CN107849143A - Sirp多肽组合物和使用方法 - Google Patents
Sirp多肽组合物和使用方法 Download PDFInfo
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- CN107849143A CN107849143A CN201680042272.5A CN201680042272A CN107849143A CN 107849143 A CN107849143 A CN 107849143A CN 201680042272 A CN201680042272 A CN 201680042272A CN 107849143 A CN107849143 A CN 107849143A
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Abstract
本文提供了用于癌症、贫血、移植、哮喘、变态反应、自身免疫疾病和病毒感染的免疫疗法和/或治疗的SIRP‑γ、SIRP‑β或SIRP‑β2诱饵型多肽。
Description
交叉引用
本申请要求提交于2015年12月11日的美国临时申请号62/266,450和提交于2015年5月18日的美国临时申请号62/163,282的权益,这两篇申请通过引用全文并入于此。
序列表
本申请含有序列表,该序列表已经以ASCII格式电子提交并通过引用全文并入于此。所述ASCII拷贝创建于2016年5月17日,命名为47815_701_601_SL.txt,大小为66,023字节。
发明背景
信号调节蛋白(SIRP)构成在髓样细胞(包括巨噬细胞、粒细胞、髓样树突细胞和肥大细胞)、淋巴细胞和神经元细胞上表达并调节其活性的细胞表面糖蛋白家族。
发明内容
本文提供了SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽及其类似物,它们都可被称为诱饵型多肽。在一个实施方案中,本文提供了一种诱饵型多肽,包括SIRP-γ、SIRP-β或SIRP-β2多肽,其中该多肽包含至少一个氨基酸修饰以使诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽与CD47结合的亲和力相比于相应的野生型SIRP-γ、SIRP-β或SIRP-β2多肽对CD47的亲和力增加。在特定方面,该多肽包括具有序列EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:1)的SIRP-γ多肽。在其他方面,该SIRP-γ多肽与野生型SIRP-γ多肽90%相同。在进一步的方面,该SIRP-γ多肽在M6、V27、L30、L31、V33、V36、L37、V42、E47、Q52、K53、E54、H56、L66、T67、V92、S98或N101处具有氨基酸置换。在其他方面,该SIRP-γ多肽在M6处具有置换,其中该置换为I、L或F。在进一步的方面,该SIRP-γ多肽在V27处具有置换,其中该置换为F、I或L。在其他方面,该SIRP-γ多肽在L30处具有置换,其中该置换为I、V、H、N或D。在进一步的方面,该SIRP-γ多肽在L31处具有置换,其中该置换为F、I或V。在其他方面,该SIRP-γ多肽在V33处具有置换,其中该置换为I、L、P、T或A。在进一步的方面,该SIRP-γ多肽在V36处具有置换,其中该置换为I。在进一步的方面,该SIRP-γ多肽在L37处具有置换,其中该置换为Q。在进一步的方面,该SIRP-γ多肽在V42处具有置换,其中该置换为A。在其他方面,该SIRP-γ多肽在E47处具有置换,其中该置换为V。在进一步的方面,该SIRP-γ多肽在Q52处具有置换,其中该置换为P、L、V、A或E。在进一步的方面,该SIRP-γ多肽在K53处具有置换,其中该置换为R。在其他方面,该SIRP-γ多肽在E54处具有置换,其中该置换为D、K、N、Q或H。在进一步的方面,该SIRP-γ多肽在H56处具有置换,其中该置换为P或R。在其他方面,该SIRP-γ多肽在L66处具有置换,其中该置换为I、V、P、T、A、R、S或G。在进一步的方面,该SIRP-γ多肽在T67处具有置换,其中该置换为I、N、F、S、Y、V、A或D。在其他方面,该SIRP-γ多肽在V92处具有置换,其中该置换为I。在进一步的方面,该SIRP-γ多肽在S98处具有置换,其中该置换为R、N、K、T、I或M。在其他方面,该SIRP-γ多肽在N101处被置换,其中该置换为K、D、E、H或Q。在进一步的方面,SIRP-γ多肽具有序列EEELQX1IQPEKLLLVTVGKTATLHCTX2TSX3X4PX5GPX6X7WFRGX8GPGRX9LIYNX10X11X12GX13FPRVTTVSDX14X15KRNNMDFSIRISSITPADVGTYYCX16KFRKGX17PEX18VEFKSGPGTEMALGAKPS(SEQID NO:2),其中X1为M、I、L或F;X2为F、I、L或V;X3为L、I、V、H、N或D;X4为F、I、L或V;X5为V、I、L、P、T或A;X6为V或I;X7为L或Q;X8为V或A;X9为E或V;X10为Q、P、L、V、A或E;X11为K或R;X12为E、D、K、N、Q或H;X13为H、P或R;X14为L、I、V、P、T、A、R、S或G;X15为T、I、N、F、S、Y、V、A或D;X16为V或I;X17为S、R、N、K、T、I或M;并且X18为N、K、D、E、H或Q。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3)。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:4)。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:5)。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:6)。在进一步的方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:7)。在其他方面,该SIRP-γ多肽具有以下序列中的一种:
HLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSHFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:8);
HLib2:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:9);
HLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:10);
HLib4:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRELIYNAREGRFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:11);
HMLib1:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRIGNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:12);
HMLib2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3);
HMLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13);
HMLib4:
EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:42);
HMLib5:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:14);
HMLib6:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTXWH(SEQ ID NO:15),其中X为A、R、N、D、C、Q、E、G、H、I、L、K、M、F、P、S、T、W、Y或V;
HMLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:16);
MLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSLLPVGPIQWFRGVGPGRELIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:17);
MLib2:
EEELQIIQPEKLLLVTVGKTATLHCTLTSLLPVGPILWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGNPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:18);
MLib3:
EEELQLIQPEKLLLVTVGKTATLHCTITSLFPPGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:19);
MLib4:
EEELQIIQPEKLLLVTVGKTATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:20);
MLib5:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPIGPILWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:21);
MLib6:
EEELQMIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:22);
MLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:23);
MLib8:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALXAKPS(SEQ ID NO:24);或
GV1.2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13)。
在其他实施方案中,所述诱饵型多肽包括具有序列EDELQVIQPEKSVSVAAGESATLRCAMTSLIPVGPIMWFRGAGAGRELIYNQKEGHFPRVTTVSELTKRNNLDFSISISNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:25)的SIRP-β多肽。在特定方面,该SIRP-β多肽与野生型SIRP-β多肽至少90%相同。在进一步的方面,该SIRP-β多肽在I6、I27、F31、Q37、V47、R53、Q54、P56、T66或I92处具有氨基酸置换。在其他方面,该SIRP-β多肽在V6处具有置换,其中该置换为I。在进一步的方面,该SIRP-β多肽在M27处具有置换,其中该置换为I。在进一步的方面,该SIRP-β多肽在I31处具有置换,其中该置换为F。在其他方面,该SIRP-β多肽在M37处具有置换,其中该置换为Q。在进一步的方面,该SIRP-β多肽在E47处具有置换,其中该置换为V。在其他方面,该SIRP-β多肽在K53处具有置换,其中该置换为R。在进一步的方面,该SIRP-β多肽在E54处具有置换,其中该置换为Q。在其他方面,该SIRP-β多肽在H56处具有置换,其中该置换为P。在进一步的方面,该SIRP-β多肽在L66处具有置换,其中该置换为T。在其他方面,该SIRP-β多肽在V92处具有置换,其中该置换为I。在进一步的方面,该SIRP-β多肽具有序列EDELQIIQPEKSVSVAAGESATLRCAITSLFPVGPIQWFRGAGAGRVLIYNQRQGPFPRVTTVSETTKRNNLDFSISISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQID NO:26)。在进一步的方面,该SIRP-β多肽具有序列EDELQX1IQPEKSVSVAAGESATLRCAX2TSLX3PVGPIX4WFRGAGAGRX5LIYNQX6X7GX8FPRVTTVSEX9TKRNNLDFSISISNITPADAGTYYCX10KFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:45),其中X1为V或I;X2为M或I;X3为I或F;X4为M或Q;X5为E或V;X6为K或R;X7为E或Q;X8为H或P;X9为L或T;并且X10为V或I。
在其他实施方案中,所述诱饵型多肽包括具有序列EEELQVIQPDKSISVAAGESATLHCTVTSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISNITPADAGTYYCVKFRKGSPDHVEFKSGAGTELSVRAKPS(SEQ ID NO:27)的SIRP-β2多肽。在特定方面,该SIRP-β2多肽与野生型SIRP-β2多肽至少90%相同。在其他方面,该SIRP-β2多肽在I6、I27、F31、V47、R53、Q54、P56、T66、I92或D101处具有氨基酸置换。在其他方面,该SIRP-β2多肽在V6处被置换,其中该置换为I。在进一步的方面,该SIRP-β2多肽在V27处被置换,其中该置换为I。在其他方面,该SIRP-β2多肽在I31处被置换,其中该置换为F。在进一步的方面,该SIRP-β2多肽在E47处被置换,其中该置换为V。在其他方面,该SIRP-β2多肽在K53处被置换,其中该置换为R。在进一步的方面,该SIRP-β2多肽在E54处被置换,其中该置换为Q。在其他方面,该SIRP-β2多肽在H56处被置换,其中该置换为P。在进一步的方面,该SIRP-β2多肽在L66处被置换,其中该置换为T。在进一步的方面,该SIRP-β2多肽在V92处被置换,其中该置换为I。在其他方面,该SIRP-β2多肽在H101处被置换,其中该置换为D。在进一步的方面,该SIRP-β2多肽具有序列EEELQIIQPDKSISVAAGESATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:28)。在进一步的方面,该SIRP-β2多肽具有序列EEELQX1IQPDKSISVAAGESATLHCTX2TSLX3PVGPIQWFRGAGPGRX4LIYNQX5X6GX7FPRVTTVSDX8TKRNNMDFSIRISNITPADAGTYYCX9KFRKGSPDX10VEFKSGAGTELSVRAKPS(SEQ ID NO:46),其中X1为V或I;X2为V或I;X3为I或F;X4为E或V;X5为K或R;X6为E或Q;X7为H或P;X8为L或T;X9为V或I;并且X10为H或D。
在其他实施方案中,本文提供了选自SIRP-γ、SIRP-β和SIRP-β2多肽的诱饵型多肽,其中该SIRP-γ多肽具有序列EEELQX1IQPEKLLLVTVGKTATLHCTX2TSX3X4PX5GPX6X7WFRGX8GPGRX9LIYNX10X11X12GX13FPRVTTVSDX14X15KRNNMDFSIRISSITPADVGTYYCX16KFRKGX17PEX18VEFKSGPGTEMALGAKPS(SEQ ID NO:2),其中X1为M、I、L或F;X2为F、I、L或V;X3为L、I、V、H、N或D;X4为F、I、L或V;X5为V、I、L、P、T或A;X6为V或I;X7为L或Q;X8为V或A;X9为E或V;X10为Q、P、L、V、A或E;X11为K或R;X12为E、D、K、N、Q或H;X13为H、P或R;X14为L、I、V、P、T、A、R、S或G;X15为T、I、N、F、S、Y、V、A或D;X16为V或I;X17为S、R、N、K、T、I或M;并且X18为N、K、D、E、H或Q,
其中该SIRP-β多肽具有序列EDELQX1IQPEKSVSVAAGESATLRCAX2TSLX3PVGPIX4WFRGAGAGRX5LIYNQX6X7GX8FPRVTTVSEX9TKRNNLDFSISISNITPADAGTYYCX10KFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:45),其中X1为V或I;X2为M或I;X3为I或F;X4为M或Q;X5为E或V;X6为K或R;X7为E或Q;X8为H或P;X9为L或T;并且X10为V或I;并且
其中该SIRP-β2多肽具有序列EEELQX1IQPDKSISVAAGESATLHCTX2TSLX3PVGPIQWFRGAGPGRX4LIYNQX5X6GX7FPRVTTVSDX8TKRNNMDFSIRISNITPADAGTYYCX9KFRKGSPDX10VEFKSGAGTELSVRAKPS(SEQ ID NO:46),其中X1为V或I;X2为V或I;X3为I或F;X4为E或V;X5为K或R;X6为E或Q;X7为H或P;X8为L或T;X9为V或I;并且X10为H或D。
在其他实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽阻断CD47与配体的结合。在特定方面,该配体为SIRP-α、SIRPγ或血小板反应蛋白-1。
在其他实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽能与细胞结合。在特定方面,该细胞为肿瘤细胞、病毒感染的细胞、细菌感染的细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
在其他实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽能实现对以下细胞的吞噬作用或ADCC:肿瘤细胞、病毒感染的细胞、细菌感染的细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
在其他实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽与免疫球蛋白Fc序列融合。在其他实施方案中,该SIRP-γ、SIRP-β或SIRP-β2多肽是多聚体的。在其他实施方案中,该SIRP-γ、SIRP-β或SIRP-β2多肽是单体的。在其他实施方案中,该诱饵型多肽进一步包含可检测标记物。
在其他实施方案中,本文提供了包含如上所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽和药学上可接受的载体或赋形剂的组合物。在特定方面,该组合物进一步包含额外的药物。在特定方面,该药物包括化疗剂、激酶抑制剂、蛋白酶体抑制剂,或病毒DNA或RNA聚合酶抑制剂中的一种或多种。在其他实施方案中,该组合物进一步包含单克隆抗体。在特定方面,该单克隆抗体能结合癌细胞(例如,骨髓瘤细胞)、免疫细胞、病原体感染的细胞或造血干细胞上的抗原。在其他方面,癌细胞上的抗原包括EGFR、Her2/neu、CD19、CD20、CD22、CD25、CD30、CD33、CD38、CD45、CD47、CD56、CD70、CD117或EpCAM。在进一步的方面,免疫细胞上的抗原包括M1prime、CD2、CD3、CD4、CD5、CD8、CD19、CD20、CD22、CD25、CD38、CD56、PD-1、PD-L1、CTLA4、BTLA、TIM3、LAG3、OX40、GITR或CD137(4-1BB)。在其他方面,病原体感染的细胞上的抗原包括巨细胞病毒(CMV)蛋白,包括UL-18、UL11、pp65、gB和pp150。在其他方面,病原体感染的细胞上的抗原包括HIV包膜蛋白,包括Gp41、Gp120、V1V2聚糖和V3聚糖,以及流感血凝素。在进一步的方面,造血干细胞上的抗原包括CD11、CD45、CD117或Sca1。
在其他实施方案中,本文提供了具有提高的持久性的如上所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽。在一些方面,该诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽的提高的持久性导致其细胞表面半衰期长于其他SIRP多肽。
在其他实施方案中,本文提供了具有增加的占据(occupancy)或受体占据的如上所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽。在一些方面,诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽的增加的占据导致该诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽与一种或多种靶细胞的结合增加。
在其他实施方案中,本文提供了编码任一种上述诱饵型多肽的分离的核酸。在其他实施方案中,本文提供了表达任一种上述诱饵型多肽的细胞。
在其他实施方案中,本文提供了调节对表达CD47的细胞的吞噬作用或ADCC的方法,该方法包括使细胞与任一种上述诱饵型多肽或组合物接触。在其他实施方案中,本文提供了治疗有需要的受试者的方法,其包括施用有效量的任一种上述诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或组合物。在特定方面,该受试者患有癌症、贫血、病毒感染、细菌感染、自身免疫疾病、哮喘、变态反应、移植排斥、动脉粥样硬化或纤维化。
在其他实施方案中,本文提供了任一种上述诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或组合物,其用于治疗癌症、病毒感染、细菌感染、自身免疫疾病、哮喘、变态反应、移植排斥、动脉粥样硬化或纤维化。在其他实施方案中,本文提供了任一种上述诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或组合物,其用于预处理(preconditioning)造血干细胞移植物。
在其他实施方案中,本文提供了使表达CD47的细胞可视化的方法,该方法包括使细胞群体与任一种上述诱饵型多肽和可检测标记物接触。在特定方面,该细胞为肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T细胞或B细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。在其他方面,该接触在体内进行。在进一步的方面,该接触在体外进行。
在其他实施方案中,本文提供了表达CD47的细胞的纯化方法,该方法包括使细胞群体与任一种上述诱饵型多肽和可检测标记物接触,以及将与该可检测标记物结合的细胞纯化。
援引并入
本说明书中提及的所有出版物、专利和专利申请都通过引用并入于此,其程度如同特别且单独地指出每个单独的出版物、专利或专利申请均通过引用而并入。
附图说明
图1A和1B示出了SIRP-γ变体GV3对人CD47的结合亲和力和动力学的基于表面等离子体共振的测量。图1A示出了所用的SIRP-γ变体GV3的浓度包括100pM、316pM、1nM、3.16nM、10nM和100nM。使用1:1 Langmuir结合模型计算的解离常数Kd为92pM。所计算的解离半衰期T1/2为约44分钟。图1B示出了与SIRP-γ变体GV3结合的生物素化人CD47的图示。
图2A和2B示出了HAC-GV3(SIRP-γ变体GV3与PD-1变体HAC的融合物)对人CD47的结合亲和力和动力学的基于表面等离子体共振的测量。图2A示出了所用的HAC-GV3融合蛋白的浓度包括100pM、316pM、1nM、3.16nM、10nM和100nM。使用1:1 Langmuir结合模型计算的解离常数Kd为160pM。所计算的解离半衰期T1/2为约40分钟。图2B示出了与包含SIRP-γ变体GV3和HAC的融合蛋白结合的生物素化人CD47的图示。
图3A和3B示出了HAC-GV3(SIRP-γ变体GV3与PD-1变体HAC的融合物)对人PD-L1的结合亲和力和动力学的基于表面等离子体共振的测量。图3A示出了所用的HAC-GV3融合蛋白的浓度包括100pM、316pM、1nM、3.16nM、10nM和100nM。使用1:1 Langmuir结合模型计算的解离常数Kd为134pM。所计算的解离半衰期T1/2为约38分钟。图3B示出了与HAC-GV3结合的生物素化人PD-L1的图示。
图4A和4B示出了人CD47和人PD-L1被HAC-GV3同时结合的结合亲和力和动力学的基于表面等离子体共振的测量。图4A示出了与单独的人GV3相比,融合蛋白HAC-GV3的结合曲线显示了与生物素化CD47结合的第一峰和与PD-L1结合的第二峰。图4B示出了与HAC-GV3融合蛋白的GV3部分结合的生物素化人CD47的图示,其中HAC部分与PD-LA结合。
图5示出了CD47+GFP-萤光素酶+DLD1-Tg细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3阻断的基于流式细胞术的测量。在CD47+细胞的存在下,将50nM生物素化SIRP-α四聚体与滴定浓度的GV3或HAC-GV3混合。将作为SIRP-α结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
图6示出了CD47+PD-L1+GFP-萤光素酶+DLD1-Tg细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3阻断的基于流式细胞术的测量。在CD47+PD-L1+细胞的存在下,将50nM生物素化SIRP-α四聚体与滴定浓度的GV3或HAC-GV3混合。将作为SIRP-α结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
图7示出了人PD-L1+酵母细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3阻断的基于流式细胞术的测量。在hPD-L1+酵母细胞的存在下,将100nM生物素化PD-1四聚体与滴定浓度的HAC或HAC-GV3混合。将作为PD-1结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
图8示出了CD47+PD-L1+GFP-萤光素酶+DLD1-Tg细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3阻断的基于流式细胞术的测量。在CD47+PD-L1+细胞的存在下,将100nM生物素化PD-1四聚体与滴定浓度的HAC或HAC-GV3混合。将作为PD-1结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
图9示出了来源于供体的人巨噬细胞对人结肠癌细胞系DLD1的吞噬作用的基于FACS的测量,表明GV3微体和HAC-GV3在广泛的调理性(opsonizing)抗体浓度下增强吞噬作用。通过将100,000个靶细胞与50,000个巨噬细胞在超低附着96孔U型底板(Corning)中的未添加抗生素或血清的IMDM+GlutaMax(Life Technologies)中共同培养两小时来进行吞噬作用的评估。通过采用CD14+全血分离试剂盒(Miltenyi)对原代人单核细胞进行基于磁珠的纯化,随后与人血清(Gemini)培养7天而生成巨噬细胞;在第7天,使用TrypLE Express(Life Technologies)从板上收获这些细胞。根据制造商的指示,用钙黄绿素AM红/橙细胞染色剂(Life Technologies)来标记巨噬细胞。将靶细胞工程化成稳定表达绿色荧光蛋白。以10nM的饱和浓度向反应孔添加二聚化微体形式的HGV3(GV3mb)或HAC-GV3融合蛋白,同时在三个对数尺度的浓度(three logs of concentration)下滴定调理性抗体西妥昔单抗。误差条表示重复实验的标准偏差。反应在装有高通量自动进样器(BD Biosciences)的LSRFortessa分析仪上进行。吞噬作用以如采用FlowJo v.9.4.10(Tree Star)分析的、表示为GFP+巨噬细胞占总巨噬细胞的百分比来评估,并如图例中所示进行归一化。
图10示出了移植有人白血病细胞的NSG小鼠的实验大纲,其使得能够估测体内人RO动力学。
图11A-D示出了与GV3相比,HAC-GV3在组织中实现了更高的受体占据和持久性。图11A示出了在总脾细胞中的受体占据和持久性。图11B示出了在脾细胞中的受体占据和持久性。图11C示出了在人CD47+PDL1+细胞中的受体占据和持久性。图11D示出了在B16-F0黑素瘤细胞中的受体占据和持久性。
具体实施方式
本文提供了SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽及其类似物,它们都可被称为诱饵型多肽。诱饵型多肽是野生型人SIRP-γ、SIRP-β或SIRP-β2蛋白的变体。在一个实施方案中,本文提供了可溶性SIRP-γ、SIRP-β或SIRP-β2多肽,其中该多肽缺少跨膜域并且与野生型SIRP-γ、SIRP-β或SIRP-β2序列相比,包含至少一个氨基酸变化,并且其中该氨基酸变化提高该SIRP-γ、SIRP-β或SIRP-β2多肽与CD47结合的亲和力,例如,使解离速率(off-rate)降低至少10倍、至少20倍、至少50倍、至少100倍、至少500倍,或更多。
信号调节蛋白(SIRP)构成在髓样细胞(包括巨噬细胞、粒细胞、髓样树突细胞和肥大细胞)和神经元细胞上表达的细胞表面糖蛋白家族。SIRP构成免疫受体的多种多基因家族,包括抑制性、激活性、非信号性和可溶性的成员。CD47是一种广泛表达的跨膜糖蛋白,起到SIRPα的细胞配体的作用,并与SIRPα的NH2-末端胞外端结合。就SIRPα在巨噬细胞对宿主细胞的吞噬作用和通过嗜中性粒细胞的抗体指导的细胞毒性(ADCC)中的抑制作用而言,其作用已得到很好的证实。特别地,髓样细胞上的SIRPα与在靶细胞上表达的CD47的结合生成负调节吞噬作用和ADCC的抑制信号。与CD47或SIRPα结合并拮抗CD47:SIRPα相互作用的药剂作用于活性巨噬细胞吞噬作用和嗜中性粒细胞ADCC,特别是针对抗体调理的细胞(Majeti等人,Cell 2009,Chao等人,Cell 2010,Zhang等人,Weiskopf等人,Science2013)。该药剂包括单克隆抗体,以及可溶性CD47和SIRPα受体“诱饵”。CD47还是SIRP-γ的配体,该SIRPγ是不同于在功能不明的淋巴细胞上表达的SIRPα的基因。SIRP-β和SIRP-β2也是与SIRPα不同的基因,尽管它们在序列和结构上与SIRPα具有相似性,但自然条件下,它们本身不会结合CD47。然而,可以通过突变来实现该结合(Hatherly等人,Molecular Cell2008)。原则上,基于SIRP-γ、SIRP-β或SIRP-β2骨架的诱饵型受体也可拮抗SIRPα-CD47相互作用,从而增强髓样细胞吞噬作用或ADCC。这些诱饵作为CD47靶向治疗剂相对于基于SIRPα的诱饵具有较大优势,这是因为SIRPα胞外域在个体之间具有高度多态性,因而在将SIRPα作为重组治疗剂施用时免疫原性的可能性会增加。相比之下,SIRP-γ、SIRP-β和SIRP-β2的胞外域不是广泛多态性的,因此避免了不必要的免疫原性序列。
在一些实施方案中,本文所述的SIRP-γ、SIRP-β或SIRP-β2多肽刺激髓样细胞(例如,巨噬细胞、单核细胞、树突细胞、嗜中性粒细胞等)引起的吞噬作用或ADCC,从而消除病原体细胞(例如,肿瘤细胞、病毒或细菌感染的细胞、自身反应性T细胞等)。在一些这样的实施方案中,将细胞选择性地消除,从而减少了毒副作用的可能性。在其他实施方案中,为了治疗效果,可使用相同的多肽来增强内源细胞的消除,如消除自身免疫疾病、哮喘和变态反应中的B或T淋巴细胞,或消除造血干细胞(HSC)以供干细胞移植。
在一些实施方案中,与本领域已知的其他SIRP多肽相比,本文所述的SIRP-γ、SIRP-β或SIRP-β2多肽具有增加的占据或受体占据。在一些实施方案中,与本领域已知的其他SIRP多肽相比,本文所述的SIRP-γ、SIRP-β或SIRP-β2多肽具有提高的持久性。如本文所用的,占据或受体占据是指与靶细胞、靶受体、靶蛋白或靶组织的结合。如本文所用的,持久性是指多肽施用至个体、受试者或患者时的血清半衰期或细胞结合半衰期。
