WO2021032116A1 - 一种免疫细胞因子及其制备与用途 - Google Patents
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Definitions
- Immunotherapy uses the body's immune system to attack or kill malignant tumor cells without affecting healthy tissues.
- the immune system has the ability to recognize and eliminate malignant tumor cells, but tumors have evolved a variety of mechanisms to evade immune surveillance. Therefore, the challenge of immunotherapy is to develop strategies that can effectively and safely enhance the body's anti-tumor immune response.
- the tumor immunotherapy strategies currently being and developed mainly include cytokine therapy, adoptive cell transfer, tumor vaccines, and monoclonal antibodies. Among them, it is particularly interesting to stimulate or activate the immune response of tumor-specific T cells or NK, and exert the killing effect of T cells or NK cells on tumors [The Potential and Promise of IL-15 in Immuno-Oncogenic Therapies].
- IL-15 superagonist The complex formed by IL-15 and IL-15Ra (IL-15 superagonist) further accelerates the pace of IL-15-based tumor immunotherapy.
- IL-15 superagonists Compared with monomeric IL-15, IL-15 superagonists have outstanding advantages: such as higher blood circulation concentration, longer half-life in vivo, and enhanced ability to stimulate NK and CD8 T cells.
- RLI such as Cytune's CYP0150
- intramolecular complexes formed by IL-15 and IL-15Ra (Such as Novartis' NIZ985, Altor's ALT-803, Xencor's XmAb24306).
- IL-15 superagonists can bias the expansion of pro-inflammatory (CD11b high CD27 high ) NK cell subsets in lymphoid organs.
- pro-inflammatory factors such as IFN ⁇ secreted by these cell subsets may cause such as body temperature. Underweight, weight loss, liver damage and other immunotoxic effects.
- IL-15 Interleukin-15
- Interleukin-15 receptor a subunit (B) Interleukin-15 receptor a subunit (IL-15Ra);
- the IL-15 is mammalian cell IL-15, preferably primate IL-15, more preferably human IL-15. In some embodiments, the IL-15 is wild-type IL-15 or an IL-15 derivative. In some embodiments, the IL-15 has a nucleic acid sequence as shown in SEQ ID NO: 71 and an amino acid sequence as shown in SEQ ID NO: 72; in some embodiments, the IL-15 has a nucleic acid sequence as shown in SEQ ID The nucleic acid sequence shown in NO: 111 and the amino acid sequence shown in SEQ ID NO: 112. In some other embodiments, the IL-15 has an amino acid sequence that is 85%-100% homologous to SEQ ID NO: 72 or SEQ ID NO: 112.
- the IL-15Ra is IL-15Ra. In some embodiments, the IL-15Ra is the Sushi domain of IL-15Ra. In some embodiments, the IL-15Ra is a variant or derivative of the IL-15RaSushi domain. In some embodiments, the IL-15Ra has the nucleic acid sequence shown in SEQ ID NO: 73 and the amino acid sequence shown in SEQ ID NO: 74. In some embodiments, the IL-15Ra has the nucleic acid sequence shown in SEQ ID NO: 87 or the amino acid sequence shown in SEQ ID NO: 88. In some other embodiments, the IL-15Ra has an amino acid sequence that is 85%-100% homologous to SEQ ID NO: 74 or SEQ ID NO: 88.
- the antibody targeting the immune monitoring point protein PD-1 has the heavy chain nucleic acid sequence shown in SEQ ID NO: 75 and the light chain nucleic acid sequence shown in SEQ ID NO: 77, or has The heavy chain amino acid sequence shown in SEQ ID NO: 76 and the light chain amino acid sequence shown in SEQ ID NO: 78.
- the immune monitoring point protein is PD-L1.
- the antibody targeting the immune monitoring point protein PD-L1 has the HCDR1, HCDR2, and HCDR3 sequence contained in the heavy chain amino acid sequence shown in SEQ ID NO: 36, and the sequence shown in SEQ ID NO: 38 The LCDR1, LCDR2, and LCDR3 sequences contained in the amino acid sequence of the light chain shown; or the HCDR1, HCDR2, and HCDR3 sequences contained in the amino acid sequence of the heavy chain shown in SEQ ID NO: 80, and such as SEQ ID NO: 82 The LCDR1, LCDR2 and LCDR3 sequences contained in the light chain amino acid sequence shown.
- the antibody targeting the immune monitoring point protein PD-L1 has a heavy chain nucleic acid sequence as shown in SEQ ID NO: 79 and a light chain nucleic acid sequence as shown in SEQ ID NO: 81, and has a nucleic acid sequence as shown in SEQ ID NO: 81.
- the tumor surface antigen is EGFR.
- the antibody targeting the tumor surface antigen EGFR has the HCDR1, HCDR2 and HCDR3 sequences contained in the heavy chain amino acid sequence shown in SEQ ID NO: 32, and the sequence shown in SEQ ID NO: 34
- the LCDR1, LCDR2, and LCDR3 sequences contained in the amino acid sequence of the light chain, or the VH sequence contained in the amino acid sequence of the heavy chain as shown in SEQ ID NO: 32, and the light chain as shown in SEQ ID NO: 34 The VL sequence contained in the amino acid sequence.
- the “heavy chain” of the immunocytokine of the present invention refers to the heavy chain variable region of an antibody targeting the therapeutically relevant cell surface antigen and the polypeptide chain of IL-15 or IL-15Ra connected to it.
- the "light chain” of an immunocytokine refers to the light chain variable region of an antibody targeted to a therapeutically relevant cell surface antigen and a polypeptide chain of IL-15Ra or IL-15 linked to it.
- IL-15 Interleukin-15
- the IL-15 is directly or through a connecting peptide to the N-terminus of the antibody heavy chain variable region and/or the N-terminus of the light chain variable region; or, the IL-15 is directly or through a connecting peptide to The C-terminus of the heavy chain constant region of the antibody or the C-terminus of the light chain constant region is connected.
- Figure 7 shows the results of antibody-based immune cytokine in vivo and antigen ELISA, where 7A is the binding of immune cytokine and antigen hEGFR; 7B is the binding of immune cytokine and antigen hPD-L1; 7C is the binding of immune cytokine and antigen hHER2 Combination.
- the IL-15 derivative or variant is an IL-15 agonist or superagonist.
- IL-15 agonists or superagonists Those skilled in the art can identify IL-15 agonists or superagonists based on methods in the prior art.
- IL-15 superagonists or superagonists those disclosed in International Application WO2005/085282 or Zhu et al. (J. Immunol, vol. 183(6), p: 3598-607, 2009) can be cited .
- the "Sushi domain of IL-15Ra" of the present invention has a generally known meaning in the art.
- the Sushi domain is the Sushi domain of mammalian IL-15Ra, preferably the Sushi domain of primate IL-15Ra, and more preferably the Sushi domain of human IL-15Ra.
- the sushi domain including human IL-15Ra has an amino acid sequence as shown in SEQ ID NO.: 74.
- connecting peptide in the present invention refers to the amino acid residues used to connect two polypeptides or a polypeptide comprising two or more amino acid residues connected by peptide bonds.
- linker polypeptides are well known in the art (see, for example, Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak et al. (1994) Structure 2: 1121-1123).
- Suitable, non-immunogenic linker peptides include, for example, GS, (G4S)n, (SG4)n, (G4S)n or G4(SG4)n peptide linkers.
- “N” is generally 1-10, usually an integer from 2 to 4.
