CN116744976A - 用于治疗实体癌的her3放射免疫疗法 - Google Patents
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Abstract
所提供的是用于治疗受试者的实体癌如HER3阳性肿瘤的组合物和方法,其通过单独或与其他治疗剂或方式联合施用有效量的用放射性核素如225Ac、177Lu、131I、90Y、213Bi、211At、213Bi、227Th或212Pb标记的HER3靶向剂。放射性标记的HER3靶向剂的有效量可以是以单次大剂量施用的最大耐受剂量或分次剂量,这些分次剂量加起来等于最大耐受剂量。
Description
相关申请的交叉引用
本申请要求2021年10月22日提交的国际申请号PCT/US21/56259及其优先权申请美国临时申请序列号63,250,725(2021年9月30日提交)和63/226,699(2021年7月28日提交);2020年11月25日提交的美国临时专利申请号63/118,181;和2020年11月20日提交的美国临时专利申请号63/116,225中的每一项的优先权,上述每项申请均通过引用的方式整体并入本文。
序列表
本申请包含序列表,该序列表已经以ASCII格式通过电子方式提交,并通过引用的方式整体并入本文。所述ASCII副本创建于2021年11月22日,名为ATNM-010PCT_SL_ST25.txt,大小为191,107字节。
技术领域
本发明涉及放射治疗学领域。
背景技术
ErbB3/HER3是一种I型跨膜糖蛋白,是酪氨酸激酶受体(EGFR、HER2、HER3和HER4)的成红细胞致癌基因B(ErbB)家族的成员。通过HER3进行的信号传导可以以配体依赖或配体非依赖的方式被激活。在没有配体的情况下,HER3受体分子通常以单体形式在细胞表面表达,其构象可防止受体二聚化。在这种构象中,子结构域II的二聚环与子结构域IV上的口袋进行分子内接触。HER3配体,例如神经调节蛋白(neuregulin,NRG),如NRG1(也称为heregulin,HRG)或NRG2,与细胞外区域的子结构域I和III结合,引起构象变化,导致子结构域II的二聚环暴露,促进受体二聚化和信号传导。HER3中的某些癌症相关突变破坏了子结构域II和IV之间的这种相互作用,即形成非活性的“闭合”构象所需的相互作用,从而导致在没有配体结合时二聚环的构成性呈现和HER3介导的信号传导的激活。
靶向HER3的抗体可被用于靶向特定的癌细胞,特别是某些实体癌。HER3在几种类型的癌症如乳腺癌、胃肠道癌和胰腺癌中过表达。已显示出HER2/HER3的表达与这些癌症从非侵入性阶段向侵入性阶段的进展之间的相关性。干扰HER3介导的信号传导的药剂,如抗HER3抗体,可能能够对癌细胞建立强大的免疫反应,而使用常规疗法是不充分的。
因此,目前公开的本发明的一个目的是提供治疗上有效的放射性标记的HER3靶向剂,例如用于治疗HER3阳性癌症。目前公开的本发明的相关目的是提供治疗方法,其包括单独或与一种或多种另外的治疗剂联合施用这种放射性标记的HER3靶向剂。
发明内容
本发明提供了一种HER3靶向剂,例如用放射性同位素标记的靶向HER3的单克隆抗体、肽或小分子,以及使用放射性标记的HER3靶向剂诊断和/或治疗HER3阳性(表达HER3)癌症的方法。
根据本发明的某些方面,用于诊断目的的放射性标记的HER3靶向剂可以是包括放射性同位素如111In、68Ga、64Cu、89Zr或177Lu的抗HER3抗体、肽或小分子。
根据某些其他方面,用于治疗干预的放射性标记的HER3靶向剂可以是包括放射性同位素,例如:131I、125I、123I、90Y、177Lu、186Re、188Re、89Sr、153Sm、32P、225Ac、213Bi、213Po、211At、212Bi、213Bi、223Ra、227Th、149Tb、137Cs、212Pb或其组合的抗HER3抗体、肽或小分子。根据某些优选方面,放射性标记的HER3靶向剂可以包括131I、90Y、177Lu、225Ac、213Bi、211At、227Th或212Pb。
根据某些方面,HER3阳性癌症可以是实体瘤。
目前公开的本发明的治疗方法通常包括向患者施用治疗有效量的放射性标记的HER3靶向剂。根据某些方面,放射性标记的HER3靶向剂的有效量可以是最大耐受剂量(MTD)或可以是分次剂量,其中分次剂量中施用的辐射总量是MTD。
根据某些方面,所提供和/或使用的是HER3靶向剂的组合物或数量,其包括HER3靶向剂的放射性标记部分和未放射性标记部分。因此,HER3靶向剂的有效量可以包括少于100mg,例如5mg至60mg或5mg至45mg的总蛋白剂量。根据某些方面,总蛋白剂量可以是0.001mg/kg至3mg/kg受试者体重,例如0.005mg/kg至2mg/kg受试者体重。根据某些方面,总蛋白剂量可以小于2mg/kg,或小于1mg/kg、小于0.5mg/kg,或甚至小于0.1mg/kg。总蛋白剂量的一部分是放射性标记的(即放射性缀合物),如所示,其中放射性标记的HER3靶向剂的有效量可取决于所选择的特定放射性同位素。用于治疗干预的优选放射性同位素包括225Ac、177Lu、131I、90Y、213Bi、211At、227Th或212Pb。因此,HER3靶向剂可以包括放射性标记部分和未标记部分。
根据某些方面,HER3靶向剂在辐射剂量(即其放射性标记部分,例如225Ac-抗HER3抗体、肽或小分子)方面的有效量,可以包括0.1至20μCi/kg受试者体重,例如0.1至10μCi/kg或0.1至5uCi/kg受试者体重,或0.5至20μCi/kg或1至10uCi/kg受试者体重的剂量。
根据某些方面,HER3靶向剂的有效量,即其放射性标记部分,例如225Ac-抗HER3抗体、肽或小分子,可取决于靶向剂的构型,即全长抗体或抗原结合抗体片段(例如Fab、Fab2、微型抗体(minibody)、纳米抗体(nanobody)等),例如本文公开的任何那些。例如,当HER3靶向剂包括作为全长抗体的225Ac-抗HER3抗体时,剂量可小于5uCi/kg受试者体重,例如0.1至5uCi/kg受试者体重。替代地,当HER3靶向剂包括作为片段的225Ac-抗HER3抗体时,剂量可大于5uCi/kg受试者体重,例如5至20uCi/kg受试者体重。
根据某些方面,HER3靶向剂是抗HER3抗体,例如单克隆抗体或其抗原结合片段,例如IgG或其抗原结合片段,例如与被以下识别的HER3表位结合的抗体:Daiichi Sankyo的帕曲妥单抗(Patritumab)、Merrimack Pharmaceuticals的瑟瑞妥单抗(Seribantumab)(MM-121)、罗氏的鲁妥珠单抗(Lumretuzumab)、诺华的依更妥单抗(Elgemtumab)、GlaxoSmithKline的GSK2849330、Celldex Therapeutics的CDX-3379、MediPharma的EV20和MP-RM-1、Isu Abxis Co.的ISU104、Hummingbird Bioscience Pte.的HMBD-001(10D1F)、Regeneron Pharmaceuticals的REGN1400和/或AVEO Oncology的AV-203。根据某些方面,抗HER3抗体选自帕曲妥单抗、瑟瑞妥单抗、鲁妥珠单抗、依更妥单抗、AV-203、CDX-3379或GSK2849330中的一种或多种。
根据某些方面,HER3靶向剂可按照选自由以下组成的组的给药计划施用:在整个治疗期间,每7、10、12、14、20、24、28、35和42天一个剂量,其中治疗期间包括至少两个剂量。
根据某些方面,HER3靶向剂可根据包括2个剂量的给药计划施用,例如在治疗期间的第1天和第5、6、7、8、9或10天,或治疗期间的第1天和第8天。
根据某些方面,HER3靶向剂可以以单个受试者特定剂量作为单次大剂量(bolus)或输注施用。
根据某些方面,所述方法可以进一步包括施用一种或多种进一步的治疗剂,例如化疗剂、小分子药物、抗炎剂、免疫抑制剂、免疫调节剂、抗骨髓瘤剂、细胞因子或其组合。示例性的化疗剂至少包括可与放射性标记的HER3靶向剂协同作用的放射增敏剂,例如替莫唑胺、顺铂和/或氟尿嘧啶。
根据某些方面,所述方法可以进一步包括施用一种或多种免疫检查点疗法。示例性的免疫检查点疗法包括针对CTLA-4、PD-1、TIM-3、VISTA、BTLA、LAG-3、TIGIT、CD28、OX40、GITR、CD137、CD40、CD40L、CD27、HVEM、PD-L1、PD-L2、PD-L3、PD-L4、CD80、CD86、CD137-L、GITR-L、CD226、B7-H3、B7-H4、BTLA、TIGIT、GALS、KIR、2B4、CD160、CGEN-15049或其任意组合的抗体。根据某些方面,免疫检查点疗法可以包括针对免疫检查点蛋白的抗体,所述抗体选自由针对PD-1、PD-L1、PD-L2、CTLA-4、CD137及其组合的抗体组成的组。
根据某些方面,可以将免疫检查点疗法以有效量施用于受试者,例如0.1mg/kg至50mg/kg患者体重的剂量,如0.1-5mg/kg或5-30mg/kg。
根据某些方面,所述方法可以进一步包括施用一种或多种DNA损伤反应抑制剂(DDRi)。示例性的DDRi剂包括一种或多种靶向聚(ADP-核糖)聚合酶的抗体或小分子(即,聚(ADP-核糖)聚合酶抑制剂或PARPi)。例如,PARPi可以包括奥拉帕尼(olaparib)、尼拉帕尼(niraparib)、鲁卡帕尼(rucaparib)、他拉唑帕尼(talazoparib)或其任意组合。根据某些方面,PARPi可以以包括0.1mg/天-1200mg/天,例如0.100mg/天-600mg/天或0.25mg/天-1mg/天的受试者有效量提供。示例性的受试者有效量包括0.1mg、0.25mg、0.5mg、0.75mg、1.0mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、750mg、800mg、900mg和1000mg,每天以一个或两个剂量口服。
另一个示例性的DDRi包括共济失调毛细管扩张突变(ATM)、共济失调毛细管扩张突变和Rad-3相关(ATR)或Wee1的抑制剂。ATM的示例性抑制剂包括KU-55933、KU-59403、渥曼青霉素(wortmannin)、CP466722和KU-60019。ATR的示例性抑制剂至少包括五味子乙素(Schisandrin B)、NU6027、NVP-BEA235、VE-821、VE-822、AZ20和AZD6738。Wee1的示例性抑制剂包括AZD-1775(即adavosertib)。
根据某些方面,所述方法可以进一步包括施用一种或多种CD47阻断剂。CD47阻断剂可以包括单克隆抗体、SIRPα-Fc融合蛋白或其他阻止CD47与SIRPα结合或以其他方式阻断或下调CD47的免疫抑制活性的分子,例如莫洛利单抗(magrolimab)、来佐利单抗(lemzoparlimab)、AO-176、AK117、IMC-002、IBI-188、IBI-322、BI 766063、ZL-1201、AXL148、RRx-001、ES004、SRF231、SHR-1603、TJC4、TTI-621或TTI-622。CD47阻断剂的示例性有效剂量包括0.05至5mg/kg患者体重。CD47阻断剂还可以包括调节CD47和/或SIRPα表达的药剂,例如核酸方法,如反义、RNAi或μRNA方法。示例性的CD47阻断剂还包括阻断CD47翻译的磷酰二胺吗啉代低聚物(phosphorodiamidate morpholino oligomer,PMO),例如MBT-001。
根据某些方面,所述方法可以进一步包括施用进一步的治疗剂的组合。示例性组合包括至少一种或多种DDRi和/或一种或多种免疫检查点疗法和/或一种或多种CD47阻断剂和/或一种或多种化疗和/或一种或多种小分子抗癌药物和/或一种或多种针对不同癌症相关抗原的靶向剂。
根据某些方面,放射性标记的HER3靶向剂和一种或多种进一步的治疗剂可以同时或依次施用。当施用一种以上的另外的治疗剂时,所述药剂可以同时或依次施用。
根据本发明的某些方面,放射性标记的HER3靶向剂可以是多特异性靶向剂,例如多特异性抗体或双特异性抗体,其中至少一部分识别HER3。因此,所述方法可以包括向受试者施用有效量的多特异性抗体,其中多特异性抗体包括:第一靶标识别组分,其与HER3的表位特异性结合,和第二靶标识别组分,其与不同于第一靶标识别组分的HER3的表位特异性结合,或与不同抗原如不同癌症相关抗原的表位结合。根据某些方面,HER3靶向剂是针对HER3的第一表位和至少HER3的第二表位,或针对HER3和至少第二(不同)抗原的多特异性抗体。根据本发明,可被放射性标记用于诊断和/或治疗用途的示例性多特异性抗体包括针对HER3/HER2的双特异性抗体,例如Merrimack Pharmaceuticals的MM-111或Merus N.V.的MCLA-128;或针对IGF-1R/HER3的双特异性抗体,例如Merrimack Pharmaceuticals的MM-141(即艾司妥单抗(Istiratumab));或针对EGFR/HER3的双特异性抗体,例如罗氏的MEHD7945A(即杜力戈图单抗(Duligotumab))或Zyngenia Inc.的任何基于西妥昔单抗(cetuximab)的双特异性或多特异性zybodies。
根据某些方面,提供了一种组合物,其包括HER3靶向剂如针对HER3的抗体和一种或多种进一步的靶向剂如抗体的混合物,靶向/针对一种或多种不同的癌症相关抗原,其中一种或多种HER3靶向剂和其他靶向剂可以以任意组合放射性标记或未放射性标记。包括抗体混合物的示例性抗体组合物至少包括来自Symphogen的Sym013,其具有六个针对EGFR(HER1)、HER2和HER3的单克隆抗体。在一个方面,Sym013的一种或多种抗体可以是放射性标记的,以任意组合,例如至少一种HER3抗体和没有或一种或多种针对EGFR和HER2的抗体。
本发明的其他特征、优点和方面可通过考虑以下详细描述、附图(如果有的话)和权利要求书来阐述或变得明显。此外,应当理解的是,前述的发明内容和以下的具体实施方式都是示例性的,旨在提供进一步的解释而不是限制本发明的保护范围。
附图说明
图1提供了可体现在本发明各方面的HER3单克隆抗体的重链和轻链的N末端区、互补决定区和可变区的氨基酸序列。
图2提供了可体现在本发明各方面的HER3单克隆抗体的全长重链和轻链的氨基酸序列,包括和不包括前导序列。
图3显示了Ac225标记的DOTA缀合的抗HER3单克隆抗体与未修饰的抗HER3抗体和非特异性抗体(IgG)的ELISA测定结合特征,表明修饰不会对HER3的免疫反应性产生实质性影响。
图4是显示检查225Ac-HER3-ARC、未修饰的抗HER3 mAb、非特异性抗体对照(IgG)和仅第二抗体对照与HER3阳性的NCI-H1975细胞(人类肺腺癌,NSCLC)和BxPC-3细胞(人类胰腺癌)的结合的流式细胞术测定的结果的图。
图5是显示225Ac-HER3-ARC对HER3阳性细胞系NCI-H1975的体外细胞毒性效果与辐射剂量的函数的图。
图6A是显示225Ac-HER3-ARC在NCI-H1975细胞中上调细胞表面钙网蛋白(CRT)的图。
图6B是显示225Ac-HER3-ARC上调NCI-H1975细胞上的CD47的图。
图7A是显示吞噬作用测定的结果的图,表明225Ac-HER3-ARC和抗CD47阻断抗体的组合与单独任一种处理相比增强了BxPC-3细胞的吞噬作用。
图7B是显示吞噬作用测定的结果的图,表明225Ac-HER3-ARC和抗CD47阻断抗体的组合与单独任一种处理相比增强了NCI-H1975细胞的吞噬作用。
图8是显示在人类肿瘤(NCI-H1975细胞)小鼠异种移植模型中,225Ac-HER3-ARC在不同的辐射剂量下和与抗CD47阻断抗体的组合对肿瘤生长的影响。
图9是显示图8中描述的实验的受试者的体重随时间变化的图。
图10是显示图8中描述的实验的实验组受试者的生存概率随时间变化的图。
图11是显示在使用HER2阳性的SK-OV3人类卵巢癌细胞系的NGS小鼠异种移植模型中,载体(对照)、单独的CD47阻断抗体莫洛利单抗、单独的225Ac-曲妥珠单抗(trastuzumab)以及莫洛利单抗和225Ac-曲妥珠单抗的组合对肿瘤生长的比较效果的图。
图12是显示在使用SK-OV3人类卵巢癌细胞系的NGS小鼠异种移植模型中,载体(对照)、单独的莫洛利单抗、单独的177Lu-曲妥珠单抗以及莫洛利单抗和177Lu-曲妥珠单抗的组合对肿瘤生长的比较效果的图。
具体实施方式
在一个方面,目前公开的本发明提供了用于治疗表达HER3的癌症,即HER3阳性癌症的组合物和方法。该方面一般包括向需要治疗的哺乳动物受试者,例如人类患者,单独或与一种或多种另外的治疗剂和/或治疗方式/治疗方法联合施用有效量的放射性标记的HER3靶向剂,例如靶向HER3的放射性标记的抗体、肽或小分子。
可使用的另外的治疗剂和方式包括,例如,至少一种或多种免疫检查点疗法和/或一种或多种DNA损伤反应途径的组分的抑制剂(即,DNA损伤反应抑制剂,DDRi,例如一种或多种针对聚(ADP-核糖)聚合酶的药剂,即PARPi)和/或一种或多种CD47/SIRPα轴阻断剂和/或一种或多种化疗剂,如放射增敏剂,和/或一种或多种小分子肿瘤药物,如酪氨酸激酶抑制剂,和/或一种或多种针对不同抗原的靶向剂。
目前公开的本发明进一步提供了用于识别、成像和/或诊断受试者中的HER3阳性癌症的方法。目前公开的本发明进一步提供了用于识别、成像和/或诊断受试者中的HER3阳性癌症,随后根据本文公开的任何方法治疗这些受试者的方法。
定义和缩略词
单数形式“一个”、“一种”、“所述”等包括复数指代,除非上下文另外明确规定。因此,例如,对“一个”抗体的提及包括单个抗体和多个不同的抗体。
如本说明书和权利要求书中所用,“包含”一词和“包含”一词的形式以及“包括”一词和“包括”一词的形式并不限制包含超出所指代的要素。另外,尽管在整个本公开中,其各方面或要素以“包括”或“包含”的方式描述,但以“基本上由……组成”或“由……组成”的方式描述的其相应方面或要素也同样公开。例如,虽然本发明的某些方面已经以“包括”或“包含”施用放射性标记的靶向剂的方法的方式进行了描述,但记载了“基本上由”或“由”施用放射性标记的靶标组成的相应方法也在所述方面的范围内,并由本公开内容所公开。
当在本公开中使用时与数字指定或数值相关联时,例如在描述温度、时间、数量和浓度时,包括在描述范围时,术语“大约”表示±10%的差异,以及在该较大的差异中,数字指定或数值的±5%或±1%的差异。
如本文所用,就诸如抗体、抗体片段、Fab片段或适体的靶向剂而言,“施用”是指通过适合抗体递送的任何已知方法将药剂递送到受试者体内。具体的施用方式包括但不限于静脉内、经皮、皮下、腹膜内、鞘内和肿瘤内施用。抗体的示例性施用方法可以基本上如国际公开号WO 2016/187514中所述,其通过引用的方式并入本文。
此外,在本发明中,例如可以使用一种或多种常规使用的药学上可接受的载体和赋形剂来配制抗体。这样的载体和赋形剂是本领域技术人员熟知的。例如,可注射的药物递送系统包括溶液、悬浮液、凝胶、微球和聚合的可注射物,并且可以包括赋形剂如溶解度改变剂(例如乙醇、丙二醇和蔗糖)和聚合物(例如聚辛内酯和PLGA’s)。
如本文所用,术语“抗体”包括但不限于:(a)包括两条重链和两条轻链且识别抗原的免疫球蛋白分子;(b)多克隆和单克隆免疫球蛋白分子;(c)其单价和二价片段,例如Fab、双Fab、scFvs、双抗体、微型抗体和纳米抗体(sdAb);(d)天然存在的和非天然存在的,例如全合成抗体、IgG-Fc沉默和嵌合体;和(e)其双特异性和多特异性形式。免疫球蛋白分子可以来源于任何通常已知的类别,包括但不限于IgA、分泌型IgA、IgG和IgM。IgG亚类也是本领域技术人员熟知的,包括但不限于人类IgG1、IgG2、IgG3和IgG4。每条链的N末端限定了约100至110个或更多个氨基酸的“可变区”,主要负责抗原识别。术语可变轻链(VL)和可变重链(VH)分别指轻链和重链的这些区域。抗体可以是人类的、人源化的或非人类的。当目前公开的本发明的具体方面提及或记载“抗体”时,它被设想为指本文公开的任何全长抗体或其片段,除非另外明确表示。
“人源化”抗体是指其中非人类抗体的CDR结构域外的一些、大部分或所有氨基酸被来源于人免疫球蛋白的相应氨基酸取代的抗体。在抗体的人源化形式的一个实施方案中,CDR结构域外的一些、大部分或所有氨基酸已被来自人免疫球蛋白的氨基酸取代,而一个或多个CDR区内的一些、大部分或所有氨基酸未改变。氨基酸的少量添加、缺失、插入、取代或修饰是允许的,只要它们不消除抗体与特定抗原结合的能力。“人源化”抗体保留了与原始抗体相似的抗原特异性。
“嵌合抗体”是指其中可变区来源于一个物种而恒定区来源于另一物种的抗体,例如其中可变区来源于小鼠抗体而恒定区来源于人类抗体的抗体。
“互补决定区”或“CDR”是指一起限定天然免疫球蛋白结合位点的可变区的结合亲和力和特异性的氨基酸序列。抗体的轻链和重链中各有三个CDR。
“框架区”或“FR”是指插在CDR之间的氨基酸序列,通常是保守的,其作为CDR之间的支架。
“恒定区”是指抗体分子的一部分,其对于一类抗体来说是一致并且由轻链和重链的类型来限定。例如,轻链恒定区可以是κ或λ链类型,重链恒定区可以是五种链亚型中的一种:α、δ、ε、γ或μ。一般来说,该恒定区可以赋予抗体所表现出的效应功能。各种亚类的重链(例如IgG亚类的重链)主要负责不同的效应功能。
如本文所用,HER3靶向剂例如可以是本文定义的抗体,例如全长抗体、微型抗体或纳米抗体,其与HER3的任何可用表位(例如人类HER3)结合,具有高免疫活性。
