CN117377488A - 靶向dll3和pd-1的组合疗法的给药方案 - Google Patents
靶向dll3和pd-1的组合疗法的给药方案 Download PDFInfo
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Abstract
本发明提供一种治疗DLL3阳性癌症或SCLC的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD‑1抗体。还披露了该抗DLL3药剂的阶梯给药。
Description
优先权
本申请要求2021年5月10日提交的美国临时申请号63/186,569的权益,将其内容特此通过引用以其全文并入。
以ASCII文本文件提交序列表
以下以ASCII文本文件提交的内容是通过引用以其整体并入本文中:序列表的计算机可读形式(CRF)(文件名:A-2789-WO 01-SEC_Sequence Listing_ST25,创建日期:2022年5月6日,大小:123,163字节)。
技术领域
本申请涉及靶向DLL3和PD-1的组合疗法的剂量和施用以治疗癌症。
背景技术
δ样3(DLL3)是一种1型跨膜蛋白和非经典Notch配体。DLL3是开发T细胞疗法的有希望的靶标,因为它在神经内分泌肿瘤的细胞表面高表达,并且在正常组织中的定位最少,主要是细胞质定位(Owen等人,J Hematol Oncol.[血液与肿瘤学杂志],12:61(2019))。小细胞肺癌(SCLC)是神经内分泌癌,其中DLL3差异表达。使用免疫组织化学(IHC),85%的SCLC肿瘤对DLL3(模式与膜性表达和胞浆表达一致)染色阳性。相比之下,在正常脑、胰岛和垂体中用胞质染色模式检测到低水平的DLL3蛋白表达(Saunders等人,Sci Transl Med.[科学转化医学]7:302ra136(2015))。
SCLC是侵袭形式的肺癌,预后差且治疗选择有限,并代表约10%-15%的肺癌。数十年来,存活率仍然很低,只有5%的SCLC患者存活五年,这在很大程度上是由于缺乏新的疗法来对抗这种形式的肺癌。SCLC的特征是神经内分泌分化、生长分数高、倍增时间快和广泛转移病灶的早期建立。大约三分之一的患者表现为局限期疾病。大多数患者表现为广泛期疾病,定义为肿瘤只存在于胸部的一侧,并且其适合于单一的辐射场。这些期影响了可利用的治疗方案,其中局限期疾病用化疗和辐射治疗,而广泛期疾病仅用化疗治疗。
SCLC患者通常对目前的一线疗法(包括依托泊苷和顺铂)应答良好,但化学抗性疾病总是很快复发,对于此目前没有可用的治疗选择。复发性难治性情况的预后非常差,具有快速的疾病进展和少于六个月的短期中值存活期。患有扩展性疾病SCLC的患者发展为抗药性并在诊断后10到12个月的中值时间时死于疾病。
AMG 757是双特异性T细胞接合剂分子,靶向癌细胞上的DLL3和T细胞上的CD3。它是为治疗神经内分泌癌,例如SCLC而开发的。AMG 757正在一项治疗SCLC的临床试验中进行评估。
派姆单抗和纳武单抗/>是针对程序性细胞死亡-1(PD-1)的抗体。两者均已在美国获批用于治疗在基于铂的化疗和至少一种其他疗法线后出现进展的转移性SCLC患者。然而,批准是基于相对较低的缓解率(派姆单抗为19%,纳武单抗为12%)。评估纳武单抗作为二线或维持疗法的研究未能达到其主要终点(Reck等人,Annalsof Oncology.[肿瘤学年鉴]29:x39-x43(2018))。
对于开发治疗SCLC的疗法,存在未满足的医疗需求。
发明内容
基于本文提供的披露内容,本领域技术人员将认知到或者仅使用常规实验就能够确定本文所述的本发明的特定实施例的许多等同物。此类等同物旨在由以下实施例(E)所涵盖。
E1:一种治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中该抗DLL3药剂以0.3mg至30mg或3mg至100mg的剂量每两周一次施用,并且其中该PD-1抗体以约480mg的剂量每四周一次施用。
E2:一种治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中该抗DLL3药剂根据以下计划以28天的周期施用:a)第1周期第1天的第一剂量0.3mg或1mg,b)第1周期第8天的第二剂量,和c)第1周期第15天的第三剂量,和e)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量,并且其中第二、第三和后续剂量相同,各自为0.3mg至30mg或3mg至100mg,并且高于第一剂量,并且其中抗PD-1抗体以480mg的剂量每四周一次施用。
E3:如E1或E2所述的方法,其中该抗DLL3阳性癌症是小细胞肺癌(SCLC)。
E4:如E1-E3中任一项所述的方法,其中该抗DLL3阳性癌症是复发性/难治性(RR)SCLC或广泛性疾病(ED)SCLC。
E5:如E1-E4中任一项所述的方法,其中该抗DLL3药剂是双特异性T细胞接合抗原结合多肽,其包含两个结合结构域:第一结构域与人DLL3结合,并且第二结构域与人CD3结合。
E6:如E4所述的方法,其中该DLL3结合结构域与包含在SEQ ID NO:29的氨基酸序列内的人DLL3的表位结合。
E7:如E5或E6所述的方法,其中该DLL3结合结构域包含(a)重链可变区(VH),该重链可变区包含:(i)VH互补性决定区1(CDR-H1),其包含SEQ ID NO:1的氨基酸序列;(ii)CDR-H2,其包含SEQ ID NO:2的氨基酸序列;以及(iii)CDR-H3,其包含SEQ ID NO:3的氨基酸序列;和(b)轻链可变区(VL),该轻链可变区包含:(i)VL互补性决定区1(CDR-L1),其包含SEQ ID NO:4的氨基酸序列;(ii)CDR-L2,其包含SEQ ID NO:5的氨基酸序列;以及(iii)CDR-L3,其包含SEQ ID NO:6的氨基酸序列。
E8:如E5-E7中任一项所述的方法,其中该DLL3结合结构域包含:(1)包含SEQ IDNO:7的氨基酸序列的VH和包含SEQ ID NO:8的氨基酸序列的VL,或(2)包含SEQ ID NO:11的氨基酸序列的VH和包含SEQ ID NO:12的氨基酸序列的VL。
E9:如E5-E8中任一项所述的方法,其中该DLL3结合结构域的VH和VL通过接头连接以形成单链Fv(scFv)。
E10:如E9所述的方法,其中该接头包含选自SEQ ID NO:42-50中任一个的序列。
E11:如E9或E10所述的方法,其中该接头包含(Gly4Ser)x,其中x是1或更大的整数(例如1、2、3或4)。
E12:如E5-E11中任一项所述的方法,其中该DLL3结合结构域包含SEQ ID NO:9或SEQ ID NO:13的氨基酸序列。
E13:如E5-E12中任一项所述的方法,其中该CD3结合结构域包含:(a)VH,其包含:包含SEQ ID NO:18的氨基酸序列的CDR-H1,包含SEQ ID NO:19的氨基酸序列的CDR-H2,和包含SEQ ID NO:20的氨基酸序列的CDR-H3;和VL,其包含:包含SEQ ID NO:15的氨基酸序列的CDR-L1,包含SEQ ID NO:16的氨基酸序列的CDR-L2,以及包含SEQ ID NO:17的氨基酸序列的CDR-L3。
E14:如E5-E13中任一项所述的方法,其中该CD3结合结构域包含:包含SEQ ID NO:21的氨基酸序列的VH和包含SEQ ID NO:22的氨基酸序列的VL。
E15:如E13或E14所述的方法,其中该CD3结合结构域的VH和VL通过接头连接以形成单链Fv(scFv)。
E16:如E15所述的方法,其中该接头包含选自SEQ ID NO:42-50中任一个的序列。
E17:如E15或E16所述的方法,其中该接头包含(Gly4Ser)x,其中x是1或更大的整数(例如1、2、3或4)。
E18:如E13-E17中任一项所述的方法,其中该CD3结合结构域包含SEQ ID NO:23的氨基酸序列。
E19:如E5-E18中任一项所述的方法,其中该DLL3结合结构域和该CD3结合结构域通过接头连接。
E20:如E19所述的方法,其中该接头是包含选自SEQ ID NO:42-50中任一个的序列的肽接头。
E21:如E19或E20所述的方法,其中该接头是包含(Gly4Ser)x的肽接头,其中x是1或更大的整数(例如,1、2、3或4)。
E22:如E5-E21中任一项所述的方法,该抗DLL3药剂是双特异性T细胞接合抗原结合多肽,其包含DLL3结合结构域和CD3结合结构域。该DLL3结合结构域包含(a)重链可变区(VH),该重链可变区包含:(i)VH互补性决定区1(CDR-H1),其包含SEQ ID NO:1的氨基酸序列;(ii)CDR-H2,其包含SEQ ID NO:2的氨基酸序列;以及(iii)CDR-H3,其包含SEQ ID NO:3的氨基酸序列;和(b)轻链可变区(VL),该轻链可变区包含:(i)VL互补性决定区1(CDR-L1),其包含SEQ ID NO:4的氨基酸序列;(ii)CDR-L2,其包含SEQ ID NO:5的氨基酸序列;以及(iii)CDR-L3,其包含SEQ ID NO:6的氨基酸序列。该CD3结合结构域包含(a)VH,其包含:(i)包含SEQ ID NO:18的氨基酸序列的CDR-H1,(ii)包含SEQ ID NO:19的氨基酸序列的CDR-H2,和(iii)包含SEQ ID NO:20的氨基酸序列的CDR-H3;和(b)VL,其包含:(i)包含SEQ IDNO:15的氨基酸序列的CDR-L1,(ii)包含SEQ ID NO:16的氨基酸序列的CDR-L2,以及(iii)包含SEQ ID NO:17的氨基酸序列的CDR-L3。
E23:如E5-E22中任一项所述的方法,该DLL3结合结构域包含含有SEQ ID NO:7的氨基酸序列的VH和含有SEQ ID NO:8的氨基酸序列的VL,并且该CD3结合结构域包含含有SEQ ID NO:21的氨基酸序列的VH和含有SEQ ID NO:22的氨基酸序列的VL。
E24:如E5-E22中任一项所述的方法,该DLL3结合结构域包含含有SEQ ID NO:11的氨基酸序列的VH和含有SEQ ID NO:12的氨基酸序列的VL,并且该CD3结合结构域包含含有SEQ ID NO:21的氨基酸序列的VH和含有SEQ ID NO:22的氨基酸序列的VL。
E25:如E5-E23中任一项所述的方法,其中该DLL3结合结构域包含SEQ ID NO:9的氨基酸并且该CD3结合结构域包含SEQ ID NO:23的氨基酸。
E26:如E5-E21或E24中任一项所述的方法,该DLL3结合结构域包含SEQ ID NO:13的氨基酸并且该CD3结合结构域包含SEQ ID NO:23的氨基酸。
E27:如E25所述的方法,其中该抗DLL3药剂包含SEQ ID NO:10的氨基酸序列。
E28:如E27所述的方法,其中该抗DLL3药剂包含SEQ ID NO:14的氨基酸序列。
E29:如E5-E28中任一项所述的方法,其中该抗DLL3药剂进一步包含延长或增强该抗DLL3药剂的血清半衰期的第三结构域。
E30:如E29所述的方法,其中该第三结构域包含选自SEQ ID NO:51-58中任一个的氨基酸序列。
E31:如E5-E22、E24、E26、E28-E30中任一项所述的方法,其中该抗DLL3药剂包含SEQ ID NO:27或59的氨基酸。
E32:如E5-E31中任一项所述的方法,其中该抗PD-1抗体包含(a)VH,其包含:(i)包含SEQ ID NO:32的氨基酸序列的CDR-H1,(ii)包含SEQ ID NO:33的氨基酸序列的CDR-H2,(iii)包含SEQ ID NO:34的氨基酸序列的CDR-H3;和(b)VL,其包含:(i)包含SEQ ID NO:35的氨基酸序列的CDR-L1,(ii)包含SEQ ID NO:36的氨基酸序列的CDR-L2,(iii)包含SEQ IDNO:37的氨基酸序列的CDR-L3。
E33:如E5-E32中任一项所述的方法,其中该抗PD-1抗体包含含有SEQ ID NO:38的氨基酸序列的VH和含有SEQ ID NO:39的氨基酸序列的VL。
E34:如E5-E33中任一项所述的方法,其中该抗PD-1抗体包含重链(HC)和轻链(LC),该重链包含EQ ID NO:40的氨基酸序列并且该轻链包含SEQ ID NO:41的氨基酸序列。
E35:如E1或E3-E34中任一项所述的方法,其中该抗DLL3药剂以以下剂量每两周一次施用:约0.3mg至约30mg、约1mg至约30mg、约3mg至约30mg或约10mg至约30mg。
E36:如E35所述的方法,其中该抗DLL3药剂以约0.3mg、1mg、3mg、10mg、25mg或30mg的剂量每两周一次施用。
E37:如E1或E3-E34中任一项所述的方法,其中该抗DLL3药剂以以下剂量每两周一次施用:约3mg至约100mg、约10mg至约100mg或约30mg至约100mg。
E38:如E37所述的方法,其中该抗DLL3药剂以约3mg,10mg、25mg、30mg、50mg、75mg或100mg的剂量每两周一次施用。
E39:如E2-E34中任一项所述的方法,其中该抗DLL3药剂的第二剂量、第三剂量和后续剂量各自是约0.3mg至约30mg、约1mg至约30mg、约3mg至约30mg或约10mg至约30mg。
E40:如E39中任一项所述的方法,其中该抗DLL3药剂的第二剂量、第三剂量和后续剂量各自是约0.3mg、1mg、3mg、10mg、25mg或30mg的剂量。
