CN113045664B - 一种分离的结合抗原axl的蛋白及其用途 - Google Patents
一种分离的结合抗原axl的蛋白及其用途 Download PDFInfo
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- CN113045664B CN113045664B CN201911187949.6A CN201911187949A CN113045664B CN 113045664 B CN113045664 B CN 113045664B CN 201911187949 A CN201911187949 A CN 201911187949A CN 113045664 B CN113045664 B CN 113045664B
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Abstract
本申请提供一种分离的抗原结合蛋白,其包含氨基酸序列如SEQ ID NO:1所示的VH中的至少一个CDR;且包含氨基酸序列如SEQ ID NO:2所示的VL中的至少一个CDR。本申请还提供包含所述分离的抗原结合蛋白的免疫缀合物、编码所述分离的抗原结合蛋白的核酸、包含所述分离的抗原结合蛋白的载体、包含所述核酸或所述载体的细胞、制备所述分离的抗原结合蛋白的方法以及所述分离的抗原结合蛋白的用途。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种分离的结合抗原AXL的蛋白及其用途。
背景技术
AXL(受体酪氨酸激酶)是激酶的Tyro-3家族的成员,其可通过配体Gas6(与抗凝血因子蛋白S同源的70-kDa蛋白)的结合来激活。AXL激活导致通过PI-3-激酶/Akt(Franke等人,Oncogene 22:8983-8998,2003)和其他主要途径如Ras/Erk和β-联蛋白/TCF(Goruppi等人,Mol.Cell Biol.21:902-915,2001)的信号转导。
在肿瘤细胞中,AXL在调节细胞的侵袭和迁移中起重要作用。AXL的过度表达不仅与预后不良相关,也与乳房、结肠、食管癌、肝细胞、胃、神经胶质瘤、肺、黑色素瘤、骨肉瘤、卵巢、前列腺、横纹肌肉瘤、肾、甲状腺和子宫内膜癌中所报告的各种人癌症的侵袭增加相关(Linger R.M.Adv.Cancer Res.2008,100,35-83以及Verma A.Mol.Cancer Ther.(2011).10,1763-1773)。
鉴于AXL的治疗潜能,需要制备特异性结合AXL蛋白的抗体。
发明内容
一方面,本申请提供一种分离的抗原结合蛋白,其包含氨基酸序列SEQ ID NO:1所示的VH中的至少一个CDR;且包含氨基酸序列SEQ ID NO:2所示的VL中的至少一个CDR。
在某些实施方式中,本申请所述的分离的抗原结合蛋白具有下述性质中的一种或多种:
1)能够以1×10-7M或更低的KD与AXL蛋白相结合;
2)能够特异性识别在细胞表面表达的AXL蛋白;
3)结合在细胞表面表达的AXL蛋白后能够介导内化。
在某些实施方式中,所述AXL蛋白包括人AXL蛋白。
在某些实施方式中,所述人AXL蛋白包含SEQ ID NO:39所示的氨基酸序列。
在某些实施方式中,所述AXL蛋白包含细胞外结构域。
在某些实施方式中,所述细胞外结构域包含SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中,所述细胞包括肿瘤细胞。
在某些实施方式中,所述肿瘤包括AXL阳性肿瘤。
在某些实施方式中,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在某些实施方式中,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在某些实施方式中,所述细胞包括人的细胞。
在某些实施方式中,所述细胞选自下组:人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞和人多发性骨髓瘤RPMI8226细胞。
在某些实施方式中,所述VH包含HCDR1、HCDR2和HCDR3。
在某些实施方式中,所述HCDR1包含SEQ ID NO:25所示的氨基酸序列。
在某些实施方式中,所述HCDR2包含SEQ ID NO:26所示的氨基酸序列。
在某些实施方式中,所述HCDR3包含SEQ ID NO:27所示的氨基酸序列。
在某些实施方式中,所述VL包含LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述LCDR1包含SEQ ID NO:28所示的氨基酸序列。
在某些实施方式中,所述LCDR2包含SEQ ID NO:29所示的氨基酸序列。
在某些实施方式中,所述LCDR3包含SEQ ID NO:30所示的氨基酸序列。
在某些实施方式中,所述VH包含框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在某些实施方式中,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:7所示的氨基酸序列。
在某些实施方式中,所述H-FR1包含SEQ ID NO:11、15中任一项所示的氨基酸序列。
在某些实施方式中,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:8所示的氨基酸序列。
在某些实施方式中,所述H-FR2包含SEQ ID NO:12所示的氨基酸序列。
在某些实施方式中,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:9所示的氨基酸序列。
在某些实施方式中,所述H-FR3包含SEQ ID NO:13所示的氨基酸序列。
在某些实施方式中,所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO:10所示的氨基酸序列。
在某些实施方式中,所述H-FR4包含SEQ ID NO:14所示的氨基酸序列。
在某些实施方式中,所述VH包含SEQ ID NO:3、5中任一项所示的氨基酸序列。
在某些实施方式中,所述VL包含框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在某些实施方式中,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:16所示的氨基酸序列。
在某些实施方式中,所述L-FR1包含SEQ ID NO:20、24中任一项所示的氨基酸序列。
在某些实施方式中,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:17所示的氨基酸序列。
在某些实施方式中,所述L-FR2包含SEQ ID NO:21所示的氨基酸序列。
在某些实施方式中,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:18所示的氨基酸序列。
在某些实施方式中,所述L-FR3包含SEQ ID NO:22所示的氨基酸序列。
在某些实施方式中,所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO:19所示的氨基酸序列。
在某些实施方式中,所述L-FR4包含SEQ ID NO:23所示的氨基酸序列。
在某些实施方式中,所述VL包含SEQ ID NO:4、6中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
在某些实施方式中,所述抗体重链恒定区源自人IgG1重链恒定区或人IgG4重链恒定区。
在某些实施方式中,所述抗体重链恒定区包含SEQ ID NO:33、41中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含抗体轻链恒定区,且所述抗体轻链恒定区包含人Igκ恒定区。
在某些实施方式中,所述抗体轻链恒定区包含SEQ ID NO:34所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含抗体重链,且所述抗体重链包含SEQ ID NO:35、37中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包含抗体轻链,且所述抗体轻链包含SEQ ID NO:36、38中任一项所示的氨基酸序列。
在某些实施方式中,本申请所述的分离的抗原结合蛋白包括抗体或其抗原结合片段。
在某些实施方式中,所述抗体选自下组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体、人源化抗体和全人源抗体。
在某些实施方式中,所述抗原结合片段选自下组:Fab、Fab’、F(ab)2、Fv、F(ab’)2、scFv、di-scFv和dAb片段。
另一方面,本申请提供一种免疫缀合物,其包含本申请所述的分离的抗原结合蛋白。
在某些实施方式中,所述的免疫缀合物还包含选自下组的至少一种其他试剂:化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂。
在某些实施方式中,所述分离的抗原结合蛋白与所述其他试剂通过连接分子相连。
在某些实施方式中,所述分离的抗原结合蛋白及所述其他试剂分别与所述连接分子共价相连。
在某些实施方式中,所述其他试剂包括美登素或其衍生物。
在某些实施方式中,所述美登素衍生物包括美登素衍生物DM1。
另一方面,本申请提供分离的一种或多种核酸分子,其编码本申请所述的分离的抗原结合蛋白。
另一方面,本申请提供载体,其包含本申请所述的核酸分子。
另一方面,本申请提供细胞,其包含本申请所述的核酸分子或本申请所述的载体。
另一方面,本申请提供一种药物组合物,其包含本申请所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体和/或所述的细胞,以及任选地药学上可接受的佐剂。
另一方面,本申请提供制备本申请所述的分离的抗原结合蛋白的方法,所述方法包括在使得所述的分离的抗原结合蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
在某些实施方式中,所述肿瘤包括AXL阳性肿瘤。
在某些实施方式中,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在某些实施方式中,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
另一方面,本申请提供所述的分离的抗原结合蛋白在制备诊断剂中的用途,所述诊断剂用于诊断与AXL蛋白的表达相关的疾病或病况。
另一方面,本申请提供诊断受试者中与AXL蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
另一方面,本申请提供检测样品中AXL的方法,所述方法包括施用所述的分离的抗原结合蛋白。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下:
图1显示本申请所述的分离的抗原结合蛋白结合抗原的能力。
图2显示本申请所述的抗原结合蛋白6G12M11与不同靶抗原的结合情况。
图3显示本申请所述的抗原结合蛋白6G12M21与不同靶抗原的结合情况。
图4显示本申请所述的分离的抗原结合蛋白与A549细胞表面的抗原的结合情况。
图5显示本申请所述的分离的抗原结合蛋白与MDA-MB-231细胞表面的抗原的结合情况。
图6显示本申请所述的分离的抗原结合蛋白与786-O细胞表面的抗原的结合情况。
图7显示本申请所述的分离的抗原结合蛋白在A549细胞上的内化效率。
图8显示本申请所述的分离的抗原结合蛋白在MDA-MB-231细胞上的内化效率。
图9显示本申请所述的分离的抗原结合蛋白在786-O细胞上的内化效率。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
以下对本申请做进一步描述:在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
在本申请中,术语“分离的”通常指从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
在本申请中,术语“分离的抗原结合蛋白”通常指从天然状态下经人工手段获得的具有抗原结合能力的蛋白。该“分离的抗原结合蛋白”可以包含结合抗原的部分和任选地,允许抗原结合部分采用促进所述抗原结合部分结合抗原的构象的支架或构架部分。抗原结合蛋白可以包含例如抗体来源的蛋白支架或具有移植的CDR或CDR衍生物的备选蛋白支架或人工支架。此类支架包括,但不限于包含被引入例如以稳定抗原结合蛋白的三维结构的突变的抗体来源的支架以及包含例如生物相容性聚合物的完全合成的支架。参见例如Korndorfer等,2003,Proteins:Structure,Function,andBioinformatics,53(1):121-129(2003);Roque等,Biotechnol.Prog.20:639-654(2004)。此外,肽抗体模拟物("PAMs")以及利用纤连蛋白组分基于抗体模拟物的支架可以用作支架。
在本申请中,术语“KD”(同样地,“KD”或“KD”)通常指“亲和常数”或“平衡解离常数”,并指在滴定测量中在平衡时、或者通过将解离速率常数(kd)除以结合速率常数(ka)所获得的值。使用结合速率常数(ka)、解离速率常数(kd)和平衡解离常数(KD)表示结合蛋白(例如本申请所述的分离的抗原结合蛋白)对抗原(例如AXL蛋白)的结合亲和力。确定结合和解离速率常数的方法为本领域熟知。使用基于荧光的技术提供了高灵敏度以及在生理缓冲液中在平衡时检查样品的能力。例如,可以通过Octet测定所述KD值,也可以使用其他实验途径和仪器例如BIAcore(生物分子相互作用分析)测定(例如,可以从BIAcoreInternationalA B,aGEHealthcarecompany,Uppsala,瑞典获得的仪器)。另外,也可以使用可以从Sapidyn eInstruments(Boise,Idaho)获得的KinExA(动态排阻测定(KineticExclusionAssay))测定所述KD值,或者使用表面等离子共振仪(SPR)测定所述KD值。
在本申请中,术语“EC50”或“EC50”,又叫半最大效应浓度,通常是指引起50%最大效应的抗体浓度。
在本申请中,术语“AXL蛋白”通常是指axl基因所编码的蛋白质受体酪氨酸激酶。AXL(Ark、UFO、Tyro-7)是激酶的Tyro-3家族的成员,其可通过配体Gas6(与抗凝血因子蛋白S同源的70-kDa蛋白)的结合来激活。在一些癌症(例如,肺癌、肾癌或乳腺癌)的细胞中,可能存在着AXL蛋白的过表达。人AXL蛋白是894个氨基酸的蛋白质,其氨基酸序列可以如SEQID NO:39所示;其中第1-26位氨基酸残基为信号肽;第27-451位为AXL蛋白的细胞外结构域(其氨基酸序列如SEQ ID NO:40所示)。
在本申请中,术语“细胞外结构域”通常是指位于细胞外的多肽或蛋白结构域。例如,所述细胞外结构域可以为AXL蛋白的细胞外结构域,其氨基酸序列可如SEQ ID NO:40所示。AXL蛋白的细胞外结构域可以具有接近细胞粘附分子所需的结构。所述AXL蛋白的细胞外结构域可以为两个免疫球蛋白样结构域的组合物,能够结合Gas6配体(Sasaki T等人,EMBO J.(2006).25,80-87)。
在本申请中,术语“特异性结合”或“特异性的”通常指可测量的和可再现的相互作用,比如靶标和抗体之间的结合,可在分子(包括生物分子)的异质群体存在的情况可决定靶标的存在。例如,特异性结合靶标(其可以为表位)的抗体是以比它结合其它靶标更大的亲和性、亲合力、更容易、和/或以更大的持续时间结合该靶标的抗体。在一个实施方案中,抗体结合无关靶标的程度小于抗体对靶标的结合的约10%,如例如通过放射免疫分析(RIA)测量的。例如,在本申请中,所述分离的抗原结合蛋白能够以<1x10-7M或更低的解离常数(KD)与AXL蛋白相结合。在某些实施方案中,抗体特异性结合蛋白质上的表位,所述表位在不同种属的蛋白质中是保守的。在另一个实施方案中,特异性结合可以包括但不要求排他性地结合。
在本申请中,术语“内化”通常是指抗体或其抗原结合片段或多肽与细胞表面的受体特异性结合,形成受体-抗体复合物,然后借助该受体介导的胞吞作用进入到细胞内的过程。此时这样的抗体或其抗原结合片段(如Fab片段)可以成为内化抗体。所述内化抗体可以作为定向运载药物、酶或DNA的载体。在某些情形下,所述内化可抑制肿瘤细胞的增殖。例如,所述内化抗体可用于偶联抗肿瘤的化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂,并作为肿瘤生物治疗的候选分子。