如本文所用,“免疫活性”是指衡量免疫球蛋白识别和结合到特定抗原的能力。“特异性结合”或“特异性地结合”或“结合”是指抗体与抗原或抗原内的表位结合,其亲和力比其他抗原更强,例如在相关环境中,如在哺乳动物受试者如人类患者的体内。可体现在本发明各方面或可用于本发明各方面的抗体例如可以与抗原或抗原内的表位结合,其平衡解离常数(KD)为约1×10-8M或更小、例如约1×10-9M或更小、约1×10-10M或更小、约1×10-11M或更小或约1×10-12M或更小,通常KD比其与非特异性抗原(例如BSA、酪蛋白)结合的KD至少小100倍。解离常数可以用标准程序测量。然而,与抗原或抗原内的表位特异性结合的抗体可能对其他相关抗原具有交叉反应性,例如对其他物种的同一抗原(同源物),例如人类或猴子,如食蟹猕猴(Macaca fascicularis)(猕猴,cyno)、黑猩猩(Pan troglodytes)(黑猩猩,chimp)或普通狨(Callithrix jacchus)(普通狨猴,marmoset)。
“表位”是指能够被诸如抗体、抗体片段、Fab片段或适体的靶向剂识别并结合的靶分子位点(例如,抗原的至少一部分)。例如,对于蛋白质抗原,这可能是指被抗体结合的蛋白质区域(即氨基酸,特别是其侧链)。重叠的表位包括至少1至5个共同的氨基酸残基。鉴定抗体表位的方法是本领域技术人员已知的,包括例如在Antibodies,ALaboratory Manual,Cold Spring Harbor Laboratory,Ed Harlow and David Lane(1988)中所述的方法。
如本文公开的放射性标记的HER3靶向剂可用于治疗HER3阳性,即表达HER3的癌症或癌前病况,例如实体瘤。所谓“HER3阳性”或“表达HER3”是指患者体内至少一些癌细胞,如肿瘤内的癌细胞,表达或过表达HER3。
如本文所用,术语“增殖性病症”和“癌症”可以互换使用,并且可以包括但不限于实体癌(例如,肿瘤)和癌前增殖性病症。可由本发明各方面治疗且可为HER3阳性的“实体癌”包括但不限于骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑色素瘤、子宫癌、卵巢癌、前列腺癌、直肠癌、肛门区癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、小儿肿瘤、膀胱癌、肾癌或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊髓轴肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、环境诱发的癌症(包括由石棉诱发的癌症)。
根据某些方面,可由本发明各方面治疗且可为HER3阳性的实体癌可以是乳腺癌(如他莫昔芬敏感性乳腺癌、他莫昔芬抗性乳腺癌、HER2阳性乳腺癌、HER2阴性乳腺癌或三阴性乳腺癌(TNBC))、胃癌、膀胱癌、宫颈癌、子宫内膜癌、皮肤癌如黑色素瘤、胃癌、睾丸癌、食道癌、支气管肺泡癌、前列腺癌如去势抵抗性前列腺癌(CRPC)、结直肠癌、卵巢癌、宫颈表皮癌、肝癌如肝细胞癌(HCC)或胆管癌、胰腺癌、肺癌如非小细胞肺癌(NSCLC)、肾癌、头颈癌如头颈部鳞状细胞癌、癌、肉瘤或其任意组合。这类癌症可以是转移性或非转移性的。
根据某些方面,HER3靶向剂可以用放射性同位素/放射性核素进行标记。如本文所用,“放射性同位素”或“放射性核素”可以是α发射同位素、β发射同位素和/或γ发射同位素。可用于标记HER3靶向剂或其他靶向剂的示例性放射性核素包括以下:131I、125I、123I、90Y、177Lu、186Re、188Re、89Sr、153Sm、32P、225Ac、213Bi、213Po、211At、212Bi、213Bi、223Ra、227Th、149Tb、137Cs、212Pb、103Pd、134Ce、43Sc、44Sc、47Sc、55Co、60Cu、61Cu、62Cu、64Cu、67Cu、66Ga、67Ga、68Ga、82Rb、86Y、87Y、89Zr、97Ru、105Rh、109Pd、111In、117mSn、149Pm、149Tb、153Sm、177Lu、199Au、201Tl和203Pb。将放射性同位素附着在蛋白质如抗体或抗体片段上(即用放射性同位素“标记”蛋白质)的方法是本领域熟知的。用于标记的具体组合物和方法描述于例如国际公开号WO 2017/155937和2019年12月9日提交的美国临时专利申请号63/042,651和2020年11月30日提交的63/119,093,题为“Compositions and methods for preparation of site-specificradioconjugates”,每篇专利通过引用的方式并入本文。含有一个或多个半胱氨酸残基的HER3靶向剂和其他靶向剂,例如肽、蛋白质、抗体和蛋白质抗体模拟物,可以例如与美国专利11,000,604中公开的题为“Reagent for site-selective bioconjugation ofproteins or antibodies”的用于放射性核素标记的任何携带螯合剂的(例如携带DOTA的)稳定接头化学缀合。
根据某些方面,HER3靶向剂可以是用225Ac放射性标记的(“225Ac标记的”)抗体、肽或小分子,并且有效量例如可以为或小于50.0μCi/kg(即,其中向受试者施用的225Ac的量递送小于50.0μCi/千克受试者体重的辐射剂量)。根据某些方面,当HER3靶向剂为225Ac标记的时,有效量小于50μCi/kg、40μCi/kg、30μCi/kg、20μCi/kg、10μCi/kg、5μCi/kg、4μCi/kg、3μCi/kg、2μCi/kg、1μCi/kg或0.5μCi/kg。根据某些方面,当HER3靶向剂为225Ac标记的时,有效量为至少0.05μCi/kg,或0.1μCi/kg、0.2μCi/kg、0.3μCi/kg、0.4μCi/kg、0.5μCi/kg、1μCi/kg、2μCi/kg、3μCi/kg、4μCi/kg、5μCi/kg、6μCi/kg、7μCi/kg、8μCi/kg、9μCi/kg、10μCi/kg、12μCi/kg、14μCi/kg、15μCi/kg、16μCi/kg、18μCi/kg、20μCi/kg、30μCi/kg或40μCi/kg。根据某些方面,225Ac标记的抗体可以以包括本文所述的上限和下限的任意组合的剂量施用,例如从至少0.1μCi/kg到5μCi/kg或以下,或从至少5μCi/kg到20μCi/kg或以下。
根据某些方面,HER3靶向剂可以是225Ac标记的抗体、肽或小分子,并且有效量可以为或小于2mCi(即,其中225Ac以非基于重量的剂量向受试者施用)。根据某些方面,225Ac标记的HER3靶向剂的有效剂量可小于1mCi,例如0.9mCi、0.8mCi、0.7mCi、0.6mCi、0.5mCi、0.4mCi、0.3mCi、0.2mCi、0.1mCi、90μCi、80μCi、70μCi、60μCi、50μCi、40μCi、30μCi,20μCi、10μCi或5μCi。225Ac标记的HER3靶向剂的有效量可以为至少2μCi,例如至少5μCi、10μCi、20μCi、30μCi、40μCi、50μCi、60μCi、70μCi、80μCi、90μCi、100μCi、200μCi、300μCi、400μCi、500μCi、600μCi、700μCi、800μCi、900μCi、1mCi、1.1mCi、1.2mCi、1.3mCi、1.4mCi或1.5mCi。根据某些方面,225Ac标记的HER3靶向剂可以以包括本文所述的上限和下限的任意组合的剂量施用,例如从至少2μCi到1mCi或以下,或者从至少2μCi到250μCi或以下,或者从75μCi到400μCi或以下。
根据某些方面,225Ac标记的HER3靶向剂包括向受试者递送少于12Gy、或少于8Gy、或少于6Gy、或少于4Gy、或少于2Gy的单剂量,例如2Gy至8Gy的剂量,例如主要向靶向实体瘤递送。
根据某些方面,HER3靶向剂可以是用177Lu放射性标记的(“177Lu标记的”)抗体、肽或小分子,并且有效量可以是例如小于1mCi/kg(即,其中向受试者施用的177Lu标记的抗体的量递送小于1000μCi/千克受试者体重的辐射剂量)。根据某些方面,当抗体是177Lu标记的时,有效量小于900μCi/kg、800μCi/kg、700μCi/kg、600μCi/kg、500μCi/kg、400μCi/kg、300μCi/kg、200μCi/kg、150μCi/kg、100μCi/kg、80μCi/kg、60μCi/kg、50μCi/kg、40μCi/kg、30μCi/kg、20μCi/kg、10μCi/kg、5μCi/kg或1μCi/kg。根据某些方面,177Lu标记的抗体的有效量为至少1μCi/kg、2.5μCi/kg、5μCi/kg、10μCi/kg、20μCi/kg、30μCi/kg、40μCi/kg、50μCi/kg、60μCi/kg、70μCi/kg、80μCi/kg、90μCi/kg、100μCi/kg、150μCi/kg、200μCi/kg、250μCi/kg、300μCi/kg、350μCi/kg、400μCi/kg或450μCi/kg。根据某些方面,177Lu标记的抗体可以以包括本文所述的上限和下限的任意组合的剂量施用,例如从至少5mCi/kg到50μCi/kg或以下,或从至少50mCi/kg到500μCi/kg或以下。
根据某些方面,HER3靶向剂可以是177Lu标记的抗体,并且有效量可以小于45mCi,例如小于40mCi、30mCi、20mCi、10mCi、5mCi、3.0mCi、2.0mCi、1.0mCi、800μCi、600μCi、400μCi、200μCi、100μCi或50μCi。177Lu标记的HER3靶向剂的有效量可以是至少10μCi,例如至少25μCi、50μCi、100μCi、200μCi、300μCi、400μCi、500μCi、600μCi、700μCi、800μCi、900μCi、1mCi、2mCi、3mCi、4mCi、5mCi、10mCi、15mCi、20mCi、25mCi、30mCi。根据某些方面,177Lu标记的抗体可以以包括本文所述的上限和下限的任意组合的剂量施用,例如从至少10mCi到30mCi或以下,或从至少100μCi到3mCi或以下,或从3mCi到30mCi或以下。
根据某些方面,HER3靶向剂可以是用131I放射性标记的(“131I标记的”)抗体、肽或小分子,并且有效量可以小于例如1200mCi(即,其中向受试者施用的131I的量以非基于重量的剂量递送小于1200mCi的总身体辐射剂量)。根据某些方面,131I标记的靶向剂的有效量可以小于1100mCi、小于1000mCi、小于900mCi、小于800mCi、小于700mCi、小于600mCi、小于500mCi、小于400mCi、小于300mCi、小于200mCi、小于150mCi或小于100mCi。根据某些方面,131I标记的靶向剂的有效量可以小于200mCi,例如小于190mCi、180mCi、170mCi、160mCi、150mCi、140mCi、130mCi、120mCi、110mCi、100mCi、90mCi、80mCi、70mCi、60mCi或50mCi。根据某些方面,131I标记的靶向剂的有效量可以是至少1mCi,例如至少2mCi、3mCi、4mCi、5mCi、6mCi、7mCi、8mCi、9mCi、10mCi、20mCi、30mCi、40mCi、50mCi、60mCi、70mCi、80mCi、90mCi、100mCi、110mCi、120mCi、130mCi、140mCi、150mCi、160mCi、170mCi、180mCi、190mCi、200mCi、250mCi、300mCi、350mCi、400mCi、450mCi、500mCi。根据某些方面,131I标记的靶向剂可以以包括本文所述的上限和下限的任意组合的剂量施用,例如从至少1mCi到100mCi或以下,或至少10mCi到200mCi或以下。
虽然本文详细讨论了选择放射性核素,但任何放射性核素,例如本文公开的任何放射性核素,可用于放射性标记的靶向剂,例如本文公开的放射性标记的HER3靶向剂。
如本文所用,包括HER3靶向剂的组合物包括“患者特异性组合物”,其包括放射性核素标记部分和未标记部分。根据本发明的某些方面,当HER3靶向剂用放射性同位素标记时,向患者施用的大部分靶向剂(抗体、抗体片段等)可以由未标记的靶向剂组成,少数是放射性标记的靶向剂。标记的靶向剂与未标记的靶向剂的比例可以用已知的方法进行调整。根据本发明的某些方面,患者特异性组合物可以包括HER3靶向剂,其中标记的HER3靶向剂:未标记的HER3靶向剂的比例为约0.01:10至1:1,例如0.1:10至1:1标记的:未标记的。
根据本发明的某些方面,HER3靶向剂可以以至多100mg,例如至多60mg,例如5mg至45mg的总蛋白或肽量提供,或者以0.001mg/kg患者体重至3.0mg/kg患者体重,例如0.005mg/kg患者体重至2.0mg/kg患者体重,或0.01mg/kg患者体重至1mg/kg患者体重,或0.1mg/kg患者体重至0.6mg/kg患者体重,或0.3mg/kg患者体重,或0.4mg/kg患者体重,或0.5mg/kg患者体重,或0.6mg/kg患者体重的总蛋白量提供。
本发明的抗体或其他靶向剂的放射性标记部分和未标记部分的组合允许组合物为特定的患者定制,其中抗体或其他靶向剂的放射剂量和蛋白剂量中的每一个都基于至少一个患者特定参数而对该患者进行个性化定制。因此,组合物的每个小瓶可以为特定的患者制作,其中小瓶的全部内容以单剂量向该患者递送。当治疗方案需要多个剂量时,每个剂量可以被配制成小瓶中的患者特定剂量,作为“单剂量”(即小瓶中的全部内容一次施用)向患者施用。随后的剂量可以以类似的方式配制,从而使该方案中的每一剂量在单剂量容器中提供患者特定剂量。这种组合物的优点之一是不会有需要被医务人员丢弃或处理的剩余的辐射,例如,不需要稀释或其他操作来获得患者的剂量。当以单剂量容器提供时,该容器可以简单地放在输注管组中,以便向患者输注。此外,体积可以被标准化,这样就大大降低了医疗错误(即,由于组合物的整个体积将在一次输注中被施用而递送错误的剂量)的可能性。
因此,根据某些方面,HER3靶向剂可以作为单剂量组合物提供,所述组合物可以为特定的患者定制,其中组合物中的放射性标记的和未标记的HER3靶向剂的量可以取决于患者体重、年龄、性别、疾病状态和/或健康状态中的一个或多个,例如详见国际公开号WO2016/187514和美国专利号10,736,975。根据某些方面,HER3靶向剂可以作为多剂量治疗剂提供,其中治疗方案中的每一剂量作为患者特定的组合物提供。患者特定的组合物包括放射性标记的和未标记的HER3靶向剂,其中每种的量取决于患者体重、年龄、性别、疾病状态和/或健康状况中的一个或多个。
如本文所用,术语“受试者”和“患者”可以互换,并包括但不限于哺乳动物,例如人类、非人类灵长类、狗、猫、马、绵羊、山羊、牛、兔、猪、大鼠和小鼠。如果受试者是人类,受试者可以是任何年龄。例如,受试者可以是60岁或以上、65岁或以上、70岁或以上、75岁或以上、80岁或以上、85岁或以上或90岁或以上。替代地,受试者可以是50岁或以下、45岁或以下、40岁或以下、35岁或以下、30岁或以下、25岁或以下或20岁或以下。对于患有癌症的人类受试者,该受试者可以是新诊断的,或复发和/或难治的,或处于缓解期的。
如本文所用,“治疗”患有癌症的受试者应包括但不限于,(i)减缓、停止或逆转癌症的进展,(ii)减缓、停止或逆转癌症症状的进展,(iii)减少癌症复发的可能性,和/或(iv)减少癌症症状将复发的可能性。根据某些优选的方面,治疗患有癌症的受试者是指(i)逆转癌症的进展,理想地达到消除癌症的程度,和/或(ii)逆转癌症症状的进展,理想地达到消除症状的程度,和/或(iii)减少或消除复发的可能性(即巩固,其理想地导致破坏任何剩余的癌细胞)。
在本发明的背景下,“化疗剂”应指抑制或杀死生长中的细胞并且可用于或被批准用于治疗癌症的化学化合物。示例性的化疗剂包括在细胞核分裂或细胞质分裂水平上防止、干扰、破坏或推迟细胞分裂的细胞抑制剂。这类药剂可以稳定微管,例如紫杉烷类(taxanes),特别是多西他赛或紫杉醇,和埃博霉素类(epothilones),特别是埃博霉素A、B、C、D、E和F,或者可以破坏微管的稳定性,例如长春碱类(vinca alkaloids),特别是长春花碱、长春新碱、长春地辛和长春瑞滨。示例性的化疗剂还包括可与放射性标记的HER3协同作用的放射增敏剂,例如替莫唑胺、顺铂和/或氟尿嘧啶。
“治疗有效量”或“有效量”是指在必要的剂量和时间段内达到预期的治疗效果的有效的量。治疗有效量可根据诸如个体的疾病状态、年龄、性别和体重等因素以及治疗剂或治疗剂组合在个体中引起所需反应的能力而变化。有效的治疗剂或治疗剂组合的示例性指标包括,例如,患者的健康得到改善,肿瘤负担减轻,肿瘤的生长停止或减缓,和/或没有癌细胞转移到身体的其他位置。根据某些方面,“治疗有效量”或“有效量”是指放射性标记的HER3靶向剂的量,当单独使用或与其他药剂和/或治疗方式联合或一起使用时,可耗尽表达HER3的细胞或导致表达HER3的细胞的总数减少和/或可抑制表达HER3的细胞生长。
如本文所用,就表达HER3的细胞而言,“耗尽”应指降低表达或过表达HER3的至少一种类型细胞的群体(例如,实体瘤中或在受试者血液中循环的HER3阳性细胞)。根据本发明的某些方面,在开始用HER3靶向剂治疗之前和之后,通过比较受试者血液中或组织活检中(例如来自实体瘤)的HER3阳性细胞的数量来确定减少。因此,作为示例,如果受试者的HER3阳性细胞降低,例如降低至少10%、20%、30%、40%、50%、60%、70%、80%、90%或99%,则可认为该群体被耗尽。
“抑制生长”是指当与治疗剂或治疗剂或药物的组合接触时,与没有治疗剂或治疗药物组合时相同细胞或组织生长的减少或延迟相比,恶性细胞或组织(例如肿瘤)在体外或体内的生长有可测量的减少或延迟。恶性细胞或组织在体外或体内的生长抑制可以是至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或100%。
术语“免疫检查点疗法”是指能够以积极或消极的方式调节免疫检查点蛋白的功能以促进针对癌细胞的免疫反应的分子。术语“免疫检查点”是指在正常生理条件下直接或间接参与免疫途径的蛋白质,其作用是防止不受控制的免疫反应,从而维持自我耐受性和/或组织保护。
在本发明的背景下,免疫检查点疗法包括诸如能够下调至少部分抑制性免疫检查点(拮抗剂)的功能和/或上调至少部分刺激性免疫检查点(激动剂)的功能的抗体等疗法。作为示例,免疫检查点疗法可指针对免疫检查点抑制剂(ICI)的抗体,该抗体在某些癌症中可能被上调,因此可抑制ICI的功能。
术语“DDRi”是指DNA损伤反应途径蛋白的抑制剂,其中PARPi是一个实例。术语“PARPi”是指聚(ADP-核糖)聚合酶的抑制剂。在本发明的背景下,术语PARPi包括可与聚(ADP-核糖)聚合酶结合并抑制其功能的分子,例如抗体、肽或小分子。
术语“CD47阻断剂”是指阻止CD47与SIRPα结合的药剂,例如与CD47或SIRPα中的任一个结合的阻断剂,或那些调节CD47或SIRPα表达的药剂,或那些以其他方式抑制CD47/SIRPα轴的药剂。不限于此,CD47阻断剂至少包括与CD47结合的抗体,例如莫洛利单抗、来佐利单抗和AO-176,SIRPα融合蛋白,例如TTI-621和TTI-622,调节CD47和/或SIRPα表达的药剂,例如阻断CD47翻译的磷酰二胺吗啉代低聚物(PMO),和小分子药剂,例如RRx-001。
如本文所用,将一种或多种另外的疗法,例如免疫检查点疗法和/或DDRi和/或CD47阻断剂和/或放射增敏剂中的一种或多种与HER3靶向剂“一起”施用于受试者是指在施用HER3靶向剂之前、期间和/或之后施用另外的疗法。这种施用包括但不限于以下情况:(i)首先施用另外的疗法,其次施用HER3靶向剂;(ii)另外的疗法与HER3靶向剂同时施用(例如,DDRi每天口服施用一次,持续n天,HER3靶向剂在DDRi方案的第2至n-1天中的某一天以单剂量静脉内施用);(iii)另外的疗法与HER3靶向剂同时施用(例如,DDRi口服施用超过一个月的持续时间,例如每天口服一次,持续35天、42天、49天或更长的时间,在此期间接受治疗的癌症没有进展且在此期间DDRi没有引起不可接受的毒性,并且在DDRi方案的第一个月内的某一天以单剂量静脉内施用HER3靶向剂;以及(iv)首先施用HER3靶向剂(例如,(iv)在数周的期间内以单剂量或多个剂量静脉内施用),其实施用另外的疗法(例如,DDRi每天口服施用一次,持续21天、28天、35天、42天、49天或更长的时间,在此期间接受治疗的癌症没有进展且在此期间DDRi没有引起不可接受的毒性)。对本领域技术人员来说是显而易见的另外的排列组合是可能的,并且在本发明要求保护的范围内。
“制品”表示含有对治疗、预防和/或诊断本文所述的病症有用的材料的包装。所述制品可以包括容器和容器上或与容器相关的标签或包装插页。合适的容器包括,例如,瓶子、小瓶、注射器、静脉注射液袋等。容器可由各种材料形成,例如玻璃或塑料。容器盛放组合物,所述组合物本身或与另一种有效治疗、预防和/或诊断病况的组合物相结合,并可有无菌进入口(例如,容器可以是静脉注射液袋或具有可被皮下注射针头刺穿的塞子的小瓶)。所述组合物中的至少一种活性剂可以是根据目前公开的本发明的方面的放射性标记的HER3靶向剂。
