、氯化钠等。此外,可通过加入能延迟吸收的物质例如单硬脂酸铝和明胶来延长可注射药物形式的吸收。
药学上可接受的运载体包括无菌水溶液或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。药学活性物质的这类介质和试剂的用法是本领域熟知的。除非任何常规介质或试剂都与活性化合物不相容,否则应考虑在本发明的药物组合物中使用这些介质或试剂。补充性活性化合物也可掺入所述组合物。
可将所需量的活性化合物和一种上述组分的组合根据需要掺入合适溶剂后灭菌微滤,从而制备无菌注射液。通常,分散系可通过将活性活化物加入含有碱性分散介质和上述其它所需成分的无菌载剂中来制备。在制备无菌注射液的无菌粉剂时,优选的制备方法是真空干燥和冷冻干燥(冻干),由之前已经无菌过滤的活性组分和任意其它所需组分的溶液得到活性组分和任意其它所需组分的粉末。
可与运载体物质组合以产生单一剂型的活性成分的量将根据所治疗的对象和特定的给药方式而变化。可与运载体物质组合以产生单一剂型的活性成分的量通常将是产生治疗效果的组合物的量。一般而言,在100%中,该量将是活性成分的约0.01%至约99%,优选约0.1%至约70%,最优选约1%至约30%的活性成分与药学上可接受的运载体的组合。
给药方案经调节以提供最优的所需效果(例如治疗效果)。例如,可以给予单次次推注,一段时间内多个分剂量,或者根据治疗情况的紧急性成比例地降低或增加剂量。尤其有利的是配制成单位剂型的胃肠道外组合物以便于给药和剂量均一性。本文所用单位剂型是指适合作为待治疗对象的单位剂量的物理上离散的单元,各单元包含经测算产生所需治疗效果的预定量的活性化合物与所需药物运载体。本发明单位剂型的规格取决于或直接依赖于(a)活性化合物的独特特性和待实现的具体治疗效果,以及(b)复合这种活性化合物用于治疗个体中灵敏度的领域中的固有限制。
对于抗-CD205-DM4 ADC的给予,剂量范围为:约0.8至10mg/kg宿主体重,例如,1.0mg/kg至8.0mg/kg、1.2mg/kg至7.5mg/kg、1.4mg/kg至7.0mg/kg、1.6至6.0mg/kg、1.6至5mg/kg、2.0至4mg/kg、2.5至3.6mg/kg宿主体重。例如,剂量可以是0.8mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg体重、2.0mg/kg体重、2.5mg/kg体重、3.5mg/kg体重、4mg/kg体重或5mg/kg体重。示例性治疗方案需要每周一次、每两周一次、每三周一次、每四周一次、每月一次、每6周一次、每3个月一次或每三至6个月一次给予。
用于本发明方法的抗-CD205-DM4 ADC的优选剂量方案包括2.0mg/kg体重、2.5mg/kg体重、3.0mg/kg体重或3.5mg/kg体重,通过静脉内给予,并使用以下给药方案之一给予抗体药物偶联物:(i)每3周一次,共六剂;(ii)每三周一次;(iii)2.5mg/kg体重一次,随后每三周2mg/kg体重。
用于本发明方法的抗-CD205抗体药物偶联物的进一步优选剂量方案包括通过静脉内给予0.8mg/kg体重、1.0mg/kg体重、1.2mg/kg体重或1.4mg/kg体重,使用以下给药方案之一给予抗体药物偶联物:(i)每周一次;(ii)每周一次,共4剂;(iii)每周一次,共3剂;(iv)每周三次,每三周一次。
对于PD1抗体的给予,剂量范围为200mg至480mg,例如200mg、240mg、400mg或480mg。示例性治疗方案需要每两周一次、每三周一次、每四周一次、每五周一次或每六周一次给予。
对于PD-L1抗体的给予,剂量范围为800mg至1500mg,例如800mg、1200mg或1500mg。示例性治疗方案需要每两周一次、每三周一次或每四周一次给予。
在一些方法中,同时给予具有不同结合特异性的两种或更多种单克隆抗体,在这种情况下,给予的每种抗体的剂量在所指示的范围内。
本文发明的药物组合中活性成分的实际剂量水平可以各不相同,从而获得就特定患者、组合物与给药方式而言能够有效时限所需治疗反应且对患者无毒的活性成分量。所选剂量水平取决于多种药代动力学因素,包括所用本文所述特定组合物或其酯、盐或酰胺的活性,给药途径,给药时间,所用具体化合物的排出速率,治疗时长,与所用特定组合物联用的其它药物、化合物和/或物质,受治患者的年龄、性别、体重、状况、总体健康状况和既往医疗史等医药领域众所周知的因素。
本发明的抗-CD205抗体或组合的“治疗有效剂量”优选导致疾病症状严重性降低,无疾病症状期的频率和持续时间增加,或预防由于疾病折磨引起的损伤或残疾。例如,对于治疗CD205或PD1/PD-L1介导的肿瘤,“治疗有效剂量”优选相对于未治疗的对象,抑制细胞生长或肿瘤生长至少约20%,至少约30%,更优选至少约40%,至少约50%,甚至更优选至少约60%,至少约70%,还更优选至少约80%或至少约90%。可以在预测人类肿瘤功效的动物模型系统中评估化合物抑制肿瘤生长的能力。或者,可以通过检查化合物抑制细胞生长的能力来评价组合物的这种特性,这种抑制可以通过技术人员已知的试验在体外测量。治疗有效量的治疗化合物可以减小肿瘤大小,或以其它方式改善对象的症状。本领域普通技术人员将能够基于例如对象重量,对象症状的严重程度和选定的特定组合物或给予途径等因素来确定这样的量。
本发明的药物组合可以使用本领域已知的多种方法中的一种或多种通过一种或多种给药途径给药。可以通过相同途径或不同途径来给予组分(a)和(b)。本领域技术人员会明白,给药途径和/或方式根据所需结果而有所不同。本发明抗体的优选给药途径包括静脉内,肌肉内,皮内,腹膜内,皮下,脊髓或其它肠胃外给药途径,例如通过注射或输注。本文所用短语“胃肠道外给药”表示除肠道和局部给药外的给药形式,通常通过注射,包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眼内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下(subcapsular)、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注给药。
或者,抗体可通过非肠胃外途径给药,例如局部、表皮或粘膜给药途径,例如鼻内、口腔、阴道、直肠、舌下或局部给药。
活性化合物可以与保护化合物免于快速释放的运载体一起制备,例如控释制剂,包括植入物,透皮贴剂和微囊化递送系统。可以使用可生物降解的生物相容性聚合物,例如乙烯-乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。用于制备此类制剂的许多方法已获得专利或为本领域技术人员公知[参见例如,《缓释与控释药物递送系统》(Sustained and Controlled Release Drug Delivery Systems)(1978)J.R.Robinson编,马塞尔·德克尔公司(Marcel Dekker,Inc.),纽约州]。
治疗组合物可以用本领域已知的医疗装置给予。例如,在一个优选的实施方式中,一种或多种抗体可以用无针皮下注射装置给予,例如美国专利号5,399,163;5,383,851;5,312,335;5,064,413;4,941,880;4,790,824;或4,596,556中公开的装置;用于本发明的众所周知的植入物和模块的实例包括:美国专利号4,487,603,它公开了一种可植入的微型输液泵,用于以受控速率分配药物;美国专利号4,486,194,其公开了一种通过皮肤给予的治疗装置;美国专利号4,447,233,其公开了一种药物输液泵,用于以精确的输液速度输送药物;美国专利号4,447,224,其公开了一种用于连续给予的可变流量植入式输液装置;美国专利号4,439,196,其公开了一种包含多室隔室的渗透药物递送系统;和美国专利号4,475,196,其公开了一种渗透性药物递送系统。这些专利通过引用纳入本文。许多其他这样的植入物、输送系统和模块是本领域技术人员已知的。
在某些实施方式中,可以配制抗-CD205和/或抗-PD1/PD-L1抗体以确保体内恰当分布。例如,血脑屏障(BBB)排除了许多高度亲水的化合物。为了确保治疗化合物穿过BBB(如果需要),它们可以被配制在例如脂质体中。对于制造脂质体的方法,参见例如美国专利4,522,811;5,374,548;和5,399,331。脂质体可包含一个或多个选择性地向特定细胞或器官内转运的部分,由此增强靶向性药物递送[参见例如V.V.Ranade,1989,J.Clin.Pharmacol.29:685]。示例性靶向部分包括叶酸或生物素(参见例如美国专利5,416,016.);甘露糖苷[Umezawa等.(1988)Biochem.Biophys.Res.Commun.153:1038];抗体[P.G.Bloeman等.(1995)FEBS Lett.357:140;M.Owais等.(1995)Antimicrob.AgentsChemother.39:180];表面活性剂蛋白A受体[Briscoe等.(1995)Am.J.Physiol.1233:134];p120(Schreier等.(1994)J.Biol.Chem.269:9090];还参见K.Keinanen;M.L.Laukkanen(1994)FEBS Lett.346:123;J.J.Killion;I.J.Fidler(1994)Immunomethods 4:273。
用途和方法
本文所用术语“对象”旨在包括人和非人动物。非人类动物包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人类灵长类动物、绵羊、狗、猫、牛、马、鸡、两栖动物和爬行动物。优选的对象包括患有由CD205活性和/或PD1/PD-L1活性介导的病症的人患者。体内和体外给予抗体组合物(例如,单克隆抗体和免疫偶联物)的合适途径是本领域公知的并且可由普通技术人员选择。例如,抗体组合物可以通过注射(例如,静脉内或皮下)给药。所用分子的合适剂量将取决于对象的年龄和体重以及抗体组合物的浓度和/或制剂。
如先前所描述的,抗CD205和/或抗PD1/PD-L1抗体可以与一种或其他多种治疗剂(例如,细胞毒性剂、放射毒性剂或免疫抑制剂)共同给予。抗体可以与试剂连接(免疫复合物形式)或可以与试剂分开给予。在后一种情况下(分开给予),抗体可以在药剂之前,之后或同时给药,或者可以与其它已知疗法(例如抗癌疗法,例如放射)共同给予。此类治疗剂尤其包括抗肿瘤剂。适合与本发明的抗体共同给予的其他试剂包括用于治疗癌症的其他试剂,例如胃癌、子宫内膜癌、结直肠癌、前列腺癌、乳腺癌、卵巢癌或肺癌。本发明的抗CD205抗体或其抗原结合片段与化学治疗剂的共同给药提供了两种抗癌剂,它们通过不同的机制起作用,对人肿瘤细胞产生细胞毒性作用。这种共同给药可以解决由于对药物产生抗药性或肿瘤细胞抗原性变化而引起的问题,所述抗原性改变将使它们不与抗体反应。
本发明的药物组合还可以与血清和/或补体一起给予。当补体位于抗体附近时,这些组合物可能是有利的。或者,抗体和补体或血清可以分开给予。
包含组分(a)和(b)以及使用说明书的试剂盒也在本发明的范围内。所述试剂盒还可包含一种或多种其它试剂,例如免疫抑制剂,细胞毒剂或放射毒剂,或一种或多种其它抗体(例如,具有与CD205抗原的表位结合的互补活性的、不同于第一抗体的抗体)。
因此,用本发明的药物组合治疗的患者可以(在给予本文公开的抗体之前,同时或之后)另外给予另一种治疗剂,例如细胞毒剂或放射毒剂,其增强或放大所述抗体的治疗效果。
本说明书中引用的所有参考文献,包括但不限于所有论文,出版物,专利,专利申请,演示文稿,文本,报告,手稿,手册,书籍,互联网张贴,期刊文章,期刊,产品情况说明书等,特此一份以引用的方式将其全部内容纳入本说明书。此处对参考文献的讨论仅旨在总结其作者所作的断言,并不承认任何参考文献构成现有技术,并且申请人保留质疑所引用参考文献的准确性和相关性的权利。
虽然出于阐明目的已经通过说明和举例的方式详细描述了本发明,但本领域普通技术人员根据本发明的教导不难了解,可以在不背离所附权利要求书的构思或范围的情况下做出某些改变和修改。
通过以下实施例进一步说明本发明,但不应将其解释为进一步限制。
实施例
实施例1:抗CD205-抗原的人单克隆抗体的产生
按照标准程序,用全长CD205转染的CHO细胞对小鼠(异种小鼠(xenomouse)IgG1)进行免疫。
通过流式细胞术在用CD205转染的HEK293细胞上以及随后在表达CD205的HT29细胞上测试针对CD205产生的抗体的特异性。为了测试抗体与细胞表面CD205蛋白结合的能力,将抗体与表达CD205的细胞一起孵育。将细胞在FACS缓冲液(DPBS,2%FBS)中洗涤,离心并重悬于100μl稀释的第一CD205抗体(也在FACS缓冲液中稀释)中。将抗体-细胞系复合物在冰上孵育60分钟,然后如上所述用FACS缓冲液洗涤两次。将细胞-抗体沉淀重悬于100μl稀释的二抗(也在FACS缓冲液中稀释)中并在冰上孵育60分钟。如前所述洗涤沉淀并重悬于200μl FACS缓冲液中。将样品加载到BD FACScanto II流式细胞仪上,并使用BD FACSdiva软件分析数据(结果未显示)。
实施例2:CD205单克隆抗体的结构表征。
使用标准PCR技术获得编码CD205_A1单克隆抗体重链和轻链可变区的cDNA序列,并使用标准DNA测序技术进行测序。
抗体序列可被诱变以在一个或多个残基处恢复至种系残基。
CD205_A1的重链可变区的核苷酸和氨基酸序列分别示于SEQ ID NO:3和1。
CD205_A1的轻链可变区的核苷酸和氨基酸序列分别示于SEQ ID NO:4和2。
使用Kabat系统的CDR区确定进行的CD205_A1 VH序列的进一步分析获得对于重链CDR1、CDR2和CDR3区的描绘,分别如SEQ ID NO:5、6和7所示。CD205_A1 CDR1、CDR2和CDR3VH序列的序列如图1所示。
使用Kabat系统的CDR区确定进行的CD205_A1 VK序列的进一步分析获得对于轻链CDR1、CDR2和CDR3区的描绘,分别如SEQ ID NO:8、9和10所示。CD205_A1 CDR1、CDR2和CDR3VK序列的序列如图2所示。
实施例3:不同DM4偶联的抗LY75单克隆抗体在Raji和THP1细胞中的功效
THP-1和Raji细胞的接种密度为3,000个细胞/孔(1.5x105个细胞/mL),并添加到测定板中(20μL/孔)。
THP-1细胞在RPMI GLUTAMAX生长(2ME)中制备。Raji细胞在RPMI 1640ATCC生长无AB(10%)中制备。
将各偶联抗体一式三份制备至起始浓度为终浓度的2倍,并在RPMI 1640ATCC生长无AB(10%)中稀释至终浓度。将抗体转移至所需的测定板并孵育96小时。
测定孵育后,将Cell-Titer Glo添加到各板中,并使用设置为积分时间为0.2秒的发光的读板器读取。
使用阴性对照(仅靶细胞)将原始数据转换为特定死亡%(数据未显示)并计算EC50。抗体对两种细胞系的EC50值如表3所示。从表3可以看出,抗体偶联物CD205_A1显示出比其他2种测试的抗体更低的EC50,然而,所有3种偶联物都显示出针对Raji和THP1两种细胞的细胞毒性。
表3
细胞系 | 抗体 | EC50(pM) | 细胞毒性 |
Raji | 16A5(CD205_A1) | 727.6 | 是 |
Raji | 8A3 | 1008.0 | 是 |
Raji | 16H10 | 2168.0 | 是 |
THP1 | 16A5(CD205_A1) | 37.5 | 是 |
THP1 | 8A3 | 98.8 | 是 |
THP1 | 16H10 | 46.9 | 是 |
实施例4:偶联DM1和偶联DM4的抗CD205单克隆抗体在食蟹猴(Cynomolgus
