CN116143902A - SIRPα变体及其应用 - Google Patents
SIRPα变体及其应用 Download PDFInfo
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- CN116143902A CN116143902A CN202111376099.1A CN202111376099A CN116143902A CN 116143902 A CN116143902 A CN 116143902A CN 202111376099 A CN202111376099 A CN 202111376099A CN 116143902 A CN116143902 A CN 116143902A
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Abstract
本申请涉及一种SIRPα变体及其融合蛋白。所述融合蛋白可特异性阻断CD47蛋白与SIRPα的相互作用,且不引起凝血反应。本申请所述融合蛋白还可以抑制肿瘤或肿瘤细胞的生长和/或增殖。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种SIRPα变体及其融合蛋白,及其应用。
背景技术
CD47蛋白是一种跨膜糖蛋白,属于免疫球蛋白超家族成员,在包括红细胞在内许多细胞表面表达。CD47的配体包括整合素(intergrins)、凝血栓蛋白1(thrombospondin-1)以及信号调节蛋白(SIRPs)。CD47影响多种生物学功能,包括细胞迁移,T细胞、树突状细胞活化,轴突发育等。除此之外,CD47通过与SIRPα相互作用可抑制巨噬细胞的吞噬作用,保护血细胞等正常细胞不被巨噬细胞吞噬。研究发现,除正常组织细胞表达CD47以外,许多肿瘤细胞过度表达CD47,并通过与巨噬细胞表面的SIRPα相结合而阻止巨噬细胞对肿瘤细胞的吞噬,这被视为肿瘤逃避机体免疫监视的一种机制。阻断CD47蛋白和SIRPα的相互作用,可抑制肿瘤增长(Theocharides APA,et al.,2012)。
然而,现有的用于阻断CD47蛋白和SIRPα相互作用的试剂识别活性有限,其与CD47蛋白的亲和力往往不足,且对肿瘤的抑制能力有限。另一方面,现有靶向CD47的抗体类药物存在引起贫血反应或者血小板减少的副作用(白银鹏等,Chin J Clin Oncol.,2017Vol44.No.7)。亟需开发能够有效阻断CD47蛋白和SIRPα相互作用、且副作用小的新型疗法。
发明内容
本申请提供了一种SIRPα变体及SIRPα-Fc融合蛋白,以及其应用。所述融合蛋白能够特异性结合CD47蛋白。本申请所述的SIRPα变体及其融合蛋白具有下述性质中的一种或多种:以较高的亲和力特异性与CD47蛋白相结合;2)特异性阻断CD47蛋白与SIRPα的相互作用;3)不引起凝血反应;4)抑制肿瘤或肿瘤细胞的生长和/或增殖。本申请还提供了所述SIRPα变体及其融合蛋白的制备方法和应用。
一方面,本申请提供了一种SIRPα变体,其与人SIRPα变体1的结构域或其片段相比,包含在N110的氨基酸残基处具有氨基酸取代。
在某些实施方式中,所述人SIRPα变体1的结构域或其片段包含人SIRPα变体1的第33位-第149位氨基酸残基。
在某些实施方式中,所述人SIRPα变体1的第33位-第149位氨基酸残基包含SEQ IDNO:2所示的氨基酸序列。
在某些实施方式中,所述SIRPα变体包含N110A的氨基酸取代。
在某些实施方式中,所述SIRPα变体还包含在选自下组的一个或多个残基处包含氨基酸取代:L44、I61、E77、Q82、K83、E84和V132。
在某些实施方式中,所述SIRPα变体还包含选自下组的一个或多个氨基酸取代:L44V、I61L/V/F、E77I/N/Q/K/H/M/R/N/V/L、Q82S/R/G/N、K83R、E84Q/K/H/D/R/G和V132L/R/I/S。
在某些实施方式中,所述SIRPα变体包含在在L44、I61、E77、Q82、K83、E84、N110和V132的残基处包含氨基酸取代。
在某些实施方式中,所述SIRPα变体包含L44V、I61F、E77I、Q82R、K83R、E84Q、N110A和V132I的氨基酸突变。
在某些实施方式中,所述SIRPα变体包含SEQ ID NO:1所示的氨基酸序列。
另一方面,本申请还提供了融合蛋白,其包含本申请所述的SIRPα变体,和免疫球蛋白Fc区。
在某些实施方式中,所述免疫球蛋白Fc区包含IgG的Fc区或其变体。
在某些实施方式中,所述IgG选自下组:IgG1、IgG2、IgG3和IgG4。
在某些实施方式中,所述融合蛋白中所述SIRPα变体位于所述免疫球蛋白Fc区的N端。
在某些实施方式中,所述免疫球蛋白Fc区包含选自下组的氨基酸序列:SEQ IDNO:4-5。
在某些实施方式中,所述融合蛋白包含SEQ ID NO:6-7中任一项所示的氨基酸序列。
在某些实施方式中,所述融合蛋白特异性结合CD47蛋白,并且具有以下特性中的至少一项:1)以1×10-8M或更低的KD值与CD47蛋白相结合;2)特异性阻断CD47蛋白与SIRPα的相互作用;3)不引起凝血反应;以及4)抑制肿瘤或肿瘤细胞的生长和/或增殖。
在某些实施方式中,所述CD47蛋白为人CD47蛋白。
另一方面,本申请还提供了分离的一种或多种核酸分子,其编码本申请所述的SIRPα变体,或本申请所述的融合蛋白。
另一方面,本申请还提供了载体,其包含本申请所述的核酸分子。
另一方面,本申请还提供了宿主细胞,其包含所述核酸分子或所述载体。
另一方面,本申请还提供了制备所述SIRPα变体或所述融合蛋白的方法,所述方法包括在使得所述SIRPα变体或所述融合蛋白表达的条件下,培养所述宿主细胞。
另一方面,本申请还提供了组合物,其包含所述SIRPα变体、所述融合蛋白、所述核酸分子、所述载体和/或所述宿主细胞,以及任选地药学上可接受地佐剂。
另一方面,本申请还提供了所述SIRPα变体、所述融合蛋白、所述核酸分子、所述载体、所述宿主细胞和/或所述组合物在制备药物和/或试剂盒中的用途,所述药物和/或试剂盒用于预防或治疗肿瘤或自免疫疾病。
在某些实施方式中,所述肿瘤选自下组:CD47阳性血液肿瘤或CD47阳性实体瘤。
在某些实施方式中,所述自免疫疾病选自下组:克罗恩氏病、过敏性哮喘和类风湿性关节炎。
另一方面,本申请还提供了CD47蛋白与SIRPα相互作用的方法,所述方法包括施用所述融合蛋白或所述组合物。在某些实施方式中,所述方法为体外方法。在某些实施方式中,所述方法为离体方法。
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。对附图简要说明如下:
图1显示的是载体pTM的物理结构示意图。
图2显示的是检测SIRPα截短结构域及其突变体与CD47间相互作用的方法示意图。
图3显示的是SIRPα截短结构域流式富集筛选的结果。
图4显示的是本申请的融合蛋白识别CD47蛋白的结果。
图5显示的是本申请的融合蛋白与CD47的亲和力检测结果。
图6显示的是本申请的融合蛋白阻断CD47与SIRPα的结合的结果。
图7显示的是本申请的融合蛋白与Raji细胞和A549细胞的结合结果。
图8显示的是本申请的融合蛋白与人红细胞的结合检测结果。
图9显示的是本申请的融合蛋白的抗红细胞凝集作用的效果。
图10显示的是本申请的融合蛋白的体内抑瘤作用检测。
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。
术语定义