“标签”或“包装插页”用于指通常包括在治疗产品的商业包装中的说明书,其包含有关涉及此类治疗产品的使用的适应症、用法、剂量、施用、联合疗法、禁忌症和/或警告的信息。如本文所用,标签可以表明所述组合物用于治疗HER3阳性癌症,并且可以任选地表明施用途径和/或方法。此外,所述制品可以包括(a)第一容器,其中含有组合物,其中所述组合物包括HER3靶向剂;和(b)第二容器,其中含有组合物,其中所述组合物包括根据目前公开的本发明的方面的进一步的细胞毒性剂或其他治疗剂。替代地或另外地,所述制品可以进一步包括第二(或第三)容器,其包括药学上可接受的缓冲剂,例如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格氏溶液和葡萄糖溶液。它可以进一步包括从商业和用户角度来看可取的其他材料,包括其他缓冲剂、稀释剂、过滤器、针头和注射器。
在整个本申请中,引用了各种专利、专利申请和其他出版物,其中的每一个都通过引用的方式整体并入本文。
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同含义。尽管在本文所述的实践或测试中可以使用与本文所述的方法和材料相似或等效的方法和材料,但下文描述了合适的方法和材料。
实验结果
制备了一种由重链SEQ ID NO:77和轻链SEQ ID NO:78组成的抗HER3 IgG单克隆抗体,使用p-SCN-Bn-DOTA与螯合剂DOTA缀合,并通过与锕-225螯合进行放射性标记,以如下文结合图3-11所述进行进一步研究。
图3显示了Ac225标记的DOTA缀合的抗HER3单克隆抗体(“HER3-ARC”)与未修饰的抗HER3抗体和非特异性抗体(IgG)的ELISA测定结合特征,表明修饰不会对HER3的免疫反应性产生实质性影响。
通过ELISA评估了225Ac-HER3-ARC的结合特性。在96孔板上涂覆人重组HER3过夜,然后将抗HER3、225Ac-HER3-ARC和IgG(免疫球蛋白1,非特异性IgG1对照)的连续稀释液(0-100μg/ml)在室温下孵育1小时。加入第二抗体(山羊抗人IgG F(ab’)20-HRP)并在冰上孵育30分钟,然后用1M盐酸显色10分钟。在450nm处测量样品的吸光度。通过ELISA,225Ac-HER3-ARC显示出与天然抗体相似的结合特性(HER3-ARC:EC50=0.0017μg/ml,HER3 EC50=0.0022μg/ml)。
图4是显示检查225Ac-HER3-ARC、未修饰的抗HER3 mAb、非特异性抗体对照(IgG)和仅第二抗体对照与HER3阳性的NCI-H1975细胞(人肺腺癌,NSCLC)和BxPC-3细胞(人胰腺癌)的结合的流式细胞仪术测定的结果的图。
在HER3+细胞(NCI-H1975和BxPC3)中通过流式细胞术评估225Ac-HER3-ARC的结合特性。将抗HER3、225Ac-HER3-ARC和IgG(免疫球蛋白1,非特异性IgG1)的溶液(100μg/ml)加入到HER+细胞中并在室温下孵育1小时。加入PE标记的第二抗体并在冰上孵育30分钟。使用流式细胞术测量样品的荧光。225Ac-HER3-ARC与HER3+阳性细胞系的结合特性类似于未修饰的抗HER3 mAb的结合特性。
图5是显示225Ac-HER3-ARC对HER3阳性细胞系NCI-H1975的体外细胞毒性效应作为辐射剂量的函数的图。
225Ac-HER3-ARC对HER3+细胞系NCI-H1975的细胞毒性作用是用CellTiterAQueous非放射性细胞增殖测定(MTS)在比色测定中进行评估的。NCI-H1975细胞与225Ac-HER3-ARC在37℃下孵育24小时。然后除去未结合的225Ac-HER3-ARC,并在37℃下培养细胞72小时。测量490nm处的吸光度,并计算细胞活力的百分比。225Ac-HER3-ARC显示出对HER3+细胞系NCI-H1975强大的体外细胞毒性。
图6A是显示225Ac-HER3-ARC在NCI-H1975细胞中上调细胞表面钙网蛋白(CRT)的图,图6B是显示225Ac-HER3-ARC在NCI-H1975细胞上上调CD47的图。
使用流式细胞术检查225Ac-HER3-ARC对HER3+细胞系NCI-H1975的钙网蛋白(CRT)和CD47的细胞表面表达的影响。用225Ac-HER3-ARC(100nCi/ml)或PBS(对照)处理细胞72小时。处理后,对细胞进行CRT和CD47染色。结果表明,NCI-H1975细胞中的CRT(图6A)和CD47(图6B)中的每一种都被225Ac-HER3-ARC上调。
图7A是显示吞噬作用测定的结果的图,表明225Ac-HER3-ARC和抗CD47阻断抗体的组合与单独任一种处理相比增强了BxPC-3细胞的吞噬作用。图7B是显示吞噬作用测定的结果的图,表明225Ac-HER3-ARC和抗CD47阻断抗体的组合与单独任一种处理相比增强了NCI-H1975细胞的吞噬作用。同样的关键适用于图7A和7B。
通过流式细胞术来评估结合225Ac-HER3-ARC和抗CD47对体外吞噬作用的影响。将BxPC-3(图7A)和NCI-H1975(图7B)细胞播种在6孔板中24小时,随后在37℃下与225Ac-HER3-ARC孵育24小时。在225Ac-HER3-ARC处理后,将细胞在37℃下培养72小时。
BxPC-3和NCI-H1975细胞用Vybrant DiD细胞标记液进行染色,并用抗人CD47(BioX Cell,Cat#BE0019)和小鼠IgG1亚型对照(Bio X Cell,Cat#BE0083)在37℃下处理1小时。人巨噬细胞用Vybrant DiO细胞标记液进行染色。将标记的人巨噬细胞和靶细胞在37℃下共培养2小时。通过评估双重标记的细胞(DiD+/DiO+)来评估吞噬作用。
图8是显示在人类肿瘤(NCI-H1975细胞)小鼠异种移植模型中,225Ac-HER3-ARC在不同辐射剂量(100nCi、200nCi、400nCi、600nCi)下单独和在200nCi下与抗CD47阻断抗体组合、未标记的抗HER3 mAb、单独的抗CD47阻断抗体和仅载体对照对肿瘤生长的影响。值得注意的是,225Ac-HER-ARC在辐射剂量200nCi、400nCi、600nCi时以及225Ac-HER-ARC(200nCi)与抗CD47 mAb的组合几乎完全抑制了肿瘤生长。
图9是显示图8中描述的实验的受试者的体重随时间变化的图。
图10是显示图8中描述的实验的实验组受试者的生存概率随时间变化的图。
还进行了肿瘤异种移植研究,其检查HER2-ARC治疗单独和与CD47阻断剂组合对HER2阳性肿瘤生长的影响。使用p-SCN-Bn-DOTA将抗HER2 mAb曲妥珠单抗与DOTA化学缀合,并用锕-225或镥-177通过螯合作用进行标记,用于这些实验。
图11是显示在使用HER2阳性的SK-OV3人类卵巢癌细胞系的NGS小鼠异种移植模型中,仅载体(对照)、单独的莫洛利单抗(10mg/kg)、单独的225Ac-曲妥珠单抗(0.025μCi/动物)以及莫洛利单抗(10mg/kg)和225Ac-曲妥珠单抗(0.025μCi/动物)的组合对肿瘤生长的比较效果的图。每个队列由8只动物组成。
图12是显示在使用HER2阳性的SK-OV3人类卵巢癌细胞系的NGS小鼠异种移植模型中,仅载体(对照)、单独的莫洛利单抗(10mg/kg)、单独的177Lu-曲妥珠单抗(25μCi/动物)以及莫洛利单抗(10mg/kg)和177Lu-曲妥珠单抗(25μCi/动物)的组合对肿瘤生长的比较效果的图。每个队列由8只动物组成。
本发明的方面
在临床前和临床研究中都有充分的记录,HER3的水平在施用HER3靶向抗体后可以变得下调(Mishra,2018)。在使用鲁妥珠单抗的临床前模型中,如通过免疫组化和蛋白质印迹(Maneses-Lorenta,2015;Mirshberger,2013)所测量的,HER3有剂量依赖性(1-10mg/kg)的下调。最低剂量的鲁妥珠单抗(0.3mg/kg)没有导致HER3靶标下调(Maneses-Lorenta,2015),这些低水平的鲁妥珠单抗(0.1mg/kg和0.3mg/kg)在控制表达HER3的肿瘤方面是无效的(Mirshberger,2013)。在鲁妥珠单抗的临床研究中,在所有测试的剂量水平(100-2000mg;Meulendijks,2016)中,92%的患者在连续肿瘤活检中观察到表面HER3的下调。另外地,在用40mg/kg的HER3靶向抗体LJM716治疗的患者中,在五个配对的肿瘤活检样品的三个中观察到总HER3水平下降(Reynolds,2017)。
虽然HER3的内化和降解可能有利于减少HER3的磷酸化和随后的信号传导活性,但HER3表面水平的降低可能会阻碍抗体对肿瘤的靶向。因此,如果希望或需要重复施用HER3靶向抗体以获得疗效,那么施用HER3靶向抗体可能会导致靶标的下调,并排除重新给药。本发明人发现,使用抗体放射性缀合物(ARC)可以规避与HER3的剂量依赖性下调有关的问题,因为在治疗方法中有用的较低抗体剂量可能不会导致HER3下调。因此,本发明人发现,包括放射性同位素的HER3靶向剂作为诊断剂和治疗剂是有效的,以改进肿瘤靶向和杀死表达HER3的癌细胞,例如某些实体瘤。特别是,可以包括多剂量的HER3靶向剂的治疗方法可提供改进的肿瘤靶向和杀伤,而不引起有害的HER3下调水平。
因此,根据目前公开的本发明的某些方面,提供了使用放射性标记的HER3靶向剂治疗HER3阳性癌症的治疗方法。所述方法还可以包括诊断步骤,以确定患者是否和/或在多大程度上具有HER3阳性癌症和/或这种癌症的定位,例如,通过识别和/或量化实体瘤内的或患者血液样品中循环的HER3阳性细胞。
根据某些方面,治疗方法包括单独或与一种或多种另外的治疗剂或方式联合施用放射性标记的HER3靶向剂,例如靶向HER3的放射性标记的抗体、肽或小分子。根据某些方面,另外的药剂或方式可以是施用免疫检查点疗法、DDRi、CD47阻断剂、化疗剂、小分子肿瘤药物、外束辐射(external beam radiation)和近距离放射治疗(brachytherapy)中的任何一种或多种。
根据某些方面,放射性标记的HER3靶向剂可在患者特定的组合物中以一个或多个剂量向患者施用。
根据某些方面,在治疗期间可间隔监测患者的HER3阳性细胞的存在,以评估HER3阳性细胞的减少。与治疗前的HER3阳性细胞的数量相比,在用HER3靶向剂治疗后检测到HER3阳性细胞的数量减少可表明HER3靶向剂在治疗哺乳动物受试者的HER3阳性癌症中的有效性。
根据某些方面,治疗癌症的方法包括通过识别HER3阳性细胞来识别具有HER3阳性癌症的患者,并单独或与另外的治疗方法联合向患者施用有效量的HER3靶向剂。根据某些方面,另外的治疗方法可以是施用免疫检查点疗法、DDRi、CD47阻断剂、化疗剂、小分子肿瘤药物、外束辐射和近距离放射治疗中的任何一种或多种。
根据某些方面,化疗剂是放射增敏剂。
根据某些方面,可将放射性标记的HER3靶向剂施用于已经接受,例如最近接受治疗的患者,例如用于治疗癌症的手术,例如切除全部或部分实体瘤。因此,例如,放射性标记的HER3靶向剂可以在围手术期或术后施用。
HER3靶向剂
目前公开的本发明的一个目的是提供用于诊断用途和/或治疗用途,例如用于诊断和/或治疗HER3阳性癌症的放射性标记的HER3靶向剂,例如人类HER3靶向剂。放射性标记的HER3靶向剂可以通过向细胞递送破坏DNA的电离辐射,例如诱发双链DNA断裂和细胞死亡的α粒子,来实现治疗反应。
示例性的抗HER3抗体(在本文中也称为“HER3抗体”),例如抗人HER3抗体,其可被放射性标记并体现在和/或用于目前公开的本发明的各个方面,包括但不限于以下抗体,以及诸如但不限于免疫球蛋白的抗体,例如但不限于IgG,其(i)包括HER3抗体或重链的重链可变区,(ii)包括HER3抗体或重链的1、2或3个重链CDR(例如,根据Kabat的定义)或所述的那些,(iii)包括HER3抗体或轻链的轻链可变区,和/或(iv)包括HER3抗体或轻链的1、2或3个轻链CDR(例如,根据Kabat的定义)或所述的那些。还应当理解的是,在公开的HER3抗体重链或HER3抗体轻链包括N末端前导序列的情况下,还打算公开的体现在和用于本发明各方面的是缺乏前导序列的相应重链和相应轻链。
可被放射性标记并体现在和/或用于目前公开的本发明的示例性的HER3抗体例如可以包括针对HER3的鼠单克隆抗体,其包括具有如SEQ ID NO:9或11所示的氨基酸序列的重链和/或具有如SEQ ID NO:10或12所示的氨基酸序列的轻链,或抗体,例如从所述序列中的一个或多个衍生的人源化抗体。可被放射性标记并体现在和/或用于目前公开的本发明的示例性的HER3抗体可以包括具有如SEQ ID NO:13所示的序列的N末端区的重链和/或具有如SEQ ID NO:14所示的序列的N末端区的轻链。可类似地体现在或用于本发明各方面的HER3抗体例如可以包括具有如SEQ ID NO:7所示的氨基酸序列的重链可变区,和/或具有如SEQ ID NO:8所示的氨基酸序列的轻链可变区;和/或包括分别具有如SEQ ID NO:1-3所示的氨基酸序列的CDR1、CDR2和CDR3中的一个或多个的重链,和/或包括分别具有如SEQ IDNO:4-6所示的氨基酸序列的CDR1、CD2和CDR3中的一个或多个的轻链。关于这些序列的进一步描述,见图1和图2。体现在和/或用于本发明任何方面的HER3抗体例如可以包括上述轻链序列和/或重链序列的任意组合。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:15的CDR-H1、包括SEQ ID NO:16的CDR-H2和包括SEQ ID NO:17的CDR-H3,和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:18的CDR-L1、包括SEQ ID NO:19的CDR-L2和包括SEQ ID NO:20的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:21的免疫球蛋白重链可变区和/或包括SEQ ID NO:22的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:23的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:24的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:25的CDR-H1、包括SEQ ID NO:26的CDR-H2和包括SEQ ID NO:27的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:28的CDR-L1、包括SEQ ID NO:29的CDR-L2和包括SEQ ID NO:30的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:31的免疫球蛋白重链可变区和/或包括SEQ ID NO:32的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:33的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:34的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:35的CDR-H1、包括SEQ ID NO:36的CDR-H2和包括SEQ ID NO:37的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:38的CDR-L1、包括SEQ ID NO:39的CDR-L2和包括SEQ ID NO:40的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:41的免疫球蛋白重链可变区和/或包括SEQ ID NO:42的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:43的免疫球蛋白重链氨基酸序列和SEQ ID NO:44的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:45的CDR-H1、包括SEQ ID NO:46的CDR-H2和包括SEQ ID NO:47的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:48的CDR-L1、包括SEQ ID NO:29的CDR-L2和包括SEQ ID NO:49的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:50的免疫球蛋白重链可变区和/或包括SEQ ID NO:51的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:52的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:53的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:54的CDR-H1、包括SEQ ID NO:55的CDR-H2和包括SEQ ID NO:56的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:28的CDR-L1、包括SEQ ID NO:29的CDR-L2和包括SEQ ID NO:30的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:57的免疫球蛋白重链可变区和/或包括SEQ ID NO:58的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:59的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:60的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:61的CDR-H1、包括SEQ ID NO:62的CDR-H2和包括SEQ ID NO:63的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:64的CDR-L1、包括SEQ ID NO:65的CDR-L2和包括SEQ ID NO:66的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:67的免疫球蛋白重链可变区和/或包括SEQ ID NO:68的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:69的免疫球蛋白重链氨基酸序列和SEQ ID NO:70的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括免疫球蛋白重链可变区,其包含包括SEQ ID NO:71的CDR-H1、包括SEQ ID NO:72的CDR-H2和包括SEQ ID NO:66的CDR-H3;和/或免疫球蛋白轻链可变区,其包含包括SEQ ID NO:28的CDR-L1、包括SEQ ID NO:29的CDR-L2和包括SEQ ID NO:30的CDR-L3。示例性的HER3抗体包含包括SEQ ID NO:73的免疫球蛋白重链可变区和/或包括SEQ ID NO:74的免疫球蛋白轻链可变区。示例性的HER3抗体包括SEQ ID NO:75的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:76的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包括SEQ ID NO:77的免疫球蛋白重链氨基酸序列和/或SEQ IDNO:78的免疫球蛋白轻链氨基酸序列。
示例性的HER3抗体包含包括SEQ ID NO:86、87、88、89、90或91的免疫球蛋白轻链可变区和/或包括SEQ ID NO:79、80、81、82、83、84或85的重链可变区。
示例性的HER3抗体包含包括SEQ ID NO:92、94、95、98或99的免疫球蛋白重链序列和/或包括SEQ ID NO:93、96、97、100或101的免疫球蛋白轻链序列。
示例性的HER3抗体还包括Isu Abxis Co的Barecetamab(ISU104)和美国专利号10,413,607中公开的任何HER3抗体。
示例性的HER3抗体还包括Hummingbird Bioscience Pte.的HMBD-001(10D1F)以及国际公开号WO 2019185164和WO2019185878、美国专利10,662,241;和美国公开号20190300624、20210024651和20200308275中公开的任何HER3抗体。
示例性的HER3抗体还包括Merus N.V.的HER2/HER3双特异性抗体MCLA-128(即泽妥珠单抗(Zenocutuzumab));和美国公开号20210206875、20210155698、20200102393、20170058035和20170037145中公开的任何HER3抗体,无论是单特异性还是多特异性。
示例性的HER3抗体还包括HER3抗体帕曲妥单抗(U3-1287),它是一种包括重链序列SEQ ID NO:106和/或轻链序列SEQ ID NO:7的抗体,这些序列是帕曲妥单抗的报告链,以及美国专利号9,249,230和7,705,130和国际公开号WO2007077028中公开的任何HER3抗体。
示例性的HER3抗体还包括HER3抗体MM-121和美国专利号7,846,440和国际公开号WO2008100624中公开的任何HER3抗体。示例性的HER3抗体还包括EGFR/HER3双特异性抗体DL1以及美国专利号9,327,035和8,597,652、美国公开号20140193414和国际公开号WO2010108127中公开的任何HER3抗体,无论是单特异性还是多特异性。