E41:如E2-E34中任一项所述的方法,其中该抗DLL3药剂的第二剂量、第三剂量和后续剂量各自是约3mg至约100mg、约10mg至约100mg、或约30mg至约100mg。
E42:如E41所述的方法,其中该抗DLL3药剂的第二剂量、第三剂量和后续剂量各自是约3mg,10mg、25mg、30mg、50mg、75mg或100mg的剂量。
E43:如E1或E3-E38中任一项所述的方法,其中在28天周期的第1天和第15天施用该抗DLL3药剂,并且在28天周期的第1天、第8天或第15天施用该抗PD-1抗体。
E44:如E43所述的方法,其中在28天周期的第一周期中的第1天、第8天或第15天施用该抗PD-1抗体,并且然后在从第二周期开始的第1天或第15天及之后施用。
E45:如E2-E34或E39-E42中任一项所述的方法,其中在28天周期的第1周期中的第1天、第8天或第15天施用该抗PD-1抗体,并且然后在从第二周期开始的第1天或第15天及之后施用。
E46:如E44或E45所述的方法,其中a)如果在第一周期的第1天或第8天施用该抗PD-1抗体,则在从第二周期开始的第1天及之后施用该抗体,或b)如果在第一周期的第15天施用该抗PD-1抗体,则在第2周期的第15天及之后施用该抗体。
E47:如E1-E46中任一项所述的方法,其中该方法进一步包括向该受试者施用一种或多种另外治疗剂。
E48:如E47所述的方法,其中该一种或多种另外治疗剂是皮质类固醇(例如***)、盐水或托珠单抗。
E49:如E47或E48中任一项所述的方法,其中在其中施用该抗DLL3药剂的第一周期中将该一种或多种另外治疗剂施用给该受试者。
E50:如E1-E50中任一项所述的方法,其中该抗DLL3药剂通过以下过程制备,在该过程中,在允许该抗DLL3药剂表达的条件下培养包含编码如E5-E31中任一项所述的抗DLL3药剂的核酸的宿主细胞并且然后从细胞培养物中回收表达的抗DLL3药剂,并且其中该抗PD-1抗体通过以下过程制备,在该过程中,在允许该抗PD-1抗体表达的条件下培养包含编码如E32-E34中任一项所述的抗PD-1抗体的核酸的宿主细胞并且然后从细胞培养物中回收表达的抗PD-1抗体
E51:如E1-E50中任一项所述的方法,其中该受试者是人。
E52:一种抗DLL3药剂和抗PD-1抗体,其用于在如实施例E1-E51中任一项所述的方法中使用。
E53:一种抗DLL3药剂和抗PD-1抗体,其用于在治疗DLL3阳性癌症(例如SCLC)中使用,其中该抗DLL3药剂和该抗PD-1抗体如实施例E1-E51中任一项所述施用。
E54:抗DLL3药剂和抗PD-1抗体用于制备用于治疗SCLC的药物的用途,其中该药物准备如实施例E1-E51中任一项所述施用。
E55:抗DLL3药剂和抗PD-1抗体在制备用于治疗DLL3阳性癌症的药物中的用途,其中该抗DLL3药剂和该抗PD-1抗体如实施例E1-E51中任一项所述施用。
附图说明
图1显示了实例2中举例说明的临床研究中的AMG 757和AMG 404剂量水平。
具体实施方式
AMG 757是开发用于治疗SCLC的半衰期延长的(双特异性T细胞衔接子)分子。AMG 757的活性需要同时结合至靶细胞(DLL3+细胞)和T细胞两者。AMG 757的药理作用是通过先前引发的细胞毒性CD8+或CD4+T淋巴细胞的特异性重定向来介导以杀伤DLL3+细胞。AMG 757正在SCLC受试者的首次人体研究中进行评估(研究20160323),发现从每两周一次(Q2W)0.3mg的剂量水平开始具有抗肿瘤活性,并且在剂量高达100mg Q2W时具有可接受的安全性。
AMG 404是完全人抗体,以高亲和力结合人PD-1,并阻断该受体与其配体、程序性死亡配体1(PD-L1)和程序性死亡配体2(PD-L2)相互作用的能力。AMG 404正在实体瘤受试者的1期研究(研究20180143)中进行评估,并被发现对实体瘤有效。
最近启动了多项临床试验,用于使用PD1/PDL1抑制剂与其他抗癌剂组合治疗小细胞肺癌。参见例如NCT04702880和NCT04256421(SKYSCRAPER-02)。然而,最近宣布的SKYSCRAPER-02试验失败凸显了将PD1/PDL1抑制剂与其他抗癌剂组合治疗这种难以治疗的癌症的不确定性。在靶向这种肿瘤类型方面仍然存在高度未满足的需求和持续的挑战。
与单独的AMG 757相比,AMG 757和抗PD-1抗体的组合增加了表达DLL3的肿瘤细胞的T细胞介导的重定向裂解(美商安进公司研究报告R20190104)。人们认为,肿瘤微环境中PD1/PDL1的上调是对BiTE疗法产生抗性的机制,而抗PD1疗法治疗可能会减轻这种抗性。
如本文所披露和举例说明的,使用靶向DLL3的药剂(例如,AMG 757)和PD-1的药剂(例如,派姆单抗或AMG 404)进行了1期临床研究以治疗SCLC。
1.定义
本文披露的一些示例性双特异性抗DLL3药剂(例如分子)是双特异性T细胞接合抗原结合多肽。这些多肽是包含两个结合结构域的重组蛋白,每个结构域衍生自全长抗体的抗原结合片段。这种抗原结合片段保留了特异性结合抗原的能力(优选具有基本相同的结合亲和力)。抗原结合片段的实例包括(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,其是包含由二硫桥在铰链区连接的两个Fab片段的双价片段;(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体单臂的VL和VH结构域组成的Fv片段,以及(v)dAb片段(Ward等人,1989Nature[自然]341:544-546),其由VH结构域组成。此外,虽然Fv片段的两个结构域VL和VH是由单独的基因编码的,但是可以使用重组方法将这两个结构域通过使它们能够形成为单一蛋白链的合成接头来相连,其中VL区和VH区配对形成单价分子(被称为单链Fv(scFv);参见例如,Bird等人Science[科学]242:423-426(1988)和Huston等人,1988,Proc.Natl.Acad.Sci.USA[美国科学院院报]85:5879-5883。
“可变结构域”是指抗体轻链(VL)的可变区域或抗体重链(VH)的可变区域,无论是单独的还是组合的。如本领域所知,重链和轻链的可变区域各自由被三个互补性决定区(CDR)连接的四个框架区(FR)组成,并且有助于抗体的抗原结合位点的形成。
序列表中提供了靶向DLL3和PD-1的示例性药剂的“互补决定区”(CDR)。可以根据Kabat、Chothia、Kabat和Chothia的累积、AbM、contact、North和/或构象定义或本领域众所周知的任何CDR测定方法来定义CDR。参见,例如,Kabat等人,1991,Sequences of Proteinsof Immunological Interest[免疫学目的蛋白的序列],第5版(hypervariable regions[高变区]);Chothia等人,1989,Nature[自然]342:877-883(structural loop structures[结构环结构])。CDR的AbM定义是Kabat和Chothia之间的折衷方案,并使用了牛津大学分子公司(Oxfbrd Molecular)的AbM抗体建模软件可以使用本领域众所周知的方法来确定构成CDR的特定抗体中氨基酸残基的特性。
术语“治疗”包括预防性和/或治疗性治疗。如果在病症的临床表现之前施用,则认为该治疗是预防性的。治疗性治疗包括,例如,改善或降低疾病的严重程度,或缩短疾病的长度。此外,术语“治疗”以及与之相关的词语不一定隐含100%或完全治疗。更确切些,存在本领域中普通技术人员认为具有潜在益处或治疗作用的不同程度的治疗。在此方面,本披露内容的癌症治疗方法可提供任何量或任何水平的治疗。此外,由本披露内容的方法提供的治疗可包括治疗所治疗癌症的一种或多种病状或症状或体征。由本披露内容的方法提供的治疗还可涵盖减缓癌症的进展。例如,这些方法可通过增强T细胞活性或针对癌症的免疫应答,减少肿瘤或癌症生长,减少肿瘤细胞转移,增加肿瘤或癌细胞的细胞死亡等而治疗癌症。在示例性方面中,方法借助于延迟癌症发作或复发1天、2天、4天、6天、8天、10天、15天、30天、两个月、4个月、6个月、1年、2年、4年或更长时间而进行治疗。在示例性方面中,这些方法借助于增加受试者的存活而治疗。在各个方面,由本披露的方法提供的治疗提供根据实体瘤缓解评估标准(RECIST)或其他类似标准的治疗性缓解。RECIST是由美国国家癌症研究所、加拿大国家癌症研究所临床试验组和欧洲癌症研究和治疗组织共同建立的一组评估肿瘤和/或癌细胞的进展、稳定化或应答性的标准。根据RECIST,在评估(例如,临床试验)的开始测量某些肿瘤,以为与用药物治疗后作比较提供基线。Eisenhauer等人,Eur J Cancer[欧洲癌症杂志]45:228-247(2009)和Litière等人,Journal of Clinical Oncology[临床肿瘤学杂志]37(13):1102-1110(2019)DOI:10.1200/JCO.18.01100发表了肿瘤的缓解评定和评估标准。在各种情况下,本披露的方法提供的治疗提供根据修改的RECIST肿瘤缓解评估的治疗性缓解,如下:
CR=完全缓解;NA=不可用;ND=未完成;PR=部分缓解;RECIST=
实体瘤缓解评估标准;UE=无法评估
a相对于基线评估的减少。相对于最低点评估的增加。
b缓解:CR和PR需要≥4周后进行确认评估,也可以等到下一次计划的成像
c进展:疾病进展需要在观察到初始放射学疾病进展后4至6周进行确认评估
d仅具有非指标病灶的受试者
因此,本文提供了用于以下的方法:减缓受试者中DLL3阳性癌症的进展,增强受试者中针对DLL3阳性癌症的T细胞活性或免疫应答,减少受试者中DLL3阳性肿瘤或DLL3阳性癌症的生长,减少受试者中DLL3阳性肿瘤细胞的转移,增加受试者中DLL3阳性肿瘤或癌细胞的细胞死亡,延迟受试者中DLL3阳性癌症的发作或复发和/或增加受试者的存活。此外,还提供了治疗DLL3阳性癌症以在受试者中提供根据修改的RECIST1.1的完全缓解(CR)、部分缓解(PR)或疾病稳定(SD)的方法。在各个方面,该方法包括向受试者施用根据本披露的抗DLL3药剂和抗PD-1抗体。例如,在各个方面,该方法包括施用包含SEQ ID NO:13和23的氨基酸序列的抗DLL3药剂和包含SEQ ID NO:38和39的氨基酸序列的抗PD-1抗体,其中抗DLL3药剂以0.3mg至30mg或3mg至100mg的剂量每两周一次施用,并且其中抗PD-1抗体以480mg的剂量每四周一次施用。在各种情况下,抗DLL3药剂根据以下计划以28天的周期施用:a)第1周期第1天的第一剂量0.3mg或1mg,b)第1周期第8天的第二剂量,c)第1周期第15天的第三剂量,和d)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量,其中第二、第三和后续剂量相同,各自为0.3mg至30mg或3mg至100mg,并且高于第一剂量,并且其中抗PD-1抗体以480mg的剂量每四周一次施用。在各个方面,该方法包括施用包含SEQ ID NO:13和23的氨基酸序列的抗DLL3药剂和监管机构(例如FDA或EMA)批准的抗PD-1抗体,其中抗DLL3药剂以0.3mg至30mg或3mg至100mg的剂量每两周一次施用,并且其中抗PD-1抗体以监管机构批准的剂量施用。
“约”或“大约”与可测量的数值变量结合使用时,指变量的指示值和变量的所有值,这些值在指示值的实验误差范围内(例如,在平均值的95%置信区间内)或指示值的±10%,以较大者为准。数字范围包括定义该范围的数字。
“第一阶梯剂量”当与施用抗DLL3药剂以治疗癌症(例如,SCLC)相关使用时,是指抗DLL3药剂在阶梯剂量计划或方案中的初始剂量。通常,第一阶梯剂量等于或低于观察到第一剂量效应(例如,细胞因子释放综合征(CRS))时的剂量。如本领域所知,可通过对安全性和药代动力学数据的建模和模拟来确定第一阶梯剂量。例如,第一阶梯剂量可以是抗DLL3药剂的最大耐受剂量(MTD),其中未观察到CRS或低于某个等级(例如,2级)的CRS。
“目标剂量”当关于用于治疗癌症(例如SCLC)的抗DLL3药剂的施用时,是指达到抗DLL3药剂的目标效应(例如,改善或降低SCLC的严重程度,或缩短SCLC的长度)的剂量。
“阶梯剂量”当与施用抗DLL3药剂以治疗癌症(例如,SCLC)相关使用时,是指阶梯剂量计划或方案中高于先前施用抗DLL3药剂剂量的剂量。阶梯剂量包括从第一阶梯剂量增加达到目标剂量的一个或多个剂量。
2.靶向DLL3的药剂
DLL3是一种非典型Notch配体,主要在胚胎发育过程中(在体节发生过程中起作用)表达。DLL3在正常组织的高尔基体中积累(Geffers等人,J Cell Biol.[细胞生物学杂志]178:465-476(2007))。通过分析DLL3在28例SCLC肿瘤和一大批正常组织中的差异表达,DLL3被鉴定为肿瘤相关抗原和是基于T细胞治疗的引人注目的靶标(研究123658)。
人DLL3蛋白包含八个胞外结构域:信号肽、N-末端、DSL、EGF1、EGF2、EGF3、EGF4、EGF5和EGF6。人DLL3、EGF3结构域、EGF4结构域以及组合的EGF3和EGF4结构域的氨基酸序列在序列表中分别显示为SEQ ID NO:28、29、30和31。
