CD80变体免疫调节蛋白及其用途制造技术

本文提供了变体CD80多肽、包含变体CD80多肽的免疫调节蛋白和编码此类蛋白质的核酸。免疫调节蛋白提供了针对各种免疫学和肿瘤学病况的治疗效用。提供了用于制备和使用此类蛋白质的组合物和方法。

CD80 Variant Immunoregulatory Protein and Its Application

【技术实现步骤摘要】
【国外来华专利技术】CD80变体免疫调节蛋白及其用途相关申请的交叉引用本申请要求2016年4月15日提交的标题为“CD80配体变体免疫调节蛋白及其用途(CD80LigandVariantImmunomodulatoryProteinsandUsesThereof)”的美国临时申请号62/323,595、2016年9月14日提交的标题为“CD80配体变体免疫调节蛋白及其用途(CD80LigandVariantImmunomodulatoryProteinsandUsesThereof)”的美国临时申请号62/394,743、2016年10月20日提交的标题为“ICOS配体变体免疫调节蛋白及其用途(ICOSLigandVariantImmunomodulatoryProteinsandUsesThereof)”的美国临时申请号62/410,844、2017年3月16日提交的标题为“CD80配体变体免疫调节蛋白及其用途(CD80LigandVariantImmunomodulatoryProteinsandUsesThereof)”的美国临时申请号62/472,570、以及2017年3月22日提交的标题为“CD本文档来自技高网...

【技术保护点】
1.一种变体CD80多肽，其包含IgV结构域或其特异性结合片段、IgC结构域或其特异性结合片段、或两者，其中该变体CD80多肽包含未修饰的CD80或其特异性结合片段中的一个或多个氨基酸修饰，该一个或多个氨基酸修饰对应于关于SEQ ID NO:28编号的位置4、9、10、11、12、13、14、15、16、17、18、20、21、22、24、25、27、28、29、30、31、33、36、37、38、40、41、42、43、44、47、48、50、52、53、54、59、60、61、62、63、64、65、66、67、68、69、70、72、74、76、77、80、81、83、85、86、87、...

【技术特征摘要】
【国外来华专利技术】2016.04.15 US 62/323,595;2016.09.14 US 62/394,743;1.一种变体CD80多肽，其包含IgV结构域或其特异性结合片段、IgC结构域或其特异性结合片段、或两者，其中该变体CD80多肽包含未修饰的CD80或其特异性结合片段中的一个或多个氨基酸修饰，该一个或多个氨基酸修饰对应于关于SEQIDNO:28编号的位置4、9、10、11、12、13、14、15、16、17、18、20、21、22、24、25、27、28、29、30、31、33、36、37、38、40、41、42、43、44、47、48、50、52、53、54、59、60、61、62、63、64、65、66、67、68、69、70、72、74、76、77、80、81、83、85、86、87、88、89、90、91、92、93、94、95、96、97、99、102、103、104、107、108、109、110、114、115、116、117、118、120、121、122、126、127、128、129、130、133、137、140、142、143、144、148、149、152、154、160、162、164、168、169、174、175、177、183、178、185、188、190、192、193或199。2.权利要求1的变体CD80多肽，其中该一个或多个氨基酸修饰包括一个或多个氨基酸取代、插入或缺失。3.权利要求1或2的变体CD80多肽，其中该未修饰的CD80是哺乳动物CD80。4.权利要求1-3中任一项的变体CD80多肽，其中该CD80是人CD80。5.权利要求1-4中任一项的变体CD80多肽，其中该变体CD80多肽包含：IgV结构域或其特异性结合片段；和IgC结构域或其特异性结合片段。6.权利要求1-5中任一项的变体CD80多肽，其中该未修饰的CD80包括(i)SEQIDNO:28所示的氨基酸序列，(ii)与SEQIDNO:28具有至少95％序列一致性的氨基酸序列；或(iii)是(i)或(ii)的一部分，其包含IgV结构域或IgC结构域或其特异性结合片段。7.权利要求1-6中任一项的变体CD80多肽，其中：该IgV结构域或该IgC结构域的该特异性结合片段的长度为至少50、60、70、80、90、100、110或更多个氨基酸；该IgV结构域的该特异性结合片段的长度为SEQIDNO:1的氨基酸35-135所示的IgV结构域长度的至少80％；或该IgC结构域的该特异性结合片段的长度为SEQIDNO:1的氨基酸145-230所示的IgC结构域长度的至少80％。8.权利要求1-7中任一项的变体CD80多肽，其中该变体CD80多肽包含多达1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个氨基酸修饰，任选氨基酸取代。9.权利要求1-8中任一项的变体CD80多肽，其中该变体CD80多肽包含显示出与SEQIDNO:28或其特异性结合片段至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列一致性的氨基酸序列。10.权利要求1-9中任一项的变体CD80多肽，其中与该未修饰的CD80相比，该变体CD80显示出与CD28、PD-L1或CTLA-4的胞外域改变的结合特异性。11.权利要求9的变体CD80多肽，其中该改变的结合是改变的结合亲和力和/或改变的结合选择性。12.权利要求1-11中任一项的变体CD80多肽，其中该一个或多个氨基酸取代是V4M、K9E、E10R、V11S、A12G、A12T、A12V、T13N、L14A、S15V、S15F、C16S、C16G、C16L、G17W、H18L、H18R、H18Y、V20L、S21P、V22A、E24G、L25P、Q27R、T28A、T28S、R29C、R29D、R29H、R29V、I30V、Y31F、Y31H、Y31L、Q33H、K36E、K36G、K37E、K37Q、M38I、M38L、M38T、M38V、L40M、T41A、T41G、T41D、T41I、M42T、M43I、M43Q、M43R、M43V、S44P、M47T、N48I、N48D、W50G、E52G、Y53C、K54M、F59L、F59S、D60V、I61N、T62S、N63S、N64S、L65H、S66H、I67F、I67T、V68A、V68M、I69T、L70Q、L70P、L70R、L72P、P74L、D76G、E77G、E77K、Y80N、E81A、E81R、E81