Abstract
本发明提供了一种IL-15与IL-15Ra分别融合在靶向细胞表面抗原的抗体的免疫细胞因子,可有效地将IL-15与IL-15Ra的复合物特异性靶向肿瘤微环境,激活肿瘤内或附近的相关免疫细胞,达到特异性杀伤肿瘤的目标,同时可以避免因全身性过度激活NK细胞诱导的免疫毒性。
Description
本发明属于生物制药领域,具体涉及一种IL-15与IL-15Ra分别融合于抗体的免疫细胞因子或者IL-15单独与抗体融合的免疫细胞因子及其制备和用途。
在过去几年中,免疫疗法已被用于治疗人类的各种肿瘤。免疫疗法利用人体的免疫系统去攻击或杀死恶性肿瘤细胞,同时对健康组织无影响。免疫系统具有识别和清除恶性肿瘤细胞的能力,但是,肿瘤进化出多种逃避免疫监视的机制。因此,免疫疗法的挑战在于开发出能有效、安全地增强机体抗肿瘤免疫反应的策略。目前正在进行和开发的肿瘤免疫治疗策略主要有细胞因子治疗、过继细胞转移、肿瘤疫苗、单克隆抗体等。其中刺激或活化肿瘤特异性的T细胞或NK的免疫反应,发挥T细胞或NK细胞对肿瘤的杀伤作用是特别令人感兴趣的[The Potential and Promise of IL-15 in Immuno-Oncogenic Therapies]。
IL-15是一种具有与IL-2类似的结构的细胞因子,其可有效调节效应天然杀伤细胞(NK)、记忆CD8+T细胞的发育、增殖和活化。IL-15Ra是与IL-15具有高亲和力的跨膜蛋白,其与IL-15结合后通过反式递呈作用将IL-15递呈至表达IL2R beta和gamma链的NK细胞和T细胞表面,促进这些细胞的增殖和活化,增强这些细胞的肿瘤杀伤活性。另外,与IL-2不同,IL-15不会导致Treg细胞的激活,目前作为肿瘤免疫治疗制剂正在进行广泛的临床前和临床研究。
IL-15与IL-15Ra形成的复合物(IL-15超激动剂)进一步加快了以IL-15为基础的肿瘤免疫治疗的步伐。与单体IL-15相比,IL-15超激动剂具有突出的优势:如更高的血液循环浓度、更长的体内半衰期以及增强的刺激NK和CD8T细胞的能力。目前正在开发的IL-15超激动剂主要有两大类:IL-15通过linker与IL-15Ra融合形成的RLI(如Cytune的CYP0150)、以及IL-15与IL-15Ra形成的分子内复合物(如诺华的NIZ985、Altor的ALT-803、Xencor的XmAb24306)。CYP0150,由于不含有Fc,在体内易被清除,半衰期很短,需频繁给药;NIZ985和ALT-803分子中,IL-15和IL-15Ra通过分子间的作用力形成 复合物,不仅分子本身不稳定,而且制备工艺较繁琐。XmAb24306通过将IL-15和IL-15Ra分别融合在Fc的N端,形成的分子内复合物较为稳定,而且具有较长的体内半衰期。大量的临床前研究表明,与天然IL-15相比,IL-15超激动剂的生理活性及抗肿瘤活性大大增强。一些研究表明,其他免疫疗法如Nivolumab(anti-PD-1单抗)、Rituximab(anti-CD20单抗)可有效增强ALT-803对于进展性肿瘤患者的抗肿瘤效应。另外,全身性施用IL-15超激动剂可偏向性地扩增淋巴器官中促炎症(CD11b
highCD27
high)NK细胞亚群,这些细胞亚群分泌的大量IFNγ等促炎症因子可能会导致诸如体温过低、体重减少、肝损伤等免疫毒性作用。
本发明人发现,将IL-15与IL-15Ra分别融合在靶向肿瘤抗原的抗体形成的免疫细胞因子,可以特异性靶向肿瘤微环境。在肿瘤微环境内,该免疫细胞因子中的IL-15/IL15Ra形成的复合物,可以激活肿瘤内或附近的相关免疫细胞,发挥肿瘤微环境内T细胞或者NK细胞对肿瘤的特异性杀伤作用,同时可以避免全身性过度激活T细胞或者NK细胞诱导的免疫毒性。
本发明简述
本发明人发现,将IL15与IL-15Ra分别融合在靶向治疗相关细胞表面抗原的抗体形成的免疫细胞因子,可以有效地将免疫细胞因子特异性靶向肿瘤微环境,激活肿瘤内或附近的相关免疫细胞,达到特异性杀伤肿瘤的目标,同时可以避免因全身性过度激活NK细胞诱导的免疫毒性。
本发明的一个方面,提供了一种免疫细胞因子,所述免疫细胞因子包括:
(A)白介素-15(IL-15);
(B)白介素-15受体a亚基(IL-15Ra);
(C)靶向治疗相关细胞表面抗原的抗体;
其中,所述IL-15直接或通过连接肽与所述抗体的重链可变区N端连接,所述IL-15Ra直接或通过连接肽与所述抗体的轻链可变区N端连接;或者,所述IL-15直接或通过连接肽与所述抗体的轻链可变区N端连接,所述IL-15Ra直接或通过连接肽与所述抗体的重链可变区N端连接;或者,所述IL-15直接或通过连接肽与所述抗体的轻链恒定区CL的C端连接,所述IL-15Ra直接或通过连接肽与所述抗体的重链恒定区CH1的C端连接;或者所述IL-15直接或通过连接肽与所述抗体的重链恒定区CH1的C端连接,所述IL-15Ra直接或通过连接肽与所述抗体的轻链恒定区CL的C端连接。在一些实施方案中,所述连接肽为 裂解性连接肽或非裂解性连接肽。在一些实施方案中,其中所述连接肽独立地选自但不限于GGGGSGGGGSGGGGSG、GSPLGVRGS、GSPLGVR、PLGVR、GGGGSGPLGVRGGGGSG或GGGGSGPLGVR等。
在一些实施方案中,所述IL-15为哺乳动物细胞IL-15,优选灵长类IL-15,更优选人类IL-15。在一些实施方案中,所述IL-15为野生型IL-15或IL-15衍生物。在一些实施方案中,所述IL-15具有如SEQ ID NO:71所示的核酸序列和SEQ ID NO:72所示的氨基酸序列;在一些实施方案中,所述IL-15具有如SEQ ID NO:111所示的核酸序列和SEQ ID NO:112所示的氨基酸序列。在另外的一些实施方案中,所述IL-15具有如与SEQ ID NO:72或SEQ ID NO:112 85%-100%同源的氨基酸序列。
在一些实施方案中,所述IL-15Ra为IL-15Ra。在一些实施方案中,所述IL-15Ra为IL-15Ra的Sushi结构域。在一些实施方案中,所述IL-15Ra为IL-15RaSushi结构域的变异体或者衍生物。在一些实施方案中,所述IL-15Ra具有如SEQ ID NO:73所示的核酸序列和SEQ ID NO:74所示的氨基酸序列。在一些实施方案中,所述IL-15Ra具有如SEQ ID NO:87所示的核酸序列或SEQ ID NO:88所示的氨基酸序列。在另外的一些实施方案中,所述IL-15Ra具有与SEQ ID NO:74或SEQ ID NO:88 85%-100%同源的氨基酸序列。
在一些实施方案中,所述治疗相关细胞表面抗原为CD抗原。在一些实施方案中,所述CD抗原选自但不限于CD19、CD20、CD47、CD40、CD73、CD33、CD38、CD123、CD30、CD3、CD22、CD25、CD133、CD27、CD39、CD138、CD46、CD56、CD70、CD32、CD11b、CD135、CD171、CD174、CD147、CD155、CD16、CD162、CD16a、CD200、CD21、CD28、CD44、CD52、CD54、CD7、CD80、CD88、CD13、CD130、CD150、CD160、CD200R1、CD267、CD29、CD3E、CD4、CD51或CD8等。
在一些实施方案中,所述治疗相关细胞表面抗原为免疫监测点蛋白。在一些实施方案中,所述免疫监测点蛋白选自但不限于PD-1、PD-L1、CTLA-4、LAG-3、OX40、CD28、CD40、CD47、CD70、CD80、CD122、GTIR、A2AR、B7-H3(CD276)、B7-H4、IDO、KIR、Tim-3或4-1BB(CD137)等。在一些实施方案中,所述免疫监测点蛋白为PD-1。在一些实施方案中,靶向免疫监测点蛋白PD-1的抗体具有如SEQ ID NO:76所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:78所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列,或者具有如SEQ ID NO:76所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:78所示的轻链氨基 酸序列中所含的VL序列。在一些实施方案中,所述靶向免疫监测点蛋白PD-1的抗体具有如SEQ ID NO:75所示的重链核酸序列和SEQ ID NO:77所示的轻链核酸序列,或者具有如SEQ ID NO:76所示的重链氨基酸序列和SEQ ID NO:78所示的轻链氨基酸序列。