SIRP多肽和SIRP多肽变体
信号调节蛋白(SIRP,CD172)是参与白细胞功能的膜蛋白家族。SIRP蛋白家族包括信号调节蛋白γ(SIRP-γ,CD172g)、信号调节蛋白β(SIRP-β,信号调节蛋白β1,CD172b,SIRP-β1)和信号调节蛋白β2(SIRP-β2,PTPN1L)。
人SIRP-γ的氨基酸序列可在SWISS-PROT数据库中作为Q9P1W8获得。SIRP-γ包括三种同种型。人SIRP-β的氨基酸序列可在SWISS-PROT数据库中作为O00241和Q5TFQ8获得。SIRP-β包括三种同种型。SIRP-β2的氨基酸序列可在SWISS-PROT数据库中作为Q5JXA9获得。SIRP-β2包括三种同种型。
在本文呈现的实施方案的范围内考虑到作为CD47的诱饵并激活吞噬作用的SIRP-γ、SIRP-β和SIRP-β2多肽的变体。在一些实施方案中,诱饵型多肽包括SIRP-γ、SIRP-β或SIRP-β2多肽,其中该多肽包含至少一个氨基酸修饰以使诱饵型SIRP-γ、SIRP-β和SIRP-β2多肽与CD47结合的亲和力相比于相应的野生型SIRP-γ、SIRP-β和SIRP-β2多肽对CD47的亲和力增加。
如本文所用的,“与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列基本上相同的序列”意指在一个实施方案中,序列与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列至少80%相同。在其他实施方案中,“与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列基本上相同的序列”意指序列与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列至少85%相同。在其他实施方案中,“与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列基本上相同的序列”意指序列与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列至少90%相同。在其他实施方案中,“与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列基本上相同的序列”意指序列与野生型SIRP-γ、SIRP-β或SIRP-β2多肽序列至少95%相同。
在一些实施方案中,本文所述的诱饵型多肽包括SIRP-γ、SIRP-β或SIRP-β2多肽的高亲和力同系物或变体(例如,SIRP-γ、SIRP-β或SIRP-β2的变体)。因此,本文呈现的实施方案包括具有与野生型SIRP-γ、SIRP-β或SIRP-β2多肽的氨基酸序列相似但不相同的序列的SIRP-γ、SIRP-β或SIRP-β2多肽的使用。因此,在本文提供的实施方案的范围内还考虑与野生型SIRP-γ、SIRP-β或SIRP-β2多肽的序列具有99%、98%、97%、96%、95%、94%、93%、92%、91%、90%、89%、88%、87%、86%、85%、84%、83%、82%、81%或80%序列同一性并且以高亲和力与CD47结合的SIRP-γ、SIRP-β或SIRP-β2多肽的使用。
在一些实施方案中,将SIRP-γ、SIRP-β或SIRP-β2多肽变体修饰成含有保守变异,以便改变非关键残基或非关键区域中的残基。不关键的氨基酸通过已知的方法鉴别,如定点诱变、结晶、核磁共振、光亲和标记或丙氨酸扫描诱变(Cunningham等人,Science,244:1081-1085(1989);Smith等人,J.Mol.Biol.,224:899-904(1992);de Vos等人,Science,255:306-312(1992))。经由诸如体外活性或体内活性的方法来测试经修饰的蛋白质与CD47结合的活性或能力。
在一些实施方案中,SIRP-γ、SIRP-β或SIRP-β2多肽变体包含改善SIRP-γ、SIRP-β或SIRP-β2多肽稳定性的1、2、3、4、5个或更多个氨基酸置换,或置换为改善SIRP-γ、SIRP-β或SIRP-β2多肽抗氧化稳定性的不同疏水性氨基酸,或置换为改善SIRP-γ、SIRP-β或SIRP-β2多肽对蛋白酶的稳定性的不同氨基酸。因此,“变异”SIRP-γ、SIRP-β或SIRP-β2多肽与野生型SIRP-γ、SIRP-β或SIRP-β2多肽所代表的序列在氨基酸序列上的区别在于一个或多个置换、缺失、插入、倒位、截短、修改或其组合。这样的变体任选地含有用具有相似特征的另一种氨基酸置换给定氨基酸的氨基酸置换。保守置换包括脂肪族氨基酸中,丙氨酸、缬氨酸、亮氨酸和异亮氨酸的互换;羟基残基丝氨酸与苏氨酸的互换,酸性残基天冬氨酸与谷氨酸的交换,酰胺残基天冬酰胺与谷氨酰胺之间的置换,碱性残基赖氨酸与精氨酸的交换,以及芳香族残基苯丙氨酸与酪氨酸之间的替换。参见Bowie等人,Science,247:1306-1310(1990)。
SIRP-γ、SIRP-β或SIRP-β2多肽是如下详细描述的变体,其中该变体保留或改善CD47结合的特征。
在一些实施方案中,SIRP-γ、SIRP-β或SIRP-β2多肽变体是SIRP-γ、SIRP-β或SIRP-β2蛋白的片段。在一些实施方案中,SIRP-γ、SIRP-β或SIRP-β2多肽变体包括抗蛋白水解切割的SIRP-γ、SIRP-β或SIRP-β2多肽片段,或含有一个或多个非天然氨基酸如D-氨基酸的SIRP-γ、SIRP-β或SIRP-β2多肽片段。这样的衍生物将具有循环半衰期增加的益处,同时保留CD47结合的有益特征。
在另一个实施方案中,SIRP-γ、SIRP-β或SIRP-β2多肽变体包括诱饵型多肽。在某些实施方案中,该诱饵型多肽包括具有序列EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:1)的SIRP-γ多肽,或与野生型SIRP-γ序列基本相同的多肽。在特定方面,该SIRP-γ多肽在M6、V27、L30、L31、V33、V36、L37、V42、E47、Q52、K53、E54、H56、L66、T67、V92、S98或N101处具有至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个氨基酸置换。在进一步的方面,该SIRP-γ多肽在M6处具有置换,其中该置换为I、L或F。在其他方面,该SIRP-γ多肽在V27处具有置换,其中该置换为F、I或L。在进一步的方面,该SIRP-γ多肽在L30处具有置换,其中该置换为I、V、H、N或D。在其他方面,该SIRP-γ多肽在L31处具有置换,其中该置换为F、I或V。在进一步的方面,该SIRP-γ多肽在V33处具有置换,其中该置换为I、L、P、T或A。在其他方面,该SIRP-γ多肽在V36处具有置换,其中该置换为I。在其他方面,该SIRP-γ多肽在L37处具有置换,其中该置换为Q。在其他方面,该SIRP-γ多肽在V42处具有置换,其中该置换为A。在进一步的方面,该SIRP-γ多肽在E47处具有置换,其中该置换为V。在其他方面,该SIRP-γ多肽在Q52处具有置换,其中该置换为P、L、V、A或E。在其他方面,该SIRP-γ多肽在K53处具有置换,其中该置换为R。在进一步的方面,该SIRP-γ多肽在E54处具有置换,其中该置换为D、K、N、Q或H。在进一步的方面,该SIRP-γ多肽在H56处具有置换,其中该置换为P或R。在其他方面,该SIRP-γ多肽在L66处具有置换,其中该置换为I、V、P、T、A、R、S或G。在进一步的方面,该SIRP-γ多肽在T67处具有置换,其中该置换为I、N、F、S、Y、V、A或D。在进一步的方面,该SIRP-γ多肽在V92处具有置换,其中该置换为I。在其他方面,该SIRP-γ多肽在S98处具有置换,其中该置换为R、N、K、T、I或M。在进一步的方面,该SIRP-γ多肽在N101处被置换,其中该置换为K、D、E、H或Q。在其他方面,该SIRP-γ多肽具有序列EEELQX1IQPEKLLLVTVGKTATLHCTX2TSX3X4PX5GPX6X7WFRGX8GPGRX9LIYNX10X11X12GX13FPRVTTVSDX14X15KRNNMDFSIRISSITPADVGTYYCX16KFRKGX17PEX18VEFKSGPGTEMALGAKPS(SEQ ID NO:2),其中X1为M、I、L或F;X2为F、I、L或V;X3为L、I、V、H、N或D;X4为F、I、L或V;X5为V、I、L、P、T或A;X6为V或I;X7为L或Q;X8为V或A;X9为E或V;X10为Q、P、L、V、A或E;X11为K或R;X12为E、D、K、N、Q或H;X13为H、P或R;X14为L、I、V、P、T、A、R、S或G;X15为T、I、N、F、S、Y、V、A或D;X16为V或I;X17为S、R、N、K、T、I或M;并且X18为N、K、D、E、H或Q。在其他方面,该诱饵型多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3)。在进一步的方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:4)。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQID NO:5)。在其他方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:6)。在进一步的方面,该SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:7)。在其他方面,该SIRP-γ多肽具有以下序列中的一种:
HLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSHFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:8);
HLib2:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:9);
HLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:10);
HLib4:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRELIYNAREGRFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:11);
HMLib1:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRIGNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:12);
HMLib2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3);
HMLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13);
HMLib4:
EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:42);
HMLib5:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:14);
HMLib6:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTXWH(SEQ ID NO:15),其中X为A、R、N、D、C、Q、E、G、H、I、L、K、M、F、P、S、T、W、Y或V;
HMLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:16);
MLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSLLPVGPIQWFRGVGPGRELIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:17);
MLib2:
EEELQIIQPEKLLLVTVGKTATLHCTLTSLLPVGPILWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGNPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:18);
MLib3:
EEELQLIQPEKLLLVTVGKTATLHCTITSLFPPGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:19);
MLib4:
EEELQIIQPEKLLLVTVGKTATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:20);
MLib5:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPIGPILWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:21);
MLib6:
EEELQMIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:22);
MLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:23);
MLib8:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALXAKPS(SEQ ID NO:24);或
GV1.2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13)。
在其他实施方案中,所述诱饵型多肽包括具有序列EDELQVIQPEKSVSVAAGESATLRCAMTSLIPVGPIMWFRGAGAGRELIYNQKEGHFPRVTTVSELTKRNNLDFSISISNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:25)的SIRP-β多肽。在特定方面,该SIRP-β多肽与野生型SIRP-β多肽至少90%相同。在其他方面,该SIRP-β多肽在V6、M27、I31、M37、E47、K53、E54、H56、L66或V92处具有氨基酸置换。在进一步的方面,该SIRP-β多肽在V6处具有置换,其中该置换为I。在其他方面,该SIRP-β多肽在M27处具有置换,其中该置换为I。在进一步的方面,该SIRP-β多肽在I31处具有置换,其中该置换为F。在其他方面,该SIRP-β多肽在M37处具有置换,其中该置换为Q。在进一步的方面,该SIRP-β多肽在E47处具有置换,其中该置换为V。在其他方面,该SIRP-β多肽在K53处具有置换,其中该置换为R。在进一步的方面,该SIRP-β多肽在E54处具有置换,其中该置换为Q。在其他方面,该SIRP-β多肽在H56处具有置换,其中该置换为P。在进一步的方面,该SIRP-β多肽在L66处具有置换,其中该置换为T。在其他方面,该SIRP-β多肽在V92处具有置换,其中该置换为I。在进一步的方面,该SIRP-β多肽具有序列EDELQIIQPEKSVSVAAGESATLRCAITSLFPVGPIQWFRGAGAGRVLIYNQRQGPFPRVTTVSETTKRNNLDFSISISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQID NO:26)。在进一步的方面,该SIRP-β多肽具有序列EDELQX1IQPEKSVSVAAGESATLRCAX2TSLX3PVGPIX4WFRGAGAGRX5LIYNQX6X7GX8FPRVTTVSEX9TKRNNLDFSISISNITPADAGTYYCX10KFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:45),其中X1为V或I;X2为M或I;X3为I或F;X4为M或Q;X5为E或V;X6为K或R;X7为E或Q;X8为H或P;X9为L或T;并且X10为V或I。
在进一步的实施方案中,所述诱饵型多肽包括具有序列EEELQVIQPDKSISVAAGESATLHCTVTSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISNITPADAGTYYCVKFRKGSPDHVEFKSGAGTELSVRAKPS(SEQ ID NO:27)的SIRP-β2多肽。在特定方面,该SIRP-β2多肽与野生型SIRP-β2多肽至少90%相同。在其他方面,该SIRP-β2多肽在V6、V27、I31、E47、K53、E54、H56、L66、V92或H101处具有氨基酸置换。在进一步的方面,该SIRP-β2多肽在V6处被置换,其中该置换为I。在其他方面,该SIRP-β2多肽在V27处被置换,其中该置换为I。在进一步的方面,该SIRP-β2多肽在I31处被置换,其中该置换为F。在其他方面,该SIRP-β2多肽在E47处被置换,其中该置换为V。在进一步的方面,该SIRP-β2多肽在K53处被置换,其中该置换为R。在其他方面,该SIRP-β2多肽在E54处被置换,其中该置换为Q。在进一步的方面,该SIRP-β2多肽在H56处被置换,其中该置换为P。在其他方面,该SIRP-β2多肽在L66处被置换,其中该置换为T。在进一步的方面,该SIRP-β2多肽在V92处被置换,其中该置换为I。在其他方面,该SIRP-β2多肽在H101处被置换,其中该置换为D。在进一步的方面,该SIRP-β2多肽具有序列EEELQIIQPDKSISVAAGESATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:28)。在进一步的方面,该SIRP-β2多肽具有序列EEELQX1IQPDKSISVAAGESATLHCTX2TSLX3PVGPIQWFRGAGPGRX4LIYNQX5X6GX7FPRVTTVSDX8TKRNNMDFSIRISNITPADAGTYYCX9KFRKGSPDX10VEFKSGAGTELSVRAKPS(SEQ ID NO:46),其中X1为V或I;X2为V或I;X3为I或F;X4为E或V;X5为K或R;X6为E或Q;X7为H或P;X8为L或T;X9为V或I;并且X10为H或D。
在一些实施方案中,所述诱饵型多肽阻断CD47与结合配偶体或配体的结合。在特定方面,该结合配偶体或配体包括SIRPα(SIRPA)、SIRPγ(SIRPG)或血小板反应蛋白-1(TSP-1,THBS1)中的一种或多种。
在一些实施方案中,所述诱饵型多肽能与细胞结合。在特定方面,该诱饵型多肽与细胞的结合激活、实现、诱导或引起吞噬细胞如专业的吞噬细胞(例如,单核细胞、巨噬细胞、嗜中性粒细胞、树突细胞或肥大细胞)、非专业的吞噬细胞(例如,上皮细胞、内皮细胞、成纤维细胞或间充质细胞)或二者对该细胞的吞噬作用。在其他方面,该细胞为肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自反应性细胞如自反应性T细胞或B细胞,或体内的其他不需要或致病的细胞或组织,如损伤的红细胞、动脉斑块或纤维化组织。在其他方面,该细胞为健康的正常细胞如造血干细胞,健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
在一些实施方案中,所述诱饵型多肽为嵌合体或融合蛋白。在特定方面,该诱饵型多肽与免疫球蛋白Fc序列、绿色荧光蛋白、红色荧光蛋白、生物素、HIS标签、MYC标签、FLAG或其他多肽序列融合。在一些实施方案中,该诱饵型多肽与PD-1(PDCD1)、PD-L1(CD274)、PD-L2(PDCD1LG2)、CTLA4、TIM3(HAVCR2)、CEACAM1、LAG3、BTLA、TNFRSF14、TIGIT、PVR、LIGHT、IL2、IL12A、IL15、IL10、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、LILRA1、LILRA2、LILRA3、LILRA4、LILRA5、LILRA6、CD40、CD40L、OX40、OX40L、CD137(4-1BB,TNFRSF9)、TNFSF9(4-1BBL)、B7-H4(VCTN1)、SIRPA、CD47、CD33、CD44、C5、C3或其他蛋白质的野生型亚单元融合。在一些实施方案中,该诱饵型多肽与这样的亚单元融合,该亚单元是PD-1(PDCD1)、PD-L1(CD274)、PD-L2(PDCD1LG2)、CTLA4、TIM3(HAVCR2)、CEACAM1、LAG3、BTLA、TNFRSF14、TIGIT、PVR、LIGHT、IL2、IL12A、IL15、IL10、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、LILRA1、LILRA2、LILRA3、LILRA4、LILRA5、LILRA6、CD40、CD40L、OX40、OX40L、CD137(4-1BB,TNFRSF9)、TNFSF9(4-1BBL)、B7-H4(VCTN1)、SIRPA、CD47、CD33、CD44、C5、C3或其他免疫调节蛋白的变体,其经工程化用于以高亲和力与其相应配体结合。在一些实施方案中,该诱饵型多肽与这样的亚单元融合,该亚单元是PD-1(PDCD1)、PD-L1(CD274)、PD-L2(PDCD1LG2)、CTLA4、TIM3(HAVCR2)、CEACAM1、LAG3、BTLA、TNFRSF14、TIGIT、PVR、LIGHT、IL2、IL12A、IL15、IL10、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、LILRA1、LILRA2、LILRA3、LILRA4、LILRA5、LILRA6、CD40、CD40L、OX40、OX40L、CD137(4-1BB,TNFRSF9)、TNFSF9(4-1BBL)、B7-H4(VCTN1)、SIRPA、CD47、CD33、CD44、C5、C3或其他蛋白质的变体,其经工程化用于以降低的亲和力与其相应配体结合。在一些实施方案中,该诱饵型多肽与这样的亚单元融合,该亚单元是PD-1(PDCD1)、PD-L1(CD274)、PD-L2(PDCD1LG2)、CTLA4、TIM3(HAVCR2)、CEACAM1、LAG3、BTLA、TNFRSF14、TIGIT、PVR、LIGHT、IL2、IL12A、IL15、IL10、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、LILRA1、LILRA2、LILRA3、LILRA4、LILRA5、LILRA6、CD40、CD40L、OX40、OX40L、CD137(4-1BB,TNFRSF9)、TNFSF9(4-1BBL)、B7-H4(VCTN1)、SIRPA、CD47、CD33、CD44、C5、C3或其他蛋白质的变体,其经工程化用于以改变的亲和力与其天然配体之外的其他配体结合。在其他方面,该诱饵型多肽与单克隆抗体融合,或与单克隆抗体联合施用,该单克隆抗体例如是抗-CD20抗体、抗-EGFR抗体、抗-Her2/Neu(ERBB2)抗体、抗-EPCAM抗体、抗-GL2抗体、抗-GD2、抗-GD3、抗-CD2、抗-CD3、抗-CD4、抗-CD8、抗-CD19、抗-CD22、抗-CD30、抗-CD33、抗-CD45、抗-CD47、抗-CD52、抗-CD56、抗-CD70、抗-CD117、抗-SIRPA抗体、抗-CD47抗体、抗-LILRB1抗体、抗-PD-1抗体、抗-PD-L1抗体、抗-PD-L2抗体,或设计用于结合至肿瘤细胞、病毒或细菌感染的细胞、免疫细胞或健康的正常细胞,或结合至细胞因子、趋化因子或任何类型的激素的任何抗体。
在一些实施方案中,诱饵型多肽包括多聚体形式的SIRP-γ、SIRP-β或SIRP-β2多肽。在特定方面,该诱饵型多肽包括二聚体、三聚体、四聚体、五聚体或其他多聚体。在其他实施方案中,该诱饵型多肽包括单体形式的SIRP-γ、SIRP-β或SIRP-β2多肽。
在一些实施方案中,所述诱饵型多肽包含可检测标记物。在特定方面,该可检测标记物包括酶标记物,如辣根过氧化物酶(HRP)、碱性磷酸酶(AP)或葡萄糖氧化酶。在其他方面,该可检测标记物包括荧光标记物,如Alexa 350、Alexa 405、Alexa488、Alexa 532、Alexa 546、Alexa 555、Alexa568、Alexa 594、Alexa 647、Alexa 680、Alexa750、 FL、香豆素、荧光素(FITC)、OregonPacific BlueTM、Pacific GreenTM、Pacific OrangeTM、四甲基罗丹明(TRITC)、Texas 或其他荧光标记物。在进一步的方面,该可检测标记物包括螯合基团,如Cyclen、Cyclam、DO2A、DOTP、DOTMA、TETA、DOTAM、CB-T2A、DOTA或NOTA。在进一步的方面,该可检测标记物包括放射性同位素,如32P、33P、3H、14C、125I、18F、68Ga、64Cu、89Zr、11C、13N、15O、62Cu、124I、76Br、82Rb或其他放射性同位素。
在其他实施方案中,所述诱饵型多肽为融合多肽或嵌合多肽。在其他实施方案中,该诱饵型多肽包括与包含免疫检查点抑制剂、共刺激分子或细胞因子或减毒的细胞因子的多肽序列融合的SIRP-γ多肽序列,其中该序列由具有不同长度和组成的Gly-Ser连接体连接。例如,该连接体序列包含序列GGGGSGGGGS(SEQ ID NO:29)。还可以改变两个多肽序列在N-或C-末端的顺序。在其他实施方案中,该诱饵型多肽是多特异性高亲和力的SIRP-γ剂。在进一步的实施方案中,该诱饵型多肽包含以下序列中的一种:
1)与免疫检查点抑制剂融合
a.PD-1/PD-L1拮抗剂
实例:HAC-GV3(与GV3融合的高亲和力PD-1诱饵)
DSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFHVVWHRESPSGQTDTLAAFPEDRSQPGQDARFRVTQLPNGRDFHMSVVRARRNDSGTYVCGVISLAPKIQIKESLRAELRVTERGGGGSGGGGSEEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:30);
b.BTLA/CD160拮抗剂
实例:GV3-BTLA诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSWNIHGKESCDVQLYIKRQSEHSILAGDPFELECPVKYCANRPHVTWCKLNGTTCVKLEDRQTSWKEEKNISFFILHFEPVLPNDNGSYRCSANFQSNLIESHSTTLYVTDVK(SEQ ID NO:31);
c.磷脂酰丝氨酸拮抗剂
实例:GV3-MFGE8诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSELNGCANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGNDQWLQVDLGSSKEVTGIITQGARNFGSVQFVASYKVAYSNDSANWTEYQDPRTGSSKIFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC(SEQ ID NO:32);
实例:GV3-Tim1诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSVAGSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVPPKVTT(SEQ ID NO:33);
实例:GV3-Tim3诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPA(SEQ ID NO:34);
实例:GV3-Tim4诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSTSETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKYRLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTDEKFNLKLVIKPAKVTPA(SEQ ID NO:35);
2)与共刺激分子融合
d.CD40激动剂
实例:GV3-CD40L
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL(SEQ ID NO:36);
e.41BB(CD137)激动剂
实例:GV3-41BBL
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQMELRRVVAGEGSGSVSLALHLMPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPA(SEQ IDNO:37);
3)与细胞因子和减毒的细胞因子融合
实例:GV3-IL2
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:38);
实例:GV3-IL2(具有突变F42A/D20T的“减毒”细胞因子)
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLTLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:39)。
SIRP多肽修饰
SIRP-γ、SIRP-β或SIRP-β2多肽变体包括下述衍生物或类似物,所述衍生物或类似物中(i)氨基酸被不是由遗传密码编码的氨基酸残基置换,(ii)成熟多肽与另一种化合物如聚乙二醇融合,或(iii)另外的氨基酸与SIRP-γ、SIRP-β或SIRP-β2多肽融合,如前导序列或分泌序列或用于纯化该多肽的序列。
典型的修饰包括但不限于乙酰化、酰化、ADP-核糖基化、酰胺化、黄素的共价附接、血红素部分的共价附接、核苷酸或核苷酸衍生物的共价附接、脂质或脂质衍生物的共价附接、磷脂酰肌醇的共价附接、交联、环化、二硫键形成、去甲基化、共价交联的形成、胱氨酸形成、焦谷氨酸形成、甲酰化、γ羧化、糖基化、GPI锚形成、羟基化、碘化、甲基化、肉豆蔻酰化、氧化、蛋白水解处理、磷酸化、异戊二烯化、外消旋化、硒化(selenoylation)、硫酸化、转运RNA介导的氨基酸向蛋白质的添加,如精氨酰化,以及泛素化。
在SIRP-γ、SIRP-β或SIRP-β2多肽中的任何位置进行修饰,包括肽主链、氨基酸侧链和氨基或羧基末端。可用于修饰SIRP-γ、SIRP-β或SIRP-β2多肽的某些常见肽修饰包括糖基化、脂质附接、硫酸化、谷氨酸残基的γ-羧化、羟基化、多肽中氨基或羧基基团(或二者)通过共价修饰的封端,以及ADP-核糖基化。
此外,以保守的方式改变核心序列的一个或多个氨基酸,使得必需的CD47结合得到维持或增加。典型的置换在以下氨基酸组中进行:(a)G、A、V、L和I;(b)G和P;(c)S、C、T、M;(d)F、Y和W;(e)H、K和R;以及(f)D、E、N和Q。其他置换包括下组:(i)S和T;(ii)P和G;以及(iii)A、V、L和I。
在本文提供的实施方案的范围内还考虑到这样的SIRP-γ、SIRP-β或SIRP-β2多肽修饰,其中该多肽接合至通常与之不相缔合的另一多肽(例如,谷胱甘肽S-转移酶(GST)融合蛋白、β-半乳糖苷酶融合物、酵母双杂交GAL融合物、聚-His融合物、Ig融合物等)。因此,SIRP-γ、SIRP-β或SIRP-β2多肽任选地在其N-末端或C-末端处可操作地连接至具有与SIRP-γ、SIRPβ或SIRP-β2多肽基本上不同源的氨基酸序列的异源多肽。“可操作地连接”表示SIRP-γ、SIRP-β或SIRP-β2多肽和异源多肽都符合读框(in-frame)。这样的融合蛋白可改变(例如,增强,减弱)SIRP-γ、SIRP-β或SIRP-β2多肽或其功能性变体结合CD47的能力。这样的融合蛋白还可改变(增强,减弱)SIRP-γ、SIRP-β或SIRP-β2多肽在人类患者或实验动物中的药代动力学半衰期。该融合蛋白还可改变SIRP-γ、SIRP-β或SIRP-β2多肽赋予髓样细胞的活性——包括吞噬作用和ADCC——的活性。