Monkeys)中的毒性
将6只雄性猴子分配至研究,每组2只猴子。载剂(PBS)、CD205_DM4(可裂解的)或CD205_DM1(不可裂解的)通过15分钟静脉内输注以0mg/kg/剂(PBS、载剂)、5mg/kg/剂(CD205_DM4,可裂解的)或10mg/kg/剂(CD205_DM1,不可裂解的)给予两次(第1天和第29天)。在开始给药前(第1天)以及每次给药后1、2、3、7、14、21和28天收集血样用于毒代动力学评估。在开始给药前(第1天)以及每次给药后1、3、7、14、21和28天(第一次给药后28天对于第二次给药也作为给药前时间点)收集用于临床病理学分析的血样。在第57天最后一次采血后,所有研究动物均被安乐死并进行尸检。从每次抽血中分离的血浆被分离、冷冻并运送至牛津生物治疗公司(Oxford BioTherapeutics,Inc.),以通过ELISA分析ADC浓度。
与治疗相关的临床病理学发现包括轻度再生性贫血和血液白细胞分布的瞬时下降,最值得注意的是中性粒细胞计数。在用5mg/kg CD205_DM4治疗的两只动物中和在用10mg/kg CD205_DM1治疗的两只动物中的一只中观察到贫血。在所有动物中都观察到严重的中性粒细胞减少症,在给药后一周达到最低点,并且计数迅速恢复;CD205_DM4治疗的动物中绝对中性粒细胞计数的最低点较低。APTT和PT凝血参数没有与测试品相关的影响。血清化学变化包括给予5mg/kg CD205_DM4和10mg/kg CD205_DM1后AST、CK、LDH(各个治疗组2只动物中的1只)和球蛋白的瞬时增加。此外,仅在CD205 DM4治疗的动物中观察到肝脏特异性酶ALT的瞬时增加。血清化学参数增加的持续时间短和/或增加的幅度表明它们不是不利的。没有与测试品相关的尿液分析发现。4周恢复期后进行尸检时,没有发现与治疗相关的大体病理学发现或绝对和相对器官重量的变化。仅在甲状腺(滤泡中胶体形态的改变)和肾脏(外皮质中的小管扩张)中的组织病理学发现被评为最低严重程度;与其他研究参数的变化无关;并且没有不良反应且毒理学意义极小。结论:5mg/kg CD205_DM4或10mg/kg CD205_DM1的两剂的重复给药治疗在食蟹猴中具有良好的耐受性。所有与治疗相关的毒性发现在4周恢复期后均可逆转。
实施例5:CD205免疫组织化学方案。
使用免疫组织化学(IHC)染色测定在福尔马林固定石蜡包埋(FFPE)的人肿瘤中评估CD205靶标表达水平。在旋转式切片机上将FFPE组织切成4-6微米厚的切片,并封固在带正电的载玻片上。将封固的切片在载玻片上于室温下风干过夜,或在37℃下风干30分钟,然后在60℃下烘烤30分钟。将载玻片在二甲苯中换液三次脱蜡,每次5分钟,并在分级乙醇中再水化,首先使用3次100%乙醇换液,然后使用95%乙醇换液1次,80%乙醇换液1次,用去离子水冲洗两次,每次换液3分钟。脱蜡和再水化过程后,载玻片在Biocare DecloakerNxGen压力锅中的Diva Decloaker溶液(DDV2004)中进行热诱导表位修复(HIER)。将载玻片暴露在110℃的温度下15分钟,并在取出前在单元中再冷却10分钟。从压力锅中取出后,将载玻片平衡至室温用去离子水或蒸馏水逐渐更换热Diva修复液。将载玻片在Tris缓冲盐水(TBS)(TWB945)中冲洗,然后装入intelliPATH自动染色仪器(IPS0001US)的染色架中。将载玻片在300ul过氧化物1(PX968)中孵育5分钟以阻断内源过氧化物酶。然后除去过氧化物1,并将载玻片在300ul背景惩罚剂(Background Punisher)(IP974G20)中孵育10分钟,以阻断非特异性蛋白质-蛋白质相互作用。然后用TBS洗涤载玻片并应用一抗。一抗是针对CD205的小鼠单克隆抗体,由莱卡生物系统(Leica Biosystems)提供(目录号NCL-L-CD205),在达芬奇绿稀释液(PD900)中以1:80(0.5ug/mL)稀释。将300ul稀释液中的一抗涂于载玻片上,并在室温下孵育30分钟。一抗孵育后,将载玻片在TBS中洗涤,并施用300ul二抗检测抗体聚合物MACH 2小鼠HRP(MHRP520)并在室温下温育30分钟。将载玻片在TBS中洗涤并在300ul的intelliPATH FLX DAB发色体中显色5分钟。显色后,将载玻片在去离子水或蒸馏水中洗涤并用苏木精轻微复染20秒,并再次在去离子水中冲洗。然后将染色的载玻片通过在70%、90%、95%、100%分级的组织学级乙醇中交换3-5分钟进行脱水,并在二甲苯中交换3次,然后封固在Permount中。
染色的评分范围为0(阴性)至3+(高阳性),1+为低阳性,2+为中度阳性。由评分病理学家评估并报告每个强度水平下显示膜染色的肿瘤细胞的百分比(例如:0=5%,1+=50%,2+=35%,3+=10%)
显示出大于50% CD205肿瘤表达为至少2+的患者被选择为适合使用CD205-DM4ADC进行治疗。为了避免疑问,CD205-DM4-ADC的抗体部分包含抗体CD205_A1。
实施例6:抗CD205 DM4 ADC对胃癌患者血液中T细胞群的影响。
患有转移性胃癌的患者以2.5mg/kg的剂量(第0天)给予CD205-DM4 ADC。在治疗后第1、8、15和21天从胃癌患者身上抽取血液。
方法
所有步骤均在室温下进行。将100μl患者血液等分到每个微量离心管中,并以适当的浓度添加抗体(见表)。血样在室温下染色20分钟,并添加1ml1xRBC裂解缓冲液。将细胞再孵育15分钟并在300g下离心5分钟。除去缓冲液,并用1ml FACS染色缓冲液(2%FCS+PBS+0.05%叠氮化钠)洗涤沉淀。
将沉淀重悬于500-700μl的FACS缓冲液中并通过FACS分析来分析样品。
表4
FACS门选策略
最初使用CD45-PE抗体从血液中分离淋巴细胞。然后使用CD3-PerCp-Cy5.5抗体分离T细胞。分别使用CD4-PECY7和CD8-FITC分离不同的CD4+和CD8+细胞群。随后使用CD205-Alexa Fluor 647和PD1-BV421筛选CD4+和CD8+细胞的CD205表达和PD1表达。
结果
在图3中,左分图显示在给予CD205-DM4 ADC药物后,在21天的时间过程的第8天到第21天之间,患者血液中存在的CD8+T细胞数量增加了三倍。右分图显示,在给予CD205-DM4ADC药物后,在21天时间过程的第8天到第21天之间,患者血液中存在的CD4+T细胞数量增加了3.4倍。可以看出,CD8+和CD4+T细胞的数量在第15天之前保持相对恒定。此后,T细胞水平在第15天至第21天之间迅速增加约3倍。
图4左分图中显示,CD4+和CD8+T细胞比例占T细胞群总数的百分比随时间推移保持相对恒定。
右分图显示同时也是PD1+的CD4+和CD8+T细胞的百分比。从CD4+和CD8+中可以看出,PD1阳性T细胞的百分比从第8天开始迅速上升,并在第15天达到峰值。
图5中左分图显示了患者血液中存在的CD8+同时也是PD1+的T细胞数量随时间过程的变化。右分图显示患者血液中存在的CD4+同时也是PD1+的T细胞数量随时间过程的变化。可以看出,CD8+PD1+T细胞的数量最初略有下降,但随后从第8天到第21天增加了约4倍。CD4+PD1+T细胞也存在类似的模式。
相比之下,图6和图7显示,CD8+CD205+和CD4+205+免疫细胞群在第8天时急剧下降至非常低的水平,甚至在第21天也没有恢复。
此前已有报道,CD8+CD205+免疫细胞可以诱导Foxp3+调节性T细胞,已知其介导免疫自我耐受并抑制免疫反应(Yamazaki,S;等,J.Immunol.,181(10),6923,[2008])。
结论
CD205-DM4 ADC诱导CD4+CD205+和CD8+CD205+免疫调节细胞下降一周后,T细胞数量增加,支持使用CD205-DM4 ADC作为重新激活患者受抑制的免疫系统的治疗模态以诱导针对肿瘤的免疫反应。此外,CD205-DM4 ADC治疗后PD1+T细胞数量的增加支持使用免疫检查点抑制剂PD1/PD-L1来防止肿瘤随后阻断CD205-DM4 ADC诱导的免疫反应。
实施例7:抗CD205 DM4 ADC对胃癌患者血液中树突细胞群的影响。
方法
所有步骤均在室温下进行。将100μl患者血液等分到每个微量离心管中,并添加适当的抗体(见表)。血样在室温下染色20分钟,并添加1ml 1xRBC裂解缓冲液。将细胞再孵育15分钟并在300g下离心5分钟。除去缓冲液并用1ml FACS染色缓冲液(2%FCS+PBS+0.05%叠氮化钠)洗涤沉淀。
将沉淀重悬于500-700μl的FACS缓冲液中并通过FACS分析来分析样品。
FACS门选策略
最初使用HLA-DR FITC和Lineage BV510抗体从血液中分离树突状细胞。然后使用CD11c(mDC)和CD123(pDC)抗体将树突状细胞分为pDC和mDC。随后使用CD205-Alexa Fluor647和PD-L1-PE筛选不同的mDC和pDC群体的CD205表达和PD-L1表达。
结果
在图8中,左上图显示,在给药后21天的时间过程中,外周血中的mDC总数增加了4.5倍。左下图显示,在最初下降后,外周pDC总数在给药后21天的时间过程中翻倍。右分图显示CD205+mDC和pDC的类似模式,在CD205最初下降后第8天到21天之间出现急剧上升。
实施例8:胃癌患者对2.0-2.5mg/kgCD205-DM4ADC治疗的临床反应。
化疗难治性晚期胃癌患者,其肿瘤MSI稳定、PD-L1阴性,之前接受过两线化疗治疗(第一线多西他赛/顺铂/5FU;第二线雷莫芦单抗/紫杉醇)且病情进展,且患者有淋巴结转移,并且通过IHC筛选恶性腹水的CD205肿瘤表达。IHC显示,原发肿瘤表现出60%2+CD205表达符合治疗标准(数据未显示)。该患者接受了2.5mg/kg的CD205-DM4 ADC治疗,21天为一个周期。第一个周期后,剂量减少至2.0mg/kg。3个治疗周期后,对患者进行评估。显示原发胃肿瘤缩小了约40%,淋巴结转移已消失,腹水也已消失(见表5)。向患者给予另外两个周期的CD205-DM4 ADC治疗,随后接受1个周期的派姆单抗(200mg)治疗(最后一个周期的CD205-DM4 ADC后约4周)。在接受派姆单抗治疗后,对患者进行了检查,发现原发胃肿瘤完全缓解。
表5
实施例9:患者血液样品分析。
对第1周期第1天从胃癌患者(患者1)采集的血液样品进行CD205+表达分析。发现患者中表达CD205的CD4+和CD8+T细胞均表现出高水平(见表6)。
此外,一名食管癌患者(患者2)接受了CD205 DM4 ADC,病情稳定(数据未显示),在治疗的第1周期的第1天从血液样品中分离出的CD4+和CD8+T细胞也均显示出高水平的CD205表达。
患者3-5显示CD4+和CD8+T细胞上CD205的低水平表达。患者没有表现出与患者1和2相同的反应。
另一位子宫内膜癌患者(患者6)在使用CD205 DM4 ADC治疗两个周期且使用派姆单抗治疗一个周期后表现出完全缓解,CD4+和CD8+T细胞上均显示出具有高水平的CD205表达。
表6
患者 | 1 | 2 | 3 | 4 | 5 | 6 |
CD8+CD205+(占CD8+细胞的%) | 49.9% | 99.1% | 0.74% | 0.25% | 1.47% | 70.4% |
CD4+CD205+(占CD4+细胞的%) | 85.0% | 99.7% | 0.84% | 0.4% | 1.67% | 87.7% |
鉴于癌症患者血液中高水平的CD205+T细胞与CD205-DM4 ADC治疗的抗肿瘤功效之间的相关性,该测量可用于选择适合接受该疗法治疗的患者。
实施例10:子宫内膜癌患者对3.0mg/kgCD205-DM4ADC治疗的临床反应。
患有肺和肝转移的晚期子宫内膜癌患者(上述患者6),其肿瘤MSI稳定且PD-L1表达低(TPS10%;不适格CPI治疗),先前接受过两线化疗治疗且病情进展(第一线卡铂/紫杉醇/赫赛汀;第二线来曲唑/依维莫司)通过IHC筛选CD205肿瘤表达。IHC显示,原发肿瘤表现出100%3+CD205表达,符合治疗标准(数据未显示)。该患者接受了3mg/kg的CD205-DM4 ADC治疗,21天为一个周期。2个周期的治疗后,患者接受1个周期的派姆单抗(200mg)(CD205-DM4 ADC最后一个周期后约3周)。在接受派姆单抗治疗后,对患者进行了检查,发现原发子宫内膜肿瘤以及肝和肺转移完全缓解。
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<110> 牛津生物疗法有限公司(Oxford BioTherapeutics Ltd)
<120> 包含抗-CD205抗体和免疫检查点抑制剂的药物组合
<130> P1137PC00
<150> GB2107518.9
<151> 2021-05-26
<150> GB2108387.8
<151> 2021-06-11
<150> GB2109271.3
<151> 2021-06-28
<160> 120
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<213> 人
<400> 7
Phe Gly Val Val Ser Phe Asp Tyr
1 5
<210> 8
<211> 11
<212> PRT
<213> 人
<400> 8
Arg Ala Ser Gln Ser Ile Ser Asp Tyr Leu Ser
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 人
<400> 9
Ala Ala Ser Asn Leu Lys Thr
1 5
<210> 10
<211> 9
<212> PRT
<213> 人
<400> 10
Gln Gln Ser Tyr Arg Ser Pro Trp Thr
1 5
<210> 11
<211> 1722
<212> PRT
<213> 人
<400> 11
Met Arg Thr Gly Trp Ala Thr Pro Arg Arg Pro Ala Gly Leu Leu Met
1 5 10 15
Leu Leu Phe Trp Phe Phe Asp Leu Ala Glu Pro Ser Gly Arg Ala Ala
20 25 30
Asn Asp Pro Phe Thr Ile Val His Gly Asn Thr Gly Lys Cys Ile Lys
35 40 45
Pro Val Tyr Gly Trp Ile Val Ala Asp Asp Cys Asp Glu Thr Glu Asp
50 55 60
Lys Leu Trp Lys Trp Val Ser Gln His Arg Leu Phe His Leu His Ser
65 70 75 80
Gln Lys Cys Leu Gly Leu Asp Ile Thr Lys Ser Val Asn Glu Leu Arg
85 90 95
Met Phe Ser Cys Asp Ser Ser Ala Met Leu Trp Trp Lys Cys Glu His
100 105 110
His Ser Leu Tyr Gly Ala Ala Arg Tyr Arg Leu Ala Leu Lys Asp Gly
115 120 125
His Gly Thr Ala Ile Ser Asn Ala Ser Asp Val Trp Lys Lys Gly Gly
130 135 140
Ser Glu Glu Ser Leu Cys Asp Gln Pro Tyr His Glu Ile Tyr Thr Arg
145 150 155 160
Asp Gly Asn Ser Tyr Gly Arg Pro Cys Glu Phe Pro Phe Leu Ile Asp