示例性的HER3抗体还包括HER2/HER3双特异性抗体MM-111以及美国公开号20130183311和20090246206和国际公开号W02006091209和WO2005117973中公开的任何HER3抗体,无论是单特异性还是多特异性。
根据某些方面,HER3靶向剂包括抗HER3抗体,其与以下所识别的HER3的表位结合:Daiichi Sankyo的帕曲妥单抗、Merrimack Pharmaceuticals的瑟瑞妥单抗(MM-121)、罗氏的鲁妥珠单抗、诺华的依更妥单抗、GlaxoSmithKline的GSK2849330,CelldexTherapeutics的CDX-3379、MediPharma的EV20和MP-RM-1、Isu Abxis Co.的Barecetamab(ISU104)、Hummingbird Bioscience Pte.的HMBD-001(10D1F)、RegeneronPharmaceuticals的REGN1400和/或AVEO Oncology的AV-203。根据某些方面,抗HER3抗体选自帕曲妥单抗、瑟瑞妥单抗或包括重链序列SEQ ID NO:108和/或轻链序列SEQ ID NO:109(这些序列被报道为瑟瑞妥单抗、鲁妥珠单抗所有)的抗体、或包括重链序列SEQ ID NO:110和/或轻链序列SEQ ID NO:111(这些序列被报道为鲁妥珠单抗、依更妥单抗所有)的抗体、或包括重链序列SEQ ID NO:112和/或轻链序列SEQ ID NO:113(这些序列被报道为依更妥单抗、AV-203、CDX-3379、GSK2849330、EV20、MP-RM-1、ISU104、HMBD-001(10D1F)和REGN1400所有)的抗体中的一种或多种。表1中还描述了示例性抗体以及示例性治疗适应症。
表1
应当理解的是,在本公开中公开了针对HER3或针对任何靶标的特异性抗体、特异性抗体重链和特异性抗体轻链的情况下,还打算公开的体现在和用于本发明各方面的是抗体,例如但不限于免疫球蛋白,例如但不限于IgG,其(i)包括所公开的抗体或重链的重链可变区,(ii)包括所公开的抗体或重链的1、2或3个重链CDR(例如,根据Kabat的定义),(iii)包括所公开的抗体或轻链的轻链可变区,和/或(iv)包括所公开的抗体或轻链的1、2或3个轻链CDR(例如,根据Kabat的定义)。还应当理解的是,在本公开中公开了包括N末端前导序列的抗体重链或抗体轻链的情况下,还打算公开的体现在和用于本发明各方面的是缺乏前导序列的相应重链和相应轻链。
此外,本发明提供了任何所述氨基酸序列的修饰版本,其中进行了一个或多个具有精确质量的同分异构氨基酸取代,例如Leu取代Ile或反之亦然(例如在图1和2中列出的SEQ ID NO:1-14中的任何一个)。替代地,这些序列的某些部分可以被取代,例如被来自人类免疫球蛋白的相关部分取代,以形成嵌合免疫球蛋白(即嵌合或人源化HER3)。示例性的取代包括人类前导序列的全部或部分,和/或来自人IgG1、IgG2或IgG4重链和/或人κ轻链的保守区域。
人HER3、人HER2和人EGFR(HER1)的序列和结构是已知的。人HER3前体蛋白的氨基酸序列(受体酪氨酸-蛋白激酶erbB-3同种型1前体NCBI参考序列:NP_001973.2)在本文中提供为SEQ ID NO:115。本领域技术人员将很容易理解,鉴于已知的靶蛋白氨基酸序列,可使用本领域已确立的免疫和/或平移和/或抗体工程技术生产用于本发明各方面的各种类型的对HER3(例如人HER3)的细胞外结构域具有特异性的合适的抗体和抗体模拟物。
用于本发明各实施方案的放射性标记的HER3靶向剂可以,例如,包括HER3结合肽,例如携带螯合剂的HER3结合肽,例如携带DOTA的HER3结合肽,例如美国公开号20200121814中公开的任何那些。
根据某些方面,HER3靶向剂包括/是多特异性靶向剂,例如多特异性抗体,针对HER3的第一表位和至少HER3的第二表位,或针对HER3和一个或多个不同的抗原,例如EGFR(HER1)、HER2、TROP2和T细胞受体γ(TCRγ)链交替阅读框蛋白(TRAP)中的一个或多个。可使用的示例性的多特异性抗体包括针对HER3/HER2的双特异性抗体,例如MerrimackPharmaceuticals的MM-111或Merus N.V.的MCLA-128(即泽妥珠单抗);或针对IGF-1R/HER3的双特异性抗体,例如Merrimack Pharmaceuticals的MM-141(即艾司妥单抗);或针对EGFR/HER3的双特异性抗体,例如罗氏的MEHD7945A(即杜力戈图单抗)或Zyngenia Inc.的任何基于西妥昔单抗的双特异性或多特异性zybodies。
根据某些方面,提供和/或使用包括HER3靶向剂(例如针对HER3的抗体)和一种或多种针对一种或多种不同抗原的抗体的混合物的组合物,其中一种或多种抗体是放射性标记的。包括抗体混合物的示例性抗体组合物至少包括Symphogen的Sym013,其具有六种针对EGFR(HER1)、HER2和HER3的单克隆抗体。在本发明的一个方面,Sym013中的一种或多种抗体,例如抗HER3抗体可以是放射性标记的。本发明的相关方面提供了一种组合物,其包括针对EGFR(HER1)、HER2和HER3的靶向剂,例如抗体,其中一种或多种在任意组合中或全部是放射性标记的。
本发明进一步提供了治疗增殖性疾病或病症的多特异性靶向剂、组合物和相关方法,其包括施用(i)针对HER3的两个或更多个表位的多特异性抗体,或针对HER3的表位和一种或多种另外的不同抗原的表位的多特异性抗体,和/或(ii)施用HER3靶向剂,例如抗体和一种或多种针对一种或多种癌症相关抗原的离散靶向剂,其中一种或多种靶向剂,例如HER3靶向剂是放射性标记的。例如,另外的不同抗原可以是在涉及各种疾病或病症,例如增殖性病症,例如实体瘤癌症(例如其中HER3也上调或也可上调的那些)的细胞上表达上调的抗原。例如,另外的不同抗原可以选自包括以下的组:间皮素、TSHR、CD19、CD123、CD22、CD30、CD45、CD171、CD138、CS-1、CLL-1、GD2、GD3、B细胞成熟抗原(BCMA)、Tn Ag、前列腺特异性膜抗原(PSMA)、ROR1、FLT3、TROP2、T细胞受体γ(TCRγ)链交替阅读框蛋白(TRAP)、成纤维细胞激活蛋白(FAP)、钙网蛋白、磷脂酰丝氨酸、GRP78(BiP)、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、白细胞介素-11受体a(IL-llRa)、PSCA、PRSS21、VEGFR2、LewisY、CD24、血小板衍生生长因子受体-β(PDGFR-β)、SSEA-4、CD20、叶酸受体α(FRa)、ERBB2(Her2/neu)、MUCl、表皮生长因子受体(EGFR)、EGFRvIII、NCAM、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受体、CAIX、LMP2、gplOO、bcr-abl、酪氨酸酶、EphA2、岩藻糖酰GM1、sLe、GM3、DR5、5T4、TGS5、HMWMAA、o-乙酰-GD2、叶酸受体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、多唾液酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、legumain、HPV E6,E7、MAGE Al、MAGEA3、MAGEA3/A6、ETV6-AML、精子蛋白17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos相关抗原1、prostein、生存素(survivin)和端粒酶、PCTA-l/半乳糖凝集素8、KRAS、MelanA/MARTl、Ras突变体、hTERT、肉瘤易位断点、ML-IAP、ERG(TMPRSS2 ETS融合基因)、NA17、PAX3、雄性激素受体、细胞周期蛋白B l、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、人类端粒酶逆转录酶、RU1、RU2、肠道羧酸酯酶、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、GPA7和IGLL1。
可用于本发明的放射性标记的、未标记的或药物缀合的示例性DR5(死亡受体5)靶向剂包括单克隆抗DR5抗体马帕木单抗(mapatumumab)、可那木单抗(conatumumab)、来沙木单抗(lexatumumab)、替加组单抗(tigatuzumab)、曲齐妥单抗(drozitumab)和LBY-135。例如,这样的DR5靶向剂可与放射性标记的HER3靶向剂联合用于治疗卵巢癌、乳腺癌、宫颈癌、前列腺癌、胃癌、膀胱癌、肺癌、黑色素瘤、结直肠癌和鳞状细胞癌以及本文公开的任何癌症。
可用于本发明的放射性标记的、药物缀合的或未标记的示例性5T4(滋养细胞糖蛋白(TBPG))靶向剂包括抗5T4单克隆抗体MED10641、ALG.APV-527、Tb535、H6-DM5和ZV0508,以及埃托-那普妥莫单抗(Naptumomab estafenatox)或其Fab部分。例如,这样的5T4靶向剂可与放射性标记的HER3靶向剂联合用于治疗卵巢癌、头颈癌、乳腺癌、前列腺癌、胃癌、膀胱癌、肺癌、黑色素瘤、结直肠癌和鳞状细胞癌以及本文公开的任何癌症。
可用于本发明的放射性标记的、药物缀合的或未标记的示例性HER2(ERBB2)靶向剂包括单克隆抗体曲妥珠单抗和帕妥珠单抗(pertuzumab)。申请人已经成功地将曲妥珠单抗与p-SCN-DOTA缀合,并用225Ac或177Lu对组合物进行放射性标记。可使用的靶向HER2的示例性ADC包括fam-德喜曲妥珠单抗(trastuzumab deruxtecan)-nxki(AstraZeneca/Daiichi Sankyo)和恩美曲妥珠单抗(Trastuzumab emtansine)(罗氏/Gentech)。例如,抗HER2抗体也可以是针对HER3/HER2的任何可用表位的多特异性抗体,例如双特异性抗体,例如Merrimack Pharmaceuticals的MM-111和MM-141/艾司妥单抗、MerusNV的MCLA-128和Genentech的MEHD7945A/杜力戈图单抗。例如,HER2靶向剂可与放射性标记的HER3靶向剂联合用于治疗表达HER2的癌症,例如卵巢癌、乳腺癌、转移性乳腺癌、食道癌、肺癌、宫颈癌和子宫内膜癌,包括但不限于那些同时为HER2阳性和HER3阳性的癌症。/>
DrugBank Online报告的曲妥珠单抗的重链和轻链的氨基酸序列为:重链(SEQ IDNO:102)和轻链(SEQ ID NO:103),包括所述链中的一个或两个的HER2结合抗体可体现在或用于本发明的各个实施方案中。
DrugBank Online报告的帕妥珠单抗的重链和轻链的氨基酸序列为:重链(SEQ IDNO:104)和轻链(SEQ ID NO:105),包括所述链中的一个或两个的HER2结合抗体可体现在或用于本发明的各个实施方案中。
可用于本发明的放射性标记的、药物缀合的或未标记的示例性CD33靶向剂包括单克隆抗体林妥珠单抗(lintuzumab)、吉妥珠单抗(gemtuzumab)和伐达妥昔单抗(vadastuximab)。与本文公开的放射性标记的HER3靶向剂联合,CD33靶向治疗剂例如可用于治疗实体癌,例如卵巢癌、乳腺癌、宫颈癌、前列腺癌、胃癌、膀胱癌、肺癌、黑色素瘤、结直肠癌和鳞状细胞癌以及本文公开的任何癌症,例如,通过耗尽骨髓源性抑制细胞(MDSC)。在一个方面,与放射性标记的HER3靶向剂联合使用的CD33靶向剂是225Ac-林妥珠单抗。在另一个方面,与放射性标记的HER3靶向剂联合使用的CD33靶向剂是ADC吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)(辉瑞)。
可用于本发明的放射性标记的、药物缀合的或未标记的示例性CD38靶向剂包括抗CD38单克隆抗体,例如达雷妥尤单抗(daratumumab)(强生)和伊沙妥昔单抗(isatuximab)(/>赛诺菲)或其抗原结合片段。例如,这样的CD38靶向剂可与放射性标记的HER3靶向剂联合用于治疗例如可能被CD38阳性抑制性免疫细胞浸润的实体瘤,例如但不限于卵巢癌、乳腺癌、宫颈癌、前列腺癌、胃癌、膀胱癌、肺癌、黑色素瘤、结直肠癌和鳞状细胞癌以及本文公开的任何癌症。
根据本发明的各个方面,可由多特异性抗体靶向的示例性的不同抗原(超过HER3)至少包括HER1(EGFR)、HER2和IGF-1R。示例性的HER3多特异性靶向剂包括多特异性抗体,例如Merrimack Pharmaceuticals的MM-111或Merus N.V.的MCLA-128(即泽妥珠单抗);或针对IGF-1R/HER3的抗体,例如Merrimack Pharmaceuticals的MM-141(即艾司妥单抗);或针对EGFR/HER3的抗体,例如罗氏的MEHD7945A(即杜力戈图单抗)、Zyngenia Inc.的基于西妥昔单抗的双特异性zybody和Symphogen的多特异性抗体组合物Sym-013。进一步的描述和示例性适应症另请参见表2。
表2
本发明还提供了治疗增殖性疾病或病症的方法,所述方法包括施用针对HER3的至少一个表位的第一抗体,以及施用第二抗体,其中第二抗体针对HER3的与第一抗体不同的表位,或者针对不同抗原的表位,例如选自上述不同抗原的列表的一个或多个抗原。一种或多种HER3抗体可以是放射性标记的。例如,针对不同抗原的抗体也可以以任意组合方式进行放射性标记。
如上所述,以多特异性抗体或一个以上的单克隆抗体呈现的此类组合可提供与仅有针对HER3的抗体的单药疗法的效果相当的协同治疗效果,同时减少单药疗法的不良副作用。此外,该组合可提供比单药疗法更好的效果,例如,可通过肿瘤细胞总数的减少、复发时间的增加和其他患者健康指标来衡量。
当所述方法包括施用多特异性抗体时,第一靶标识别组分例如可以包括以下之一:第一全长重链和第一全长轻链、第一Fab片段、第一单链可变片段(scFv)或其他类型的抗体。第二靶标识别组分例如可以包括以下之一:第二全长重链和第二全长轻链、第二Fab片段、或第二单链可变片段(scFv)或其他类型的抗体。此外,第二靶标识别组分可以衍生自HER3抗原的不同表位,或者可以衍生自上述任何抗原。
HER3靶向剂可以包括放射性同位素,并且任何针对其他抗原的另外的抗体可以任选地包括放射性同位素。根据本发明的某些方面,当免疫疗法包括双特异性抗体时,第一靶标识别组分和第二靶标识别组分中的一个或两个,或双特异性靶向剂的任何部分,可以包括放射性同位素。
根据本发明的某些方面,放射性标记的靶向剂可以对抗原表现出与对照靶向剂基本相同的免疫反应性,其中对照靶向剂包括针对与放射性标记的靶向剂相同的抗原表位(即HER3)的裸的靶向剂或其他未标记的靶向剂。
根据本发明的某些方面,靶向剂可以用225Ac标记,并且在引起HER3阳性细胞的细胞死亡方面可以比对照单克隆抗体至少有效5倍,其中对照单克隆抗体包括针对与225Ac标记的抗体相同的抗原表位的裸的或未标记的抗体。例如,225Ac标记的单克隆抗体在引起HER3阳性细胞的细胞死亡方面可能比对照单克隆抗体至少有效10倍、至少有效20倍、至少有效50倍或至少有效100倍。
根据本发明的某些方面,所述方法可以包括施用HER3靶向剂的标记和未标记(例如“裸”)的部分,例如抗体、抗体片段等。例如,未标记的部分可以包括与标记的部分相同的针对同一表位的抗体。这样,抗体的总放射性可以变化,或者可以保持恒定,而整个抗体蛋白浓度可以分别保持恒定或变化。例如,施用的未标记的抗体部分的总蛋白浓度可根据要治疗的疾病的确切性质、患者的年龄和体重、单克隆抗体的特性以及为标记单克隆抗体而选择的标记(例如放射性核素)而变化。
根据本发明的某些方面,抗HER3抗体的有效量是抗HER3抗体的最大耐受剂量(MTD)。
根据本发明的某些方法方面,当施用一种以上的抗体时,可以同时施用抗体。因此,根据本发明的某些方面,可以在单一组合物中提供抗体。替代地,这两种抗体可以依次施用。因此,放射性标记的HER3靶向剂可以在第二抗体之前、在第二抗体之后或在第二抗体之前和之后施用。此外,第二抗体可以在放射性标记的HER3靶向剂之前、在放射性标记的HER3靶向剂之后或在放射性标记的HER3靶向剂之前和之后施用。
根据本发明的方法的某些方面,可以根据选自由以下组成的组的给药计划来施用放射性标记的HER3靶向剂:在整个治疗期间,每7、10、12、14、20、24、28、35和42天施用一次,其中治疗期间包括至少2个剂量。
根据本发明的某些方面,可以根据包括2个剂量的给药计划来施用放射性标记的HER3靶向剂,例如在治疗期的第1和5、6、7、8、9或10天,或治疗期间的第1和8天。
除其他治疗剂外,本发明的放射性标记的HER3靶向剂的施用可根据是否需要局部或全身治疗以及待治疗的区域以多种方式提供。施用可以是气管内、鼻内、表皮和经皮、口服或肠外。肠外施用包括静脉内、动脉内、皮下、腹膜内或肌肉内注射或输注;或颅内,例如鞘内或心室内施用。在一些实施方案中,可以施用包括靶向剂和/或其他治疗剂的缓释制剂。各种药剂可作为单一治疗或以一系列治疗施用,这些治疗根据需要继续进行并持续一定的时间,使癌症的一个或多个症状得到减轻或改善,或达到另一个期望的效果。
剂量可以变化,例如,取决于受试者的身份、大小和状况,进一步取决于组合物施用的途径和期望的效果。治疗剂的适当剂量取决于与要调节的表达或活性有关的效力。治疗剂可以在开始时以相对较低的剂量向动物(例如人)施用,随后增加剂量,直到获得适当的反应。
放射性标记的HER3靶向剂可与一种或多种另外的治疗剂同时或依次施用。此外,当包括一种以上的另外的治疗剂时,另外的治疗剂可与彼此和/或与放射性标记的HER3靶向剂同时或依次施用。
放射性标记的HER3靶向剂
本文公开的HER3靶向剂和其他靶向剂例如可以通过缀合螯合剂分子并将放射性同位素螯合到其中而用放射性同位素如β发射体(例如177Lu)或α发射体(例如225Ac)标记。根据某些方面,靶向剂可以是在恒定区,例如在重链CH2结构域的天冬酰胺-297(Asn-297,N297;Kabat号)处被去糖基化的抗体,目的是发现独特的缀合位点谷氨酰胺(即Gln-295,Q295),以便它可与双功能螯合剂分子缀合。
根据某些方面,放射治疗剂可以是抗体,其可以具有还原的二硫键,例如通过使用还原剂,然后可以转化为脱氢丙氨酸以与双功能螯合剂分子缀合。
根据某些方面,放射治疗剂可以是抗体,其二硫键已经用还原剂还原,然后通过芳基桥与双功能螯合剂分子缀合。例如,根据某些方面,可使用接头分子如3,5-双(溴甲基)苯来桥接抗体上的游离巯氢基。
根据某些方面,放射治疗剂可以是抗体,其可以用半胱氨酸取代某些特定的现有氨基酸,然后可以用于特定位点的标记。
在本发明的各个方面,可与靶向剂连接的示例性螯合剂包括:1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A)或其衍生物;1,4,7-三氮杂环壬烷-1,4-二乙酸(NODA)或其衍生物;1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)或其衍生物;1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)或其衍生物;1,4,7-三氮杂环壬烷,1-戊二酸-4,7-二乙酸(NODAGA)或其衍生物;1,4,7,10-四氮杂环壬烷,1-戊二酸-4,7,10-三乙酸(DOTAGA)或其衍生物;1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸(TETA)或其衍生物;1,4,8,11-四氮杂双环[6.6.2]十六烷-4,11-二乙酸(CB-TE2A)或其衍生物;二乙烯三胺五乙酸(DTPA)、其二酯或其衍生物;2-环己基二乙烯三胺五乙酸(CHX-A”-DTPA)或其衍生物;去铁胺(DFO)或其衍生物;1,2-[[6-羧基吡啶-2-基]甲基氨基]乙烷(H2dedpa)或其衍生物;DADA或其衍生物;1,4,7,10-四氮杂环十二烷-1,4,7,10-四(亚甲基膦酸)(DOTP)或其衍生物;4-氨基-6-[[16-[(6-羧基吡啶-2-基)甲基]-1,4,10,13-tetraoxa-7,16-二氮杂环十八烷-7-基]甲基]吡啶-2-羧酸(MACROPA-NH2)或其衍生物;MACROPA或其衍生物;1,4,7,10-四(氨基甲酰基甲基)-l,4,7,10-四氮杂环十二烷(TCMC)或其衍生物;{4-[2-(双-羧基甲胺基)-乙基]-7-羧甲基-[1,4,7]triazonan-1-基}-乙酸(NETA)或其衍生物;Diamsar或其衍生物;1,4,7-三氮杂环壬烷-1,4,7-三[甲基(2-羧基乙基)膦酸(TRAP,PRP9,TRAP-Pr)或其衍生物;N,N’-双(6-羧基-2-吡啶基甲基)乙二胺-N,N’-二乙酸(H4octapa)或其衍生物;N,N’-[1-苄基-1,2,3-三唑-4-基]甲基-N,N’-[6-(羧基)吡啶-2-基]-1,2-乙二胺(H2azapa)或其衍生物;N,N”-[[6-(羧基)吡啶-2-基]甲基]二亚乙基三胺-N,N’,N”-三乙酸(H5decapa)或其衍生物;N,N’-双(2-羟基-5-磺酸基苄基)乙二胺-N,N’-二乙酸(SHBED)或其衍生物;N,N’-双(2-羟基苄基)乙二胺-N,N’-二乙酸(HBED)或其衍生物;3,6,9,15-四氮杂双环[9.3.1]十五烷-1(15),11,13-三烯-3,6,9,-三乙酸(PCTA)或其衍生物;去铁草酰胺B(desferrioxamine B)(DFO)或其衍生物;N,N’-(亚甲基膦酸)-N,N’-[6-(甲氧基羰基)吡啶-2-基]甲基-1,2-乙二胺(H6phospa)或其衍生物;1,4,7,10,13,16-六氮杂环十六烷-N,N’,N”,N”’,N””,N””’-六乙酸(HEHA)或其衍生物;1,4,7,10,13-五氮杂环十五烷-N,N’,N”,N”’,N””-五乙酸(PEPA)或其衍生物;或3,4,3-LI(1,2-HOPO)或其衍生物。