V、V83A、V83I、L85I、L85R、K86E、Y87N、E88D、E88G、K89E、K89N、K89R、D90K、D90L、D90N、A91E、A91G、A91S、A91T、F92L、F92N、F92P、F92Y、K93I、K93E、K93Q、K93R、K93V、R94G、R94L、R94F、E95K、H96R、L97R、E99D、E99G、L102S、S103L、S103P、V104A、V104L、D107N、F108L、P109S、P109H、T110A、D115G、S114T、F116S、F116L、E117V、E117G、I118V、I118A、I118T、T120S、S121P、N122S、I126L、I126V、I127T、C128Y、C128R、S129L、S129P、T130A、G133D、P137L、S140T、L142S、E143G、N144D、N144S、L148S、N149D、N149S、N152T、T154I、T154A、E160G、E162G、Y164H、S168G、K169E、K169I、K169S、M174T、M174V、T175A、N177S、H178R、L183H、K185E、H188D、H188Q、R190S、N192D、Q193L、T199S或其保守氨基酸取代。13.权利要求1-12中任一项的变体CD80多肽，其中该一个或多个氨基酸取代是V4M/L70Q/A91G/T120S/T130A、A12T/H18L/M43V/F59L/E77K/P109S/I118T、A12V/S15F/Y31H/T41G/T130A/P137L/N152T、V20L/L70Q/A91S/T120S/T130A、V22A/L70Q/S121P、E24G/L25P/L70Q/T120S、T28S/L70Q/A91G/E95K/T120S/T130A、E24G/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/F59L/E81V/L85R/K89N/A91T/F92P/K93V/R94L/H96R、R29D/Y31L/Q33H/K36G/M38I/T41A/M42T/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/L148S/N149S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/N149S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/N149S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/N144S/N149S、R29H/Y31H/T41G/Y87N/E88G/K89E/D90N/A91G/P109S、R29H/E52G/L70R/E88G/A91G/T130A、R29H/E52G/T120S/T130A、R29V/Y31F/K36G/M38L/M43Q/E81R/V83I/L85I/K89R/D90L/A91E/F92N/K93Q/R94G、R29V/M43Q/E81R/L85I/K89R/D90L/A91E/F92N/K93Q/R94G、Y31H/T41G/L70Q/A91G/T120S/T130A、K36G、K36G/K37Q/M38I/L40M、K36G/K37Q/M38I/F59L/E81V/L85R/K89N/A91T/F92P/K93V/R94L/E99G/T130A/N149S、K36E/I67T/L70Q/A91G/T120S/T130A/N152T、K37E/F59S/L70Q/A91G/T120S/T130A、M38T/L70Q/E77G/A91G/T120S/T130A/N152T、M38V/T41D/M43I/W50G/D76G/V83A/K89E/T120S/T130A、T41I/A91G、S44P/L70Q/A91G/T130A、E52G/L70Q/A91G/T120S/T130A、K54M/A91G/T120S、D60V/A91G/T120S/T130A、N63S/L70Q/A91G/T120S/T130A、S66H/D90G/T110A/F116L、I67F/L70R/E88G/A91G/T120S/T130A、I67T/L70Q/A91G/T120S、V68A/T110A、V68M/L70P/L72P/K86E、L70Q/A91G/T110A/T120S/T130A、L70Q/E81A/A91G/T120S/I127T/T130A、L70Q/Y87N/A91G/T130A、L70Q/A91G、L70Q/A91G/E117G/T120S/T130A、L70Q/A91G/T120S/T130A、L70Q/A91G/T130A、L70Q/A91G/I118A/T20S/T130A、L70R/A91G/T120S/T130A、E88D/K89R/D90K/A91G/F92Y/K93R、K89E/T130A、K89R/D90K/A91G/F92Y/K93R、E88D/K89R/D90K/A91G/F92Y/K93R/N122S/N177S、K89R/D90K/A91G/F92Y/K93R/N122S/N177S、A91G、A91G/F92L/F108L/T120S、A91G/L102S、A91G/S103P、A91G/T120S/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/T130A/M174T、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/F59L/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/H188D、H18R/R29D/Y31L/Q33H/K36G/K37E/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/E143G/K169E/M174V/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/F108L/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/C128Y/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94F/T130A/K169E、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93I/R94L/L97R/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93I/R94L/L97R/T130A/L148S、