在本申请中,术语“肿瘤”通常指由异常细胞生长形成的赘生物或实体病变。在本申请中,肿瘤可以是实体瘤或血液瘤。例如,在本申请中,肿瘤可以是AXL阳性的肿瘤,其中所述AXL阳性的肿瘤可以选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。在某些实施方式中,所述AXL阳性的肿瘤可以选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在本申请中,术语“可变结构域”通常指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”(或者分别称为“VH”和“VL”)。这些结构域通常是抗体的变化最大的部分(相对于相同类型的其它抗体),且包含抗原结合位点。
在本申请中,术语“可变”通常指在抗体之间可变结构域的某些区段在序列上存在很大差异的事实。V结构域介导抗原结合并决定特定抗体对其特定抗原的特异性。然而,可变性并非在整个可变结构域范围内均匀分布。相反,它集中在轻链和重链可变结构域中称为高变区(CDR或HVR)的三个区段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,大多数采用β-折叠构型,通过三个CDR连接,其形成环形连接,并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起,并且来自另一条链的CDR一同促进抗体的抗原结合位点的形成(参见Kabat et al,Sequences of Immunological Interest,Fifth Edition,NationalInstitute of Health,Bethesda,Md.(1991))。恒定结构域不直接参与抗体与抗原的结合,但显示出各种效应子功能,例如抗体参与抗体依赖性细胞毒性。
在本申请中,术语“抗体”通常指免疫球蛋白或其片段或其衍生物,涵盖包括抗原结合位点的任何多肽,无论其是在体外还是体内产生的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂化的、突变的和移植的抗体。除非另外被术语“完整的”修饰,如在“完整的抗体”中,为了本发明的目的,术语“抗体”也包括抗体片段,比如Fab、F(ab')2、Fv、scFv、Fd、dAb和保持抗原结合功能(例如,特异性结合AXL)的其它抗体片段。通常,这样的片段应当包括抗原结合结构域。基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元与另外一个称为J链的多肽组成,且含有10个抗原结合位点,而IgA抗体包括2-5个可以与J链相结合聚合形成多价组合的基本4链单元。就IgG而言,4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个取决于H链同种型的二硫键相互连接。每个H和L链还具有规则间隔的链内二硫化桥键。每个H链在N末端具有可变结构域(VH),对于α和γ链各自继之以三个恒定结构域(CH)、对于μ和ε同种型继之以四个CH结构域。每个L链在N末端具有可变结构域(VL),在其另一端具有恒定结构域。VL与VH对应,且CL与重链的第一恒定结构域(CH1)相对应。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质,参见例如Basic and ClinicalImmunology,8th Edition,Daniel P.Sties,Abba I.Terr and Tristram G.Parsolw(eds),Appleton&Lange,Norwalk,Conn.,1994,第71页和第6章。来自任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列被分为两种明显不同的类型中的一种,称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列,可以将免疫球蛋白分为不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别被命名为α、δ、ε、γ和μ的重链。基于CH序列和功能方面的相对小的差异,将γ和α类进一步分成亚类,例如,人表达下述亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
在本申请中,术语“CDR”通常指抗体可变结构域的区域,其序列是高度可变的和/或形成结构定义环。通常,抗体包括六个CDR;在VH中三个(HCDR1、HCDR2、HCDR3),和在VL中三个(LCDR1、LCDR2、LCDR3)。在天然抗体中,HCDR3和LCDR3显示所述六个CDR的大多数多样性,并且特别地HCDR3被认为在赋予抗体的精细特异性方面起独特作用。参见,例如Xu etal,Immunity 13:37-45(2000);Johnson and Wu,in Methods in Molecular Biology248:1-25(Lo,ed.,Human Press,Totowa,N.J.,2003)。实际上,仅由重链组成的天然存在的骆驼抗体在缺乏轻链的情况功能正常且稳定。参见,例如,Hamers-Casterman et al.,Nature363:446-448(1993);Sheriff et al,Nature Struct.Biol.3:733-736(1996)。
在本申请中,术语“FR”通常指抗体可变结构域的更高度保守的部分,其被称为框架区。通常,天然重链和轻链的可变结构域各自包含四个FR区,即在VH中四个(H-FR1,H-FR2,H-FR3,和H-FR4),和在VL中四个(L-FR1,L-FR2,L-FR3,和L-FR4)。例如,本申请所述的分离的抗原结合蛋白的VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。本申请所述的分离的抗原结合蛋白的VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,术语“抗原结合片段”通常指具有特异结合抗原(例如,AXL蛋白)能力的一个或多个片段。在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,术语“单克隆抗体”或“单抗”或“单克隆抗体组成”通常是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
在本申请中,术语“单链抗体”通常是指包含抗体重链可变区和轻链可变区的分子。例如,所述单链抗体可以由抗体重链可变区和轻链可变区通过连接分子(linker)(例如,连接肽)连接而成。
在本申请中,术语“人源抗体”通常是指可变区框架和CDR区得自人种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自人种系免疫球蛋白序列。本申请的人源抗体可以包含不由人种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“人源抗体”不包括在人框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“鼠源抗体”通常是指可变区框架和CDR区得自小鼠种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自小鼠种系免疫球蛋白序列。本申请的鼠源抗体可以包含不由小鼠种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“鼠源抗体”不包括在小鼠框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“嵌合抗体”通常是指通过组合非人源遗传物质与人源遗传物质而得来的抗体。或者更笼统地说,嵌合抗体是指组合有一个物种的遗传物质与另一物种遗传物质的抗体。
在本申请中,术语“多特异性抗体”通常是指可以同时识别两个或两个以上抗原或者表位的抗体分子。所述多特异性抗体可以通过化学偶联法、杂交-杂交瘤法、基因工程抗体制备法等方法在真核表达系统或者在原核表达系统中获得。
在本申请中,术语“人源化抗体”通常是指来源于非人物种但其蛋白序列已经被修改以增加其与人天然生成抗体的相似度的抗体。
在本申请中,术语“全人源抗体”通常是指全人抗体,即抗体的恒定区和可变区均来源于人。所述全人源抗体可以通过噬菌体抗体库技术、转基因小鼠制备人源性抗体、核糖体展示技术、EBV转化B细胞克隆技术、单个B细胞克隆等技术来实现。
在本申请中,术语“识别抗原的抗体”以及“对抗原特异的抗体”在本文中与术语“特异结合抗原的抗体”交替使用。
在本申请中,术语“直接相连”与术语“间接相连”相对,术语“直接相连”通常是指直接连接。例如,所述直接相连可以为物质间没有间隔子而直接相连的情况。所述间隔子可以是连接子。例如,所述连接子可以为肽连接子。术语“间接相连”通常是指物质间不直接相连的情况。例如,所述间接相连可以为通过间隔子而连接的情况。例如,在本申请所述的分离的抗原结合蛋白中,所述L-FR1的C末端与所述LCDR1的N末端可以直接或间接相连。
在本申请中,术语“免疫缀合物”通常是指所述其他试剂(例如,化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂)与所述分离的抗原结合蛋白缀合(例如,通过连接分子共价相连)而形成的缀合物,该缀合物可以通过所述分离的抗原结合蛋白与靶细胞上的抗原的特异性结合,将所述其他试剂递送至靶细胞(例如,肿瘤细胞)。然后所述免疫缀合物经所述内化,最终进入靶细胞内部(例如,进入溶酶体等泡囊体),此时所述免疫缀合物中的连接分子可以裂解,释放所述其他试剂从而发挥其细胞毒性效应。此外,所述抗原也可以由所述靶细胞分泌,并位于所述靶细胞外的间隙。
在本申请中,术语“化疗剂”通常是指可以抑制肿瘤和/或肿瘤细胞增殖的化疗用试剂。所述化疗剂可以选自以下组:有丝分裂抑制剂、激酶抑制剂、烷基化试剂、抗代谢药、嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、组蛋白脱乙酰基酶抑制剂、抗存活剂、生物学应答调节剂、抗激素例如抗雄激素和抗血管生成剂。例如,所述化疗剂可以选自以下组:卡培他滨、柔红霉素、道诺霉素、放线菌素D、多柔比星、表柔比星、伊达比星、依索比星、博来霉素、马磷酰胺、异环磷酰胺、阿糖胞苷、双氯乙基亚硝脲、白消安、丝裂霉素C、放线菌素D、普卡霉素、泼尼松、羟孕酮、睾酮、他莫昔芬、达卡巴嗪、丙卡巴肼、六甲蜜胺、五甲蜜胺、米托蒽醌、安吖啶、苯丁酸氮芥、甲基环己基亚硝基脲、氮芥、美法仑、环磷酰胺、6-巯嘌呤、6-硫鸟嘌呤、阿糖胞苷(CA)、5-氮杂胞苷、羟基脲、脱氧助间型霉素、4-羟基过氧环磷酰胺、5-氟尿嘧啶(5-FU)、5-氟脱氧尿苷(5-FUdR)、甲氨喋呤(MTX)、秋水仙碱、泰素(taxol)、长春新碱、长春碱、依托泊苷、三甲曲沙、替尼泊苷和/或己烯雌酚(DES)。
在本申请中,术语“放射性元素”通常是指可以抑制肿瘤和/或肿瘤细胞增殖的放疗用元素。所述放射性元素可以选自以下组:3H、14C、15N、35S、90Y、99Tc、111In、125I和/或131I。
在本申请中,术语“细胞生长抑制剂”通常是指通过抑制促进肿瘤细胞生长和复制的生长因子从而抑制肿瘤的试剂。生长因子与在细胞表面的受体结合后激活了细胞内的信号通路,复杂的通路可能促使细胞失控生长,从而导致细胞过度的分裂并发展为肿瘤。所述细胞生长抑制剂能够抑制这些生长因子的作用。所述细胞生长抑制剂可以选自以下组:血管生成抑制因子、脱乙酰化酶(HDAC)抑制因子、Hedgehog信号通路阻滞剂、mTOR抑制剂、p53/mdm2抑制剂、PARP抑制剂、蛋白酶体抑制剂和/或酪氨酸激酶抑制剂。
在本申请中,术语“细胞毒性剂”通常是指通过对作用的细胞产生毒素,抑制肿瘤和/或肿瘤细胞增殖的试剂。所述细胞毒性剂可以选自以下组:烷化剂,如白消安、六甲蜜胺、噻替派、环磷酰胺、氮芥、乌拉莫司汀、美法仑、苯丁酸氮芥、卡莫司汀、链脲霉素、达卡巴嗪、替莫唑胺、异环磷酰胺等;抗肿瘤剂,如丝裂霉素C等;抗代谢物,如甲氨蝶呤、咪唑硫嘌呤、巯基嘌呤、氟达拉滨、5-氟尿嘧啶等;含铂的抗癌剂,如顺铂、卡铂等;蒽环霉素,如柔红霉素、阿霉素、表柔比星、伊达比星、米托蒽醌等;植物生物碱和萜类化合物,如长春新碱、长春碱、长春瑞滨、长春地辛、鬼臼毒素、多西他赛等;拓扑异构酶抑制剂,如伊立替康、安吖啶、托泊替康、依托泊苷、替尼泊苷等;抗体类,如利妥昔单抗、曲妥珠单抗、贝伐珠单抗、厄洛替尼、更生霉素等;非那雄胺;芳香化酶抑制剂;他莫昔芬;戈舍瑞林;紫杉醇和/或甲磺酸伊马替尼。所述细胞毒性剂可以通过口服、注射等方式施用。
在本申请中,术语“连接分子”通常是指连接或联接两个分子的功能分子。例如,所述连接分子可以连接一个分子和另一个分子(例如,一个分子为蛋白质分子,另一个分子也为蛋白质分子,或者可以为小分子药物)。所述连接分子可以用于所述免疫缀合物的构建中。在所述免疫缀合物中,所述连接分子可以具备两个功能特征:1、具有循环系统稳定性,在所述免疫缀合物到达靶细胞前在循环系统中不能发生裂解释放所述其他试剂,避免产生毒性作用;2、在进入靶细胞过后,所述连接分子需要快速有效地断裂,使所述其他试剂有效释放发挥应有的药理活性。所述连接分子可以由极性或非极性氨基酸组成。所述连接分子也可以为包含杂原子(如氮原子、硫原子等)的碳链。所述连接分子的长度可以为2至100个原子,例如为2至50个原子之间,也可以为3、5、10、15、20、25、30、35、40、45或50个原子;又例如,所述连接子的长度可以为20至26个(20、21、22、23、24、25或26个)原子。所述连接分子可以包括选自以下组的取代基取代:氢原子、烷基、烯基、炔基、氨基、烷基氨基、二烷基氨基、三烷基氨基、羟基、烷氧基、卤素、芳基、杂环、芳香族杂环、氰基、酰胺、氨基甲酰基、羧酸、酯、硫醚、烷基硫醚、巯基和脲基。此外,所述连接分子可以选自以下组:pH敏感连接分子、蛋白酶可切割连接分子、核酸酶敏感连接分子、脂肪酶敏感连接分子、糖苷酶连接分子、缺氧连接分子、光切割连接分子、热不稳定连接分子和超声敏感连接分子。
在本申请中,术语“共价”通常是指共价键,即两个或多个原子存在共用电子对,达到电子饱和的状态从而形成比较稳定的化学结构。共价键的形成是相邻两个原子之间自旋方向相反的电子相互配对,此时原子轨道相互重叠,两核间的电子云密度相对地增大,从而增加对两核的引力。共价键可以具备饱和性与方向性。共价键可以分为非极性共价键、极性共价键和配价键。只含有共价键的化合物可称为共价化合物。
在本申请中,术语“美登素”通常是指从美登木属植物分离得到(参见美国专利US3896111)的化合物,其属于一种抗有丝分裂细胞毒素,结构式为:
所述美登素的CAS号为35846-53-8。美登素可以对各种肿瘤,如L-1210、P-388白血病、S-180、W-256、路易斯肺癌和体外鼻咽癌均有显著疗效。所述美登素衍生物可以包括具有美登素的环结构且其环上具有一个或一个以上取代基修饰的化合物,例如美登素衍生物DM1、DM4。
在本申请中,术语“美登素衍生物DM1”通常是指具备以下结构式的化合物:
CAS号为139504-50-0。所述美登素衍生物DM1可以为一种抗有丝分裂细胞毒素。
在本申请中,术语“与AXL蛋白的表达相关的疾病或病况”通常是指与AXL蛋白的表达相关,或者AXL蛋白的表达上调会导致的疾病或病况。例如,与AXL蛋白的表达相关的疾病或病况可以为肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和/或骨髓瘤。
在本申请中,术语“分离的核酸分子”通常指任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物。
在本申请中,术语“载体”通常指可将编码某蛋白的多聚核苷酸插入其中并使蛋白获得表达的一种核酸运载工具。载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。举例来说,载体包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可能含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。载体还有可能包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
在本申请中,术语“细胞”通常指可以是或已经是受试者质粒或载体的接受者的单个细胞、细胞系或细胞培养物,其包括本发明所述的核酸分子或本发明所述的载体。细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。细胞可包括用本申请所述的载体在体外转染的细胞。细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、CHO-K1细胞、LNCAP细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞、人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞或人多发性骨髓瘤RPMI8226细胞。在某些实施方案中,细胞为哺乳动物细胞。在某些实施方案中,哺乳动物细胞为HEK293细胞。