在一些实施方案中,所述免疫监测点蛋白为PD-L1。在一些实施方案中,所述靶向免疫监测点蛋白PD-L1的抗体具有SEQ ID NO:36所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:38所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有SEQ ID NO:80所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:82所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列。在一些实施方案中,所述靶向免疫监测点蛋白PD-L1的抗体具有SEQ ID NO:36所示的氨基酸序列中所含的VH序列,以及如SEQ ID NO:38所示的氨基酸序列中所含的VL序列;或者具有SEQ ID NO:80所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:82所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,所述靶向免疫监测点蛋白PD-L1的抗体具有如SEQ ID NO:35所示的重链核酸序列和SEQ ID NO:37所示的轻链核酸序列,或者具有如SEQ ID NO:36所示的重链氨基酸序列和SEQ ID NO:38所示的轻链氨基酸序列。在一些实施方案中,所述靶向免疫监测点蛋白PD-L1的抗体具有如SEQ ID NO:79所示的重链核酸序列和SEQ ID NO:81所示的轻链核酸序列,具有如SEQ ID NO:80所示的重链氨基酸序列和SEQ ID NO:82所示的轻链氨基酸序列。
在一些实施方案中,所述治疗相关细胞表面抗原选自肿瘤表面抗原。在一些实施方案中,所述肿瘤表面抗原选自但不限于EGFR、HER2、HER3、HER4、NY-ESO-1、GPC-3、CLL-1、BCMA、GD2、EpCAM、化学趋化因子受体家族(CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCL27、CCL28、CX3CR1、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6)、mucin家族(MUC1、MUC2、MUC3A、MUC3B、MUC4、MUC5AC、MUC5B、MUC6、MUC7、MUC8、MUC12、MUC13、MUC15、MUC16、MUC17、MUC19、MUC20)、PSMA、CEA、HDAC6、Mesothelin、TERT、TLR、TLR9、TLR4、CD33、GITR、Survivin、CD123、TIGIT、成纤维细胞生长因子受体(FGFR)、血管内皮生长因子受体(FLT1、KDR/Flk-1、VEGFR-3)、肝细胞生长因子受体(HGFR)、神经生长因子受体(NGFR)、胰岛素样生长因子受体(IGFR)、血小板衍生生长因子受体(PDGFR)或激素受体(黑皮质素1受体(MC1R,MSHR)等。
在一些实施方案中,所述肿瘤表面抗原为EGFR。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:32所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列,或者具有如SEQ ID NO:32所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:29所示的重链核酸序列和SEQ ID NO:33所示的轻链核酸序列,或者具有如SEQ ID NO:30所示的重链氨基酸序列和SEQ ID NO:34所示的轻链氨基酸序列。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:31所示的重链核酸序列和SEQ ID NO:33所示的轻链核酸序列,或者具有如SEQ ID NO:32所示的重链氨基酸序列和SEQ ID NO:34所示的轻链氨基酸序列。
在一些实施方案中,所述肿瘤表面抗原为HER2。在一些实施方案中,靶向HER2的抗体具有如SEQ ID NO:18所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列,或者靶向HER2的抗体具有如SEQ ID NO:18所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,靶向HER2的抗体具有如SEQ ID NO:17所示的重链核酸序列和SEQ ID NO:19所示的轻链核酸序列,或者具有如SEQ ID NO:18所示的重链氨基酸序列和SEQ ID NO:20所示的轻链氨基酸序列。
在一些实施方案中,所述细胞表面抗原选自病毒相关抗原。在一些实施方案中,所述病毒相关抗原选自但不限于RSV F、HPV E6、HPV E7、HPV L2、HPV 16、HPV E6/7、HPV L1、HPV16 E6、HPV16 E7等。在一些具体的实施方案中,所述病毒相关抗原为RSV F。在一些实施方案中,靶向RSV病毒F蛋白的抗体具有SEQ ID NO:54所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:56所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有SEQ ID NO:54所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:56所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,靶向病毒相关抗原RSV F蛋白的抗体具有如SEQ ID NO:53所示的重链核酸序列和SEQ ID NO:55所示的轻链核酸序列,或者具有如SEQ ID NO:54所示的重链氨基酸序列和SEQ ID NO:56所示的轻链氨基酸序列。
在一些实施方案中,所述免疫细胞因子由分别具有如下氨基酸序列的重链和轻链组成:SEQ ID NO:2和SEQ ID NO:8;SEQ ID NO:6和SEQ ID NO:4;SEQ ID NO:68和SEQ ID NO:8;SEQ ID NO:70和SEQ ID NO:4;SEQ ID NO:10和SEQ ID NO:12;SEQ ID NO:14和SEQ ID NO:16;SEQ ID NO:22和SEQ ID NO:24;SEQ ID NO:26和SEQ ID NO:28;SEQ ID NO:40和SEQ ID NO:24;SEQ ID NO:44和SEQ ID NO:28;SEQ ID NO:46和SEQ ID NO:48;SEQ ID NO:42和SEQ ID NO:58;SEQ ID NO:84和SEQ ID NO:86;SEQ ID NO:60和SEQ ID NO:62;SEQ ID NO:64和SEQ ID NO:66;SEQ ID NO:115和SEQ ID NO:116;SEQ ID NO:117和SEQ ID NO:118;SEQ ID NO:119和SEQ ID NO:12;SEQ ID NO:120和SEQ ID NO:16。本领域技术人员容易理解,本发明的免疫细胞因子的“重链”指包含靶向治疗相关细胞表面抗原的抗体的重链可变区及与之连接的IL-15或IL-15Ra的多肽链,免疫细胞因子的“轻链”指包含靶向治疗相关细胞表面抗原的抗体的轻链可变区及与之连接的IL-15Ra或IL-15的多肽链。
在一些实施方案中,所述免疫细胞因子由分别具有如下氨基酸序列的重链和轻链组成:SEQ ID NO:1和SEQ ID NO:7;SEQ ID NO:5和SEQ ID NO:3;SEQ ID NO:67和SEQ ID NO:7;SEQ ID NO:69和SEQ ID NO:3;SEQ ID NO:9和SEQ ID NO:11;SEQ ID NO:13和SEQ ID NO:15;SEQ ID NO:21和SEQ ID NO:23;SEQ ID NO:25和SEQ ID NO:27;SEQ ID NO:39和SEQ ID NO:23;SEQ ID NO:43和SEQ ID NO:27;SEQ ID NO:45和SEQ ID NO:47;SEQ ID NO:41和SEQ ID NO:57;SEQ ID NO:83和SEQ ID NO:85;SEQ ID NO:59和SEQ ID NO:61;SEQ ID NO:63和SEQ ID NO:65。