亲和力
作为主题,与野生型SIRP-γ、SIRP-β或SIRP-β2多肽对CD47的亲和力相比,并且/或者与相对于野生型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,如上所定义的野生型SIRP-γ、SIRP-β或SIRP-β2多肽)的相应序列不具有氨基酸变化的SIRP-γ、SIRP-β或SIRP-β2多肽对CD47的亲和力相比,SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47具有增加的亲和力。
在一些实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47具有1x10- 7M或更小(例如,10-8M或更小、10-9M或更小、10-10M或更小、10-11M或更小、10-12M或更小、10-13M或更小、10-14M或更小、10-15M或更小或10-16M或更小)的Kd的亲和力。在一些情况下,该SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47具有1fM至1μM(例如,1fM至800nM、10fM至500nM、100fM至100nM、500fM至50nM、800fM至50nM、1pM至50nM、10pM至50nM、50pM至50nM、100pM至50nM、500fM至100nM、800fM至100nM、1pM至100nM、10pM至100nM、50pM至100nM,或100pM至100nM)的亲和力。在一些情况下,SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽以1μM或更高(例如,800nM或更高、500nM或更高、200nM或更高、100nM或更高、50nM或更高、10nM或更高、1nM或更高、900pM或更高、750pM或更高、500pM或更高、200pM或更高、100pM或更高、10pM或更高、1pM或更高,等等,其中亲和力随数值的减小而增加)的亲和力结合CD47。
在一些实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47的亲和力是野生型SIRP-γ、SIRP-β或SIRP-β2蛋白对CD47的亲和力的2倍或更多(例如,5倍或更多、10倍或更多、100倍或更多、500倍或更多、1000倍或更多、5000倍或更多、104倍或更多、105倍或更多、106倍或更多、107倍或更多、108倍或更多,等等);并且/或者是相对于野生型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,如上所定义的野生型SIRP-γ、SIRP-β或SIRP-β2多肽)的相应序列不具有氨基酸变化的SIRP-γ、SIRP-β或SIRP-β2多肽对CD47的亲和力的2倍或更多(例如,5倍或更多、10倍或更多、100倍或更多、500倍或更多、1000倍或更多、5000倍或更多、104倍或更多、105倍或更多、106倍或更多、107倍或更多、108倍或更多,等等)。
在一些实施方案中,所述SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47的解离半衰期是野生型SIRP-γ、SIRP-β或SIRP-β2蛋白对CD47的解离半衰期的2倍或更多(例如,5倍或更多、10倍或更多、100倍或更多、500倍或更多、1000倍或更多、5000倍或更多、104倍或更多、105倍或更多、106倍或更多、107倍或更多、108倍或更多,等等);并且/或者是相对于野生型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,如上所定义的野生型SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽)的相应序列不具有氨基酸变化的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽对CD47的解离半衰期的2倍或更多(例如,5倍或更多、10倍或更多、100倍或更多、500倍或更多、1000倍或更多、5000倍或更多、104倍或更多、105倍或更多、106倍或更多、107倍或更多、108倍或更多,等等)。例如,在一些情况下,野生型SIRP-γ、SIRP-β或SIRP-β2多肽(如上所定义的)对CD47的解离半衰期小于1秒,而主题SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽可具有5秒或更长(例如,30秒或更长、1分钟或更长、5分钟或更长、10分钟或更长、20分钟或更长、30分钟或更长、40分钟或更长,等等)的解离半衰期。例如,主题SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽的氨基酸置换可通过使解离速率降低至少10倍、至少20倍、至少50倍、至少100倍、至少500倍或更多而提高亲和力。
例如,可通过SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽与涂覆在测定板上、呈现在微生物细胞表面上、溶液中等的CD47结合的能力来确定与CD47结合的亲和力。可通过将配体(例如,CD47)或SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽固定至珠子、基底、细胞等上来测定本公开内容的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽与CD47的结合活性。可在合适的缓冲液中添加药剂并将结合配偶体在给定温度下温育一段时间。在洗涤以去除未结合的物质后,可利用例如SDS、高pH缓冲液等来释放所结合的蛋白质,并通过例如表面等离子体共振(SPR)对其进行分析。
例如,还可通过测量未标记的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽与标记的SIRP-γ、SIRP-β或SIRP-β2多肽(例如,如上所定义的标记的野生型SIRP-γ、SIRP-β或SIRP-β2多肽)竞争结合CD47的能力来确定结合。因此,可通过将使用候选未标记的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽的结果与使用未标记的野生型SIRP-γ、SIRP-β或SIRP-β2多肽(如上所定义的,相对于野生型SIRP-γ、SIRP-β或SIRP-β2的相应序列不具有氨基酸变化的野生型SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽)的结果进行比较来评估相对结合。
可采用任何方便的方法来生成主题SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽。作为一个非限制性实例,可进行诱变(从野生型SIRP-γ、SIRP-β或SIRP-β2多肽开始,或从SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽开始以便生成具有更高亲和力的多肽)来生成突变的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽的集合。诱变可以以在特定氨基酸处产生变化为目标,或者诱变可以是随机的。然后,可针对其结合CD47蛋白的能力筛选突变的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽。例如,可对CD47蛋白(或CD47蛋白的变体,例如,缺少跨膜域的型式)进行标记(例如,利用直接标记物如放射性同位素、荧光部分等;或利用间接标记物如抗原、亲和标签、生物素等),并可随后用于接触候选SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽(例如,其中该候选SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽可附接至固体表面或呈现在细胞例如酵母细胞的膜上)。通过改变所用的CD47浓度,可在候选物中(即,从突变的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽的集合中)鉴别出高亲和力SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽。
治疗方法
在一些实施方案中,本文提供了用于刺激有需要的个体的免疫系统的方法和用途,其包括施用本文所述的诱饵型多肽(例如,SIRP-γ、SIRP-β或SIRP-β2多肽变体)。在一些情况下,本文描述的诱饵型多肽的施用诱导并且/或者维持表达CD47的细胞的吞噬作用。在其他情况下,本文描述的诱饵型多肽的施用诱导并且/或者维持不表达CD47的细胞的吞噬作用。在一些情况下,该细胞为癌细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T细胞或B细胞、损伤的红细胞、动脉斑块或纤维化组织。在另外的情况下,该细胞为健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
本文还提供了用于治疗有需要的个体的癌症的方法和用途,其包括施用本文所述的诱饵型多肽。在一些这样的实施方案中,该个体罹患癌症。在其他实施方案中,该个体疑似罹患癌症。在其他实施方案中,该个体易患癌症(例如,易患乳腺癌的个体)。在某些实施方案中,该癌症选自乳腺癌、肺癌、肺腺癌、鳞状细胞肺癌、小细胞肺癌、非小细胞肺癌、头颈癌、脑癌、腹部癌症、结肠癌、结直肠癌、食管癌、咽旁癌、胃肠癌、神经胶质瘤、肝癌、口腔癌、舌癌、神经母细胞瘤、骨肉瘤、卵巢癌、肾癌、膀胱癌、尿道癌、胰腺癌、视网膜母细胞瘤、宫颈癌、子宫癌、维尔姆斯瘤、多发性骨髓瘤、皮肤癌、淋巴瘤、白血病、血癌、甲状腺癌、骨癌、腺囊肿瘤、软骨肉瘤、胰岛细胞瘤、神经内分泌瘤、前列腺癌、卵巢癌、胶质母细胞瘤、子宫内膜癌、子宫内膜癌症、平滑肌肉瘤、胆囊癌、肝细胞癌、血液系统癌症、多发性骨髓瘤、急性骨髓性白血病、急性/慢性成淋巴细胞白血病、毛细胞白血病、滤泡性淋巴瘤、多发性骨髓瘤、浆细胞瘤、弥漫性大B细胞淋巴瘤。在一些实施方案中,该癌症为血液系统癌症。在特定方面,该癌症为多发性骨髓瘤、急性/慢性骨髓性白血病、急性/慢性成淋巴细胞白血病、毛细胞白血病、滤泡性淋巴瘤、多发性骨髓瘤、浆细胞瘤或弥漫性大B细胞淋巴瘤(breast cancer,lung cancer,adenocarcinoma of the lung,squamous cell lung cancer,small celllung cancer,non-small cell lung cancer,head and neck cancer,brain cancer,abdominal cancer,colon cancer,colorectal cancer,esophageal cancer,parapharyngeal cancer,gastrointestinal cancer,glioma,liver cancer,oralcancer,tongue cancer,neuroblastoma,osteosarcoma,ovarian cancer,renal cancer,urinary bladder cancer,urinary tract cancer,pancreatic cancer,retinoblastoma,cervical cancer,uterine cancer,Wilm's tumor,multiple myeloma,skin cancer,lymphoma,leukemia,blood cancer,thyroid cancer,bone cancer,adenocystic tumor,chondrosarcoma,pancreatic islet cell tumor,neuroendocrine tumor,prostatecancer,ovarian cancer,glioblastoma,endometrial carcinoma,endometrial cancer,leiomyosarcoma,gall bladder cancer,hepatocellular cancer,hematologicalcancer,multiple myeloma,acute myelogenous leukemia,acute/chroniclymphoblastic leukemia,hairy-cell leukemia,follicular lymphoma,multiplemyeloma,plasmacytoma,diffuse large B-cell lymphoma.In some embodiments,thecancer is a hematological cancer.In particular aspects,the cancer is multiplemyeloma,acute/chronic myelogenous leukemia,acute/chronic lymphoblasticleukemia,hairy-cell leukemia,follicular lymphoma,multiple myeloma,plasmacytoma or diffuse large B-cell lymphoma)。
在一些实施方案中,所述癌症与CD47的表达相关,包括但不限于急性髓样白血病(AML)、急性淋巴细胞白血病(ALL)、霍奇金淋巴瘤(HL)、非霍奇金B细胞淋巴瘤(NHBCL)、慢性淋巴细胞白血病(B-CLL)、多发性骨髓瘤(MM)、胰腺腺癌、胰腺神经内分泌肿瘤(PanNET)、神经胶质瘤、髓母细胞瘤、星形细胞瘤、前列腺癌、骨肉瘤、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、黑素瘤、鳞状细胞头颈癌、前列腺癌、卵巢癌、乳腺癌、结肠癌、肾癌和膀胱癌(Acute myeloid leukemia(AML),Acute leukocytic leukemia(ALL),Hodgkin’slymphoma(HL),Non-Hodgkin’s B cell lymphoma(NHBCL),Chronic leukocytic leukemia(B-CLL),Multiple myeloma(MM),pancreatic adenocarcinoma,pancreaticneuroendocrine tumor(PanNET),glioma,medulloblastoma,astrocytoma,prostatecancer,osteosarcoma,small cell lung carcinoma(SCLC),non-small cell lungcarcinoma(NSCLC),melanoma,squamous cell head and neck carcinoma,prostatecarcinoma,ovarian cancer,breast cancer,colon cancer,renal cancer,and bladdercancer)。在一些实施方案中,该癌症与实体瘤相关。在某些情况下,该实体瘤是晚期的,例如,3期或4期的。在某些情况下,该实体瘤在组织学上与CD47的表达相关。
在一些实施方案中,如本文所用的,“治疗”是指治疗性治疗,其中目的在于减缓(减轻)不期望的生理病况、病症或疾病,或获得有益或期望的临床结果。对于本文所述的目的,有益或期望的临床结果包括但不限于症状缓和;病况、病症或疾病的程度的降低;病况、病症或疾病的状态的稳定(即,不恶化);病况、病症或疾病的进展的发生延迟或减缓;病况、病症或疾病状态减轻;以及可检测的或不可检测的缓解(无论是部分还是全部),或者病况、病症或疾病的增强或改善。治疗包括引起临床显著的反应,而没有过量水平的副作用。治疗还包括与未接受治疗时所预期的生存期相比延长生存期。在其他实施方案中,“治疗”是指预防性措施,其中目的在于延迟例如易患疾病的人(例如,携带疾病如乳腺癌的遗传标志物的个体)的不期望的生理学病况、病症或疾病的发生或降低其严重性。
本文所述的治疗方法治疗癌症的各个时期,包括局部进展期、转移期和/或复发期。在癌症分期中,局部进展一般被定义为已经从局部区域扩散至附近组织和/或淋巴结的癌症。在罗马数字分期系统中,局部进展通常被分为II期或III期。转移的癌症是癌症通过全身扩散至远处组织和器官的时期(IV期)。指定为复发的癌症通常被定义为通常在缓解期后或肿瘤已明显被消除后的一段时间后癌症复发。复发可以是局部的(即,出现在与原始部位相同的位置),或远离的(即,出现在身体的不同部位)。在某些情况下,可通过本文所述的联合疗法治疗的癌症是不可切除的,或不能通过手术移除。
在一些这样的实施方案中,本文描述的治疗方法为针对个体开具的任何其他癌症疗法提供辅助疗法。因此,在一些实施方案中,本文所述的诱饵型多肽与任意其他的抗癌剂联合施用,该抗癌剂包括但不限于氨甲喋呤(甲氨蝶呤)、环磷酰胺沙利度胺吖啶甲酰胺、放线菌素、17-N-烯丙基氨基-17-去甲氧基格尔德霉素、氨基喋呤、安吖啶、蒽环霉素、抗肿瘤药、抗瘤酮、5-氮杂胞苷、硫唑嘌呤、BL22、苯达莫司汀、比立考达、博莱霉素、硼替佐米、苔藓抑素、白消安、花萼海绵诱癌素、喜树碱、卡培他滨、卡铂、西妥昔单抗、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、阿糖胞苷、达卡巴嗪、达沙替尼、柔红霉素、地西他滨、二氯乙酸、盘皮海绵内酯、多西他赛、多柔比星、表柔比星、爱波喜龙、艾立布林、雌氮芥、依托泊甙、依沙替康、依昔舒林、铁锈醇、氟尿苷、氟达拉滨、氟尿嘧啶、磷雌酚、福莫司汀、更昔洛韦、吉西他滨、羟基脲、IT-101、伊达比星,异环磷酰胺、咪喹莫特、伊立替康、伊罗夫文、伊沙匹隆、拉尼喹达、拉帕替尼、来那度胺、洛莫司汀、勒托替康、马磷酰胺、马索罗酚、氮芥、美法仑、巯基嘌呤、丝裂霉素、米托坦、米托蒽醌、奈拉滨、尼罗替尼、奥利默森、奥沙利铂、PAC-1、紫杉醇、培美曲塞、喷司他丁、哌泊溴烷、匹克生琼、普卡霉素、丙卡巴肼、蛋白酶体抑制剂(例如,硼替佐米)、雷替曲塞、蝴蝶霉素、芦比替康、SN-38、salinosporamide A、沙铂、链脲霉素、苦马豆素、他立喹达、紫杉烷、替加氟-尿嘧啶、替莫唑胺、睾内酯、噻替派、硫鸟嘌呤、托泊替康、曲贝替定、维a酸、四硝酸三铂、三(2-氯乙基)胺、曲沙他滨、尿嘧啶氮芥、戊柔比星、长春碱、长春新碱、长春瑞滨、伏林司他、佐舒喹达(methotrexate(Amethopterin)cyclophosphamidethalidomideacridine carboxamide,actinomycin,17-N-allylamino-17-demethoxygeldanamycin,aminopterin,amsacrine,anthracycline,antineoplastic,antineoplaston,5-azacytidine,azathioprine,BL22,bendamustine,biricodar,bleomycin,bortezomib,bryostatin,busulfan,calyculin,camptothecin,capecitabine,carboplatin,cetuximab,chlorambucil,cisplatin,cladribine,clofarabine,cytarabine,dacarbazine,dasatinib,daunorubicin,decitabine,dichloroacetic acid,discodermolide,docetaxel,doxorubicin,epirubicin,epothilone,eribulin,estramustine,etoposide,exatecan,exisulind,ferruginol,floxuridine,fludarabine,fluorouracil,fosfestrol,fotemustine,ganciclovir,gemcitabine,hydroxyurea,IT-101,idarubicin,ifosfamide,imiquimod,irinotecan,irofulven,ixabepilone,laniquidar,lapatinib,lenalidomide,lomustine,lurtotecan,mafosfamide,masoprocol,mechlorethamine,melphalan,mercaptopurine,mitomycin,mitotane,mitoxantrone,nelarabine,nilotinib,oblimersen,oxaliplatin,PAC-1,paclitaxel,pemetrexed,pentostatin,pipobroman,pixantrone,plicamycin,procarbazine,proteasome inhibitors(e.g.,bortezomib),raltitrexed,rebeccamycin,rubitecan,SN-38,salinosporamide A,satraplatin,streptozotocin,swainsonine,tariquidar,taxane,tegafur-uracil,temozolomide,testolactone,thioTEPA,tioguanine,topotecan,trabectedin,tretinoin,triplatin tetranitrate,tris(2-chloroethyl)amine,troxacitabine,uracil mustard,valrubicin,vinblastine,vincristine,vinorelbine,vorinostat,zosuquidar)等。
在其他实施方案中,本文所述的治疗方法,即,本文所述的诱饵型多肽制剂与如下单克隆抗体联合施用:3F8、8H9、阿巴伏单抗、阿昔单抗、Abituzumab、Abrilumab、Actoxumab、阿达木单抗、阿德木单抗、Aducanumab、阿非莫单抗、阿托珠单抗、培化阿珠单抗、ALD518、阿仑珠单抗、Alirocumab、喷替酸阿妥莫单抗、Amatuximab、马安莫单抗、Anetumab ravtansine、Anifrolumab、安芦珠单抗(IMA-638)、阿泊珠单抗、阿西莫单抗、Ascrinvacumab、阿塞珠单抗、Atezolizumab、Atinumab、Atlizumab(妥珠单抗)、阿托木单抗、巴匹珠单抗、巴利昔单抗、巴维昔单抗、贝妥莫单抗、Begelomab、贝利木单抗、Benralizumab、柏替木单抗、贝索单抗、贝伐珠单抗、Bezlotoxumab、比西单抗、Bimagrumab、Bimekizumab、Bivatuzumab mertansine、兰妥莫单抗、Blosozumab、Bococizumab、Brentuximab vedotin、布雷奴单抗、Brodalumab、Brolucizumab、Brontictuzumab、卡那奴单抗、美坎珠单抗、Cantuzumab ravtansine、Caplacizumab、卡罗单抗喷地肽、Carlumab、卡妥索单抗、cBR96-多柔比星免疫缀合物、CC49、西地珠单抗、培化舍珠单抗、西妥昔单抗、Ch.14.18、泊西他珠单抗、西妥木单抗、Clazakizumab、克立昔单抗、Clivatuzumabtetraxetan、Codrituzumab、Coltuximab ravtansine、可那木单抗、Concizumab、Crenezumab、CR6261、达西珠单抗、达克珠单抗、Dalotuzumab、Dapirolizumab pegol、达雷木单抗、Dectrekumab、Demcizumab、Denintuzumab mafodotin、地舒单抗、Derlotuximabbiotin、地莫单抗、Dinutuximab、Diridavumab、阿度莫单抗、Drozitumab、Duligotumab、Dupilumab、Durvalumab、Dusigitumab、依美昔单抗、依库珠单抗、埃巴单抗、依屈洛单抗、依法珠单抗、依芬古单抗、Eldelumab、Elgemtumab、依洛珠单抗、Elsilimomab、Emactuzumab、Emibetuzumab、Enavatuzumab、Enfortumab vedotin、培化恩莫单抗、Enoblituzumab、Enokizumab、Enoticumab、Ensituximab、西依匹莫单抗、依帕珠单抗、厄利珠单抗、厄马索单抗、埃达珠单抗、Etrolizumab、Evinacumab、Evolocumab、艾韦单抗、Fanolesomab、法拉莫单抗、法利珠单抗、Fasinumab、FBTA05、泛维珠单抗、非扎奴单抗、Ficlatuzumab、芬妥木单抗、Firivumab、Flanvotumab、Fletikumab、芳妥珠单抗、Foralumab、福拉韦单抗、夫苏木单抗、Fulranumab、Futuximab、加利昔单抗、Ganitumab、更汀芦单抗、加维莫单抗、吉姆单抗奥佐米星、Gevokizumab、吉瑞昔单抗、Glembatumumab vedotin、戈利木单抗、Gomiliximab、Guselkumab、伊巴珠单抗、替伊莫单抗、Icrucumab、Idarucizumab、伊戈伏单抗、IMAB362、Imalumab、英西单抗、Imgatuzumab、Inclacumab、Indatuximab ravtansine、Indusatumabvedotin、英利昔单抗、英妥木单抗、伊诺莫单抗、伊珠单抗奥加米星、伊匹木单抗、伊妥木单抗、Isatuximab、Itolizumab、Ixekizumab、凯利昔单抗、拉贝珠单抗、Lambrolizumab、Lampalizumab、来金珠单抗、来马索单抗、Lenzilumab、乐德木单抗、来沙木单抗、利韦单抗、Lifastuzumab vedotin、Ligelizumab、Lilotomab satetraxetan、林妥珠单抗、Lirilumab、Lodelcizumab、Lokivetmab、Lorvotuzumab mertansine、鲁卡木单抗、Lulizumab pegol、鲁昔单抗、Lumretuzumab、马帕木单抗、Margetuximab、马司莫单抗、Mavrilimumab、马妥珠单抗、美泊珠单抗、美替木单抗、米拉珠单抗、明瑞莫单抗、米妥莫单抗、Mogamulizumab、莫罗木单抗、莫维珠单抗、Moxetumomab pasudotox、莫罗单抗-CD3、他那可单抗、Namilumab、他那莫单抗、纳瑞特单抗、那他珠单抗、奈巴库单抗、奈昔木单抗、Nemolizumab、奈瑞莫单抗、Nesvacumab、尼妥珠单抗、Nivolumab、巯诺莫单抗、Obiltoxaximab、Ocaratuzumab、奥瑞珠单抗、奥度莫单抗、奥法木单抗、Olaratumab、Olokizumab、奥马珠单抗、Onartuzumab、Ontuxizumab、Opicinumab、莫奥珠单抗、奥戈伏单抗、Orticumab、奥昔珠单抗、Otlertuzumab、Oxelumab、Ozanezumab、Ozoralizumab、帕昔单抗、帕利珠单抗、帕木单抗、Pankomab、帕诺库单抗、Parsatuzumab、帕考珠单抗、Pasotuxizumab、Pateclizumab、Patritumab、Pembrolizumab、Pemtumomab、Perakizumab、培妥珠单抗、培克珠单抗、Pidilizumab、Pinatuzumab vedotin、平妥单抗、Placulumab、Polatuzumab vedotin、Ponezumab、普立昔单抗、Pritoxaximab、普立木单抗、PRO 140、Quilizumab、雷妥莫单抗、Radretumab、雷韦单抗、Ralpancizumab、雷莫芦单抗、雷珠单抗、雷昔库单抗、Refanezumab、瑞加韦单抗、瑞利珠单抗、利妥木单抗、Rinucumab、利妥昔单抗、罗妥木单抗、Roledumab、Romosozumab、罗利珠单抗、罗维珠单抗、芦利珠单抗、Samalizumab、Sarilumab、沙妥莫单抗喷地肽、Secukinumab、Seribantumab、Setoxaximab、司韦单抗、西罗珠单抗、SGN-CD19A、SGN-CD33A、西法木单抗、司妥昔单抗、Simtuzumab、西利珠单抗、Sirukumab、Sofituzumabvedotin、苏兰珠单抗、Solitomab、Sonepcizumab、松妥珠单抗、司他芦单抗、硫索单抗、Suvizumab、Tabalumab、Tacatuzumab tetraxetan、他度珠单抗、他利珠单抗、他尼珠单抗、帕他莫单抗、Tarextumab、替非珠单抗、阿替莫单抗、替妥莫单抗、替奈昔单抗、替利珠单抗、替妥木单抗、Tesidolumab、TGN1412、Ticilimumab(曲美木单抗)、Tildrakizumab、替加珠单抗、TNX-650、托珠单抗(atlizumab)、托利珠单抗、Tosatoxumab、托西莫单抗、Tovetumab、Tralokinumab、曲妥珠单抗、TRBS07、Tregalizumab、曲美木单抗、西莫白介素单抗、妥韦单抗、Ublituximab、Ulocuplumab、Urelumab、乌珠单抗、乌司奴单抗、Vandortuzumabvedotin、Vantictumab、Vanucizumab、伐利昔单抗、Varlilumab、Vatelizumab、维多珠单抗、维妥珠单抗、维帕莫单抗、Vesencumab、维西珠单抗、伏洛昔单抗、Vorsetuzumabmafodotin、伏妥木单抗、扎芦木单抗、扎木单抗、Zatuximab、齐拉木单抗或阿佐莫单抗(3F8,8H9,Abagovomab,Abciximab,Abituzumab,Abrilumab,Actoxumab,Adalimumab,Adecatumumab,Aducanumab,Afelimomab,Afutuzumab,Alacizumab pegol,ALD518,Alemtuzumab,Alirocumab,Altumomab pentetate,Amatuximab,Anatumomab mafenatox,Anetumab ravtansine,Anifrolumab,Anrukinzumab(IMA-638),Apolizumab,Arcitumomab,Ascrinvacumab,Aselizumab,Atezolizumab,Atinumab,Atlizumab(tocilizumab),Atorolimumab,Bapineuzumab,Basiliximab,Bavituximab,Bectumomab,Begelomab,Belimumab,Benralizumab,Bertilimumab,Besilesomab,Bevacizumab,Bezlotoxumab,Biciromab,Bimagrumab,Bimekizumab,Bivatuzumab mertansine,Blinatumomab,Blosozumab,Bococizumab,Brentuximab vedotin,Briakinumab,Brodalumab,Brolucizumab,Brontictuzumab,Canakinumab,Cantuzumab mertansine,Cantuzumabravtansine,Caplacizumab,Capromab pendetide,Carlumab,Catumaxomab,cBR96-doxorubicin immunoconjugate,CC49,Cedelizumab,Certolizumab pegol,Cetuximab,Ch.14.18,Citatuzumab