CN107073109A - Vista激动剂和拮抗剂抑制或增强体液免疫的用途 - Google Patents
Vista激动剂和拮抗剂抑制或增强体液免疫的用途 Download PDFInfo
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Abstract
本发明涉及单独使用VISTA激动剂或与其他免疫抑制剂,优选地另一种体液免疫抑制剂,诸如iNOS/NO促进剂或一氧化氮或PD‑1或PD‑L1激动剂或CD40拮抗剂相结合来治疗或预防其中体液免疫抑制在治疗上是有益的病症。本发明还涉及单独使用VISTA拮抗剂或与其他免疫激动剂,优选地另一种体液免疫增强剂,诸如iNOS/NO抑制剂或PD‑1或PD‑L1拮抗剂或抗CTLA‑4抗体或CD40激动剂相结合来治疗或预防其中体液免疫增强在治疗上是有益的病症。另外,本发明涉及单独使用VISTA拮抗剂或与另一种免疫激动剂,例如iNOS/NO抑制剂或CD40激动剂相结合来促进治疗性和预防性疫苗,例如抗肿瘤和抗病毒疫苗的功效。
Description
相关申请
本申请要求2014年6月11日提交的美国临时序列号62/010,736的优先权。该申请以引用方式全文并入本文。
发明领域
本发明涉及VISTA调节(抑制)B细胞反应的发现。基于该发现,本发明涉及单独使用VISTA激动剂或与其他免疫抑制剂(immune suppresser)诸如iNOS/NO抑制剂相结合来抑制B细胞反应以及治疗其中降低的B细胞反应在治疗上是有益的病症。另外,本发明涉及单独使用或结合使用VISTA拮抗剂来促进B细胞反应以及治疗其中增强的B细胞反应在治疗上是有益的病症。
髓源性抑制细胞(MDSC)对T细胞反应的抑制在肿瘤微环境中是明确的。本发明人证实了(2013,J.Viral.87:2058-2071)在LP-BM5逆转录病毒感染易感B6小鼠的过程中对单核MDSC的诱导,这导致明显的免疫缺陷。这些MDSC在离体抑制分析中不仅抑制了T细胞反应还抑制了B细胞反应。虽然MDSC对经刺激的T细胞增殖和IFN-γ生成的抑制几乎完全依赖于iNOS/NO,但MDSC对B细胞反应的抑制仅有大约50%依赖于iNOS/NO,如通过使用iNOS抑制剂和iNOS敲除小鼠作为MDSC来源所显示。
在这里,我们通过调查VISTA(一种新近描述的负向检查点调节剂),进一步研究了在B细胞反应的MDSC抑制中的另外抑制机理。使用抗VISTA阻断抗体和LP-BM5感染的VISTA-/-MDSC,B细胞反应的MDSC抑制部分依赖于MDSC表达的VISTA。组合使用阻断iNOS/NO和VISTA两者的试剂导致对B细胞反应的MDSC抑制的相加(如果不是协同)消除。这些结果与MDSC在LP-BM5诱导的免疫缺陷中的作用相符,并在对B细胞反应的MDSC抑制正在进行研究的领域中强调了涉及多样且独特的抑制途径。
发明内容
如上所述,本发明涉及VISTA调节(抑制)B细胞反应的发现。基于该发现,本发明涉及使用VISTA激动剂来抑制B细胞反应以及治疗其中降低的B细胞反应在治疗上是有益的病症。另外,本发明涉及使用VISTA拮抗剂来促进B细胞反应以及治疗其中增强的B细胞反应在治疗上是有益的病症。
具体地讲,将激动性抗人VISTA抗体或抗体片段或VISTA多肽(例如VISTA融合蛋白)用于治疗其中期望降低B细胞反应的人病症。具体地讲,这在治疗其中疾病病理学中涉及到B细胞反应的自身免疫、过敏或炎性病症时在治疗上可能是期望的。
另外,拮抗性抗人VISTA抗体或抗体片段或VISTA多肽(例如VISTA片段和缀合物)可单独使用或与抗原和可能另一种免疫激动剂相结合,以便治疗其中期望增加B细胞反应的人病症。具体地讲,这在治疗癌症、感染性疾病以及在促进疫苗(例如预防性疫苗和治疗性疫苗)在引起对所需抗原(例如肿瘤抗原、自身抗原、或对感染因子或由感染因子感染的细胞特异性的抗原)的保护性B细胞免疫反应的功效时在治疗上可能是期望的。