在本申请中,术语“CD47蛋白”又称整联蛋白相关蛋白(integrin associatedprotein,IAP),其属于免疫球蛋白超家族,可与膜整合素(membrane integrins)结合,并与其配体凝血栓蛋白-1(thrombospondin-1,TSP-1)和信号调节蛋白α(signal-regulatoryprotein alpha,SIRPα)结合。CD47蛋白广泛表达于细胞膜表面,是由特定的整联蛋白、G蛋白及胆固醇组成的超分子复合物。在本申请中,所述CD47蛋白可为人CD47蛋白。例如,所述CD47蛋白可为在细胞表面表达的CD47蛋白。
在本申请中,术语“CD47阳性”通常是指在生物体或细胞表面表达CD47蛋白或其片段的特性。特别地,本申请所述的“CD47阳性”细胞可以为过表达CD47的那些细胞,这些CD47阳性细胞通常为疾病细胞,并且其表面的CD47蛋白密度超过指定细胞类型所具有的正常CD47蛋白密度。在某些实施方式中,所述肿瘤或肿瘤细胞可为CD47阳性。例如,所述肿瘤可选自下组:CD47阳性血液肿瘤或CD47阳性实体瘤。
在本申请中,术语“KD”可与“KD”互换使用,通常是指特定的抗体-抗原相互作用的解离平衡常数,单位为M(mol/L)。KD可通过物质AB和其解离得到的物质A和物质B的浓度来计算:KD=c(A)*c(B)/c(AB)。由该公式可知,KD值越大,说明解离越多,代表物质A、B之间的亲和力越弱;反之,KD值越小,说明解离越少,代表物质A、B之间的亲和力越强。
在本申请中,术语“SIRPα”通常是指来自SIRP家族的调节性膜糖蛋白,其可作为CD47蛋白的配体。SIRPα是一种跨膜蛋白,其胞外区含具有3个免疫球蛋白超家族样区域,其中N末端的区域介导与CD47结合,主要表达于巨噬细胞、树突状细胞和神经细胞表面。
在本申请中,术语“人SIRPα结构域”通常是指野生型、内源的成熟形式的人SIRPα、其片段或功能性变体。在人类中,发现SIRPα蛋白主要有两种形式,一种形式(变体1或V1型)的氨基酸序列作为NCBI RefSeq NP_542970.1列出(残基31-504构成成熟型)。另一种形式(变体2或V2型)与所述变体1或V1型有13个氨基酸不同并且氨基酸序列在GenBank中作为CAA71403.1列出。这种两种形式的SIRPα构成了存在于人类中的大约80%的各种类型的SIRPα。
在本申请中,术语“免疫球蛋白Fc区”通常是指抗体结构Y形结构的基座区域,又叫做片段可结晶区(Fragment crystallizable region,Fc region)。在IgG、IgA和IgD抗体同种型中,Fc区由两个相同的蛋白质片段组成,其来自抗体两条重链的第二和第三恒定结构域;IgM和IgE的Fc区在每条多肽链中含有三个重链恒定结构域。IgG的Fc区具有高度保守的N-糖基化位点。在某些实施方式中,所述免疫球蛋白Fc区可包含IgG的Fc区。例如,所述免疫球蛋白Fc区可包含选自下组的氨基酸序列或者其功能性变体:SEQ ID NO:4-5。
在本申请中,术语“IgG”通常是指免疫球蛋白G(Immunoglobulin G)。IgG是人的免疫球蛋白之一,其他还有lgA、lgM、IgD和lgE。根据IgG分子中的γ链抗原性差异,人IgG有四个亚型:IgG1、IgG2、IgG3和IgG4。在本申请中,术语“IgG1”通常是指IgG中占比最高的一类亚型,与Fc受体有较高亲和性。例如,所述IgG可为人IgG。又例如,所述IgG可选自下组:IgG1和IgG4。
在本申请中,所述人SIRPα结构域可位于所述免疫球蛋白Fc区的N端。例如,所述人SIRPα结构域与所述免疫球蛋白Fc可以通过连接子相连。例如,在本申请中,所述人SIRPα结构域可包含SEQ ID NO:1所示的氨基酸序列。
在本申请中,所述人SIRPα结构域可包含人SIRPα变体1的结构域、其片段或变体,其序列可包含SEQ ID NO:2所示的氨基酸序列或其功能性变体。例如,所述人SIRPα结构域可包含人SIRPα变体1的IgV结构域、其片段或变体,其序列可包含SEQ ID NO:3所示氨基酸序列中的第38-145位残基或其功能性变体。又例如,所述人SIRPα结构域可包含人SIRPα变体1的截短结构域,其可包含如SEQ ID NO:2所示的氨基酸序列(即SEQ ID NO:3所示氨基酸序列中的第33-149位残基)或其功能性变体。本申请所述的人SIRPα结构域可包含人SIRPα的胞外结构域,其片段或变体。例如,所述人SIRPα结构域可包含人SIRPα的IgV结构域、其片段或变体。
在本申请中,所述融合蛋白可以包括能够特异性结合所述CD47蛋白的人SIRPα结构域和免疫球蛋白Fc区,其中所述人SIRPα结构域与所述免疫球蛋白Fc区直接或间接相连。
本申请所述的SIRPα结构域的变体可包含与SEQ ID NO:1所示的氨基酸序列具有至少80%(例如,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%,或至少100%)序列同源性的氨基酸序列。
本申请所述的融合蛋白的变体可包含与SEQ ID NO:6-7中任一项所示的氨基酸序列具有至少80%(例如,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%,或至少100%)序列同源性的氨基酸序列。
在本申请中,术语“序列同源性”通常是指两个或更多个多核苷酸序列间或者两个或更多个多肽序列间的序列相似性或可互换性。当使用计算机程序或软件(例如,EmbossNeedle或BestFit)来确定不同氨基酸序列间的序列同一性、相似性或同源性时,可使用默认的参数设置。也可以选择适当的记分矩阵,例如blosum45或blosum80,来优化同一性、相似性或同源性分数。在某些实施方式中,同源的多核苷酸包括下述多核苷酸:其能够在严谨条件下与对照多核苷酸序列杂交并且与对照多核苷酸序列相比具有至少60%、至少65%、至少70%、至少80%、至少90%、至少95%、至少97%、至少98%、至少99%甚至至少100%序列同一性。同源的多肽可以是下述多肽:当在优化条件下进行序列比对时,其与对照多肽序列具有至少80%、至少85%、至少90%、至少95%、至少97%、至少98%、至少99%、甚至至少100%的序列同一性。
为了确定序列同一性,可进行序列比对,其可通过本领域技术人员了解的各种方式进行,例如,使用BLAST、BLAST-2、ALIGN、NEEDLE或Megalign(DNASTAR)软件等。本领域技术人员能够确定用于比对的适当参数,包括在所比较的全长序列中实现最优比对所需要的任何算法。
在本申请中,氨基酸序列(例如,蛋白结构域或蛋白片段,如本申请所述的人SIRPα结构域,或者本申请所述的融合蛋白)的变体可包含1个或几个氨基酸残基的取代、缺失或添加。在本申请中,所述变体(例如人SIRPα结构域的变体)可在选自下组的一个或多个残基处包含氨基酸取代:L44、I61、E77、Q82、K83、E84、N110和V132。
在本申请中,所述氨基酸取代中氨基酸残基的位置以SEQ ID NO:3所示氨基酸序列为基准确定的残基编号。
在本申请中,“残基Xn”是指相应于SEQ ID NO:3所示氨基酸序列中第n位的残基X,其中n为正整数,X为任意氨基酸残基的缩写。例如,“残基I61”表示相应于SEQ ID NO:3所示氨基酸序列中第61位氨基酸残基I。
在本申请中,按照上述编号方案,SEQ ID NO:2所示的氨基酸序列的第一个氨基酸的编号为第33位氨基酸。因此,“残基I61”表示相应于SEQ ID NO:2所示的氨基酸序列中第29个的氨基酸残基I。即,SEQ ID NO:2所示的氨基酸序列的第29个氨基酸的编号为第61位氨基酸。