bogatox,Cixutumumab,Clazakizumab,Clenoliximab,Clivatuzumab tetraxetan,Codrituzumab,Coltuximab ravtansine,Conatumumab,Concizumab,Crenezumab,CR6261,Dacetuzumab,Daclizumab,Dalotuzumab,Dapirolizumabpegol,Daratumumab,Dectrekumab,Demcizumab,Denintuzumab mafodotin,Denosumab,Derlotuximab biotin,Detumomab,Dinutuximab,Diridavumab,Dorlimomab aritox,Drozitumab,Duligotumab,Dupilumab,Durvalumab,Dusigitumab,Ecromeximab,Eculizumab,Edobacomab,Edrecolomab,Efalizumab,Efungumab,Eldelumab,Elgemtumab,Elotuzumab,Elsilimomab,Emactuzumab,Emibetuzumab,Enavatuzumab,Enfortumabvedotin,Enlimomab pegol,Enoblituzumab,Enokizumab,Enoticumab,Ensituximab,Epitumomab cituxetan,Epratuzumab,Erlizumab,Ertumaxomab,Etaracizumab,Etrolizumab,Evinacumab,Evolocumab,Exbivirumab,Fanolesomab,Faralimomab,Farletuzumab,Fasinumab,FBTA05,Felvizumab,Fezakinumab,Ficlatuzumab,Figitumumab,Firivumab,Flanvotumab,Fletikumab,Fontolizumab,Foralumab,Foravirumab,Fresolimumab,Fulranumab,Futuximab,Galiximab,Ganitumab,Gantenerumab,Gavilimomab,Gemtuzumab ozogamicin,Gevokizumab,Girentuximab,Glembatumumab vedotin,Golimumab,Gomiliximab,Guselkumab,Ibalizumab,Ibritumomabtiuxetan,Icrucumab,Idarucizumab,Igovomab,IMAB362,Imalumab,Imciromab,Imgatuzumab,Inclacumab,Indatuximab ravtansine,Indusatumab vedotin,Infliximab,Intetumumab,Inolimomab,Inotuzumab ozogamicin,Ipilimumab,Iratumumab,Isatuximab,Itolizumab,Ixekizumab,Keliximab,Labetuzumab,Lambrolizumab,Lampalizumab,Lebrikizumab,Lemalesomab,Lenzilumab,Lerdelimumab,Lexatumumab,Libivirumab,Lifastuzumab vedotin,Ligelizumab,Lilotomab satetraxetan,Lintuzumab,Lirilumab,Lodelcizumab,Lokivetmab,Lorvotuzumabmertansine,Lucatumumab,Lulizumab pegol,Lumiliximab,Lumretuzumab,Mapatumumab,Margetuximab,Maslimomab,Mavrilimumab,Matuzumab,Mepolizumab,Metelimumab,Milatuzumab,Minretumomab,Mitumomab,Mogamulizumab,Morolimumab,Motavizumab,Moxetumomab pasudotox,Muromonab-CD3,Nacolomab tafenatox,Namilumab,Naptumomabestafenatox,Narnatumab,Natalizumab,Nebacumab,Necitumumab,Nemolizumab,Nerelimomab,Nesvacumab,Nimotuzumab,Nivolumab,Nofetumomab merpentan,Obiltoxaximab,Ocaratuzumab,Ocrelizumab,Odulimomab,Ofatumumab,Olaratumab,Olokizumab,Omalizumab,Onartuzumab,Ontuxizumab,Opicinumab,Oportuzumab monatox,Oregovomab,Orticumab,Otelixizumab,Otlertuzumab,Oxelumab,Ozanezumab,Ozoralizumab,Pagibaximab,Palivizumab,Panitumumab,Pankomab,Panobacumab,Parsatuzumab,Pascolizumab,Pasotuxizumab,Pateclizumab,Patritumab,Pembrolizumab,Pemtumomab,Perakizumab,Pertuzumab,Pexelizumab,Pidilizumab,Pinatuzumab vedotin,Pintumomab,Placulumab,Polatuzumab vedotin,Ponezumab,Priliximab,Pritoxaximab,Pritumumab,PRO 140,Quilizumab,Racotumomab,Radretumab,Rafivirumab,Ralpancizumab,Ramucirumab,Ranibizumab,Raxibacumab,Refanezumab,Regavirumab,Reslizumab,Rilotumumab,Rinucumab,Rituximab,Robatumumab,Roledumab,Romosozumab,Rontalizumab,Rovelizumab,Ruplizumab,Samalizumab,Sarilumab,Satumomab pendetide,Secukinumab,Seribantumab,Setoxaximab,Sevirumab,Sibrotuzumab,SGN-CD19A,SGN-CD33A,Sifalimumab,Siltuximab,Simtuzumab,Siplizumab,Sirukumab,Sofituzumab vedotin,Solanezumab,Solitomab,Sonepcizumab,Sontuzumab,Stamulumab,Sulesomab,Suvizumab,Tabalumab,Tacatuzumab tetraxetan,Tadocizumab,Talizumab,Tanezumab,Taplitumomab paptox,Tarextumab,Tefibazumab,Telimomab aritox,Tenatumomab,Teneliximab,Teplizumab,Teprotumumab,Tesidolumab,TGN1412,Ticilimumab(tremelimumab),Tildrakizumab,Tigatuzumab,TNX-650,Tocilizumab(atlizumab),Toralizumab,Tosatoxumab,Tositumomab,Tovetumab,Tralokinumab,Trastuzumab,TRBS07,Tregalizumab,Tremelimumab,Tucotuzumabcelmoleukin,Tuvirumab,Ublituximab,Ulocuplumab,Urelumab,Urtoxazumab,Ustekinumab,Vandortuzumab vedotin,Vantictumab,Vanucizumab,Vapaliximab,Varlilumab,Vatelizumab,Vedolizumab,Veltuzumab,Vepalimomab,Vesencumab,Visilizumab,Volociximab,Vorsetuzumab mafodotin,Votumumab,Zalutumumab,Zanolimumab,Zatuximab,Ziralimumab,or Zolimomab aritox)。
在其他实施方案中,本文所述的治疗方法,即,本文所述的诱饵型多肽制剂与靶向以下一项或多项的单克隆抗体联合施用:VWF、波形蛋白、VEGFR2、VEGFR-1、VEGF-A、TYRP1(糖蛋白75)、TWEAK受体、MUC1的肿瘤特异性糖基化、肿瘤抗原CTAA16.88、TRAIL-R2、TRAIL-R1、TNF-α、TGF-β、TGFβ2、TGFβ1、TFPI、腱生蛋白C、TEM1、TAG-72、T细胞受体、STEAP1、鞘氨醇-1-磷酸、SOST、SLAMF7、选择蛋白P、SDC1、硬化蛋白(sclerostin)、RTN4、RON、猕猴因子、RHD、呼吸道合胞病毒、RANKL、狂犬病病毒糖蛋白、血小板源性生长因子受体β、磷脂酰丝氨酸、磷酸-钠共转运蛋白、PDGF-Rα、PDCD1、PD-1、PCSK9、oxLDL、OX-40、NRP1、Notch受体4、Notch受体3、Notch受体2、Notch受体1、NOGO-A、NGF、神经细胞凋亡调节蛋白酶1、NCA-90(粒细胞抗原)、NARP-1、N-羟乙基神经氨酸、筒箭毒碱、髓磷脂相关的糖蛋白、粘蛋白CanAg、MUC1、MSLN、MS4A1、MIF、间皮素、MCP-1、LTA、LOXL2、脂磷壁酸、LINGO-1、LFA-1(CD11a)、Lewis-Y抗原、L-选择蛋白(CD62L)、KIR2D、ITGB2(CD18)、ITGA2、干扰素α/β受体、干扰素受体、干扰素γ诱导的蛋白质、整联蛋白αvβ3、整联蛋白αIIbβ3、整联蛋白α7β7、整联蛋白α5β1、整联蛋白α4β7、整联蛋白α4、胰岛素样生长因子I受体、甲型流感血凝素、ILGF2、IL9、IL6、IL4、IL31RA、IL23、IL17A、IL-6受体、IL-6、IL-5、IL-4、IL-23、IL-22、IL-1β、IL-17A、IL-17、IL-13、IL-12、IL-1、IL 20、IGHE、IgG4、IGF-I、IGF-1受体、IgE Fc区、IFN-γ、IFN-α、ICAM-1(CD54)、人TNF、人散射因子受体激酶、Hsp90、HNGF、HLA-DR、HIV-1、组蛋白复合物、HHGFR、HGF、HER3、HER2/neu、HER1、乙型肝炎表面抗原、血凝素、GUCY2C、GPNMB、GMCSF受体α链、磷脂酰肌醇聚糖3、GD3神经节苷脂、GD2、神经节苷脂GD2、卷曲(Frizzled)受体、叶酸受体1、叶酸水解酶、纤连蛋白胞外域-B、血纤蛋白II、β链、FAP、呼吸道合胞病毒的F蛋白、ERBB3、抗粘着因子、EpCAM、内毒素、EGFR、EGFL7、大肠杆菌2型志贺毒素、大肠杆菌1型志贺毒素、DR5、DPP4、DLL4、达比加群、巨细胞病毒糖蛋白B、CTLA-4、CSF2、CSF1R、聚集因子A、CLDN18.2、ch4D5、CFD、CEA相关抗原、CEA、CD80、CD79B、CD74、CD70、CD6、CD56、CD52、CD51、CD5、CD44v6、CD41、CD40配体、CD40、CD4、CD38、CD37、CD33、CD30(TNFRSF8)、CD3ε、CD3、CD28、CD274、CD27、CD25(IL-2受体α链)、CD23(IgE受体)、CD221、CD22、CD200、CD20、CD2、CD19、CD154、CD152、CD15、CD147(basigin)、CD140a、CD125、CD11、CD-18、CCR5、CCR4、CCL11(嗜酸性粒细胞趋化因子-1)、心肌肌球蛋白、碳酸酐酶9(CA-IX)、狼犬(Canis lupus familiaris)IL31、CA-125、C5、C242抗原、4型C-X-C趋化因子受体、β-淀粉样蛋白、BAFF、B7-H3、B-淋巴瘤细胞、AOC3(VAP-1)、炭疽毒素、保护性抗原、血管生成素3、血管生成素2、甲胎蛋白、AGS-22M6、腺癌抗原、ACVR2B、激活蛋白受体样激酶1、5T4、5AC、4-1BB或1-40-β-淀粉样蛋白。
在其他实施方案中,本文所述的治疗方法,即,本文所述的诱饵型多肽制剂与放疗(例如,γ射线、X射线和/或放射性同位素向肿瘤细胞的直接递送、微波、UV辐射等)联合施用。在其他实施方案中,本文所述的治疗方法,即,本文所述的诱饵型多肽制剂与基因疗法联合施用。治疗性基因包括细胞增殖诱导基因(癌基因)的反义形式、细胞增殖抑制基因(肿瘤阻抑基因)或程序性细胞死亡诱导基因(促凋亡基因)。在一些实施方案中,本文所述的联合疗法与手术(例如,切除术)一起施用。
在其他实施方案中,本文所述的治疗方法,即,本文所述的诱饵型多肽制剂与止泻剂、止吐剂、镇痛药、阿片样物质和/或非甾体抗炎剂联合施用。
在进一步的实施方案中,将本文所述的诱饵型多肽(例如,包含SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)施用至已用环磷酰胺,或伊马替尼,或达克珠单抗和/或任何其他抗癌剂预先治疗的个体。在其他实施方案中,将本文所述的诱饵型多肽施用至未用环磷酰胺和/或任何其他抗癌剂预先治疗的个体。
在一些上述实施方案中,用本文所述的诱饵型多肽(例如,包含SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)进行的治疗延长寿命,并且/或者提高罹患癌症的个体的存活率。在一些上述实施方案中,用本文所述的诱饵型多肽(例如,包含SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)进行的治疗改善罹患癌症的个体的生活质量(例如,当用本文所述的诱饵型多肽治疗个体时,该个体需要的引起副作用的抗癌药的剂量更低)。
在一些上述实施方案中,用本文所述的诱饵型多肽(例如,包含SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)进行的治疗诱导并且/或者维持个体中的吞噬作用或ADCC。吞噬作用包括专业的吞噬细胞(例如,单核细胞、巨噬细胞、嗜中性粒细胞、树突细胞或肥大细胞)、非专业的吞噬细胞(例如,上皮细胞、内皮细胞、成纤维细胞或间充质细胞)或二者引起的吞噬作用。ADCC包括髓样细胞(包括嗜中性粒细胞、单核细胞和天然杀伤细胞)引起的抗体依赖性细胞介导的细胞毒性。吞噬作用和ADCC的测量通过任何已知的方法来完成,包括例如荧光显微术或流式细胞术。
在进一步的实施方案中,用本文所述的诱饵型多肽(例如,包含SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)进行的治疗通过将SIRP-β或SIRP-γ药剂与患有哮喘或变态反应的个体中针对M1prime或CD38的抗体组合来诱导并且/或者增强产生IgE的B细胞和浆细胞的抗体依赖性细胞介导的吞噬作用(ADCP)或ADCC。
本文还提供了用于治疗个体的病毒感染、病症或病况的方法,其包括向患有病毒感染、病症或病况的个体施用本文所述的诱饵型多肽。在特定方面,该病毒感染、病症或病况是慢性的。在进一步的方面,该病毒感染、病症或病况是急性的。在进一步的方面,该病毒感染、病症或病况为腺病毒科,如腺病毒;疱疹病毒科,如1型单纯疱疹、2型单纯疱疹、水痘-带状疱疹病毒、EB病毒、人巨细胞病毒、8型人疱疹病毒;乳头瘤病毒科,如人乳头瘤病毒;多瘤病毒科,如BK病毒或JC病毒;痘病毒科,如天花;嗜肝DNA病毒科,如乙型肝炎病毒;细小病毒科,如人博卡病毒或细小病毒;星形病毒科,如人星形病毒;嵌杯样病毒科,如诺沃克病毒;小RNA病毒科,如柯萨奇病毒、甲型肝炎病毒、脊髓灰质炎病毒、鼻病毒;冠状病毒科,如严重急性呼吸综合征病毒;黄病毒科,如丙型肝炎病毒、黄热病毒、登革热病毒、西尼罗病毒;披膜病毒科,如风疹病毒;肝炎病毒科,如戊型肝炎病毒;逆转录病毒科,如人免疫缺陷病毒(HIV);正粘病毒科,如流感病毒;砂粒病毒科,如Guanarito病毒、呼宁病毒、拉沙病毒、马秋博病毒、Sabiá病毒;布尼亚病毒科,如Crimean-Congo出血热病毒;纤丝病毒科,如埃博拉病毒、马尔堡病毒;副粘液病毒科,如麻疹病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人偏肺病毒、Hendra病毒、Nipah病毒;弹状病毒科,如狂犬病病毒;丁型肝炎病毒;或呼肠孤病毒科,如轮状病毒、环状病毒、科蜱病毒、Banna病毒。在特定方面,病毒感染、病症或病况为人免疫缺陷病毒(HIV)、人巨细胞病毒、EB病毒、丙型肝炎病毒或乙型肝炎病毒(anAdenoviridae such as,Adenovirus;a Herpesviridae such as Herpes simplex,type1,Herpes simplex,type 2,Varicella-zoster virus,Epstein-barr virus,Humancytomegalovirus,Human herpesvirus,type 8;a Papillomaviridae such as Humanpapillomavirus;a Polyomaviridae such as BK virus or JC virus;a Poxviridaesuch as Smallpox;a Hepadnaviridae such as Hepatitis B virus;a Parvoviridaesuch as Human bocavirus or Parvovirus;a Astroviridae such as Humanastrovirus;a Caliciviridae such as Norwalk virus;a Picornaviridae such ascoxsackievirus,hepatitis A virus,poliovirus,rhinovirus;a Coronaviridae suchas Severe acute respiratory syndrome virus;a Flaviviridae such as Hepatitis Cvirus,yellow fever virus,dengue virus,West Nile virus;a Togaviridae such asRubella virus;a Hepeviridae such as Hepatitis E virus;a Retroviridae such asHuman immunodeficiency virus(HIV);a Orthomyxoviridae such as Influenza virus;a Arenaviridae such as Guanarito virus,Junin virus,Lassa virus,Machupo virus,Sabiá virus;a Bunyaviridae such as Crimean-Congo hemorrhagic fever virus;aFiloviridae such as Ebola virus,Marburg virus;a Paramyxoviridae such asMeasles virus,Mumps virus,Parainfluenza virus,Respiratory syncytial virus,Human metapneumovirus,Hendra virus,Nipah virus;a Rhabdoviridae such as Rabiesvirus;Hepatitis D virus;or a Reoviridae such as Rotavirus,Orbivirus,Coltivirus,Banna virus.In particular aspects,the viral infection,disorder orcondition is Human immunodeficiency virus(HIV),Human cytomegalovirus,Epstein-barr virus,Hepatitis C virus,or Hepatitis B virus)。
本文还提供了用于治疗个体的细菌感染、病症或病况的方法,其包括向患有细菌感染、病症或病况的个体施用本文所述的诱饵型多肽。在特定方面,该细菌感染、病症或病况是慢性的。在其他方面,该细菌感染、病症或病况是急性的。在进一步的方面,该细菌感染是芽孢杆菌属(Bacillus),如炭疽芽孢杆菌(Bacillus anthracis)或蜡状芽孢杆菌(Bacillus cereus);巴尔通氏体属(Bartonella),如汉赛巴尔通氏体(Bartonellahenselae)或五日热巴尔通氏体(Bartonella quintana);博德特氏菌属(Bordetella),如百日咳博德特菌(Bordetella pertussis);疏螺旋体属(Borrelia),如布氏疏螺旋体(Borrelia burgdorferi)、嘎氏疏螺旋体(Borrelia garinii)、阿氏疏螺旋体(Borreliaafzelii)、回归热疏螺旋体(Borrelia recurrentis);布鲁氏菌属(Brucella),如流产布鲁氏菌(Brucella abortus)、狗布鲁氏菌(Brucella canis)、马尔他布鲁氏菌(Brucellamelitensis)或猪布鲁氏菌(Brucella melitensis);弯曲杆菌属(Campylobacter),如空肠弯曲杆菌(Campylobacter jejuni);衣原体属(Chlamydia)或嗜衣原体属(Chlamydophila),如肺炎衣原体(Chlamydia pneumoniae)、砂眼衣原体(Chlamydiatrachomatis)、鹦鹉热衣原体(Chlamydophila psittaci);梭菌属(Clostridium),如肉毒梭菌(Clostridium botulinum)、艰难梭菌(Clostridium difficile)、产气荚膜梭菌(Clostridium perfringens)、破伤风梭菌(Clostridium tetani);棒杆菌属(Corynebacterium),如白喉棒杆菌(Corynebacterium diphtheriae);肠球菌属(Enterococcus),如粪肠球菌(Enterococcus faecalis)或屎肠球菌(Enterococcusfaecium);埃希氏菌属(Escherichia),如大肠杆菌(Escherichia coli);弗朗西斯菌属(Francisella),如土拉弗朗西斯菌(Francisella tularensis);嗜血杆菌属(Haemophilus),如流感嗜血杆菌(Haemophilus influenzae);螺杆菌属(Helicobacter),如幽门螺杆菌(Helicobacter pylori);军团菌属(Legionella),如嗜肺军团菌(Legionella pneumophila);钩端螺旋体属(Leptospira),如问号钩端螺旋体(Leptospirainterrogans)、圣他罗西亚钩端螺旋体(Leptospira santarosai)、韦氏钩端螺旋体(Leptospira weilii)或者野口氏钩端螺旋体(Leptospira noguchii);李斯特菌属(Listeria),如单核细胞增生李斯特菌(Listeria monocytogenes);分枝杆菌属(Mycobacterium),如麻风分枝杆菌(Mycobacterium leprae)、结核分枝杆菌(Mycobacterium tuberculosis)或溃疡分枝杆菌(Mycobacterium ulcerans);支原体属(Mycoplasma),如肺炎支原体(Mycoplasma pneumoniae);奈瑟氏球菌属(Neisseria),如淋病奈瑟氏球菌(Neisseria gonorrhoeae)或脑膜炎奈瑟氏球菌(Neisseriameningitidis);假单胞菌属(Pseudomonas),如铜绿假单胞菌(Pseudomonas aeruginosa);立克次体属(Rickettsia),如立氏立克次体(Rickettsia rickettsii);沙门氏菌属(Salmonella),如伤寒沙门氏菌(Salmonella typhi)或鼠伤寒沙门氏菌(Salmonellatyphimurium);志贺氏菌属(Shigella),如索氏志贺氏菌(Shigella sonnei);葡萄球菌属(Staphylococcus),如金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus);链球菌属(Streptococcus),如无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes);密螺旋体属(Treponema),如苍白密螺旋体(Treponema pallidum);弧菌属(Vibrio),如霍乱弧菌(Vibrio cholerae);耶尔森氏菌属(Yersinia),如鼠疫耶尔森氏菌(Yersinia pestis)、小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)或假结核耶尔森氏菌(Yersiniapseudotuberculosis)。
本文还提供了用于治疗个体的贫血的方法,其包括向患有贫血的个体施用本文所述的诱饵型多肽。在具体实施方案中,该贫血为地中海贫血、再生障碍性贫血、溶血性贫血、镰状细胞性贫血、恶性贫血或范可尼贫血。
本文还提供了用于治疗正经历移植的人的方法,其包括向正经历器官移植的个体施用本文所述的诱饵型多肽。在特定的方面,移植物为心脏、肺、心脏和肺、肾、肝、胰腺、肠、胃、睾丸、手、角膜、皮肤、胰岛、骨髓、干细胞、血液、血管、心脏瓣膜或骨骼。
本文还提供了用于治疗患有自身免疫疾病的人的方法,其包括向患有自身免疫疾病的个体施用本文所述的诱饵型多肽。在特定方面,该自身免疫疾病为急性播散性脑脊髓炎(ADEM)、急性坏死性出血性白质脑炎、艾迪生病、无丙种球蛋白血症、斑秃、淀粉样变性、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂综合征(APS)、自身免疫性血管性水肿、自身免疫性再生障碍性贫血、自身免疫性自主神经机能异常、自身免疫性肝炎、自身免疫性高脂血症、自身免疫性免疫缺陷、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性胰腺炎、自身免疫性视网膜病变、自身免疫性血小板减少性紫癜(ATP)、自身免疫性甲状腺疾病、自身免疫性荨麻疹、轴突和神经元神经病、Balo病、Behcet病、大疱性类天疱疮、心肌病、Castleman病、腹腔疾病、Chagas病、慢性疲劳综合征、慢性炎性脱髓鞘多神经病(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、Churg-Strauss综合征、瘢痕性类天疱疮/良性粘膜类天疱疮、克罗恩病、Cogans综合征、冷凝集素病、先天性心脏传导阻滞、柯萨奇病毒性心肌炎、CREST病、特发性混合型冷球蛋白血症、脱髓鞘性神经病、疱疹样皮炎、皮肌炎、Devic病(视神经脊髓炎)、盘状狼疮、Dressler综合征、子宫内膜异位症、嗜酸细胞性食管炎、嗜酸细胞性筋膜炎、结节性红斑、实验性变应性脑脊髓炎、Evans综合征、纤维肌痛、纤维化肺泡炎、巨细胞动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球肾炎、Goodpasture综合征、伴有多血管炎的肉芽肿病(GPA)(以前称为韦格纳肉芽肿病)、Graves病、Guillain-Barre综合征、桥本脑炎、桥本甲状腺炎、溶血性贫血、Henoch-Schonlein紫癜、妊娠疱疹、低丙种球蛋白血症、特发性血小板减少性紫癜(ITP)、IgA肾病、IgG4相关性硬化性疾病、免疫调节脂蛋白、包涵体肌炎、间质性膀胱炎、幼年型关节炎、幼年型糖尿病(1型糖尿病)、幼年型肌炎、Kawasaki综合征、Lambert-Eaton综合征、白细胞分裂性血管炎、扁平苔癣、硬化性苔癣、木样结膜炎、线性IgA疾病(LAD)、狼疮(SLE)、Lyme病、慢性Meniere病、显微镜下多血管炎、混合性结缔组织病(MCTD)、Mooren溃疡、Mucha-Habermann病、多发性硬化、重症肌无力、肌炎、发作性睡病、视神经脊髓炎(Devic病)、中性粒细胞减少症、眼瘢痕性类天疱疮、视神经炎、复发性风湿病、PANDAS(伴链球菌感染性小儿自身免疫性神经精神病)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿(PNH)、Parry Romberg综合征、Parsonnage-Turner综合征、睫状体扁平部炎(外周葡萄膜炎)、天疱疮、周围神经病、静脉周脑脊髓炎、恶性贫血、POEMS综合征、结节性多动脉炎、I型、II型和III型自身免疫性多腺体综合征、风湿性多肌痛、多发性肌炎、心肌梗塞后综合征、心包切开后综合征、黄体酮皮炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、银屑病、银屑病关节炎、特发性肺纤维化、坏疽性脓皮病、单纯红细胞再生障碍、Raynauds现象、反应性关节炎、反射性交感神经营养障碍、Reiter综合征、复发性多软骨炎、不宁腿综合征、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施密特综合征、巩膜炎、硬皮病、舍格伦综合征、精子和睾丸自身免疫、僵人综合征、亚急性细菌性心内膜炎(SBE)、Susac综合征、交感性眼炎、Takayasu动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(TTP)、Tolosa-Hunt综合征、横贯性脊髓炎、1型糖尿病、溃疡性结肠炎、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、水疱大疱性皮肤病、白癜风或韦格纳肉芽肿病(现称为伴有多血管炎的肉芽肿病(GPA))(Acute Disseminated Encephalomyelitis(ADEM),Acutenecrotizing hemorrhagic leukoencephalitis,Addison’s disease,Agammaglobulinemia,Alopecia areata,Amyloidosis,Ankylosing spondylitis,Anti-GBM/Anti-TBM nephritis,Antiphospholipid syndrome(APS),Autoimmune angioedema,Autoimmune aplastic anemia,Autoimmune dysautonomia,Autoimmune hepatitis,Autoimmune hyperlipidemia,Autoimmune immunodeficiency,Autoimmune inner eardisease(AIED),Autoimmune myocarditis,Autoimmune oophoritis,Autoimmunepancreatitis,Autoimmune retinopathy,Autoimmune thrombocytopenic purpura(ATP),Autoimmune thyroid disease,Autoimmune urticaria,Axonal&neuronal neuropathies,Balo disease,Behcet’s disease,Bullous pemphigoid,Cardiomyopathy,Castlemandisease,Celiac