VISTA是免疫球蛋白(Ig)家族配体,命名为T细胞活化的V型结构域免疫球蛋白抑制剂(V-domain Immunoglobulin Suppressor of T cell Activation,VISTA)(GenBank:JN602184)75。VISTA的关键特征包括以下这些。VISTA具有与PD-L1的有限同源性,但因其独特的结构而不属于B7家族。VISTA仅在造血区室(hematopoietic compartment)内表达,其中在CD11b.sup.高骨髓细胞上的表达水平极高,而在CD4+和CD8+ T细胞以及Treg上的表达水平较低。在APC上表达的可溶性VISTA-Ig融合蛋白或VISTA充当通过与PD-1无关的尚未鉴定的受体来抑制CD4+和CD8+ T细胞增殖和细胞因子产生的配体。抗VISTA mAb(13F3)通过增强抗肿瘤T细胞反应在多种鼠肿瘤模型中体外逆转VISTA介导的T细胞抑制并抑制肿瘤生长。在肿瘤细胞上的VISTA过表达削弱了接种疫苗的宿主中的保护性抗肿瘤免疫。VISTA KO小鼠产生导致外周耐受损失的炎症表型。参见美国专利No.8,236,304和8,231,872,已公布的国际申请WO/2011/120013和WO/2006/116181,美国已公布的申请No.2008/0287358、2011/0027278和2012/0195894,以及美国临时申请序列No.60/674,567(2005年4月25日提交)、61/663,431(2012年6月22日提交)、序列No.61/663,969(2012年6月25日提交)、61/390,434(2010年10月6日提交)、61/436,379(2011年1月26日提交)和61/449,882(2011年3月7日提交),这些专利的每一者据此以引用方式全文并入。
因此,众所周知的是,VISTA是一种关键性调节T细胞相关免疫反应的免疫检查点蛋白配体。然而,在本发明之前,尚不清楚VISTA还调节B细胞反应。
髓源性抑制细胞(MDSC)对T细胞反应的抑制在肿瘤微环境中是明确的。然而,它们对B细胞反应的作用远不够清楚。在这里,我们证实了在B细胞反应的MDSC抑制中的另外抑制机理涉及VISTA,一种负向检查点调节剂。使用抗VISTA阻断抗体和LP-BM5感染的VISTA-/-MDSC,B细胞反应的MDSC抑制部分依赖于MDSC表达的VISTA。组合使用阻断iNOS/NO和VISTA两者的试剂导致了对B细胞反应的MDSC抑制的相加(如果不是协同)消除。这些结果表明MDSC在LP-BM5诱导的免疫缺陷中发挥积极作用,并在对B细胞反应的MDSC抑制正在进行研究的领域中强调了涉及多样且独特的抑制途径。
本发明的示例性实施方案
本发明提供抑制或逆转有需要的受试者中的VISTA介导的体液免疫抑制的方法,该方法包括例如在包括其中B细胞免疫受到抑制的癌症或感染性疾病病症的受试者中单独或与另一种免疫激动剂相结合施用VISTA拮抗剂。
本发明还提供促进或增加有需要的受试者中的VISTA介导的体液免疫抑制的方法,该方法包括例如在包括其中疾病病理学中涉及到B细胞或抗体反应的自身免疫、过敏、炎性或感染性病症的受试者中单独或与另一种免疫拮抗剂相结合施用VISTA激动剂。
本发明还提供抑制有需要的受试者中的B细胞增殖或B细胞反应(包括但不限于抗原特异性抗体反应)的方法,该方法包括施用VISTA激动剂,例如包括其中疾病病理学中涉及到B细胞或抗体反应的自身免疫、过敏、炎性或感染性病症的受试者。
本发明还提供增加有需要的受试者中的B细胞增殖或B细胞反应(包括但不限于抗原特异性抗体反应)的方法,该方法包括施用VISTA激动剂,例如包括其中B细胞免疫受到抑制的癌症或感染性疾病病症的受试者
本发明还提供促进针对抗原或治疗性抗体引起的体液免疫反应的方法,该方法包括在包括使用VISTA拮抗剂的治疗性方案中施用此类抗原或抗体,例如,其中抗原是肿瘤抗原、自身抗原、过敏原或感染因子抗原,或抗体是肿瘤抗原、自身抗原、过敏原或感染因子抗原特异性的。
本发明还提供促进由治疗性或预防性疫苗引起的体液免疫反应的方法,该方法包括在包括使用VISTA拮抗剂的治疗性方案中施用此类疫苗,例如,其中疫苗含有肿瘤抗原、自身抗原、过敏原或感染因子抗原。