165 170 175
Gly Thr Trp His His Asp Cys Ile Leu Asp Glu Asp His Ser Gly Pro
180 185 190
Trp Cys Ala Thr Thr Leu Asn Tyr Glu Tyr Asp Arg Lys Trp Gly Ile
195 200 205
Cys Leu Lys Pro Glu Asn Gly Cys Glu Asp Asn Trp Glu Lys Asn Glu
210 215 220
Gln Phe Gly Ser Cys Tyr Gln Phe Asn Thr Gln Thr Ala Leu Ser Trp
225 230 235 240
Lys Glu Ala Tyr Val Ser Cys Gln Asn Gln Gly Ala Asp Leu Leu Ser
245 250 255
Ile Asn Ser Ala Ala Glu Leu Thr Tyr Leu Lys Glu Lys Glu Gly Ile
260 265 270
Ala Lys Ile Phe Trp Ile Gly Leu Asn Gln Leu Tyr Ser Ala Arg Gly
275 280 285
Trp Glu Trp Ser Asp His Lys Pro Leu Asn Phe Leu Asn Trp Asp Pro
290 295 300
Asp Arg Pro Ser Ala Pro Thr Ile Gly Gly Ser Ser Cys Ala Arg Met
305 310 315 320
Asp Ala Glu Ser Gly Leu Trp Gln Ser Phe Ser Cys Glu Ala Gln Leu
325 330 335
Pro Tyr Val Cys Arg Lys Pro Leu Asn Asn Thr Val Glu Leu Thr Asp
340 345 350
Val Trp Thr Tyr Ser Asp Thr Arg Cys Asp Ala Gly Trp Leu Pro Asn
355 360 365
Asn Gly Phe Cys Tyr Leu Leu Val Asn Glu Ser Asn Ser Trp Asp Lys
370 375 380
Ala His Ala Lys Cys Lys Ala Phe Ser Ser Asp Leu Ile Ser Ile His
385 390 395 400
Ser Leu Ala Asp Val Glu Val Val Val Thr Lys Leu His Asn Glu Asp
405 410 415
Ile Lys Glu Glu Val Trp Ile Gly Leu Lys Asn Ile Asn Ile Pro Thr
420 425 430
Leu Phe Gln Trp Ser Asp Gly Thr Glu Val Thr Leu Thr Tyr Trp Asp
435 440 445
Glu Asn Glu Pro Asn Val Pro Tyr Asn Lys Thr Pro Asn Cys Val Ser
450 455 460
Tyr Leu Gly Glu Leu Gly Gln Trp Lys Val Gln Ser Cys Glu Glu Lys
465 470 475 480
Leu Lys Tyr Val Cys Lys Arg Lys Gly Glu Lys Leu Asn Asp Ala Ser
485 490 495
Ser Asp Lys Met Cys Pro Pro Asp Glu Gly Trp Lys Arg His Gly Glu
500 505 510
Thr Cys Tyr Lys Ile Tyr Glu Asp Glu Val Pro Phe Gly Thr Asn Cys
515 520 525
Asn Leu Thr Ile Thr Ser Arg Phe Glu Gln Glu Tyr Leu Asn Asp Leu
530 535 540
Met Lys Lys Tyr Asp Lys Ser Leu Arg Lys Tyr Phe Trp Thr Gly Leu
545 550 555 560
Arg Asp Val Asp Ser Cys Gly Glu Tyr Asn Trp Ala Thr Val Gly Gly
565 570 575
Arg Arg Arg Ala Val Thr Phe Ser Asn Trp Asn Phe Leu Glu Pro Ala
580 585 590
Ser Pro Gly Gly Cys Val Ala Met Ser Thr Gly Lys Ser Val Gly Lys
595 600 605
Trp Glu Val Lys Asp Cys Arg Ser Phe Lys Ala Leu Ser Ile Cys Lys
610 615 620
Lys Met Ser Gly Pro Leu Gly Pro Glu Glu Ala Ser Pro Lys Pro Asp
625 630 635 640
Asp Pro Cys Pro Glu Gly Trp Gln Ser Phe Pro Ala Ser Leu Ser Cys
645 650 655
Tyr Lys Val Phe His Ala Glu Arg Ile Val Arg Lys Arg Asn Trp Glu
660 665 670
Glu Ala Glu Arg Phe Cys Gln Ala Leu Gly Ala His Leu Ser Ser Phe
675 680 685
Ser His Val Asp Glu Ile Lys Glu Phe Leu His Phe Leu Thr Asp Gln
690 695 700
Phe Ser Gly Gln His Trp Leu Trp Ile Gly Leu Asn Lys Arg Ser Pro
705 710 715 720
Asp Leu Gln Gly Ser Trp Gln Trp Ser Asp Arg Thr Pro Val Ser Thr
725 730 735
Ile Ile Met Pro Asn Glu Phe Gln Gln Asp Tyr Asp Ile Arg Asp Cys
740 745 750
Ala Ala Val Lys Val Phe His Arg Pro Trp Arg Arg Gly Trp His Phe
755 760 765
Tyr Asp Asp Arg Glu Phe Ile Tyr Leu Arg Pro Phe Ala Cys Asp Thr
770 775 780
Lys Leu Glu Trp Val Cys Gln Ile Pro Lys Gly Arg Thr Pro Lys Thr
785 790 795 800
Pro Asp Trp Tyr Asn Pro Asp Arg Ala Gly Ile His Gly Pro Pro Leu
805 810 815
Ile Ile Glu Gly Ser Glu Tyr Trp Phe Val Ala Asp Leu His Leu Asn
820 825 830
Tyr Glu Glu Ala Val Leu Tyr Cys Ala Ser Asn His Ser Phe Leu Ala
835 840 845
Thr Ile Thr Ser Phe Val Gly Leu Lys Ala Ile Lys Asn Lys Ile Ala
850 855 860
Asn Ile Ser Gly Asp Gly Gln Lys Trp Trp Ile Arg Ile Ser Glu Trp
865 870 875 880
Pro Ile Asp Asp His Phe Thr Tyr Ser Arg Tyr Pro Trp His Arg Phe
885 890 895
Pro Val Thr Phe Gly Glu Glu Cys Leu Tyr Met Ser Ala Lys Thr Trp
900 905 910
Leu Ile Asp Leu Gly Lys Pro Thr Asp Cys Ser Thr Lys Leu Pro Phe
915 920 925
Ile Cys Glu Lys Tyr Asn Val Ser Ser Leu Glu Lys Tyr Ser Pro Asp
930 935 940
Ser Ala Ala Lys Val Gln Cys Ser Glu Gln Trp Ile Pro Phe Gln Asn
945 950 955 960
Lys Cys Phe Leu Lys Ile Lys Pro Val Ser Leu Thr Phe Ser Gln Ala
965 970 975
Ser Asp Thr Cys His Ser Tyr Gly Gly Thr Leu Pro Ser Val Leu Ser
980 985 990
Gln Ile Glu Gln Asp Phe Ile Thr Ser Leu Leu Pro Asp Met Glu Ala
995 1000 1005
Thr Leu Trp Ile Gly Leu Arg Trp Thr Ala Tyr Glu Lys Ile Asn
1010 1015 1020
Lys Trp Thr Asp Asn Arg Glu Leu Thr Tyr Ser Asn Phe His Pro
1025 1030 1035
Leu Leu Val Ser Gly Arg Leu Arg Ile Pro Glu Asn Phe Phe Glu
1040 1045 1050
Glu Glu Ser Arg Tyr His Cys Ala Leu Ile Leu Asn Leu Gln Lys
1055 1060 1065
Ser Pro Phe Thr Gly Thr Trp Asn Phe Thr Ser Cys Ser Glu Arg
1070 1075 1080
His Phe Val Ser Leu Cys Gln Lys Tyr Ser Glu Val Lys Ser Arg
1085 1090 1095
Gln Thr Leu Gln Asn Ala Ser Glu Thr Val Lys Tyr Leu Asn Asn
1100 1105 1110
Leu Tyr Lys Ile Ile Pro Lys Thr Leu Thr Trp His Ser Ala Lys
1115 1120 1125
Arg Glu Cys Leu Lys Ser Asn Met Gln Leu Val Ser Ile Thr Asp
1130 1135 1140
Pro Tyr Gln Gln Ala Phe Leu Ser Val Gln Ala Leu Leu His Asn
1145 1150 1155
Ser Ser Leu Trp Ile Gly Leu Phe Ser Gln Asp Asp Glu Leu Asn
1160 1165 1170
Phe Gly Trp Ser Asp Gly Lys Arg Leu His Phe Ser Arg Trp Ala
1175 1180 1185
Glu Thr Asn Gly Gln Leu Glu Asp Cys Val Val Leu Asp Thr Asp
1190 1195 1200
Gly Phe Trp Lys Thr Val Asp Cys Asn Asp Asn Gln Pro Gly Ala
1205 1210 1215
Ile Cys Tyr Tyr Ser Gly Asn Glu Thr Glu Lys Glu Val Lys Pro
1220 1225 1230
Val Asp Ser Val Lys Cys Pro Ser Pro Val Leu Asn Thr Pro Trp
1235 1240 1245
Ile Pro Phe Gln Asn Cys Cys Tyr Asn Phe Ile Ile Thr Lys Asn
1250 1255 1260
Arg His Met Ala Thr Thr Gln Asp Glu Val His Thr Lys Cys Gln
1265 1270 1275
Lys Leu Asn Pro Lys Ser His Ile Leu Ser Ile Arg Asp Glu Lys
1280 1285 1290
Glu Asn Asn Phe Val Leu Glu Gln Leu Leu Tyr Phe Asn Tyr Met
1295 1300 1305
Ala Ser Trp Val Met Leu Gly Ile Thr Tyr Arg Asn Lys Ser Leu
1310 1315 1320
Met Trp Phe Asp Lys Thr Pro Leu Ser Tyr Thr His Trp Arg Ala
1325 1330 1335
Gly Arg Pro Thr Ile Lys Asn Glu Lys Phe Leu Ala Gly Leu Ser
1340 1345 1350
Thr Asp Gly Phe Trp Asp Ile Gln Thr Phe Lys Val Ile Glu Glu
1355 1360 1365
Ala Val Tyr Phe His Gln His Ser Ile Leu Ala Cys Lys Ile Glu
1370 1375 1380
Met Val Asp Tyr Lys Glu Glu Tyr Asn Thr Thr Leu Pro Gln Phe
1385 1390 1395
Met Pro Tyr Glu Asp Gly Ile Tyr Ser Val Ile Gln Lys Lys Val
1400 1405 1410
Thr Trp Tyr Glu Ala Leu Asn Met Cys Ser Gln Ser Gly Gly His
1415 1420 1425
Leu Ala Ser Val His Asn Gln Asn Gly Gln Leu Phe Leu Glu Asp
1430 1435 1440
Ile Val Lys Arg Asp Gly Phe Pro Leu Trp Val Gly Leu Ser Ser
1445 1450 1455
His Asp Gly Ser Glu Ser Ser Phe Glu Trp Ser Asp Gly Ser Thr
1460 1465 1470
Phe Asp Tyr Ile Pro Trp Lys Gly Gln Thr Ser Pro Gly Asn Cys
1475 1480 1485
Val Leu Leu Asp Pro Lys Gly Thr Trp Lys His Glu Lys Cys Asn
1490 1495 1500
Ser Val Lys Asp Gly Ala Ile Cys Tyr Lys Pro Thr Lys Ser Lys
1505 1510 1515
Lys Leu Ser Arg Leu Thr Tyr Ser Ser Arg Cys Pro Ala Ala Lys
1520 1525 1530
Glu Asn Gly Ser Arg Trp Ile Gln Tyr Lys Gly His Cys Tyr Lys
1535 1540 1545
Ser Asp Gln Ala Leu His Ser Phe Ser Glu Ala Lys Lys Leu Cys
1550 1555 1560