disease,Chagas disease,Chronic fatigue syndrome,Chronicinflammatory demyelinating polyneuropathy(CIDP),Chronic recurrent multifocalostomyelitis(CRMO),Churg-Strauss syndrome,Cicatricial pemphigoid/benignmucosal pemphigoid,Crohn’s disease,Cogans syndrome,Cold agglutinin disease,Congenital heart block,Coxsackie myocarditis,CREST disease,Essential mixedcryoglobulinemia,Demyelinating neuropathies,Dermatitis herpetiformis,Dermatomyositis,Devic’s disease (neuromyelitis optica),Discoid lupus,Dressler’s syndrome,Endometriosis,Eosinophilic,esophagitis,Eosinophilicfasciitis,Erythema nodosum,Experimental allergic encephalomyelitis,Evanssyndrome,Fibromyalgia,Fibrosing alveolitis,Giant cell arteritis(temporalarteritis),Giant cell myocarditis,Glomerulonephritis,Goodpasture’s syndrome,Granulomatosis with Polyangiitis(GPA)(formerly called Wegener’sGranulomatosis),Graves’disease,Guillain-Barre syndrome,Hashimoto’sencephalitis,Hashimoto’s thyroiditis,Hemolytic anemia,Henoch-Schonleinpurpura,Herpes gestationis,Hypogammaglobulinemia,Idiopathic thrombocytopenicpurpura(ITP),IgA nephropathy,IgG4-related sclerosing disease,Immunoregulatorylipoproteins,Inclusion body myositis,Interstitial cystitis,Juvenilearthritis,Juvenile diabetes(Type 1 diabetes),Juvenile myositis,Kawasakisyndrome,Lambert-Eaton syndrome,Leukocytoclastic vasculitis,Lichen planus,Lichen sclerosus,Ligneous conjunctivitis,Linear IgA disease(LAD),Lupus(SLE),Lyme disease,chronic,Meniere’s disease,Microscopic polyangiitis,Mixedconnective tissue disease(MCTD),Mooren’s ulcer,Mucha-Habermann disease,Multiple sclerosis,Myasthenia gravis,Myositis,Narcolepsy,Neuromyelitis optica(Devic’s),Neutropenia,Ocular cicatricial pemphigoid,Optic neuritis,Palindromic rheumatism,PANDAS(Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcus),Paraneoplastic cerebellar degeneration,Paroxysmal nocturnal hemoglobinuria(PNH),Parry Romberg syndrome,Parsonnage-Turner syndrome,Pars planitis(peripheral uveitis),Pemphigus,Peripheralneuropathy,Perivenous encephalomyelitis,Pernicious anemia,POEMS syndrome,Polyarteritis nodosa,Type I,II,&III autoimmune polyglandular syndromes,Polymyalgia rheumatica,Polymyositis,Postmyocardial infarction syndrome,Postpericardiotomy syndrome,Progesterone dermatitis,Primary biliarycirrhosis,Primary sclerosing cholangitis,Psoriasis,Psoriatic arthritis,Idiopathic pulmonary fibrosis,Pyoderma gangrenosum,Pure red cell aplasia,Raynauds phenomenon,Reactive Arthritis,Reflex sympathetic dystrophy,Reiter’ssyndrome,Relapsing polychondritis,Restless legs syndrome,Retroperitonealfibrosis,Rheumatic fever,Rheumatoid arthritis,Sarcoidosis,Schmidt syndrome,Scleritis,Scleroderma,Sjogren’s syndrome,Sperm&testicular autoimmunity,Stiffperson syndrome,Subacute bacterial endocarditis(SBE),Susac’s syndrome,Sympathetic ophthalmia,Takayasu’s arteritis,Temporal arteritis/Giant cellarteritis,Thrombocytopenic purpura(TTP),Tolosa-Hunt syndrome,Transversemyelitis,Type 1diabetes,Ulcerative colitis,Undifferentiated connective tissuedisease(UCTD),Uveitis,Vasculitis,Vesiculobullous dermatosis,Vitiligo orWegener’s granulomatosis(now termed Granulomatosis with Polyangiitis(GPA)))。上述疾病属于这一类别;自身反应性T细胞或B细胞的耗尽都可以是用于治疗所列出的自身免疫疾病的方案的一部分。
可视化方法
本文还提供了用于使表达CD47的细胞可视化的方法,其包括使细胞群体与本文所述的诱饵型多肽和可检测标记物接触。在本文所述方法的一些实施方案中,该方法包括肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T细胞、损伤的红细胞、动脉斑块或纤维化组织的可视化。在另外的实施方案中,该细胞为健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。在本文所述方法的其他实施方案中,该方法包括细胞的体内可视化、细胞的离体可视化或细胞的体外可视化。在特定方面,该方法为显微术、荧光显微术、荧光激活细胞分选或正电子发射断层扫描(PET)成像。在特定方面,该可检测标记物包括酶标记物,如辣根过氧化物酶(HRP)、碱性磷酸酶(AP)或葡萄糖氧化酶。在其他方面,该可检测标记物包括荧光标记物,如Alexa 350、Alexa 405、Alexa 488、Alexa 532、Alexa 546、Alexa 555、Alexa 568、Alexa 594、Alexa647、Alexa 680、Alexa 750、 FL、香豆素、荧光素(FITC)、Oregon Pacific BlueTM、Pacific GreenTM、Pacific OrangeTM、四甲基罗丹明(TRITC)、Texas 或其他荧光标记物。在进一步的方面,该可检测标记物包括放射性同位素,如32P、33P、3H、14C、125I或其他放射性同位素。在进一步的方面,该方法是诊断性的。
剂量
当本文所述的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽(例如,变异SIRP-γ、SIRP-β或SIRP-β2多肽)被给予至个体时,本领域技术人员理解,剂量取决于几个因素,包括但不限于个体的体重和疾病状态。通常,如本文所用的,接受本文所述的SIRP-γ、SIRP-β或SIRP-β2诱饵型多肽(例如,包含变体SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)的个体是单个生物体。在某些实施方案中,个体是哺乳动物。特别地,个体是人,包括男性或女性。在许多实施方案中,个体是患者,或等待或正接受医疗护理和治疗的个体。
在一些实施方案中,向个体施用相对于个体体重标准化的剂量。在一些实施方案中,在单次或累积的施加中向个体施用约10μg/kg、约50μg/kg、约100μg/kg、约200μg/kg、约300μg/kg、约400μg/kg、约500μg/kg、约600μg/kg、约700μg/kg、约800μg/kg、约900μg/kg、约1,000μg/kg、约1,100μg/kg、1,200μg/kg、1,300μg/kg、1,400μg/kg、1,500μg/kg、1,600μg/kg、1,700μg/kg、1,800μg/kg、1,900μg/kg、约2,000μg/kg、约3000μg/kg、约4000μg/kg、约5000μg/kg、约6000μg/kg、约7000μg/kg、约8000μg/kg、约9000μg/kg、约10mg/kg、约20mg/kg、约30mg/kg、约40mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg about 90mg/kg、约100mg/kg、约200mg/kg、约300mg/kg、约400mg/kg、约500mg/kg、约600mg/kg、约700mg/kg、约800mg/kg、约900mg/kg或约1000mg/kg剂量的本文所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,包含变异SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)。在特定实施方案中,给予个体的剂量为每周约7000mg/kg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周约70mg/kg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周约7mg/kg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周约1000μg/kg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周500μg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周250μg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周100μg诱饵型多肽。在特定实施方案中,给予个体的剂量为每周50μg诱饵型多肽。
在一些实施方案中,个体例如每日多次、每日、每隔一日、每周一次、每隔一周一次、每三周一次、每月一次或以任何其他合适的给药方案接受一定剂量的本文所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,包含变异SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)。在一个实施方案中,个体接受作为连续输注的一定剂量的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽。在一个实施方案中,常规施用包括施用一定剂量的本文所述的诱饵多肽,每周一次,持续一段时间。当然,给药方案任选地包含诱饵型多肽递送的其他排列。也就是说,根据医师的判断,诱饵型多肽每周施用一次、两次、三次、四次、五次、六次或更多次。在一些实施方案中,个体在一段时间内被给予至少5个剂量。在其他实施方案中,个体被给予大于或小于5个剂量。因此,在一个实施方案中,个体每周接受约10mg/kg剂量的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽。或者,个体接受两个5mg/kg剂量,每周两次,或在五天内接受每日2mg/kg剂量。
这些剂量实例并非限制性的,并且仅用来例示用于施用约10mg/kg的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽的特定给药方案。例如,如果在给定情况下合适的剂量为每周10mg/kg,则任选地将该剂量分解成任意个排列,例如,每周四次2.5mg/kg注射。这也适用于在特定情况下合适的剂量大于或小于10mg/kg的情况。
在一些实施方案中,向个体施用诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽(例如,包含变异SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)的时间段是由疾病的阶段、患者的病史和主治医师的判断确定的任何合适的时段。这样的合适时段的实例包括但不限于至少约3个月、至少约4个月、至少约5个月、至少约6个月、至少约7个月、至少约8个月、至少约9个月、至少约10个月、至少约11个月、至少约12个月、至少约13个月、至少约14个月、至少约15个月、至少约16个月、至少约17个月、至少约18个月、至少约19个月、至少约20个月、至少约21个月、至少约22个月、至少约23个月,或至少约24个月,或更长。在特定方面,如果需要,治疗时段持续超过24个月,如持续30个月、31个月、32个月、33个月、34个月、35个月、36个月或超过36个月。在一些实施方案中,该时段为6个月、1年或2年。
在另一实施方案中,对于任何本文所述的方法,给药的时间段持续至少约2周、至少约4周、至少约8周、至少约16周、至少约17周、至少约18周、至少约19周、至少约20周、至少约24周、至少约28周、至少约32周、至少约36周、至少约40周、至少约44周、至少约48周、至少约52周、至少约60周、至少约68周、至少约72周、至少约80周、至少约88周、至少约96周,或至少约104周。
在一些实施方案中,本文所述的任意诱饵型多肽(例如,包含变异SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)在不同的治疗期中施用。例如,诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽在治疗期和维持期中施用。在一些实施方案中,治疗期包括以每周剂量施用诱饵型多肽制剂,而维持期持续较长的时间段,如约每6周、约每7周、约每8周、约每9周、约每10周、约每11周、约每12周,或更长。在一些情况下,在治疗期给予的剂量大于在维持期给予的剂量。然而,治疗期和维持期是针对特定个体设计的,因此,治疗期与维持期之间的时间和剂量与上述实例不同。通常,维持期在认为合适的任何时间开始。例如,在一些实施方案中,治疗期为八周,而维持期持续个体的整个一生。在其他实施方案中,只进行治疗期或维持期。
在更进一步的实施方案中,预防性地给予本文所述的诱饵型多肽(例如,包含变异SIRP-γ、SIRP-β或SIRP-β2多肽的组合物)。在这些实施方案中,诱饵型多肽的施用防止个体(例如,在遗传学上易于发展出癌症如乳腺癌的个体;易于发展出细菌或病毒感染的个体;将经历器官移植的个体;或易于发展出贫血或自身免疫疾病的个体)中疾病的发作。
个体应保持使用本文所述诱饵型多肽的时间长度由主治医师决定。在一些情况下,在个体剩余的一生中施用诱饵型多肽是有利的。在一些这样的实施方案中,诱饵型多肽在身体的四个象限(quadrant)中施用,例如在淋巴结附近(例如,在每个腋窝)、在每侧臀部(例如,皮下)中等施用。在一些这样的实施方案中,诱饵型多肽经由泵施用。在一些实施方案中,将泵和/或递送装置植入个体中,以允许长期给药。可植入式泵的实例包括但不限于渗透泵。
试剂盒
本文提供了用于分配本文所述的诱饵型多肽的试剂盒。这样的试剂盒包含含有诱饵型多肽(包括SIRP-γ、SIRP-β或SIRP-β2多肽)的第一药物产品小瓶和含有如本文所述的用于重建的合适无菌液体的第二小瓶。在一些实施方案中
例如,在一个实施方案中,这样的试剂盒包含第一小瓶,即,含有300μg诱饵型多肽(包括SIRP-γ、SIRP-β或SIRP-β2多肽)的药物产品小瓶,该小瓶为120%填充。该过量旨在便于指定剂量的抽取和施用。该试剂盒进一步包含含有至多1mL 0.9%注射用氯化钠溶液的第二小瓶。在药物产品用0.6mL注射用氯化钠溶液(0.9%w/v)重建之后,药物产品小瓶产生用于递送的0.5mL溶液,其对应于250μg诱饵型多肽(包括SIRP-γ、SIRP-β或SIRP-β2多肽)。举例来说,如果总剂量为1mg,则每个剂量需要4个小瓶。
某些定义
如本文所用的,术语“诱饵”、“抑制剂”和“阻断剂”是指防止CD47与其结合配偶体结合的分子。出于开发的目的,该结合可以在实验条件下进行,例如,使用分离的蛋白质作为结合配偶体、使用蛋白质部分作为结合配偶体、使用蛋白质或蛋白质部分的酵母展示作为结合配偶体,等等。出于生理相关的目的,CD47与其结合配偶体的结合通常是两个细胞之间的事件,其中每个细胞表达一种结合配偶体。特别感兴趣的是SIRP多肽在吞噬细胞如巨噬细胞上的表达;以及可能是吞噬作用的靶标的细胞(例如,肿瘤细胞、循环造血细胞等)上CD47的表达。可使用受体或配体结合或信号传导的体外和体内测定来鉴别抑制剂。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用,以指代氨基酸残基的聚合物。这些术语也适用于其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。
如本文所用的,术语“氨基酸”是指天然存在的和合成的氨基酸,以及以与天然存在的氨基酸相似的方式起作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的那些氨基酸,以及后来被修饰的那些氨基酸,例如,羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。如本文所用的,术语“氨基酸类似物”是指具有与天然存在的氨基酸相同的基本化学结构(即,与氢、羧基、氨基和R基团结合的α碳)的化合物,例如,高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。这样的类似物具有修饰的R基团(例如,正亮氨酸)或修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。如本文所用的,术语“氨基酸模拟物”是指具有与氨基酸的一般化学结构不同的结构,但以与天然存在的氨基酸类似的方式起作用的化学化合物。
术语“接受者”、“个体”、“受试者”、“宿主”和“患者”在本文中可互换使用,并且指需要诊断、治疗或疗法的任何哺乳动物受试者,特别是人。用于治疗目的的“哺乳动物”是指被归类为哺乳动物的任何动物,包括人、家畜和农场动物,以及实验室动物、动物园动物、运动动物或宠物,如狗、马、猫、牛、绵羊、山羊、猪、小鼠、大鼠、兔、豚鼠、猴等。在一些实施方案中,该哺乳动物是人。
如本文所用的,“癌症”包括任何形式的癌症,包括但不限于实体肿瘤癌症(例如,肺癌、前列腺癌、乳腺癌、膀胱癌、结肠癌、卵巢癌、胰腺癌、肾癌、肝癌、胶质母细胞瘤、髓母细胞瘤、平滑肌肉瘤、头颈鳞状细胞癌、黑素瘤,神经内分泌瘤等)和液体癌症(例如,血液系统癌症);癌;软组织肿瘤;肉瘤;畸胎瘤;黑素瘤;白血病;淋巴瘤;以及脑癌,包括微小残留病,并且包括原发性和转移性肿瘤。任何癌症都是适于通过本方法和组合物治疗的癌症。
如本文所用的,术语“结合配偶体”是指特异性结合对(即,两个分子,通常是两个不同的分子,其中一个分子,例如第一结合配偶体,通过非共价手段特异性结合另一分子,例如,第二结合配偶体)的成员。
如本文所用的,术语“治疗”等是指出于获得效果的目的,施用药剂或实施程序。就完全或部分预防疾病或其症状而言,该效果可以是预防性的,并且/或者就部分或完全治愈疾病和/或疾病症状而言,该效果可以是治疗性的。如本文所用的,“治疗”可包括治疗哺乳动物特别是人的肿瘤,并且包括:(a)预防可能易患疾病但尚未被诊断为患有该疾病(例如,包括可能与原发疾病相关或由原发疾病引起的疾病)的受试者发生该疾病或疾病症状;(b)抑制该疾病,即,阻止其发展;和(c)缓解该疾病,即,引起疾病的消退。治疗可指成功治疗或改善或预防癌症的任何标志,包括任何客观或主观的参数,如症状减轻;缓解;减少,或使患者更耐受疾病病况;减缓退化或衰退的速率;或者使退化的终点变得不那么使人虚弱。症状的治疗或改善可基于客观或主观的参数;包括医师的检查结果。因此,术语“治疗”包括施用本发明的化合物或药剂,以预防或延缓、缓和或阻止或抑制与癌症或其他疾病相关的症状或病况的发展。术语“治疗效果”是指减少、消除或阻止受试者的疾病、疾病症状或疾病副作用。
在某些实施方案中,“与...组合”、“联合疗法”和“组合产品”是指向患者同时施用第一治疗剂和如本文所用的化合物。当联合施用时,每种组分可同时或在不同时间点以任何顺序依次施用。因此,每种组分可分开但在时间上足够紧密地施用,以便提供期望的治疗效果。
“剂量单位”是指适合作为单位剂量用于待治疗的特定个体的物理上分散的单位。每个单位均可含有经计算用于与所需的药物载体一起产生期望治疗效果的预定量的活性化合物。剂量单位形式的规格可由(a)活性化合物的独特特征和待实现的特定治疗效果,以及(b)在配制这类活性化合物的领域中固有的限制来决定。
“药学上可接受的赋形剂”意指可用于制备通常安全、无毒且合乎需要的药物组合物的赋形剂,并且包括对于兽医用途以及人类药物用途可接受的赋形剂。这样的赋形剂可以是固体、液体、半固体,或者在气雾剂组合物的情况下是气态的。
术语“药学上可接受的”、“生理上可接受的”及其语法上的变化形式在涉及组合物、载体、稀释剂和试剂时可互换使用,并表示该物质能够施用于人体,而不会以将会禁止组合物施用的程度产生不期望的生理效应。
“治疗有效量”是指当向受试者施用以治疗疾病时足以实现对该疾病的治疗的量。
术语“抗体”以最广泛的含义使用,并且具体涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如,双特异性抗体)、肽体(peptibodies)、人抗体、人源化抗体、驼类抗体(包括驼类单结构域抗体)、替代骨架抗体(alternative scaffoldantibodies)(例如,亲和体(affibodies)、avimer、Fn3结构域、DARPin、Kunitz结构域、SMIP、结构域抗体、BiTE、Adnectin、纳米抗体、稳定的scFv、Anticalin)和抗体片段,只要它们表现出期望的生物学活性。“抗体”(Ab)和“免疫球蛋白”(Ig)是具有相同结构特征的糖蛋白。抗体对特定抗原表现出结合特异性,而免疫球蛋白包括抗体和缺乏抗原特异性的其他抗体样分子。
实施例
实施例1:方法
蛋白质表达和纯化。使用杆状病毒从粉纹夜蛾(Hi-5)细胞中分泌具有C15G突变和C-末端8x组氨酸标签(SEQ ID NO:40)的人CD47 lgSF结构域(残基1-117),并通过Ni-NTA进行纯化。使用含有在MBP标签和C-末端8x组氨酸标签(SEQ ID NO:40)之后的鼻病毒3C蛋白酶切割位点的修饰的pMal-p2X表达载体(New England Biolabs)将单体SIRP-γ、SIRP-β和SIRP-β2变体在BL-21(DE3)大肠杆菌的周质中表达为MBP-融合物。用1mM IPTG在0.8的OD-600下诱导细胞,并在22℃振荡下温育24小时。通过渗透压休克获得周质蛋白,并使用镍-次氮基三乙酸(Ni-NTA)层析来纯化MBP融合蛋白。将洗脱的蛋白质在4℃下用3C蛋白酶消化12小时以去除MBP,并通过额外的Ni-NTA层析步骤进一步纯化。如先前所述使用Triton X-114来去除内毒素,并使用ToxinSensor Chromogenic LAL Endotoxin Assay Kit(Genscript)来确认内毒素去除。通过将SIRP-γ、SIRP-β和SIRP-β2变体克隆至具有IL-2信号序列和工程化Ser228Pro突变的修饰的pFUSE-hIgG4-Fc载体(lnvivogen)中而产生SIRP-γ、SIRP-β和SIRP-β2-Fc融合物。通过在Freestyle 293-F细胞(Invitrogen)中瞬时转染来表达蛋白质,并在HiTrap蛋白A柱(GE Healthcare)上进行纯化。
通过与羧基末端生物素受体肽标签(GLNDIFEAQKIEWHE(SEQ ID NO:41))一起表达来获得生物素化的蛋白质,并如上所述纯化。用BirA连接酶在体外将经纯化的蛋白质生物素化,并随后通过Ni-NTA层析将其从反应混合物中重新纯化。
SIRP-γ、SIRP-β或SIRP-β2变体的酵母展示和文库生成。SIRP-γ、SIRP-β或SIRP-β2的N-末端V集合结构域在所述pYDS649HM载体中在酿酒酵母菌株BJ5465的表面上展示。通过使用具有简并密码子的引物组将SIRP-γ、SIRP-β或SIRP-β2的CD47接触残基和疏水性'核心'残基进行随机化的装配PCR反应来生成文库。进一步用与pYDS649HM载体具有同源性的引物来扩增PCR产物,将其与线性化pYDS649HM载体DNA合并,并共电穿孔至BJ5465酵母中。所得的文库含有4.0-8.0x108个转化子。
文库的选择。将转化的酵母在30℃的SD-W液体培养基中扩展,并在20℃的SG-W液体培养基中诱导。所有培养基都补充有100mM麦芽糖以防止絮凝。所有选择步骤都在4℃下进行。对于第一轮选择,将代表文库转化子数目的10倍覆盖的8x109个诱导的酵母重悬在5ml PBE(补充有0.5%牛血清白蛋白和0.5mM EDTA的磷酸盐缓冲盐水)中。将酵母与500μl预包被有生物素化CD47的顺磁性链霉亲和素微珠(Miltenyi)混合,并将混合物旋转温育1小时。通过在5,000x g下离心五分钟来将酵母沉淀,并用1ml PBE洗涤两次。将磁性标记的酵母重悬在5ml PBE中,并根据制造商的说明(Miltenyi)用LS MAGS柱进行分离。将洗脱的酵母沉淀,重悬在SD-W培养基中,并扩展以供下一轮选择。额外轮次的选择与第一轮类似地进行,具有以下改变:将1x108个酵母重悬在含有Alexa Fluor 488标记的抗-HA抗体(CellSignaling)或浓度从100nM至1nM逐渐降低的生物素化CD47蛋白的500μl PBE中。在温育一小时后,用PBE洗涤酵母并用于采用CD47进行选择,用链霉亲和素-PE(Invitrogen)或链霉亲和素-Alexa Fluor 647(内部生产)标记15分钟。将酵母用PBE洗涤超过两次,并用50μl合适的抗荧光团微珠(抗-FITC、抗-PE或抗-Alexa Fluor 647;Miltenyi)磁性地标记15分钟。将酵母洗涤一次,重悬在3ml PBE中,并与第一轮中相同地用LS柱分离。
对于最后轮次的选择,进行动力学选择。简言之,将酵母用10nM生物素化CD47染色一小时,用PBE洗涤,并随后重悬在含有1μM未生物素化CD47的500μl PBE中。将细胞在25℃下温育300分钟,随后用冰冷PBE洗涤,并用荧光标记的链霉亲和素进行染色。然后,将酵母用Alexa Fluor 488标记的抗-HA和链霉亲和素-Alexa Fluor 647共同标记,并用FACS细胞分选仪进行选择。
表面等离子体共振(SPR)。实验利用Biacore T100在25℃下进行。利用Nanodrop2000光谱仪(Thermo Scientific)通过280nm吸光度来对蛋白质浓度进行定量。使用Biacore SA传感器芯片(GE Healthcare)来捕获生物素化的CD47(Rmax约150RU)。将不相关的生物素化蛋白质固定,其RU值与参比表面的RU值相匹配,以用于非特异性结合的对照。用SIRP-γ、SIRP-β或SIRP-β2变体在HBS-P+缓冲液(GE Healthcare)中的系列稀释液进行测量。通过三次60秒的2M MgCI2注射来再生CD47表面。采用1:1 Langmuir结合模型用Biacore T100评价软件2.0版来分析所有数据。
细胞系和GFP-萤光素酶+转导。在补充有10%胎牛血清(Omega Scientific)、100U/ml青霉素和100μg/ml链霉素(Invitrogen)的RPMI+GlutaMax(Invitrogen)中培养DLD-1细胞(ATCC)、HT-29细胞(ATCC)、Raji细胞(ATCC)、Jurkat细胞(ATCC)和639-V细胞(DSMZ)。通过使用工程化为表达eGFP-萤光素酶2(pgl4)融合蛋白的基于pCDH-CMV-MCS-EF1puro HIV的慢病毒载体(Systems Biosciences)进行转导来生成GFP-萤光素酶+细胞系。通过在FACS细胞分选仪上对GFP表达进行分选来产生稳定的细胞系。
基于细胞的CD47结合测定。将不同浓度的生物素化SIRP-γ、SIRP-β或SIRP-β2单体、SIRP-γ、SIRP-β或SIRP-β2-hlgG4融合蛋白与癌细胞一起温育。使用100nM AlexaFluor 647-缀合的链霉亲和素作为第二染色试剂来检测生物素化单体的结合,并在AccuriC6流式细胞仪(BD Biosciences)上进行分析。用山羊抗-人lgG抗体(Invitrogen)来检测SIRP-γ、SIRP-β或SIRP-β2-hlgG4融合蛋白或抗CD47抗体的结合,并在Accuri C6流式细胞仪上进行分析。数据表示为相对于对每类试剂的最大结合归一化的平均荧光强度,并且使用Prism 5(Graphpad)将各个点拟合至S形剂量-响应曲线。
基于细胞的CD47阻断测定。将生物素化SIRP-γ、SIRP-β或SIRP-β2变体与AlexaFluor 647-缀合的链霉亲和素一起温育,以形成SIRP-γ、SIRP-β或SIRP-β2变体四聚体。将100nM SIRP-γ、SIRP-β或SIRP-β2变体四聚体与滴定浓度的CD47拮抗剂合并,并同时添加至50,000个GFP-萤光素酶+Raji细胞。在4℃下将细胞温育30min,随后洗涤以去除未结合的四聚体。用DAPI(Sigma)将样品染色以排除死细胞,并使用Accuri C6流式细胞仪来测定荧光。数据表示为相对于最大四聚体结合归一化的几何平均荧光强度,并且使用Prism 5(Graphpad)拟合至S形剂量响应曲线。