本发明还提供使用VISTA拮抗剂和iNOS/NO抑制剂促进体液免疫反应的方法,该抑制剂例如为精氨酸衍生物,任选地NG-硝基-L-精氨酸甲酯、NG-乙基-L-精氨酸、N-亚氨乙基-L-精氨酸、L-NG-甲基精氨酸和NG-硝基-L-精氨酸或该抑制剂为NG-硝基-L-精氨酸甲酯或洛伐他汀(lovastatin)、苯乙酸钠盐(NaPA)、FPT抑制剂II、N-乙酰半胱氨酸(NAC)以及cAMP或US 6,586,474、6,545,170、6,593,372、6,787,668、6,809,117、6,591,889、7,196,118、7,049,058中所公开的任何iNOS/NO抑制剂;所有这些专利均以引用方式全文并入本文。
本发明还提供使用VISTA激动剂和iNOS/NO促进剂(例如一氧化氮或包含一氧化氮的化合物)抑制体液免疫反应的方法。
在前述实施方案的任一个中,VISTA拮抗剂可包括拮抗性抗VISTA抗体、或VISTA的片段。
在前述实施方案的任一个中,VISTA激动剂可包括激动性抗人VISTA抗体或抗体片段或VISTA-Ig缀合物或VISTA的多聚形式,例如,其中VISTA-Ig包含IgG1、IgG2、IgG3或IgG4Fc区或其片段,其可任选地进行修饰以便削弱或增强至少一种效应功能,或可包含人抗体或人源化抗体。
在前述实施方案的任一个中,VISTA拮抗剂或激动剂可与PD-1或PD-L1激动剂或PD-1或PD-L1拮抗剂(例如,抗PD-1抗体、或抗PD-L1抗体)或PD-1融合蛋白、或表达PD-1或PD-L1的细胞结合使用。
在前述实施方案的任一个中,VISTA拮抗剂和iNOS/NO抑制剂一起施用。
在前述实施方案的任一个中,VISTA激动剂和iNOS/NO促进剂一起施用。
在前述实施方案的任一个中,VISTA拮抗剂和iNOS/NO抑制剂在促进B细胞免疫的治疗性方案中分开施用。
在前述实施方案的任一个中,VISTA拮抗剂化合物和iNOS/NO抑制剂化合物以相对于单独施用的这些化合物中的任一种足以引起对体液免疫的协同作用的量施用。
在前述实施方案的任一个中,VISTA激动剂化合物和iNOS/NO促进剂或一氧化氮以相对于单独施用的这些化合物中的任一种足以引起对体液免疫的协同作用的量施用。
附图简述
图1A-B示出了脾细胞VISTA表达因体内LP-BM5感染而增加。
图2A-C示出了Ly6C+CD11b+纯化的脾细胞对于抑制体外B和T细胞增殖具有不同的机理要求。
图3示出了将以3:1的反应细胞与抑制细胞(R:S)比率与a-VISTA预处理的Ly6C+CD11b+ MDSC混合的初始VISTA-/-反应脾细胞用α-CD40和IL-4刺激三天。
图4示出了得自指定品系的5周LP-BM5感染小鼠的纯化单核MDSC(Ly6C+CD11b+)显示出不同的对初始VISTA-/-脾细胞增殖的抑制模式,如通过流式细胞术所评估。
图5A-B示出了B细胞增殖的单核细胞抑制取决于两大机理iNOS/NO和VISTA。
具体实施方式
在详细描述本发明前,提供以下定义。
除非另外定义,否则本文使用的所有技术和科学术语都具有与本发明所属领域的普通技术人员通常所理解相同的含义。虽然与本文所述的那些类似或等效的方法和材料均可用于本发明或本发明的测试,但是本文描述合适的方法和材料。材料、方法和实例仅为说明性的,并且无意进行限制。
如本文描述和随附权利要求书通篇所用,除非上下文另外明确规定,否则“一个(种)(a,an)”和“该(所述)(the)”的含义包括多个指代物。