根据某些方面,靶向剂可以通过化学缀合合适的双功能螯合剂来进行放射性标记,所述双功能螯合剂可以螯合一种或多种放射性核素。可使用的示例性螯合剂分子包括p-SCN-Bn-DOTA、NH2-DOTA、NH2-(CH2)1-20-DOTA、NH2-(PEG)1-20-DOTA、HS-DOTA、HS-(CH2)1-20-DOTA、HS-(PEG)1-20-DOTA、二溴-S-(CH2)1-20-DOTA、二溴-S-(PEG)1-20-DOTA、p-SCN-Bn-DOTP、NH2-DOTP、NH2-(CH2)1-20-DOTP、NH2-(PEG)1-20-DOTP、HS-DOTP、HS-(CH2)1-20-DOTP、HS-(PEG)1-20-DOTP、二溴-S-(CH2)1-20-DOTP和二溴-S-(PEG)1-20-DOTP。
螯合剂分子例如可以通过接头分子连接到靶向剂。示例性的接头分子包括:
-CH2(C6H4)NH2或-CH2(C6H4)NH-X-Y,
其中,X是
-R2-CH2CH2O(CH2CH2O)nCH2CH2-,
-R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O)nCH2CH2-,
-R2-(CH2)nCH2-,
-R2-CH2CH2NHC(O)(CH2)nCH2-,
-R2-CH(C(O)R3)CH2-,其中R3是-OH或短肽(1-20个氨基酸),
-R2-CH2CH2O(CH2CH2O)nCH2C(O)O-,或
-R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O)nCH2CC(O)O-,
其中,n是1-20,和
R2是-C(O)-或-C(S)NH-;和
Y是-NH2或-SR4-,其中R4是-H或-CH2-3,5-双(溴甲基)苯。
靶向剂,例如蛋白质靶向剂,例如抗体和抗原结合抗体片段,以及肽靶向剂,可以例如与螯合剂缀合,用于通过螯合放射性核素对靶向剂进行放射性标记。这种蛋白质或肽靶向剂,例如,其包括赖氨酸,可以方便地使用双功能剂S-2-(4-异硫氰苄基)-1,4,7,10-四氮杂环十二烷四乙酸a/k/a/“p-SCN-Bn-DOTA”(登录号#B205;Macrocyclics,Inc.,Plano,TX,USA)缀合到DOTA螯合部分。p-SCN-Bn-DOTA可以通过美国专利号4,923,985中充分描述的多步有机合成法来合成。DOTA部分对放射性核素的螯合作用可在抗体与p-SCN-Bn-DOTA的化学缀合之前和/或在所述缀合之后进行。
实施例1中描述了用示例性放射性核素标记螯合剂缀合的靶向剂的方法。
诊断方面
目前公开的方法可以包括诊断受试者以确定是否存在HER3阳性细胞、其程度如何和/或其定位。HER3阳性细胞可存在于多个生物样本中,例如存在于受试者血液样品中的循环细胞或受试者活检中的肿瘤细胞。在一个方面,诊断步骤一般可以包括从受试者获得血液或组织样品,并将样品安装在基质上。可以使用诊断抗体、肽或小分子来检测HER3抗原是否存在,其中诊断抗体肽或小分子用本领域已知的任何标准成像标签进行标记。示例性的标记剂包括,例如,放射性标记,如3H、14C、32P、35S和125I;荧光或化学发光化合物,如异硫氰酸荧光素、罗丹明或荧光素;和酶,如碱性磷酸酶、β-半乳糖苷酶或辣根过氧化物酶。用于此类诊断测定的示例性HER3靶向剂包括针对HER3的人或人源化抗体。
在另一个方面,所述方法可以包括使用标记有放射性核素的HER3靶向剂,例如用于PET成像的18F、11C、68Ga、64Cu、89Zr或124I中的任何一种,或用于SPECT成像的99mTc或111In,对受试者进行诊断以确定是否存在HER3阳性细胞。因此,所述方法可以包括向受试者施用标记有18F、11C、68Ga、64Cu、89Zr、124I、99mTc或111In中的一种或多种的HER3靶向剂,并对受试者进行非侵入性成像技术,例如对受试者进行PET或SPECT扫描。所述方法可以包括向受试者施用用于成像的放射性标记的HER3靶向剂,并在足以使靶向剂与受试者组织中的靶标结合的时间后,进行成像。足以使靶向剂与受试者组织中的靶标结合的时间可以是,例如,至少20分钟、至少30分钟、至少60分钟或20分钟至360分钟范围内的任何数量或次范围的分钟。根据所述方法的某一个方面,放射性标记的HER3靶向剂可以包括68Ga、89Zr或111In,并且可以使用本文公开的任何方法(例如,实例例1中公开的方法)进行标记。
如果受试者具有HER3阳性的癌细胞,例如超过预定或预选的阈值水平,或HER3阳性的癌症/肿瘤的其他适应症,则可以进行目前公开的本发明的治疗方法,即可以单独或与一种或多种另外的治疗剂联合施用治疗有效量的放射性标记的HER3靶向剂。
另外的治疗剂和治疗方式
包括单独或与其他靶向剂联合施用放射性标记的HER3靶向剂治疗剂的本发明的方法可以进一步包括施用另外的治疗剂或治疗方式。根据某些方面,另外的药剂可以与被放射性标记的HER3靶向剂治疗的疾病或病况有关。这种施用可以与有效量的HER3靶向剂的施用同时、分开或依次进行。对于同时施用,可酌情将药剂作为一个组合物或作为分开的组合物施用。
可与放射性标记的HER3靶向剂联合或一起使用的示例性的另外的治疗剂和治疗方式至少包括化疗剂、小分子肿瘤药物、抗炎剂、免疫抑制剂、免疫调节剂,包括免疫检查点疗法、DDR抑制剂、CD47阻断剂、外束辐射、近距离放射治疗或其任意组合。可与单独的放射性标记的HER3靶向剂或与放射性标记的HER3靶向剂联合本文公开的其他靶向剂联合或一起使用的示例性的另外的药剂和治疗方式在下文进一步描述。
A.化疗剂和其他小分子药剂
示例性的化疗剂包括但不限于抗肿瘤药物,包括烷基化药物,包括:氮芥类,例如二氯甲基二乙胺(mechlorethamine)、环磷酰胺、异环磷酰胺、美法仑和苯丁酸氮芥(chlorambucil);亚硝基脲类,例如卡莫司汀(BCNU)、洛莫司汀(CCNU)和司莫司汀(甲基-CCNU);TemodalTM(替莫唑胺)、亚乙基亚胺(ethylenimines)/甲基蜜胺(methylmelamine),例如三乙烯蜜胺(TEM)、三乙烯、三胺硫磷(thiotepa)、六甲基蜜胺(HMM,altretamine);烷基磺酸盐,例如白消安;三嗪类,例如达卡巴嗪(DTIC);抗代谢药,包括叶酸类似物,例如甲氨蝶呤和三甲曲沙(trimetrexate),嘧啶类似物,例如5-氟尿嘧啶(5FU)、氟脱氧尿苷、吉西他滨、阿糖胞苷(AraC,cytarabine)、5-氮杂胞苷、2,2’-二氟脱氧胞苷,嘌呤类似物,例如6-mercaρtopurine、6-thioguamne、硫唑嘌呤、T-脱氧助间型霉素(T-deoxycoformycin)(喷司他丁(pentostatin))、erythrohydroxynonyladenine(EHNA)、磷酸氟达拉滨和2-氯脱氧腺苷(克拉屈滨(cladribine),2-CdA);天然产物,包括抗有丝分裂药物(antimitotic drug),例如紫杉醇、长春花生物碱,包括长春花碱(VLB)、长春新碱和长春瑞滨,泰索帝(taxotere)、雌莫司汀(estramustine)和磷酸雌莫司汀;鬼臼毒素(pipodophylotoxins),例如依托泊苷(etoposide)和替尼泊苷(teniposide);抗生素,例如放线菌素D、道诺霉素(红比霉素)、多柔比星、米托蒽醌(mitoxantrone)、伊达比星(idarubicin)、博来霉素、普卡霉素(plicamycin)(光神霉素(mithramycin))、丝裂霉素C和放线菌素;酶,例如L-天冬酰胺酶;生物反应调节剂,例如干扰素-α、IL-2、G-CSF和GM-CSF;其他药物,包括铂配位复合物,例如奥沙利铂(oxaliplatin)、顺铂和卡铂;蒽醌类,例如米托蒽醌,取代的尿素,例如羟基脲,甲基肼衍生物,包括N-甲基肼(MIH)和丙卡巴肼(procarbazine),肾上腺皮质抑制剂,例如米托坦(o,p-DDD)和氨鲁米特(aminoglutethimide);激素和拮抗剂,包括肾上腺皮质类固醇拮抗剂,例如泼尼松和等效物、地塞米松和氨鲁米特;GemzarTM(吉西他滨),孕激素,例如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮;雌激素,例如二乙基己烯雌酚和乙炔雌二醇等效物;抗雌激素,例如他莫昔芬;雄激素,包括丙酸睾丸素和氟甲睾酮/等效物;抗雄激素,例如氟他胺、促性腺激素释放激素类似物和亮丙瑞林;以及非类固醇抗雄激素,例如氟他胺。
针对表观遗传机制的疗法包括但不限于:(i)组蛋白脱乙酰酶(HDAC)抑制剂,例如伏立诺他(Vorinostat)(辛二酰苯胺异羟肟酸;SAHA)、罗米地辛(Romidepsin)、贝利司他(Belinostat)(PDX101)、帕比司他(Panobinostat)(LBH589)和西达本胺(Tucidinostat),脱甲基剂(例如阿扎胞苷(Vidaza));(ii)LSD1抑制剂,例如seclidemstat、TCP(强内心百乐明(tranylcypromine))、ORY-1001(亚达司他(iadademstat))、GSK2879552(GSK)、INCB059872(Imago BioSciences)、IMG-7289(Bomedemstat;Imago BioSciences)、ORY-2001(伐德司他(Vafidemstat))和CC-90011(Celgene);和(iii)释放转录抑制(ATRA)疗法,也可与本文公开的放射性标记的HER3靶向剂和/或其他放射性标记的靶向剂及其组合联合或一起使用。
根据本发明的某些方面,化疗剂至少包括放射增敏剂,例如替莫唑胺、顺铂和/或氟尿嘧啶。
另外的药剂例如可以包括bcl-2抑制剂,例如navitoclax或维奈托克(venetoclax)(Abbvie),并且该组合例如可以用于治疗实体瘤,例如乳腺癌和肺癌,如小细胞肺癌(SCLC)。
另外的药剂例如可以包括细胞周期蛋白依赖性激酶CDK4和CDK6抑制剂,例如帕博西尼(palbociclib)(辉瑞),并且该组合例如可以用于治疗实体癌,例如乳腺癌,如HR阳性和HER2阴性乳腺癌,同时有或没有芳香酶抑制剂。
另外的药剂例如可以包括厄洛替尼(erlotinib)(罗氏),并且该组合例如可以用于治疗实体瘤癌症,例如非小细胞肺癌(NSCLC),例如具有表皮生长因子受体(EGFR)突变,和胰腺癌。
另外的药剂例如可以包括西罗莫司(sirolimus)或依维莫司(everolimus)(诺华),并且该组合例如可以用于治疗实体瘤癌症,例如黑色素瘤和乳腺癌。
另外的药剂例如可以包括培美曲塞(pemetrexed)(Eli Lilly),并且该组合例如可以用于治疗实体癌,例如间皮瘤如胸间皮瘤,和肺癌如非小细胞肺癌(NSCLC)。
另外的治疗剂例如可以按照本领域已知的任何标准剂量制度施用。例如,治疗剂可按1至500mg/m2的浓度给药,其量按患者表面积(m2)的函数计算。例如,化疗药物紫杉醇的示例性剂量可以包括15mg/平方米至275mg/平方米,多西紫杉醇的示例性剂量可以包括60mg/平方米至100mg/平方米,依匹斯汀的示例性剂量可以包括10mg/平方米至20mg/平方米,而卡利卡霉素的示例性剂量可以包括1mg/平方米至10mg/平方米。虽然这里列出了示例性剂量,但这种剂量仅用于参考,而不是为了限制本发明所公开的药物制剂的剂量范围。
B.外束辐射和/或近距离放射治疗
与HER3靶向剂和任选地本文公开的任何其他另外的疗法一起施用的另外的治疗方式可以是电离辐射,例如通过外束辐射或近距离放射治疗施用。这种辐射一般是指使用X射线、伽马射线或带电粒子(例如质子或电子)来产生电离辐射,例如通过放置在患者身体外的机器(外束辐射疗法)或通过放置在患者身体内的源(内部辐射疗法或近距离放射治疗)来提供。
外束辐射或近距离放射治疗可增强由放射性标记的HER3靶向剂提供的靶向辐射损伤,并因此可与HER3靶向剂依次提供,例如在HER3靶向剂之前和/或之后,或与HER3靶向剂同时。
外束辐射或近距离放射治疗可与基于成像的技术如计算机断层扫描(CT)和/或磁共振成像(MRI)一起计划和实施,以准确确定要实施的辐射的剂量和位置。例如,用本文公开的任何放射性标记的HER3靶向剂治疗的患者可以用CT或MRI成像,以确定由外束辐射或近距离放射治疗实施的辐射的剂量和位置。
在各个实施方案中,放射疗法可以选自由全身放射疗法、常规外束辐射疗法、立体定向放射手术、立体定向身体放射疗法、3-D适形放射疗法、强度调节放射疗法、图像引导放射疗法、断层疗法和近距离放射治疗组成的组。根据某些方面,放射疗法可以以单剂量或分次剂量的形式提供,例如,以2次或更多分次的形式。例如,剂量的施用可以使每个分次包括2-20Gy(例如,50Gy的辐射剂量可以分成10个分次,每个分次包括5Gy)。2个或更多分次可以在连续或顺序的日子里施用,例如2天一次、3天一次、4天一次、5天一次、6天一次、7天一次或以其组合方式。
C.免疫检查点疗法
与HER3靶向剂一起施用的另外的药剂可以是免疫检查点疗法。癌细胞已经发展出逃避免疫系统标准检查点的手段。例如,已经发现癌细胞通过减少肿瘤抗原的表达、下调MHC I类和II类分子导致肿瘤抗原呈递减少、分泌免疫抑制细胞因子如TGFb、招募或诱导免疫抑制细胞如调节性T细胞(Treg)或骨髓源性抑制细胞(MDSC)以及过表达某些抑制宿主现有的抗肿瘤免疫力的配体[例如程序性死亡配体-1(PD-L1)]来逃避免疫监视。
癌细胞免疫抑制的另一个主要机制是被称为“T细胞衰竭”的过程,其是由长期暴露于肿瘤抗原引起的,并以抑制性受体的上调为特征。这些抑制性受体作为免疫检查点,以防止不受控制的免疫反应。
文献中已经描述了作用于T细胞免疫不同水平的各种免疫检查点,包括PD-1(即程序性细胞死亡蛋白1)及其配体PD-L1和PD-L2、CTLA 4(即细胞毒性T淋巴细胞相关蛋白-4)及其配体CD80和CD86、LAG3(即淋巴细胞激活基因3)、B和T淋巴细胞减弱剂、TIGIT(具有Ig和ITIM结构域的T细胞免疫受体)、TIM-3(即T细胞免疫球蛋白和含粘蛋白结构域的蛋白3)和VISTA(T细胞激活的V结构域免疫球蛋白抑制剂)。
通过治疗性干预来增强免疫系统的功效是癌症治疗中一个特别令人兴奋的发展。如已经指出的,检查点抑制剂如CTLA-4和PD-1可防止自身免疫,一般可保护组织免受免疫附带损害。此外,刺激性检查点如OX40(即肿瘤坏死因子受体超家族成员4;TNFR-SF4)、CD137(即TNFR-SF9)、GITR(即糖皮质激素诱导的TNFR)、CD27(即TNFR-SF7)、CD40(即分化簇40)和CD28激活和/或促进T细胞的扩增。通过抑制或过表达这些蛋白质来调节免疫系统是目前有希望的研究领域。
因此,一个有希望的治疗策略是与本文公开的HER3靶向剂联合使用免疫检查点疗法,所述疗法可消除免疫系统上被癌细胞利用的某些阻断剂。例如,针对某些免疫检查点抑制剂(ICI)的抗体可阻断检查点抑制剂蛋白与它们的配体之间的相互作用,因此阻止本来会导致抑制针对肿瘤细胞的免疫反应的信号传导事件。
此外,越来越多的临床前证据支持辐射与ICI抗体协同作用的能力,这一点也在临床上得到了探索,越来越多的临床试验评估了外束辐射与免疫检查点疗法在各种肿瘤类型和ICI抗体中的组合(Lamichhane,2018)。支持这种组合的临床证据已经在黑色素瘤中产生,有两项研究证明了使用辐射与抗细胞毒性T淋巴细胞相关蛋白4(CTLA-4)ICI抗体伊匹单抗(Ipilimumab)组合的临床益处(Twyman-Saint Vistor,2015)。
因此,目前公开的本发明的一个目的是提供使用HER3靶向剂联合一种或多种免疫检查点疗法(例如ICI抗体)治疗癌症的疗法。
本发明的免疫检查点疗法包括完全或部分减少、抑制、干扰或调节一种或多种检查点蛋白的分子。检查点蛋白调节T细胞的激活或功能。免疫检查点疗法可通过与检查点结合或以其他方式禁用检查点抑制,解除对现有免疫反应的抑制。免疫检查点疗法可以包括单克隆抗体、人源化抗体、完全的人类抗体、抗体片段、小分子治疗剂或其组合。
示例性的免疫检查点疗法可以特异性结合并抑制检查点蛋白,例如抑制性受体CTLA-4、PD-1、TIM-3、VISTA、BTLA、LAG-3和TIGIT,和/或激活性受体CD28、OX40、CD40、GITR、CD137、CD27和HVEM。另外地,免疫检查点疗法可以与上述任何检查点蛋白的配体结合,例如PD-L1、PD-L2、PD-L3和PD-L4(PD-1的配体);CD80和CD86(CTLA-4的配体);CD137-L(CD137的配体);和GITR-L(GITR的配体)。其他示例性免疫检查点疗法可以与检查点蛋白结合,例如CD226、B7-H3、B7-H4、BTLA、TIGIT、GALS、KIR、2B4(属于分子的CD2家族,在所有NK、γδ和记忆型CD8+(αβ)T细胞上表达)、CD160(也被称为BY55)和CGEN-15049。
免疫检查点过程的核心是CD137、CTLA-4和PD-1免疫检查点途径。
CTLA-4和PD-1途径被认为在免疫反应的不同阶段起作用。CTLA-4被认为是免疫检查点抑制剂(ICI)的“领导者”,因为它在幼稚T细胞激活的初始阶段(通常在淋巴结)阻止潜在的自体反应T细胞。PD-1途径在免疫反应的后期阶段(主要在外周组织)调节先前激活的T细胞。此外,进展中的癌症患者已被证明缺乏由肿瘤细胞或肿瘤浸润的免疫细胞引起的PD-L1的上调。因此,针对PD-1途径的免疫检查点疗法可能在这种免疫抑制轴运作的肿瘤中特别有效,并且将平衡扭转到免疫保护环境会重新点燃并加强先前存在的抗肿瘤免疫反应。PD-1阻断可以通过各种机制完成,包括结合PD-1或其配体PD-L1的抗体。
根据目前公开的本发明的某些方面,免疫检查点疗法可以包括PD-1检查点的抑制剂,其可以减少、阻断、抑制、废除或干扰由PD-1与其结合伙伴中的一个或多个(例如PD-L1和PD-L2)的相互作用导致的信号转导。PD-1检查点的抑制剂可以是抗PD-1抗体、抗原结合片段、融合蛋白、寡肽以及其他减少、阻断、抑制、废除或干扰由PD-1与PD-L1和/或PD-L2的相互作用产生的信号转导的分子。在一些实施方案中,PD-1检查点抑制剂减少由T淋巴细胞上表达的细胞表面蛋白介导的负性共刺激信号,从而使功能失调的T细胞减少功能失调(例如,增强对抗原识别的效应物反应)。在一些实施方案中,PD-1检查点疗法是抗PD-1抗体。
因此,根据本发明的某些方面,免疫检查点疗法可以包括针对免疫检查点抑制剂(ICI)的单克隆抗体,例如针对CTLA-4、PD-1或PD-L1。
根据某些方面,ICI抗体可以是针对PD-1的抗体。ICI抗体可以是抗PD-1抗体,例如纳武单抗(nivolumab)。例如,美国专利号7,029,674中公开的PD-1生物活性(或其配体)的抑制剂。示例性的针对PD-1的抗体包括:BioXcell的抗小鼠PD-1抗体克隆J43(Cat#BE0033-2);BioXcell的抗小鼠PD-1抗体克隆RMP1-14(Cat#BE0146);小鼠抗PD-1抗体克隆EH12;Merck的MK-3475抗小鼠PD-1抗体(派姆单抗(pembrolizumab),lambrolizumab);和AnaptysBio的抗PD-1抗体,称为ANB011;抗体MDX-1 106(ONO-4538);Bristol-Myers Squibb的人IgG4单克隆抗体纳武单抗(/>BMS-936558,MDX1106);阿斯利康的AMP-514和AMP-224;和CureTech Ltd的匹地利珠单抗(Pidilizumab)(CT-011)。
根据某些方面,免疫检查点疗法是PD-L1的抑制剂。PD-L1的示例性抑制剂包括抗体(例如,抗PD-L1抗体,即ICI抗体)、RNAi分子(例如,抗PD-L1 RNAi)、反义分子(例如,抗PD-L1反义RNA)、显性负性蛋白(例如,显性负性PD-L1蛋白)和小分子抑制剂。示例性的抗PD-L1抗体包括克隆EH12。示例性的针对PD-L1的抗体包括:Genentech的MPDL3280A(RG7446);BioXcell的抗小鼠PD-L1抗体克隆10F.9G2(Cat#BE0101);Bristol-Meyer’sSquibb的抗PD-L1单克隆抗体MDX-1105(BMS-936559)和BMS-935559;MSB0010718C;小鼠抗PD-L1克隆29E.2A3;和AstraZeneca的MEDI4736(度伐利尤单抗(Durvalumab))。
根据某些方面,免疫检查点疗法是PD-L2的抑制剂或者可以减少PD-1与PD-L2之间的相互作用。PD-L2的示例性抑制剂包括抗体(例如,抗PD-L2抗体,即ICI抗体)、RNAi分子(例如,抗PD-L2 RNAi)、反义分子(例如,抗PD-L2反义RNA)、显性负性蛋白(例如,显性负性PD-L2蛋白)和小分子抑制剂。抗体包括单克隆抗体、人源化抗体、去免疫化抗体和Ig融合蛋白。
根据某些方面,免疫检查点疗法可以是CTLA-4的抑制剂,例如抗CTLA-4抗体,即ICI抗体。根据一个方面,ICI抗体可以是伊匹单抗。抗CTLA-4抗体可以阻断CTLA-4与抗原呈递细胞上表达的CD80(B7-1)和/或CD86(B7-2)的结合。示例性的针对CTLA-4的抗体包括:Bristol Meyers Squibb的抗CTLA-4抗体伊匹单抗(也称为MDX-010、BMS-734016和MDX-101);Millipore的抗CTLA4抗体,克隆9H10;辉瑞的替西木单抗(tremelimumab)(CP-675,206,ticilimumab);和Abcam的抗CTLA-4抗体克隆BNI3。根据某些方面,免疫检查点抑制剂可以是CTLA-4表达的核酸抑制剂。