靶向DLL3的示例性药剂是结合DLL3和CD3的双特异性T细胞接合抗原结合多肽,例如分子。/>分子是由两个柔性连接的结合结构域制成的重组蛋白,每个结构域都源自抗体。/>分子的一个结合结构域对肿瘤相关表面抗原(例如DLL3)是特异性的;第二结合结构域对CD3(T细胞上的T细胞受体复合物的亚基)具有特异性。通过其特定设计,抗体构建体独特地适合于将T细胞与靶细胞瞬时连接,并且同时强有力地激活T细胞对靶细胞的固有细胞溶解潜力。参见例如,WO 99/54440、WO 2005/040220、和WO 2008/119567。
因此,在一些实施例中,所描述的靶向DLL3的药剂包含两个结合结构域:第一结构域与DLL3(优选地人DLL3)结合,并且第二结构域与CD3(优选地人CD3)结合。优选地,第一结构域与包含在SEQ ID NO:31的氨基酸序列内的DLL3的表位结合。更优选地,第一结构域与包含在SEQ ID NO:29的氨基酸序列内的DLL3的表位结合。
在某些实施例中,DLL3结合结构域包含(a)重链可变区(VH),所述重链可变区包含:(i)VH互补性决定区1(CDR-H1),其包含SEQ ID NO:1的氨基酸序列;(ii)CDR-H2,其包含SEQ ID NO:2的氨基酸序列;以及(iii)CDR-H3,其包含SEQ ID NO:3的氨基酸序列;和(b)轻链可变区(VL),该轻链可变区包含:(i)VL互补性决定区1(CDR-L1),其包含SEQ ID NO:4的氨基酸序列;(ii)CDR-L2,其包含SEQ ID NO:5的氨基酸序列;以及(iii)CDR-L3,其包含SEQID NO:6的氨基酸序列。
在某些实施例中,DLL3结合结构域包含:包含SEQ ID NO:7的氨基酸序列的VH和包含SEQ ID NO:8的氨基酸序列的VL。在某些优选的实施例中,DLL3结合结构域包含:包含SEQID NO:11的氨基酸序列的VH和包含SEQ ID NO:12的氨基酸序列的VL。
在一些实施例中,VH和VL通过接头连接以形成单链Fv(scFv)。在一些实施例中,接头是包含选自SEQ ID NO:42-50中任一个的序列的肽接头。在一些实施例中,接头是GS接头,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO:43)或其聚合物,即(Gly4Ser)x,其中x是1或更大的整数(例如,2或3)(例如,SEQ ID NO:49、50)。
在某些实施例中,DLL3结合结构域包含SEQ ID NO:9的氨基酸序列。在某些优选的实施例中,DLL3结合结构域包含SEQ ID NO:13的氨基酸序列。
在某些实施例中,CD3结合结构域包含:(a)VH,其包含:包含SEQ ID NO:18的氨基酸序列的CDR-H1,包含SEQ ID NO:19的氨基酸序列的CDR-H2,和包含SEQ ID NO:20的氨基酸序列的CDR-H3;和VL,其包含:包含SEQ ID NO:15的氨基酸序列的CDR-L1,包含SEQ IDNO:16的氨基酸序列的CDR-L2,以及包含SEQ ID NO:17的氨基酸序列的CDR-L3。
在某些实施例中,CD3结合结构域包含:包含SEQ ID NO:21的氨基酸序列的VH和包含SEQ ID NO:22的氨基酸序列的VL。在一些实施例中,VH和VL通过接头连接以形成单链Fv(scFv)。在一些实施例中,接头是包含选自SEQ ID NO:42-50中任一个的序列的肽接头。在一些实施例中,接头是GS接头,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO:43)或其聚合物,即(Gly4Ser)x,其中x是1或更大的整数(例如,2或3)。
在某些实施例中,CD3结合结构域包含SEQ ID NO:23的氨基酸序列。
在某些实施例中,DLL3结合结构域和CD3结合结构域通过接头连接。在一些实施例中,接头是包含选自SEQ ID NO:42-50中任一个的序列的肽接头。在一些实施例中,接头是GS接头,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO:43)或其聚合物,即(Gly4Ser)x,其中x是1或更大的整数(例如,2或3)。
在某些实施例中,本文公开的抗DLL3药剂包含两个结构域。第一结构域与DLL3(优选地人DLL3)结合并且包含(a)重链可变区(VH),所述重链可变区包含:(i)VH互补性决定区1(CDR-H1),其包含SEQ ID NO:1的氨基酸序列;(ii)CDR-H2,其包含SEQ ID NO:2的氨基酸序列;以及(iii)CDR-H3,其包含SEQ ID NO:3的氨基酸序列;和(b)轻链可变区(VL),该轻链可变区包含:(i)VL互补性决定区1(CDR-L1),其包含SEQ ID NO:4的氨基酸序列;(ii)CDR-L2,其包含SEQ ID NO:5的氨基酸序列;以及(iii)CDR-L3,其包含SEQ ID NO:6的氨基酸序列。第二结构域与CD3(优选地人CD3)结合并且包含(a)VH,所述VH包含:(i)包含SEQ ID NO:18的氨基酸序列的CDR-H1,(ii)包含SEQ ID NO:19的氨基酸序列的CDR-H2,和(iii)包含SEQ ID NO:20的氨基酸序列的CDR-H3;和(b)VL,其包含:(i)包含SEQ ID NO:15的氨基酸序列的CDR-L1,(ii)包含SEQ ID NO:16的氨基酸序列的CDR-L2,以及(iii)包含SEQ ID NO:17的氨基酸序列的CDR-L3。
在某些实施例中,本文所述的抗DLL3药剂包含两个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含:包含SEQ ID NO:7的氨基酸序列的VH和包含SEQ ID NO:8的氨基酸序列的VL;和(b)第二结构域与CD3(优选地人CD3)结合并且包含:包含SEQ ID NO:21的氨基酸序列的VH和包含SEQ ID NO:22的氨基酸序列的VL。在某些优选的实施例中,本文所述的抗DLL3药剂包含两个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含:包含SEQ ID NO:11的氨基酸序列的VH和包含SEQ ID NO:12的氨基酸序列的VL;和(b)第二结构域与CD3(优选地人CD3)结合并且包含:包含SEQ ID NO:21的氨基酸序列的VH和包含SEQ ID NO:22的氨基酸序列的VL。
在某些实施例中,本文所述的抗DLL3药剂包含两个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含SEQ ID NO:9的氨基酸序列,(b)第二结构域与CD3(优选地人CD3)结合并且包含SEQ ID NO:23的氨基酸序列。在某些实施例中,本文所述的抗DLL3药剂包含两个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含SEQ ID NO:13的氨基酸序列,(b)第二结构域与CD3(优选地人CD3)结合并且包含SEQ ID NO:23的氨基酸序列。
在某些实施例中,本文所述的抗DLL3药剂包含SEQ ID NO:10的氨基酸序列。在某些实施例中,本文所述的抗DLL3药剂包含SEQ ID NO:14的氨基酸序列。
在某些实施例中,本文所述的抗DLL3药剂进一步包含延长或增强抗DLL3药剂的血清半衰期的第三结构域。在某些实施例中,第三结构域包含由接头连接的两个多肽,每个肽包含人IgG的铰链、CH2和CH3结构域。在某些实施例中,第三结构域按N端至C端的顺序包含:铰链-CH2-CH3-接头-铰链-CH2-CH3。在一些实施例中,接头是GS接头,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO:43)或其聚合物,即(Gly4Ser)x,其中x是1或更大的整数(例如,6)。在某些实施例中,第三结构域包含选自SEQ ID NO:51-58中任一个的氨基酸序列。
在某些实施例中,DLL3结合结构域和CD3结合结构域通过第一接头连接以形成肽,该肽通过第二接头连接到第三结构域。在某些实施例中,第一接头是肽接头,其包含选自SEQ ID NO:42-50中任一个的序列,并且第二接头包含选自SEQ ID NO:42、43、45、46、47、49和50中任一个的序列。在一些实施例中,第一接头是GS接头,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO:42)或其聚合物,即(Gly4Ser)x,其中x是1或更大的整数(例如,2或3)并且第二接头包含选自SEQ ID NO:42、43、45、46、47、49和50中任一个的序列。
在某些实施例中,本文所述的抗DLL3药剂包含三个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含SEQ ID NO:9的氨基酸序列,(b)第二结构域与CD3(优选地人CD3)结合并且包含SEQ ID NO:23的氨基酸序列以及(c)第三结构域包含选自SEQ ID NO:51-58中任一个的氨基酸序列。在某些实施例中,本文所述的抗DLL3药剂包含三个结构域:(a)第一结构域与DLL3(优选地人DLL3)结合并且包含SEQ ID NO:13的氨基酸序列,(b)第二结构域与CD3(优选地人CD3)结合并且包含SEQ ID NO:23的氨基酸序列以及(c)第三结构域包含选自SEQ ID NO:51-58中任一个的氨基酸序列。在某些实施例中,本文所述的抗DLL3药剂包含SEQ ID NO:27的氨基酸序列。在某些实施例中,本文所述的抗DLL3药剂包含SEQ IDNO:59的氨基酸序列。
本文所述的抗DLL3药剂可以通过本领域已知的重组DNA技术产生。例如,抗DLL3药剂可以通过这样的方法产生,其中包含编码本文所述抗DLL3药剂的核酸的宿主细胞(例如,中国仓鼠卵巢细胞)在允许抗DLL3表达的条件下培养然后从细胞培养物中回收表达的抗DLL3药剂。在各种实施例中,抗DLL3药剂是塔拉他单抗(tarlatamab)(国际药物非专利名称(INN):建议的INN:清单123,WHO药物信息34(2):395-397(2020)),也称为AMG 757。塔拉他单抗是免疫球蛋白scFv-scFv-scFc,抗[智人DLL3(δ样配体3)]和抗[智人CD3E(CD3ε,Leu-4)],单克隆抗体单链(scFv)2-scFc,双特异性;IG单链scFv-scFv-scFc,抗DLL3和抗CD3E(1-982)[scFv-VH-V-κ抗DLL3(1-241)[VH(智人IGHV4-59*01G49>C(44)(96.9%)-(IGHD)-IGHJ4*01(100%))CDR-IMGT[8.7.12](26-33.51-57.96-107)(1-118)-15-mer三(四甘氨酰-丝氨酰)接头(119-133)-V-KAPPA(智人IGKV3-20*01(91.7%)-IGKJ2*01Q120>C(234)(90.9%))CDRIMGT[7.3.9](160-166.184-186.223-231)(134-241)]-6-mer丝氨酰-四甘氨酰-丝氨酰接头(242-247)-scFv-VH-V-λantiCD3E(248-496)[VH(小家鼠IGHV10-1*02(91.9%)-(IGHD)-IGHJ3*01(86.7%)/智人IGHV3-73*01(87.0%)-(IGHD)-IGHJ5*01(100%))CDR-IMGT[8.10.16](273-280.298-307.346-361)(248-372)-15-mer-三(四甘氨酰-丝氨酰)接头(373-387)-V-LAMBDA(智人IGLV7-43*01(85.1%)-IGLJ3*02(100%))CDR-IMGT[9.3.9](413-421.439-441.478-486)(388-496)]-4-mer-四甘氨酰接头(497-500)-scFc(h-CH2-CH3)-(h-CH2-CH3)(501-982)[智人IGHG1*03h-CH2-CH3,nG1m1(铰链6-15(501-510),CH2 R83>C(572),N84.4>G(577),V85>C(582)(511-620),CH3 E12(636),M14(638)(621-725),CHS>del)(501-725)-30-mer六(四甘氨酰-丝氨酰)接头(726-755)-智人IGHG1*03h-CH2-CH3,nG1m1(铰链6-15(756-765),CH2 R83>C(827),N84.4>G(832),V85>C(837)(766-875),CH3 E12(891),M14(893)(876-980),CHS(981-982))(756-982)]],非糖基化,由中国仓鼠卵巢(CHO)细胞产生;免疫调节剂,抗肿瘤药。
3.靶向PD-1的药剂