在本申请中,术语“药物组合物”通常指涉及适合施用于患者、优选人患者的组合物。例如,本申请所述的药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的免疫缀合物、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。此外,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在本申请中,术语“药学上可接受的佐剂”通常指与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂等,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在本申请中,术语“受试者”通常指人类或非人类动物,包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,术语“包含”通常是指包括明确指定的特征,但不排除其他要素。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
分离的抗原结合蛋白
一方面本申请提供了一种分离的抗原结合蛋白,其包含氨基酸序列如SEQ ID NO:1所示的VH中的至少一个CDR;且包含氨基酸序列如SEQ ID NO:2所示的VL中的至少一个CDR。
QVQL X1 QSGPGLVKPSQSLSLTC X2 V X3 G X4 SISSGYYWNWIRQ X5 PG X6 X7 LEWMGYRSYDGSNNYNPSLKNRISITRDTSKNQFFLKLNSVT X8 EDTATYYCARGWLLHY TMDYWGQGT X9VTVSS(SEQ ID NO:1),其中,X1可以是K或V,X2可以是S或A,X3可以是T或S,X4可以是F、Y、D或S,X5可以是F或S,X6可以是N或Q,X7可以是K或G,X8可以是T或S,X9可以是S或T。
X1X2VMTQSP X3 S X4 X5 VTLG X6 SASISCRSSRSLLHSNGFTYLYWY X7 QKPGQSPQLLIYQMSNLASGVPDRFS X8 SGSGTDFTL X9 ISRVEAEDVGVYYCGQNLELPLTFG X1 0 GTKLE X11 K(SEQ ID NO:2),其中,X1可以是E或D,X2可以是L或I,X3可以是F或S,X4可以是N或V,X5可以是A或S,X6可以是T或Q,X7可以是L或Q,X8可以是S或G,X9可以是R或K,X10可以是A或G,X11可以是L或I。
本申请所述分离的抗原结合蛋白的VH可以通过在6G12抗体VH(SEQ ID NO:31)中的一个或多个位置处的氨基酸突变获得,具体而言,可以通过6G12抗体VH的框架区(FR)中的一个或多个位置处的氨基酸突变来获得本申请所述分离的抗原结合蛋白。
例如,在6G12抗体VH中,从N端到C端,第5位的K可以突变成V,第23位的S可以突变成A,第25位的T可以突变成S,第27位的F可以突变成Y、D或S,第41位的F可以突变成S,第44位的N可以突变成Q,第45位的K可以突变成G,第88位的T可以突变成S,第114位的S可以突变成T。
本申请所述分离的抗原结合蛋白的VL可以通过在6G12抗体VL(SEQ ID NO:32)中的一个或多个位置处的氨基酸突变获得,具体而言,可以通过6G12抗体VL的框架区(FR)中的一个或多个位置处的氨基酸突变来获得本申请所述分离的抗原结合蛋白。
例如,在6G12抗体VL中,从N端到C端,第1位的E可以突变成D,第2位的L可以突变成I,第9位的F可以突变成S,第11位的N可以突变成V,第12位的A可以突变成S,第17位的T可以突变成Q,第42位的L可以突变成Q,第69位的S可以突变成G,第79位的R可以突变成K,第105位的A可以突变成G,第111位的L可以突变成I。
所述分离的抗原结合蛋白的性质
在本申请中,所述分离的抗原结合蛋白可以具有下述性质中的一种或多种:
1)能够以1×10-7M或更低的KD与AXL蛋白相结合;
2)能够特异性识别在细胞表面表达的AXL蛋白;
3)结合在细胞表面表达的AXL蛋白后能够介导内化。
在本申请中,所述分离的抗原结合蛋白能够以1×10-7M或更低的KD与AXL蛋白相结合。例如,本申请所述的分离的抗原结合蛋白结合源自人的AXL蛋白的KD值可以为≤1×10- 7M、≤9×10-8M、≤8×10-8M、≤7×10-8M、≤6×10-8M、≤5×10-8M、≤4×10-8M、≤3×10-8M、≤2×10-8M、≤1.5×10-8M、≤1.2×10-8M、≤1.15×10-8M、≤1.1×10-8M、≤1.05×10-8M、≤1×10-8M、≤5×10-9M或≤1×10-9M。又例如,本申请所述的分离的抗原结合蛋白结合源自鼠的AXL蛋白的KD值可以为≤1×10-7M、≤9×10-8M、≤8×10-8M、≤7×10-8M、≤6×10-8M、≤5×10-8M、≤4×10-8M、≤3×10-8M、≤2×10-8M、≤1.5×10-8M、≤1.2×10-8M、≤1.15×10-8M、≤1.1×10-8M、≤1.05×10-8M、≤1×10-8M、≤5×10-9M或≤1×10-9M。又例如,本申请所述的分离的抗原结合蛋白结合源自猴的AXL蛋白的KD值可以为≤1×10-7M、≤9×10-8M、≤8×10- 8M、≤7×10-8M、≤6×10-8M、≤5×10-8M、≤4×10-8M、≤3×10-8M、≤2×10-8M、≤1.5×10-8M、≤1.2×10-8M、≤1.15×10-8M、≤1.1×10-8M、≤1.05×10-8M、≤1×10-8M、≤5×10-9M或≤1×10-9M。
在本申请中,所述KD值还可以通过ELISA、竞争ELISA或BIACORE或KINEXA进行测定。
在本申请中,所述竞争性结合的能力可以通过测定所述分离的抗原结合蛋白的抗体-抗原相互作用的解离平衡常数来衡量。检测所述解离平衡常数的方法可以选自以下组:酶联免疫吸附法、表面等离振子共振(SRP)法、电位滴定法、分光光度法、细管电泳法、荧光法和薄层色谱pH法。例如,所述分离的抗原结合蛋白可以经SRP法(例如,使用生物大分子相互作用仪)检测。
在本申请中,所述分离的抗原结合蛋白能够特异性结合细胞表面表达的AXL蛋白。所述特异性结合可以通过FACS测定。例如,可以通过FACS测定中的EC50来反映本申请所述分离的抗原结合蛋白特异性结合细胞表面的AXL蛋白的情况,例如,EC50越低说明特异性结合越好。例如,所述分离的抗原结合蛋白在FACS测定中结合非小细胞肺癌A549细胞表面的AXL蛋白的EC50值可以为0.01μg/ml~0.10μg/ml、0.01μg/ml~0.15μg/ml、0.01μg/ml~0.20μg/ml、0.01μg/ml~0.25μg/ml、0.01μg/ml~0.30μg/ml、0.01μg/ml~0.35μg/ml、0.01μg/ml~0.40μg/ml、0.01μg/ml~0.45μg/ml、0.01μg/ml~0.50μg/ml、0.01μg/ml~0.55μg/ml、0.01μg/ml~0.60μg/ml、0.01μg/ml~0.65μg/ml、0.01μg/ml~0.70μg/ml、0.01μg/ml~0.75μg/ml或0.01μg/ml~0.80μg/ml。又例如,所述分离的抗原结合蛋白在FACS测定中结合人乳腺癌MDA-MB-231细胞表面的AXL蛋白的EC50值可以为0.01μg/ml~0.10μg/ml、0.01μg/ml~0.15μg/ml、0.01μg/ml~0.20μg/ml、0.01μg/ml~0.25μg/ml、0.01μg/ml~0.30μg/ml、0.01μg/ml~0.35μg/ml、0.01μg/ml~0.40μg/ml、0.01μg/ml~0.45μg/ml、0.01μg/ml~0.50μg/ml、0.01μg/ml~0.55μg/ml、0.01μg/ml~0.60μg/ml、0.01μg/ml~0.65μg/ml、0.01μg/ml~0.70μg/ml、0.01μg/ml~0.75μg/ml或0.01μg/ml~0.80μg/ml。又例如,所述分离的抗原结合蛋白在FACS测定中结合肾透明细胞腺癌786-O细胞表面的AXL蛋白的EC50值可以为0.01μg/ml~0.10μg/ml、0.01μg/ml~0.15μg/ml、0.01μg/ml~0.20μg/ml、0.01μg/ml~0.25μg/ml、0.01μg/ml~0.30μg/ml、0.01μg/ml~0.35μg/ml、0.01μg/ml~0.40μg/ml、0.01μg/ml~0.45μg/ml、0.01μg/ml~0.50μg/ml、0.01μg/ml~0.55μg/ml、0.01μg/ml~0.60μg/ml、0.01μg/ml~0.65μg/ml、0.01μg/ml~0.70μg/ml、0.01μg/ml~0.75μg/ml或0.01μg/ml~0.80μg/ml。
在本申请中,所述分离的抗原结合蛋白可以结合在细胞表面表达的AXL蛋白后能够介导内化。例如,所述内化可以包括以下的步骤:当所述分离的抗原结合蛋白可以结合到细胞(例如肿瘤细胞)的质膜上,或者,可以响应于细胞微环境(例如肿瘤细胞微环境)中的蛋白水解活性后在细胞内释放。从而,所述分离的抗原结合蛋白可以被细胞膜吞没,并吸入该细胞中。在某些实施方式中,所述免疫缀合物中的所述分离的抗原结合蛋白,和/或与之缀合的所述其他试剂,也可以在所述分离的抗原结合蛋白结合到细胞的质膜上后,被细胞膜吞没,并吸入该细胞中。
在本申请中,所述AXL蛋白可以为人AXL蛋白(NP_068713);也可以为食蟹猴AXL蛋白(Genbank登录号HB387229.1)。例如,所述AXL蛋白可以为人AXL蛋白,其氨基酸序列如SEQID NO:39所示。
所述AXL蛋白可以包括AXL蛋白的变体。例如,所述变体可以为:1)在所述AXL蛋白的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和2)与所述AXL蛋白具有至少约85%(例如,具有至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
所述AXL蛋白还可以包括AXL蛋白的片段。例如,所述AXL蛋白可以为人AXL蛋白的细胞外结构域,其氨基酸序列如SEQ ID NO:40所示。
在本申请中,所述细胞可以包括肿瘤细胞。例如,所述肿瘤可以为AXL阳性肿瘤。例如,所述肿瘤可以选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。又例如,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在本申请中,所述细胞可以包括人的细胞。例如,所述细胞可以包括选自下组的细胞:人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞和人多发性骨髓瘤RPMI8226细胞。
所述分离的抗原结合蛋白的种类
在本申请中,所述分离的抗原结合蛋白可以包括抗体或其抗原结合片段。例如,本申请所述的分离的抗原结合蛋白可以包括但不限于重组抗体、单克隆抗体、人抗体、鼠源抗体、人源化抗体、嵌合抗体、双特异性抗体、单链抗体、双抗体、三抗体、四抗体、Fv片段、scFv片段、Fab片段、Fab'片段、F(ab')2片段和骆驼化单结构域抗体。
在本申请中,所述抗体可以为人源化抗体。换句话说,本申请所述的分离的抗原结合蛋白,其可以为免疫特异性结合至相关抗原(例如人类AXL)且包含基本上具有人类抗体的氨基酸序列的框架(FR)区及基本上具有非人类抗体的氨基酸序列的互补决定区(CDR)的抗体或其变异体、衍生物、类似物或片段。此处的“基本上”在CDR的情况下是指CDR的氨基酸序列与非人类抗体CDR的氨基酸序列至少80%、优选至少85%、至少90%、至少95%、至少98%或至少99%同一。所述人源化抗体基本上可以包含所有至少一个且通常两个可变域(Fab、Fab′、F(ab′)2、FabC、Fv),其中所有或基本上所有CDR区对应于非人类免疫球蛋白(即抗体)的CDR区且所有或基本上所有框架区为具有人类免疫球蛋白共有序列的框架区。优选地,人源化抗体还包含至少一部分免疫球蛋白恒定区(例如,Fc),通常为人类免疫球蛋白的恒定区。在一些实施例中,人源化抗体含有轻链以及重链的至少可变域。抗体还可包括重链的CH1、铰链、CH2、CH3及CH4区。在一些实施例中,人源化抗体仅含人源化轻链。在一些实施例中,人源化抗体仅含人源化重链。在特定实施例中,人源化抗体仅含轻链和/或人源化重链的人源化可变域。
在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
CDR
抗体的CDR又称互补决定区,是可变区的一部分。该区域的氨基酸残基与抗原或抗原表位接触。抗体CDR可以通过多种编码系统来确定,如CCG、Kabat、Chothia、IMGT、综合考虑Kabat/Chothia等。这些编码系统为领域内已知,具体可参见http://www.bioinf.org.uk/abs/index.html#kabatnum。本领域技术人员可以根据抗体的序列和结构,用不同的编码系统确定出CDR区。使用不同的编码系统,CDR区可能存在差别。本申请所述的分离的抗原结合蛋白的CDR可以使用Kabat确定出来。
在本申请中,所述分离的抗原结合蛋白的所述VH可以包含HCDR1、HCDR2和HCDR3。
在本申请中,所述HCDR1可以包含SEQ ID NO:25所示的氨基酸序列。
在本申请中,所述HCDR2可以包含SEQ ID NO:26所示的氨基酸序列。
在本申请中,所述HCDR3可以包含SEQ ID NO:27所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:25所示的氨基酸序列,HCDR2可包含SEQ ID NO:26所示的氨基酸序列,HCDR3可包含SEQ ID NO:27所示的氨基酸序列。
在本申请中,所述LCDR1可以包含SEQ ID NO:28所示的氨基酸序列。
在本申请中,所述LCDR2可以包含SEQ ID NO:29所示的氨基酸序列。
在本申请中,所述LCDR3可以包含SEQ ID NO:30所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的LCDR1可包含SEQ ID NO:28所示的氨基酸序列,LCDR2可包含SEQ ID NO:29所示的氨基酸序列,LCDR3可包含SEQ ID NO:30所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:25所示的氨基酸序列,HCDR2可包含SEQ ID NO:26所示的氨基酸序列,HCDR3可包含SEQ ID NO:27所示的氨基酸序列,且LCDR1可包含SEQ ID NO:28所示的氨基酸序列,LCDR2可包含SEQ IDNO:29所示的氨基酸序列,LCDR3可包含SEQ ID NO:30所示的氨基酸序列。
FR
在本申请中,所述分离的抗原结合蛋白的所述VH可以包含框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,所述H-FR1的C末端可以与所述HCDR1的N末端直接或间接相连,且所述H-FR1可以包含SEQ ID NO:7所示的氨基酸序列。
QVQL X1 QSGPGLVKPSQSLSLTC X2 V X3 G X4SIS(SEQ ID NO:7),其中,X1可以是K或V,X2可以是S或A,X3可以是T或S,X4可以是F、Y、D或S。
例如,在本申请中,所述H-FR1可以包含SEQ ID NO:11、15中任一项所示的氨基酸序列。
在本申请中,所述H-FR2可以位于所述HCDR1与所述HCDR2之间,且所述H-FR2可以包含SEQ ID NO:8所示的氨基酸序列。
WIRQ X1 PG X2 X3 LEWMG(SEQ ID NO:8),其中,X1可以是F或S,X2可以是N或Q,X3可以是K或G。
例如,在本申请中,所述H-FR2可以包含SEQ ID NO:12所示的氨基酸序列。
在本申请中,所述H-FR3可以位于所述HCDR2与所述HCDR3之间,且所述H-FR3可以包含SEQ ID NO:9所示的氨基酸序列。
RISITRDTSKNQFFLKLNSVT X1 EDTATYYCAR(SEQ ID NO:9),其中,X1可以是T或S。
例如,在本申请中,所述H-FR3可以包含SEQ ID NO:13所示的氨基酸序列。