术语“癌症”和“癌性”是指或描述哺乳动物中特征通常在于不受调节的细胞生长的生理状况。癌症的实例包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤、肉瘤和白血病。此类癌症的更具体实例包括鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)和各种类型的头颈癌以及B细胞淋巴瘤(包括低级/滤泡非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma;NHL);小淋巴细胞性(SL)NHL;中级/滤泡NHL;中级弥漫性NHL;高级成免疫细胞性NHL;高级成淋巴细胞性NHL;高级小无核裂细胞性NHL;肿块性疾病NHL(bulky disease NHL);套细胞淋巴瘤;AIDS相关淋巴瘤;和瓦尔登斯特伦氏巨球蛋白血症(Macroglobulinemia));慢性淋巴细胞性白血病(CLL);急性成淋巴细胞性白血病(ALL);毛细胞白血病;慢性成髓细胞性白血病;多发性骨髓瘤和移植后淋巴细胞增生性障碍(PTLD)。
依从本发明的治疗的示例性癌症包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤和白血病或淋巴恶性疾病。此类癌症的更具体实例包括结直肠癌、膀胱癌、卵巢癌、黑素瘤、鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌瘤和各种类型的头颈癌以及B细胞淋巴瘤(包括低级/滤泡非霍奇金氏淋巴瘤(NHL);小淋巴细胞性(SL)NHL;中级/滤泡NHL;中级弥漫性NHL;高级成免疫细胞性NHL;高级成淋巴细胞性NHL;高级小无核裂细胞性NHL;肿块性疾病NHL;套细胞淋巴瘤;AIDS相关淋巴瘤;和瓦尔登斯特伦氏巨球蛋白血症);慢性淋巴细胞性白血病(CLL);急性成淋巴细胞性白血病(ALL);毛细胞白血病;慢性成髓细胞性白血病;和移植后淋巴细胞增生性障碍(PTLD),以及与瘢痣病相关的异常血管增殖、水肿(如与脑肿瘤相关的水肿)和梅格斯氏综合征(Meigs'syndrome)。优选地,癌症选自结直肠癌、乳腺癌、结直肠癌、直肠癌、非小细胞肺癌、非霍奇金氏淋巴瘤(NHL)、肾细胞癌、前列腺癌、肝癌、胰腺癌、软组织肉瘤、卡波西氏肉瘤(kaposi's sarcoma)、类癌瘤癌、头颈癌、黑素瘤、卵巢癌、间皮瘤和多发性骨髓瘤。在一个示例性实施方案中,癌症是早期或晚期(包括转移性)膀胱癌、卵巢癌或黑素瘤。在另一个实施方案中,癌症是结直肠癌。依从本发明的治疗的癌性病症包括转移性癌症,其中髓源性抑制细胞的VISTA表达会抑制抗肿瘤反应和抗侵袭性免疫反应。本发明的方法特别适于治疗血管化肿瘤。
本发明还适用于与化学疗法或放射疗法或其他生物制品组合治疗癌症并且适于增强其活性,即在其中髓源性抑制细胞的VISTA表达会抑制抗肿瘤反应和化学疗法或放射疗法的功效或生物制品功效的个体中增强其活性。可根据本发明使用表现出抗癌活性的任何化学治疗剂。优选地,化学治疗剂选自烷化剂、抗代谢物、叶酸类似物、嘧啶类似物、嘌呤类似物及相关抑制剂、长春花生物碱、表鬼臼毒素、抗生素、L-天冬酰胺酶、拓扑异构酶抑制剂、干扰素、铂配位复合物、蒽二酮取代的脲、甲基肼衍生物、肾上腺皮质抑制剂、肾上腺皮质激素、孕酮、雌激素、抗雌激素、雄激素、抗雄激素和促性腺激素释放激素类似物。更优选地,化学治疗剂选自5-氟尿嘧啶(5-FU)、亚叶酸(LV)、伊立替康(irinotecan)、奥沙利铂(oxaliplatin)、卡培他滨(capecitabine)、紫杉醇(paclitaxel)和多西他赛(docetaxel)。两种或更多种化学治疗剂可以按混合物的形式用于与抗VEGF抗体的施用组合施用。一种优选的组合化学疗法基于氟尿嘧啶,其包含5-FU和一种或多种其他化学治疗剂。组合化学疗法的合适给药方案在本领域中是已知的并且在例如Saltz等(1999)Proc.ASCO 18:233a和Douillard等(2000)Lancet 355:1041-7中有所描述。生物制品可以是另一免疫增效剂,诸如PD-L1、PD-L2、CTLA-4的抗体和PD-L1、PD-L2、CTLA-4融合蛋白以及细胞因子、生长因子拮抗剂和激动剂、激素和抗细胞因子抗体。