本发明的一个方面,提供了一种免疫细胞因子,所述免疫细胞因子包括:
(A)白介素-15(IL-15);
(B)靶向治疗相关细胞表面抗原的抗体;
其中,所述IL-15直接或者通过连接肽与所述抗体重链可变区的N端和/或轻链可变区的N端连接;或者,所述IL-15直接或者通过连接肽与所述抗体重链恒定区的C端或轻链恒定区的C端连接。
在一些实施方案中,所述连接肽为裂解性连接肽或非裂解性连接肽。在一些实施方案中,其中所述连接肽独立地选自但不限于GGGGSGGGGSGGGGSG、GSPLGVRGS、GSPLGVR、PLGVR、GGGGSGPLGVRGGGGSG或GGGGSGPLGVR等。
在一些实施方案中,所述IL-15为哺乳动物细胞IL-15,优选灵长类IL-15,更优选人类IL-15。在一些实施方案中,所述IL-15为野生型IL-15或IL-15衍生物。在一些实施 方案中,所述IL-15具有如SEQ ID NO:71所示的核酸序列和SEQ ID NO:72所示的氨基酸序列;在一些实施方案中,所述IL-15具有如SEQ ID NO:111所示的核酸序列和SEQ ID NO:112所示的氨基酸序列。在另外的一些实施方案中,所述IL-15具有如与SEQ ID NO:72或SEQ ID NO:112 85%-100%同源的氨基酸序列。
在一些实施方案中,所述治疗相关细胞表面抗原选自肿瘤表面抗原。在一些实施方案中,所述肿瘤表面抗原选自但不限于EGFR、HER2、HER3、HER4、NY-ESO-1、GPC-3、CLL-1、BCMA、GD2、EpCAM、化学趋化因子受体家族(CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCL27、CCL28、CX3CR1、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6)、mucin家族(MUC1、MUC2、MUC3A、MUC3B、MUC4、MUC5AC、MUC5B、MUC6、MUC7、MUC8、MUC12、MUC13、MUC15、MUC16、MUC17、MUC19、MUC20)、PSMA、CEA、HDAC6、Mesothelin、TERT、TLR、TLR9、TLR4、CD33、GITR、Survivin、CD123、TIGIT、成纤维细胞生长因子受体(FGFR)、血管内皮生长因子受体(FLT1、KDR/Flk-1、VEGFR-3)、肝细胞生长因子受体(HGFR)、神经生长因子受体(NGFR)、胰岛素样生长因子受体(IGFR)、血小板衍生生长因子受体(PDGFR)或激素受体(黑皮质素1受体(MC1R,MSHR)等。
在一些实施方案中,所述肿瘤表面抗原为EGFR。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:32所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列,或者具有如SEQ ID NO:32所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:29所示的重链核酸序列和SEQ ID NO:33所示的轻链核酸序列,或者具有如SEQ ID NO:30所示的重链氨基酸序列和SEQ ID NO:34所示的轻链氨基酸序列。在一些实施方案中,所述靶向肿瘤表面抗原EGFR的抗体具有如SEQ ID NO:31所示的重链核酸序列和SEQ ID NO:33所示的轻链核酸序列,或者具有如SEQ ID NO:32所示的重链氨基酸序列和SEQ ID NO:34所示的轻链氨基酸序列。
在一些实施方案中,所述肿瘤表面抗原为HER2。在一些实施方案中,靶向HER2的抗体具有如SEQ ID NO:18所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的LCDR1、LCDR2和 LCDR3序列,或者靶向HER2的抗体具有如SEQ ID NO:18所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的VL序列。在一些实施方案中,靶向HER2的抗体具有如SEQ ID NO:17所示的重链核酸序列和SEQ ID NO:19所示的轻链核酸序列,或者具有如SEQ ID NO:18所示的重链氨基酸序列和SEQ ID NO:20所示的轻链氨基酸序列。
在一些实施方案中,所述免疫细胞因子由分别具有如下氨基酸序列的重链和轻链组成:SEQ ID NO:90和SEQ ID NO:34;SEQ ID NO:92和SEQ ID NO:34;SEQ ID NO:94和SEQ ID NO:34;SEQ ID NO:96和SEQ ID NO:34;SEQ ID NO:98和SEQ ID NO:20;SEQ ID NO:100和SEQ ID NO:20;SEQ ID NO:110和SEQ ID NO:102;SEQ ID NO:110和SEQ ID NO:104;SEQ ID NO:98和SEQ ID NO:102;SEQ ID NO:98和SEQ ID NO:104;SEQ ID NO:100和SEQ ID NO:102;SEQ ID NO:100和SEQ ID NO:104;SEQ ID NO:106和SEQ ID NO:20;SEQ ID NO:110和SEQ ID NO:108;SEQ ID NO:106和SEQ ID NO:108;SEQ ID NO:113和SEQ ID NO:34;SEQ ID NO:114和SEQ ID NO:34。
在一些实施方案中,所述免疫细胞因子由分别具有如下氨基酸序列的重链和轻链组成:SEQ ID NO:89和SEQ ID NO:33;SEQ ID NO:91和SEQ ID NO:33;SEQ ID NO:93和SEQ ID NO:33;SEQ ID NO:95和SEQ ID NO:33;SEQ ID NO:97和SEQ ID NO:19;SEQ ID NO:99和SEQ ID NO:19;SEQ ID NO:109和SEQ ID NO:101;SEQ ID NO:109和SEQ ID NO:103;SEQ ID NO:97和SEQ ID NO:101;SEQ ID NO:97和SEQ ID NO:103;SEQ ID NO:99和SEQ ID NO:101;SEQ ID NO:99和SEQ ID NO:103;SEQ ID NO:105和SEQ ID NO:19;SEQ ID NO:109和SEQ ID NO:107;SEQ ID NO:105和SEQ ID NO:107。
一方面,本发明提供了编码如上所述免疫细胞因子的核酸。
一方面,本发明提供了一种含有如上所述免疫细胞因子核酸序列的载体。
一方面,本发明提供了一种宿主细胞,其包含如上所述的载体。
一方面,本发明提供了一种药物组合物,其包含药学上可接受的载体或制剂以及如上所述的免疫细胞因子。
另一方面,本发明提供了一种治疗有需要的受试者炎症性疾病或癌症的方法,所述方法包括对所述受试者施用治疗有效量的组合物,所述组合物包含药学可接受形式的如上所述的免疫细胞因子。
构成本申请的附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定,在附图中:
图1为基于抗体的免疫细胞因子构建体(名称参见表1)的SDS-PAGE图。各小图中M为蛋白marker,图1A和1B中泳道上方标示的A代表BSIC-01,B代表BSIC-10,C代表BSIC-09,D代表BSIC-05,E代表BSIC-06,F代表BSIC-03。“-”表示不加beta-巯基乙醇后上样,“+”表示加beta-巯基乙醇后上样。
图2为基于抗体的免疫细胞因子凝胶层析结果,其中2A为BSIC-03、2B为BSIC-05、2C为BSIC-06、2D为BSIC-09、2E为BSIC-10、2F为BSIC-24。