程序性细胞死亡蛋白1(PD-1),也称为CD279、SLEB2和hSLE1,是跨膜蛋白,表达于活化的T细胞、自然杀伤细胞(NK)和B淋巴细胞、巨噬细胞、树突状细胞(DC)和单核细胞上。值得注意的是,PD-1在肿瘤特异性T细胞上高度表达(Han等人,Am J Cancer Res[美国癌症研究杂志]10(3):727-742(2020))。PD-1与B7蛋白家族成员、PD-1配体1(PD-L1;也称为CD279和B7-H1)和PD-1配体2(也称为PD-L2、CD273和B7-DC)结合。PD-L1在T细胞和B细胞、巨噬细胞和树突状细胞上组成型表达,而PD-L2表达通常仅限于活化的DC和巨噬细胞(Xing等人,Oncoimmunology[肿瘤免疫学]7(3):e1356144(2017)(doi:10.1080/2162402X.2017.1356144))。PD-1抑制适应性和先天性免疫应答。PD-1/PD-L1轴与癌症中T细胞免疫应答的抑制有关。已在临床上在许多实体瘤适应症中证实此路径的拮抗剂。PD-1抑制剂纳武单抗、派姆单抗和西米普利单抗(cemiplimab)以及PD-L1抑制剂阿特珠单抗(atezolizumab)、阿维鲁单抗(avelumab)和德瓦鲁单抗(durvalumab)靶向PD-1/PD-L1通路,并且每一种都已获得美国食品药品监督管理局(FDA)和/或欧洲药品管理局(EMA)批准用于治疗各种癌症。靶向PD-1的其他示例性药剂包括替雷利珠单抗(tislelizumab)、多星单抗(dostarlimab)、笔普利单抗(penpulimab)、信迪利单抗(sintilimab)、特瑞普利单抗(toripalimab)、多星单抗(dostarlimab)、卡瑞利珠单抗(camrelizumab)、津贝利单抗(zimberelimab)和普罗戈利单抗(prolgolimab)。在某些实施例中,可用于本文披露的治疗的PD-1靶向剂是纳武单抗、派姆单抗、塞米普利单抗(cemiplimab)、替雷利珠单抗、多星单抗、笔普利单抗、信迪利单抗、特瑞普利单抗、多星单抗、卡瑞利珠单抗、津贝利单抗或普罗戈利单抗。在某些实施例中,PD-1靶向剂是纳武单抗,派姆单抗、塞米普利单抗、替雷利珠单抗或信迪利单抗。在某些实施例中,PD-1靶向剂是纳武单抗或派姆单抗。
靶向PD-1的其他示例性药剂包括国际公布号WO 2019/140196(其全部内容通过引用并入本文)中描述的PD-1抗原结合蛋白(例如,抗PD-1抗体、其抗原结合抗体片段,和抗PD-1抗体蛋白产物)。在示例性方面,PD-1抗原结合蛋白结合人PD-1,其具有在美国国家生物技术信息中心(NCBI)参考序列号NP_005009.2或SEQ ID NO:60中描述的氨基酸序列,或其由SEQ ID NO:60的氨基酸21-288代表的成熟形式(例如,缺乏信号肽)。在示例性方面,PD-1抗原结合蛋白结合食蟹猴PD-1,其具有NCBI参考序列号NP_001271065.1或SEQ ID NO:61中描述的氨基酸序列,或其成熟形式。在示例性实例中,PD-1抗原结合蛋白与人PD-1和食蟹猴PD-1两者结合。在示例性实施例中,抗PD-1抗体包含SEQ ID NO:32-37的氨基酸序列。在示例性实施例中,抗PD-1抗体包含SEQ ID NO:32-37的六个CDR氨基酸序列。在示例性实施例中,抗PD-1抗体包含SEQ ID NO:32的重链(HC)互补决定区(CDR)1氨基酸序列、SEQ IDNO:33的HC CDR2氨基酸序列、SEQ ID NO:34的HC CDR3氨基酸序列、SEQ ID NO:35的轻链(LC)CDR1氨基酸序列、SEQ ID NO:36的LC CDR2氨基酸序列和SEQ ID NO:37的LC CDR3氨基酸序列。在某些实施例中,抗PD-1抗体包含PD-1结合结构域,该PD-1结合结构域包含(a)重链可变区(VH),该重链可变区包含:(i)VH互补性决定区1(CDR-H1),其包含SEQ ID NO:32的氨基酸序列;(ii)CDR-H2,其包含SEQ ID NO:33的氨基酸序列;以及(iii)CDR-H3,其包含SEQ ID NO:34的氨基酸序列;和(b)轻链可变区(VL),该轻链可变区包含:(i)VL互补性决定区1(CDR-L1),其包含SEQ ID NO:35的氨基酸序列;(ii)CDR-L2,其包含SEQ ID NO:36的氨基酸序列;以及(iii)CDR-L3,其包含SEQ ID NO:37的氨基酸序列。在某些实施例中,PD-1结合结构域包含:包含SEQ ID NO:38的氨基酸序列的VH和包含SEQ ID NO:39的氨基酸序列的VL。在某些实施例中,抗PD-1抗体包含:包含SEQ ID NO:38的氨基酸序列的VH和包含SEQ IDNO:39的氨基酸序列的VL。在某些优选的实施例中,抗PD-1抗体包含:包含SEQ ID NO:40的氨基酸序列的HC和包含SEQ ID NO:41的氨基酸序列的LC。在各种情况下,抗PD-1抗体是泽鲁伐利单抗(zeluvalimab)(国际药物非专利名称(INN):建议的INN:清单124,WHO药物信息34(4):929-1102(2020)),也称为AMG 404。泽鲁伐利单抗是免疫球蛋白G1-κ,抗[智人PDCD1(程序性细胞死亡1,PD-1,PD1,CD279)],包含γ1重链的单克隆抗体(1-450)[VH(智人IGHV3-23*03(92.8%)-(IGHD)-IGHJ3*01(92.3%))CDR-IMGT[8.8.13](26-33.50-58.97-109)(1-120)-智人IGHG1*03v,G1m3>G1m17,nG1m1(CH1 R120>K(217)(121-218),铰链1-15(219-233),CH2 R83>C(295),N84.4>G(300),V85>C(305)(234-343),CH3 E12(359),M14(361)(344-448),CHS(449-450))(121-450)],(223-214')-与κ轻链(1'-214')[V-KAPPA(H智人IGKV1-12*01(96.8%)-IGKJ4*01(100%))CDR-IMGT[6.3.9](27-32.50-52.89-97)(1'-107')-智人IGKC*01(100%),Km3 A45.1(153),V101(191)(108'-214')]的二硫化物;二聚体(229-229”:232-232”)-双二硫化物,在中国仓鼠卵巢(CHO)细胞中产生,非糖基化免疫调节剂,抗肿瘤药。
3.使用靶向DLL3和PD-1的药剂的给药方案
本文披露了治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用靶向DLL3和PD-1的药剂的组合。靶向DLL3的药剂包括本文披露的抗DLL3药剂,靶向PD-1的药剂包括本文披露的抗PD-1抗体。在一个实施例中,本文披露了治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体的组合,其中抗DLL3药剂以约0.3mg至约30mg或约3mg至约100mg的剂量每两周一次施用。在各种实施例中,抗PD-1抗体是纳武单抗、派姆单抗、泽鲁伐利单抗(zeluvalimab)、或替雷利珠单抗。在某些实施例中,DLL3阳性癌症是小细胞肺癌(SCLC)。在某些实施例中,SCLC是复发性/难治性SCLC(RRSCLC)或广泛性疾病SCLC(ED SCLC)。在某些实施例中,受试者是患有SCLC(例如,RR SCLC或ED SCLC)的人。在某些实施例中,SCLC在至少一种先前的基于铂的治疗后在受试者中复发。
在某些实施例中,抗DLL3药剂以如下剂量每两周一次施用:约0.3mg至约30mg、约1mg至约30mg、约3mg至约30mg或约10mg至约30mg。在某些实施例中,抗DLL3药剂以约0.3mg、1mg、3mg、10mg、25mg或30mg的剂量每两周一次施用。
在某些实施例中,抗DLL3药剂以如下剂量每两周一次施用:约3mg至约100mg、约10mg至约100mg或约30mg至约100mg。在某些实施例中,抗DLL3药剂以约3mg,10mg、25mg、30mg、50mg、75mg或100mg的剂量每两周一次施用。
抗DLL3药剂可由任何合适的方式施用,包括肠胃外、肺内、鼻内和/或病灶内施用。肠胃外施用包括肌肉内、静脉内、动脉内、腹膜内或皮下施用。在一些实施例中,抗DLL3药剂通过静脉内(IV)输注(例如短静脉内输注(大约60分钟)),每两周一次施用。
在其中以上述剂量施用抗DLL3药剂的一些实施例中,抗PD-1抗体是泽鲁伐利单抗并且抗PD-1抗体以480mg剂量每四周一次施用。在某些实施例中,抗DLL3药剂和泽鲁伐利单抗以28天的周期施用,并且两种药剂都可以在第1周期的第1天施用。为了减轻AMG 757的第一剂量效应(例如,细胞因子释放综合征(CRS))的可能风险(在第1周期第1天组合抗PD-1抗体可能会加剧这种效应),抗PD-1抗体可在第1周期第8天或第15天施用。因此,在某些实施例中,抗DLL3药剂在28天周期的第1天和第15天施用,并且抗PD-1抗体在28天周期的第1天、第8天或第15天施用。
在此类28天周期给药方案的某些实施例中,抗DLL3药剂在第1天和第15天施用,泽鲁伐利单抗在第1周期的第1天、第8天或第15天施用,然后在从第2周期开始的第1天或第15天及之后施用。在此类实施例中,如果在第1周期的第1天或第8天施用泽鲁伐利单抗,则在从第2周期开始的第1天及之后施用该抗体;可替代地,如果在第1周期的第15天施用泽鲁伐利单抗,则在从第2周期开始的第15天及之后施用该抗体。
其他已知的抗PD-1抗体(例如,派姆单抗和纳武单抗)也可以在本文披露的方法中与抗DLL3药剂组合使用。当组合使用时,这些其他抗PD-1抗体的剂量和方案与监管机构(例如FDA)批准的相同。例如,如实例1中所述,在SCLC患者的临床研究中,抗DLL3药剂与派姆单抗联合使用,其中派姆单抗以200mg的剂量每三周施用。因此,在其中以上述剂量施用抗DLL3药剂的一些实施例中,抗PD-1抗体是派姆单抗并且抗PD-1抗体以200mg剂量每三周一次施用。在其中以上述剂量施用抗DLL3药剂的一些实施例中,抗PD-1抗体是纳武单抗并且抗PD-1抗体以240mg剂量每两周一次施用。在其中以上述剂量施用抗DLL3药剂的一些实施例中,抗PD-1抗体是替雷利珠单抗并且抗PD-1抗体以200mg剂量每三周一次施用。
在其中每两周一次施用抗DLL3药剂和每三周一次施用抗PD-1抗体的实施例中,抗PD-1抗体可以在第1周期的第15天开始,以尽量最小化第一剂量效应(例如,CRS)。因此,在某些实施例中,其中施用抗DLL3药剂和抗PD-1抗体的第一周期是28天的周期,抗DLL3药剂在第1天和第15天施用并且抗PD-1抗体在第15天施用,此后,每两周一次施用抗DLL3药剂,并且每三周一次施用抗PD-1抗体。
抗PD-1抗体可以通过任何合适的方式施用,包括肠胃外。在一些实施例中,取决于抗体通过每两周一次、每三周一次或每四周一次静脉内IV输注来施用抗PD-1抗体。
如本文所用,“组合疗法”或“与...组合”是指除了一种治疗方式(例如,抗PD-1抗体)之外还施用另一种治疗方式(例如,抗DLL3药剂)。因此,“组合疗法”或“与...组合”是指在将一种治疗方式施用给个体(例如,患有SCLC的人)之前、期间或之后施用另一种治疗方式。然而,组合疗法不包括在一种治疗方式的施用结束和另一种治疗方式开始之间已经过去28天或更长时间的情况。
3.1阶梯给药
由于其作用机制,受试者在初始输注AMG 757后可能处于第一剂量效应(例如CRS)的风险增加,与抗PD-1抗体组合可能会加剧这种风险。为了减轻风险,可以实施阶梯给药方案。例如,如果受试者经历第一剂量效应(例如,CRS),则可确定并实施不超过观察到CRS事件的剂量的适当的第一剂量。也可以确定和实施一个或多个阶梯剂量,直到达到目标剂量。这些剂量和给药计划能以对于AMG 757可用的新出现的药代动力学和安全性数据和信息为指导。
下表显示了28天周期中抗DLL3药剂(例如,AMG 757)的示例性阶梯给药计划(仅第1周期),此后每两周一次施用抗DLL3药剂。
表1.示例性单和多阶梯给药计划(仅第1周期)
*:此后每2周以与第15天的相同剂量施用AMG 757
**:根据当前研究以及正在进行的FIH研究(20160323)中新出现的药代动力学、药效学和安全性数据,在两阶梯给药中在第4天的阶梯剂量(选项1)或在三阶梯给药中在第8天的阶梯剂量可以等于目标剂量。
因此,本文披露了治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中抗DLL3药剂根据阶梯给药计划(例如上面表1中列出的那些)施用。抗PD-1抗体可以是纳武单抗、派姆单抗、泽鲁伐利单抗或替雷利珠单抗。例如,在对AMG 757实施阶梯给药方案的各种实施例中,抗PD-1抗体是泽鲁伐利单抗并以480mg的剂量每四周一次施用。
在某些实施例中,根据一阶梯给药计划施用抗DLL3药剂。在此类实施例中,本文披露了治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中抗DLL3药剂根据以下计划以28天的周期施用:a)第1周期第1天的第一剂量约0.3mg或1mg,b)第1周期第8天的第二剂量,c)第1周期第15天的第三剂量,和d)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量,并且其中第二剂量、第三剂量和后续剂量相同,各自为约0.3mg至约30mg或约3mg至约100mg,并且高于第一剂量。在一些实施例中,抗PD-1抗体是泽鲁伐利单抗并且以约480mg的剂量每四周一次施用。在一些实施例中,抗PD-1抗体是以监管机构批准的剂量/方案施用的纳武单抗、派姆单抗或替雷利珠单抗。