Ser Lys His Asp His Ser Ala Thr Ile Val Ser Ile Lys Asp Glu
1565 1570 1575
Asp Glu Asn Lys Phe Val Ser Arg Leu Met Arg Glu Asn Asn Asn
1580 1585 1590
Ile Thr Met Arg Val Trp Leu Gly Leu Ser Gln His Ser Val Asp
1595 1600 1605
Gln Ser Trp Ser Trp Leu Asp Gly Ser Glu Val Thr Phe Val Lys
1610 1615 1620
Trp Glu Asn Lys Ser Lys Ser Gly Val Gly Arg Cys Ser Met Leu
1625 1630 1635
Ile Ala Ser Asn Glu Thr Trp Lys Lys Val Glu Cys Glu His Gly
1640 1645 1650
Phe Gly Arg Val Val Cys Lys Val Pro Leu Gly Pro Asp Tyr Thr
1655 1660 1665
Ala Ile Ala Ile Ile Val Ala Thr Leu Ser Ile Leu Val Leu Met
1670 1675 1680
Gly Gly Leu Ile Trp Phe Leu Phe Gln Arg His Arg Leu His Leu
1685 1690 1695
Ala Gly Phe Ser Ser Val Arg Tyr Ala Gln Gly Val Asn Glu Asp
1700 1705 1710
Glu Ile Met Leu Pro Ser Phe His Asp
1715 1720
<210> 12
<211> 30
<212> PRT
<213> 人
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser
20 25 30
<210> 13
<211> 14
<212> PRT
<213> 人
<400> 13
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
1 5 10
<210> 14
<211> 32
<212> PRT
<213> 人
<400> 14
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
20 25 30
<210> 15
<211> 11
<212> PRT
<213> 人
<400> 15
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 16
<211> 23
<212> PRT
<213> 人
<400> 16
Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 17
<211> 15
<212> PRT
<213> 人
<400> 17
Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile Tyr
1 5 10 15
<210> 18
<211> 32
<212> PRT
<213> 人
<400> 18
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Thr Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 19
<211> 11
<212> PRT
<213> 人
<400> 19
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
1 5 10
<210> 20
<211> 440
<212> PRT
<213> 人
<400> 20
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 21
<211> 214
<212> PRT
<213> 人
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 22
<211> 5
<212> PRT
<213> 人
<400> 22
Asn Ser Gly Met His
1 5
<210> 23
<211> 17
<212> PRT
<213> 人
<400> 23
Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 24
<211> 4
<212> PRT
<213> 人
<400> 24
Asn Asp Asp Tyr
1
<210> 25
<211> 11
<212> PRT
<213> 人
<400> 25
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 26
<211> 7
<212> PRT
<213> 人
<400> 26
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 27
<211> 9
<212> PRT
<213> 人
<400> 27
Gln Gln Ser Ser Asn Trp Pro Arg Thr
1 5
<210> 28
<211> 447
<212> PRT
<213> 小鼠
<400> 28
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 29
<211> 218
<212> PRT
<213> 小鼠
<400> 29
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 30
<211> 5
<212> PRT
<213> 小鼠
<400> 30
Asn Tyr Tyr Met Tyr
1 5
<210> 31
<211> 17
<212> PRT
<213> 小鼠
<400> 31
Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys
1 5 10 15
Asn
<210> 32
<211> 11
<212> PRT
<213> 小鼠
<400> 32
Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr
1 5 10
<210> 33
<211> 15
<212> PRT
<213> 小鼠
<400> 33
Arg Ala Ser Lys Gly Val Ser Thr Ser Gly Tyr Ser Tyr Leu His
1 5 10 15
<210> 34
<211> 7
<212> PRT
<213> 小鼠
<400> 34
Leu Ala Ser Tyr Leu Glu Ser
1 5
<210> 35
<211> 9
<212> PRT
<213> 小鼠
<400> 35
Gly His Ser Arg Asp Leu Pro Leu Thr
1 5
<210> 36
<211> 444
<212> PRT
<213> 人
<400> 36
Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 37
<211> 214
<212> PRT
<213> 人
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 38
<211> 8
<212> PRT
<213> 人
<400> 38
Gly Phe Thr Phe Ser Asn Phe Gly
1 5
<210> 39
<211> 8
<212> PRT
<213> 人
<400> 39
Ile Ser Gly Gly Gly Arg Asp Thr
1 5
<210> 40
<211> 10
<212> PRT
<213> 人
<400> 40
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr
1 5 10
<210> 41
<211> 6
<212> PRT
<213> 人
<400> 41
Leu Ser Ile Asn Thr Phe
1 5
<210> 42
<211> 3
<212> PRT
<213> 人
<400> 42
Ala Ala Ser
1
<210> 43
<211> 9
<212> PRT
<213> 人
<400> 43
Gln Gln Ser Ser Asn Thr Pro Phe Thr
1 5
<210> 44
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 44
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Gln Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Pro Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 45
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 45
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Tyr Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Ser Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 46
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 46
Ser Tyr Asp Met Ser
1 5
<210> 47
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 47
Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Gln Asp Ser Val Lys
1 5 10 15
Gly
<210> 48
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 48
Pro Tyr Tyr Ala Met Asp Tyr
1 5
<210> 49
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 49
Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala
1 5 10
<210> 50
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 50
Trp Ala Ser Thr Leu His Thr
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 51
Gln His Tyr Ser Ser Tyr Pro Trp Thr
1 5
<210> 52
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 52
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Val Ile Asp Pro Gly Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Glu Lys Phe Gly Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 53
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 53
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 54
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 54
Gly Tyr Thr Phe Thr Asp Tyr Glu
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 55
Ile Asp Pro Gly Thr Gly Gly Thr Ala
1 5
<210> 56
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 56
Thr Ser Glu Lys Phe Gly Ser Asn Tyr Tyr Phe Asp Tyr
1 5 10
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 57
Gln Thr Ile Val His Ser Asp Gly Asn Thr Tyr
1 5 10
<210> 58
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 58
Lys Val Ser
1
<210> 59
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 59
Phe Gln Gly Ser His Val Pro Leu Thr
1 5
<210> 60
<211> 450
<212> PRT
<213> 人
<400> 60
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 61
<211> 216
<212> PRT
<213> 人
<400> 61
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 62
<211> 5
<212> PRT
<213> 人
<400> 62
Ser Tyr Ile Met Met
1 5
<210> 63
<211> 17
<212> PRT
<213> 人
<400> 63
Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 64
<211> 11
<212> PRT
<213> 人
<400> 64
Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr
1 5 10
<210> 65
<211> 14
<212> PRT
<213> 人
<400> 65
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 66
<211> 7
<212> PRT
<213> 人
<400> 66
Asp Val Ser Asn Arg Pro Ser
1 5
<210> 67
<211> 10
<212> PRT
<213> 人
<400> 67
Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val
1 5 10
<210> 68
<211> 451
<212> PRT
<213> 人
<400> 68
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 69
<211> 215
<212> PRT
<213> 人
<400> 69
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 70
<211> 10
<212> PRT
<213> 人
<400> 70