在本申请中,“氨基酸取代Xn”是指在相应于SEQ ID NO:3所示氨基酸序列中第n位的残基X处发生氨基酸取代,其中n为正整数,X为任意氨基酸残基的缩写。例如,“氨基酸取代I61”表示在相应于SEQ ID NO:3所示氨基酸序列中第61位的残基I处发生氨基酸取代,也表示在相应于SEQ ID NO:2所示的氨基酸序列中第29个氨基酸残基处发生氨基酸取代。
在本申请中,某氨基酸序列中的某残基“相应于”另一氨基酸序列中的某残基通常是指,在优化条件下进行氨基酸序列比对时所获得的残基对应关系。所述序列比对可通过本领域技术人员了解的方式进行,例如,使用BLAST、BLAST-2、ALIGN、NEEDLE或Megalign(DNASTAR)软件等。本领域技术人员能够确定用于比对的适当参数,包括在所比较的全长序列中实现最优比对所需要的任何算法。
本申请所述的氨基酸取代可以为非保守取代。所述非保守取代可包括以非保守的形式改变目标蛋白或多肽中的氨基酸残基,例如将具有某种侧链大小或某种特性(例如,亲水性)的氨基酸残基变为具有不同侧链大小或不同特性(例如,疏水性)的氨基酸残基。
所述氨基酸取代也可以为保守取代。所述保守取代可包括以保守的形式改变目标蛋白或多肽中的氨基酸残基,例如将具有某种侧链大小或某种特性(例如,亲水性)的氨基酸残基变为具有相同或相似侧链大小或者相同或相似特性(例如,仍为亲水性)的氨基酸残基。这样的保守取代通常不会对所产生的蛋白质的结构或功能带来很大影响。在本申请中,作为所述融合蛋白或其片段的氨基酸序列变体可包括不显著改变蛋白质结构或其功能(例如,阻断CD47与其配体结合的能力)的保守氨基酸取代。
作为示例,下述各组中每组内各氨基酸间的相互取代在本申请中可被认为是保守取代:
具有非极性侧链的氨基酸组:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸和甲硫氨酸。
不带电荷、具有极性侧链的氨基酸组:甘氨酸、丝氨酸、苏氨酸,半胱氨酸,酪氨酸,天冬酰胺和谷氨酰胺。
带负电荷、具有极性侧链的氨基酸组:天冬氨酸和谷氨酸。
带正电荷的碱性氨基酸:赖氨酸、精氨酸和组氨酸。
带苯基的氨基酸:苯丙氨酸、色氨酸和酪氨酸。
在本申请中,氨基酸取代“XnY/Z”是指按照本申请所述的编号方案,氨基酸序列中第n位的残基X被取代为氨基酸残基Y或者氨基酸残基Z,其中n为正整数,X、Y和Z分别独立地为任意氨基酸残基的缩写,且X不同于Y或Z。例如,氨基酸取代“I61L/V/F”是指第61位的残基I被取代为氨基酸残基L、V或F。
发明详述
SIRPα变体
一方面,本申请提供SIRPα变体,所述SIRPα变体与人SIRPα变体1的结构域或其片段相比,包含在N110的氨基酸残基处具有氨基酸取代。
在某些实施方式中,所述人SIRPα变体1的结构域可以包含人SIRPα变体1的胞外结构域。在某些实施方式中,所述人SIRPα变体1的结构域可以包含人SIRPα变体1的IgV结构域。在某些实施方式中,所述人SIRPα变体1的结构域或其片段可以包含人SIRPα变体1的截短结构域。
在某些实施方式中,所述人SIRPα变体1的截短结构域可以具有如SEQ ID NO:3所示的氨基酸序列的中的第33-149位残基。例如,所述人SIRPα变体1的截短结构域可以包含SEQ ID NO:2所示的氨基酸序列。
在某些实施方式中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,可以包含氨基酸取代N110A。
在某些实施方式中,所述SIRPα变体与人SIRPα变体1的结构域或其片段相比,包含在L44的氨基酸残基处具有氨基酸取代。
在某些实施方式中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,可以包含氨基酸取代L44V。
在某些实施方式中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,其还可以包含在选自下组的一个或多个残基处包含氨基酸取代:L44、I61、E77、Q82、K83、E84、N110和V132。在某些实施方式中,所述氨基酸取代可以选自:L44V、I61L/V/F、E77I/N/Q/K/H/M/R/N/V/L、Q82S/R/G/N、K83R、E84Q/K/H/D/R/G和V132L/R/I/S。
在某些实施方式中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,其可以包含在L44、I61、E77、Q82、K83、E84、N110和V132的残基处包含氨基酸取代。在某些实施方式中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,其可以包含L44V、I61F、E77I、Q82R、K83R、E84Q、N110A和V132I的氨基酸突变。
在某些实施方式中,所述SIRPα变体可以包含SEQ ID NO:1所示的氨基酸序列。
融合蛋白
另一方面,本申请提供了一种融合蛋白,其包含本申请所述的SIRPα变体。在某些实施方式中,所述融合蛋白可以特异性结合CD47蛋白,以1×10-8M或更低的KD值与CD47蛋白相结合,例如:所述KD值不高于9×10-9M、不高于8×10-9M、不高于7×10-9M、不高于6.2×10- 9M、不高于6×10-9M、不高于5×10-9M、不高于4.8×10-9M、不高于4.5×10-9M、不高于2×10- 9M、不高于1.5×10-9M、不高于1×10-9M或不高于1×10-10M或以下。
在某些实施方式中,所述融合蛋白可特异性阻断CD47蛋白与SIRPα的相互作用,从而激活巨噬细胞吞噬肿瘤细胞。此外,本申请所述的融合蛋白可不引起凝血反应,例如,用血凝板进行测试,向其中加入所述融合蛋白和红细胞溶液后,红细胞沉于孔底而不平铺呈网状。所述融合蛋白还可以抑制肿瘤或肿瘤细胞的生长和/或增殖,例如,可以使肿瘤面积或肿瘤体积减少,或可以使携带肿瘤的受试者的存活率提高。
在本申请中,术语“融合蛋白”通常指一种复合多肽,即由两种(或更多种)多肽组成的单个连续氨基酸序列。融合蛋白一般可以使用重组核酸的方法或化学合成的方法人工制备得到。
在本申请中,所述融合蛋白可以包含SIRPα变体,以及免疫球蛋白Fc区。在某些实施方式中,所述免疫球蛋白Fc区包含IgG的Fc区或其变体。例如,所述IgG可以选自IgG1、IgG2、IgG3和IgG4。
例如,所述融合蛋白可以包含SIRPα变体,以及免疫球蛋白Fc区,其中,所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,在L44、I61、E77、Q82、K83、E84、N110和V132的残基处包含氨基酸取代。
例如,所述融合蛋白可以包含SIRPα变体,以及免疫球蛋白Fc区,其中所述SIRPα变体与SEQ ID NO:2所示的氨基酸序列相比,包含L44V、I61F、E77I、Q82R、K83R、E84Q、N110A和V132I的氨基酸突变。
例如,所述IgG1的Fc区可以包含SEQ ID NO:4所示的氨基酸序列。例如,所述IgG4的Fc区可以包含SEQ ID NO:5所示的氨基酸序列。
在本申请中,所述融合蛋白可以包含SEQ ID NO:1所示的SIRPα变体序列,及SEQID NO:4或SEQ ID NO:5所示的Fc区序列。
在本申请中,所述融合蛋白可以包含SEQ ID NO:6-7中任一项所示的氨基酸序列。
在本申请中,所述融合蛋白能够特异性结合CD47蛋白,且具有以下特性中的至少一项:1)以1×10-8M或更低的KD值与CD47蛋白相结合;2)特异性阻断CD47蛋白与SIRPα的相互作用;3)不引起凝血反应;以及4)抑制肿瘤或肿瘤细胞的生长和/或增殖。
在某些实施方式中,所述CD47蛋白可以为人CD47蛋白。
核酸分子、载体、宿主细胞