在其中根据一阶梯给药计划施用抗DLL3药剂的某些实施例中,抗DLL3药剂的第一剂量是约0.3mg或1mg,第二剂量、第三剂量和后续剂量各自是:约0.3mg至约30mg、约1mg至约30mg、约3mg至约30mg或约10mg至约30mg。在某些实施例中,抗DLL3药剂的第一剂量是约0.3mg,第二剂量、第三剂量和后续剂量各自是约1mg、3mg、10mg、25mg或30mg。在某些实施例中,抗DLL3药剂的第一剂量是约1mg,第二剂量、第三剂量和后续剂量各自是约3mg、10mg、25mg或30mg。
在其中根据一阶梯给药计划施用抗DLL3药剂的某些实施例中,抗DLL3药剂的第一剂量是约0.3mg或1mg,第二剂量、第三剂量和后续剂量各自是约3mg至约100mg、约10mg至约100mg或约30mg至约100mg。在某些实施例中,第一剂量是约0.3mg,第二剂量、第三剂量和后续剂量各自是约1mg,10mg,25mg、30mg、50mg、75mg或100mg。在某些实施例中,第一剂量是约1mg,第二剂量、第三剂量和后续剂量各自是约10mg,25mg、30mg、50mg、75mg或100mg。
在某些实施例中,抗PD-1抗体是泽鲁伐利单抗并且在第1周期的第1天、第8天或第15天施用,然后在从第2周期开始的第1天或第15天及之后施用。如果在第1周期的第1天或第8天施用抗PD-1抗体,则在从第2周期开始的第1天及之后施用该抗体。可替代地,如果在第1周期的第15天施用泽鲁伐利单抗,则在第2周期的第15天及之后施用该抗体。
在某些实施例中,根据两阶梯给药计划施用抗DLL3药剂。因此,本文披露了治疗DLL3阳性癌症的方法,该方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中抗DLL3药剂根据下面的计划I或计划II以28天的周期施用,抗PD-1抗体以480mg剂量每四周一次施用,并且其中
计划I:a)第1周期第1天的第一剂量(第一阶梯剂量)0.3mg或1mg,b)第1周期第4天的第二剂量(阶梯剂量),c)第1周期第8天的第三剂量(阶梯剂量,等于目标剂量),d)第1周期第15天的第四剂量(目标剂量),和e)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量(目标剂量),并且其中第二剂量高于第一剂量,第三剂量、第四剂量及后续剂量相同,各自是约0.3mg至30mg或3mg至100mg,且高于第二剂量。或
计划II:a)第1周期第1天的第一剂量(第一阶梯剂量)0.3mg或1mg,b)第1周期第8天的第二剂量(阶梯剂量),c)第1周期第15天的第三剂量(阶梯剂量,等于目标剂量),和c)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量(目标剂量),并且其中第二剂量高于第一剂量,第三剂量及后续剂量相同,各自是约0.3mg至30mg或3mg至100mg,且高于第二剂量。
在某些实施例中,如果认为药代动力学和安全性数据令人满意,则上述计划I的第1周期第4天的阶梯剂量可以高于或等于目标剂量。但是,没有阶梯剂量或目标剂量超过100mg的量。相信这样的给药计划是有益的,因为它们可以导致改善的PD活性(例如,有助于快速达到所需的血清AMG 757水平)。
在某些实施例中,本文公开了治疗DLL3阳性癌症的方法,所述方法包括向需要的受试者施用抗DLL3药剂,其中根据三阶梯给药计划施用抗DLL3药剂。在此类实施例中,本文披露了治疗DLL3阳性癌症的方法,这些方法包括向有需要的受试者施用抗DLL3药剂和抗PD-1抗体,其中所述抗DLL3药剂根据以下计划以28天的周期施用:a)第1周期第1天的第一剂量(第一阶梯剂量)约0.3mg或1mg,b)第1周期第4天的第二剂量(阶梯剂量),c)第1周期第8天的第三剂量(阶梯剂量),d)第1周期第15天的第四剂量(阶梯剂量,等于目标剂量),和e)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量(目标剂量),并且其中第二剂量高于第一剂量,第三剂量高于第二剂量,第四剂量和后续剂量相同,各自是约0.3mg至约30mg或约3mg至约100mg,并且高于第三剂量,并且其中抗PD-1抗体是以上述剂量和计划施用的纳武单抗、派姆单抗、泽卢瓦利单抗或替雷利珠单抗。在某些实施例中,抗PD-1抗体是泽鲁伐利单抗并且以约480mg的剂量每四周一次施用。在其他实施例中,抗PD-1抗体是派姆单抗并且以200mg的剂量每三周一次施用。
在某些实施例中,如果认为药代动力学和安全性数据令人满意,则上述三阶梯给药方案的第1周期第8天的阶梯剂量可以等于目标剂量。相信这样的给药计划是有益的,因为它们有助于快速达到所需的血清AMG 757水平。
抗DLL3药剂和抗PD-1抗体可由任何合适的方式施用,包括肠胃外、肺内、鼻内和/或病灶内施用。肠胃外施用包括肌肉内、静脉内、动脉内、腹膜内或皮下施用。在一些实施例中,抗DLL3药剂通过IV输注施用,并且抗PD-1抗体通过IV输注施用。
在某些实施例中,DLL3阳性癌症是小细胞肺癌(SCLC)。在某些实施例中,SCLC是复发性/难治性SCLC(RR SCLC)或广泛性疾病SCLC(ED SCLC)。在某些实施例中,受试者是患有SCLC,例如,RR SCLC或ED SCLC的人。在某些实施例中,SCLC在至少一种先前的基于铂的化疗后在受试者中复发。
3.2另外的治疗剂
在一些实施例中,本文披露的方法进一步包括使用一种或多种另外治疗剂来预防、降低或减轻与施用抗DLL3药剂和抗PD-1抗体相关的副作用的风险。与使用抗DLL3药剂相关的主要副作用是CRS。可用于预防、降低或减轻CRS风险的一种或多种另外治疗剂包括皮质类固醇(例如,***)、液体(例如,盐水)、依那西普(例如,Enbrel)和抗IL6抗体(例如,托珠单抗或司妥昔单抗(siltuximab))。可以在AMG 757的所有第1周期剂量(包括所有阶梯剂量)之前通过IV施用***,可以在第1周期的所有AMG 757剂量后IV施用盐水(例如1升),并且可以根据需要(例如,受试者对IV流体无应答性)施用抗IL6抗体(托珠单抗或司妥昔单抗)。***的示例性剂量包括8mg/施用(最大24mg/天)。托珠单抗的示例性剂量包括8mg/kg(不超过800mg)。CRS的症状包括发烧、恶心、疲劳、头痛、肌痛、乏力,并且也可以使用可用于治疗这些症状的治疗剂(例如,用于发烧的对乙酰氨基酚/醋氨酚)。
抗PD-1抗体施用后的不良事件可能包括免疫相关不良反应,这些不良反应可能在第一治疗剂量后不久至最后一个治疗剂量后几个月发生。与抗PD-1抗体相关的免疫相关不良反应包括肺炎、结肠炎/腹泻、免疫介导的肝炎、肾上腺功能不全、肾炎和肾功能不全、脑病、皮疹、甲状腺功能减退、甲状腺功能亢进和糖尿病。一种或多种用于预防、降低或减轻此类免疫相关不良反应(例如,肺炎、结肠炎/腹泻、免疫介导的肝炎、肾上腺功能不全、肾炎和肾功能不全、脑病、皮疹、甲状腺功能减退、甲状腺功能亢进和糖尿病中的一种或多种)的另外治疗剂包括皮质类固醇(例如,强的松、氢化可的松和***)、胰岛素疗法(用于糖尿病)、甲状腺激素补充剂(用于甲状腺功能减退)和β-阻滞剂(例如,针对甲状腺功能亢进的阿替洛尔、***)。
因此,在某些实施例中,本文披露的方法进一步包括施用一种或多种选自皮质类固醇(例如,***、氢化可的松和***)、液体(盐水)、抗IL-6抗体(例如,托珠单抗或司妥昔单抗)、胰岛素疗法、甲状腺激素补充剂和β-阻滞剂(例如,阿替洛尔、***)的另外治疗剂。在某些实施例中,这些方法进一步包括施用一种或多种选自皮质类固醇(例如***)、液体(盐水)和托珠单抗或司妥昔单抗的另外治疗剂。在某些实施例中,皮质类固醇、液体和抗IL-6抗体(例如,托珠单抗或司妥昔单抗)中的一种或多种在其中施用AMG 757的第1周期中施用。
在其中施用一种或多种另外治疗剂的任何一种方法的某些实施例中,受试者是人。
4.制品
本文公开了包含如下的制品:(a)包含抗DLL3药剂的容器;和(b)包装插页,其中载有通过将抗DLL3药剂(例如AMG 757)与抗PD-1抗体(例如派姆单抗或AMG 404)组合施用来治疗受试者的DLL3阳性癌症(或治疗SCLC)的说明书,其中说明书指定抗DLL3药剂以约0.3mg至约30mg或约3mg至约100mg(或本文披露的任何剂量范围)的剂量每两周一次施用于受试者,例如在28天周期的第1天和第15天。在某些实施例中,制品进一步包括包含抗PD-1抗体的容器。
说明书还可以指定抗DLL3药剂按照以下计划以28天的周期施用:a)第1周期第1天的第一剂量0.3mg或1mg,b)第1周期第8天的第二剂量,c)第1周期第15天的第三剂量,和d)从第2周期第1天开始并且之后每两周一次的一个或多个后续剂量,第二剂量、第三剂量和后续剂量相同,各自是0.3mg至30mg或3mg至100mg(或本文披露的任何剂量范围),并且为高于第一剂量。
说明书还可以指定抗PD-1抗体在28天周期的第1天、第8天或第15天施用,例如抗PD-1抗体在第1周期的第1天,第8天或第15天施用,然后在从第2周期开始的第1天或第15天以及之后施用。说明书还可以指定,如果在第1周期的第1天或第8天施用抗PD-1抗体,则在从周期开始的第1天及之后施用该抗体;可替代地,如果在第1周期的第15天施用抗PD-1抗体,则在从周期开始的第15天及之后施用该抗体。
除了抗DLL3药剂和抗PD-1抗体外,说明书还可以进一步指定将一种或多种治疗剂施用于受试者。一种或多种治疗剂可以选自皮质类固醇(例如,***、***、氢化可的松)、盐水、依那西普和抗IL6抗体(托珠单抗或司妥昔单抗)。在某些实施例中,说明书指定***、盐水和抗IL6抗体(托珠单抗或司妥昔单抗)中的一种或多种在其中施用抗DLL3药剂的第一周期中施用。在某些实施例中,说明书指定了***在施用抗DLL3药剂的第一周期中进一步施用(例如,在抗DLL3药剂的第1周期给药前通过静脉内施用)。
5.受试者
在当前披露的方法的各种情况下,受试者是人受试者。在示例性实例中,人受试者患有小细胞肺癌(SCLC),任选地,组织学或细胞学证实的SCLC。在各个方面,人是患有SCLC的男性或女性和/或大于或等于18岁。在示例性方面,人受试者已经用基于铂的化疗治疗。在示例性方面,人受试者具有任选地在至少一种基于铂的化疗后进展或复发的RR SCLC。在示例性实例中,人受试者具有0-1的东部肿瘤协作组(ECOG)表现状态(Oken等人,Am J ClinOncol[美国临床肿瘤学杂志]5:649-655(1982)。在各个方面,人受试者具有一种或多种已被治疗的脑转移瘤。在各个方面,基于铂的化疗包括卡铂或顺铂、铂-依托泊苷或铂-伊立替康。
6.癌症
在各个方面,通过目前披露的方法治疗的癌症是DLL3阳性癌症。在各种情况下,通过目前披露的方法治疗的癌症是小细胞肺癌(SCLC)。在示例性方面,SCLC是组织学或细胞学证实的SCLC。任选地,SCLC可通过修改的实体瘤缓解标准(RECIST)1.1测量,其中可测量的病灶包括(a)具有清晰边界的非结节病灶,其可以在轴向平面的一个维度中准确且连续地测量(最长直径≥10mm,通过磁共振成像/计算机断层扫描(MRI/CT)测量,扫描切片厚度≤5mm)和/或(b)根据MRI/CT垂直于长轴(短轴)的最长直径≥15mm的结节病灶,和/或排除单纯性囊肿、胸膜/心包积液和腹水。
实例
实例1AMG 757与派姆单抗组合在患有SCLC的受试者中的安全性、耐受性、PK和抗肿瘤活性
在患有SCLC的受试者中使用AMG 757与派姆单抗组合进行了一项临床研究。该研究的主要目标是评估AMG 757当与派姆单抗组合施用时的安全性和耐受性,并确定AMG 757与派姆单抗组合施用时的最大耐受剂量(MTD)或推荐的2期剂量(RP2D)。该研究的次要目标是表征AMG 757当与派姆单抗组合施用时的PK,并评估AMG 757与派姆单抗体组合施用时的初步抗肿瘤活性。
下表总结了关键的合格标准
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AMG 757的起始剂量为每两周一次0.1mg IV。AMG 757的剂量递增如下:0.1mg、0.3mg、1mg、3mg、10mg、30mg和100mg通过IV每两周一次。派姆单抗的剂量固定为每3周200mgIV。在第1周期第15天施用第一剂量的派姆单抗。
截至2022年4月,8名受试者接受了AMG 757和派姆单抗的组合治疗。受试者接受每3周派姆单抗200mg IV给药,每2周AMG 757IV 0.1mg(N=5)或0.3mg(N=3)。在8名受试者中,3名受试者达到作为最佳总体缓解的疾病稳定,客观缓解率为0%,疾病控制率为37.5%。一名研究受试者在2020年6月AMG 757的第一剂量后继续接受治疗22个月,疾病稳定。
所有受试者都经历了至少一种治疗中出现的不良事件,其中最常见的是5/8(62.5%)的疲劳。一名受试者(0.3mg AMG 757)经历了与治疗相关的目的不良事件(等级≥3CRS)。没有受试者有导致治疗中止的一种或多种治疗中出现的不良事件。在受试者中探索的剂量下,没有记录到针对组合的致命不良事件。
实例3研究评估AMG 757与AMG 404组合在患有SCLC的受试者中的安全性和功效
目标和终点
下表总结了本研究(研究20200439)的目标和终点。
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研究设计
研究20200439是一项1b期、多中心、开放标签研究,评估AMG 757与AMG 404组合在患有SCLC的受试者中的安全性、耐受性、PK、PD和功效。该研究由剂量探索(第1部分)和剂量扩展(第2部分)组成。