图3为基于抗体的免疫细胞因子与IL-15结合(图3A)或IL-15RaSushi结合(图3B)的ELISA检测结果,其中阳性1为IL-15RaSushi-Fc融合蛋白(Novoprotein),阳性2为IL-15-Fc融合蛋白(金斯瑞生物)
图4为基于抗体的免疫细胞因子促进Mo7e细胞增殖的检测结果,其中阳性3为IL-15与IL-15RaSushi-Fc通过非共价相互作用形成的异二聚体。
图5显示了aEGFR(5A)、aHER2(5B)、aPD1(5C)、aPDL1(5D和5E)、synagis(5F)抗体重链和轻链可变区,互补决定区(CDRs)为下划线标出的部分。
图6为基于抗体的免疫细胞因子刺激脾脏(6A)和PBMC(6B)中淋巴细胞FACS检测结果,其中阳性3为IL-15与IL-15RaSushi-Fc通过非共价相互作用形成的异二聚体,阴性为DPBS。
图7为基于抗体的免疫细胞因子体内与抗原ELISA检测结果,其中7A为免疫细胞因子与抗原hEGFR的结合;7B为免疫细胞细胞因子与抗原hPD-L1的结合;7C为免疫细胞因子与抗原hHER2的结合。
本发明的详述
本发明在此通过对使用下述定义和实施例的引用进行详细描述。所有在本文中提及的专利和公开文献的内容,包括在这些专利和公开中披露的所有序列,明确地通过提述并入本文。
本文所述的“免疫细胞因子”(immunocytokines)是指细胞因子与抗体的融合物。
本文的术语“抗体”以最广泛的含义使用,并且包括各种抗体结构,包括但不限于单克隆抗体及其衍生物和工程化抗体,包括如多特异性抗体(例如DVD-Ig、CrossMab、 ART-Ig、FIT-Ig、Duobody等双特异性抗体,三特异性抗体)和抗体片段,包括但不限于Fab、Fab’、(Fab’)
2、Fv、Diabody等等,只要它们表现出所期望的治疗相关细胞表面抗原结合活性,且具有能够在N端与IL-15和IL-15Ra连接的重链可变区和轻链可变区。在某些情形下,例如在IL-15或IL-15Ra与轻链CL或重链CH1的C端连接的场合,抗体亦可包含重链和轻链恒定区或其部分。在这样的情形中,抗体可以是,例如,Fab的形式。
术语“CDR”是指在免疫球蛋白可变区序列内的互补决定区。对于各重链和轻可变区,在重链和轻链的各可变区中存在三个CDR,其被命名为CDR1、CDR2和CDR3。术语“CDR组”是指在能够结合抗原的单一可变区中出现的三个CDR的组。这些CDR的确切边界已根据不同系统不同地定义。由Kabat(Kabat等(1987)和(1991))描述的系统,不仅提供了可适用于抗体或结合蛋白的任何可变区的明确残基编号系统,而且还提供了定义各重链或轻链序列中的三个CDR的精确残基边界。这些CDR可以被称为Kabat CDR。Chothia和同事(Chothia和Lesk(1987)J.Mol.Biol.196:901-917;Chothia等(1989)Nature342:877-883)发现Kabat CDR内的某些亚部分采取几乎相同的肽骨架构象,尽管在氨基酸序列水平上具有大的多样性。这些亚部分被命名为L1、L2和L3或H1、H2和H3,其中“L”和“H”分别指轻链和重链区域。这些区域可以被称为Chothia CDR,所述Chothia CDR具有与Kabat CDR重叠的边界。定义与Kabat CDR重叠的CDR的其它边界已由Padlan(1995)FASEB J.9:133-139和MacCallum(1996)J.Mol.Biol.262(5):732-45)描述。还有其它CDR边界定义可以不严格遵循本文系统之一,但仍将与Kabat CDR重叠,尽管鉴于特定残基或残基组或甚至整个CDR不显著影响抗原结合的预测或实验发现,它们可以缩短或加长。本文综合了Kabat和Contact定义CDR的方法(详见
http://www.bioinf.org.uk/abs/)。
术语“同源性”或“同一性”指两个聚合物分子之间(例如,在两个核酸分子(如,两个DNA分子或两个RNA分子之间)或在两个多肽分子之间)的次级单位序列同一性。当这两个分子中的次级单位位置被相同单体性次级单位占据时,例如,若两个DNA分子中每个分子中的某位置被腺嘌呤占据,则它们在该位置是同源或相同的。两个序列之间的同一性直接随匹配位置或同源位置的数目而变化,例如,如果两个序列中一半位置(例如长度为十个次级单位的聚合物中的五个位置)是同源的,则这两个序列是50%同源的(亦可称具有50%同源性或50%同一性);如果90%的位置(例如10个位置中9个位置)是匹配或同源的,则这两个序列是90%同源的(亦可称具有90%同源性或90%同一性)。
本发明的“IL-15”为哺乳动物细胞白介素15(IL-15),优选灵长类IL-15,更优选 IL-15。本发明的“IL-15”指具有与选自由SEQ ID NO:72氨基酸序列至少85%(即,相当于约20个氨基酸改变)的同一性百分数的氨基酸序列,优选地至少99%(相当于约1个氨基酸改变),但仍保持与野生型IL-15相当的生理活性的IL-15衍生物或变体。本领域技术人员可基于其知识和本专利申请的教导鉴定这样的衍生物。也应当理解天然氨基酸可以被化学修饰的氨基酸所替代。通常,这样的化学修饰的氨基酸提高多肽半衰期(见国际专利申请WO/2015/131994)。如前述使用的两个氨基酸序列之间“同一性百分数”的定义参加国际专利申请WO/2015/131994。
优选地,IL-15衍生物或变体为IL-15激动剂或超激动剂。本领域技术人员可以基于现有技术的方法鉴定IL-15激动剂或超激动剂。作为IL-15超激动剂或超激动剂的实例,可以引用在国际申请WO2005/085282或Zhu等的(J.Immunol,vol.183(6),p:3598-607,2009)中公开的那些。
更优先地,所述IL-15激动剂或超激动剂包括选自下组的取代:L45D、L45E、S51D、L52D、N72D、N72E、N72A、N72S、N72Y和N72P(上述氨基酸位点参照人IL-15的序列,SEQ ID NO.:72)。
本发明的“IL-15Ra的Sushi结构域”具有本领域中一般公知的含义。所述Sushi结构域为哺乳动物IL-15Ra的Sushi结构域,优选灵长类IL-15Ra的Sushi结构域,更优选人IL-15Ra的Sushi结构域。优选地,包括人IL-15Ra的sushi结构域具有如SEQ ID NO.:74所示的氨基酸序列。
如本文使用,术语“IL-15Ra的sushi结构域的衍生物”是指与SEQ ID NO:74所示氨基酸序列至少85%(即相当于约10个氨基酸改变)的同一性百分数的氨基酸序列,优选地至少99%(相当于约1个氨基酸改变)的IL-15Ra的sushi结构域的衍生物。本领域技术人员可基于其个人的知识和本专利申请的教导鉴定这样的衍生物。也应当理解天然氨基酸可以被化学修饰的氨基酸所替代。通常,这样的化学修饰的氨基酸可提高多肽半衰期(见国际专利申请WO/2015/131994)。如前述使用的两个氨基酸序列之间“同一性百分数”的定义,参见例如WO/2015/131994。
本发明的“治疗相关细胞表面抗原”指表达在细胞表面的、可以被靶向以进行IL-15介导的疾病治疗的抗原。本发明的“治疗相关细胞表面抗原”包括CD抗原、免疫监测点抗原、肿瘤相关抗原、肿瘤特异性抗原、病毒诱发的肿瘤抗原,且可选自但不限于下面所述抗原:CD19、PD-1、PD-L1、HER2、STAT3、STEAP1、CTLA-4、IDO、NY-ESO-1、CD40、CSF1R、BCMA、MUC1、ADORA2A、CD20、GD2、TLR7、WT1、IFNAR1、CD47;Neoantigen、EGFR、LAG-3、OX40、PSMA、Mesothelin、TERT、TLR、TLR9、 4-1BB、IL2R、TLR4、CD33、GITR、HPV E6、Survivin、CD123、TIGITTIM-3、CD73、HPV E7、TLR3、CD38、EBV、STING、CD22、GPC3、HDAC1、CXCR4、GMCSFR、CD30、CEACAM5、HDAC6、HPV、CD3、MAGE-A3、TNF、PSA、CD25、CEA、EPCAM、CMV、IL12、PRAME、IL12R、5T4、Beta