如本文所用的“活化受体”泛指结合抗原、复合抗原(例如在MHC分子的情形下)、Ig-融合蛋白、配体或抗体的免疫细胞受体。活化受体但不限于T细胞受体(TCR)、B细胞受体(BCR)、细胞因子受体、LPS受体、补体受体和Fc受体。例如,T细胞受体存在于T细胞上并且与CD3分子相关联。T细胞受体在MHC分子的情形下受抗原的刺激(以及受多克隆T细胞活化试剂的刺激)。通过TCR发生的T细胞活化导致许多变化,例如蛋白质磷酸化、膜脂质变化、离子流、环核苷酸改变、RNA转录变化、蛋白质合成变化以及细胞容积变化。例如,T细胞受体存在于T细胞上并且与CD3分子相关联。T细胞受体在MHC分子的情形下受抗原的刺激(以及受多克隆T细胞活化试剂的刺激)。通过TCR发生的T细胞活化导致许多变化,例如蛋白质磷酸化、膜脂质变化、离子流、环核苷酸改变、RNA转录变化、蛋白质合成变化以及细胞容积变化。
如本文所用,“抗原呈递细胞”泛指专职性抗原呈递细胞(例如B淋巴细胞、单核细胞、树突状细胞和朗格汉斯细胞(Langerhans cell))以及其他抗原呈递细胞(例如角质细胞、内皮细胞、星形胶质细胞、成纤维细胞和少突胶质细胞)。
如本文所用,“氨基酸”泛指天然存在的氨基酸和合成的氨基酸,以及以类似于天然存在的氨基酸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氨基酸,以及随后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)。氨基酸类似物是指基本化学结构与天然存在的氨基酸相同(即,碳结合至氢、羧基、氨基)并且具有R基团(例如高丝氨酸、正亮氨酸、蛋氨酸亚砜、蛋氨酸甲基锍)的化合物。类似物可以具有经修饰的R基团(例如正亮氨酸)或经修饰的肽主链,但是保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指结构不同于氨基酸的一般化学结构,但仍以类似于天然存在的氨基酸的方式起作用的化合物。
如本文所用,“无变应性”或“耐受性”泛指对活化受体介导的刺激的折射性。折射性通常为抗原特异性的,并在停止暴露于耐受抗原后仍然存在。例如,T细胞中的无变应性(与无反应性相对)的特征在于缺乏细胞因子的产生,如IL-2。在T细胞暴露于抗原并在不存在第二信号(共刺激信号)下收到第一信号(T细胞受体或CD-3介导的信号)时发生T细胞无变应性。在这些条件下,再次将细胞暴露于相同的抗原(即便在存在共刺激分子的情况下发生再次暴露)将导致不能产生细胞因子,并因此不能增殖。然而,无变应性T细胞可对不相关抗原发生反应,并且可在用细胞因子(如IL-2)培养时增殖。例如,T细胞无变应性也可通过T淋巴细胞缺乏IL-2的产生而观测到,如通过ELISA或通过使用指示细胞系进行增殖分析来测量。或者,可使用报告基因构建体。例如,无变应性T细胞不能引发由异源启动子在5'IL-2基因增强子控制下诱导的或由可见于增强子内的API序列的多聚体诱导的IL-2基因转录(Kang等(1992)Science,257:1134)。共刺激信号的调节导致免疫细胞的效应功能的调节。因此,术语“PD-L3或VISTA活性”包括PD-L3或VISTA多肽结合其天然结合伴侣的能力、调节免疫细胞共刺激或抑制信号的能力以及调节免疫反应的能力。免疫细胞中抑制信号的调节导致免疫细胞增殖和/或免疫细胞分泌细胞因子受到调节。
如本文所用,“抗体”泛指抗体的“抗原结合部分”(还可与“抗体部分”、“抗原结合片段”、“抗体片段”互换使用)以及整个抗体分子。如本文所用,术语“抗原结合部分”是指保留特异性结合至抗原(例如VISTA(PD-L3)的能力的抗体的一个或多个片段。抗体的抗原结合功能可通过全长抗体的片段执行。术语抗体的“抗原结合部分”所涵盖的抗原结合片段的实例包括:(a)Fab片段,其为由VL、VH、CL和CH1结构域组成的单价片段;(b)F(ab')2片段,其为包含由铰链区的二硫桥连接的两个Fab片段的二价片段;(c)由VH和CH1结构域组成的Fd片段;(d)由抗体的单臂的VL和VH结构域组成的Fv片段;(e)dAb片段(Ward等(1989)Nature,341:544-546),其由VH结构域组成;以及(f)分离的互补决定区(CDR)。