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/I61N/E81V/L85R/K89N/A91T/F92P/K93V/R94F/V104A/T120S/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/F92P/K93V/R94F/I118V/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/T62S/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E/T175A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/F116S/T130A/H188D、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/L142S/H188D、C16S/H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T110A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/A91G/T120S/I127T/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/D76G/A91G/S103L/T120S/I127T/T130A、Q33缺失/Y53C/L85R/K89N/A91T/F92P/K93V/R94L/T120S/I127T/T130A/K169E、T62S/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T120S/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/S129L/H188D、K9E/E10R/V11S/A12G/T13N/K14A/S15V/C16L/G17W/H18Y/Y53C/L70Q/D90G/T130A/N149D/N152T/H188D、H18L/R29D/Y31L/Q33H/K36G/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/H188D、K89E/K93E/T130A、S21P/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/N48I/V68A/E81V/L85R/K89N/A91T/F92P/K93V/R94L/P109H/I126L/K169I、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/P74L/Y80N/E81V/L85R/K89N/A91T/F92P/K93V/R94L/L97R、S21P/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/P74L/Y80N/E81V/L85R/K89N/D90N/A91T/F92P/K93V/R94L/T130A/N149S/E162G、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68M/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68M/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A/N149S/R190S、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/P74L/Y80N/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A/R190S、C16G/V22A/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68M/D76G/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/S140T/N149S/K169I/H178R/N192D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94F/E117V/I118T/N149S/S168G/H188Q、V22A/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68M/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/N64S/E81V/L85R/K89N/A91T/F92P/K93V/R94F/I118T/T130A/N149S/K169I、V22A/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68M/E81V/L85R/K89N/A91T/F92P/K93V/R94L/D115G/I118T/T130A/G133D/N149S、S129P、A91G/S129P、I69T/L70Q/A91G/T120S、Y31H/S129P、T28A/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/V104L/T130A/N149S、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/L97R/N149S/H188Q、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/L97R/N149S、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68A/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A/N149S/T154I、A12G/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/V68A/E81V/L85R/K89N/A91T/F92P/K93V/R94L/L97R/T130A/L183H、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/S140T/N149S/K169S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/N149S/K169I/Q193L、V22A/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/N149S