巨噬细胞衍生和吞噬作用测定。从匿名供体获得白细胞减少系统(LRS)室,并通过在Ficoll-Paque Premium(GE Healthcare)上的密度梯度离心来富集外周血单个核细胞。使用抗-CD14微珠(Miltenyi)在AutoMACS(Miltenyi)上纯化单核细胞,并通过在补充有10%AB-人血清(Invitrogen)和100U/ml青霉素和100μg/ml链霉素(Invitrogen)的IMDM+GlutaMax(Invitrogen)中培养7-10天而使其分化成巨噬细胞。通过将50,000个巨噬细胞与100,000个GFP+肿瘤细胞共同培养2小时,然后使用具有高通量进样器的LSRFortessa细胞分析仪(BD Biosciences)进行分析来进行吞噬作用测定。用于治疗的抗体包括:小鼠IgG1同种型对照(eBioscience)、抗-CD47克隆203(eBioscience)、抗-EpCam(Biolegend)、西妥昔单抗(Bristol-Myers Squibb)和利妥昔单抗(Genentech)。使用抗-CD14、抗-CD45或抗-CD206抗体(Biolegend),通过流式细胞术来鉴别巨噬细胞。通过用DAPI(Sigma)染色而将死细胞从分析中排除。吞噬作用被评价为GFP+巨噬细胞的百分比,并相对于每个独立供体对每个细胞系的最大响应进行归一化。通过具有Bonferroni事后检验的双向ANOVA来确定统计学显著性,并且当指示时,使用Prism 5(Graphpad)将数据拟合至S形剂量响应曲线。
基于FACS的吞噬作用测定。通过将100,000个靶细胞与50,000个巨噬细胞在超低附着96孔U型底板(Corning)中的未添加抗生素或血清的IMDM+GlutaMax(LifeTechnologies)中共同培养两小时来进行吞噬作用的评估。通过采用CD14+全血分离试剂盒(Miltenyi)对原代人单核细胞进行基于磁珠的纯化,随后与人血清(Gemini)培养7天而生成巨噬细胞;在第7天,使用TrypLE Express(Life Technologies)从板上收获这些细胞。根据制造商的指示,用钙黄绿素AM红/橙细胞染色剂(Life Technologies)来标记巨噬细胞。将靶细胞工程化成稳定表达绿色荧光蛋白。将蛋白质治疗剂添加至靶细胞与巨噬细胞的共培养物中,并将混合物在37℃下温育2小时。反应在装有高通量自动进样器(BDBiosciences)的LSRFortessa分析仪上进行。吞噬作用以如采用FlowJov.9.4.10(TreeStar)分析的、表示为GFP+巨噬细胞占总巨噬细胞的百分比来评估,并如图例中所示进行归一化。
小鼠。将Nod.Cg-PrkdcscidIL2rgtm1Wjl/SzJ(NSG)小鼠用于所有体内实验。小鼠在约6-10周龄时植入肿瘤,并且用年龄和性别匹配的8-15只小鼠的队列进行实验。
肿瘤模型。为模拟人结肠癌,将1x105个GFP-萤光素酶+DLD-1细胞注射至NSG小鼠的腹膜腔中。通过将25%Matrigel(BD Biosciences)中的1.25x105个GFP-萤光素酶+639-V细胞植入NSG小鼠的背部皮下组织中来对膀胱癌建模。对于人淋巴瘤的局部模型,在下胁处皮下植入1×106个GFP-萤光素酶+Raji细胞。在所有模型中,治疗均在植入确认后开始并根据指示继续进行。对于所有治疗,通过每日腹膜内注射来施用200μg SIRP-γ、SIRP-β或SIRP-β2变体或抗体。通过生物发光成像来监控肿瘤生长,并测量肿瘤尺寸以根据椭球公式(π/6x长度x宽度2)来计算体积。视情况通过Mann-Whitney检验或具有Dunn's事后检验的Kruskai-Wallis来确定统计学显著性。通过Mantel-Cox检验来分析存活。
生物发光成像。向麻醉的小鼠注射200μl在无菌PBS中以16.67mg/ml重建的D-萤光素(萤火虫)钾盐(Biosynth)。使用IVIS光谱(Caliper Life Sciences)进行生物发光成像超过20分钟,以记录最大辐射率。使用Living Image 4.0(Caliper Life Sciences)从感兴趣的解剖学区域评估总流量值峰值并用于分析。
蛋白质序列。本文所述的实施例中所用的蛋白质包括:
野生型SIRPγ:
EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:1)
GV1(高亲和力SIRPγ):
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3)
GV1.2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13)
HGV1:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:4)
HGV2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:5)
HGV3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:6)
MGV1:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:7)
SIRP-γ文库残基:
野生型SIRPβ:
EDELQVIQPEKSVSVAAGESATLRCAMTSLIPVGPIMWFRGAGAGRELIYNQKEGHFPRVTTVSELTKRNNLDFSISISNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:43)
BV1(高亲和力SIRPβ):
EDELQIIQPEKSVSVAAGESATLRCAITSLFPVGPIQWFRGAGAGRVLIYNQRQGPFPRVTTVSETTKRNNLDFSISISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:26)
野生型SIRPβ2:
EEELQVIQPDKSISVAAGESATLHCTVTSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISNITPADAGTYYCVKFRKGSPDHVEFKSGAGTELSVRAKPS(SEQ ID NO:44)
B2V1(高亲和力SIRPβ2):
EEELQIIQPDKSISVAAGESATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:28)
SIRP-γ多肽的其他蛋白质序列包括:
HLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSHFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:8);
HLib2:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:9);
HLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:10);
HLib4:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRELIYNAREGRFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:11);
HMLib1:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRIGNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:12);
HMLib2:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3);
HMLib3:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13);
HMLib4:
EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:42);
HMLib5:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:14);
HMLib6:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTXWH(SEQ ID NO:15),其中X为A、R、N、D、C、Q、E、G、H、I、L、K、M、F、P、S、T、W、Y或V;
HMLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:16);
MLib1:
EEELQIIQPEKLLLVTVGKTATLHCTITSLLPVGPIQWFRGVGPGRELIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:17);
MLib2:
EEELQIIQPEKLLLVTVGKTATLHCTLTSLLPVGPILWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGNPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:18);
MLib3:
EEELQLIQPEKLLLVTVGKTATLHCTITSLFPPGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:19);
MLib4:
EEELQIIQPEKLLLVTVGKTATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:20);
MLib5:
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPIGPILWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:21);
MLib6:
EEELQMIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:22);
MLib7:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:23);以及
MLib8:
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALXAKPS(SEQ ID NO:24)。
在其他实施方案中,所述诱饵型多肽为融合多肽或嵌合多肽。在其他实施方案中,该诱饵型多肽包括与包含免疫检查点抑制剂、共刺激分子或细胞因子或减毒的细胞因子的多肽序列融合的SIRP-γ多肽序列,其中该序列由具有不同长度和组成的Gly-Ser连接体连接。在进一步的实施方案中,该诱饵型多肽包含以下序列中的一种:
1)与免疫检查点抑制剂融合
a.PD-1/PD-L1拮抗剂
实例:HAC-GV3(与GV3融合的高亲和力PD-1诱饵)
DSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFHVVWHRESPSGQTDTLAAFPEDRSQPGQDARFRVTQLPNGRDFHMSVVRARRNDSGTYVCGVISLAPKIQIKESLRAELRVTERGGGGSGGGGSEEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:30);
b.BTLA/CD160拮抗剂
实例:GV3-BTLA诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSWNIHGKESCDVQLYIKRQSEHSILAGDPFELECPVKYCANRPHVTWCKLNGTTCVKLEDRQTSWKEEKNISFFILHFEPVLPNDNGSYRCSANFQSNLIESHSTTLYVTDVK(SEQ ID NO:31);
c.磷脂酰丝氨酸拮抗剂
实例:GV3-MFGE8诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSELNGCANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGNDQWLQVDLGSSKEVTGIITQGARNFGSVQFVASYKVAYSNDSANWTEYQDPRTGSSKIFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC(SEQ ID NO:32);
实例:GV3-Tim1诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSVAGSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVPPKVTT(SEQ ID NO:33);
实例:GV3-Tim3诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPA(SEQ ID NO:34);
实例:GV3-Tim4诱饵
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSTSETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKYRLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTDEKFNLKLVIKPAKVTPA(SEQ ID NO:35);
2)与共刺激分子融合
a.CD40激动剂
实例:GV3-CD40L
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL(SEQ ID NO:36);
b.41BB(CD137)激动剂
实例:GV3-41BBL
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQMELRRVVAGEGSGSVSLALHLMPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPA(SEQ IDNO:37);
3)与细胞因子或减毒的细胞因子融合
实例:GV3-IL2
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:38);
实例:GV3-IL2(具有突变F42A/D20T的“减毒”细胞因子)
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLTLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:39)。
实施例2:SIRP-γ变体GV3对人CD47的结合亲和力和动力学的基于表面等离子体共振
的测量
使用上述表面等离子体共振法,可以测量SIRP-γ变体GV3对人CD47的结合亲和力和动力学。例如,如图1A所示,将不同浓度的SIRP-γ变体GV3(包括100pM、316pM、1nM、3.16nM、10nM和100nM)用于与已知浓度的生物素化人CD47进行结合反应。使用1:1Langmuir结合模型计算的解离常数Kd为92pM。所计算的解离半衰期T1/2为约44分钟。图1B示出了与SIRP-γ变体GV3结合的生物素化人CD47的图示。
实施例3:HAC-GV3(SIRP-γ变体GV3与高亲和力PD-1变体HAC的融合蛋白)对人CD47的
结合亲和力和动力学的基于表面等离子体共振的测量
使用上述表面等离子体共振法,可以测量HAC-GV3(SIRP-γ变体GV3与高亲和力PD-1变体HAC的融合蛋白)对人CD47的结合亲和力和动力学。例如,如图2A所示,将不同浓度的HAC-GV3融合蛋白(包括100pM、316pM、1nM、3.16nM、10nM和100nM)用于与已知浓度的生物素化人CD47进行结合反应。使用1:1 Langmuir结合模型计算的解离常数Kd为160pM。所计算的解离半衰期T1/2为约40分钟。图2B示出了与包含SIRP-γ变体GV3和HAC的融合蛋白结合的生物素化人CD47的图示。
实施例4:PD-1变体HAC对人PD-L1的结合亲和力和动力学的基于表面等离子体共振的
测量
在另一实例中,使用表面等离子体共振来测量PD-1变体HAC对人PD-L1的结合亲和力和动力学。将不同浓度的HAC(包括100pM、316pM、1nM、3.16nM、10nM和100nM)用于与已知浓度的生物素化人PD-L1进行结合反应。使用1:1 Langmuir结合模型计算的解离常数Kd为110pM。所计算的解离半衰期T1/2为约42分钟。
实施例5:HAC-GV3(SIRP-γ变体GV3与PD-1变体HAC的融合物)对人PD-L1的结合亲和力
和动力学的基于表面等离子体共振的测量
使用上述表面等离子体共振法,可以测量HAC-GV3(SIRP-γ变体GV3与PD-1变体HAC的融合物)对人PD-L1的结合亲和力和动力学。例如,如图3A所示,将不同浓度的HAC-GV3融合蛋白(包括100pM、316pM、1nM、3.16nM、10nM和100nM)添加至与已知浓度的生物素化人PD-L1进行的结合反应。使用1:1 Langmuir结合模型计算的解离常数Kd为134pM。所计算的解离半衰期T1/2为约38分钟。图3B示出了与HAC-GV3结合的生物素化人PD-L1的图示。
实施例6:人CD47和人PD-L1被HAC-GV3同时结合的基于表面等离子体共振的测量
在基于表面等离子体共振的测量的另一实例中,通过将不同浓度的HGV3或HAC-GV3添加至已知浓度的生物素化人CD47中,测量了人CD47和人PD-L1被HAC-GV3同时结合的结合亲和力和动力学。如图4A所示,与单独的人GV3相比,融合蛋白HAC-GV3的结合曲线显示出了两个不同的峰——与生物素化CD47结合的第一峰和与PD-L1结合的第二峰。图4B示出了与HAC-GV3融合蛋白的GV3部分结合的生物素化人CD47的图示,其中HAC部分与PD-LA结合。
实施例7:CD47+细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3阻断的基于流式
细胞术的测量
使用上述基于细胞的CD47阻断测定,在CD47+细胞的存在下,将50nM生物素化SIRP-α四聚体与滴定浓度的GV3或HAC-GV3混合。图5示出了CD47+GFP-萤光素酶+DLD1-Tg细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3阻断的基于流式细胞术的测量。将作为SIRP-α结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
实施例8:CD47+PD-L1+细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3阻断的基
于流式细胞术的测量
在上述基于细胞的CD47阻断测定的另一实例中,使用流式细胞术来测量CD47+PD-L1+GFP-萤光素酶+DLD1-Tg细胞表面上的CD47/SIRP-α相互作用被GV3和HAC-GV3的阻断。如图6所示,在CD47+PD-L1+细胞的存在下,将50nM生物素化SIRP-α四聚体与滴定浓度的GV3或HAC-GV3混合。将作为SIRP-α结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
实施例9:PD-L1+细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3阻断的基于流式
细胞术的测量
在基于细胞的CD47阻断测定的另一实例中,使用流式细胞术来测量人PD-L1+酵母细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3的阻断。如图7所示,在hPD-L1+酵母细胞的存在下,将100nM生物素化PD-1四聚体与滴定浓度的HAC或HAC-GV3混合。将作为PD-1结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
实施例10:CD47+PD-L1+细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3阻断的基
于流式细胞术的测量
在基于细胞的CD47阻断测定的另一实例中,使用流式细胞术来测量人CD47+PD-L1+GFP-萤光素酶+DLD1-Tg细胞表面上的PD-1/PD-L1相互作用被HAC和HAC-GV3的阻断。如图8所示,在CD47+PD-L1+细胞的存在下,将100nM生物素化PD-1四聚体与滴定浓度的HAC或HAC-GV3混合。将作为PD-1结合的读出的荧光强度中值百分比(%MFT)相对于浓度(M)对数作图。
实施例11:基于FACS的吞噬作用测量表明GV3微体和HAC-GV3在广泛的调理性抗体浓度
下增强吞噬作用
图9示出了来源于供体的人巨噬细胞对人结肠癌细胞系DLD1的吞噬作用的基于FACS的测量,表明GV3微体和HAC-GV3在广泛的调理性抗体浓度下增强吞噬作用。通过将100,000个靶细胞与50,000个巨噬细胞在超低附着96孔U型底板(Corning)中的未添加抗生素或血清的IMDM+GlutaMax(Life Technologies)中共同培养两小时来进行吞噬作用的评估。通过采用CD14+全血分离试剂盒(Miltenyi)对原代人单核细胞进行基于磁珠的纯化,随后与人血清(Gemini)培养7天而生成巨噬细胞;在第7天,使用TrypLE Express(LifeTechnologies)从板上收获这些细胞。根据制造商的指示,用钙黄绿素AM红/橙细胞染色剂(Life Technologies)来标记巨噬细胞。将靶细胞工程化成稳定表达绿色荧光蛋白。以10nM的饱和浓度向反应孔添加二聚化微体形式的HGV3(GV3mb)或HAC-GV3融合蛋白,同时在三个对数浓度下滴定调理性抗体西妥昔单抗。误差条表示重复实验的标准偏差。反应在装有高通量自动进样器(BD Biosciences)的LSRFortessa分析仪上进行。吞噬作用以如采用FlowJo v.9.4.10(Tree Star)分析的、表示为GFP+巨噬细胞占总巨噬细胞的百分比来评价,并如图例中所示进行归一化。
实施例12:HAC-GV3和GV3的占据和持久性
用于确定HAC-GV3和GV3的占据和持久性的实验总结在图10中。为测试HAC-GV3和GV3的占据和持久性,在第0天向NSG小鼠注射B16-F0(皮下),以及未修饰HL60和HL60-Tg(hPDL1,GFP)的混合物(静脉内)。在第11、12和13天,向小鼠注射PBS、GV3或HAC-GV3。在最后注射后的1小时或24小时,从处死的小鼠收获脾脏或肿瘤,并在不使用酶消化的情况下在冰上将细胞解离成单细胞悬浮液。使用FACS来分析SIRPA-四聚体与小鼠脾细胞、小鼠实体瘤细胞(B16F0)或人肿瘤细胞(HL60-Tg(hPDL1,GFP))的结合。
HAC-GV3和GV3的占据和持久性在图11A-11D中示出。据显示,在1小时和24小时,与GV3和PBS对照相比,HAC-GV3在总脾细胞中具有增加的占据和持久性(图11A)。据显示,在1小时和24小时,与GV3和PBS对照相比,HAC-GV3在小鼠脾细胞中具有增加的占据和持久性(图11B)。据观察,在1小时和24小时,与GV3和PBS对照相比,HAC-GV3在从脾脏分离的人细胞中具有增加的占据和持久性(图11C)。据显示,在1小时和24小时,与GV3和PBS对照相比,HAC-GV3在从肿瘤分离的B16-F0黑素瘤细胞中具有增加的占据(图11D)。
实施例13:用于测试诱饵型多肽治疗B细胞淋巴瘤的效果的临床试验
这是一项前瞻性开放标签、带对照、随机化研究,用于检测诱饵型多肽用于治疗IIIB或IV期B细胞淋巴瘤患者的安全性和有效性。为了符合条件,进入该试验的患者应在一线治疗(单独化疗,或化疗和放疗)后已表现出稳定的疾病或临床反应并且具有0、1或2的ECOG表现状态。在3周的清除期之后,患者将按疾病状态进行分层,并随机分配至单独的抗-CD20抗体(例如,利妥昔单抗)或抗-CD20抗体加诱饵多肽。
在第0、1、2、3、4、5、6和7周施用10mg/kg诱饵型多肽的八周皮下治疗。所有患者都在第0周额外用375mg/m2抗-CD20治疗,并在第1、2、3、4、5、6和7周用500mg/m2抗-CD20治疗。
主要结果指标是记录诱饵型多肽的安全性特征,以及两个试验分组中患者存活率的比较。次要结果指标在于测量由诱饵型多肽引起的吞噬作用的激活,并且评价经历免疫疗法的患者的生活质量。
实施例14:用于测试晚期实体瘤患者中诱饵型多肽的最大耐受剂量和/或推荐剂量的
临床试验
这是开放标签、I期剂量递增研究,用于评价在患有经先前治疗的3期或4期实体瘤(包括但不限于:乳腺癌、非小细胞肺癌、卵巢癌、结直肠癌、胃癌、前列腺癌、胰腺癌和肾细胞癌)的患者中重复剂量接种诱饵型多肽的安全性和免疫原性。
第1部分评价了在8周内每隔一周(Q2W)皮下施用一次(总共4个剂量)或8周内每周(QW)皮下施用一次(总共8个剂量)的剂量水平递增的诱饵型多肽,并且使用3+3剂量递增设计来鉴别每个给药时间表的最大耐受剂量(MTD)和/或推荐剂量(RD),以供在该研究的第2部分中进一步评价。第2部分在各有15名患者的队列中评价了在Q2W和QW MTD/RD下经8周施用的实施例1的诱饵型多肽的安全性、免疫原性和潜在的抗肿瘤活性。在8周的施用期后,评价了患者直到第20周的安全性、免疫应答和肿瘤反应。
研究群体包括具有经先前治疗的3期或4期实体瘤的患者。
入选标准:
·同意时年龄18-70岁
·在研究者看来,预期寿命至少6个月
·患有组织学确认的乳腺癌、非小细胞肺癌、卵巢癌、结直肠癌、胃癌、前列腺癌、胰腺癌或肾细胞癌或其他肿瘤类型
·在针对局部进展或转移性疾病进行至少一个疗程的全身性疗法(包括化疗、靶向疗法或免疫疗法)后,有持续性、复发性或进行性疾病的证据
·临床3期或4期疾病
·ECOG为0或1
·足够的血液学、肾功能和肝功能参数
排除标准:
·在研究药物给药的4周内接受过任何全身化疗、放疗或实验药物的治疗
·具有需要长期类固醇或免疫抑制疗法的任何先前存在的医学病况
·HIV,乙型肝炎或丙型肝炎阳性
给药模式:按照队列分配(cohort assignment),从第1天开始,皮下施用诱饵型多肽。所有患者都在四个单独的注射部位(在手臂或大腿的右上方,手臂或大腿的左上方,以及腹部的右下方和左下方各注射一次)接受作为四次单独注射而施用的诱饵型多肽的剂量。起始剂量为0.01mg/kg诱饵型多肽。采用剂量加倍设计来选择剂量水平。当MTD小于1000mg/kg时,考虑中等剂量水平750mg/kg。
在八周施用的第2部分评价和评估中,措施(measures)包括测量吞噬作用的活性。如RECIST或Immune RECIST 1.1所定义地评估肿瘤反应。
虽然本文已经示出并描述了本发明的优选实施方案,但对于本领域技术人员而言显而易见的是,这样的实施方案仅作为示例提供。在不偏离本发明的情况下,本领域技术人员现将想到许多变化、改变和替换。应理解,可使用本文描述的本发明实施方案的各种替代方案来实施本发明。旨在用以下权利要求来限定本发明的范围,并且由此涵盖这些权利要求范围内的方法和结构及其等同物。
序列表
<110> 起源生物医药公司
<120> SIRP多肽组合物和使用方法
<130> 47815-701.601
<140>
<141>
<150> 62/266,450
<151> 2015-12-11
<150> 62/163,282
<151> 2015-05-18
<160> 46
<170> PatentIn版本3.5
<210> 1
<211> 119
<212> PRT
<213> 未知序列
<220>
<223> 对未知序列的描述
野生型多肽
<400> 1
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asn Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 2
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<220>
<221> MOD_RES
<222> (6)..(6)
<223> Met、Ile、Leu或Phe
<220>
<221> MOD_RES
<222> (27)..(27)
<223> Phe、Ile、Leu或Val
<220>
<221> MOD_RES
<222> (30)..(30)
<223> Leu、Ile、Val、His、Asn或Asp
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Phe、Ile、Leu或Val
<220>
<221> MOD_RES
<222> (33)..(33)
<223> Val、Ile、Leu、Pro、Thr或Ala
<220>
<221> MOD_RES
<222> (36)..(36)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (37)..(37)
<223> Leu或Gln
<220>
<221> MOD_RES
<222> (42)..(42)
<223> Val或Ala
<220>
<221> MOD_RES
<222> (47)..(47)
<223> Glu或Val
<220>
<221> MOD_RES
<222> (52)..(52)
<223> Gln、Pro、Leu、Val、Ala或Glu
<220>
<221> MOD_RES
<222> (53)..(53)
<223> Lys或Arg
<220>
<221> MOD_RES
<222> (54)..(54)
<223> Glu、Asp、Lys、Asn、Gln或His
<220>
<221> MOD_RES
<222> (56)..(56)
<223> His、Pro或Arg
<220>
<221> MOD_RES
<222> (66)..(66)
<223> Leu、Ile、Val、Pro、Thr、Ala、Arg、Ser或Gly
<220>
<221> MOD_RES
<222> (67)..(67)
<223> Thr、Ile、Asn、Phe、Ser、Tyr、Val、Ala或Asp
<220>
<221> MOD_RES
<222> (92)..(92)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (98)..(98)
<223> Ser、Arg、Asn、Lys、Thr、Ile或Met
<220>
<221> MOD_RES
<222> (101)..(101)
<223> Asn、Lys、Asp、Glu、His或Gln
<400> 2
Glu Glu Glu Leu Gln Xaa Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Xaa Thr Ser Xaa Xaa Pro
20 25 30
Xaa Gly Pro Xaa Xaa Trp Phe Arg Gly Xaa Gly Pro Gly Arg Xaa Leu
35 40 45
Ile Tyr Asn Xaa Xaa Xaa Gly Xaa Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Xaa Xaa Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Xaa Lys Phe Arg Lys
85 90 95
Gly Xaa Pro Glu Xaa Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 3
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 3
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asn Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 4
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 4
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 5
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 5
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 6