CD137(也称为“TNF受体超家族成员9”)是肿瘤坏死因子受体超家族的刺激性受体成员,介导CD28依赖性和非依赖性T细胞共刺激(Bartkowiak,2015)。CD137由T细胞、自然杀伤(NK)细胞、树突状细胞(DC)、B细胞和免疫系统的其他细胞诱导表达。该蛋白质由255个氨基酸的蛋白质组成,其具有短的N末端细胞质部分、跨膜区和具有3个富含半胱氨酸的基序的细胞外结构域。CD137被其配体CD137L(4-1BBL;TNFSF9)连接,该配体主要(尽管不是唯一)在抗原呈递细胞(APC)上表达,唤起各种T细胞反应,例如细胞扩增、细胞因子分泌增加和防止激活引起的细胞死亡。因此,这种连接的作用是激活免疫系统。然而,CD137和CD137L之间的顺式相互作用也能有效地下调CD137L的表达(Kwon,2015)。因此,CD137配体的功能是控制CD137介导的免疫系统激活的程度和动力学(Kwon,2015)。值得注意的是,在人类NK细胞上表达的CD137在与已与肿瘤细胞结合的抗肿瘤抗体结合后变得上调(Wei,2014)。
因此,根据目前公开的本发明的某些方面,免疫检查点疗法可以包括针对CD137的抗体,其可用于激活免疫系统,从而与目前公开的HER3靶向剂联合提供用于癌症的疗法。可使用的示例性抗CD137抗体在美国公开号20140274909;20130280265;20130273078;20130071403;20120058047;20110104049;20110097313;20080166336;20080019905;20060188439;20060182744;20060121030和20030223989中公开。
根据本发明的某些方面,免疫检查点疗法可以包括一个以上的免疫检查点蛋白的调节剂。因此,免疫检查点疗法可以包括针对第一免疫检查点蛋白的第一抗体或抑制剂和针对第二免疫检查点蛋白的第二抗体或抑制剂。
D.DNA损伤反应抑制剂
与HER3靶向剂一起施用的另外的药剂可以是一种或多种DNA损伤反应抑制剂(DDRi)。DNA损伤可能是由于内源性因素,例如自发或酶促反应、化学反应或复制中的错误,或者可能是由于外源性因素,例如紫外线或电离辐射或遗传毒性化学品。克服这种损伤的修复途径被统称为DNA损伤反应或DDR。这种信号传导网络的作用是检测和协调细胞对某些形式的DNA损伤的反应,最显著的是双链断裂和复制压力。在接受许多类型的DNA损伤药物和电离辐射治疗后,细胞的生存依赖于DDR。已经证明,破坏DDR可以增加癌细胞对这些DNA损伤药物的敏感性,因此可以改善患者对这种疗法的反应。
在DDR中,有几种DNA修复机制,包括碱基切除修复、核苷酸切除修复、错配修复、同源重组修复和非同源末端连接。大约有450个人类DDR基因编码在生理过程中发挥作用的蛋白质。DDR的失调导致各种病症,包括遗传性、神经退行性、免疫性、心血管性和代谢性疾病或病症以及癌症。例如,基因OGG1和XRCC1是DDR的碱基切除修复机制的一部分,这些基因中的突变在肾癌、乳腺癌和肺癌中被发现,而基因BRCA1和BRCA2参与同源重组修复机制,这些基因中的突变导致乳腺癌、卵巢癌、前列腺癌、胰腺癌以及胃肠道癌和血液癌和黑色素瘤的风险增加。表3中提供了示例性的DDR基因。
目前公开的本发明的一个目的是施用放射性标记的HER3靶向剂,该制剂与DDRi联合提供电离辐射。因此,根据某些方面,与HER3靶向剂一起施用的另外的药剂可以靶向DDR中的蛋白质,即DDR抑制剂或DDRi,从而最大限度地增加DNA损伤或抑制修复,如果损伤例如在G1和S期,和/或阻止G2中的修复,确保DNA损伤的最大数量被带入有丝分裂,导致细胞死亡。
表3
此外,可针对一个或多个DDR途径以确保细胞死亡,即对靶向的癌细胞的致命性。例如,仅BRCA1和2基因的突变可能不足以确保细胞死亡,因为其他途径如PARP1碱基切除途径可能发挥作用以修复DNA损伤。因此,多种DDRi抑制剂的组合或将DDRi与抗血管生成剂或免疫检查点抑制剂相结合(如本文所列)是可能的,并且是目前公开的本发明的目标。
示例性的DDRi-ATM和ATR抑制剂
共济失调毛细管扩张突变(ATM)以及共济失调毛细管扩张突变和Rad-3相关(ATR)是丝氨酸/苏氨酸蛋白激酶的磷脂酰肌醇3-激酶相关激酶(PIKK)家族的成员。
ATM是一种丝氨酸/苏氨酸蛋白激酶,其被DNA双链断裂招募和激活。ATM使几个启动DNA损伤检查点的激活的关键蛋白质磷酸化,导致细胞周期停止、DNA修复或细胞凋亡。这些靶标中的一些,包括p53、CHK2和H2AX,是肿瘤抑制剂。该蛋白质因ATM突变引起的病症共济失调毛细管扩张而被命名。ATM属于磷脂酰肌醇3-激酶相关激酶(PIKK)的超家族,其包括六个丝氨酸/苏氨酸蛋白激酶,显示出与磷脂酰肌醇3-激酶(PI3K)的序列相似性。
与ATM一样,ATR是参与DDR的核心激酶之一。ATR被单链DNA结构激活,所述结构例如可能出现在切除的DNADSB或停滞的复制叉上。当DNA聚合酶在DNA复制过程中停滞时,复制螺旋酶继续在复制叉前解开DNA,导致产生长段的单链DNA(ssDNA)。
已经发现ATM通过提供对化疗剂的抗性来帮助癌细胞,从而有利于肿瘤的生长和生存。抑制ATM和/或ATR可能明显增加癌细胞对DNA损伤剂的敏感性,例如由放射性标记的HER3靶向剂提供的电离辐射。因此,目前公开的本发明的一个目的包括与HER3靶向剂联合施用ATM(ATMi)和/或ATR(ATRi)的抑制剂,以抑制或杀死癌细胞,例如那些表达或过表达HER3的癌细胞。
ATM(ATMi)或ATR(ATRi)的抑制剂可以是分别靶向ATM或ATR的抗体、肽或小分子。替代地,ATMi或ATRi可以减少或消除一种或多种信号传导分子、蛋白质或其他化合物对ATM或ATR的激活,或者可以导致减少或消除所有信号传导分子、蛋白质或其他化合物对ATM或ATR的激活。ATMi和/或ATRi还包括抑制其表达的化合物(例如,抑制ATM或ATR转录或翻译的化合物)。示例性的ATMi KU-55933可抑制细胞增殖并诱导细胞凋亡。其他示例性的ATMi至少包括KU-59403、渥曼青霉素、CP466722和KU-60019。示例性的ATRi至少包括五味子乙素、NU6027、NVP-BEA235、VE-821、VE-822、AZ20和AZD6738。
示例性的DDRi-Wee1抑制剂
检查点激酶Wee1催化CDK1(CDC2)和CDK2在酪氨酸15上的抑制性磷酸化,从而在对外源性诱导的DNA损伤的反应中停止细胞周期。失调的Wee1表达或活性被认为是几种类型的癌症的病理特征。例如,Wee1在胶质母细胞瘤、恶性黑色素瘤、肝细胞癌、乳腺癌、结肠癌、肺癌和头颈部鳞状细胞癌中经常过表达。基因组不稳定性水平增加的晚期肿瘤可能需要功能检查点,以允许修复这种致命的DNA损伤。因此,本发明人认为,在晚期肿瘤中,Wee1代表了一个有吸引力的靶标,在这些晚期肿瘤中,对它的抑制被认为会导致不可修复的DNA损伤。因此,目前公开的本发明的一个目的包括与HER3靶向剂联合施用Wee1的抑制剂,以抑制或杀死癌细胞,例如那些表达或过表达HER3的癌细胞。
Wee1抑制剂可以是靶向Wee1的抗体、肽或小分子。替代地,Wee1抑制剂可以减少或消除一种或多个信号传导分子、蛋白质或其他化合物对Wee1的激活,或者可以导致减少或消除所有信号传导分子、蛋白质或其他化合物对Wee1的激活。该术语还包括减少或消除Wee1对一种或多种蛋白质或细胞信号传导组分的激活或失活的化合物(例如,Wee1抑制剂可以减少或消除细胞周期蛋白和Cdk活性的Wee1依赖性失活)。Wee1抑制剂还包括抑制Wee1表达的化合物(例如,抑制Wee1转录或翻译的化合物)。
示例性的Wee1抑制剂包括AZD-1775(即adavosertib),以及诸如在例如以下专利中描述的抑制剂:美国专利号7,834,019;7,935,708;8,288,396;8,436,004;8,710,065;8,716,297;8,791,125;8,796,289;9,051,327;9,181,239;9,714,244;9,718,821;和9,850,247;美国公开号20100113445和20160222459;以及国际公开号WO2002090360、2015019037、2017013436、2017216559、2018011569和2018011570。
进一步的Wee1抑制剂包括吡唑并嘧啶衍生物、吡啶并嘧啶、4-(2-氯苯基)-9-羟基吡咯并[3,4-c]咔唑-1,3-(2H,6H)-二酮(CAS号622855-37-2)、6-丁基-4-(2-氯苯基)-9-羟基吡咯并[3,4-c]咔唑-1,3-(2H,6H)-二酮(CAS号62285550-9)、4-(2-苯基)-9-羟基吡咯并[3,4-c]咔唑-1,3-(2H,6H)-二酮(CAS号1177150-89-8)和抗Wee1小干扰RNA(siRNA)分子。
示例性的DDRi-PARP抑制剂
可使用的另一个示例性DDRi类型是聚(ADP-核糖)聚合酶(“PARP”)的抑制剂。DNA修复蛋白PARP的抑制剂,单独和统称为“PARPi”,已被批准用于一系列实体瘤,例如乳腺癌和卵巢癌,特别是用于具有BRCA1/2突变的患者。BRCA1和2的功能是同源重组修复(HRR)。当发生突变时,它们通过将DNA修复过程从保守和精确的HRR转变为非保真方法,例如DNA末端连接,这可以通过缺失和插入产生突变,从而诱发基因组不稳定性。
PARPi已被证明在BRCA1/2突变体细胞中表现出合成致死性,如通过强大的单药剂活性所表现的。这基本上阻止了单链DNA断裂的修复。由于HRR在这些肿瘤细胞中没有功能,所以导致细胞死亡。因为大多数肿瘤不携带BRCA1或BRCA2突变,因此PARPi在这类肿瘤中的效力远没有那么明显。
迄今为止,FDA已经批准了四种PARPi药物(奥拉帕尼、尼拉帕尼、鲁卡帕尼和他拉唑帕尼)作为单药治疗剂,特别是对BRCA1和BRCA2基因的种系和体细胞突变的患者。与维利帕尼(veliparib)一起,奥拉帕尼、尼拉帕尼和鲁卡帕尼是进入临床试验的第一代PARPi之一。它们的IC50值被发现在纳摩尔范围内。相比之下,第二代PARPi如他拉唑帕尼的IC50值在皮摩尔范围内。
这些PARPi都与PARP1和PARP2的催化结构域中的辅因子b烟酰胺腺嘌呤二核苷酸(b-NAD+)的结合位点结合。PARP家族的酶利用NAD+将聚(ADP-核糖)(PAR)链共价添加到靶蛋白上,这一过程被称为“PAR化”。PARP1(它是研究得最好的成员)和PARP2是DNA损伤反应(DDR)途径的重要组分。PARP1参与单链DNA断裂的修复,也可能参与其他DNA损伤的修复(Woodhouse,et al.;Krishnakumar,et al.)。通过其锌指结构域,PARP1与受损的DNA结合,然后使一系列DNA修复效应蛋白PAR化,释放出烟酰胺作为副产品(Krishnakumar,et al.)。随后,PARP1自动PAR化导致蛋白质从DNA中释放出来。然而,可用的PARPi在将PARP1捕获在DNA上的能力方面有所不同,这似乎与细胞毒性和药物疗效相关。具体而言,像他拉唑帕尼和奥拉帕尼这样的药物在捕获PARP1方面比维利帕尼更有效(Murai,et al.,2012;Murai,et al.,2014)。
PARPi对卵巢癌和乳腺癌患者(这些患者具有BRCA1或BRCA2基因的功能缺失突变)的疗效主要归因于合成致死性的遗传学概念:BRCA1和2的蛋白质通常通过介导DNA修复过程,即所谓的同源重组修复(HRR)来维持基因组的完整性;而PARPi导致持续的DNA损伤,正常情况下,该损伤会通过HR得到修复。在PARPi存在的情况下,PARP1被困在DNA上,从而使复制叉的进展停滞。这种停滞是有细胞毒性的,除非及时由HR系统修复。在缺乏有效的HR的细胞中,它们无法有效地修复这些DNA损伤,从而死亡。
同样,BRCA基因和HRR系统中的其他基因的突变在许多癌症类型中并不普遍。因此,为了更好地利用PARPi在此类癌症中的治疗效果,人们可以通过将PARPi与化疗或放疗配对来诱导“人工”合成致死性。临床前研究表明,将放疗和PARPi结合起来可以增加BRCA1/2突变肿瘤细胞对PARP抑制的敏感性,并延长非突变BRCA肿瘤对PARP抑制的敏感性。其他研究表明,电离辐射(IR)本身可以介导PARPi在肿瘤细胞中的合成致死性。
因此,目前公开的本发明的一个目的是施用放射性标记的HER3靶向剂,所述HER3靶向剂与PARPi联合提供电离辐射。
在本发明的各个实施方案中,PARPi可以是任何执行该功能的已知药剂,并且优选地,是由FDA批准的。优选地,PARPi是奥拉帕尼尼拉帕尼/>鲁卡帕尼/>或他拉唑帕尼/>
在临床上,用PARPi治疗已经在一系列癌症中产生了持续的抗肿瘤反应,包括卵巢癌、前列腺癌、胰腺癌和三阴性乳腺癌(TNBC)。在一项临床试验中,具有种系BRCA1/2突变的TNBC患者接受了PARPi、奥拉帕尼的治疗。虽然这种疗法在BRCA1/2突变患者中显示出比非突变患者更高的疾病稳定率,但在两个队列中都没有取得持续的反应(Gelmon,2011)。
本发明人意识到,PARPi的效果可以通过HER3靶向剂提供的电离辐射诱导的dsDNA断裂的增加而得到改善,而这些修复途径被PARPi阻断。示例性的PARPi包括奥拉帕尼、尼拉帕尼、鲁卡帕尼和他拉唑帕尼。
E.CD47阻断剂
与HER3靶向剂一起施用的另外的药剂可以是CD47阻断剂,例如通过与CD47或SIRPα的相互作用干扰或减少CD47(例如,在靶细胞上)和SIRPα(例如,在吞噬细胞上)之间的活性和/或信号传导的任何药剂。合适的CD47阻断剂的非限制性实例包括CD47和/或SIRPα试剂,包括但不限于SIRPα多肽、抗SIRPα抗体、可溶性CD47多肽和抗CD47抗体或抗体片段。
CD47阻断剂的其他实例包括调节CD47和/或SIRPα的表达的药剂。例如,这样的药剂可以包括核酸方法,例如阻断CD47翻译的磷酰二胺吗啉代低聚物(PMO)或调节,例如阻断、抑制、减少、拮抗、中和或以其他方式干扰CD47表达的人类CD47特异性抗体。CD47抗体或反义方法可以抑制CD47的表达(例如,抑制CD47的细胞表面表达)、活性和/或信号传导,或者可以干扰CD47和SIRPα之间的相互作用。本文提供的药剂在与CD47,例如人CD47结合或以其他方式相互作用后,完全或部分减少或以其他方式调节CD47的表达或活性。在抗体与人CD47多肽和/或肽之间的相互作用下,CD47的生物功能的减少或调节是完全的、显著的或部分的。当在有抗体存在的情况下,CD47表达或活性水平与没有与本文所述的抗体相互作用,例如结合的情况下的CD47表达或活性水平相比,减少了至少50%,例如60%、70%、80%、90%、95%、96%、98%、99%或100%时,则认为这些药剂抑制了CD47表达或活性。
根据某些方面,抗CD47药剂是特异性结合CD47的抗体(即抗CD47抗体),并减少一个细胞(例如受感染的细胞)上的CD47和另一个细胞(例如吞噬细胞)上的SIRPα之间的相互作用。合适的抗体的非限制性实例包括克隆B6H12、5F9、8B6和C3以及国际公开号WO2011/143624和美国公开20210246206中描述的任何一种。合适的抗CD47抗体包括此类抗体的完全人类、人源化或嵌合版本。
由于其低抗原性而对人类体内应用特别有用的示例性人或人源化抗体至少包括针对CD47的单克隆抗体,例如Hu5F9-G4,这是一种可从Gilead获得的人源化单克隆抗体莫洛利单抗(Sikic,et al.(2019)Journal of Clinical Oncology37:946);I-MabBiopharma的来佐利单抗和TJC4;Arch Oncology,Inc的AO-176;Akesobio Australia Pty的AK117;Innovent Biologics的IMC-002;Zia Lab的ZL-1201;江苏恒瑞医药有限公司的SHR-1603;以及Surface Oncology的SRF231。双特异性单克隆抗体也是可获得的,例如Innovent Biologics的IBI-322,同时靶向CD47和PD-L1。针对SIRPα的抗体也是可能的,例如Alx Oncology的ALX148;OSE的BI 765063(OSE-172);以及小分子抑制剂,例如EpicentRx的RRx-001(1-溴乙酰基-3,3二硝基氮杂环丁烷)和阿折地平(Azelnidipine)(CAS号123524-52-7)或其药学上可接受的盐。有关示例性药剂的进一步描述,还请参见表4。
表4
据报道,AO-176除了通过阻断CD47-SIRPα相互作用来诱导肿瘤吞噬作用外,还相对于正常细胞(尤其是其结合可忽略不计的RBC)优先结合肿瘤细胞,并相对于正常细胞直接杀死肿瘤细胞。
根据某些方面,SIRPα试剂可以包括足以以可识别的亲和力结合CD47的SIRPα部分,该部分通常位于信号序列和跨膜结构域之间,或其保留结合活性的片段。合适的SIRPα试剂可以减少(例如,阻断、防止等)天然蛋白SIRPα和CD47之间的相互作用。例如,本发明各方面使用的CD47阻断剂可以是美国专利号9,969,789中公开的任何一种,包括但不限于其中公开的SIRPα-IgG Fc融合蛋白,例如TTI-621和TTI-622,它们都优先结合肿瘤细胞上的CD47,同时也参与活化Fc受体。例如,可以使用包括氨基酸序列SEQ ID NO:116、SEQ ID NO:117或SEQ ID NO:118的SIRPα-IgG Fc融合蛋白。
抗CD47抗体或其他蛋白CD47抑制剂的治疗有效剂量可以是导致蛋白的持续血清水平达到约40μg/ml或更多(例如,约50ug/ml或更多、约60ug/ml或更多、约75ug/ml或更多、约100ug/ml或更多、约125ug/ml或更多或约150ug/ml或更多)的剂量。CD47阻断剂,例如抗CD47抗体或SIRPα融合蛋白或小分子的治疗有效剂量或施用包括例如0.05-10mg/kg(药剂重量/受试者重量)的量,例如至少0.1mg/kg、0.5mg/kg、1.0mg/kg、1.5mg/kg、2.0mg/kg、2.5mg/kg、3.0mg/kg、3.5mg/kg、4.0mg/kg、4.5mg/kg、5.0mg/kg、5.5mg/kg、6.0mg/kg、6.5mg/kg、7.0mg/kg、7.5mg/kg、8.0mg/kg、8.5mg/kg、9.0mg/kg;或不超过10mg/kg、9.5mg/kg、9.0mg/kg、8.5mg/kg、8.0mg/kg、7.5mg/kg、7.0mg/kg、6.5mg/kg、6.0mg/kg、5.5mg/kg、5.0mg/kg、4.5mg/kg、4.0mg/kg、3.5mg/kg、3.0mg/kg、2.5mg/kg、2.0mg/kg、1.5mg/kg、1.0mg/kg,或这些上限和下限的任意组合。例如,小分子CD47阻断剂的治疗有效剂量,例如本文所公开的那些,例如还包括0.01mg/kg至1000mg/kg以及其中的任何子范围或mg/kg值,例如0.01mg/kg至500mg/kg,或0.05mg/kg至500mg/kg,或0.5mg/kg至200mg/kg,或1.0mg/kg至100mg/kg,或10mg/kg至50mg/kg。
根据某些方面,抗CD47药剂是可溶性CD47多肽,其特异性结合SIRPα并减少一个细胞(例如,受感染的细胞)上的CD47和另一个细胞(例如,吞噬细胞)上的SIRPα之间的相互作用。合适的可溶性CD47多肽可以结合SIRPα而不通过SIRPα激活或刺激信号传导,因为SIRPα的激活会抑制吞噬作用。相反,合适的可溶性CD47多肽有利于优先吞噬受感染的细胞而不是非受感染的细胞。那些相对于正常的、非靶细胞(正常细胞)表达更高水平的CD47的细胞(例如感染的细胞)将被优先吞噬。因此,合适的可溶性CD47多肽特异性结合SIRPα,而不激活/刺激足够的信号传导反应以抑制吞噬作用。在一些情况下,合适的可溶性CD47多肽可以是融合蛋白(例如,如美国公开号20100239579中所述)。
有利的是,CD47阻断剂可以增强放射性标记的靶向剂,例如放射性标记的HER3和/或HER2靶向剂的细胞毒性和促吞噬作用,同时减少靶向剂的剂量限制性放射性毒性,从而改善耐受性并允许在治疗受试者时使用/耐受靶向剂的更高辐射剂量。
实施例
实施例1:放射性标记的HER3靶向剂的生产
HER3靶向剂,例如针对HER3的单克隆抗体,可以根据国际公开号WO 2017/155937和2019年12月9日提交的题为“Compositions and methods for preparation of site-specific radioconjugates”的美国临时专利申请号63/042,651中详述的程序,用铟-111(111In)或锕-225(225Ac)标记。
放射性标记:作为示例,抗体可以与携带螯合剂的接头缀合,例如,如本文或前面的专利申请中所述。示例性的接头至少包括十二烷四乙酸(DOTA),其中缀合反应的目标是使DOTA-抗体的比例达到3:1至5:1。然后可以进行与放射性核素111In或225Ac的螯合,并通过HPLC和iTLC确定所产生的111In或225Ac标记的抗HER3抗体的效率和纯度。