此外,虽然Fv片段的两个结构域VL和VH由单独的基因编码,但是它们可通过合成连接子使用重组方法而接合,所述合成连接子使得它们能够被制备成单条蛋白质链,其中VL和VH区配对形成单价分子(称为单链Fv(scFv))。参见例如Bird等(1988)Science 242:423-426;Huston等(1988)ProcNatl.Acad.Sci.USA 85:5879-5883;和Osbourn等(1998)Nat.Biotechnol.16:778。单链抗体也旨在被涵盖在术语抗体的“抗原结合部分”的范围内。特定scFv的任何VH和VL序列都可连接至人免疫球蛋白恒定区cDNA或基因组序列,以产生编码完整IgG分子或其他同种型的表达载体。VH和VL也可使用蛋白化学或重组DNA技术用于产生Fab、Fv或免疫球蛋白的其他片段。其他形式的单链抗体诸如双体抗体(diabody)也涵盖在内。双体抗体是二价双特异性抗体,其中VH和VL结构域在单条多肽链上表达,但使用太短而不能在同一链上的两个结构域之间配对的连接子,从而迫使所述结构域与另一条链的互补结构域配对并产生两个抗原结合位点。参见例如Holliger等(1993)Proc Natl.Acad.Sci.USA 90:6444-6448;Poljak等(1994)Structure 2:1121-1123。
更进一步地,抗体或其抗原结合部分(抗原结合片段、抗体片段、抗体部分)可以是通过抗体或抗体部分与一种或多种其他蛋白质或肽的共价或非共价缔合而形成的较大免疫粘附分子的一部分。免疫粘附分子的实例包括使用链霉亲和素核心区制备四聚scFv分子(Kipriyanov等(1995)Hum.Antibodies Hybridomas 6:93-101)以及使用半胱氨酸残基、标记肽和C端多组氨酸标签制备二价和生物素化scFv分子。Kipriyanov等(1994)MolImmunol.31:1047-1058。抗体部分诸如Fab和F(ab')2片段可使用常规技术(诸如分别通过完整抗体的木瓜酶或胃蛋白酶消化)从整个抗体制备。此外,抗体、抗体部分和免疫粘附分子可使用标准重组DNA技术获得,如本文所述。
抗体可以是多克隆的、单克隆的、异种的、同种异体的、同基因的、或其修饰形式,例如人源化的、嵌合的。优选地,本发明的抗体特异性结合或基本上特异性结合至VISTA(PD-L3)分子。如本文所用,术语“单克隆抗体”和“单克隆抗体组合物”是指这样一群抗体分子,其仅含有一个种类的能够与抗原的特定表位免疫反应的抗原结合位点,而术语“多克隆抗体”和“多克隆抗体组合物”是指这样一群抗体分子,其含有多个种类的能够与特定抗原相互作用的抗原结合位点。单克隆抗体组合物通常显示出对与其发生免疫反应的特定抗原的单一结合亲和力。
如本文所用,“抗原”泛指能够由抗体结合的分子或分子的一部分,其另外能够诱导动物产生能够结合至所述抗原的表位的抗体。抗原可以具有一个表位或具有一个以上的表位。在本文中提及的特异性反应表示抗原将以高度选择性的方式与其相应抗体而非与众多可能由其他抗原激发的其他抗体反应。在对所关注的特定抗原有所需增强的免疫反应的情况下,抗原包括但不限于示例性的感染性疾病抗原,针对其可引发保护性免疫反应。
如本文所用,“过敏性疾病”泛指涉及过敏反应的疾病。更具体地讲,将“过敏性疾病”定义为一种鉴定出过敏原的疾病,其中在暴露于该过敏原与病理变化发作之间有强相关性,并且其中已经证明所述病理变化具有免疫学机理。在本文中,免疫学机理意指白细胞显示对过敏原刺激的免疫反应。
如本文所用,“反义核酸分子”泛指与编码蛋白质的“有义”核酸互补(例如与双链cDNA分子的编码链互补)、与mRNA序列互补或与基因的编码链互补的核苷酸序列。因此,反义核酸分子可通过氢键结合至有义核酸分子。
如本文所用,“哮喘”泛指特征在于炎症、气管变窄和气管对吸入剂的反应性提高的呼吸系统的病状。哮喘经常但不是仅仅与特应性或过敏性症状相关。
如本文所用,“凋亡”泛指程序性细胞死亡,其可使用在本领域中已知的技术表征。凋亡性细胞死亡的特征可在于在细胞分裂中以细胞收缩、膜起泡和染色质凝聚告终。正经历凋亡的细胞还显示核小体间DNA裂解的特征模式。