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/N149S、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118T/T130A/N149S/K169I、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94F/T130A/N149S/K169I、I118T/C128R、Q27R/R29C/M42T/S129P/E160G、S129P/T154A、S21P/L70Q/D90G/T120S/T130A、L70Q/A91G/N144D、L70Q/A91G/I118A/T120S/T130A/K169E、V4M/L70Q/A91G/I118V/T120S/T130A/K169E、L70Q/A91G/I118V/T120S/T130A/K169E、L70Q/A91G/I118V/T120S/T130A、V20L/L70Q/A91S/I118V/T120S/T130A、L70Q/A91G/E117G/I118V/T120S/T130A、A91G/I118V/T120S/T130A、L70R/A91G/I118V/T120S/T130A/T199S、L70Q/E81A/A91G/I118V/T120S/I127T/T130A、T28S/L70Q/A91G/E95K/I118V/T120S/I126V/T130A/K169E、N63S/L70Q/A91G/S114T/I118V/T120S/T130A、K36E/I67T/L70Q/A91G/I118V/T120S/T130A/N152T、E52G/L70Q/A91G/D107N/I118V/T120S/T130A/K169E、K37E/F59S/L70Q/A91G/I118V/T120S/T130A/K185E、D60V/A91G/I118V/T120S/T130AK169E、K54M/L70Q/A91G/Y164H/T120S、M38T/L70Q/E77G/A91G/I118V/T120S/T130A/N152T、Y31H/T41G/M43L/L70Q/A91G/I118V/T120S/I126V/T130A、L65H/D90G/T110A/F116L、R29H/E52G/D90N/I118V/T120S/T130A、I67T/L70Q/A91G/I118V/T120S、L70Q/A91G/T110A/I118V/T120S/T130A、M38V/T41D/M43I/W50G/D76G/V83A/K89E/I118V/T120S/I126V/T130A、A12V/S15F/Y31H/M38L/T41G/M43L/D90N/T130A/P137L/N149D/N152T、I67F/L70R/E88G/A91G/I118V/T120S/T130A、E24G/L25P/L70Q/A91G/I118V/T120S/N152T、A91G/F92L/F108L/I118V/T120S、E88D/K89R/D90K/A91G/F92Y/K93R/N122S/N177S、K36G/K37Q/M38I/L40M/F59L/E81V/L85R/K89N/A91T/F92P/K93V/R94L/E99G/T130A/N149S、K36G/L40M、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E/M174T、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/N48D/F59L/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/H188D、H18R/R29D/Y31L/Q33H/K36G/K37E/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/E143G/K169E/M174V/H188D、R29D/I30V/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/F108L/I118V/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/N149D/K169E/H188D、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/C128Y/T130A/H188D、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/E99D/T130A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/I61N/E81V/L85R/K89N/A91T/F92P/K93V/R94F/V104A/I118V/T120S/I126V/T130A、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94F/I118V/T120S/T130A、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/L142S/H188D、C16S/H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T110A/I118V/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/A91G/I118V/T120S/I127T/T130A/H188D、R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/L70Q/D76G/A91G/S103L/I118V/T120S/I127T/T130A、Y53C/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/K169E、T62S/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/T130A/K169E、Y53C/L70Q/D90G/T130A/N149D/N152T/H188D、H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/I118V/T120S/I127T/T130A/H188D、或H18L/R29D/Y31L/Q33H/K36G/M38I/T41A/M43R/M47T/E81V/L85R/K89N/A91T/F92P/K93V/R94L/T130A/N149S。14.权利要求1-13中任一项的变体CD80多肽，其包括SEQIDNO:55-108、280-346、414-475中任一个所示的氨基酸序列或其特异性结合片段，或显示出与SEQIDNO:55-108、280-346、414-475中任一个或其特异性结合片段至少95％序列一致性并且含有一个或多个氨基酸取代的氨基酸序列。