225Ac的示例性标记反应如下:可以在Eppendorf反应管中混合包括15μl 0.15MNH4OAc缓冲液,pH=6.5和2μL(10μg)DOTA-抗HER3(5mg/ml)的反应,随后加入4μL在0.05MHCl中的225Ac(10μCi)。可以用移液器吸头混合管中的内容物,并将反应混合物在37℃下孵育90分钟,以100rpm摇动。在孵育期结束时,可向反应混合物中加入3μL的1mM DTPA溶液,并在室温下孵育20分钟,以将未反应的225Ac结合到225Ac-DTPA复合物中。采用10cm硅胶条和10mM EDTA/生理盐水流动相的即时薄层色谱法可通过分离225Ac标记的抗HER3(225Ac-DOTA-抗HER3)和游离的225Ac(225Ac-DTPA)来确定225Ac-DOTA-抗HER3的放射化学纯度。在这个系统中,放射性标记的抗体停留在施加点上,而225Ac-DTPA随溶剂前移。可以将条状物切成两半,在配备有多通道分析仪的伽马计数器中使用通道72-110对225Ac进行计数以排除其子体。
纯化:示例性的放射性标记的HER3靶向剂,例如225Ac-DOTA-抗HER3,可在用1%HSA预阻断的PD10柱上或在Vivaspin离心浓缩器上纯化,MW截留为50kDa,以2x1.5 mL清洗,每次旋转3分钟。纯化后的225Ac-DOTA-抗HER3的HPLC分析可使用配备有流动式Waters UV和Bioscan Radiation检测器的Waters HPLC系统进行,使用TSK3000SW XL柱在pH=7.4和1ml/min的流速下用PBS洗脱。
稳定性测定:示例性的放射性标记的HER3靶向剂,例如225Ac-DOTA-抗HER3,可用于稳定性测定,其中225Ac-DOTA-抗HER3可在原体积中或用工作缓冲液(0.15M NH4OAc)稀释(2-10倍)后进行测试,在室温(rt)下孵育48小时或在4℃下孵育96小时并通过ITLC进行测试。稳定性是通过比较孵育前后完整的放射性标记的抗HER3来确定的。其他用225Ac标记的抗体已被发现在4℃下稳定达96小时。
免疫反应性(IR)测定:示例性的放射性标记的HER3靶向剂,例如225Ac-DOTA-抗HER3,可用于免疫反应性实验。HER3阳性细胞和对照HER3阴性细胞可按每个样品100万-750万个细胞的量使用,来研究结合量(几次洗涤后与细胞结合的放射性百分比;或使用免疫反义性部分(IRF)珠子测定可根据如Sharma,2019公开的方法进行)。之前对用111In或225Ac放射性标记的其他抗体的测定显示了大约50-60%的免疫反应性。
实施例2:示例性的PARPi施用和给药方案
(A)奥拉帕尼
-正常和减量的给药方案
奥拉帕尼由阿斯利康以品牌名称出售。/>以100mg和150mg的片剂形式出售。剂量为每天口服两次,每次300mg,每天总剂量为600mg。给药持续到疾病进展或不可接受的毒性为止。这种给药方案在本文中被称为/>的“正常”人体给药方案,与治疗的病症无关。任何持续时间较短(例如21天)或涉及施用较少的/>(例如300mg/天)的给药方案在本文中被称为“减量的”人体给药方案。减量的人体给药方案的实例包括如下:(i)550mg/天;(ii)500mg/天;(iii)450mg/天;(iv)400mg/天;(v)350mg/天;(vi)300mg/天;(vii)250mg/天;(viii)200mg/天;(ix)150mg/天;(x)100mg/天;或(xi)50mg/天。
(B)尼拉帕尼
-正常和减量的给药方案
尼拉帕尼由Tesaro以品牌名称出售。/>以100mg的胶囊形式出售。剂量为每天口服一次,每次300mg。给药持续到疾病进展或不可接受的不良反应为止。这种给药方案在本文中被称为/>的“正常”人体给药方案,与治疗的病症无关。任何持续时间较短(例如21天)或涉及施用较少的/>(例如150mg/天)的给药方案在本文中被称为“减量的”人体给药方案。减量的人体给药方案的实例包括如下:(i)250mg/天;(ii)200mg/天;(iii)150mg/天;(iv)100mg/天;或(v)50mg/天。
(C)鲁卡帕尼 --正常和减量的给药方案/>
鲁卡帕尼由Clovis Oncology,Inc.以品牌名称RubracaTM出售。RubracaTM以200mg和300mg的片剂形式出售。剂量为每天口服两次,每次600mg,每天总剂量为1,200mg。给药持续到疾病进展或不可接受的毒性为止。这种给药方案在本文中被称为RubracaTM的“正常”人体给药方案,与治疗的病症无关。任何持续时间较短(例如21天)或涉及施用较少的RubracaTM(例如600mg/天)的给药方案在本文中被称为“减量的”人体给药方案。减量的人体给药方案的实例包括如下:(i)1,150mg/天;(ii)1,100mg/天;(iii)1,050mg/天;(iv)1,000mg/天;(v)950mg/天;(vi)900mg/天;(vii)850mg/天;(viii)800mg/天;(ix)750mg/天;(x)700mg/天;(xi)650mg/天;(xii)600mg/天;(xiii)550mg/天;(xiv)500mg/天;(xv)450mg/天;(xvi)400mg/天;(xvii)350mg/天;(xviii)300mg/天;(xix)250mg/天;(xx)200mg/天;(xxi)150mg/天;或(xxii)100mg/天。
(D)他拉唑帕尼(TalzennaTM)-正常和减量的给药方案
他拉唑帕尼由辉瑞实验室以品牌名称TalzennaTM出售。TalzennaTM以1mg的胶囊形式出售。剂量为口服1mg。给药持续到疾病进展或不可接受的毒性为止。这种给药方案在本文中被称为TalzennaTM的“正常”人体给药方案,与治疗的病症无关。任何持续时间较短(例如21天)或涉及施用较少的TalzennaTM(例如0.5mg/天)的给药方案在本文中被称为“减量的”人体给药方案。减量的人体给药方案的实例包括如下:(i)0.9mg/天;(ii)0.8mg/天;(iii)0.7mg/天;(iv)0.6mg/天;(v)0.5mg/天;(vi)0.4mg/天;(vii)0.3mg/天;(viii)0.2mg/天;或(ix)0.1mg/天。
实施例3:HER3靶向剂和PARPi的给药方案
人类患者可根据以下方案进行治疗。根据实施例2中列出的给药方案之一口服施用奥拉帕尼、尼拉帕尼、鲁卡帕尼或他拉唑帕尼(PARPi)中的一种,伴随着静脉内施用本文详述的放射性标记的HER3靶向剂,以单次或分次施用。例如,给药方案包括,举例来说:(a)PARPi和HER3靶向剂同时施用,其中(i)每一种都在同一天开始施用,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)PARPi每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间;或(b)同时施用PARPi和HER3靶向剂,其中(i)PARPi的施用先于HER3靶向剂的施用至少一周,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)PARPi每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间。
实施例4:HER3靶向剂和CD47阻断剂的给药方案
根据本发明的某些方面,CD47阻断剂可以例如是阻止CD47与SIRPα结合的单克隆抗体。示例性的蛋白CD47阻断剂包括莫洛利单抗、来佐利单抗、AO-176、TTI-621、TTI-622或其组合。CD47阻断剂可替代地或另外地包括调节CD47和/或SIRPα表达的药剂,例如阻断CD47翻译的磷酰二胺吗啉代低聚物(PMO),如MBT-001(PMO,吗啉代,序列:5’-CGTCACAGGCAGGACCCACTGCCCA-3’)[SEQ ID NO:114])或在美国专利号8,557,788、美国专利号8,236,313、美国专利号10,370,439和国际公开号WO2008060785中的任何一个中公开的任何PMO低聚体CD47抑制剂。抗CD47抗体的治疗有效剂量包括至少0.05-10mg/kg。因此,本发明的方法可以包括施用一种或多种抗CD47抗体或其他药剂,伴随着静脉内施用本文详述的放射性标记的HER3靶向剂,以单次或分次施用。例如,给药方案包括,举例来说:(a)抗CD47抗体或药剂和HER3靶向剂同时施用,其中(i)各自在同一天开始施用,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)抗CD47抗体或药剂每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间;或(b)抗CD47抗体或药剂和HER3靶向剂同时施用,其中(i)抗CD47抗体或药剂的施用先于HER3靶向剂的施用至少一周,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)抗CD47抗体或药剂每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间。
实施例5:HER3靶向剂和ICI的给药方案
根据本发明的某些方面,免疫检查点抑制剂(ICI)可以是针对PD-1、PD-L1、PD-L2、CTLA-4、CD137中的任何一种的单克隆抗体。这些抗体的治疗有效剂量包括至少0.05-10mg/kg。因此,本发明的方法包括施用一种或多种ICI,伴随着静脉内施用本文详述的放射性标记的HER3靶向剂,以单次或分次施用。例如,给药方案包括,举例来说:(a)ICI和HER3靶向剂同时施用,其中(i)各自在同一天开始施用,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)ICI每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间;或(b)ICI和HER3靶向剂同时施用,其中(i)抗CD47抗体的施用先于HER3靶向剂的施用至少一周,(ii)HER3靶向剂以单剂量或间隔不少于一周的分次剂量施用,和(iii)ICI每天一次或每天两次(视情况而定)施用,且持续时间等于或超过HER3靶向剂施用的持续时间。
不限于此,本公开还提供了以下方面:
方面1.一种用于治疗哺乳动物受试者如人类患者的实体癌的方法,所述方法包括:向受试者施用治疗有效量的放射性标记的HER3靶向剂。
方面2.根据前述任何方面的方法,其中实体癌是乳腺癌、胃癌、膀胱癌、宫颈癌、子宫内膜癌、皮肤癌、胃癌、睾丸癌、食道癌、支气管肺泡癌、前列腺癌、结直肠癌、卵巢癌、宫颈表皮样癌、胰腺癌、肺癌、肾癌、头颈癌或其任意组合。
方面3.根据前述任何方面的方法,其中实体癌是结直肠癌、胃癌、卵巢癌、非小细胞肺癌、头颈部鳞状细胞癌、胰腺癌、肾癌或其任意组合。
方面4.根据前述任何方面的方法,其中实体癌是HER3阳性癌症,例如HER3阳性的实体瘤。
方面5.根据前述任何方面的方法,其中放射性标记的HER3靶向剂包括选自131I、125I、123I、90Y、177Lu、186Re、188Re、89Sr、153Sm、32P、225Ac、213Bi、213Po、211At、212Bi、213Bi、223Ra、227Th、149Tb、137Cs、212Pb、103Pd或本文公开的任意那些,或其任意组合的放射性标记。
方面6.根据前述任何方面的方法,其中放射性标记的HER3靶向剂包括选自131I、90Y、177Lu、225Ac、213Bi、211At、213Bi、227Th、212Pb或其任意组合的放射性标记。
方面7.根据前述任何方面的方法,其中放射性标记的HER3靶向剂包括针对HER3的抗体。
方面8.根据前述任何方面的方法,其中HER3靶向剂包括抗HER3单克隆抗体,例如本文公开的任意那些,例如选自帕曲妥单抗、瑟瑞妥单抗(MM-121)、鲁妥珠单抗、依更妥单抗、GSK2849330和AV-203及其任意组合的HER3抗体。
方面9.根据前述任何方面的方法,其中HER3靶向剂包括单克隆抗体,所述单克隆抗体:(i)具有包括SEQ ID NO:77的重链序列和/或包括SEQ ID NO:78的轻链序列;(ii)具有免疫球蛋白重链可变区,其包含包括SEQ ID NO:15的CDR-H1、包括SEQ ID NO:16的CDR-H2和/或包括SEQ ID NO:17的CDR-H3,和/或免疫球蛋白轻链可变区,其包含包括SEQ IDNO:18的CDR-L1、包括SEQ ID NO:19的CDR-L2和/或包括SEQ ID NO:20的CDR-L3;(iii)具有包括SEQ ID NO:21的免疫球蛋白重链可变区和/或包括SEQ ID NO:22的免疫球蛋白轻链可变区;或(iv)具有SEQ ID NO:23的免疫球蛋白重链氨基酸序列和/或SEQ ID NO:24的免疫球蛋白轻链氨基酸序列。
方面10.根据前述任何方面的方法,其中HER3靶向剂包括单克隆抗体,所述单克隆抗体包括具有如SEQ.ID NO:7所示的氨基酸序列的重链可变区和/或具有如SEQ.ID NO:8所示的氨基酸序列的轻链可变区。
方面11.根据前述任何方面的方法,其中HER3靶向剂包括单克隆抗体,所述单克隆抗体包括重链N末端区和互补决定区(CDR)中的一个或多个,其氨基酸序列分别如SEQ.IDNO:13和/或1-3所示;和/或包括轻链N末端区和CDR中的一个或多个,其氨基酸序列分别如SEQ.ID NO:14和/或4-6所示。
方面12.根据前述任何方面的方法,其中放射性标记的HER3靶向剂的有效量是最大耐受剂量。
方面13.根据前述任何方面的方法,其中放射性标记的HER3靶向剂是225Ac标记的、177Lu标记的或131I标记的。
方面14.根据前述任何方面的方法,其中放射性标记的HER3靶向剂的治疗有效量包括向受试者递送小于2Gy或小于8Gy的单剂量,例如2Gy至8Gy的剂量。
方面15.根据前述任何方面的方法,其中放射性标记的HER3靶向剂是225Ac标记的,并且225Ac标记的HER3靶向剂的有效量包括0.1至50uCi/kg受试者体重、或0.2至20uCi/kg受试者体重、或0.5至10uCi/kg受试者体重的剂量。
方面16.根据前述任何方面的方法,其中放射性标记的HER3靶向剂是225Ac标记的针对HER3的全长抗体,并且225Ac标记的HER3靶向剂的有效量包括小于5uCi/kg受试者体重,例如0.1至5uCi/kg受试者体重。
方面17.根据方面1至6中任一项的方法,其中放射性标记的HER3靶向剂是抗体片段,例如225Ac标记的针对HER3的微型抗体或纳米抗体,并且225Ac标记的HER3靶向剂的有效量包括大于5uCi/kg体重的受试者,例如5至20uCi/kg受试者体重。
方面18.根据方面1至14中任一项的方法,其中放射性标记的HER3靶向剂是225Ac标记的,并且225Ac标记的HER3靶向剂的有效量包括2μCi至2mCi,或2μCi至250μCi,或75μCi至400μCi。
方面19.根据方面1至14中任一项的方法,其中放射性同位素标记的HER3靶向剂是177Lu标记的,并且HER3靶向剂的有效量包括小于1000uCi/kg受试者体重的剂量,例如1至900uCi/kg受试者体重的剂量,或5至250uCi/kg受试者体重,或50至450uCi/kg体重。
方面20.根据方面1至14中任一项的方法,其中放射性同位素标记的HER3靶向剂是177Lu标记的,并且177Lu标记的HER3靶向剂的有效量包括10mCi到30mCi或以下的剂量,或从至少100μCi到3mCi或以下,或从3mCi到30mCi或以下。
方面21.根据方面1至14中任一项的方法,其中放射性标记的HER3靶向剂是131I标记的,并且131I标记的HER3靶向剂的有效量包括小于1200mCi的剂量,例如25至1200mCi的剂量,或100至400mCi,或300至600mCi,或500至1000mCi。
方面22.根据方面1至14中任一项的方法,其中放射性标记的HER3靶向剂是131I标记的,并且131I标记的HER3靶向剂的有效量包括小于200mCi的剂量,例如1至200mCi的剂量,或25至175mCi,或50至150mCi。
第23方面。根据前述任何方面的方法,其中有效量的HER3靶向剂包括小于受试者3mg/kg体重的蛋白剂量,例如从0.001mg/kg患者体重到3.0mg/kg患者体重,或从0.005mg/kg患者体重到2.0mg/kg患者体重,或从0.01mg/kg患者体重到1mg/kg患者体重,或从0.1mg/kg患者体重到0.6mg/kg患者体重,或0.3mg/kg患者体重,或0.4mg/kg患者体重,或0.5mg/kg患者体重,或0.6mg/kg患者体重。
方面24.根据前述任何方面的方法,其中HER3靶向剂根据选自以下一组的给药计划给药:在整个治疗期间每7、10、12、14、20、24、28、36和42天一次,其中治疗期间包括至少两次给药。
方面25.根据方面1至6中任一项的方法,其中HER3靶向剂是肽或小分子。
方面26.根据前述任何方面的方法,进一步包括向受试者施用治疗有效量的免疫检查点疗法、化疗剂、DNA损伤反应抑制剂(DDRi)、CD47阻断剂或其组合。
方面27.根据方面26的方法,其中免疫检查点疗法包括针对CTLA-4、PD-1、TIM-3、VISTA、BTLA、LAG-3、TIGIT、CD28、OX40、GITR、CD137、CD40、CD40L、CD27、HVEM、PD-L1、PD-L2、PD-L3、PD-L4、CD80、CD86、CD137-L、GITR-L、CD226、B7-H3、B7-H4、BTLA、TIGIT、GALS、KIR、2B4、CD160或CGEN-15049的抗体或其他阻断剂,或这些抗体和阻断剂的任意组合。
方面28.根据方面27的方法,其中免疫检查点疗法包括针对PD-1、PD-L1、PD-L2、CTLA-4、CD137或其组合的抗体。
方面29.根据方面26的方法,其中DDRi包括聚(ADP-核糖)聚合酶抑制剂(PARPi)、共济失调毛细管扩张突变抑制剂(ATMi)、共济失调毛细管扩张突变和Rad-3相关抑制剂(ATRI)或Wee1抑制剂。
方面30.根据方面29的方法,其中PARPi包括奥拉帕尼、尼拉帕尼、鲁卡帕尼和他拉唑帕尼中的一种或多种。
方面31.根据方面29的方法,其中ATMi包括KU-55933、KU-59403、渥曼青霉素、CP466722或KU-60019中的一种或多种。
方面32.根据方面29的方法,其中ATRi包括五味子乙素、NU6027、NVP-BEA235、VE-821、VE-822、AZ20或AZD6738中的一种或多种。
方面33.根据方面29的方法,其中Wee1抑制剂包括AZD-1775(即,adavosertib)。
方面34.根据方面26所述的方法,其中CD47阻断剂包括药剂,例如阻止CD47与SIRPα结合的单克隆抗体和/或调节CD47表达的药剂。
方面35.根据方面34的方法,其中CD47阻断剂包括莫洛利单抗、来佐利单抗、AO-176、TTI-621、TTI-622中的一种或多种或其组合;和/或其中调节CD47表达的药剂包括减少CD47表达的磷酰二胺吗啉代低聚物(PMO)(例如MBT-001)。
方面36.根据方面34的方法,其中CD47阻断剂的治疗有效量包括0.05至5mg/Kg患者体重。
方面37.根据方面26的方法,其中HER3靶向剂在免疫检查点疗法和/或DDRi和/或CD47阻断剂之前至少一周施用;或其中免疫检查点疗法和/或DDRi和/或CD47阻断剂在HER3靶向剂之前至少一周施用。
方面38.根据方面26的方法,其中HER3靶向剂与免疫检查点疗法或DDRi或CD47阻断剂中的一种一起施用,并且免疫检查点疗法或DDRi或CD47阻断剂中的其他在HER3靶向剂之前或之后施用。
方面39.根据方面26的方法,其中HER3靶向剂与免疫检查点疗法和/或DDRi和/或CD47阻断剂同时施用。
方面40.根据前述任何方面的方法,其中HER3靶向剂是多特异性抗体,其中多特异性抗体包括:第一靶标识别组分,其与HER3的表位特异性结合,和第二靶标识别组分,其与不同于第一靶标识别组分的HER3的表位特异性结合,或与不同抗原的表位特异性结合。
方面41.根据方面40的方法,其中HER3靶向剂包括针对HER3/HER2的双特异性抗体,例如MM-111或MCLA0-128,或针对IGF-1R/HER3的双特异性抗体,例如MM-141(即艾司妥单抗),和/或针对HER1/HER3的双特异性抗体,例如MEHD7945A(即杜力戈图单抗)。
方面42.一种治疗增殖性疾病或病症的方法,所述方法包括:诊断受试者的HER3阳性细胞;以及如果受试者具有HER3阳性细胞,则根据方面1至41的任何方法向受试者施用治疗有效量的HER3靶向剂。
方面43.根据方面42的方法,其中诊断包括从受试者获得血液或组织的样品;将样品安装在基质上;以及使用诊断抗体检测是否存在HER3抗原,其中诊断抗体包括用放射性标记如3H、14C、32P、35S和1257I标记的针对HER3的抗体;荧光或化学发光化合物,例如异硫氰酸荧光素、罗丹明或荧光素;或酶,例如碱性磷酸酶、β-半乳糖苷酶或辣根过氧化物酶。
方面44.根据方面42的方法,其中诊断包括向受试者施用HER3靶向剂,其中HER3靶向剂包括选自包括18F、11C、68Ga、64Cu、89Zr、124I、99mTc或111In的组的放射性标记;等待足够的时间以使HER3靶向剂在组织部位积累;以及用非侵入性成像技术对组织成像以检测是否存在HER3阳性细胞。
方面45.根据方面44的方法,其中非侵入性成像技术包括用于18F、11C、68Ga、64Cu、89Zr或124I标记的HER3靶向剂的正电子发射断层扫描(PET成像),或用于99mTc或111In标记的HER3靶向剂的单光子发射计算机断层扫描(SPECT成像)。
虽然本文已经说明和描述了各种具体的实施方案,但可以理解的是,在不背离本发明的精神和范围的情况下可以做出各种改变。此外,就本发明的一个方面所描述的特征可与本发明的其他方面结合使用,即使在其中没有明确地结合举例说明。
参考文献
Mishra R,Patel H,Alanazi S,Yuan L,Garrett JT.HER3 signaling andtargeted therapy in cancer.Oncol Rev.2018;12(1).