Gly Phe Thr Phe Ser Arg Tyr Trp Met Ser
1 5 10
<210> 71
<211> 17
<212> PRT
<213> 人
<400> 71
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 72
<211> 12
<212> PRT
<213> 人
<400> 72
Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr
1 5 10
<210> 73
<211> 12
<212> PRT
<213> 人
<400> 73
Arg Ala Ser Gln Arg Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 74
<211> 7
<212> PRT
<213> 人
<400> 74
Asp Ala Ser Ser Arg Ala Thr
1 5
<210> 75
<211> 9
<212> PRT
<213> 人
<400> 75
Gln Gln Tyr Gly Ser Leu Pro Trp Thr
1 5
<210> 76
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 76
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 77
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 77
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 78
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 78
Gly Phe Thr Phe Ser Asp Ser Trp Ile His
1 5 10
<210> 79
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 79
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 80
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 80
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 81
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 81
Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 82
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 82
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 83
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人源化序列
<400> 83
Gln Gln Tyr Leu Tyr His Pro Ala Thr
1 5
<210> 84
<211> 123
<212> PRT
<213> 人
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 85
<211> 106
<212> PRT
<213> 人
<400> 85
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 86
<211> 5
<212> PRT
<213> 人
<400> 86
Thr Tyr Ala Ile Ser
1 5
<210> 87
<211> 17
<212> PRT
<213> 人
<400> 87
Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 88
<211> 14
<212> PRT
<213> 人
<400> 88
Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val
1 5 10
<210> 89
<211> 11
<212> PRT
<213> 人
<400> 89
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 90
<211> 7
<212> PRT
<213> 人
<400> 90
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 91
<211> 8
<212> PRT
<213> 人
<400> 91
Gln Gln Arg Ser Asn Trp Pro Thr
1 5
<210> 92
<211> 439
<212> PRT
<213> 人
<400> 92
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Asn Gly Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
180 185 190
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
195 200 205
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
210 215 220
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
225 230 235 240
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
245 250 255
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
260 265 270
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
275 280 285
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
290 295 300
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
305 310 315 320
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
325 330 335
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
340 345 350
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
355 360 365
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
370 375 380
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
385 390 395 400
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
405 410 415
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
420 425 430
Leu Ser Leu Ser Leu Gly Lys
435
<210> 93
<211> 214
<212> PRT
<213> 人
<400> 93
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 94
<211> 5
<212> PRT
<213> 人
<400> 94
Ser Tyr Gly Met His
1 5
<210> 95
<211> 17
<212> PRT
<213> 人
<400> 95
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 96
<211> 4
<212> PRT
<213> 人
<400> 96
Asn Gly Asp His
1
<210> 97
<211> 11
<212> PRT
<213> 人
<400> 97
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 98
<211> 7
<212> PRT
<213> 人
<400> 98
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 99
<211> 9
<212> PRT
<213> 人
<400> 99
Gln Gln Tyr Asn Asn Trp Pro Arg Thr
1 5
<210> 100
<211> 468
<212> PRT
<213> 人
<400> 100
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr
35 40 45
Ser Asn Ala Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp
65 70 75 80
Tyr Ala Ala Pro Val Gln Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
85 90 95
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Thr Ile Phe Gly Val Val Ser Phe Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
225 230 235 240
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 101
<211> 234
<212> PRT
<213> 人
<400> 101
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
35 40 45
Ile Ser Asp Tyr Leu Ser Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro
50 55 60
Asn Leu Leu Ile Tyr Ala Ala Ser Asn Leu Lys Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Thr Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
100 105 110
Arg Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 102
<211> 1404
<212> DNA
<213> 人
<400> 102
atggaatgga gctgggtgtt cctgttcttt ctgtccgtga ccacaggcgt gcattctgaa 60
gttcagctgg tcgaaagcgg aggaggtctg gtgaaacccg gtggctccct gaggctgagc 120
tgcgccgcct ccggctttac ttacagtaat gcctggatgt cctgggtcag acaggcccca 180
ggtaagggtc tggagtgggt gggtaggatt aagtctaaaa ctgatggcgg gacaacagac 240
tatgccgccc cagtgcaagg acggttcacc atttctaggg acgactctaa gaatacactg 300
tatctgcaga tgaacagcct caaaacagaa gacactgccg tttactactg taccatcttt 360
ggcgttgtct cctttgatta ttggggacag ggtacactcg tgaccgtttc ttccgcaagt 420
acaaaggggc catcagtgtt tccactggcc ccatcctcta agagcactag tggcggcaca 480
gccgccctgg gatgtctggt gaaggactat ttcccagagc ctgtgaccgt cagctggaac 540
agtggtgctc tcacctcagg tgtgcacaca ttccccgctg tgctccaatc cagtggcctc 600
tacagtctga gcagcgttgt gactgttccc agtagctcac tgggcaccca aacctacata 660
tgcaatgtga accataaacc tagcaatacc aaagtggaca agaaagtgga acctaagtcc 720
tgtgacaaga ctcatacctg tcctccttgt cctgccccag agctgctcgg aggcccttcc 780
gtctttctct tcccaccaaa gccaaaggat accctgatga tcagccggac acctgaggtt 840
acctgcgttg tggtcgacgt ttcacacgag gatcctgaag tcaaattcaa ctggtacgtt 900
gatggagtcg aggtccacaa cgccaaaacc aagcctcgcg aagaacaata caatagcaca 960
tatagggtgg tgtctgtgct cactgtcctg caccaggact ggctgaacgg caaggagtac 1020
aaatgcaagg ttagtaacaa ggccctgccc gcacccattg agaagactat cagtaaagct 1080
aagggccagc ctcgcgagcc tcaggtttac accctgcctc cctctagaga ggaaatgaca 1140
aagaaccagg tgtctctcac ctgcctggtt aaaggattct atccatccga cattgctgtg 1200
gaatgggaat ccaacggaca gcccgaaaac aactataaga caacaccacc tgttctggat 1260
tccgatggtt ccttctttct gtattccaaa ctcacagtgg acaagagtcg ctggcagcaa 1320
ggtaacgtgt tttcttgctc cgtgatgcac gaagcactcc acaatcacta cactcagaag 1380
agtctcagcc tctctccagg caaa 1404
<210> 103
<211> 702
<212> DNA
<213> 人
<400> 103
atgtctgtgc ctacccaggt gctgggactg ctgctgctgt ggctgacaga cgcccgctgt 60
gatgttcaga tgacacagtc tccaagtagt ctcagcgcaa gcgttggcga cagagtgact 120
atcacatgca gagcctctca gtctatctct gactatctgt cttggtacca gcagaggcca 180