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 6
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 7
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 7
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 8
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 8
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser His Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 9
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 9
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 10
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 10
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 11
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 11
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Ala Arg Glu Gly Arg Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 12
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 12
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 13
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 13
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Glu Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 14
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 14
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 15
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<220>
<221> MOD_RES
<222> (111)..(111)
<223> 任何氨基酸
<400> 15
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Xaa Trp
100 105 110
His
<210> 16
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 16
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 17
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 17
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 18
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 18
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Leu Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Ile Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Asn Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 19
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 19
Glu Glu Glu Leu Gln Leu Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Pro Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 20
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 20
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 21
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 21
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Ile Gly Pro Ile Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 22
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 22
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 23
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 23
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ile Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 24
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<220>
<221> MOD_RES
<222> (115)..(115)
<223> 任何氨基酸
<400> 24
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Thr Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Xaa Ala Lys Pro Ser
115
<210> 25
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 25
Glu Asp Glu Leu Gln Val Ile Gln Pro Glu Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu Arg Cys Ala Met Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Met Trp Phe Arg Gly Ala Gly Ala Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Leu Thr Lys Arg Asn Asn Leu Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 26
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 26
Glu Asp Glu Leu Gln Ile Ile Gln Pro Glu Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu Arg Cys Ala Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Ala Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Thr Thr Lys Arg Asn Asn Leu Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 27
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 27
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Ile Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp His Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 28
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 28
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Ile Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 29
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
肽
<400> 29
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 30
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 30
Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe Ser Pro Ala Leu
1 5 10 15
Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe Thr Cys Ser Phe Ser
20 25 30
Asn Thr Ser Glu Ser Phe His Val Val Trp His Arg Glu Ser Pro Ser
35 40 45
Gly Gln Thr Asp Thr Leu Ala Ala Phe Pro Glu Asp Arg Ser Gln Pro
50 55 60
Gly Gln Asp Ala Arg Phe Arg Val Thr Gln Leu Pro Asn Gly Arg Asp
65 70 75 80
Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp Ser Gly Thr Tyr
85 90 95
Val Cys Gly Val Ile Ser Leu Ala Pro Lys Ile Gln Ile Lys Glu Ser
100 105 110
Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu
130 135 140
Leu Leu Val Thr Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr
145 150 155 160
Ser Leu Phe Pro Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro
165 170 175
Gly Arg Val Leu Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val
180 185 190
Thr Thr Val Ser Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile
195 200 205
Arg Ile Ser Ser Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val
210 215 220
Lys Phe Arg Lys Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro
225 230 235 240
Gly Thr Glu Met Ala Leu Gly Ala Lys Pro Ser
245 250
<210> 31
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 31
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Trp Asn Ile His Gly Lys Glu Ser Cys Asp Val Gln Leu Tyr Ile
130 135 140
Lys Arg Gln Ser Glu His Ser Ile Leu Ala Gly Asp Pro Phe Glu Leu
145 150 155 160
Glu Cys Pro Val Lys Tyr Cys Ala Asn Arg Pro His Val Thr Trp Cys
165 170 175
Lys Leu Asn Gly Thr Thr Cys Val Lys Leu Glu Asp Arg Gln Thr Ser
180 185 190
Trp Lys Glu Glu Lys Asn Ile Ser Phe Phe Ile Leu His Phe Glu Pro
195 200 205
Val Leu Pro Asn Asp Asn Gly Ser Tyr Arg Cys Ser Ala Asn Phe Gln
210 215 220
Ser Asn Leu Ile Glu Ser His Ser Thr Thr Leu Tyr Val Thr Asp Val
225 230 235 240
Lys
<210> 32
<211> 291
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 32
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Glu Leu Asn Gly Cys Ala Asn Pro Leu Gly Leu Lys Asn Asn Ser
130 135 140
Ile Pro Asp Lys Gln Ile Thr Ala Ser Ser Ser Tyr Lys Thr Trp Gly
145 150 155 160
Leu His Leu Phe Ser Trp Asn Pro Ser Tyr Ala Arg Leu Asp Lys Gln
165 170 175
Gly Asn Phe Asn Ala Trp Val Ala Gly Ser Tyr Gly Asn Asp Gln Trp
180 185 190
Leu Gln Val Asp Leu Gly Ser Ser Lys Glu Val Thr Gly Ile Ile Thr
195 200 205
Gln Gly Ala Arg Asn Phe Gly Ser Val Gln Phe Val Ala Ser Tyr Lys
210 215 220
Val Ala Tyr Ser Asn Asp Ser Ala Asn Trp Thr Glu Tyr Gln Asp Pro
225 230 235 240
Arg Thr Gly Ser Ser Lys Ile Phe Pro Gly Asn Trp Asp Asn His Ser
245 250 255
His Lys Lys Asn Leu Phe Glu Thr Pro Ile Leu Ala Arg Tyr Val Arg
260 265 270
Ile Leu Pro Val Ala Trp His Asn Arg Ile Ala Leu Arg Leu Glu Leu
275 280 285
Leu Gly Cys
290
<210> 33
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 33
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Val Ala Gly Ser Val Lys Val Gly Gly Glu Ala Gly Pro Ser Val
130 135 140
Thr Leu Pro Cys His Tyr Ser Gly Ala Val Thr Ser Met Cys Trp Asn
145 150 155 160
Arg Gly Ser Cys Ser Leu Phe Thr Cys Gln Asn Gly Ile Val Trp Thr
165 170 175
Asn Gly Thr His Val Thr Tyr Arg Lys Asp Thr Arg Tyr Lys Leu Leu
180 185 190
Gly Asp Leu Ser Arg Arg Asp Val Ser Leu Thr Ile Glu Asn Thr Ala
195 200 205
Val Ser Asp Ser Gly Val Tyr Cys Cys Arg Val Glu His Arg Gly Trp
210 215 220
Phe Asn Asp Met Lys Ile Thr Val Ser Leu Glu Ile Val Pro Pro Lys
225 230 235 240
Val Thr Thr
<210> 34
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 34
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln Asn Ala Tyr Leu
130 135 140
Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu Val Pro Val Cys
145 150 155 160
Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly Asn Val Val Leu
165 170 175
Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser Arg Tyr Trp Leu
180 185 190
Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr Ile Glu Asn Val
195 200 205
Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile Gln Ile Pro Gly
210 215 220
Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val Ile Lys Pro Ala
225 230 235 240
Lys Val Thr Pro Ala
245
<210> 35
<211> 263
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 35
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Thr Ser Glu Thr Val Val Thr Glu Val Leu Gly His Arg Val Thr
130 135 140
Leu Pro Cys Leu Tyr Ser Ser Trp Ser His Asn Ser Asn Ser Met Cys
145 150 155 160
Trp Gly Lys Asp Gln Cys Pro Tyr Ser Gly Cys Lys Glu Ala Leu Ile
165 170 175
Arg Thr Asp Gly Met Arg Val Thr Ser Arg Lys Ser Ala Lys Tyr Arg
180 185 190
Leu Gln Gly Thr Ile Pro Arg Gly Asp Val Ser Leu Thr Ile Leu Asn
195 200 205
Pro Ser Glu Ser Asp Ser Gly Val Tyr Cys Cys Arg Ile Glu Val Pro
210 215 220
Gly Trp Phe Asn Asp Val Lys Ile Asn Val Arg Leu Asn Leu Gln Arg
225 230 235 240
Ala Ser Thr Thr Thr Asp Glu Lys Phe Asn Leu Lys Leu Val Ile Lys
245 250 255
Pro Ala Lys Val Thr Pro Ala
260
<210> 36
<211> 275
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 36
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser Glu Ala
130 135 140
Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly Tyr Tyr
145 150 155 160
Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln Leu Thr
165 170 175
Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr Phe Cys
180 185 190
Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser Leu Cys
195 200 205
Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala Ala Asn
210 215 220
Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His Leu Gly
225 230 235 240
Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn Val Thr
245 250 255
Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe Gly Leu
260 265 270
Leu Lys Leu
275
<210> 37
<211> 296
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 37
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Asp Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln
130 135 140
Leu Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr
145 150 155 160
Ser Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr
165 170 175
Lys Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr
180 185 190
Val Phe Phe Gln Met Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser
195 200 205
Gly Ser Val Ser Leu Ala Leu His Leu Met Pro Leu Arg Ser Ala Ala
210 215 220
Gly Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser
225 230 235 240
Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu
245 250 255
Ser Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala
260 265 270
Arg His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe
275 280 285
Arg Val Thr Pro Glu Ile Pro Ala
290 295
<210> 38
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 38
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr
260
<210> 39
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 39
Glu Glu Glu Leu Gln Ile Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Val Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Lys Asp Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Gly Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr
260
<210> 40
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
8xHis标签
<400> 40
His His His His His His His His
1 5
<210> 41
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
肽
<400> 41
Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu
1 5 10 15
<210> 42
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<400> 42
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asn Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 43
<211> 119
<212> PRT
<213> 未知序列
<220>
<223> 对未知序列的描述
野生型多肽
<400> 43
Glu Asp Glu Leu Gln Val Ile Gln Pro Glu Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu Arg Cys Ala Met Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Met Trp Phe Arg Gly Ala Gly Ala Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Leu Thr Lys Arg Asn Asn Leu Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 44
<211> 119
<212> PRT
<213> 未知序列
<220>
<223> 对未知序列的描述
野生型多肽
<400> 44
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Ile Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp His Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 45
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<220>
<221> MOD_RES
<222> (6)..(6)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (27)..(27)
<223> Met或Ile
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Ile或Phe
<220>
<221> MOD_RES
<222> (37)..(37)
<223> Met或Gln
<220>
<221> MOD_RES
<222> (47)..(47)
<223> Glu或Val
<220>
<221> MOD_RES
<222> (53)..(53)
<223> Lys或Arg
<220>
<221> MOD_RES
<222> (54)..(54)
<223> Glu或Gln
<220>
<221> MOD_RES
<222> (56)..(56)
<223> His或Pro
<220>
<221> MOD_RES
<222> (66)..(66)
<223> Leu或Thr
<220>
<221> MOD_RES
<222> (92)..(92)
<223> Val或Ile
<400> 45
Glu Asp Glu Leu Gln Xaa Ile Gln Pro Glu Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu Arg Cys Ala Xaa Thr Ser Leu Xaa Pro
20 25 30
Val Gly Pro Ile Xaa Trp Phe Arg Gly Ala Gly Ala Gly Arg Xaa Leu
35 40 45
Ile Tyr Asn Gln Xaa Xaa Gly Xaa Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Xaa Thr Lys Arg Asn Asn Leu Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Xaa Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
<210> 46
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 对人工序列的描述:合成的
多肽
<220>
<221> MOD_RES
<222> (6)..(6)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (27)..(27)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (31)..(31)
<223> Ile或Phe
<220>
<221> MOD_RES
<222> (47)..(47)
<223> Glu或Val
<220>
<221> MOD_RES
<222> (53)..(53)
<223> Lys或Arg
<220>
<221> MOD_RES
<222> (54)..(54)
<223> Glu或Gln
<220>
<221> MOD_RES
<222> (56)..(56)
<223> His或Pro
<220>
<221> MOD_RES
<222> (66)..(66)
<223> Leu或Thr
<220>
<221> MOD_RES
<222> (92)..(92)
<223> Val或Ile
<220>
<221> MOD_RES
<222> (101)..(101)
<223> His或Asp
<400> 46