另一方面,本申请提供分离的一种或多种核酸分子,其可编码本申请所述的SIRPα变体或本申请所述的融合蛋白。
另一方面,本申请提供一种或多种载体,其可包含本申请所述的一种或多种核酸分子。在另一方面,本申请提供一种细胞(例如宿主细胞),其可包含本申请所述的核酸分子或本申请所述的载体。
在本申请中,术语“核酸分子”通常是指从其天然环境中分离的或人工合成的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其类似物。本申请所述的核酸分子可以为分离的。例如,其可以是通过以下方法产生或合成的:(i)在体外扩增的,例如通过聚合酶链式反应(PCR)扩增产生的,(ii)通过克隆重组产生的,(iii)纯化的,例如通过酶切和凝胶电泳分级分离,或者(iv)合成的,例如通过化学合成。在某些实施方式中,所述分离的核酸是通过重组DNA技术制备的核酸分子。在本申请中,可以通过本领域已知的多种方法来制备编码所述抗体或其抗原结合片段的核酸,这些方法包括但不限于,采用限制性片段操作或采用合成性寡核苷酸的重叠延伸PCR,具体操作可参见Sambrook等人,MolecularCloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.,1989;和Ausube等人Current Protocols in Molecular Biology,GreenePublishing and Wiley-Interscience,New York N.Y.,1993。
在本申请中,术语“载体”通常是指能够在合适的宿主中自我复制的核酸分子,其将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体,以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常,通过培养包含所述载体的合适的宿主细胞,所述载体可以产生期望的表达产物。在本申请中,所述载体中可包含一种或多种所述核酸分子。此外,所述载体中还可包含其他基因,例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外,所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的,例如,可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。在某些实施方式中,所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化,但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。例如,5’非转录表达控制序列可包含启动子区,启动子区可包含用于转录控制功能性连接核酸的启动子序列。在本申请中,所述载体可以是pTM载体。
在本申请中,术语“宿主细胞”、“细胞”、“宿主”可以互换地使用,通常是指可以或已经含有包括本申请所述的核酸分子的质粒或载体,或者能够表达本申请所述的融合蛋白、其片段或变体的个体细胞,细胞系或细胞培养物。所述宿主细胞可以包括单个宿主细胞的子代。由于天然的、意外的或故意的突变,子代细胞与原始亲本细胞在形态上或在基因组上可能不一定完全相同,但能够表达本申请所述的抗体或其抗原结合片段即可。所述宿主细胞可以通过使用本申请所述的载体体外转染细胞而得到。所述宿主细胞可以是原核细胞(例如大肠杆菌),也可以是真核细胞(例如酵母细胞,例如COS细胞,中国仓鼠卵巢(CHO)细胞,HeLa细胞,HEK293细胞,COS-1细胞,NS0细胞或骨髓瘤细胞)。在本申请中,所述宿主细胞可以是CHO细胞。
组合物、制备方法及应用
另一方面,本申请可提供制备所述SIRPα变体或所述融合蛋白的方法,所述方法可包括在使得所述融合蛋白表达的条件下,培养宿主细胞。
另一方面,本申请可提供一种组合物,其可包含所述的SIRPα变体、所述的融合蛋白、所述的核酸分子、所述的载体和/或所述的宿主细胞,以及任选地药学上可接受的佐剂。
在本申请中,术语“药学上可接受的佐剂”可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
所述药学上可接受的佐剂可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
在本申请中,可按照本领域的常规技术手段将所述药物组合物与可药用载体或稀释剂以及任何其他已知的辅剂和赋形剂配制在一起,例如按照Remington:The Scienceand Practice of Pharmacy,第十九版,Gennaro编辑,Mack Publishing Co.,Easton,PA,1995中公开的技术进行操作。
在本申请中,所述组合物可被配制用于口服给药,静脉内给药,肌肉内给药,在肿瘤部位的原位给药,吸入,直肠给药,阴道给药,经皮给药或通过皮下储存库给药。
在本申请中,所述组合物可以用于抑制肿瘤生长。例如,本申请的组合物可以抑制或延缓疾病(例如肿瘤或自免疫疾病)的发展或进展,(例如,可以减小肿瘤大小,甚至基本消除肿瘤),和/或可以减轻和/或稳定疾病状态。
本申请所述的药物组合物可以包含治疗有效量的所述融合蛋白。所述治疗有效量是能够预防和/或治疗(至少部分治疗)患有或具有发展风险的受试者中疾病(例如肿瘤或自免疫疾病)和/或其任何并发症而所需的剂量。
另一方面,本申请提供本申请所述的SIRPα变体、融合蛋白、核酸分子、载体、宿主细胞和/或组合物在制备药物和/或试剂盒中的用途,其中所述药物和/或试剂盒可用于预防或治疗肿瘤或自免疫疾病。
在本申请中,术语“肿瘤”通常是指机体局部组织细胞增生所形成的新生物,由于这种新生物多呈占位性块状凸起,也称赘生物。根据新生物的细胞特性及对机体的危害性程度,又将肿瘤分为良性肿瘤和恶性肿瘤两类,癌症是恶性肿瘤的总称。本申请中所述的肿瘤可以包括,但不限于CD47阳性血液肿瘤或CD47阳性实体瘤。
在本申请中,术语“CD47阳性血液肿瘤”通常是指过表达CD47的血液肿瘤,其中可包括各类白血病、淋巴瘤和骨髓瘤。所述“白血病”通常是指血液的一种癌症,其中产生了过多的对抵抗感染不起作用的白细胞,由此挤占了组成血液的其他部分,如血小板和红细胞。白血病可分为急性或慢性白血病。白血病的某些形式可以为,例如,急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、骨髓增殖性失调/肿瘤(MPDS)和骨髓增生异常综合征。所述“淋巴瘤”可以指霍奇金淋巴瘤、惰性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)等。所述骨髓瘤可以指多发性骨髓瘤(MM)、巨细胞骨髓瘤、重链骨髓瘤(heavy chain myeloma)、轻链骨髓瘤(light chian myeloma)或本斯-琼斯氏骨髓瘤(Bence-Jones myeloma)。
在本申请中,术语“CD47阳性实体瘤”通常是指过表达CD47的实体瘤或有形瘤,其可以通过临床检查,例如,X线摄片、CT扫描、B超或者触诊检查出有形肿块。主要类别可包括癌症(carcinoma)和肉瘤(sarcoma)。例如,所述CD47阳性实体瘤可以包括尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、膀胱癌、卵巢癌、前列腺癌、肺癌、结肠癌、乳腺癌、胰腺癌、星形细胞癌、胶质母细胞瘤和肾细胞癌等。
在本申请中,所述自免疫疾病可包括克罗恩氏病、过敏性哮喘和类风湿性关节炎。
在本申请中,术语“克罗恩氏病”通常是指一种原因不明的肠道炎症性疾病,在胃肠道的任何部位均可发生,但好发于末端回肠和右半结肠。所述克罗恩氏病和慢性非特异性溃疡性结肠炎两者统称为炎症性肠病(IBD)。