在本申请中,所述H-FR4的N末端可以与所述HCDR3的C末端相连,且所述H-FR4可以包含SEQ ID NO:10所示的氨基酸序列。
WGQGT X1 VTVSS(SEQ ID NO:10),其中,X1可以是S或T。
例如,在本申请中,所述H-FR4可以包含SEQ ID NO:14所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:11所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列。
再例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:15所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的VL可以包含框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在本申请中,所述L-FR1的C末端可以与所述LCDR1的N末端直接或间接相连,且所述L-FR1可以包含SEQ ID NO:16所示的氨基酸序列。
X1 X2 VMTQSP X3S X4 X5 VTLG X6 SASISC(SEQ ID NO:16),其中,X1可以是E或D,X2可以是L或I,X3可以是F或S,X4可以是N或V,X5可以是A或S,X6可以是T或Q。
例如,在本申请中,所述L-FR1可以包含SEQ ID NO:20、24中任一项所示的氨基酸序列。
在本申请中,所述L-FR2可以位于所述LCDR1与所述LCDR2之间,且所述L-FR2可以包含SEQ ID NO:17所示的氨基酸序列。
WY X1 QKPGQSPQLLIY(SEQ ID NO:17),其中,X1可以是L或Q。
例如,在本申请中,所述L-FR2可以包含SEQ ID NO:21所示的氨基酸序列。
在本申请中,所述L-FR3可以位于所述LCDR2与所述LCDR3之间,且所述L-FR3可以包含SEQ ID NO:18所示的氨基酸序列。
GVPDRFS X1 SGSGTDFTL X2 ISRVEAEDVGVYYC(SEQ ID NO:18),其中,X1可以是S或G,X2可以是R或K。
例如,在本申请中,所述L-FR3可以包含SEQ ID NO:22所示的氨基酸序列。
在本申请中,所述L-FR4的N末端可以与所述LCDR3的C末端相连,且所述L-FR4可以包含SEQ ID NO:19所示的氨基酸序列。
FG X1 GTKLE X2 K(SEQ ID NO:19),其中,X1可以是A或G,X2可以是L或I。
例如,在本申请中,所述L-FR4可以包含SEQ ID NO:23所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:20所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。
又例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:24所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。
再例如,例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:11所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列,且L-FR1可包含SEQID NO:20所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。
再例如,例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:15所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列,且L-FR1可包含SEQID NO:24所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。
VH和VL
本申请所述的分离的抗原结合蛋白可包含抗体轻链可变区VH和抗体重链可变区VL。
在本申请中,所述VH可包含SEQ ID NO:3、5中任一项所示的氨基酸序列。
在本申请中,所述VL可包含SEQ ID NO:4、6中任一项所示的氨基酸序列。
例如,所述VH可包含SEQ ID NO:3所示的氨基酸序列,所述VL可包含SEQ ID NO:4所示的氨基酸序列。
又例如,所述VH可包含SEQ ID NO:5所示的氨基酸序列,所述VL可包含SEQ ID NO:6所示的氨基酸序列。
恒定区、重链和轻链
在本申请中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG重链恒定区。
在某些实施方式中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG1重链恒定区。在另一些实施方式中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG4重链恒定区。
例如,所述抗体重链恒定区可以包含SEQ ID NO:33、41中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包括抗体轻链恒定区,且所述抗体轻链恒定区可以包括人Igκ恒定区。例如,所述抗体轻链恒定区可以包含SEQ ID NO:34所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体重链HC,且所述HC可以包含SEQ ID NO:35、37中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体轻链LC,且所述LC可以包含SEQ ID NO:36、38中任一项所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可以包含抗体重链和抗体轻链。
例如,所述重链可包含SEQ ID NO:35所示的氨基酸序列,所述轻链可包含SEQ IDNO:36所示的氨基酸序列。
例如,所述重链可包含SEQ ID NO:37所示的氨基酸序列,所述轻链可包含SEQ IDNO:38所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的重链可包含SEQ ID NO:35所示的氨基酸序列,且轻链可包含SEQ ID NO:36所示的氨基酸序列。其中,所述分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:25所示的氨基酸序列,HCDR2可包含SEQ ID NO:26所示的氨基酸序列,HCDR3可包含SEQ ID NO:27所示的氨基酸序列,且LCDR1可包含SEQ ID NO:28所示的氨基酸序列,LCDR2可包含SEQ ID NO:29所示的氨基酸序列,LCDR3可包含SEQ ID NO:30所示的氨基酸序列。此外,所述分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:11所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列,且L-FR1可包含SEQ ID NO:20所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。此外,所述VH可包含SEQ ID NO:3所示的氨基酸序列,且所述VL可包含SEQ ID NO:4所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为6G12M11抗体。
在本申请中,所述分离的抗原结合蛋白的重链可包含SEQ ID NO:37所示的氨基酸序列,且轻链可包含SEQ ID NO:38所示的氨基酸序列。其中,所述分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:25所示的氨基酸序列,HCDR2可包含SEQ ID NO:26所示的氨基酸序列,HCDR3可包含SEQ ID NO:27所示的氨基酸序列,且LCDR1可包含SEQ ID NO:28所示的氨基酸序列,LCDR2可包含SEQ ID NO:29所示的氨基酸序列,LCDR3可包含SEQ ID NO:30所示的氨基酸序列。此外,所述分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:15所示的氨基酸序列,H-FR2可包含SEQ ID NO:12所示的氨基酸序列,H-FR3可包含SEQ ID NO:13所示的氨基酸序列,H-FR4可包含SEQ ID NO:14所示的氨基酸序列,且L-FR1可包含SEQ ID NO:24所示的氨基酸序列,L-FR2可包含SEQ ID NO:21所示的氨基酸序列,L-FR3可包含SEQ ID NO:22所示的氨基酸序列,L-FR4可包含SEQ ID NO:23所示的氨基酸序列。此外,所述VH可包含SEQ ID NO:5所示的氨基酸序列,且所述VL可包含SEQ ID NO:6所示的氨基酸序列。例如,所述分离的抗原结合蛋白可以为6G12M21抗体。
此外,需要说明的是,本申请所述分离的抗原结合蛋白可以包含与6G12M11或6G12M21抗体存在一个或多个保守序列修饰的重链和/或轻链序列。所谓“保守序列修饰”是指不会显著影响或改变抗体结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和删除。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请所述分离的抗原结合蛋白中。保守氨基酸替换是氨基酸残基用具有相似侧链的氨基酸残基进行替换。具有相似侧链的氨基酸残基组在领域内已知。这些氨基酸残基组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。在某些实施方式中,本申请所述分离的抗原结合蛋白的CDR区中的一个或多个氨基酸残基可以用同侧链组的其他氨基酸残基替换。本领域内的技术人员知道,一些保守序列修改不会使抗原结合性消失,具体可以参见,例如,Brummell et al.,(1993)Biochem 32:1180-8;de Wildt et al.,(1997)Prot.Eng.10:835-41;Komissarov et al.,(1997)J.Biol.Chem.272:26864-26870;Hall et al.,(1992)J.Immunol.149:1605-12;Kelley and O'Connell(1993)Biochem.32:6862-35;Adib-Conquy et al.,(1998)Int.Immunol.10:341-6 and Beers et al.,(2000)Clin.Can.Res.6:2835-43。
在本申请中涉及的蛋白质、多肽和/或氨基酸序列,还应理解为至少包含以下的范围:与该所述蛋白质或多肽具备相同或类似功能的变体或同源物。
在本申请中,所述变体可以为,在所述蛋白质和/或所述多肽(例如,本申请所述分离的抗原结合蛋白)的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽。例如,所述变体可包含已经通过至少1个,例如1-30个、1-20个或1-10个,又例如1个、2个、3个、4个或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的蛋白质或多肽。所述功能性变体可基本上保持改变(例如取代、缺失或添加)之前的所述蛋白质或所述多肽的生物学特性。例如,所述功能性变体可保持改变之前的所述蛋白质或所述多肽的至少60%,70%,80%,90%,或100%的生物学活性(例如特异性结合AXL蛋白的能力)。
在本申请中,所述同源物可以为,与所述蛋白质和/或所述多肽(例如,本申请所述抗体或其抗原结合片段)的氨基酸序列具有至少约80%(例如,具有至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述同源性通常是指两个或多个序列之间的相似性或关联的程度。可以通过以下方式计算“序列同源性百分比”:将两条待比对的序列在比较窗中进行比较,确定两条序列中存在相同核酸碱基(例如,A、T、C、G、I)或相同氨基酸残基(例如,Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys和Met)的位置的数目以得到匹配位置的数目,将匹配位置的数目除以比较窗中的总位置数(即,窗大小),并且将结果乘以100,以产生序列同源性百分比。为了确定序列同源性百分数而进行的比对,可以按本领域已知的多种方式实现,例如,使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适宜参数,包括为实现正在比较的全长序列范围内或目标序列区域内最大比对所需要的任何算法。所述同源性也可以通过以下的方法测定:FASTA和BLAST。对FASTA算法的描述可以参见W.R.Pearson和D.J.Lipman的“用于生物学序列比较的改进的工具”,美国国家科学院院刊(Proc.Natl.Acad.Sci.),85:2444-2448,1988;和D.J.Lipman和W.R.Pearson的“快速灵敏的蛋白质相似性搜索”,Science,227:1435-1441,1989。对BLAST算法的描述可参见S.Altschul、W.Gish、W.Miller、E.W.Myers和D.Lipman的“一种基本的局部对比(alignment)搜索工具”,分子生物学杂志,215:403-410,1990。
免疫缀合物、核酸分子、载体、细胞和药物组合物
免疫缀合物
另一方面,本申请提供了一种免疫缀合物,其包含所述的分离的抗原结合蛋白。
例如,所述的免疫缀合物可以包含选自下组的至少一种其他试剂:化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂。在某些实施方式中,所述的免疫缀合物中所述分离的抗原结合蛋白与所述至少一种其他试剂可以通过连接分子相连。例如,所述的免疫缀合物中所述分离的抗原结合蛋白及所述至少一种其他试剂可以分别与所述连接分子共价相连。
在本申请中,所述其他试剂可以包括美登素(maytansine)或其衍生物。例如,所述美登素衍生物可以包括美登素衍生物DM1。
核酸分子
另一方面,本申请还提供了分离的一种或多种核酸分子,其可以编码本申请所述的分离的抗原结合蛋白。本申请所述的分离的一种或多种核酸分子可以为任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物,但可以编码本申请所述的分离的抗原结合蛋白。
载体
另一方面,本申请还提供了载体,其可以包含本申请所述的核酸分子。所述载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。例如,载体可以包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。又例如,所述载体可以含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,所述载体还可以含有复制起始位点。此外,所述载体还可以包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
细胞
另一方面,本申请还提供了细胞,其可以包含本申请所述的核酸分子或本申请所述的载体。所述细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。在某些实施方式中,所述细胞还可以包括用本发明所述的载体在体外转染的细胞。在某些实施方式中,所述细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、CHO-K1细胞、LNCAP细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞、骨髓瘤细胞、人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞或人多发性骨髓瘤RPMI8226细胞。在某些实施方案中,所述细胞可以为哺乳动物细胞。在某些实施方案中,所述哺乳动物细胞可以为HEK293细胞。
药物组合物
另一方面,本申请还提供了药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的免疫缀合物、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。