catenin、CCR2、PMEL、CXCL12、IGF1、CD46、CXCR1、GMCSF、IL15R、ROR1、TGFBR2、CCR4、FLT-3、FOLR1、GCSFR、ICOS、JAK2、KRAS、VISTA、CD133、CD27、CD39、CEACAM6、NKG2D、STAT5、TGFB1、TLR2、USP7、ANG1、ANG2、B7-H3、CLEC12A、IL13RA2、RIG-I、TRP2、VEGF、AFP、Alpha-Gal、COX-2、EPHA2、gp96、MUC16、p53、TGF-β、CD138、CDw136、CS1、CXCR2、EGFRvIII、Gelactin-3、Globo H、GR、IFNAR2、IFNGR1、IL6、JAK1、MLANA、RAS、SLAMF7、TDO、TGFB2、TLR8、ALK、Arginase、CCR1、CD56、CD70、FAP、GD3、IDH1、IL6R、IRAK4、MAGE-A4、MERTK、MIF、PSCA、PTGER4、SIRPA、TGFB、TGFBR1、ACPP、ADORA2B、AR、Brachyury、CA19-9、CD32、CEACAM1、Gastrin、HDAC、HPV L2、IFNAR、IFNGR、IGF1R、IGF2、IL15、IL17R、IL1B、IL7R、JAK、MAGE-A、MAGE-A1、MAGE-A6、P38、、RORC、TLR5、VEGFR2、ADORA3、ATRT、B7-H4、c-KIT、CCR7、CD11b、CD135、CD171、CD174、CDH3、CX3CR1、Gelactin-1、GM3、HLA-A2、HSP70、IL10、IL17、IL2RB、JAK3、MDA5、NKG2A、PBF、PVRIG、SPAM1、URLC10、VEGFR1、ABCB5、ADABP、ADAM17、ADP、AEG1、Alpha-lactalbumin、AMHR2、ASPH、AXL、BCL2、BTE6-LX-8b、BTE6-X-15-7、Carbohydrate antigens、CCL20、CCL3、CCNB1、CD147、CD155、CD16、CD162、CD16a、CD200、CD21、CD28、CD44、CD52、CD54、CD7、CD80、CD88、Claudin 18、cMET、COX2、CSF1、CTCFL、CXCR5、CXCR7、E1A、EIF2AK3、ERG、FGF2、FN1、GC、GM2、gpA33、HBV、Hemagglutinin、HER3、HILPDA、HLA-DR、HMW-MAA、HP59、HPV 16、HPV E6/7、HPV L1、HSP105、HSP65、HVEM、Hyaluronan、IL13RA1、IL2、IL21R、IL8、KIF20A、KIR2DL1、KIR2DL3、LXR、MAGE-A10、MAGE-C2、Mammaglobin A、MAPK、MICA、MiHA、MMP-11、MVP、Myeloblastin、N-Myc、NKp46、NLRP3、NR2F6、Oncofetal Antigen、P2RX7、RhoC、SIM-2、SSTR2、SSX2、STAT1、STn、TAG72、TAMA、TFDP3、TGFBR、TSA、TYK2、Tyrosinase、VEGFA、5'Nucleotidase(Ecto 5'Nucleotidase or CD73 or NT5E or EC 3.1.3.5)、ADAM9、AIM2、B7-H6、BAFF-R、BAI1、BARD1、BOB-1、CA9、Cancer testis antigen、CB2、CBLB、CCR9、CD13、CD130、CD150、CD160、CD200R1、CD267、CD29、CD3E、CD4、CD51、CD8、CGEN- XXXX、Claudin 6、CLEC2D、COX、COX-1、CPEB4、CPEG4、CRBN、CRLF2、CSPG4、CTA、CXCL1、CXCR3、Cytosine deaminase、DCK、DKK1、DLL3、DR3、DR5、EBNA3C、EGF、EGFR5、ELVAL4、EPHA3、EPS8、EVI1、FAIM-3、FasR、FCU1、FLT3、FOLR、FOXM1、FSHR、Galectin-3、GalNAc、GARP、Gelactin-9、Gelatcin-1/3/9、GLD18、GNRHR、GP160、GP73、H3.3K27M、HAGE、HDAC2、HDAC8、HPV16E6、HPV16E7、HSP、Hypoxia、ICAM、ICAM7、IDO1、IFNG、IFNGR2、IGF2R、IGFBP2、IGK、IL10RA、IL12RB1、IL13、IL13R、IL13Ralpha2、IL15RA、IL17A、IL17B、IL1A、IL1R1、IL1R3、IL21、IL22R、IL27R、IL2RA、IL35、IL9R、Integrin beta-7、IRAK1、ITGB5、Kappa myeloma antigen、KIR2DL2、Kynurenine、L1CAM、Lambda Myeloma Antigen、LAMP、LLO、LXRA、LXRB、Mas receptor、MG7、MHCI、MHCII、MIC、MOSPD2、MRP-3、MRP1、MRP3765、muGNTP01、MYB、MYBL2、NFAT、NGcGM3、Nrf2、p38 MAP Kinase(EC 2.7.11.24)、P55、PAM4、PAP、PASD1、PCDH18、PD-L2、PI3K-delta、POTE、PPT、Protein tolemerase、PTGER2、RANKL、RBL001、RNF43、ROR2、S100A9、SEREX、SLAMF1、STAT、TACSTD2、TASTD2、TDO2、TEM、thymidine kinase、Thymidylate synthase、TIE2、TIMP3、TM4SF5、TOP1、TRBC1、TRBC2、TRIF、Tryptophan、TSHR、TWEAK、UTA2-1、VDBP、VRP、VSIG-4、XAGE1、XAGE1A、ZP1、ZP3。
本发明的术语“连接肽”是指用于连接2个多肽的氨基酸残基或包含2个或更多个通过肽键连接的氨基酸残基的多肽。这样的接头多肽是本领域众所周知的(参见,例如,Holliger等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Poljak等人(1994)Structure 2:1121-1123)。合适的,非免疫原性的连接肽包括例如GS,(G4S)n,(SG4)n,(G4S)n或G4(SG4)n肽接头。“n”一般是1至10,通常是2至4的整数。在某些实施方案中,所述连接肽是可裂解的连接肽,例如,可自断裂、可酶促断裂或可化学断裂的连接肽。参见WO2011/034605,将其全部按引用并入本文中。例如,但不限于,连接肽的酶断裂可以包括使用内肽酶或外肽酶。内肽酶的非限制性实例包括MMP2(基质金属蛋白酶2)、尿激酶、Lys-C、Asp-N、Arg-C、V8、Glu-C、胰凝乳蛋白酶、胰蛋白酶、胃蛋白酶、木瓜蛋白酶、凝血酶、Genenase、因子Xa、TEV(烟草蚀刻病毒半胱氨酸蛋白酶)、肠激酶、HRV C3(人鼻病毒C3蛋白酶)、ininogenase、枯草芽孢杆菌蛋白酶样前蛋白转化酶(例如,Furin(PC1)、PC2或PC3)和N-精氨酸二碱基转化酶(N-arginine dibasic convertase)。外肽酶的非限制性实例包括羧基肽酶A、羧基肽酶B、羧基肽酶D、羧基肽酶E(也称为羧基肽酶H)、羧基肽酶M、羧基肽酶N或羧基肽酶Z。 在某些实施方案中,可以通过使用羟胺、N-氯代琥珀酰亚胺、N-溴代琥珀酰亚胺或溴化氰,进行化学断裂。
需要说明的是,在不冲突的情况下,本申请中的实施例仅为举例说明,不旨在对本发明造成任何方式上的限制。
实施例
实施例1基于抗体的免疫细胞因子的构建
分别合成编码抗EGFR抗体(aEGFR)、Palivizumab(Syn)、抗PD-1抗体(aPD-1)、抗PD-L1抗体(aPD-L1)、抗HER2抗体(aHER2)的重链(H)和轻链(L),以及IL-15、IL-15Ra、IL-15RaSushi的基因片段,采用标准分子生物学技术通过连接肽将IL-15融合在前述抗体重链的可变区的N端或CH1的C端,将IL-15Ra融合在前述抗体轻链的可变区N端或恒定区的C端,或者将IL-15融合在前述抗体轻链的可变区的N端或恒定区的C端,将IL-15Ra融合在前述抗体重链的可变区N端或CH1的C端,所有的序列都通过测序验证(见表1的序列)。
表1基于抗体的免疫细胞因子的序列
注:null表示Fc无ADCC和CDC功能或者具有减弱的ADCC和CDC功能.