该研究的剂量探索部分使用改良毒性概率区间(mTPI-2)设计估计了AMG 757与AMG 404组合的推荐的2期目标剂量。在达到MTD之前,可以根据新出现的安全性、功效和药效学数据来鉴定组合RP2D。
在整个研究过程中,AMG 404以每28天(±3天)480mg的剂量作为短期IV输注(30分钟)施用。AMG 757的起始剂量比正在进行的FIH研究(研究20160323)中确定的推荐的2期目标剂量低1个剂量水平。研究20160323中的计划剂量水平为0.003mg、0.01mg、0.03mg、0.1mg、0.3mg、1mg、3mg、10mg、30mg和100mg。在这项组合研究中,AMG 757的最高计划目标剂量不超过100mg。
为减轻CRS的风险并潜在地优化AMG 757的PD活性,将阶梯给药方法作为初始给药计划的一部分实施。根据研究20160323中选择的推荐2期目标剂量和相关给药计划,实施以下阶梯给药计划之一:一阶梯、两阶梯(选项1或选项2)或三阶梯。从第1周期第1天开始,以480mg的剂量施用AMG 404。基于新出现的安全性数据,可以调整给药计划以允许在第1周期第8天或第1周期第15天最初施用AMG 404。根据在第1周期的哪一天施用AMG 404,从第2周期开始,从第2周期第1天或第2周期第15天开始每4周施用AMG 404(注意,如果AMG 404最初在第1周期第8天施用,则第1周期第8天和第2周期第1天剂量之间有21天的间隔)。
第1部分可能包括以下一个或多个计划剂量水平的AMG 757与固定剂量的AMG 404组合(见图1):
·剂量队列水平1:从第1周期第1天开始,AMG 757(以低于推荐的2期目标剂量1个剂量水平,IV Q2W施用(阶梯给药)与AMG 404(每4周(Q4W)480mg IV)组合施用
·剂量队列水平2:从第1周期第1天开始,AMG 757(以推荐的2期目标剂量,IV Q2W施用(阶梯给药)与AMG 404(Q4W 480mg IV)组合施用
·剂量队列水平-1:从第1周期第8天开始,AMG 757(以低于推荐的2期目标剂量1个剂量水平,IV Q2W施用(阶梯给药)与AMG 404(480mg IV Q4W(如果不能很好地耐受剂量队列水平1))组合施用
·剂量队列水平-2:从第1周期第15天开始,AMG 757(以低于推荐的2期目标剂量1个剂量水平,IV Q2W施用(阶梯给药)与AMG 404(480mg IV Q4W(如果不能很好地耐受剂量队列水平-1))组合施用
·剂量队列水平-3:从第1周期第15天开始,AMG 757(以低于推荐的2期目标剂量2个剂量水平,IV Q2W施用(阶梯给药)与AMG 404(480mg IV Q4W(如果不能很好地耐受剂量队列水平-2))组合施用
根据新出现的PK、PD和安全性数据,可以探索替代(中间)剂量队列水平(包括在第1周期调整AMG404施用日期之前调整AMG 757的剂量,作为DLRM递减推荐的一部分),或一个或多个替代给药计划(包括AMG 757的另外阶梯给药策略)。
剂量递增/递减推荐以mTPI-2模型(Guo等人,2017)为指导,目标毒性概率为30%,等效毒性区间为(25%,33%),过量给药概率为95%。β(1,1)用作先验分布。
阶梯给药:在开始AMG 757治疗期间,受试者可能具有增加的细胞因子释放综合征风险。据信,最佳推荐的2期目标剂量可能需要对阶梯给药方法进行修改。此外,为了优化AMG 757和AMG 404的PD活性,可能需要对阶梯给药方法进行修改。
阶梯给药计划总结如下。按照基于新出现的安全性和PD数据的DLRT建议,剂量计划可以适合于包括一种或多种以下的措施:
·一阶梯给药,涉及第1天的第一阶梯剂量,随后是第8天的阶梯剂量(等于目标剂量)和第15天然后Q2W的目标剂量。
·两阶梯给药(选项1),涉及第1天的第一阶梯剂量,随后是第4天的阶梯剂量,第8天的阶梯剂量(等于目标剂量)和第15天然后Q2W的目标剂量。
·两阶梯给药(选项2),涉及第1天的第一阶梯剂量,随后是第8天的阶梯剂量,第15天的阶梯剂量(等于目标剂量)和在C2D1然后Q2W的目标剂量。
·三阶梯给药,涉及第1天的第一阶梯剂量,随后是第4天的阶梯剂量,第8天的阶梯剂量,第15天的阶梯剂量(等于目标剂量)和在C2D1然后Q2W的目标剂量。
如果认为PK、PD和安全性数据令人满意,则上述选项1的第1周期第4天的阶梯剂量可以高于或等于目标剂量。但是,没有阶梯剂量或目标剂量超过100mg的量。
第2部分(剂量扩展):完成研究的第1部分后,在第2部分开始招募,以确认所选剂量的安全性和耐受性,并进一步评估AMG 757与AMG 404组合的功效。
表2总结了20200439的合格标准
表2关键的合格标准
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截至2022年4月,在本研究中,5名受试者接受了AMG 757 10mg Q2W的1阶梯给药治疗和AMG 404 480mg Q4W治疗。两名受试者有未确认的部分缓解,一名完成了6个周期的治疗,另一名完成了2个周期的治疗。其余受试者处于治疗的第1周期。没有受试者出现大于2级的治疗中出现的不良事件。一名受试者发生了5级事件,该事件是由于潜在疾病且与治疗无关。没有受试者有导致治疗中止的一种或多种治疗中出现的不良事件。
根据在说明书内引用的参考文献的教导,将最彻底地理解本说明书。在说明书内的实施例提供了本发明的实施例的展示,并且不应构成对本发明范围的限制。技术人员很容易认识到,本发明涵盖了很多其他实施例。在本披露中引用的所有公开物、专利和序列通过引用以其全部内容进行结合。通过引用并入的材料在一定程度上与本说明书发生冲突或不一致时,本说明书将替代任何此类材料。在此的任何参考文献的引用都不是承认此类参考文献是本发明的现有技术。
本领域技术人员仅使用常规实验就将认识到或能够确定本文所述的本发明的特定实施例的许多等效物。此类等效实施例意在由以下实施例涵盖。
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Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
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Lys
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
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Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
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Gly Thr Lys Phe Leu Ala Pro
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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100 105
<210> 23
<211> 249
<212> PRT
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 24
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 24
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp 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
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 25
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 25
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp 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
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 26
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 26
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp 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
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 27
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 27
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp 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
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 28
<211> 618
<212> PRT
<213> 智人
<400> 28
Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gln Thr Val Ile Leu
1 5 10 15
Ala Leu Ile Phe Leu Pro Gln Thr Arg Pro Ala Gly Val Phe Glu Leu
20 25 30
Gln Ile His Ser Phe Gly Pro Gly Pro Gly Pro Gly Ala Pro Arg Ser
35 40 45
Pro Cys Ser Ala Arg Leu Pro Cys Arg Leu Phe Phe Arg Val Cys Leu
50 55 60
Lys Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly
65 70 75 80
Ala Ala Leu Ser Ala Arg Gly Pro Val Tyr Thr Glu Gln Pro Gly Ala
85 90 95
Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gln Val Pro Phe
100 105 110
Arg Asp Ala Trp Pro Gly Thr Phe Ser Phe Ile Ile Glu Thr Trp Arg
115 120 125
Glu Glu Leu Gly Asp Gln Ile Gly Gly Pro Ala Trp Ser Leu Leu Ala
130 135 140
Arg Val Ala Gly Arg Arg Arg Leu Ala Ala Gly Gly Pro Trp Ala Arg
145 150 155 160
Asp Ile Gln Arg Ala Gly Ala Trp Glu Leu Arg Phe Ser Tyr Arg Ala
165 170 175
Arg Cys Glu Pro Pro Ala Val Gly Thr Ala Cys Thr Arg Leu Cys Arg
180 185 190
Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys Ala
195 200 205
Pro Leu Glu Asp Glu Cys Glu Ala Pro Leu Val Cys Arg Ala Gly Cys
210 215 220
Ser Pro Glu His Gly Phe Cys Glu Gln Pro Gly Glu Cys Arg Cys Leu
225 230 235 240
Glu Gly Trp Thr Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser
245 250 255
Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys Leu Val
260 265 270
Pro Gly Pro Gly Pro Cys Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser
275 280 285
Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly Phe
290 295 300
Tyr Gly Leu Arg Cys Glu Val Ser Gly Val Thr Cys Ala Asp Gly Pro
305 310 315 320
Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp Pro Asp Ser Ala
325 330 335
Tyr Ile Cys His Cys Pro Pro Gly Phe Gln Gly Ser Asn Cys Glu Lys
340 345 350
Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly Leu Cys