Glu Glu Glu Leu Gln Xaa Ile Gln Pro Asp Lys Ser Ile Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Thr Leu His Cys Thr Xaa Thr Ser Leu Xaa Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Xaa Leu
35 40 45
Ile Tyr Asn Gln Xaa Xaa Gly Xaa Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Xaa Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Xaa Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Xaa Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser
115
Claims (104)
1.一种诱饵型多肽,其包括SIRP-γ、SIRP-β或SIRP-β2多肽,其中该多肽包含至少一个氨基酸修饰以使诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽与CD47结合的亲和力相比于相应的野生型SIRP-γ、SIRP-β或SIRP-β2多肽对CD47的亲和力增加。
2.如权利要求1所述的诱饵型多肽,其中所述多肽包括具有以下序列的SIRP-γ多肽:EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:1)。
3.如权利要求1或权利要求2所述的诱饵型多肽,其中所述SIRP-γ多肽与野生型SIRP-γ多肽90%相同。
4.如权利要求1至3中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在M6、V27、L30、L31、V33、V36、L37、V42、E47、Q52、K53、E54、H56、L66、T67、V92、S98或N101处具有氨基酸置换。
5.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在M6处具有置换,其中该置换为I、L或F。
6.如权利要求1至5中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在V27处具有置换,其中该置换为F、I或L。
7.如权利要求1至6中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在L30处具有置换,其中该置换为I、V、H、N或D。
8.如权利要求1至7中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在L31处具有置换,其中该置换为F、I或V。
9.如权利要求1至8中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在V33处具有置换,其中该置换为I、L、P、T或A。
10.如权利要求1至9中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在V36处具有置换,其中该置换为I。
11.如权利要求1至10中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在L37处具有置换,其中该置换为Q。
12.如权利要求1至11中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在V42处具有置换,其中该置换为A。
13.如权利要求1至12中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在E47处具有置换,其中该置换为V。
14.如权利要求1至13中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在Q52处具有置换,其中该置换为P、L、V、A或E。
15.如权利要求1至14中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在K53处具有置换,其中该置换为R。
16.如权利要求1至15中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在E54处具有置换,其中该置换为D、K、N、Q或H。
17.如权利要求1至16中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在H56处具有置换,其中该置换为P或R。
18.如权利要求1至17中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在L66处具有置换,其中该置换为I、V、P、T、A、R、S或G。
19.如权利要求1至18中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在T67处具有置换,其中该置换为I、N、F、S、Y、V、A或D。
20.如权利要求1至19中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在V92处具有置换,其中该置换为I。
21.如权利要求1至20中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在S98处具有置换,其中该置换为R、N、K、T、I或M。
22.如权利要求1至21中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽在N101处被置换,其中该置换为K、D、E、H或Q。
23.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQX1IQPEKLLLVTVGKTATLHCTX2TSX3X4PX5GPX6X7WFRGX8GPGRX9LIYNX10X11X12GX13FPRVTTVSDX14X15KRNNMDFSIRISSITPADVGTYYCX16KFRKGX17PEX18VEFKSGPGTEMALGAKPS(SEQ ID NO:2),其中X1为M、I、L或F;X2为F、I、L或V;X3为L、I、V、H、N或D;X4为F、I、L或V;X5为V、I、L、P、T或A;X6为V或I;X7为L或Q;X8为V或A;X9为E或V;X10为Q、P、L、V、A或E;X11为K或R;X12为E、D、K、N、Q或H;X13为H、P或R;X14为L、I、V、P、T、A、R、S或G;X15为T、I、N、F、S、Y、V、A或D;X16为V或I;X17为S、R、N、K、T、I或M;并且X18为N、K、D、E、H或Q。
24.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3)。
25.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:4)。
26.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:5)。
27.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:6)。
28.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:7)。
29.如权利要求1所述的诱饵型多肽,其中所述多肽包括具有以下序列的SIRP-β多肽:EDELQVIQPEKSVSVAAGESATLRCAMTSLIPVGPIMWFRGAGAGRELIYNQKEGHFPRVTTVSELTKRNNLDFSISISNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:25)。
30.如权利要求1或权利要求29所述的诱饵型多肽,其中所述SIRP-β多肽与野生型SIRP-β多肽至少90%相同。
31.如权利要求1或29至30中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在I6、I27、F31、Q37、V47、R53、Q54、P56、T66或I92处具有氨基酸置换。
32.如权利要求1或29至31中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在V6处具有置换,其中该置换为I。
33.如权利要求1或29至32中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在M27处具有置换,其中该置换为I。
34.如权利要求1或29至33中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在I31处具有置换,其中该置换为F。
35.如权利要求1或29至34中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在M37处具有置换,其中该置换为Q。
36.如权利要求1或29至35中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在E47处具有置换,其中该置换为V。
37.如权利要求1或29至36中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在K53处具有置换,其中该置换为R。
38.如权利要求1或29至37中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在E54处具有置换,其中该置换为Q。
39.如权利要求1或29至38中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在H56处具有置换,其中该置换为P。
40.如权利要求1或29至39中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在L66处具有置换,其中该置换为T。
41.如权利要求1或29至40中任一项所述的诱饵型多肽,其中所述SIRP-β多肽在V92处具有置换,其中该置换为I。
42.如权利要求1或29至41中任一项所述的诱饵型多肽,其中所述SIRP-β多肽具有序列EDELQIIQPEKSVSVAAGESATLRCAITSLFPVGPIQWFRGAGAGRVLIYNQRQGPFPRVTTVSETTKRNNLDFSISISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:26)。
43.如权利要求1所述的诱饵型多肽,其中所述多肽包括具有以下序列的SIRP-β2多肽:EEELQVIQPDKSISVAAGESATLHCTVTSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISNITPADAGTYYCVKFRKGSPDHVEFKSGAGTELSVRAKPS(SEQ ID NO:27)。
44.如权利要求1或权利要求43所述的诱饵型多肽,其中所述SIRP-β2多肽与野生型SIRP-β2多肽至少90%相同。
45.如权利要求1或43至44中任一项所述的诱饵型多肽,其中所述SIRP-β2多肽在I6、I27、F31、V47、R53、Q54、P56、T66、I92或D101处具有氨基酸置换。
46.如权利要求1或43至45中任一项所述的诱饵型多肽,所述SIRP-β2多肽在V6处被置换,其中该置换为I。
47.如权利要求1或43至46中任一项所述的诱饵型多肽,所述SIRP-β2多肽在V27处被置换,其中该置换为I。
48.如权利要求1或43至47中任一项所述的诱饵型多肽,所述SIRP-β2多肽在I31处被置换,其中该置换为F。
49.如权利要求1或43至48中任一项所述的诱饵型多肽,所述SIRP-β2多肽在E47处被置换,其中该置换为V。
50.如权利要求1或43至49中任一项所述的诱饵型多肽,所述SIRP-β2多肽在K53处被置换,其中该置换为R。
51.如权利要求1或43至50中任一项所述的诱饵型多肽,所述SIRP-β2多肽在E54处被置换,其中该置换为Q。
52.如权利要求1或43至51中任一项所述的诱饵型多肽,所述SIRP-β2多肽在H56处被置换,其中该置换为P。
53.如权利要求1或43至52中任一项所述的诱饵型多肽,所述SIRP-β2多肽在L66处被置换,其中该置换为T。
54.如权利要求1或43至53中任一项所述的诱饵型多肽,所述SIRP-β2多肽在V92处被置换,其中该置换为I。
55.如权利要求1或43至54中任一项所述的诱饵型多肽,所述SIRP-β2多肽在H101处被置换,其中该置换为D。
56.如权利要求1或43至55中任一项所述的诱饵型多肽,其中所述SIRP-β2多肽具有序列EEELQIIQPDKSISVAAGESATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:28)。
57.如权利要求1至56中任一项所述的诱饵型多肽,其中所述诱饵型多肽阻断CD47与配体的结合。
58.如权利要求57所述的诱饵型多肽,其中所述配体为SIRP-α、SIRP-γ或血小板反应蛋白-1。
59.如权利要求1至58中任一项所述的诱饵型多肽,其中所述诱饵型多肽能与细胞结合。
60.如权利要求59所述的细胞,其中所述细胞为肿瘤细胞、病毒感染的细胞、细菌感染的细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
61.如权利要求1至60中任一项所述的诱饵型多肽,其中所述诱饵型多肽能实现对以下细胞的吞噬作用或ADCC:肿瘤细胞、病毒感染的细胞、细菌感染的细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
62.如权利要求1至61中任一项所述的诱饵型多肽,其中所述多肽与免疫球蛋白Fc序列融合。
63.如权利要求1至62中任一项所述的诱饵型多肽,其中所述SIRP-γ、SIRP-β或SIRP-β2多肽是多聚体的。
64.如权利要求1至62中任一项所述的诱饵型多肽,其中所述SIRP-γ、SIRP-β或SIRP-β2多肽是单体的。
65.如权利要求1至64中任一项所述的诱饵型多肽,其中所述多肽进一步包含可检测标记物。
66.如权利要求1至64中任一项所述的诱饵型多肽,其中所述多肽具有增加的占据。
67.如权利要求1至66中任一项所述的诱饵型多肽,其中所述多肽具有提高的持久性。
68.一种组合物,其包含如权利要求1至67中任一项所述的诱饵型多肽和药学上可接受的载体或赋形剂。
69.如权利要求68所述的组合物,其进一步包含额外的药物。
70.如权利要求69所述的组合物,其中所述药物包括化疗剂、激酶抑制剂、蛋白酶体抑制剂,或病毒DNA或RNA聚合酶抑制剂中的一种或多种。
71.如权利要求68至70中任一项所述的组合物,其进一步包含单克隆抗体。
72.如权利要求71所述的组合物,其中所述单克隆抗体能结合癌细胞、免疫细胞、病原体感染的细胞或造血干细胞上的抗原。
73.如权利要求72所述的组合物,其中癌细胞上的所述抗原包括EGFR、Her2/neu、CD19、CD20、CD22、CD25、CD30、CD33、CD38、CD45、CD47、CD56、CD70、CD117或EpCAM。
74.如权利要求72所述的组合物,其中免疫细胞上的所述抗原包括M1prime、CD2、CD3、CD4、CD5、CD8、CD19、CD20、CD22、CD25、CD38、CD56、PD-1、PD-L1、CTLA4、BTLA、TIM3、LAG3、OX40、GITR或CD137(4-1BB)。
75.如权利要求72所述的组合物,其中病原体感染的细胞上的所述抗原包括:包括UL18、UL11、pp65、gB和pp150在内的CMV蛋白,包括Gp41、Gp120、V1V2聚糖和V3聚糖在内的HIV包膜蛋白,和流感血凝素。
76.如权利要求72所述的组合物,其中造血干细胞上的所述抗原包括CD11、CD45、CD117或Sca1。
77.一种编码如权利要求1至67中任一项所述的诱饵型多肽的分离的核酸。
78.一种表达如权利要求1至67中任一项所述的诱饵型多肽的细胞。
79.一种调节对表达CD47的细胞的吞噬作用或ADCC的方法,所述方法包括使所述细胞与如权利要求1至67所述的诱饵型多肽或如权利要求68至76所述的组合物接触。
80.一种治疗有需要的受试者的方法,其包括施用有效量的如权利要求1至67中任一项所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或如权利要求68至76所述的组合物。
81.如权利要求80所述的方法,其中所述受试者患有癌症、贫血、病毒感染、细菌感染、自身免疫疾病、哮喘、变态反应、移植排斥、动脉粥样硬化或纤维化。
82.如权利要求1至67中任一项所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或如权利要求68至76中任一项所述的组合物,其用于治疗癌症、病毒感染、细菌感染、自身免疫疾病、哮喘、变态反应、移植排斥、动脉粥样硬化或纤维化。
83.如权利要求1至67中任一项所述的诱饵型SIRP-γ、SIRP-β或SIRP-β2多肽或如权利要求68至76中任一项所述的组合物,其用于预处理造血干细胞移植物。
84.一种使表达CD47的细胞可视化的方法,所述方法包括使细胞群体与如权利要求1至67中任一项所述的诱饵型多肽和可检测标记物接触。
85.如权利要求84所述的方法,其中所述细胞为肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T细胞或B细胞、损伤的红细胞、动脉斑块细胞、纤维化组织细胞、健康的正常细胞如造血干细胞、健康的髓样或淋巴样前体细胞,或健康的分化的造血细胞类型,如T细胞、B细胞、浆细胞或NK细胞。
86.如权利要求84或权利要求85所述的方法,其中所述接触在体内进行。
87.如权利要求84或权利要求85所述的方法,其中所述接触在体外进行。
88.表达CD47的细胞的纯化方法,所述方法包括使细胞群体与如权利要求1至67中任一项所述的诱饵型多肽和可检测标记物接触,以及将与该可检测标记物结合的细胞纯化。
89.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13)。
90.如权利要求1至4中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽具有以下序列中的一种:
EEELQIIQPEKLLLVTVGKTATLHCTITSHFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:8);
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:9);
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:10);
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRELIYNAREGRFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:11);
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRIGNITPADAGTYYCIKFRKGSPDDVEFKSGAGTELSVRAKPS(SEQ ID NO:12);
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPVLWFRGVGPGRVLIYNQRQGPFPRVTTVSDTTKRNNMDFSIRISSITPADVGTYYCIKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:3);
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQREGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:13);
EEELQMIQPEKLLLVTVGKTATLHCTVTSLLPVGPVLWFRGVGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPENVEFKSGPGTEMALGAKPS(SEQ ID NO:42);
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:14);
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTXWH(SEQ ID NO:15),其中X为A、R、N、D、C、Q、E、G、H、I、L、K、M、F、P、S、T、W、Y或V;
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:16);
EEELQIIQPEKLLLVTVGKTATLHCTITSLLPVGPIQWFRGVGPGRELIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGTPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:17);
EEELQIIQPEKLLLVTVGKTATLHCTLTSLLPVGPILWFRGVGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGNPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:18);
EEELQLIQPEKLLLVTVGKTATLHCTITSLFPPGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:19);
EEELQIIQPEKLLLVTVGKTATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:20);
EEELQIIQPEKLLLVTVGKTATLHCTITSLFPIGPILWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:21);
EEELQMIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGAGPGRVLIYNQRDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:22);
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGIPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:23);以及
EEELQIIQPDKSVLVAAGETATLRCTITSLFPVGPIQWFRGAGPGRVLIYNQKDGPFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCIKFRKGTPEDVEFKSGPGTEMALXAKPS(SEQ ID NO:24)。
91.如权利要求1至67中任一项所述的诱饵型多肽,其中所述SIRP-γ多肽为融合多肽或嵌合多肽,并且其中所述SIRP-γ多肽通过连接体序列与包含免疫检查点抑制剂、共刺激分子或细胞因子的多肽序列融合。
92.如权利要求91所述的诱饵型多肽,其中所述连接体序列包含Gly和Ser。
93.如权利要求91所述的诱饵型多肽,其中所述连接体序列包含GGGGSGGGGS(SEQ IDNO:29)。
94.如权利要求91所述的诱饵型多肽,其中所述SIRP-γ多肽位于包含免疫检查点抑制剂、共刺激分子、细胞因子或减毒细胞因子的多肽序列的N-末端或C-末端。
95.如权利要求91所述的诱饵型多肽,其中所述免疫检查点抑制剂多肽具有PD-1或PD-L1拮抗剂、BTLA或CD160拮抗剂,或磷脂酰丝氨酸拮抗剂例如MFGE8、TIM1、TIM3或TIM4的序列。
96.如权利要求91所述的诱饵型多肽,其中所述共刺激分子多肽具有CD40激动剂、41BBL或CD137激动剂的序列。
97.如权利要求91所述的诱饵型多肽,其中所述细胞因子多肽具有IL2的序列。
98.如权利要求91所述的诱饵型多肽,其中所述细胞因子是减毒的。
99.如权利要求98所述的诱饵型多肽,其中所述IL2多肽序列含有突变D20T和F42A。
100.如权利要求91至95所述的诱饵型多肽,其中所述融合多肽或嵌合多肽具有序列DSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFHVVWHRESPSGQTDTLAAFPEDRSQPGQDARFRVTQLPNGRDFHMSVVRARRNDSGTYVCGVISLAPKIQIKESLRAELRVTERGGGGSGGGGSEEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPS(SEQ ID NO:30)。
101.如权利要求91至95所述的诱饵型多肽,其中所述融合多肽或嵌合多肽具有序列EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSWNIHGKESCDVQLYIKRQSEHSILAGDPFELECPVKYCANRPHVTWCKLNGTTCVKLEDRQTSWKEEKNISFFILHFEPVLPNDNGSYRCSANFQSNLIESHSTTLYVTDVK(SEQ ID NO:31)。
102.如权利要求91至95所述的诱饵型多肽,其中所述融合多肽或嵌合多肽具有以下序列中的一种:EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSELNGCANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGNDQWLQVDLGSSKEVTGIITQGARNFGSVQFVASYKVAYSNDSANWTEYQDPRTGSSKIFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC(SEQID NO:32);EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSVAGSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVPPKVTT(SEQ ID NO:33);EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPA(SEQ ID NO:34);或EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSTSETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKYRLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTDEKFNLKLVIKPAKVTPA(SEQ ID NO:35)。
103.如权利要求91至95或96所述的诱饵型多肽,其中所述融合多肽或嵌合多肽具有以下序列中的一种:EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL(SEQ ID NO:36);或EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQMELRRVVAGEGSGSVSLALHLMPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPA(SEQ ID NO:37)。
104.如权利要求91至95或97至99所述的诱饵型多肽,其中所述融合多肽或嵌合多肽具有以下序列中的一种:EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:38);或EEELQIIQPEKLLLVTVGKTATLHCTITSLFPVGPIQWFRGVGPGRVLIYNQKDGHFPRVTTVSDGTKRNNMDFSIRISSITPADVGTYYCVKFRKGSPEDVEFKSGPGTEMALGAKPSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLTLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:39)。
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110300766A (zh) * | 2017-03-15 | 2019-10-01 | 宜明昂科生物医药技术(上海)有限公司 | 新型重组双功能融合蛋白及其制备方法和用途 |
CN110300766B (zh) * | 2017-03-15 | 2022-04-12 | 宜明昂科生物医药技术(上海)有限公司 | 新型重组双功能融合蛋白及其制备方法和用途 |
CN109293778A (zh) * | 2018-11-01 | 2019-02-01 | 浙江蓝盾药业有限公司 | 同时抗cd70和cd47的重链抗体及其制备方法和应用 |
CN109293778B (zh) * | 2018-11-01 | 2021-09-17 | 浙江蓝盾药业有限公司 | 同时抗cd70和cd47的重链抗体及其制备方法和应用 |
WO2020177733A1 (zh) | 2019-03-06 | 2020-09-10 | 江苏恒瑞医药股份有限公司 | 双功能融合蛋白及其医药用途 |
CN112969719A (zh) * | 2019-03-06 | 2021-06-15 | 江苏恒瑞医药股份有限公司 | 双功能融合蛋白及其医药用途 |
WO2022048616A1 (zh) * | 2020-09-04 | 2022-03-10 | 江苏恒瑞医药股份有限公司 | SIRPγ变体及其融合蛋白 |
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US11407801B2 (en) | 2022-08-09 |
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CN114425077A (zh) | 2022-05-03 |
EP3298043B8 (en) | 2021-04-21 |
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JP2022036957A (ja) | 2022-03-08 |
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JP2018524282A (ja) | 2018-08-30 |
WO2016187226A1 (en) | 2016-11-24 |
EP3298043A4 (en) | 2018-12-19 |
PT3298043T (pt) | 2021-03-08 |
EP3872086A1 (en) | 2021-09-01 |
US20180155405A1 (en) | 2018-06-07 |
ES2857109T3 (es) | 2021-09-28 |
US20160340397A1 (en) | 2016-11-24 |
EP3298043A1 (en) | 2018-03-28 |
HK1252870A1 (zh) | 2019-06-06 |
CA2994935A1 (en) | 2016-11-24 |
PL3298043T3 (pl) | 2021-07-19 |
EP3298043B1 (en) | 2020-12-30 |
CN107849143B (zh) | 2021-12-10 |
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