实施例2基于抗体的免疫细胞因子的表达、纯化和凝胶排阻层析
将实施例1构建好的含有免疫细胞因子的抗体重链和轻链的表达载体瞬时转染Expi 293细胞(ThermoFisher)分别共转染,转染时重链的质粒和轻链的质粒用量为摩尔比1:1):将40ml Expi293(3-4×10
6细胞/ml)接种至125ml细胞培养瓶,80ug质粒用2ml Opti-MEM(Invitrogen)稀释后加至2ml含120μl PEI(Polysciences)的Opti-MEM中,室温静置30min,将质粒-PEI mixture加至细胞培养液中125rpm,37℃,5%CO2培养。于转染后96h收集细胞培养上清,使用Protein A Resin(Genscript)纯化,SDS-PAGE检测。
将获得的Protein A resin纯化后的免疫细胞因子用GE的AKTA chromatography过柱分析,所用的层析柱为:Superdex 200 Increase 10/300 GL凝胶排阻层析柱。凝胶排阻层析所用的溶液为PBS缓冲液(0.010M phosphate buffer,0.0027M KCl,0.14M NaCl,pH7.4)。从图1的SDS胶图和图2的色谱图说明免疫细胞因子复合物具有相当的纯度,可通过层析柱有效分离。
实施例3基于抗体的免疫细胞因子体外活性验证
3.1 IL-15或IL-15RaSushi结合活性
包被hIL-15(SinoBiological)或IL-15RaSushi(Miltenyi)(100ng/孔)(DPBS buffer,pH7.4)于96孔板,4℃孵育过夜;含2%脱脂奶粉的DPBST室温封闭1小时,含0.05%Tween-20的DPBS洗3次后,分别加入梯度稀释的免疫细胞因子室温孵育2h,含0.05%Tween-20的DPBS洗4-5次后,加入HRP conjugated anti-human kappa light chain (Cat.A18853,Thermo Fisher Scientific,1:2000)二抗室温孵育2h,含0.05%Tween-20的DPBS洗4-5次后,TMB(BioLegend)显色后于OD450处读数。Prizm Graphpad软件用log(agonist)vs.response模型对数据进行非线性回归。
结果如图3所示。与positive-1(IL-15RaSushi-Fc)相比,BSIC-01(IL15-SynH(null):IL15RaSushi-SynL)和BSIC-02(IL15RaShi-SynH(null):IL15-SynL)对IL-15的亲和力相对较低(3A),说明BSIC-01(IL15-SynH(null):IL15RaSushi-SynL)与BSIC-02(IL15RaShi-SynH(null):IL15-SynL)分子内的IL-15和IL-15RaSushi形成稳定的复合物。与positive-2(IL-15-Fc)相比,BSIC-01(IL15-SynH(null):IL15RaSushi-SynL)对IL-15的亲和力较低(3B),与骨架抗体BSIC-13Syn(null)基本一致,说明BSIC-01(IL15-SynH(null):IL15RaSushi-SynL)分子内的IL-15和IL-15RaSushi形成非常稳定的复合物;BSIC-27(IL-15RaSushi-SynH(null))对IL-15RaSushi的亲和力较高。
3.2抗原结合活性
包被hEGFR-his(SinoBiological)、hHER2(ACRO)或hPDL1(100ng/孔)于96孔板,4℃孵育过夜;含2%脱脂奶粉的PBST(0.5%Tween-20 in PBS)室温封闭1小时,分别加入梯度稀释的免疫细胞因子室温孵育2h,含2%脱脂奶粉的PBST洗4-5次后,加入HRP anti-human kappa light chain(Invitorgen)二抗室温孵育1h,含2%脱脂奶粉的PBST洗4-5次后,TMB显色试剂(BioLegend,Cat.421101)显色后于450nm处读数,或者QuantaBlu荧光过氧化物酶底物(Life technologies,Cat.15169)显色后于325nm和420nm处读数。Prizm Graphpad软件用specific binding model对数据进行非线性回归。结果如图7所示,基于抗体的免疫细胞因子对抗原具有较好的亲和力。
实施例4 Mo7e促增殖实验
培养Mo7e细胞(协和细胞资源中心)(培养条件:RPMI 1640培养基+10%胎牛血清+双抗+10ng/ml GMCSF(Peprotech)),实验之前台盼蓝检测细胞活率,确保Mo7e细胞活率超过95%方可进行后续的增殖实验。用RPMI 1640(10%FBS+双抗)培养基洗2次后将细胞重悬至密度为40,000/100ul,加入到96孔板(全黑色底部不透明)中,每孔50ul。配制含有免疫细胞因子的RPMI 1640(10%FBS+双抗)培养基,按照预先设定好的浓度梯度进行配制。将配制好的含免疫细胞因子的培养基加入到96孔板中,每孔50ul,每个梯度做三个复孔;完成后,轻轻震荡96孔板,让含有细胞因子的培养基与预先铺好的Mo7e细胞混合均匀,放入细胞培养箱培养,条件同上。72h后,根据厂家提供的说明 书,通过MTS(Promega)显色后于OD490处读数或者通过Cell TiterGLO(Promega)显色后读取荧光值。Prizm Graphpad软件用log(agonist)vs.response模型对数据进行非线性回归。
结果如图4所示。BSIC-01(IL15-SynH(null):IL15RaSushi-SynL)促进Mo7e增殖的效果弱于positive-3(IL-15与IL-15RaSushi-Fc通过非共价相互作用形成的异二聚体)和rhIL-15,但是强于BSIC-27(图4A),提示IL-15和IL-15Rasushi通过非共价相互作用形成的分子内复合物可有效促进Mo7e细胞的增殖。BSIC-07(IL15-aEGFRH(null):IL15RaSushi-aEGFRL)和BSIC-08IL15RaSushi-aEGFRH(null):IL15-aEGFRL促进Mo7e增殖的效果类似,但是稍弱于rhIL-15。BSIC-03(IL15-aHER2H(WT):IL15RaSushi-aHER2L)和BSIC-04(IL15RaSushi-aHER2(WT):IL15-aHER2L)促进Mo7e增殖的效果强于BSIC-24(IL-15-aHER2H(WT))或IL-15-aHER2L(WT)(IL-15-aHER2H(WT)),与Palivizumab或aEGFR融合的趋势一致。
实施例5淋巴细胞激活实验
将DPBS或免疫细胞因子融合蛋白腹腔注射雌性C57BL/6小鼠(6-7周),4天后后,后眼窝采集静脉血分离PBMC,同时处死小鼠取小鼠脾脏,制备脾脏细胞单细胞悬液,用流式抗体染色后检测PBMC及脾脏中不同免疫细胞的阳性率。所用的流式抗体如下:PE rat anti-mouse CD19、APC rat anti-mouse CD45、FITC rat anti-mouse CD335、FITC rat anti-mouse CD3、PE rat anti-mouse CD4、PE rat anti-mouse CD8、TruStain FcX plus(anti-mouse CD16/32),均购自Biolegend公司。结果如图6所示,基于抗体的免疫细胞因子能够有效激活小鼠体内的CD8+T细胞和NK细胞等免疫细胞。
Claims (23)
- 一种免疫细胞因子,其包括:(A)白介素-15(IL-15);(B)白介素-15受体a亚基(IL-15Ra);(C)靶向治疗相关细胞表面抗原的抗体;其中,所述IL-15直接或通过连接肽与所述抗体的重链可变区N端连接,所述IL-15Ra直接或通过连接肽与所述抗体的轻链可变区N端连接;或者,所述IL-15直接或通过连接肽与所述抗体的轻链可变区N端连接,所述IL-15Ra直接或通过连接肽与所述抗体的重链可变区N端连接;或者,所述IL-15直接或通过连接肽与所述抗体的轻链恒定区CL的C端连接,所述IL-15Ra直接或通过连接肽与所述抗体的重链恒定区CH1的C端连接;或者所述IL-15直接或通过连接肽与所述抗体的重链恒定区CH1的C端连接,所述IL-15Ra直接或通过连接肽与所述抗体的轻链恒定区CL的C端连接。
- 权利要求1的免疫细胞因子,其中所述IL-15为野生型IL-15或IL-15衍生物。
- 权利要求2的免疫细胞因子,其中所述IL-15具有与SEQ ID NO:72或SEQ ID NO:11285%-100%同源的氨基酸序列,或由这样的氨基酸序列组成。
- 权利要求1-3中任一项的免疫细胞因子,其中所述IL-15Ra为全长IL-15Ra、IL-15Ra的Sushi结构域或IL-15Ra Sushi结构域的衍生物。
- 权利要求1-3中任一项的免疫细胞因子,其中所述IL-15Ra具有与SEQ ID NO:74或SEQ ID NO:88 85%-100%同源的氨基酸序列,或由这样的氨基酸序列组成。