在本申请中,术语“过敏性哮喘”通常是指由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症。
在本申请中,术语“类风湿性关节炎”通常是指一种以关节病变为主的慢性全身自身免疫性疾病。
本申请所述的融合蛋白、核酸分子、载体、宿主细胞和/或组合物可用于预防或治疗所述肿瘤或所述自免疫疾病。
另一方面,本申请提供了预防或治疗肿瘤或自免疫疾病的方法,所述方法包括向受试者使用本申请所述的SIRPα变体、融合蛋白、核酸分子、载体、宿主细胞和/或组合物。
另一方面,本申请提供了一种阻断CD47蛋白与SIRPα相互作用的方法,所述方法可包括施用(例如,向有需要的受试者或细胞或生物学样品施用)本申请所述的SIRPα变体、融合蛋白或组合物。
另一方面,本申请提供了一种抑制肿瘤或肿瘤细胞生长和/或增殖的方法,所述方法可包括使本申请所述的SIRPα变体、融合蛋白或组合物与所述肿瘤或肿瘤细胞接触。例如,所述接触可在体外发生。
在本申请中,术语“受试者”通常是指任何人或非人动物。术语“非人动物”可包括所有脊椎动物,例如哺乳动物和非哺乳动物,例如非人灵长类动物、山羊、绵羊、狗、牛、鸡、两栖动物、爬行动物等。
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。
在本申请中,术语“包括”通常是指包含、总括、含有或包涵的含义。在某些情况下,也表示“为”、“由……组成”的含义。
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SIRPα变体、融合蛋白、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
实施例1变体的筛选
获取人SIRPα变体1(NP_542970.1)的截短结构域,其氨基酸序列如SEQ ID NO:2所示(即SEQ ID NO:3中第33-149位残基),用Discovery Studio(创腾科技)软件构建该截短结构域中与人CD47(CEJ95640.1)相互作用的结构,理论分析两个蛋白中参与相互作用的位点以及相互作用模式,确定该截短结构域中直接或间接参与与CD47相互作用的氨基酸位点为L44、I61、V63、E77、Q82、K83、E84、V93、D95、L96、K98、N100、R107、G109、N110、V132(其中,这些氨基酸取代中氨基酸残基的位置以SEQ ID NO:3所示氨基酸序列为准进行计数编号)。对这些作用位点进行随机突变,并构建突变体库。然后,将该突变体库克隆到载体pTM上。所述pTM载体含有信号肽、跨膜区序列(如图1所示),其可在细胞表面展示克隆入该载体的基因。
将构建的突变体库表达载体转染至CHO细胞(ATCC),使突变体库展示表达在细胞表面上。然后,用FITC荧光标记CD47蛋白(义翘神州)获得CD47-FITC,根据CD47-FITC与CHO细胞表面该截短结构域的突变体之间结合活性强弱,利用流式细胞技术富集筛选能与CD47-FITC结合的突变体。筛选的具体原理可参见图2,其中该截短结构域及突变体与带荧光分子CD47蛋白结合,结合的结果即可以通过荧光分子水平的高低来体现。
经过四轮筛选富集,收集与CD47-FITC结合较强的细胞(如图3所示)。然后提取其mRNA,反转录后获得cDNA,对该截短结构域突变体的基因进行测序分析。测序结果显示,前述位点L44、I61、V63、E77、Q82、K83、E84、V93、D95、L96、K98、N100、R107、G109、N110、V132存在不同突变组合。
由结果可知,在L44、I61、V63、E77、Q82、K83、E84、V93、D95、L96、K98、N100、R107、G109、N110和/或V132残基处引入不同的突变组合,可获得可特异性识别CD47的新的截短结构域突变体。
进一步分析突变位点,可以发现各位点突变的氨基酸残基为:L44V、I61L/V/F、V63I、E77I/N/Q/K/H/M/R/N/V/L、Q82S/R/G/N、K83R、E84Q/K/H/D/R/G、V93L/A、D95H/R/E、L96S/T、K98R、N100G/K/D/E、R107N/S、G109R/H、N110A、V132L/R/I/S。
根据上述位点分析,获得具有L44V、I61F、E77I、Q82R、K83R、E84Q、N110A和V132I氨基酸突变的SIRPα结构域的变体。
将人SIRPα变体1的截短结构域(或称为野生型SIRPα截短结构域,序列如SEQ IDNO:2所示)和实施例1获得的SIRPα结构域的变体(其氨基酸序列如SEQ ID NO:1所示)分别与人IgG1-Fc(其氨基酸序列如SEQ ID NO:4所示)融合表达,获得其所对应的SIRPα突变体1的截短结构域-人Fc融合蛋白(简称融合蛋白),将这些融合蛋白分别命名为SS002、m12N。
实施例2融合蛋白结合靶抗原CD47的效果检测
将靶抗原His-CD47(CD47 Protein,Human,Recombinant(ECD,His Tag),SinoBiological)包被ELISA板条,1μg/ml,4℃包被过夜;PBST洗涤后,加入10%的胎牛血清,37℃封闭1h;加入不同浓度的融合蛋白,37℃反应1h;PBST洗涤后,加入辣根过氧化物酶标记的羊抗人Fc二抗(Goat anti-Human IgG Fc Cross-Adsorbed Secondary Antibody,HRP,Invitrogen),37℃反应30min;PBST重复洗板5遍,在吸水纸上尽量拍干残留液滴;每孔加入100μlTMB(eBioscience),室温(20±5℃)避光放置2~3min;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,分析融合蛋白与CD47的结合能力。
结果如图4所示,融合蛋白能特异性识别靶抗原His-CD47,且结合活性呈显著的剂量依赖性;相比SS002,m12N与靶抗原His-CD47的结合能力更强。
实施例3融合蛋白与靶抗原CD47的亲和力检测
利用表面等离子共振(SPR)技术检测融合蛋白与His-CD47的亲和力,实验使用的仪器为Biacore T200(GE)。按照Human Antibody Capture Kit(GE)说明书,将Anti-HumanIgG(Fc)antibody(including in GE Human Antibody Capture Kit,GE)用Immobilization Buffer(including in GE Human Antibody Capture Kit,GE)稀释至25μg/ml并固定在Series S Sensor Chip CM5芯片(GE)上(10μl/min,420s);将融合蛋白用Running Buffer(1×HEPES(10mM HEPES,150mM NaCl,3mM EDTA),with 0.005%Tween-20,pH7.4)稀释至2.5μg/ml,10μl/min的流速进行捕获;以His-CD47(CD47 Protein,Human,Recombinant(ECD,His Tag),SinoBiological)作为分析物(Analyte)进行结合和解离检测(30μl/min,Association:150s;Dissociation 300s),以1:1binding模型进行拟合,分析融合蛋白与CD47的亲和力。
结果如表1和图5所示,融合蛋白均可高亲力地结合CD47分子;相比SS002,m12N与CD47分子的亲和力略强。
表1融合蛋白与His-CD47的亲和力检测结果