15.权利要求1-14中任一项的变体CD80多肽，其中该变体CD80多肽包含该IgV结构域或其特异性结合片段。16.权利要求1-15中任一项的变体CD80多肽，其中该IgV结构域或其特异性片段是该变体CD80多肽的仅CD80部分。17.权利要求1-14中任一项的变体CD80多肽，其中该IgC结构域或其特异性片段是该变体CD80多肽的仅CD80部分。18.权利要求1-17中任一项的变体CD80多肽，其包括SEQIDNO:153-195、347、373-386、476-477中任一个所示的氨基酸序列或其特异性结合片段，或显示出与SEQIDNO:153-195、347、373-386、476-477中任一个或其特异性结合片段至少95％序列一致性并且含有一个或多个氨基酸取代的氨基酸序列。19.权利要求1-17中任一项的变体CD80多肽，其中与该未修饰的CD80多肽相比，该变体CD80多肽以增加的亲和力特异性地结合至CD28、PD-L1或CTLA-4的胞外域。20.权利要求1-19中任一项的变体CD80多肽，其中与该未修饰的CD80对于CD28、PD-L1或CTLA-4的胞外域的结合相比，该变体多肽以增加的选择性特异性地结合至该胞外域。21.权利要求20的变体CD80多肽，其中该增加的选择性包括选自CD28、PD-L1和CTLA-4的一种同源结合配偶体相对于另一种同源结合配偶体的比例大于该未修饰的CD80多肽对于该一种同源结合配偶体相对于另一种同源结合配偶体的结合的比例。22.权利要求19或权利要求20的变体CD80多肽，其中与该未修饰的CD80对于CD28的胞外域的结合相比，该变体多肽以增加的选择性特异性地结合至CD28的胞外域。23.权利要求22的变体CD80多肽，其中该增加的选择性包括结合CD28相对于PD-L1或CTLA-4的比例大于该未修饰的CD80多肽对于CD28相对于PD-L1或CTLA-4的结合的比例。24.权利要求21或权利要求23的变体CD80多肽，其中该比例大至少或至少约1.5倍、2.0倍、3.0倍、4.0倍、5倍、10倍、15倍、20倍、30倍、40倍、50倍或更多倍。25.权利要求1-24中任一项的变体CD80多肽，其中与该未修饰的CD80多肽相比，该变体CD80多肽以增加的亲和力特异性地结合至CD28的胞外域。26.权利要求19或权利要求25的变体CD80多肽，其中与该未修饰的CD80对于该胞外域的结合亲和力相比，对该胞外域的该增加的亲和力增加超过1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍或60倍。27.权利要求1-26中任一项的变体CD80多肽，其中该一个或多个氨基酸取代对应于关于SEQIDNO:28编号的位置12、18、20、29、31、36、40、41、43、52、59、60、63、67、70、77、81、87、88、89、90、91、92、93、107、109、114、117、118、120、122、127、130、144、169、177或199。28.权利要求1-27中任一项的变体CD80多肽，其中该一个或多个氨基酸取代选自下组，该组由以下各项组成：A12T、H18L、V20L、R29H、Y31H、K36G、L40M、T41G、T41I、M43V、E52G、F59L、D60V、N63S、I67T、L70Q、L70R、E77K、E81A、Y87N、E88D、E88G、K89E、K89R、D90K、D90N、A91G、A91S、F92Y、K93R、D107N、P109S、S114T、E117G、I118A、I118T、I118V、T120S、I127T、T130A、N144D、K169E、N177S和T199S及其保守氨基酸取代。29.权利要求1-28中任一项的变体CD80多肽，其中该一个或多个氨基酸取代是A12T/H18L/M43V/F59L/E77K/P109S/I118T、V20L/L70Q/A91S/T120S/T130A、V20L/L70Q/A91S/I118V/T120S/T130A、R29H/Y31H/T41G/Y87N/E88G/K89E/D90N/A91G/P109S、K36G、K36G/L40M、T41I/A91G、E52G/L70/A91G/T120S/T130A、E52G/L70Q/A91G/D107N/I118V/T120S/T130A/K169E、D60V/A91G/T120S/T130A、D60V/A91G/I118V/T120S/T130A/K169E、N63S/L70Q/A91G/T120S/T130A、N63S/L70Q/A91G/S114T/I118V/T120S/T130A、I67T/L70Q/A91G/T120S、I67T/L70Q/A91G/I118V/T120S、L70Q/E81A/A91G/T120S/I127T/T130A、L70Q/E81A/A91G/I118V/T120S/I127T/T130A、L70Q/Y87N/A91G/T130A、L70Q/A91G、L70Q/A91G/N144D、L70Q/A91G/E117G/T120S/T130A、L70Q/A91G/E117G/I118V/T120S/T130A、L70Q/A91G/I118A/T120S/T130A、L70Q/A91G/I118A/T120S/T130A/K169E、L70Q/A91G/T120S/T130A、L70Q/A91G/I118V/T120S/T130A/K169E、L70R/A91G/T120S/T130A、L70R/A91G/I118V/T120S/T130A/T199S、E88D/K89R/D90K/A91G/F92Y/K93R、K89R/D90K/A91G/F92Y/K93R、E88D/K89R/D90K/A91G/F92Y/K93R/N122S/N177S或K89R/D90K/A91G/F92Y/K93R/N122S/N177S。30.权利要求1-29中任一项的变体CD80多肽，其中与该未修饰的CD80多肽相比，该变体CD80多肽以增加的亲和力特异性地结合至PD-L1的胞外域。31.权利要求30的变体CD80多肽，其中与该未修饰的CD80对于该胞外域的结合亲和力相比，对该胞外域的该增加的亲和力增加超过1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍或60倍。32.权利要求1-31中任一项的变体CD80多肽，其中与该未修饰的CD80对于PD-L1的胞外域的结合相比，该变体多肽以增加的选择性特异性地结合至该胞外域。33.权利要求32的变体CD80多肽，其中该增加的选择性包括结...

【专利技术属性】
技术研发人员：R·斯旺森，M·科纳克尔，
申请(专利权)人：高山免疫科学股份有限公司，
类型：发明
国别省市：美国,US