ggcaaagctc caaacctcct gatctatgct gccagtaatc tgaagacagg cgtgcctagt 240
agattctccg ggtccggtag tgggactgat ttcaccctga caatctccac actgcaacct 300
gaggattttg ctacctacta ttgtcagcaa tcttatcgca gcccttggac cttcggacag 360
gggactaagg ttgagattaa acgcaccgtg gcagcaccca gcgtctttat ctttcctccc 420
tccgacgagc agctcaagtc cggaacagca tcagtcgttt gcctcctgaa taacttttat 480
ccaagggagg ccaaggtcca gtggaaagtc gacaatgccc tccaatctgg taactcccag 540
gagtctgtga ctgaacaaga ttctaaggac agtacctatt cactcagctc caccctgacc 600
ctcagcaaag cagactacga aaagcataaa gtttacgctt gcgaagtgac ccaccaaggc 660
ctgtcttctc ctgtcacaaa gagttttaat agaggggagt gt 702
<210> 104
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工接头
<400> 104
Gly Phe Leu Gly
1
<210> 105
<211> 120
<212> PRT
<213> 人
<400> 105
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Val Ser Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Phe Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Leu Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Asn Ile Ala Val Ala Gly Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Val Val Thr Val Ser Ser
115 120
<210> 106
<211> 108
<212> PRT
<213> 人
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ile Ser Asp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg
100 105
<210> 107
<211> 8
<212> PRT
<213> 人
<400> 107
Gly Tyr Thr Phe Thr Gly Tyr Tyr
1 5
<210> 108
<211> 8
<212> PRT
<213> 人
<400> 108
Ile Asn Pro Asn Ser Gly Val Ser
1 5
<210> 109
<211> 11
<212> PRT
<213> 人
<400> 109
Ala Asn Ile Ala Val Ala Gly Ala Phe Asp Ile
1 5 10
<210> 110
<211> 6
<212> PRT
<213> 人
<400> 110
Gln Gly Ile Ser Asn Tyr
1 5
<210> 111
<211> 7
<212> PRT
<213> 人
<400> 111
Tyr Ala Ala Ser Ser Leu Gln
1 5
<210> 112
<211> 9
<212> PRT
<213> 人
<400> 112
Gln Gln Tyr Ile Ser Asp Pro Ile Thr
1 5
<210> 113
<211> 118
<212> PRT
<213> 人
<400> 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Thr Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Ser Gly Trp Asn Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 114
<211> 108
<212> PRT
<213> 人
<400> 114
Asp Val Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Gly Gly Leu Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Thr Arg
100 105
<210> 115
<211> 8
<212> PRT
<213> 人
<400> 115
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 116
<211> 7
<212> PRT
<213> 人
<400> 116
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 117
<211> 10
<212> PRT
<213> 人
<400> 117
Asp Lys Ser Gly Trp Asn Gly Phe Asp Tyr
1 5 10
<210> 118
<211> 6
<212> PRT
<213> 人
<400> 118
Gln Ser Val Ser Thr Tyr
1 5
<210> 119
<211> 7
<212> PRT
<213> 人
<400> 119
Tyr Ala Ala Ser Ser Leu Gln
1 5
<210> 120
<211> 9
<212> PRT
<213> 人
<400> 120
Gln Gln Ser Ser Ser Thr Pro Leu Thr
1 5
Claims (190)
1.一种治疗或预防癌症的方法,其包括向有需要的患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及治疗有效量的包含检查点调节剂的组合物。
2.如权利要求1所述的方法,其中所述检查点调节剂是针对选自下组的检查点蛋白:PD1、PD-L1、PD-L2、CTLA-4、ICOS、TIGIT、CD28、TMIGD2、CD137、CD137L、CD27、OX40、OX40L、LAG3、VISTA、GITR、DNAM-1、CD96、2B4、TIM-3、CEACAM、CRTAM、SLAMF6、半乳凝素-9、CD48、CD155、GITRL、CD40、CD40L、CD70、HVEM、B7-H7、B7-H3、B7-H4、ICOSL、CD80、CD86、BTLA、CD160、LIGHT、腺苷A2a受体、SIRPα、DC-SIGN、CD200R、DR3、TL1A、CD200、BTN2A1、CD47、IDO、TDO。
3.如权利要求1或权利要求2所述的方法,其中所述检查点调节剂是PD1或PD-L1抑制剂,优选PD1。
4.一种增强PD-1/PD-L1抑制剂在被鉴定为有需要的患者中的有效性的方法,所述方法包括向所述患者给予(a)治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及(b)包含PD-1/PD-L1相互作用抑制剂的组合物。
5.如权利要求3或权利要求4所述的方法,其中所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段以及包含PD-1/PD-L1抑制剂的组合物可以同时、分开或依次给予,优选依次给予。
6.如权利要求1-5中任一项所述的方法,其中所述检查点调节剂是抗体。
7.如权利要求6所述的方法,其中所述抗体是抗PD1或PD-L1抗体。
8.如权利要求7所述的方法,其中所述抗-PD-1抗体是:纳武单抗(MDX-1106,Opdivo;百时美施贵宝公司),派姆单抗(MK-3475,Keytruda,兰姆单抗,BMS-936558;默克公司),西米普利单抗(REGN-2810,Libtayo;再生元),多塔利单抗(TSR-042,Tesaro,Inc.),EH12.2H7(ENUM-388D4,白乐津公司,目录号329902),巴替利单抗(Agenus Inc.)。
9.如权利要求7所述的方法,其中所述抗-PD-L1抗体是:阿维鲁单抗(Bavencio;默克雪兰诺公司,辉瑞公司),德瓦鲁单抗(Imfinzi,阿斯利康),BMS-936559,阿特珠单抗(Tecentriq,基因泰克)。
10.如权利要求1-9中任一项所述的方法,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段至少1个周期、至少2个周期、至少3个周期、至少4个周期或至少5个周期之后给予所述检查点调节剂。
11.如权利要求10所述的方法,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段1-5个周期、2-4个周期或2-3个周期之后给予所述检查点调节剂。
12.如权利要求10或11所述的方法,其中所述患者随后被给予至少1个、至少2个、至少3个、至少4个或至少5个或更多周期的所述检查点调节剂。
13.如权利要求1-12中任一项所述的方法,其中在给予所述调节CD205+免疫调节细胞群的抗体或其抗原结合片段之后7天-12周给予所述检查点调节剂,优选7天-10周,或7天-8周,或7天-6周,或7天-4周,或7-21天,或10-19天,或12-16天,或14-16天,或19-28天,更优选20-25天,最优选21天-24天。
14.一种用于增加患癌患者中抗肿瘤免疫反应的方法,其包括向所述患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
15.如权利要求14所述的方法,其中所述抗肿瘤免疫反应是免疫细胞介导的肿瘤特异性反应。
16.如权利要求14或权利要求15所述的方法,其中所述抗肿瘤免疫反应是NK细胞介导的肿瘤特异性反应。
17.如权利要求14或15所述的方法,其中所述抗肿瘤免疫反应是T细胞介导的肿瘤特异性反应。
18.一种用于增加患癌患者中T细胞数量的方法,其包括向所述患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
19.一种用于减少患癌患者中肿瘤大小的方法,其包括向所述患者给予治疗有效量的调节CD205+免疫调节细胞群体的抗体或其抗原结合片段。
20.如权利要求19所述的方法,其中所述肿瘤是转移性肿瘤。
21.如权利要求20所述的方法,其中所述转移性肿瘤位于肺或肝中。
22.如权利要求1-21中任一项所述的方法,其中所述CD205+免疫调节细胞群体是CD8+。
23.如权利要求22所述的方法,其中所述CD205+CD8+免疫调节细胞群体被耗竭。
24.如权利要求1-21中任一项所述的方法,其中所述免疫调节细胞是pDC和/或mDC。
25.如权利要求24所述的方法,其中所述pDC和/或mDC群体增加。
26.如权利要求1-21中任一项所述的方法,其中所述CD205+免疫调节细胞群体是CD4+的。
27.如权利要求26所述的方法,其中所述CD205+CD4+免疫调节细胞群体被耗竭。
28.如权利要求22-23或26-27中任一项所述的方法,其中所述免疫调节细胞是T-Reg细胞。
29.如权利要求1-28中任一项所述的方法,其中所述免疫调节细胞是免疫抑制细胞。
30.如权利要求17-29中任一项所述的方法,其中所述T细胞是CD8+T细胞。
31.如权利要求17-29中任一项所述的方法,其中所述T细胞是CD4+T细胞。
32.如权利要求18-31中任一项所述的方法,其中向所述患者同时地、分开地、依次地或相继地给予癌症疫苗。
33.如权利要求18-31中任一项所述的方法,其中向所述患者同时地、分开地、依次地或相继地给予双特异性抗体。
34.如权利要求33所述的方法,其中所述双特异性抗体是T细胞接合器(BiTE)。
35.如权利要求33或34所述的方法,其中所述双特异性抗体包含与CD3结合的第一结合结构域。
36.如权利要求33-35中任一项所述的方法,其中所述双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
37.如权利要求1-36中任一项所述的方法,其中所述患者对于至少一种化疗是难治性的,或所述患者的癌症在至少一种化疗中进展。
38.如权利要求1-37中任一项所述的方法,其中所述患者对检查点调节剂治疗是难治性的。
39.如权利要求1-38中任一项所述的方法,其中所述患者对检查点调节剂治疗是不适格的。
40.如权利要求39所述的方法,其中所述检查点调节剂治疗是PD1治疗。
41.如权利要求1-40中任一项所述的方法,其中所述癌症是PDL1阴性的或低PDL1的。
42.如权利要求41所述的方法,其中所述患者患有的癌症具有低于50%、低于40%、低于30%、低于20%、低于10%、低于5%、低于4%、低于3%、低于2%或低于1%的PD-L1表达。
43.如权利要求1-42中任一项所述的方法,其中,所述癌症是MSI稳定的。
44.如前述权利要求中任一项所述的方法,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD8+细胞是CD205+的。
45.如前述权利要求中任一项所述的方法,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD4+细胞是CD205+的。
46.如前述权利要求中任一项所述的方法,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的pDC和/或mDC是CD205+的。
47.如前述权利要求中任一项所述的方法,其中所述抗体或其抗原结合部分与CD205结合。
48.如前述权利要求中任一项所述的方法,其中所述抗体或其抗原结合部分与CD205结合,且包含:
重链可变区,包括:
iii)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
iii)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;
iii)第三vlCDR,包含SEQ ID NO:10;
任选地,其中上述SEQ ID NO的任一个或多个独立地包含一个或两个氨基酸取代,优选保守取代。
49.如前述权利要求中任一项所述的方法,其中抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区与SEQ ID NO:1具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链可变区与SEQ ID NO:2具有至少80%、85%、90%、95%或99%氨基酸序列相同性。
50.如前述权利要求中任一项所述的方法,其中所述与CD205结合的抗体包含
(iii)与SEQ ID NO:100具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的重链;和
(ii)与SEQ ID NO:101具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的轻链。
51.如前述权利要求中任一项所述的方法,其中所述抗体或其抗原结合部分还包含共价连接部分。
52.如权利要求51所述的方法,其中所述部分是药物。