在某些实施方案中,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在某些实施方案中,所述药学上可接受的佐剂可以包括与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在某些实施方案中,所述药物组合物可以包含肠胃外、经皮、腔内、动脉内、鞘内和/或鼻内施用或直接注射到组织中。例如,所述药物组合物可以通过输注或注射施用于患者或者受试者。在某些实施方案中,所述药物组合物的施用可以通过不同的方式进行,例如静脉内、腹膜内、皮下、肌肉内、局部或真皮内施用。在某些实施方案中,所述药物组合物可以不间断施用。所述不间断(或连续)施用可以通过患者佩戴的小泵系统来实现,以测量流入患者体内的治疗剂,如WO2015/036583所述。
所述药物组合物的给药方案可以是施用快速灌注剂,可以随时间推移施用多个分剂量,或者剂量可以随治疗情况的危急程度成比例降低或提高。在某些实施方式中,治疗方案可以是每周施用一次、两周一次、三周一次、四周一次、一个月一次、3个月一次、或3-6个月一次。在某些实施方式中,给药方案包括静脉内施用,1mg/kg体重或3mg/kg体重,抗体以下述给药时间表中的一个进行给药:(i)每四周给药六次,然后每三个月一次;(ii)每三周一次;(iii)3mg/kg体重一次,之后1mg/kg体重每三周一次。在某些实施方式中,剂量调整成实现约1-1000μg/ml的血药浓度,例如可以为约25-300μg/ml。
制备方法和用途
制备方法
另一方面,本申请还提供了制备本申请所述的分离的抗原结合蛋白的方法,所述方法可以包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养本申请所述的细胞。
用途
另一方面,本申请还提供了所述分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
另一方面,本申请还提供了预防、缓解或治疗肿瘤的方法,所述方法可以包括向有需要的受试者施用本申请所述分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物。在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
另一方面,本申请所述分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物,其可以用于预防、缓解或治疗肿瘤。
在本申请中,所述肿瘤可以是实体瘤或血液瘤。
在本申请中,所述肿瘤可以包括AXL阳性的肿瘤。例如,所述AXL阳性的肿瘤可以选自:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。又例如,所述AXL阳性的肿瘤可以选自:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
在本申请中,所述受试者可以包括人类和非人类动物。例如,所述受试者可以包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,所述分离的抗原结合蛋白可以与一种或多种其他抗体一起施用,以便有效抑制受试者中的肿瘤生长。在某些实施方式中,可以向受试者施用所述分离的抗原结合蛋白以及一种或多种其他抗体,例如LAG-3抗体、PD-1抗体和/或CTLA-4抗体。
在本申请中,所述分离的抗原结合蛋白可以与化疗剂一起施用,所述化疗剂可以是细胞毒性剂,例如,SN-38、表阿霉素、奥沙利铂、和/或5-FU。
另一方面,本申请提供了根据所述的分离的抗原结合蛋白,其用于诊断与AXL蛋白的表达相关的疾病或病况。
另一方面,本申请提供了根据所述的抗体或其抗原结合片段用于制备诊断剂的用途,其中所述诊断剂用于诊断与AXL蛋白的表达相关的疾病或病况。
在本申请中,所述诊断剂可以单独使用或者可以与仪器、器具、设备或系统组合使用。在疾病的预防、诊断、治疗监测、预后观察、健康状态评价以及遗传性疾病的预测过程中,可以使用所述诊断剂对人体样本(例如,各种体液、细胞、组织样本等)进行体外检测。所述诊断剂可以选自以下组:试剂、试剂盒、校准品和质控品。
所述体外检测的方法可以选自以下组:Western Blot、ELISA和免疫组化法。例如,所述试剂可以包括能够测量所述AXL蛋白表达量的试剂。例如,所述试剂可以选自以下组:用以实施Western Blot的试剂、用以实施ELISA的试剂和用以实施免疫组化法的试剂。
另一方面,本申请提供了一种诊断受试者中与AXL蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
另一方面,本申请提供了一种检测样品中AXL的方法,所述方法包括施用所述的分离的抗原结合蛋白。在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
在本申请中,所述与AXL蛋白的表达相关的疾病或病况可以选自以下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤,或者,可以选自以下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
此外,本申请还可以包括以下的实施方式:
1分离的抗原结合蛋白,其包含氨基酸序列SEQ ID NO:1所示的VH中的至少一个CDR;且包含氨基酸序列SEQ ID NO:2所示的VL中的至少一个CDR。
2根据实施方式1所述的分离的抗原结合蛋白,其具有下述性质中的一种或多种:
1)能够以1×10-7M或更低的KD与AXL蛋白相结合;
2)能够特异性识别在细胞表面表达的AXL蛋白;
3)结合在细胞表面表达的AXL蛋白后能够介导内化。
3根据实施方式2所述的分离的抗原结合蛋白,所述AXL蛋白包括人AXL蛋白。
4根据实施方式3所述的分离的抗原结合蛋白,所述人AXL蛋白包含SEQ ID NO:39所示的氨基酸序列。
5根据实施方式2-4中任一项所述的分离的抗原结合蛋白,所述AXL蛋白包含细胞外结构域。
6根据实施方式5所述的分离的抗原结合蛋白,所述细胞外结构域包含SEQ ID NO:40所示的氨基酸序列。
7根据实施方式2所述的分离的抗原结合蛋白,所述细胞包括肿瘤细胞。
8根据实施方式7所述的分离的抗原结合蛋白,所述肿瘤包括AXL阳性肿瘤。
9根据实施方式8所述的分离的抗原结合蛋白,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
10根据实施方式9所述的分离的抗原结合蛋白,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
11根据实施方式2所述的分离的抗原结合蛋白,所述细胞包括人的细胞。
12根据实施方式7或11所述的分离的抗原结合蛋白,所述细胞选自下组:人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞和人多发性骨髓瘤RPMI8226细胞。
13根据实施方式1所述的分离的抗原结合蛋白,所述VH包含HCDR1、HCDR2和HCDR3。
14根据实施方式13所述的分离的抗原结合蛋白,所述HCDR1包含SEQ ID NO:25所示的氨基酸序列。
15根据实施方式13所述的分离的抗原结合蛋白,所述HCDR2包含SEQ ID NO:26所示的氨基酸序列。
16根据实施方式13所述的分离的抗原结合蛋白,所述HCDR3包含SEQ ID NO:27所示的氨基酸序列。
17根据实施方式1所述的分离的抗原结合蛋白,所述VL包含LCDR1、LCDR2和LCDR3。
18根据实施方式17所述的分离的抗原结合蛋白,所述LCDR1包含SEQ ID NO:28所示的氨基酸序列。
19根据实施方式17所述的分离的抗原结合蛋白,所述LCDR2包含SEQ ID NO:29所示的氨基酸序列。
20根据实施方式17所述的分离的抗原结合蛋白,所述LCDR3包含SEQ ID NO:30所示的氨基酸序列。
21根据实施方式1或13所述的分离的抗原结合蛋白,所述VH包含框架区H-FR1,H-FR2,H-FR3,和H-FR4。
22根据实施方式21所述的分离的抗原结合蛋白,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:7所示的氨基酸序列。
23根据实施方式22所述的分离的抗原结合蛋白,所述H-FR1包含SEQ ID NO:11、15中任一项所示的氨基酸序列。
24根据实施方式21所述的分离的抗原结合蛋白,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:8所示的氨基酸序列。
25根据实施方式24所述的分离的抗原结合蛋白,所述H-FR2包含SEQ ID NO:12所示的氨基酸序列。
26根据实施方式21所述的分离的抗原结合蛋白,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:9所示的氨基酸序列。
27根据实施方式26所述的分离的抗原结合蛋白,所述H-FR3包含SEQ ID NO:13所示的氨基酸序列。
28根据实施方式21所述的分离的抗原结合蛋白,所述H-FR4的N末端与所述HCDR3的C末端相连,且所述H-FR4包含SEQ ID NO:10所示的氨基酸序列。
29根据实施方式28所述的分离的抗原结合蛋白,所述H-FR4包含SEQ ID NO:14所示的氨基酸序列。
30根据实施方式1、13-16和22-29中任一项所述的分离的抗原结合蛋白,所述VH包含SEQ ID NO:3、5中任一项所示的氨基酸序列。
31根据实施方式1或17所述的分离的抗原结合蛋白,所述VL包含框架区L-FR1,L-FR2,L-FR3,和L-FR4。
32根据实施方式31所述的分离的抗原结合蛋白,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:16所示的氨基酸序列。
33根据实施方式32所述的分离的抗原结合蛋白,所述L-FR1包含SEQ ID NO:20、24中任一项所示的氨基酸序列。
34根据实施方式31所述的分离的抗原结合蛋白,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:17所示的氨基酸序列。
35根据实施方式34所述的分离的抗原结合蛋白,所述L-FR2包含SEQ ID NO:21所示的氨基酸序列。
36根据实施方式31所述的分离的抗原结合蛋白,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:18所示的氨基酸序列。
37根据实施方式36所述的分离的抗原结合蛋白,所述L-FR3包含SEQ ID NO:22所示的氨基酸序列。
38根据实施方式31所述的分离的抗原结合蛋白,所述L-FR4的N末端与所述LCDR3的C末端相连,且所述L-FR4包含SEQ ID NO:19所示的氨基酸序列。
39根据实施方式38所述的分离的抗原结合蛋白,所述L-FR4包含SEQ ID NO:23所示的氨基酸序列。
40根据实施方式1、17-20和32-39中任一项所述的分离的抗原结合蛋白,所述VL包含SEQ ID NO:4、6中任一项所示的氨基酸序列。
41根据实施方式1-4、6-11、13-20、22-29和32-39中任一项所述的分离的抗原结合蛋白,其包含抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
42根据实施方式41所述的分离的抗原结合蛋白,所述抗体重链恒定区源自人IgG1重链恒定区或人IgG4重链恒定区。
43根据实施方式42所述的分离的抗原结合蛋白,所述抗体重链恒定区包含SEQ IDNO:33、41中任一项所示的氨基酸序列。
44根据实施方式1-4、6-11、13-20、22-29、32-39和42-43中任一项所述的分离的抗原结合蛋白,其包含抗体轻链恒定区,且所述抗体轻链恒定区包含人Igκ恒定区。
45根据实施方式44所述的分离的抗原结合蛋白,所述抗体轻链恒定区包含SEQ IDNO:34所示的氨基酸序列。
46根据实施方式1-4、6-11、13-20、22-29、32-39、42-43和45中任一项所述的分离的抗原结合蛋白,其包含抗体重链,且所述抗体重链包含SEQ ID NO:35、37中任一项所示的氨基酸序列。
47根据实施方式1-4、6-11、13-20、22-29、32-39、42-43和45中任一项所述的分离的抗原结合蛋白,其包含抗体轻链,且所述抗体轻链包含SEQ ID NO:36、38中任一项所示的氨基酸序列。
48根据实施方式1-4、6-11、13-20、22-29、32-39、42-43和45中任一项所述的分离的抗原结合蛋白,其包括抗体或其抗原结合片段。
49根据实施方式48所述的分离的抗原结合蛋白,所述抗体选自下组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体、人源化抗体和全人源抗体。
50根据实施方式48所述的分离的抗原结合蛋白,所述抗原结合片段选自下组:Fab、Fab’、F(ab)2、Fv、F(ab’)2、scFv、di-scFv和dAb片段。
51免疫缀合物,其包含实施方式1-50中任一项所述的分离的抗原结合蛋白。
52根据实施方式51所述的免疫缀合物,其还包含选自下组的至少一种其他试剂:化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂。
53根据实施方式52所述的免疫缀合物,所述分离的抗原结合蛋白与所述其他试剂通过连接分子相连。
54根据实施方式53所述的免疫缀合物,所述分离的抗原结合蛋白及所述其他试剂分别与所述连接分子共价相连。
55根据实施方式52-54中任一项所述的免疫缀合物,所述其他试剂包括美登素或其衍生物。
56根据实施方式55所述的免疫缀合物,所述美登素衍生物包括美登素衍生物DM1。
57分离的一种或多种核酸分子,其编码实施方式1-50中任一项所述的分离的抗原结合蛋白。
58载体,其包含实施方式57所述的核酸分子。
59细胞,其包含实施方式57所述的核酸分子或实施方式58所述的载体。
60药物组合物,其包含实施方式1-50中任一项所述的分离的抗原结合蛋白、实施方式51-56中任一项所述的免疫缀合物、实施方式57所述的核酸分子、实施方式58所述的载体和/或实施方式59所述的细胞,以及任选地药学上可接受的佐剂。
61制备实施方式1-50中任一项所述的分离的抗原结合蛋白的方法,所述方法包括在使得实施方式1-50中任一项所述的分离的抗原结合蛋白表达的条件下,培养实施方式59所述的细胞。
62实施方式1-50中任一项所述的分离的抗原结合蛋白、实施方式51-56中任一项所述的免疫缀合物、实施方式57所述的核酸分子、实施方式58所述的载体、实施方式59所述的细胞和/或实施方式60所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
63根据实施方式62所述的用途,所述肿瘤包括AXL阳性肿瘤。
64根据实施方式63所述的用途,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
65根据实施方式64所述的用途,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
66实施方式1-50中任一项所述的分离的抗原结合蛋白在制备诊断剂中的用途,所述诊断剂用于诊断与AXL蛋白的表达相关的疾病或病况。
67诊断受试者中与AXL蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与实施方式1-50中任一项所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
68检测样品中AXL的方法,所述方法包括施用实施方式1-50中任一项所述的分离的抗原结合蛋白。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的蛋白质分子、制备方法和用途等,而不用于限制本申请发明的范围。实施例不包括对传统方法的详细描述,如那些用于构建载体和质粒的方法,将编码蛋白的基因插入到这样的载体和质粒的方法或将质粒引入宿主细胞的方法。这样的方法对于本领域中具有普通技术的人员是众所周知的,并且在许多出版物中都有所描述,包括Sambrook,J.,Fritsch,E.F.and Maniais,T.(1989)Molecular Cloning:A Laboratory Manual,2nd edition,Cold spring HarborLaboratory Press。
实施例
实施例1.抗体识别靶抗原