Ligand | ka(1/Ms) | kd(1/s) | KD(M) |
SS002 | 3.27E+05 | 6.39E-03 | 1.95E-08 |
m12N | 3.33E+05 | 4.45E-03 | 1.34E-08 |
实施例4融合蛋白阻断CD47与SIRPα结合
将His-SIRPα(SIRP alpha Protein,Human,Recombinant(G75A,ECD,His Tag),SinoBiological)包被ELISA板条,1μg/ml,4℃包被过夜;PBST洗涤后,加入10%的胎牛血清,37℃封闭1h;加入不同浓度的融合蛋白以及2μg/ml的CD47-Biotin(Jiaxuan Biotech),37℃反应1h;PBST洗涤后,加入辣根过氧化物酶标记的亲和素(Streptavidin,HRPconjugate,Jiaxuan Biotech),37℃反应30min;PBST重复洗板5遍,在吸水纸上尽量拍干残留液滴;每孔加入100μlTMB(eBioscience),室温(20±5℃)避光放置2~3min;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,分析融合蛋白阻断CD47与SIRPα结合的能力。
结果如图6所示,融合蛋白可阻断CD47与SIRPα的结合,且阻断活性呈显著的剂量依赖性;m12N的阻断活性较SS002更强。
实施例5融合蛋白特异性识别肿瘤细胞表面的CD47分子
利用流式分析技术(BD Accuri C6 Plus)分别检测融合蛋白与Raji细胞和A549细胞表面的CD47结合的活性。收集对数生长期的Raji和A549细胞,分别按照每管5×105个细胞加至1.5ml EP管中;分别加入不同浓度的融合蛋白,冰上避光孵育30min;FACS洗液洗涤后,加入PE荧光标记的羊抗人IgG Fc二抗(Goat Anti-Human IgG Fc SecondaryAntibody,PE,Invitrogen),冰上避光孵育30min;FACS洗液洗涤2遍;每管加入400μl 1%多聚甲醛固定液(Solarbio)固定细胞,混匀后上机检测PE荧光的相对荧光强度,分析融合蛋白与Raji细胞和A549细胞表面的CD47的结合能力。
结果如图7所示,融合蛋白能特异性识别Raji细胞和A549细胞表面的CD47,且结合活性呈显著的剂量依赖性;相比SS002,m12N与肿瘤细胞的结合能力更强。
实施例6融合蛋白与人红细胞的结合
利用流式分析技术(BD Accuri C6 Plus)检测融合蛋白与人红细胞的结合,以CD47抗体Hu5F9-G4(参见Guerriero J L,Sotayo A,Ponichtera H E,et al.Class IIaHDAC inhibition reduces breast tumours and metastases through anti-tumourmacrophages.[J].Nature,2017,543(7645):428.432以及Gholamin S,Mitra SS,FerozeAH et al.Disrupting the CD47-SIRPαanti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric braintumors.Sci.Transl.Med 2017)作为对照。采集健康供体的全血来制备人红细胞(采集自志愿者的外周血),用生理盐水(Shijiazhuang No.4Pharmaceutical)将全血稀释10倍后,洗涤3次,并制备成新鲜的1%(v/v)红细胞悬液。按照每管1×106个细胞加至1.5ml EP管中,用FACS洗液洗涤2遍(4℃,3000rpm,5min);加入100ul不同浓度的融合蛋白,冰上避光孵育30min,每10min混匀1次;FACS洗液洗涤后,加入PE荧光标记的羊抗人IgG Fc二抗(GoatAnti-Human IgG Fc Secondary Antibody,PE,Invitrogen),冰上避光孵育30min;FACS洗液洗涤2遍;每管加入400μl 1%多聚甲醛固定液(Solarbio)固定细胞,混匀后上机检测PE荧光的相对荧光强度,分析融合蛋白与人红细胞的结合能力。
结果如图8显示,m12N与人红细胞几乎不结合;而Hu5F9-G4与人红细胞有强结合,且结合活性呈显著的剂量依赖性。
实施例7融合蛋白的红细胞凝集实验
采集健康供体的全血来制备人红细胞(采集自志愿者的外周血),用生理盐水(Shijiazhuang No.4Pharmaceutical)将全血稀释10倍后,洗涤3次,并制备成新鲜的1%(v/v)红细胞悬液。取96孔圆底细胞培养板(96-well Clear Round Bottom TC-treatedMicroplate,Corning),加入不同浓度的融合蛋白(50ul/孔)和1%红细胞悬液(50ul/孔),充分混匀,放入湿盒中,37℃孵育3.5h后观察凝集现象。
结果如图9所示,m12N在0.00128μg/ml-100μg/ml浓度范围内均无红细胞凝集作用;而Hu5F9-G4在0.8μg/ml-100μg/ml浓度范围内可引起红细胞凝集。
实施例8融合蛋白体内抑制肿瘤活性检测
通过在NOD-SCID小鼠上异种移植CD47阳性的人皮肤鳞癌细胞A431建立肿瘤模型,评价融合蛋白抑制肿瘤活性。选择雌性、6-8周龄的NOD-SCID小鼠(创模医药科技(北京)有限公司)作为实验动物,将A431细胞复苏培养至所需数量后,收集对数期生长细胞,悬浮至1×106个/0.1mL浓度。然后按0.1mL/只在右侧前肢肩胛处皮下接种到NOD-SCID小鼠。接种后每周2次测量肿瘤体积及体重,当平均肿瘤体积达到99mm3时,依据肿瘤体积和体重随机分为2组,每组6只,分为溶剂对照组(G1,PBS)和实验组(G2,m12N),实验组给药剂量为7mg/kg,并在分组当天以及分组后按照每周2次的给药频率连续给药,共给药6次。观察小鼠肿瘤生长情况。
结果如图10所示,分组给药后第21天,对照组的平均肿瘤体积为1795.5±611.6mm3,而给药组的平均肿瘤体积为994.2±239.22mm3,抑瘤率为47%,呈现抑瘤效果。
序列表
<110> 杭州尚健生物技术有限公司;尚健单抗(北京)生物技术有限公司
<120> SIRPα变体及其应用
<130> 0070-PA-028
<160> 7
<170> PatentIn version 3.5
<210> 1
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SIRPa截短体突变体-m12N
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Thr Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser
165 170 175
Pro Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser
180 185 190
Asp Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser
195 200 205
Ile His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His Ser
210 215 220
Gln Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp Pro Leu
225 230 235 240