53.如权利要求52所述的方法,其中所述药物选自下组:美登木素、多拉司他汀、哈米特林、奥瑞他汀、单端孢菌素、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉、喜树碱、蒽环类、安曲霉素、噻吩并吲哚、鹅膏毒素、CC1065或紫杉醇及其衍生物。
54.如权利要求53所述的方法,其中所述药物是美登木素,选自DM4和DM1,优选DM4。
55.如前述权利要求中任一项所述的方法,其中所述癌症是CD205阳性癌症。
56.如前述权利要求中任一项所述方法,其中所述癌症选自下组:胃癌、子宫内膜癌、食道癌、肺癌、卵巢癌、胃食管连接部癌、胰腺癌、乳腺癌、结直肠癌、皮肤癌、甲状腺癌、肾癌、肝癌、头颈癌、膀胱癌、白血病,优选急性髓系白血病或慢性淋巴细胞白血病、骨髓瘤,优选多发性骨髓瘤和淋巴瘤,优选弥漫性大B细胞淋巴瘤(DLBCL)、B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、粘膜相关淋巴组织(MALT)淋巴瘤、富含T细胞/组织细胞的B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、小淋巴细胞淋巴瘤、边缘区淋巴瘤、T细胞淋巴瘤、外周T细胞淋巴瘤、间变性大细胞淋巴瘤和血管免疫母细胞性T细胞淋巴瘤。
57.如权利要求56所述的方法,其中所述癌症选自下组:胃癌、子宫内膜癌、食管癌、肺癌、卵巢癌、胃食管连接部癌、乳腺癌、膀胱癌和肾癌。
58.如前述权利要求中任一项所述的方法,其中所述患者是人。
59.一种药物组合,其包括:
iii)抗CD205抗体或其抗原结合部分,所述抗体包含:
重链可变区,包括:
iii)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
iii)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;
iii)第三vlCDR,包含SEQ ID NO:10;和
b)检查点调节剂。
60.如权利要求59所述的药物组合,其中所述药物组合是用于同时、分开或依次使用的组合制剂的形式,优选依次。
61.如权利要求59或权利要求60所述的药物组合,其中所述检查点调节剂是PD1/PD-L1抑制剂,优选所述PD1/PD-L1抑制剂是抗体。
62.如权利要求61所述的药物组合,其中所述PD1/PD-L1抑制剂选自:纳武单抗(MDX-1106,Opdivo;百时美施贵宝公司),派姆单抗(MK-3475,
Keytruda,兰姆单抗,BMS-936558;默克公司),多塔利单抗(TSR-042Tesaro,Inc.),西米普利单抗(REGN-2810,Libtayo,再生元),EH12.2H7(白乐津公司,目录号329902),巴替利单抗(Agenus Inc),阿维鲁单抗(Bavencio;默克雪兰诺公司,辉瑞公司),德瓦鲁单抗(Imfinzi,阿斯利康),BMS-936559,阿特珠单抗(Tecentriq,基因泰克)或其等同物。
63.如权利要求59-62中任一项所述的药物组合,其中所述抗CD205抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区与SEQ ID NO:1具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链可变区与SEQ ID NO:2具有至少80%、85%、90%、95%或99%氨基酸序列相同性。
64.如权利要求59-63中任一项所述的药物组合,其中所述与CD205结合的抗体包含;
(i)与SEQ ID NO:100具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的重链;和
(ii)与SEQ ID NO:101具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的轻链。
65.如权利要求59-64中任一项所述的药物组合,其中所述抗体或其抗原结合部分还包含共价连接部分。
66.如权利要求65所述的药物组合,其中所述部分是药物。
67.如权利要求66所述的药物组合,其中所述药物选自下组:美登木素、多拉司他汀、哈米特林、奥瑞他汀、单端孢菌素、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉、喜树碱、蒽环类、安曲霉素、噻吩并吲哚、鹅膏毒素、CC1065或紫杉醇及其衍生物。
68.如权利要求67所述的药物组合,其中所述药物是美登木素,选自DM4和DM1,优选DM4。
69.如权利要求59-68中任一项所述的药物组合,其包含至少一种药学上可接受的稀释剂、赋形剂或运载体。
70.一种调节CD205+免疫调节细胞群体的抗体或其抗原结合部分,用于增加患癌患者的抗肿瘤免疫反应。
71.如权利要求70所述的用途的抗体或其抗原结合部分,其中所述抗肿瘤免疫反应是免疫细胞介导的肿瘤特异性反应。
72.如权利要求70或71所述用途的抗体或其抗原结合部分,其中所述抗肿瘤免疫反应是NK细胞介导的肿瘤特异性反应。
73.如权利要求70-72中任一项所述用途的抗体或其抗原结合部分,其中所述抗肿瘤免疫反应是T细胞介导的肿瘤特异性反应。
74.一种调节CD205+免疫调节细胞群体的抗体或其抗原结合部分,用于增加患癌患者的T细胞数量。
75.如权利要求70-74中任一项所述用途的抗体或其抗原结合部分,其中所述CD205+免疫调节细胞群体是CD8+的。
76.如权利要求75所述用途的抗体或其抗原结合部分,其中所述CD205+CD8+免疫调节细胞群体被耗竭。
77.如权利要求70-74中任一项所述用途的抗体或其抗原结合部分,其中所述免疫调节细胞是pDC和/或mDC。
78.如权利要求77所述用途的抗体或其抗原结合部分,其中所述pDC和/或mDC群体被增加。
79.如权利要求70-74中任一项所述用途的抗体或其抗原结合部分,其中所述CD205+免疫调节细胞群体是CD4+的。
80.如权利要求79所述用途的抗体或其抗原结合部分,其中所述CD205+CD4+免疫调节细胞群体被耗竭。
81.如权利要求75-76或79-80中任一项所述用途的抗体或其抗原结合部分,其中所述免疫调节细胞是T-Reg细胞。
82.如权利要求70-81中任一项所述用途的抗体或其抗原结合部分,其中所述免疫调节细胞是免疫抑制细胞。
83.如权利要求73-82中任一项所述用途的抗体或其抗原结合部分,其中所述T细胞是CD8+T细胞。
84.如权利要求73-82中任一项所述用途的抗体或其抗原结合部分,其中所述T细胞是CD4+T细胞。
85.如权利要求70-84中任一项所述用途的抗体或其抗原结合部分,其中向所述患者同时地、分开地、依次地或相继地给予癌症疫苗。
86.如权利要求70-84中任一项所述用途的抗体或其抗原结合部分,其中向所述患者同时地、分开地、依次地或相继地给予双特异性抗体。
87.如权利要求86所述用途的抗体或其抗原结合部分,其中所述双特异性抗体是T细胞接合器(BiTE)。
88.如权利要求86或权利要求82所述的用途的抗体或其抗原结合部分,其中所述双特异性抗体包含与CD3结合的第一结合结构域。
89.如权利要求86-88中任一项所述用途的抗体或其抗原结合部分,其中所述双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
90.如权利要求70-89中任一项所述用途的抗体或其抗原结合部分,其中所述患者对于至少一种化疗是难治性的,或所述患者的癌症在至少一种化疗中进展。
91.如权利要求70-90中任一项所述用途的抗体或其抗原结合部分,其中所述患者对检查点调节剂治疗是难治性的。
92.如权利要求91所述用途的抗体或其抗原结合部分,其中所述检查点调节剂治疗是PD1抑制剂治疗。
93.如权利要求70-92中任一项所述用途的抗体或其抗原结合部分,其中所述癌症是PDL1阴性的或低PDL1的。
94.如权利要求93所述用途的抗体或其抗原结合部分,其中所述癌症具有低于50%、低于40%、低于30%、低于20%、低于10%、低于5%、低于4%、低于3%、低于2%或低于1%的PD-L1表达。
95.如权利要求70-94中任一项所述用途的抗体或其抗原结合部分,其中所述癌症是MSI稳定的。
96.如权利要求70-95中任一项所述用途的抗体或其抗原结合部分,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD8+细胞是CD205+的。
97.如权利要求70-95中任一项所述用途的抗体或其抗原结合部分,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD4+细胞是CD205+的。
98.如权利要求70-95中任一项所述用途的抗体或其抗原结合部分,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的pDC和/或mDC是CD205+的。
99.一种用于治疗或预防癌症的药物组合,所述组合包含;调节CD205+免疫调节细胞群体的抗体或其抗原结合部分;和包含检查点调节剂的组合物。
100.如权利要求99所述用途的药物组合,其中所述检查点调节剂是针对选自下组的检查点蛋白:PD1、PD-L1、PD-L2、CTLA-4、ICOS、TIGIT、CD28、TMIGD2、CD137、CD137L、CD27、OX40、OX40L、LAG3、VISTA、GITR、DNAM-1、CD96、2B4、TIM-3、CEACAM、CRTAM、SLAMF6、半乳凝素-9、CD48、CD155、GITRL、CD40、CD40L、CD70、HVEM、B7-H7、B7-H3、B7-H4、ICOSL、CD80、CD86、BTLA、CD160、LIGHT、腺苷A2a受体、SIRPα、DC-SIGN、CD200R、DR3、TL1A、CD200、BTN2A1、CD47、IDO、TDO。
101.如权利要求99或权利要求100所述用途的药物组合,其中所述检查点调节剂是PD1或PD-L1抑制剂,优选PD1。
102.一种用于增强PD-1/PD-L1相互作用抑制剂在患者中的有效性的药物组合,所述组合包含;调节CD205+免疫调节细胞群体的抗体或其抗原结合部分;和包含PD1/PD-L1相互作用抑制剂的组合物。
103.如权利要求99-102中任一项所述用途的药物组合,其中所述药物组合是用于同时、分开或依次使用的组合制剂的形式,优选依次。
104.如权利要求99-103中任一项所述用途的药物组合,其中所述CD205+免疫调节细胞群体是CD8+的。
105.如权利要求104中所述用途的药物组合,其中所述CD205+CD8+免疫调节细胞群体被耗竭。
106.如权利要求99-103中任一项所述用途的药物组合,其中所述免疫调节细胞是pDC和/或mDC。
107.如权利要求106所述用途的药物组合,其中所述pDC和/或mDC群体增加。
108.如权利要求99-103中任一项所述用途的药物组合,其中所述CD205+免疫调节细胞群体是CD4+的。
109.如权利要求108中所述用途的药物组合,其中所述CD205+CD4+免疫调节细胞群体被耗竭。
110.如权利要求104-105或108-109中任一项所述用途的药物组合,其中所述免疫调节细胞是T-Reg细胞。
111.如权利要求99-110中任一项所述用途的药物组合,其中所述免疫调节细胞是免疫抑制细胞。
112.如权利要求99-111中任一项所述用途的药物组合,其中向所述患者同时地、分开地、依次地或相继地给予癌症疫苗。
113.如权利要求99-111中任一项所述用途的药物组合,其中向所述患者同时地、分开地、依次地或相继地给予双特异性抗体。
114.如权利要求113所述用途的药物组合,其中所述双特异性抗体是T细胞接合器(BiTE)。
115.如权利要求113或权利要求114所述用途的药物组合,其中所述双特异性抗体包含与CD3结合的第一结合结构域。
116.如权利要求113-114中任一项所述用途的药物组合,其中所述双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
117.如权利要求99-116中任一项所述用途的药物组合,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段至少1个周期、至少2个周期、至少3个周期、至少4个周期或至少5个周期之后给予所述检查点调节剂。
118.如权利要求117所述用途的药物组合,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段1-5个周期、2-4个周期或2-3个周期之后给予所述检查点调节剂。
119.如权利要求117或118所述用途的药物组合,其中所述患者随后被给予至少1个、至少2个、至少3个、至少4个或至少5个或更多周期的所述检查点调节剂。
120.如权利要求99-119中任一项所述用途的药物组合,其中在给予所述与CD205结合的抗体或其抗原结合部分之后7天-12周给予所述检查点调节剂,优选7天-10周,或7天-8周,或7天-6周,或7天-4周,或7-21天,或10-19天,或12-16天,或14-16天,或19-28天,更优选20-25天,最优选21天-24天。
121.如权利要求99-120中任一项所述用途的药物组合,其中所述患者对于至少一种化疗是难治性的,或所述患者的癌症在至少一种化疗中进展。
122.如权利要求99-121中任一项所述用途的药物组合,其中所述患者对检查点调节剂治疗是难治性的。
123.如权利要求122所述用途的药物组合,其中所述检查点调节剂治疗是PD1抑制剂治疗。
124.如权利要求99-123中任一项所述用途的药物组合,其中所述癌症是PDL1阴性的或低PDL1的。
125.如权利要求99-124中任一项所述用途的药物组合,其中所述癌症是MSI稳定的。
126.如权利要求99-125中任一项所述用途的药物组合,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD8+细胞是CD205+的。
127.如权利要求99-125中任一项所述用途的药物组合,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的CD4+细胞是CD205+的。
128.如权利要求99-125中任一项所述用途的药物组合,其中在先前从所述患者分离的血液样品中,至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%或更多的pDC和/或mDC是CD205+的。
129.如权利要求70-128中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述抗体或其抗原结合部分与CD205结合。
130.如权利要求70-129中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述与CD205结合的抗体或其抗原结合部分包括:
重链可变区,包括:
i)第一vhCDR,包含SEQ ID NO:5;
ii)第二vhCDR,包含SEQ ID NO:6;和
iii)第三vhCDR,包含SEQ ID NO:7;和
轻链可变区,包括:
i)第一vlCDR,包含SEQ ID NO:8;
ii)第二vlCDR,包含SEQ ID NO:9;和
iii)第三vlCDR,包含SEQ ID NO:10
任选地,其中上述SEQ ID NO的任一个或多个独立地包含一个或两个氨基酸取代,优选保守取代。
131.如权利要求70-130中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述与CD205结合的抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区与SEQ ID NO:1具有至少80%、85%、90%、95%或99%氨基酸序列相同性,其中所述轻链可变区与SEQ ID NO:2具有至少80%、85%、90%、95%或99%氨基酸序列相同性。