将靶抗原AXL-His(北京义翘神州科技有限公司)包被ELISA板条,1μg/ml,4℃过夜;PBST洗涤后,加入10%的胎牛血清,37℃封闭1小时;加入不同浓度的6G12M11和6G12M21抗体,37℃反应1小时;PBST洗涤后,加入辣根过氧化物酶标记的羊抗小鼠二抗(Goat Anti-mouse IgG HRP,Abcam),37℃反应30分钟;PBST重复洗板5遍,在吸水纸上尽量拍干残留液滴;每孔加入100μl TMB(eBioscience),室温(20±5℃)避光放置1.5min;每孔加入100μl2N H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,分析抗体与靶抗原AXL结合能力。其中,6G12M11抗体的重链氨基酸序列如SEQ ID NO:35所示,轻链氨基酸序列如SEQ ID NO:36所示;6G12M21抗体的重链氨基酸序列如SEQ ID NO:37所示,轻链氨基酸序列如SEQ IDNO:38所示。
试验结果如图1所示,可以看出,6G12M11和6G12M21抗体均能特异性识别靶抗原AXL;该识别活性呈显著的剂量依赖性,6G12M11的EC50值为27.03ng/mL,6G12M21的EC50值为25.29ng/mL。
实施例2.抗体亲和力测定
本实验运用表面等离子共振技术检测AXL-His与6G12M11和6G12M21抗体的亲和力。试验仪器采用的是BIACOR生物大分子相互作用仪(GE Healthcare,T-200)。首先采用抗体捕获法将6G12M11和6G12M21抗体固定于芯片表面上,二者浓度定为0.5μg/mL,以流速10μL/min进样60秒;将配制好的AXL-His(北京义翘神州生物技术有限公司,6×His标签,分子量为47.5Kda)为流动相,使用5个浓度梯度(8、4、2、1、0.5μg/mL)分别流经芯片表面,进行相互作用测定;AXL-His以30μL/min流速结合120s,解离1800s。抗原抗体亲和力的结果如表1所示,可以看出,本申请所述的分离的抗原结合蛋白能够以1×10-7M或更低的KD与AXL蛋白相结合。
表1.抗体的亲和力测定结果
抗体 | 结合常数Ka(1/Ms) | 解离常数Kd(1/s) | 相对亲和力KD(M) |
6G12M11 | 9.742E+04 | 1.136E-03 | 1.166E-08 |
6G12M21 | 1.119E+05 | 1.137E-03 | 1.016E-08 |
实施例3.抗体特异性识别靶抗原
AXL、TRYO3、MER同属于TYRO3受体酪氨酸激酶亚家族,为验证6G12M11和6G12M21抗体的识别特异性,利用ELISA法检测抗体与AXL同家族其它成员的结合能力。
将TYRO3-Fc(ACRO Biosystems)、MER-His(ACRO Biosystems)以及AXL-His(北京义翘神州科技有限公司)分别包被ELISA板条,1μg/ml,4℃过夜;PBST洗涤后,加入10%的胎牛血清,37℃封闭1小时;加入6G12M11和6G12M21抗体,37℃反应1小时;PBST洗涤后,加入辣根过氧化物酶标记的羊抗人IgG Fab二抗(Goat Anti-Human IgG(Fab')2(HRP),Abcam),室温反应30分钟;PBST重复洗板5遍,在吸水纸上尽量拍干残留液滴;每孔加入100μl TMB(eBioscience,#85-00-420),室温(20±5℃)避光放置1.5分钟;每孔加入100μl 2N H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,分析抗体与蛋白结合能力。
结果如图2和图3所示,可以看出,6G12M11和6G12M21抗体能特异性识别靶抗原AXL,但与AXL同家族的其它蛋白TYRO3、MER均不结合。
实施例4.抗体特异性识别细胞表面抗原
利用流式分析技术检测人非小细胞肺癌A549细胞、人乳腺癌MDA-MB-231细胞和肾透明细胞腺癌786-O细胞表面的AXL与6G12M11和6G12M21抗体的结合。收集对数生长期细胞,调整细胞密度到5×106个/mL,冰上预冷。含2%FBS预冷的生理盐水稀释6G12M11和6G12M21抗体至20μg/ml。取100μl细胞,加入等体积前述稀释抗体,4℃避光反应30min。结束后,用含2%FBS预冷的生理盐水洗两次(6000rpm,45s)。用含2%FBS预冷的生理盐水按1∶5稀释二抗PE Mouse Anti-Human IgG(BD Pharmingen),取100μL重悬细胞,4℃避光反应30min。反应结束后,用含2%FBS预冷的生理盐水洗两次(6000rpm,45s)。用400μl 1%多聚甲醛重悬细胞。流式细胞仪(BD Calibur)分析抗体与细胞表面抗原的结合能力。
结果如图4、图5和图6所示,可以看出,6G12M11和6G12M21抗体能特异且剂量依赖性识别人非小细胞肺癌A549细胞、人乳腺癌MDA-MB-231细胞和肾透明细胞腺癌786-O细胞表面的AXL,6G12M11和6G12M21抗体识别能力相似。其中,6G12M11和6G12M21抗体,与A549细胞结合的EC50值分别为0.46μg/mL、0.78μg/mL;与MDA-MB-231细胞结合的EC50值分别为0.59μg/mL、0.39μg/mL;与786-O细胞结合的EC50值分别为0.43μg/mL、0.31μg/mL。
实施例5.抗体的内化活性
利用流式分析技术检测6G12M11和6G12M21抗体在人非小细胞肺癌A549细胞、人乳腺癌MDA-MB-231细胞、肾透明细胞腺癌786-O细胞上的内化效率。收集对数生长期细胞,调整细胞密度到5×10 6个/mL,冰上预冷。含2%FBS预冷的生理盐水稀释6G12M11和6G12M21抗体至不同浓度。取100μl细胞,加入等体积前述稀释抗体,4℃孵育30分钟。结束后,用含2%FBS预冷的生理盐水洗涤细胞三次。将细胞继续放置于4℃或37℃培养2小时后洗涤细胞两次。用含2%FBS预冷的生理盐水按1∶5稀释二抗PE Mouse Anti-Human IgG(BDPharmingen),取100μL重悬细胞,4℃避光反应30分钟。反应结束后,洗涤细胞三次。用400μl1%多聚甲醛重悬细胞。流式细胞仪(BD Calibur)分析抗体在不同温度下培养细胞表面的荧光强度,并按照以下公式计算出抗体的内化效率。
内化效率=(4℃表面总MFI-37℃表面总MFI)/4℃表面总MFI×100%。
结果如图7、图8和图9所示,可以看出,6G12M11和6G12M21抗体在人非小细胞肺癌A549细胞、人乳腺癌MDA-MB-231细胞、肾透明细胞腺癌786-O细胞上均可以有效的内化,内化效率相似,说明6G12M11和6G12M21抗体具备良好的内化活性。
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
序列表
<110> 尚健单抗(北京)生物技术有限公司;杭州尚健生物技术有限公司
<120> 一种分离的结合抗原AXL的蛋白及其用途
<130> 0070-PA-016
<160> 41
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VH通式
<220>
<221> X
<222> (5)..(5)
<223> X可以是K或V
<220>
<221> X
<222> (23)..(23)
<223> X可以是S或A
<220>
<221> X
<222> (25)..(25)
<223> X可以是T或S
<220>
<221> X
<222> (27)..(27)
<223> X可以是F、Y、D或S
<220>
<221> X
<222> (41)..(41)
<223> X可以是F或S
<220>
<221> X
<222> (44)..(44)
<223> X可以是N或Q
<220>
<221> X
<222> (45)..(45)
<223> X可以是K或G
<220>
<221> X
<222> (88)..(88)
<223> X可以是T或S
<220>
<221> X
<222> (114)..(114)
<223> X可以是S或T
<400> 1
Gln Val Gln Leu Xaa Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Xaa Val Xaa Gly Xaa Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Xaa Pro Gly Xaa Xaa Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Xaa Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Xaa Val Thr Val Ser Ser
115
<210> 2
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL通式
<220>
<221> X
<222> (1)..(1)
<223> X可以是E或D
<220>
<221> X
<222> (2)..(2)
<223> X可以是L或I
<220>
<221> X
<222> (9)..(9)
<223> X可以是F或S
<220>
<221> X
<222> (11)..(11)
<223> X可以是N或V
<220>
<221> X
<222> (12)..(12)
<223> X可以是A或S
<220>
<221> X
<222> (17)..(17)
<223> X可以是T或Q
<220>
<221> X
<222> (42)..(42)
<223> X可以是L或Q
<220>
<221> X
<222> (69)..(69)
<223> X可以是S或G
<220>
<221> X
<222> (79)..(79)
<223> X可以是R或K
<220>
<221> X
<222> (105)..(105)
<223> X可以是A或G
<220>
<221> X
<222> (111)..(111)
<223> X可以是L或I
<400> 2
Xaa Xaa Val Met Thr Gln Ser Pro Xaa Ser Xaa Xaa Val Thr Leu Gly
1 5 10 15
Xaa Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Xaa Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Xaa Ser Gly Ser Gly Thr Asp Phe Thr Leu Xaa Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Xaa Gly Thr Lys Leu Glu Xaa Lys
100 105 110
<210> 3
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的VH
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ala Val Thr Gly Phe Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Gln Lys Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 4
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的VL
<400> 4
Glu Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala 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 Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 5
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的VH
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Phe Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Gln Lys Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 6
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的VL
<400> 6
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala 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 Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 7
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR1通式
<220>
<221> X
<222> (5)..(5)
<223> X可以是K或V
<220>
<221> X
<222> (23)..(23)
<223> X可以是S或A
<220>
<221> X
<222> (25)..(25)
<223> X可以是T或S
<220>
<221> X
<222> (27)..(27)
<223> X可以是F、Y、D或S
<400> 7
Gln Val Gln Leu Xaa Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Xaa Val Xaa Gly Xaa Ser Ile Ser
20 25 30
<210> 8
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR2通式
<220>
<221> X
<222> (5)..(5)
<223> X可以是F或S
<220>
<221> X
<222> (8)..(8)
<223> X可以是N或Q
<220>
<221> X
<222> (9)..(9)
<223> X可以是K或G
<400> 8
Trp Ile Arg Gln Xaa Pro Gly Xaa Xaa Leu Glu Trp Met Gly
1 5 10
<210> 9
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR3通式
<220>
<221> X
<222> (22)..(22)
<223> X可以是T或S
<400> 9
Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Lys
1 5 10 15
Leu Asn Ser Val Thr Xaa Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 10
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> H-FR4通式
<220>
<221> X
<222> (6)..(6)
<223> X可以是S或T
<400> 10
Trp Gly Gln Gly Thr Xaa Val Thr Val Ser Ser
1 5 10
<210> 11
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的H-FR1
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ala Val Thr Gly Phe Ser Ile Ser
20 25 30
<210> 12
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的H-FR2
<400> 12
Trp Ile Arg Gln Phe Pro Gly Gln Lys Leu Glu Trp Met Gly
1 5 10
<210> 13
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的H-FR3
<400> 13
Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Lys
1 5 10 15
Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 14
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的H-FR4
<400> 14
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 15
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的H-FR1
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Phe Ser Ile Ser
20 25 30
<210> 16