Arg Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro Thr Leu
245 250 255
Glu Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val Thr
260 265 270
Cys Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr Trp Leu
275 280 285
Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr Glu
290 295 300
Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn Val
305 310 315 320
Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu His Asp
325 330 335
Gly Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala His
340 345 350
Pro Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser Asn
355 360 365
Glu Arg Asn Ile Tyr Ile Val Val Gly Val Val Cys Thr Leu Leu Val
370 375 380
Ala Leu Leu Met Ala Ala Leu Tyr Leu Val Arg Ile Arg Gln Lys Lys
385 390 395 400
Ala Gln Gly Ser Thr Ser Ser Thr Arg Leu His Glu Pro Glu Lys Asn
405 410 415
Ala Arg Glu Ile Thr Gln Asp Thr Asn Asp Ile Thr Tyr Ala Asp Leu
420 425 430
Asn Leu Pro Lys Gly Lys Lys Pro Ala Pro Gln Ala Ala Glu Pro Asn
435 440 445
Asn His Thr Glu Tyr Ala Ser Ile Gln Thr Ser Pro Gln Pro Ala Ser
450 455 460
Glu Asp Thr Leu Thr Tyr Ala Asp Leu Asp Met Val His Leu Asn Arg
465 470 475 480
Thr Pro Lys Gln Pro Ala Pro Lys Pro Glu Pro Ser Phe Ser Glu Tyr
485 490 495
Ala Ser Val Gln Val Pro Arg Lys
500
<210> 4
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IgG1-Fc
<400> 4
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 5
<211> 229
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IgG4-Fc
<400> 5
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
<210> 6
<211> 349
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> m12N-Fc(IgG1)
<400> 6
Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Val Val Ala Ala Gly
1 5 10 15
Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Phe Pro Val Gly
20 25 30
Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Ile Leu Ile Tyr
35 40 45
Asn Arg Arg Gln Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
50 55 60
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Ala Ile Thr
65 70 75 80
Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
85 90 95
Pro Asp Asp Ile Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val
100 105 110
Arg Ala Lys Pro Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
115 120 125
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
130 135 140
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
145 150 155 160
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
165 170 175
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
180 185 190
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
195 200 205
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
210 215 220
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
225 230 235 240
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
245 250 255
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
260 265 270
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
275 280 285
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
290 295 300
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
305 310 315 320
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
325 330 335
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 7
<211> 346
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> m12N-Fc(IgG4)
<400> 7
Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Val Val Ala Ala Gly
1 5 10 15
Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Phe Pro Val Gly
20 25 30
Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Ile Leu Ile Tyr
35 40 45
Asn Arg Arg Gln Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
50 55 60
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Ala Ile Thr
65 70 75 80
Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
85 90 95
Pro Asp Asp Ile Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val
100 105 110
Arg Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
115 120 125
Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
130 135 140
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
145 150 155 160
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
165 170 175
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
180 185 190
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
195 200 205
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
210 215 220
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
225 230 235 240
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
245 250 255
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
260 265 270
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
275 280 285
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
290 295 300
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
305 310 315 320
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
325 330 335
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
Claims (26)
1.SIRPα变体,其与人SIRPα变体1的结构域或其片段相比,包含在N110的氨基酸残基处具有氨基酸取代。
2.根据权利要求1所述的SIRPα变体,其中所述人SIRPα变体1的结构域或其片段包含人SIRPα变体1的第33位-第149位氨基酸残基。
3.根据权利要求1-2中任一项所述的SIRPα变体,其中所述人SIRPα变体1的第33位-第149位氨基酸残基包含SEQ ID NO:2所示的氨基酸序列。
4.根据权利要求1-3中任一项所述的SIRPα变体,其包含氨基酸取代N110A。
5.根据权利要求1-4中任一项所述的SIRPα变体,其还包含在选自下组的一个或多个残基处包含氨基酸取代:L44、I61、E77、Q82、K83、E84和V132。
6.根据权利要求1-5中任一项所述的SIRPα变体,其还包含选自下组的一个或多个氨基酸取代:L44V、I61L/V/F、E77I/N/Q/K/H/M/R/N/V/L、Q82S/R/G/N、K83R、E84Q/K/H/D/R/G和V132L/R/I/S。
7.根据权利要求1-6中任一项所述的SIRPα变体,其包含在L44、I61、E77、Q82、K83、E84、N110和V132的残基处包含氨基酸取代。
8.根据权利要求1-7中任一项所述的SIRPα变体,其包含L44V、I61F、E77I、Q82R、K83R、E84Q、N110A和V132I的氨基酸突变。
9.根据权利要求1-8中任一项所述的SIRPα变体,其包含SEQ ID NO:1所示的氨基酸序列。
10.融合蛋白,其包含权利要求1-9中任一项所述的SIRPα变体,和免疫球蛋白Fc区。
11.根据权利要求10所述的融合蛋白,其中所述免疫球蛋白Fc区包含IgG的Fc区或其变体。
12.根据权利要求11所述的融合蛋白,其中所述IgG选自下组:IgG1、IgG2、IgG3和IgG4。
13.根据权利要求10-12中任一项所述的融合蛋白,其中所述SIRPα变体位于所述免疫球蛋白Fc区的N端。
14.根据权利要求10-13中任一项所述的融合蛋白,其中所述免疫球蛋白Fc区包含选自下组的氨基酸序列:SEQ ID NO:4-5。
15.根据权利要求10-14中任一项所述的融合蛋白,其包含SEQ ID NO:6-7中任一项所示的氨基酸序列。
16.根据权利要求10-15中任一项所述的融合蛋白,其特异性结合CD47蛋白,并且具有以下特性中的至少一项:
1)以1×10-8M或更低的KD值与CD47蛋白相结合;
2)特异性阻断CD47蛋白与SIRPα的相互作用;
3)不引起凝血反应;以及
4)抑制肿瘤或肿瘤细胞的生长和/或增殖。
17.根据权利要求16所述的融合蛋白,其中所述CD47蛋白为人CD47蛋白。
18.分离的一种或多种核酸分子,其编码权利要求1-9中任一项所述的SIRPα变体,或权利要求10-17中任一项所述的融合蛋白。
19.载体,其包含权利要求18所述的核酸分子。
20.宿主细胞,其包含权利要求18所述的核酸分子或权利要求19所述的载体。
21.制备权利要求1-9中任一项所述的SIRPα变体或权利要求10-17中任一项所述的融合蛋白的方法,所述方法包括在使得所述SIRPα变体或所述融合蛋白表达的条件下,培养权利要求20所述的宿主细胞。
22.组合物,其包含权利要求1-9中任一项所述的SIRPα变体、权利要求10-17中任一项所述的融合蛋白、权利要求18所述的核酸分子、权利要求19所述的载体和/或权利要求20所述的宿主细胞,以及任选地药学上可接受的佐剂。
23.权利要求1-9中任一项所述的SIRPα变体、权利要求10-17中任一项所述的融合蛋白、权利要求18所述的核酸分子、权利要求19所述的载体、权利要求20所述的宿主细胞和/或权利要求22所述的组合物在制备药物和/或试剂盒中的用途,所述药物和/或试剂盒用于预防或治疗肿瘤或自免疫疾病。
24.根据权利要求23所述的用途,其中所述肿瘤选自下组:CD47阳性血液肿瘤或CD47阳性实体瘤。
25.根据权利要求23所述的用途,其中所述自免疫疾病选自下组:克罗恩氏病、过敏性哮喘和类风湿性关节炎。
26.阻断CD47蛋白与SIRPα相互作用的方法,所述方法包括施用权利要求10-17中任一项所述的融合蛋白或权利要求22所述的组合物。
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