- 权利要求1-5中任一项的免疫细胞因子,其中所述治疗相关细胞表面抗原为免疫监测点蛋白或肿瘤抗原。
- 权利要求6的免疫细胞因子,其中所述治疗相关细胞表面抗原选自:表皮生长因子受体家族(EGFR、HER2、HER3、HER4)、PD-1、PD-L1、STEAP1、CTLA-4、4-1BB(CD137)、OX40、CD28、CD40、CD47、CD70、CD80、CD122、GTIR、A2AR、B7-H3(CD276)、B7-H4、IDO、KIR、Tim-3、NY-ESO-1、GPC3、CLL-1、BCMA、mucin家族(MUC1、MUC2、MUC3A、MUC3B、MUC4、MUC5AC、MUC5B、MUC6、MUC7、MUC8、MUC12、MUC13、MUC15、MUC16、MUC17、MUC19、MUC20)、CD19、CD20、CD22、CD30、CD33、CD52、化学趋化因子受体家族 (CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCL27、CCL28、CX3CR1、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6)、PSMA、CEA、HDAC6、EpCAM、Mesothelin、TERT、TLR、TLR9、TLR4、CD33、GITR、Survivin、CD123、TIGIT、TIM-3、CD73、成纤维细胞生长因子受体(FGFR)、血管内皮生长因子受体(FLT1、KDR/Flk-1、VEGFR-3)、肝细胞生长因子受体(HGFR)、神经生长因子受体(NGFR)、胰岛素样生长因子受体(IGFR)、血小板衍生生长因子受体(PDGFR)、激素受体(黑皮质素1受体(MC1R,MSHR)。
- 权利要求6的免疫细胞因子,其中所述治疗相关细胞表面抗原选自EGFR、HER2、PD-1、PD-L1、CLL-1、GPC-3、RSV F蛋白、CD19、CD20、CD22、CD30、CD33或CD52。
- 权利要求8的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体为靶向EGFR的抗体,该抗体具有如SEQ ID NO:32所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有如SEQ ID NO:32所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:34所示的轻链氨基酸序列中所含的VL序列。
- 权利要求8的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体为靶向HER2的抗体,该抗体具有如SEQ ID NO:18所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有如SEQ ID NO:18所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:20所示的轻链氨基酸序列中所含的VL序列。
- 权利要求8的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体为靶向PD-1的抗体,该抗体具有如SEQ ID NO:76所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:78所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有如SEQ ID NO:76所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:78所示的轻链氨基酸序列中所含的VL序列。
- 权利要求8的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体为靶向PD-L1的抗体,该抗体具有SEQ ID NO:36所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:38所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有SEQ ID NO:80所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:82所示的轻链氨基酸序列中所含的LCDR1、 LCDR2和LCDR3序列,或者具有SEQ ID NO:36所示的氨基酸序列中所含的VH序列,以及如SEQ ID NO:38所示的氨基酸序列中所含的VL序列;或者具有SEQ ID NO:80所示的重链氨基酸序列中所含的VH,以及如SEQ ID NO:82所示的轻链氨基酸序列中所含的VL序列。
- 权利要求8的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体为靶向RSV病毒F蛋白的抗体,该抗体具有SEQ ID NO:54所示的重链氨基酸序列中所含的HCDR1、HCDR2和HCDR3序列,以及如SEQ ID NO:56所示的轻链氨基酸序列中所含的LCDR1、LCDR2和LCDR3序列;或者具有SEQ ID NO:54所示的重链氨基酸序列中所含的VH序列,以及如SEQ ID NO:56所示的轻链氨基酸序列中所含的VL序列。
- 权利要求1-13中任一项的免疫细胞因子,其中所述靶向治疗相关细胞表面抗原的抗体进一步含有Fc片段。
- 权利要求14的免疫细胞因子,其中所述Fc片段选自人IgG1、IgG2、IgG3或IgG4。
- 权利要求1-15中任一项的免疫细胞因子,其中所述连接肽为裂解性连接肽或非裂解性连接肽。
- 权利要求16的免疫细胞因子,其中所述连接肽独立地选自GGGGSGGGGSGGGGSG、GSPLGVRGS、GSPLGVR、PLGVR、GGGGSGPLGVRGGGGSG或GGGGSGPLGVR。
- ,权利要求1-17中任一项的免疫细胞因子,其中所述免疫细胞因子包含分别具有如下氨基酸序列的重链和轻链:SEQ ID NO:2和SEQ ID NO:8;SEQ ID NO:6和SEQ ID NO:4;SEQ ID NO:68和SEQ ID NO:8;SEQ ID NO:70和SEQ ID NO:4;SEQ ID NO:10和SEQ ID NO:12;SEQ ID NO:14和SEQ ID NO:16;SEQ ID NO:22和SEQ ID NO:24;SEQ ID NO:26和SEQ ID NO:28;SEQ ID NO:40和SEQ ID NO:24;SEQ ID NO:44和SEQ ID NO:28;SEQ ID NO:46和SEQ ID NO:48;SEQ ID NO:42和SEQ ID NO:58;SEQ ID NO:84和SEQ ID NO:86;SEQ ID NO:60和SEQ ID NO:62;SEQ ID NO:64和SEQ ID NO:66;SEQ ID NO:115和SEQ ID NO:116;SEQ ID NO:117和SEQ ID NO:118;SEQ ID NO:119和SEQ ID NO:12;SEQ ID NO:120和SEQ ID NO:16;SEQ ID NO:90和SEQ ID NO:34;SEQ ID NO:92和SEQ ID NO:34;SEQ ID NO:94和SEQ ID NO:34;SEQ ID NO:96和SEQ ID NO:34;SEQ ID NO:98和SEQ ID NO:20;SEQ ID NO:100和SEQ ID NO:20;SEQ ID NO:110和SEQ ID NO:102;SEQ ID NO:110和SEQ ID NO:104;SEQ ID NO:98和SEQ ID NO:102;SEQ ID NO:98和SEQ ID NO:104;SEQ ID NO:100和SEQ ID NO:102;SEQ ID NO:100和SEQ ID NO:104;SEQ ID NO:106和SEQ ID NO:20;SEQ ID NO:110和SEQ ID NO:108;SEQ ID NO:106和SEQ ID NO:108;SEQ ID NO:113和SEQ ID NO:34;SEQ ID NO:114和SEQ ID NO:34。
- 一种核酸,编码如权利要求1-18中任一项所述的免疫细胞因子。
- 一种载体,其包含如权利要求19所述的核酸。
- 一种宿主细胞,其包含如权利要求20所述的载体。
- 一种药物组合物,其包含药学上可接受的载体或制剂和如权利要求1-18中任一项所述的免疫细胞因子、权利要求19的核酸、或权利要求20的载体。
- 一种治疗有需要的受试者炎症性疾病或癌症的方法,所述方法包括对所述受试者施用治疗有效量的组合物,所述组合物包含药学可接受形式的权利要求1-18中任一项所述的免疫细胞因子。
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