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR1通式
<220>
<221> X
<222> (1)..(1)
<223> X可以是E或D
<220>
<221> X
<222> (2)..(2)
<223> X可以是L或I
<220>
<221> X
<222> (9)..(9)
<223> X可以是F或S
<220>
<221> X
<222> (11)..(11)
<223> X可以是N或V
<220>
<221> X
<222> (12)..(12)
<223> X可以是A或S
<220>
<221> X
<222> (17)..(17)
<223> X可以是T或Q
<400> 16
Xaa Xaa Val Met Thr Gln Ser Pro Xaa Ser Xaa Xaa Val Thr Leu Gly
1 5 10 15
Xaa Ser Ala Ser Ile Ser Cys
20
<210> 17
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR2通式
<220>
<221> X
<222> (3)..(3)
<223> X可以是L或Q
<400> 17
Trp Tyr Xaa Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 18
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR3通式
<220>
<221> X
<222> (8)..(8)
<223> X可以是S或G
<220>
<221> X
<222> (18)..(18)
<223> X可以是R或K
<400> 18
Gly Val Pro Asp Arg Phe Ser Xaa Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Xaa Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 19
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> L-FR4通式
<220>
<221> X
<222> (3)..(3)
<223> X可以是A或G
<220>
<221> X
<222> (9)..(9)
<223> X可以是L或I
<400> 19
Phe Gly Xaa Gly Thr Lys Leu Glu Xaa Lys
1 5 10
<210> 20
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的L-FR1
<400> 20
Glu Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys
20
<210> 21
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的L-FR2
<400> 21
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 22
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的L-FR3
<400> 22
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 23
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M121的L-FR4
<400> 23
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 24
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的L-FR1
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys
20
<210> 25
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的HCDR1
<400> 25
Ser Gly Tyr Tyr Trp Asn
1 5
<210> 26
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的HCDR2
<400> 26
Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
<210> 27
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的HCDR3
<400> 27
Gly Trp Leu Leu His Tyr Thr Met Asp Tyr
1 5 10
<210> 28
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的LCDR1
<400> 28
Arg Ser Ser Arg Ser Leu Leu His Ser Asn Gly Phe Thr Tyr Leu Tyr
1 5 10 15
<210> 29
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的LCDR2
<400> 29
Gln Met Ser Asn Leu Ala Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11/6G12M21/6G12 的LCDR3
<400> 30
Gly Gln Asn Leu Glu Leu Pro Leu Thr
1 5
<210> 31
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12的VH
<400> 31
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Phe Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 32
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12的VL
<400> 32
Glu Leu Val Met Thr Gln Ser Pro Phe Ser Asn Ala Val Thr Leu Gly
1 5 10 15
Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 33
<211> 330
<212> PRT
<213> Homo sapiens
<400> 33
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 34
<211> 107
<212> PRT
<213> Homo sapiens
<400> 34
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 35
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的重链
<400> 35
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ala Val Thr Gly Phe Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Gln Lys Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr 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> 36
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M11的轻链
<400> 36
Glu Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala 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 Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 37
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的重链
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Phe Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Gln Lys Leu Glu Trp
35 40 45
Met Gly Tyr Arg Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Leu His Tyr Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr 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> 38
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 6G12M21的轻链
<400> 38
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Val Thr Leu Gly
1 5 10 15
Gln Ser Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Leu His Ser
20 25 30
Asn Gly Phe Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala 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 Val Gly Val Tyr Tyr Cys Gly Gln Asn
85 90 95
Leu Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 39
<211> 894
<212> PRT
<213> Homo sapiens
<400> 39
Met Ala Trp Arg Cys Pro Arg Met Gly Arg Val Pro Leu Ala Trp Cys
1 5 10 15
Leu Ala Leu Cys Gly Trp Ala Cys Met Ala Pro Arg Gly Thr Gln Ala
20 25 30
Glu Glu Ser Pro Phe Val Gly Asn Pro Gly Asn Ile Thr Gly Ala Arg
35 40 45
Gly Leu Thr Gly Thr Leu Arg Cys Gln Leu Gln Val Gln Gly Glu Pro
50 55 60
Pro Glu Val His Trp Leu Arg Asp Gly Gln Ile Leu Glu Leu Ala Asp
65 70 75 80
Ser Thr Gln Thr Gln Val Pro Leu Gly Glu Asp Glu Gln Asp Asp Trp
85 90 95
Ile Val Val Ser Gln Leu Arg Ile Thr Ser Leu Gln Leu Ser Asp Thr
100 105 110
Gly Gln Tyr Gln Cys Leu Val Phe Leu Gly His Gln Thr Phe Val Ser
115 120 125
Gln Pro Gly Tyr Val Gly Leu Glu Gly Leu Pro Tyr Phe Leu Glu Glu
130 135 140
Pro Glu Asp Arg Thr Val Ala Ala Asn Thr Pro Phe Asn Leu Ser Cys
145 150 155 160
Gln Ala Gln Gly Pro Pro Glu Pro Val Asp Leu Leu Trp Leu Gln Asp
165 170 175
Ala Val Pro Leu Ala Thr Ala Pro Gly His Gly Pro Gln Arg Ser Leu
180 185 190
His Val Pro Gly Leu Asn Lys Thr Ser Ser Phe Ser Cys Glu Ala His
195 200 205
Asn Ala Lys Gly Val Thr Thr Ser Arg Thr Ala Thr Ile Thr Val Leu
210 215 220
Pro Gln Gln Pro Arg Asn Leu His Leu Val Ser Arg Gln Pro Thr Glu
225 230 235 240
Leu Glu Val Ala Trp Thr Pro Gly Leu Ser Gly Ile Tyr Pro Leu Thr
245 250 255
His Cys Thr Leu Gln Ala Val Leu Ser Asp Asp Gly Met Gly Ile Gln
260 265 270
Ala Gly Glu Pro Asp Pro Pro Glu Glu Pro Leu Thr Ser Gln Ala Ser
275 280 285
Val Pro Pro His Gln Leu Arg Leu Gly Ser Leu His Pro His Thr Pro
290 295 300
Tyr His Ile Arg Val Ala Cys Thr Ser Ser Gln Gly Pro Ser Ser Trp
305 310 315 320
Thr His Trp Leu Pro Val Glu Thr Pro Glu Gly Val Pro Leu Gly Pro
325 330 335
Pro Glu Asn Ile Ser Ala Thr Arg Asn Gly Ser Gln Ala Phe Val His
340 345 350
Trp Gln Glu Pro Arg Ala Pro Leu Gln Gly Thr Leu Leu Gly Tyr Arg
355 360 365
Leu Ala Tyr Gln Gly Gln Asp Thr Pro Glu Val Leu Met Asp Ile Gly
370 375 380
Leu Arg Gln Glu Val Thr Leu Glu Leu Gln Gly Asp Gly Ser Val Ser
385 390 395 400
Asn Leu Thr Val Cys Val Ala Ala Tyr Thr Ala Ala Gly Asp Gly Pro
405 410 415
Trp Ser Leu Pro Val Pro Leu Glu Ala Trp Arg Pro Gly Gln Ala Gln
420 425 430
Pro Val His Gln Leu Val Lys Glu Pro Ser Thr Pro Ala Phe Ser Trp
435 440 445
Pro Trp Trp Tyr Val Leu Leu Gly Ala Val Val Ala Ala Ala Cys Val
450 455 460
Leu Ile Leu Ala Leu Phe Leu Val His Arg Arg Lys Lys Glu Thr Arg
465 470 475 480
Tyr Gly Glu Val Phe Glu Pro Thr Val Glu Arg Gly Glu Leu Val Val
485 490 495
Arg Tyr Arg Val Arg Lys Ser Tyr Ser Arg Arg Thr Thr Glu Ala Thr
500 505 510
Leu Asn Ser Leu Gly Ile Ser Glu Glu Leu Lys Glu Lys Leu Arg Asp
515 520 525
Val Met Val Asp Arg His Lys Val Ala Leu Gly Lys Thr Leu Gly Glu
530 535 540
Gly Glu Phe Gly Ala Val Met Glu Gly Gln Leu Asn Gln Asp Asp Ser
545 550 555 560
Ile Leu Lys Val Ala Val Lys Thr Met Lys Ile Ala Ile Cys Thr Arg
565 570 575
Ser Glu Leu Glu Asp Phe Leu Ser Glu Ala Val Cys Met Lys Glu Phe