132.如权利要求70-131中任一项所述用途的抗体或药物组合,其中所述与CD205结合的抗体包含;
(i)与SEQ ID NO:100具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的重链;和
(ii)与SEQ ID NO:101具有至少80%、85%、90%、95%、99%或100%氨基酸序列相同性的轻链。
133.如权利要求70-132中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述抗体或其抗原结合部分还包含共价连接部分。
134.如权利要求133所述用途的抗体或其抗原结合部分或药物组合,其中所述部分是药物。
135.如权利要求135中所述用途的抗体或其抗原结合部分或药物组合,其中所述药物选自下组:美登木素、多拉司他汀、哈米特林、奥瑞他汀、单端孢菌素、卡奇霉素、多卡霉素、细菌免疫毒素、吡喃吲哚并喹啉、喜树碱、蒽环类、安曲霉素、噻吩并吲哚、鹅膏毒素、CC1065或紫杉醇及其衍生物。
136.如权利要求135中所述用途的抗体或其抗原结合部分或药物组合,其中所述药物是美登木素,选自DM4和DM1,优选DM4。
137.如权利要求99-136中任一项所述用途的药物组合,其中所述检查点调节剂是抗体。
138.如权利要求137所述用途的药物组合,其中所述抗体是抗PD1或PD-L1抗体。
139.如权利要求138所述用途的药物组合,其中所述抗-PD-1抗体是:纳武单抗(MDX-1106,Opdivo;百时美施贵宝公司),派姆单抗(MK-3475,Keytruda,兰姆单抗,BMS-936558;默克公司),多塔利单抗(TSR-042Tesaro,Inc.),西米普利单抗(REGN-2810,Libtayo;再生元),EH12.2H7(ENUM-388D4,白乐津公司,目录号329902),巴替利单抗(Agenus Inc.)。
140.如权利要求138所述用途的药物组合,其中所述抗-PD-L1抗体是:阿维鲁单抗(Bavencio;默克雪兰诺公司,辉瑞公司),德瓦鲁单抗(Imfinzi,阿斯利康),BMS-936559,阿特珠单抗(Tecentriq,基因泰克)。
141.如权利要求70-140中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述癌症是CD205阳性癌症。
142.如权利要求70-141中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述癌症选自下组:胃癌、子宫内膜癌、食道癌、肺癌、卵巢癌、胃食管连接部癌、胰腺癌、乳腺癌、结直肠癌、皮肤癌、甲状腺癌、肾癌、肝癌、头颈癌、膀胱癌、白血病,优选急性髓系白血病或慢性淋巴细胞白血病、骨髓瘤,优选多发性骨髓瘤和淋巴瘤,优选弥漫性大B细胞淋巴瘤(DLBCL)、B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、粘膜相关淋巴组织(MALT)淋巴瘤、富含T细胞/组织细胞的B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、小淋巴细胞淋巴瘤、边缘区淋巴瘤、T细胞淋巴瘤、外周T细胞淋巴瘤、间变性大细胞淋巴瘤和血管免疫母细胞性T细胞淋巴瘤。
143.如权利要求142所述用途的抗体或其抗原结合部分或药物组合,其中所述癌症选自下组:胃癌、子宫内膜癌、食管癌、肺癌、卵巢癌、胃食管连接部癌、乳腺癌、膀胱癌和肾癌。
144.如权利要求70-143中任一项所述用途的抗体或其抗原结合部分或药物组合,其中所述患者是人。
145.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:
鉴定其中先前从患者分离的血液样品中至少20%的CD8+细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
146.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的体外方法,其包括:
a.确定先前从所述患者分离的血液样品中CD8+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD8+细胞CD205+,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
147.如权利要求146所述的体外方法,其进一步包括向所述患者给予治疗有效量的与CD205结合的所述抗体或其抗原结合片段的步骤。
148.一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
a.从所述患者获得血液样品,
b.鉴定血液样本中是否至少20%的CD8+细胞是CD205+的。
149.如权利要求148所述的方法,如果血液样品中至少20%的CD8+细胞是CD205+的,则所述方法进一步包括向所述患者给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
150.如权利要求145-149中任一项所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+细胞是CD205+的。
151.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:
鉴定其中先前从患者分离的血液样品中至少20%的CD4+细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
152.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的体外方法,其包括:
a.确定先前从所述患者分离的血液样品中CD4+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD4+细胞CD205+,则选择患者接受结合CD205的抗体或其抗原结合片段的治疗。
153.如权利要求152所述的体外方法,其进一步包括向所述患者给予治疗有效量的与CD205结合的所述抗体或其抗原结合片段的步骤。
154.一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
a.从所述患者获得血液样品,
b.鉴定血液样品中是否至少20%的CD4+细胞是CD205+的。
155.如权利要求154所述的方法,如果血液样品中至少20%的CD4+细胞是CD205+的,则所述方法进一步包括向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
156.如权利要求151-155中任一项所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD4+细胞是CD205+的。
157.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的方法,其中所述患者患有癌症,所述方法包括:
鉴定其中先前从所述患者分离的血液样品中至少20%的CD8+和CD4+的细胞是CD205+的患者,并向所述患者给予治疗有效量的抗CD205抗体或其抗原结合片段。
158.一种选择适合用结合CD205的抗体或其抗原结合片段治疗的患者的体外方法,其包括:
a.确定先前从所述患者分离的血液样品中CD8+和CD4+细胞中CD205+细胞的百分比;和
b.如果血液样品中至少20%的CD8+和CD4+细胞CD205+,则选择所述患者接受结合CD205的抗体或其抗原结合片段的治疗。
159.如权利要求158所述的体外方法,其进一步包括向所述患者给予治疗有效量的与CD205结合的所述抗体或其抗原结合片段的步骤。
160.一种用于确定结合CD205的抗体或其抗原结合片段在治疗患者的癌症中的功效的方法,所述方法包括
a.从所述患者获得血液样品,
b.鉴定血液样品中是否至少20%的CD8+和CD4+细胞是CD205+的。
161.如权利要求160所述的方法,如果血液样品中至少20%的CD8+和CD4+细胞是CD205+的,则所述方法进一步包括向所述对象给予治疗有效量的结合CD205的抗体或其抗原结合片段的步骤。
162.如权利要求157-161中任一项所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+和CD4+细胞是CD205+的。
163.一种治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少20%的CD8+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
164.如权利要求163所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+细胞是CD205+的。
165.一种治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少20%的CD4+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
166.如权利要求165所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD4+细胞是CD205+的。
167.一种治疗或预防癌症的方法,所述方法包括:鉴定患者,其中先前从所述患者分离的血液样品中的至少20%的CD8+细胞和CD4+细胞是CD205+的,并且向所述患者给予治疗有效量的与CD205结合的抗体或其抗原结合片段。
168.如权利要求167所述的方法,其中至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的所述患者的CD8+和CD4+细胞是CD205+的。
169.一种治疗方法,其包括:
(a)计算先前从诊断患有癌症的患者分离的血液样品中CD4+和/或CD8+细胞为CD205+的百分比,以鉴定所述患者具有应答者表型;和
(b)向所述具有应答者表型的患者给予治疗有效量的结合CD205的抗体或其抗原结合片段。
170.如权利要求169所述的治疗,其中先前从诊断为患有癌症的患者中分离的血液样品中至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%的CD4+和/或CD8+细胞是CD205+阳性的。
171.如权利要求145-170中任一项所述的方法,其包括相继地给予所述患者检查点调节剂的进一步步骤。
172.如权利要求171所述的方法,其中所述检查点调节剂是针对选自下组的检查点蛋白:PD1、PD-L1、PD-L2、CTLA-4、ICOS、TIGIT、CD28、TMIGD2、CD137、CD137L、CD27、OX40、OX40L、LAG3、VISTA、GITR、DNAM-1、CD96、2B4、TIM-3、CEACAM、CRTAM、SLAMF6、半乳凝素-9、CD48、CD155、GITRL、CD40、CD40L、CD70、HVEM、B7-H7、B7-H3、B7-H4、ICOSL、CD80、CD86、BTLA、CD160、LIGHT、腺苷A2a受体、SIRPα、DC-SIGN、CD200R、DR3、TL1A、CD200、BTN2A1、CD47、IDO、TDO。
173.如权利要求172所述的方法,其中所述检查点调节剂是抗体。
174.如权利要求173所述的方法,其中所述抗体是PD1或PD-L1抑制剂,优选PD1。
175.如权利要求174所述的方法,其中所述抗-PD-1抗体是:纳武单抗(MDX-1 106,Opdivo;百时美施贵宝公司),派姆单抗(MK-3475,Keytruda,兰姆单抗,BMS-936558;默克公司),西米普利单抗(REGN-2810,Libtayo;再生元),多塔利单抗(TSR-042,Tesaro,Inc.),EH12.2H7(ENUM-388D4,白乐津公司,目录号329902),巴替利单抗(Agenus Inc.)。
176.如权利要求174所述的方法,其中所述抗-PD-L1抗体是:阿维鲁单抗(Bavencio;默克雪兰诺公司,辉瑞公司),德瓦鲁单抗(Imfinzi,阿斯利康),BMS-936559,阿特珠单抗(Tecentriq,基因泰克)。
177.如权利要求145-176中任一项所述的方法,其中向所述患者同时地、分开地、依次地或相继地给予癌症疫苗。
178.如权利要求145-176中任一项所述的方法,其中向所述患者同时地、分开地、依次地或相继地给予双特异性抗体。
179.如权利要求178所述的方法,其中所述双特异性抗体是T细胞接合器(BiTE)。
180.如权利要求178或权利要求179所述的方法,其中所述双特异性抗体包含与CD3结合的第一结合结构域。
181.如权利要求178-180中任一项所述的方法,其中所述双特异性抗体包含与肿瘤特异性抗原结合的第二结合结构域。
182.如权利要求145-181中任一项所述的方法,其中所述患者对于至少一种先前线的化疗是难治性的,或所述患者的癌症在至少一种先前线的化疗中已经进展。
183.如权利要求145-182中任一项所述的方法,其中所述患者对检查点调节剂治疗是难治性的。
184.如权利要求183所述的方法,其中所述检查点调节剂治疗是PD1治疗。
185.如权利要求145-184中任一项所述的方法,其中所述癌症是PDL1阴性的或低PDL1的。
186.如权利要求145-185中任一项所述的方法,其中,所述癌症是MSI稳定的。
187.如权利要求145-186中任一项所述的方法,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段至少1个周期、至少2个周期、至少3个周期、至少4个周期或至少5个周期之后给予所述检查点抑制剂。
188.如权利要求187所述的方法,其中向所述患者给予所述调节CD205+免疫调节细胞群体的抗体或其抗原结合片段1-5个周期、2-4个周期或2-3个周期之后给予所述检查点调节剂。
189.如权利要求171-188中任一项所述的方法,其中所述患者被给予至少1个、至少2个、至少3个、至少4个或至少5个或更多周期的所述检查点调节剂。
190.如权利要求171-189中任一项所述的方法,其中在给予所述与CD205结合的抗体或其抗原结合部分之后7天-12周给予所述检查点调节剂,优选7天-10周,或7天-8周,或7天-6周,或7天-4周,或7-21天,或10-19天,或12-16天,或14-16天,或19-28天,更优选20-25天,最优选21天-24天。
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GB2109271.3 | 2021-06-28 | ||
GBGB2109271.3A GB202109271D0 (en) | 2021-06-28 | 2021-06-28 | Pharmaceutical composition |
PCT/GB2022/051256 WO2022248835A1 (en) | 2021-05-26 | 2022-05-19 | Pharmaceutical combination comprising an anti-cd205 antibody and an immune checkpoint inhibitor |
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