Meneses-Lorente G,Friess T,Kolm I,et al.Preclinical pharmacokinetics,pharmacodynamics,and efficacy of RG7116:a novel humanized,glycoengineeredanti-HER3 antibody.Cancer Chemother Pharmacol.2015;75(4):837-850.
Mirschberger C,Schiller CB,Schraml M,et al.RG7116,a TherapeuticAntibody That Binds the Inactive HER3 Receptor and Is Optimized for ImmuneEffector Activation.Cancer Res.2013;73(16):5183-5194.
Meulendijks D,Jacob W,Martinez-Garcia M,et al.First-in-Human Phase IStudy of Lumretuzumab,a Glycoengineered Humanized Anti-HER3 MonoclonalAntibody,in Patients with Metastatic or Advanced HER3-Positive SolidTumors.Clin Cancer Res.2016;22(4):877-885.
Reynolds KL,Bedard PL,Lee S-H,et al.Aphase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients withadvanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.BMC Cancer.2017;17(1):646。
序列表
<110> 锕医药有限责任公司
<120> 用于治疗实体癌的HER3放射免疫疗法
<130> ATNM-010PCT
<140>
<141>
<150> PCT/US21/56259
<151> 2021-10-22
<150> US 63/250,725
<151> 2021-09-30
<150> US 63/226,699
<151> 2021-07-28
<150> US 63/118,181
<151> 2020-11-25
<150> US 63/116,225
<151> 2020-11-20
<160> 118
<170> PatentIn version 3.5
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Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His
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Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe
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Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
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Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
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His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
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Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
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Asp Val Leu Met Thr Gln Ile Pro Leu Ser
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Asp Tyr Ala Met Ser
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Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys
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Gly
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Ala Ala Ser Thr Leu Asp Ser
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Leu Gln Tyr Asp Ser Tyr Pro Tyr Thr
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
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Thr Leu Val Thr Val Ser Ser
115
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
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Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
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Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
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Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
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Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
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Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
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Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
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Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
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Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
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Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
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Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
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385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 24
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
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Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
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Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
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Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
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Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 25
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 25
Ser His Trp Leu His
1 5
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 26
Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe Lys
1 5 10 15
Gly
<210> 27
<211> 11
<212> PRT
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<220>
<223> 人工序列的描述:合成肽
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Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr
1 5 10
<210> 28
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 28
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 29
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 29
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 30
Phe Gln Gly Ser Tyr Val Pro Trp Thr
1 5
<210> 31
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 31
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His
20 25 30
Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 32
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 32
Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 33
<211> 463
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 33
Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser His Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn
65 70 75 80
Gln Asn Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
260 265 270
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
275 280 285
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
290 295 300
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
305 310 315 320
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
325 330 335
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
355 360 365
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
370 375 380
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
385 390 395 400
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
405 410 415
Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
420 425 430
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
435 440 445
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 34
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 34
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
100 105 110
Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 35
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 35
Thr Phe Gly Leu Ser Val Gly
1 5
<210> 36
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 36
His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala Leu Lys Ser
1 5 10 15
<210> 37
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 37
Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr
1 5 10
<210> 38
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 38
Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr
1 5 10 15
<210> 39
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 39
Arg Met Ser Asn Leu Ala Ser
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 40
Met Gln His Leu Glu Tyr Pro Phe Thr
1 5
<210> 41
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 41
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe
20 25 30
Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 42
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 42
Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 43
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 43
Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg
20 25 30
Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu
35 40 45
Ser Thr Phe Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys
50 55 60
Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr
65 70 75 80
Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser
145 150 155 160
Ser Val Thr Ser Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe
180 185 190
Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala
210 215 220
His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly
225 230 235 240
Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys
245 250 255
Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
290 295 300
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
305 310 315 320
Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile
325 330 335
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
340 345 350
Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys
355 360 365
Gly Leu Val Arg Ala Pro Gln Val Tyr Thr Leu Pro Pro Pro Ala Glu
370 375 380
Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe
385 390 395 400
Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu
405 410 415
Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr
420 425 430
Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr
435 440 445
Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr
450 455 460
Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys
465 470 475
<210> 44
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 44
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Gly Ala Ile Gly Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro
20 25 30
Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser
35 40 45
Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg
50 55 60
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe
85 90 95
Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Met Gln His Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys
115 120 125
Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro
130 135 140
Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp
165 170 175
Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys
195 200 205
Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys
210 215 220
Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 45
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 45
Asp His Ile Ile His
1 5
<210> 46
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 46
Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 47
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 47
Gly Tyr Tyr Tyr Ala Met Asp Tyr
1 5
<210> 48
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 48
Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 49
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 49
Phe Gln Gly Ser His Val Pro Phe Thr
1 5
<210> 50
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 50
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 51
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 51
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 52
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 52
Met Glu Trp Ser Trp Val Ser Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe
35 40 45
Thr Asp His Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
130 135 140
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
145 150 155 160
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
165 170 175
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
195 200 205
Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala
210 215 220
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
225 230 235 240
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
245 250 255
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
260 265 270
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
275 280 285
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
305 310 315 320
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
325 330 335
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
355 360 365
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
370 375 380
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
385 390 395 400
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
405 410 415
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
420 425 430
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
435 440 445
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 53
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 53
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Arg Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile
35 40 45
Val His Ser Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
100 105 110
Phe Gln Gly Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 54
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 54
Ser Tyr Trp Met His
1 5
<210> 55
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 55
Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe Lys
1 5 10 15
Gly
<210> 56
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 56
Asn Tyr Ser Gly Asp Tyr
1 5
<210> 57
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 57
Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 58
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 58
Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 59
<211> 458
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 59
Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Cys
1 5 10 15
Val His Ser Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe
35 40 45
Ser Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn
65 70 75 80
Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
130 135 140
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
145 150 155 160
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
165 170 175
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
195 200 205
Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
210 215 220
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
225 230 235 240
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
245 250 255
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
260 265 270
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
275 280 285
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
290 295 300
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
305 310 315 320
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
325 330 335
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
340 345 350
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
355 360 365
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
370 375 380
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
385 390 395 400
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
405 410 415
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
420 425 430
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
435 440 445
Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455
<210> 60
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 60
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
100 105 110
Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 61
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 61
Thr Tyr Gly Met Ser
1 5
<210> 62
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 62
Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 63
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 63
Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr
1 5 10
<210> 64
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 64
Ile Thr Ser Thr Asp Ile Asp Asp Asp Met Asn
1 5 10
<210> 65
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 65
Glu Gly Asn Thr Leu Arg Pro
1 5
<210> 66
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 66
Leu Gln Ser Asp Asn Leu Pro Tyr Thr
1 5
<210> 67
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 67
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 68
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 68
Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly
1 5 10 15
Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp
20 25 30
Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile
35 40 45
Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu Asn Met Leu Ser
65 70 75 80
Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 69
<211> 464
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 69
Met Gly Trp Leu Trp Asn Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ala Gln Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys
20 25 30
Pro Gly Glu Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Tyr Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu
50 55 60
Lys Trp Met Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala
65 70 75 80
Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser
85 90 95
Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr
100 105 110
Tyr Phe Cys Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr
130 135 140
Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn
145 150 155 160
Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val
195 200 205
Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val
210 215 220
Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg
225 230 235 240
Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser
245 250 255
Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu
260 265 270
Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro
275 280 285
Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala
290 295 300
Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val
305 310 315 320
Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe
325 330 335
Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile
355 360 365
Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys
370 375 380
Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp
385 390 395 400
Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp
405 410 415
Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser
420 425 430
Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly
435 440 445
Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 70
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 70
Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys Val Ser
1 5 10 15
Asp Ser Arg Ala Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Met Ala Ile Gly Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp
35 40 45
Ile Asp Asp Asp Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro
50 55 60
Lys Leu Leu Ile Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu
85 90 95
Asn Met Leu Ser Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp
100 105 110
Asn Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 71
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 71
Asn Tyr Trp Met His
1 5
<210> 72
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 72
Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe Lys
1 5 10 15
Gly
<210> 73
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 73
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 74
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 74
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 75
<211> 458
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 75
Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn
65 70 75 80
Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
130 135 140
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
145 150 155 160
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
165 170 175
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
195 200 205
Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
210 215 220
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
225 230 235 240
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
245 250 255
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
260 265 270
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
275 280 285
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
290 295 300
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
305 310 315 320
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
325 330 335
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
340 345 350
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
355 360 365
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
370 375 380
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
385 390 395 400
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
405 410 415
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
420 425 430
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
435 440 445
Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455
<210> 76
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 76
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
100 105 110
Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 77
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 77
Gln 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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 78
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 78
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
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> 79
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 79
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 Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 80
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 80
Gln 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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 81
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 81
Gln 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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 82
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 82
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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 83
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 83
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 Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 84
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 84
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 Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 85
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 85
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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 86
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 86
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 87
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 87
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 88
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 88
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 89
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 89
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 90
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 90
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 91
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 91
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Leu Gln Gln Lys Pro Gly Gly Ala Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 92
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 92
Met Asn Phe Gly Leu Ser Leu Met Phe Leu Val Leu Val Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro
65 70 75 80
Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Asn Leu Tyr Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Thr Leu 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 Arg 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> 93
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 93
Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Glu Arg Val Ser Leu Thr Cys Arg Ala Ser
35 40 45
Gln Glu Ile Ser Gly Tyr Leu Ser Trp Leu Gln Gln Lys Pro Asp Gly
50 55 60
Thr Ile Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val
65 70 75 80
Pro Lys Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr
85 90 95
Ile Gly Ser Leu Glu Ser Glu Asp Leu Ala Asp Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 94
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 94
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr
65 70 75 80
Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 95
<211> 467
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 95
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr
65 70 75 80
Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 96
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 96
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Glu Ile Ser Gly Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 97
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 97
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 98
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列的抗体重链
<400> 98
Gln 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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 99
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列的抗体重链
<400> 99
Gln 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 Phe Ser Asp Tyr
20 25 30
Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 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 Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
290 295 300
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 100
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列的抗体轻链
<400> 100
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
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> 101
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 无前导序列的抗体轻链
<400> 101
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 Glu Ile Ser Gly Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Asp Ser 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 Leu Gln Tyr Asp Ser Tyr Pro Tyr
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> 102
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 102
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg 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
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met 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 Glu Glu Met 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> 103
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 103
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 Asn 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 Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 104
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 104
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 Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg 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 Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 105
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 105
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
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 Tyr Arg Tyr Thr 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 Tyr Ile Tyr Pro Tyr
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> 106
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 106
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Glu Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg 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 Ser Ser Lys Ser Thr Ser Gly Gly 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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg 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 Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 107
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 107
Asp Ile Glu Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Asn Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 108
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 108
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 His Tyr
20 25 30
Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Gly Gly Trp Thr Leu 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
Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
290 295 300
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 109
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 109
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 Ser Tyr
20 25 30
Asn Val Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Glu Val Ser Gln 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 Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95
Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val
145 150 155 160
Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 110
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 110
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 Arg Ser Ser
20 25 30
Tyr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Ala Gly Thr Gly Ser Pro Ser Tyr Asn Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Arg Asp Tyr Tyr Ser Asn Ser Leu Thr 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
<210> 111
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 111
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 112
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 抗体重链
<400> 112
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Asn Ser Gln Gly Lys Ser Thr 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 Arg Trp Gly Asp Glu Gly Phe Asp Ile 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 Ser Ser Lys Ser Thr Ser Gly Gly 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 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg 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 Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln 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 Pro Gly
435 440 445
<210> 113
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体轻链
<400> 113
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 Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Thr
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> 114
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 吗啉代
<400> 114
cgtcacaggc aggacccact gccca 25
<210> 115
<211> 1342
<212> PRT
<213> 智人
<400> 115
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
325 330 335
Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
340 345 350
Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
355 360 365
Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
370 375 380
Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
385 390 395 400
Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
405 410 415
Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
420 425 430
Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
435 440 445
Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
450 455 460
His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
465 470 475 480
Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
485 490 495
Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
500 505 510
Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
515 520 525
Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
530 535 540
His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu
545 550 555 560
Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
565 570 575
Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
580 585 590
Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
595 600 605
Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
610 615 620
Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
625 630 635 640
His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe
645 650 655
Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln
660 665 670
Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu
675 680 685
Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe
690 695 700
Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe
705 710 715 720
Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys
725 730 735
Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser
740 745 750
Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His
755 760 765
Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln
770 775 780
Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg
785 790 795 800
Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val
805 810 815
Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His
820 825 830
Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val
835 840 845
Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys
850 855 860
Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu
865 870 875 880
Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser
885 890 895
Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr
900 905 910
Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu
915 920 925
Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met
930 935 940
Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu
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Claims (31)
1.一种用于治疗哺乳动物受试者的实体癌的方法,所述方法包括:
向所述受试者施用治疗有效量的放射性核素标记的HER3靶向剂。
2.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括选自131I、125I、123I、90Y、177Lu、186Re、188Re、89Sr、153Sm、32P、225Ac、213Bi、213Po、211At、212Bi、213Bi、223Ra、227Th、149Tb、137Cs、212Pb或103Pd或其组合的放射性标记。
3.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括选自225Ac、177Lu、131I、90Y、213Bi、211At、213Bi、227Th、212Pb或其组合的放射性标记。
4.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括针对HER3的人源化抗体。
5.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括帕曲妥单抗、瑟瑞妥单抗、鲁妥珠单抗、依更妥单抗、AV203、GSK2849330中的一种或多种。
6.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括单克隆抗体,所述单克隆抗体包括包含SEQ ID NO:77的重链序列和包含SEQ ID NO:78的轻链序列中的一种或两种。
7.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂包括单克隆抗体,所述单克隆抗体包括:
(i)以下一种或两种:
(a)免疫球蛋白重链可变区,包含包括SEQ ID NO:15的CDR-H1、包括SEQ ID NO:16的CDR-H2和/或包括SEQ ID NO:17的CDR-H3,和
(b)免疫球蛋白轻链可变区,包含包括SEQ ID NO:18的CDR-L1、包括SEQ ID NO:19的CDR-L2和/或包括SEQ ID NO:20的CDR-L3;
(ii)包括SEQ ID NO:21的免疫球蛋白重链可变区和包括SEQ ID NO:22的免疫球蛋白轻链可变区中的一种或两种;或
(iii)SEQ ID NO:23的免疫球蛋白重链氨基酸序列和SEQ ID NO:24的免疫球蛋白轻链氨基酸序列中的一种或两种。
8.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂是单克隆抗体,所述单克隆抗体包括具有氨基酸序列分别如SEQ.ID NO:13和/或1-3所示的互补决定区(CDR)的重链;和/或具有氨基酸序列分别如SEQ.ID NO:14和/或4-6所示的CDR的轻链。
9.根据权利要求1所述的方法,其中所述实体癌是乳腺癌、胃癌、膀胱癌、宫颈癌、子宫内膜癌、皮肤癌、胃癌、睾丸癌、食道癌、支气管肺泡癌、前列腺癌、结直肠癌、卵巢癌、宫颈表皮样癌、胰腺癌、肺癌、肾癌、头颈癌或其任意组合。
10.根据权利要求1所述的方法,其中所述实体癌是乳腺癌、胃癌、胰腺癌或其任意组合。
11.根据权利要求1所述的方法,其中所述实体癌包括HER3阳性癌细胞。
12.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂的有效量是最大耐受剂量。
13.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂是225Ac标记的,并且225Ac标记的HER3靶向剂的有效量包括0.1至50uCi/kg受试者体重、或0.1至5uCi/kg受试者体重、或5至20uCi/kg受试者体重的剂量。
14.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂是225Ac标记的,并且225Ac标记的HER3靶向剂的有效量包括2μCi至2mCi、或2μCi至250μCi、或75μCi至400μCi的剂量。
15.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂的有效量包括小于3mg/kg受试者体重,例如0.001mg/kg患者体重至3.0mg/kg患者体重,或0.005mg/kg患者体重至2.0mg/kg患者体重,或0.01mg/kg患者体重至1mg/kg患者体重,或0.1mg/kg患者体重至0.6mg/kg患者体重,或0.3mg/kg患者体重,或0.4mg/kg患者体重,或0.5mg/kg患者体重,或0.6mg/kg患者体重的蛋白剂量。
16.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂按照选自由以下组成的组的给药计划施用:在整个治疗期间,每7、10、12、14、20、24、28、36和42天一次,其中治疗期间包括至少两个剂量。
17.根据权利要求1所述的方法,进一步包括:
向所述受试者施用治疗有效量的免疫检查点疗法、DNA损伤反应抑制剂(DDRi)、CD47阻断剂、化疗剂或其组合。
18.根据权利要求17所述的方法,其中所述免疫检查点疗法包括针对PD-1、PD-L1、PD-L2、CTLA-4、CD137或其组合的抗体。
19.根据权利要求17所述的方法,其中所述DDRi包括聚(ADP-核糖)聚合酶抑制剂(PARPi)、共济失调毛细管扩张突变抑制剂(ATMi)、共济失调毛细管扩张突变和Rad-3相关抑制剂(ATRi)或Wee1抑制剂。
20.根据权利要求17所述的方法,其中所述CD47阻断剂包括莫洛利单抗、来佐利单抗、AO-176、TTI-621、TTI-622和CD47表达调节剂中的一种或多种。
21.根据权利要求17所述的方法,其中所述CD47阻断剂包括CD47表达调节剂。
22.根据权利要求21所述的方法,其中所述CD47表达调节剂是MBT-001。
23.根据权利要求1所述的方法,其中所述放射性核素标记的HER3靶向剂对HER2也是特异性的。
24.根据权利要求1或23所述的方法,其中所述放射性标记的HER3靶向剂包括化学缀合的螯合剂基团,所述螯合剂基团螯合放射性核素。
25.根据权利要求24所述的方法,其中所述螯合剂基团包括DOTA。
26.根据前述权利要求中任一项所述的方法,其中施用步骤包括:
向所述受试者施用治疗有效量的治疗组合物,所述治疗组合物包括HER3靶向剂的放射性标记部分和HER3靶向剂的未放射性标记部分。
27.根据权利要求26所述的方法,其中所述治疗组合物进一步包括至少一种药学上可接受的赋形剂。
28.根据前述权利要求中任一项所述的方法,进一步包括以下步骤:在施用步骤之前,诊断所述受试者患有HER3阳性癌症。
29.根据权利要求28所述的方法,其中诊断步骤包括使用放射性核素标记的HER3靶向剂对所述受试者的HER3阳性细胞进行成像。
30.根据权利要求29所述的方法,其中诊断步骤和施用步骤使用相同的HER3靶向剂。
31.根据权利要求30所述的方法,其中所述HER3靶向剂在诊断步骤中用不同于施用步骤中的放射性核素标记。
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