如本文所用,“自身免疫”或“自身免疫疾病或病症”泛指由个体自身组织产生或针对个体自身组织而产生的疾病或病状,或其共分离(co-segregate)或表现、或由其产生的病症。
如本文所用,“B细胞受体(BCR)”泛指见于B细胞上的在膜Ig(mIg)与其他跨膜多肽(例如Igα和Igβ)之间的复合物。mIg的信号转导功能由受体分子通过低聚抗原或多聚抗原交联触发。B细胞也可通过抗免疫球蛋白抗体活化。在BCR活化时,在B细胞中发生许多变化,包括酪氨酸磷酸化。
如本文所用,“癌症”泛指特征在于细胞分裂异常且不受控制从而导致恶性生长或肿瘤(例如细胞生长不受调节)的任何赘生性疾病(无论是侵袭性还是转移性的)。
如本文所用,“嵌合抗体”泛指这样一种抗体分子,其中恒定区或其部分被改变、置换或交换以使抗原结合位点(可变区)连接至不同或改变类别、效应功能和/或物种的恒定区,或赋予嵌合抗体以新的性质的完全不同的分子,例如酶、毒素、激素、生长因子、药物,其可变区或部分用具有不同或改变的抗原特异性的可变区改变、置换或交换。
如本文所用,“编码区”泛指包含翻译成氨基酸残基的密码子的核苷酸序列区,而术语“非编码区”是指不翻译成氨基酸的核苷酸序列区(例如,5'和3'非翻译区)。
如本文所用,“保守修饰的变体”适用于氨基酸和核酸序列两者,并且对于特定的核酸序列,泛指保守修饰的变体,是指编码相同或基本上相同的氨基酸序列的那些核酸,或者其中核酸不编码基本上相同的序列的氨基酸序列。因为遗传密码的简并性,所以大量功能上相同的核酸编码任何给定的蛋白。“沉默变异”是一种保守修饰的核酸变异。在本文中编码多肽的每一核酸序列都还描述该核酸的每一种可能的沉默变异。技术人员将认识到,可以修饰核酸中的每个密码子(除通常作为蛋氨酸的唯一密码子的AUG以及通常作为色氨酸的唯一密码子的TGG以外)以得到功能上相同的分子。
如本文所用,“互补决定区”、“高变区”或“CDR”泛指见于抗体轻链或重链可变区中的高变或互补决定区(CDR)中的一个或多个。参见Kabat等(1987)"Sequences of Proteinsof Immunological Interest"National Institutes of Health,Bethesda,Md。这些表述包括如由Kabat等(1983)"Sequences of Proteins of Immunological Interest"U.S.Dept.of Health and Human Services定义的高变区,或抗体3维结构中的高变环。Chothia和Lesk(1987)J Mol.Biol.196:901-917。每条链中的CDR都保持在框架区的邻近处,并且在来自其他链的CDR的存在下,有助于形成抗原结合位点。在CDR内,存在已被称为选择性决定区(SDR)的所选氨基酸,其表示在抗体-抗原相互作用中被CDR所用的关键性接触残基。Kashmiri(2005)Methods 36:25-34。
如本文所用,“对照量”泛指标志物可以是任何量或一定范围的量以与标志物的测试量进行比较。例如,标志物的对照量可以是在患有特定疾病或病症的患者或没有这种疾病或病症的人的体内标志物的量。对照量可为绝对量(例如微克/10或者相对量(例如相对信号强度)。
如本文所用,术语“共刺激受体”泛指将共刺激信号传送给免疫细胞的受体,如CD28或ICOS。如本文所用,术语“抑制性受体”包括将负信号传递给免疫细胞的受体。
如本文所用,“共刺激”泛指共刺激分子提供第二、非活化性、受体介导的信号(“共刺激信号”)的能力,所述信号诱导增殖或效应功能。例如,共刺激信号可引起细胞因子分泌(例如在收到了T细胞受体介导的信号的T细胞中)。已经收到细胞受体介导的信号(例如通过活化性受体)的免疫细胞在本文中可称为“活化的免疫细胞”。
如本文所用,“胞浆结构域”泛指延伸至细胞的细胞质中的蛋白质的部分。