355 360 365
Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala
370 375 380
Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala Cys
385 390 395 400
Ala Asn Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser
405 410 415
Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu Arg Ala Asp Pro
420 425 430
Cys Ala Ala Arg Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe
435 440 445
Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala Arg Cys
450 455 460
Glu Phe Pro Val His Pro Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro
465 470 475 480
Pro Gly Leu Arg Pro Gly Asp Pro Gln Arg Tyr Leu Leu Pro Pro Ala
485 490 495
Leu Gly Leu Leu Val Ala Ala Gly Val Ala Gly Ala Ala Leu Leu Leu
500 505 510
Val His Val Arg Arg Arg Gly His Ser Gln Asp Ala Gly Ser Arg Leu
515 520 525
Leu Ala Gly Thr Pro Glu Pro Ser Val His Ala Leu Pro Asp Ala Leu
530 535 540
Asn Asn Leu Arg Thr Gln Glu Gly Ser Gly Asp Gly Pro Ser Ser Ser
545 550 555 560
Val Asp Trp Asn Arg Pro Glu Asp Val Asp Pro Gln Gly Ile Tyr Val
565 570 575
Ile Ser Ala Pro Ser Ile Tyr Ala Arg Glu Val Ala Thr Pro Leu Phe
580 585 590
Pro Pro Leu His Thr Gly Arg Ala Gly Gln Arg Gln His Leu Leu Phe
595 600 605
Pro Tyr Pro Ser Ser Ile Leu Ser Val Lys
610 615
<210> 29
<211> 40
<212> PRT
<213> 智人
<400> 29
Ser Gly Val Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Leu Cys
1 5 10 15
Val Gly Gly Ala Asp Pro Asp Ser Ala Tyr Ile Cys His Cys Pro Pro
20 25 30
Gly Phe Gln Gly Ser Asn Cys Glu
35 40
<210> 30
<211> 37
<212> PRT
<213> 智人
<400> 30
Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly Leu Cys
1 5 10 15
Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala
20 25 30
Gly Pro Arg Cys Glu
35
<210> 31
<211> 78
<212> PRT
<213> 智人
<400> 31
Ser Gly Val Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Leu Cys
1 5 10 15
Val Gly Gly Ala Asp Pro Asp Ser Ala Tyr Ile Cys His Cys Pro Pro
20 25 30
Gly Phe Gln Gly Ser Asn Cys Glu Lys Arg Val Asp Arg Cys Ser Leu
35 40 45
Gln Pro Cys Arg Asn Gly Gly Leu Cys Leu Asp Leu Gly His Ala Leu
50 55 60
Arg Cys Arg Cys Arg Ala Gly Phe Ala Gly Pro Arg Cys Glu
65 70 75
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 32
Ser Tyr Asp Met Ser
1 5
<210> 33
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 33
Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 34
Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val
1 5 10
<210> 35
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 35
Arg Ala Ser Gln Gly Ile Ser Asn Trp Leu Ala
1 5 10
<210> 36
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 36
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 37
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 37
Gln Gln Ala Glu Ser Phe Pro His Thr
1 5
<210> 38
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 38
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu 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 Phe Cys
85 90 95
Ala Ser Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 39
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 39
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val 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
Phe Ala 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 Ala Glu Ser Phe Pro His
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 40
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu 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 Phe Cys
85 90 95
Ala Ser Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro 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 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys 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> 41
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val 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
Phe Ala 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 Ala Glu Ser Phe Pro His
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu
210
<210> 42
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 42
Gly Gly Gly Gly
1
<210> 43
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 43
Gly Gly Gly Gly Ser
1 5
<210> 44
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 44
Gly Gly Gly Gly Gln
1 5
<210> 45
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 45
Ser Gly Gly Gly Gly Ser
1 5
<210> 46
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 46
Pro Gly Gly Gly Gly Ser
1 5
<210> 47
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 47
Pro Gly Gly Asp Gly Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 48
Gly Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 49
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 49
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 50
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 50
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 51
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 51
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr
325 330 335
Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 52
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 52
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
325 330 335
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
<210> 53
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 53
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
325 330 335
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 54
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 54
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
<210> 55
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 55
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr
325 330 335
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 56
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 56
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
325 330 335
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