580 585 590
Asp His Pro Asn Val Met Arg Leu Ile Gly Val Cys Phe Gln Gly Ser
595 600 605
Glu Arg Glu Ser Phe Pro Ala Pro Val Val Ile Leu Pro Phe Met Lys
610 615 620
His Gly Asp Leu His Ser Phe Leu Leu Tyr Ser Arg Leu Gly Asp Gln
625 630 635 640
Pro Val Tyr Leu Pro Thr Gln Met Leu Val Lys Phe Met Ala Asp Ile
645 650 655
Ala Ser Gly Met Glu Tyr Leu Ser Thr Lys Arg Phe Ile His Arg Asp
660 665 670
Leu Ala Ala Arg Asn Cys Met Leu Asn Glu Asn Met Ser Val Cys Val
675 680 685
Ala Asp Phe Gly Leu Ser Lys Lys Ile Tyr Asn Gly Asp Tyr Tyr Arg
690 695 700
Gln Gly Arg Ile Ala Lys Met Pro Val Lys Trp Ile Ala Ile Glu Ser
705 710 715 720
Leu Ala Asp Arg Val Tyr Thr Ser Lys Ser Asp Val Trp Ser Phe Gly
725 730 735
Val Thr Met Trp Glu Ile Ala Thr Arg Gly Gln Thr Pro Tyr Pro Gly
740 745 750
Val Glu Asn Ser Glu Ile Tyr Asp Tyr Leu Arg Gln Gly Asn Arg Leu
755 760 765
Lys Gln Pro Ala Asp Cys Leu Asp Gly Leu Tyr Ala Leu Met Ser Arg
770 775 780
Cys Trp Glu Leu Asn Pro Gln Asp Arg Pro Ser Phe Thr Glu Leu Arg
785 790 795 800
Glu Asp Leu Glu Asn Thr Leu Lys Ala Leu Pro Pro Ala Gln Glu Pro
805 810 815
Asp Glu Ile Leu Tyr Val Asn Met Asp Glu Gly Gly Gly Tyr Pro Glu
820 825 830
Pro Pro Gly Ala Ala Gly Gly Ala Asp Pro Pro Thr Gln Pro Asp Pro
835 840 845
Lys Asp Ser Cys Ser Cys Leu Thr Ala Ala Glu Val His Pro Ala Gly
850 855 860
Arg Tyr Val Leu Cys Pro Ser Thr Thr Pro Ser Pro Ala Gln Pro Ala
865 870 875 880
Asp Arg Gly Ser Pro Ala Ala Pro Gly Gln Glu Asp Gly Ala
885 890
<210> 40
<211> 425
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人AXL蛋白的细胞外结构域
<400> 40
Pro Arg Gly Thr Gln Ala Glu Glu Ser Pro Phe Val Gly Asn Pro Gly
1 5 10 15
Asn Ile Thr Gly Ala Arg Gly Leu Thr Gly Thr Leu Arg Cys Gln Leu
20 25 30
Gln Val Gln Gly Glu Pro Pro Glu Val His Trp Leu Arg Asp Gly Gln
35 40 45
Ile Leu Glu Leu Ala Asp Ser Thr Gln Thr Gln Val Pro Leu Gly Glu
50 55 60
Asp Glu Gln Asp Asp Trp Ile Val Val Ser Gln Leu Arg Ile Thr Ser
65 70 75 80
Leu Gln Leu Ser Asp Thr Gly Gln Tyr Gln Cys Leu Val Phe Leu Gly
85 90 95
His Gln Thr Phe Val Ser Gln Pro Gly Tyr Val Gly Leu Glu Gly Leu
100 105 110
Pro Tyr Phe Leu Glu Glu Pro Glu Asp Arg Thr Val Ala Ala Asn Thr
115 120 125
Pro Phe Asn Leu Ser Cys Gln Ala Gln Gly Pro Pro Glu Pro Val Asp
130 135 140
Leu Leu Trp Leu Gln Asp Ala Val Pro Leu Ala Thr Ala Pro Gly His
145 150 155 160
Gly Pro Gln Arg Ser Leu His Val Pro Gly Leu Asn Lys Thr Ser Ser
165 170 175
Phe Ser Cys Glu Ala His Asn Ala Lys Gly Val Thr Thr Ser Arg Thr
180 185 190
Ala Thr Ile Thr Val Leu Pro Gln Gln Pro Arg Asn Leu His Leu Val
195 200 205
Ser Arg Gln Pro Thr Glu Leu Glu Val Ala Trp Thr Pro Gly Leu Ser
210 215 220
Gly Ile Tyr Pro Leu Thr His Cys Thr Leu Gln Ala Val Leu Ser Asp
225 230 235 240
Asp Gly Met Gly Ile Gln Ala Gly Glu Pro Asp Pro Pro Glu Glu Pro
245 250 255
Leu Thr Ser Gln Ala Ser Val Pro Pro His Gln Leu Arg Leu Gly Ser
260 265 270
Leu His Pro His Thr Pro Tyr His Ile Arg Val Ala Cys Thr Ser Ser
275 280 285
Gln Gly Pro Ser Ser Trp Thr His Trp Leu Pro Val Glu Thr Pro Glu
290 295 300
Gly Val Pro Leu Gly Pro Pro Glu Asn Ile Ser Ala Thr Arg Asn Gly
305 310 315 320
Ser Gln Ala Phe Val His Trp Gln Glu Pro Arg Ala Pro Leu Gln Gly
325 330 335
Thr Leu Leu Gly Tyr Arg Leu Ala Tyr Gln Gly Gln Asp Thr Pro Glu
340 345 350
Val Leu Met Asp Ile Gly Leu Arg Gln Glu Val Thr Leu Glu Leu Gln
355 360 365
Gly Asp Gly Ser Val Ser Asn Leu Thr Val Cys Val Ala Ala Tyr Thr
370 375 380
Ala Ala Gly Asp Gly Pro Trp Ser Leu Pro Val Pro Leu Glu Ala Trp
385 390 395 400
Arg Pro Gly Gln Ala Gln Pro Val His Gln Leu Val Lys Glu Pro Ser
405 410 415
Thr Pro Ala Phe Ser Trp Pro Trp Trp
420 425
<210> 41
<211> 229
<212> PRT
<213> Homo sapiens
<400> 41
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
Claims (39)
1. 分离的抗原结合蛋白,其能够与AXL蛋白相结合,所述分离的抗原结合蛋白包含重链可变区VH和轻链可变区VL,其中所述VH和VL的氨基酸序列选自以下任一组:
1) 所述VH的氨基酸序列如SEQ ID NO:3所示,所述VL的氨基酸序列如SEQ ID NO: 4所示;以及
2) 所述VH的氨基酸序列如SEQ ID NO:5所示,所述VL的氨基酸序列如SEQ ID NO: 6所示。
2.根据权利要求1所述的分离的抗原结合蛋白,其具有下述性质中的一种或多种:
1)能够以1×10-7M或更低的KD与AXL蛋白相结合;
2)能够特异性识别在细胞表面表达的AXL蛋白;
3)结合在细胞表面表达的AXL蛋白后能够介导内化。
3.根据权利要求2所述的分离的抗原结合蛋白,所述AXL蛋白为人AXL蛋白。
4. 根据权利要求3所述的分离的抗原结合蛋白,所述人AXL蛋白的氨基酸序列如SEQID NO : 39所示。
5.根据权利要求1所述的分离的抗原结合蛋白,所述AXL蛋白包含细胞外结构域。
6. 根据权利要求5所述的分离的抗原结合蛋白,所述细胞外结构域的氨基酸序列如SEQ ID NO : 40所示。
7.根据权利要求2所述的分离的抗原结合蛋白,所述细胞为肿瘤细胞。
8.根据权利要求7所述的分离的抗原结合蛋白,所述肿瘤为AXL阳性肿瘤。
9.根据权利要求8所述的分离的抗原结合蛋白,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
10.根据权利要求9所述的分离的抗原结合蛋白,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
11.根据权利要求2所述的分离的抗原结合蛋白,所述细胞为人的细胞。
12. 根据权利要求2所述的分离的抗原结合蛋白,所述细胞选自下组:人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIA PaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞和人多发性骨髓瘤RPMI8226细胞。
13.根据权利要求1所述的分离的抗原结合蛋白,其包含抗体重链恒定区,且所述抗体重链恒定区源自人IgG重链恒定区。
14.根据权利要求13所述的分离的抗原结合蛋白,所述抗体重链恒定区源自人IgG1重链恒定区或人IgG4重链恒定区。
15. 根据权利要求14所述的分离的抗原结合蛋白,所述抗体重链恒定区的氨基酸序列为SEQ ID NO: 33或SEQ ID NO: 41所示的氨基酸序列。
16.根据权利要求1所述的分离的抗原结合蛋白,其包含抗体轻链恒定区,且所述抗体轻链恒定区包含人Igκ恒定区。
17. 根据权利要求16所述的分离的抗原结合蛋白,所述抗体轻链恒定区的氨基酸序列为SEQ ID NO: 34所示的氨基酸序列。
18. 根据权利要求1所述的分离的抗原结合蛋白,其包含抗体重链,且所述抗体重链的氨基酸序列为SEQ ID NO: 35或SEQ ID NO: 37所示的氨基酸序列。
19. 根据权利要求1所述的分离的抗原结合蛋白,其包含抗体轻链,且所述抗体轻链的氨基酸序列为SEQ ID NO: 36或SEQ ID NO:38所示的氨基酸序列。
20.根据权利要求1所述的分离的抗原结合蛋白,其包括抗体或其抗原结合片段。
21.根据权利要求20所述的分离的抗原结合蛋白,所述抗体选自下组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体和/或人源化抗体。
22.根据权利要求20所述的分离的抗原结合蛋白,所述抗原结合片段选自下组:Fab、Fab’、F(ab)2、Fv、F(ab’)2、scFv和/或di-scFv。
23.免疫缀合物,其包含权利要求1-22中任一项所述的分离的抗原结合蛋白。
24.根据权利要求23所述的免疫缀合物,其还包含选自下组的至少一种其他试剂:化疗剂、放射性元素、细胞生长抑制剂和细胞毒性剂。
25.根据权利要求24所述的免疫缀合物,所述分离的抗原结合蛋白与所述其他试剂通过连接分子相连。
26.根据权利要求25所述的免疫缀合物,所述分离的抗原结合蛋白及所述其他试剂分别与所述连接分子共价相连。
27.根据权利要求24-26中任一项所述的免疫缀合物,所述其他试剂为美登素或其衍生物。
28.根据权利要求27所述的免疫缀合物,所述美登素衍生物为美登素衍生物DM1。
29.分离的一种或多种核酸分子,其编码权利要求1-22中任一项所述的分离的抗原结合蛋白。
30.载体,其包含权利要求29所述的核酸分子。
31.细胞,其包含权利要求29所述的核酸分子或权利要求30所述的载体。
32.药物组合物,其包含权利要求1-22中任一项所述的分离的抗原结合蛋白、权利要求23-28中任一项所述的免疫缀合物和/或权利要求31所述的细胞,以及任选地药学上可接受的佐剂。
33.制备权利要求1-22中任一项所述的分离的抗原结合蛋白的方法,所述方法包括在使得权利要求1-22中任一项所述的分离的抗原结合蛋白表达的条件下,培养权利要求31所述的细胞。
34.权利要求1-22中任一项所述的分离的抗原结合蛋白、权利要求23-28中任一项所述的免疫缀合物、权利要求29所述的核酸分子、权利要求30所述的载体、权利要求31所述的细胞和/或权利要求32所述的药物组合物在制备药物中的用途,所述药物用于预防、缓解和/或治疗肿瘤。
35.根据权利要求34所述的用途,所述肿瘤为AXL阳性肿瘤。
36.根据权利要求35所述的用途,所述肿瘤选自下组:肺癌、皮肤癌、肾癌、胰腺癌、血液肿瘤、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
37.根据权利要求36所述的用途,所述肿瘤选自下组:非小细胞肺癌、皮肤鳞癌、肾透明细胞腺癌、胰腺癌、红白血病、急性T细胞白血病、乳腺癌、卵巢癌、淋巴瘤和骨髓瘤。
38.权利要求1-22中任一项所述的分离的抗原结合蛋白在制备诊断剂中的用途,所述诊断剂用于诊断与AXL蛋白的表达相关的疾病或病况。
39.一种检测AXL蛋白的检测试剂盒,其包含权利要求1-22中任一项所述的分离的抗原结合蛋白,权利要求23-28中任一项所述的免疫缀合物、权利要求29所述的核酸分子、权利要求30所述的载体和/或权利要求31所述的细胞。
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JP2022530881A JP2023504244A (ja) | 2019-11-28 | 2020-11-27 | 単離結合抗原axlタンパク質及びその用途 |
CA3159802A CA3159802A1 (en) | 2019-11-28 | 2020-11-27 | Separated antigen axl binding protein and use thereof |
KR1020227021710A KR20220119389A (ko) | 2019-11-28 | 2020-11-27 | 분리된 항원 axl 결합 단백질 및 그의 용도 |
EP20893377.0A EP4067384A1 (en) | 2019-11-28 | 2020-11-27 | Separated antigen axl binding protein and use thereof |
AU2020390381A AU2020390381A1 (en) | 2019-11-28 | 2020-11-27 | Separated antigen AXL binding protein and use thereof |
US17/780,932 US20220411531A1 (en) | 2019-11-28 | 2020-11-27 | Separated antigen axl binding protein and use thereof |
PCT/CN2020/132456 WO2021104496A1 (zh) | 2019-11-28 | 2020-11-27 | 一种分离的结合抗原axl的蛋白及其用途 |
TW109141730A TW202120559A (zh) | 2019-11-28 | 2020-11-27 | 一種分離的結合抗原axl的蛋白及其用途 |
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