<210> 57
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 57
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
245 250 255
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
275 280 285
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
290 295 300
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
305 310 315 320
Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr
325 330 335
Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
340 345 350
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
370 375 380
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
385 390 395 400
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
405 410 415
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
420 425 430
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
435 440 445
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
450 455 460
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
465 470 475 480
Ser Pro Gly Lys
<210> 58
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 58
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
260 265 270
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
275 280 285
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
290 295 300
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
305 310 315 320
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
325 330 335
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
340 345 350
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
355 360 365
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
370 375 380
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
385 390 395 400
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
405 410 415
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
420 425 430
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
<210> 59
<211> 981
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 59
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp 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
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly
980
<210> 60
<211> 268
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 60
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly Leu Leu Gly Ser
145 150 155 160
Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys Ser Arg Ala Ala
165 170 175
Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro Leu Lys Glu Asp
180 185 190
Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly Glu Leu Asp Phe
195 200 205
Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro Cys Val Pro Glu
210 215 220
Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly Met Gly Thr Ser
225 230 235 240
Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg Ser Ala Gln Pro
245 250 255
Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
260 265
<210> 61
<211> 288
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 61
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Glu Ser Pro Asp Arg Pro Trp
20 25 30
Asn Ala Pro Thr Phe Ser Pro Ala Leu Leu Leu Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Ala Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Arg Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Ala Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys
180 185 190
Ser Arg Ala Ala Gln Gly Thr Ile Glu Ala Arg Arg Thr Gly Gln Pro
195 200 205
Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly
210 215 220
Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Ala Pro
225 230 235 240
Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly
245 250 255
Leu Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg
260 265 270
Ser Pro Arg Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
275 280 285
Claims (18)
1.一种治疗患有小细胞肺癌(SCLC)的受试者的方法,该方法包括向有需要的受试者施用包含SEQ ID NO:13和23的氨基酸序列的抗DLL3药剂、和抗PD-1抗体,其中该抗DLL3药剂以0.3mg至30mg或3mg至100mg的剂量每两周一次施用,并且其中该SCLC在至少一种先前的基于铂的化疗后在该受试者中复发。
2.如权利要求1所述的方法,其中该抗DLL3药剂以1mg至30mg的剂量每两周一次施用。
3.如权利要求1或2所述的方法,其中该抗DLL3药剂以3mg、10mg、25mg或30mg的剂量每两周一次施用。
4.如权利要求1所述的方法,其中该抗DLL3药剂以10mg至100mg的剂量每两周一次施用。
5.如权利要求1或4所述的方法,其中该抗DLL3药剂以10mg、25mg、30mg、50mg、75mg或100mg的剂量每两周一次施用。
6.如权利要求1-5中任一项所述的方法,其中该抗DLL3药剂在28天周期的第1天和第15天施用。
7.如权利要求6所述的方法,其中该抗PD-1抗体是纳武单抗、派姆单抗或泽鲁伐利单抗。
8.如权利要求7所述的方法,其中该抗PD-1抗体是派姆单抗,并且其中该派姆单抗以200mg的剂量每三周一次施用。
9.如权利要求7所述的方法,其中该抗PD-1抗体是纳武单抗,并且其中该纳武单抗以240mg的剂量每两周一次施用。
10.如权利要求7所述的方法,其中该抗PD-1抗体是泽鲁伐利单抗,并且其中该泽鲁伐利单抗以480mg的剂量每三周一次施用。
11.如权利要求8所述的方法,其中如果派姆单抗和该抗DLL3药剂两者在同一天施用,则派姆单抗在该抗DLL3药剂之前施用。
12.如权利要求1-11中任一项所述的方法,该方法进一步包括向该受试者施用一种或多种另外治疗剂。
13.如权利要求11所述的方法,其中该一种或多种另外治疗剂是皮质类固醇、盐水或托珠单抗。
14.如权利要求12所述的方法,其中该皮质类固醇是***。
15.如权利要求11-13中任一项所述的方法,其中该一种或多种另外治疗剂在其中施用该抗DLL3药剂的第1周期中施用。
16.如权利要求1-14中任一项所述的方法,其中该基于铂的化疗是铂-依托泊苷疗法。
17.如权利要求1-15中任一项所述的方法,其中通过静脉内输注施用该抗DLL3药剂。
18.如权利要求1-16中任一项所述的方法,其中该受试者是人。
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US202163186569P | 2021-05-10 | 2021-05-10 | |
US63/186,569 | 2021-05-10 | ||
PCT/US2022/028135 WO2022240688A1 (en) | 2021-05-10 | 2022-05-06 | Dosing regimen for combination therapy targeting dll3 and pd-1 |
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CN (1) | CN117377488A (zh) |
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CA (1) | CA3217141A1 (zh) |
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TWI793062B (zh) * | 2015-07-31 | 2023-02-21 | 德商安美基研究(慕尼黑)公司 | Dll3及cd3抗體構築體 |
EA201890530A1 (ru) * | 2015-08-20 | 2018-09-28 | ЭББВИ СТЕМСЕНТРКС ЭлЭлСи | Конъюгаты антитела к dll3 и лекарственного средства и способы их применения |
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- 2022-05-06 EP EP22808092.5A patent/EP4337252A1/en active Pending
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CA3217141A1 (en) | 2022-11-17 |
MX2023013227A (es) | 2024-01-29 |
TW202309092A (zh) | 2023-03-01 |
JP2024518947A (ja) | 2024-05-08 |
KR20240006585A (ko) | 2024-01-15 |
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