如本文所用,“诊断”泛指鉴定病理状况的存在或性质。诊断方法的灵敏性和特异性存在差异。诊断分析法的“灵敏性”是测试阳性的患病个体的百分比(“真阳性”的百分比)。分析法未检出的患病个体是“假阴性”。将没有患病和在分析法中测试阴性的受试者称为“真阴性”。诊断分析法的“特异性”是1减去假阳性率,其中将“假阳性”率定义为没有疾病而测试为阳性的受试者的比例。虽然特定的诊断方法可能不提供对病症的明确诊断,但是如果所述方法提供有助于诊断的阳性指示,那么也就够了。
如本文所用,“诊断”泛指对疾病或症状分类、确定疾病严重性、监测疾病进展、预测疾病后果和/或痊愈希望。术语“检测”也可以任选地涵盖任一前述内容。在一些实施方案中,可如下实现根据本发明来诊断疾病:确定在得自受试者的生物样品中本发明的多核苷酸或多肽的水平,其中可将所确定的水平与疾病倾向或存在或不存在所述疾病相关联。应当注意,“得自受试者的生物样品”也可以任选地包括还没有从受试者身体上取出的样品。
如本文所用,“有效量”泛指化合物、抗体、抗原或细胞当施用于患者以治疗疾病时足以实现对疾病的这种治疗的量。有效量可为有效用于预防的量和/或有效用于防止的量。有效量可为有效减轻体征/症状的量、有效防止体征/症状的出现、降低体征/症状出现的严重性、消除体征/症状出现、减缓体征/症状出现的发展、防止体征/症状出现的发展和/或实现体征/症状出现的预防的量。“有效量”可根据待治疗患者的疾病及其严重性以及年龄、体重、病史、易感性和预先存在的病症而变化。为了本发明的目的,术语“有效量”与“治疗有效量”同义。
如本文所用,“胞外结构域”泛指从细胞表面延伸出的蛋白质的部分。
如本文所用,“表达载体”泛指用于在任何细胞(包括原核、酵母、真菌、植物、昆虫或哺乳动物细胞)中在体外或体内组成型或诱导型表达本发明的核酸序列的目的的任何重组表达系统。该术语包括线性或环状表达系统。该术语包括保持游离型或整合到宿主细胞基因组中的表达系统。表达系统可具有自我复制的能力或不具有该能力,即仅驱动在细胞中的瞬时表达。该术语包括重组表达盒,该重组表达盒仅含有重组核酸的转录所需的最小元件。
如本文所用,“家族”泛指本发明的多肽和核酸分子,其旨在意指具有共同结构域或基序并且具有足够氨基酸或核苷酸序列同源性(如本文所定义)的两个或更多个多肽或核酸分子。家族成员可以为天然或非天然存在的并且可来自相同或不同的物种。例如,家族可含有人来源以及其他来源的第一多肽、人来源的不同多肽,或者可含有非人来源的同系物(例如猴多肽)。家族成员也可以具有共同的功能特征。
如本文所用,“Fc受体”(FcR)泛指免疫球蛋白分子(Ig)的Fc部分的细胞表面受体。Fc受体见于许多参与免疫反应的细胞。在迄今为止已经鉴定的人FcR之中,有识别IgG(命名为FcγR)、IgE(FcεR1)、IgA(FeαR)和聚合IgM/A(FcμαR)的那些。FcR见于以下细胞类型中:FcεRI(肥大细胞)、FcεRII(许多白细胞)、FcαR(嗜中性粒细胞)和FcμαR(腺上皮、肝细胞)。Hogg(1988)Immunol Today 9:185-86。广泛研究的FcγR为细胞免疫防御中的核心,并且负责刺激自身免疫疾病的发病机理中涉及到的炎症和水解酶的介体的释放。Unkeless(1988)Annu.Rev.Immunol.6:251-87。FcγR在效应细胞与分泌Ig的淋巴细胞之间提供重要联系,因为巨噬细胞/单核细胞、多形核白细胞和自然杀伤(NK)细胞FcγR赋予由IgG介导的特异性识别的元件。人白细胞具有IgG的至少三个不同的受体:hFcγRI(见于单核细胞/巨噬细胞上)、hFcγ.RII(见于单核细胞、嗜中性粒细胞、嗜酸性粒细胞、血小板、可能有Β细胞和K562细胞系上)以及FcγIII(见于NK细胞、嗜中性粒细胞、嗜酸性粒细胞和巨噬细胞上)。
对于T细胞,共刺激信号向T细胞的传送涉及不受环孢菌素A抑制的信号传导途径。另外,共刺激信号可在T细胞中诱导细胞因子分泌(例如IL-2和/或IL-10)和/或可在T细胞中防止诱导对抗原的无反应性、诱导无变应性或诱导细胞死亡。
如本文所用,“框架区”或“FR”泛指在抗体轻链和重链的可变区内的框架区中的一个或多个。参见Kabat等(1987)"Sequences of Proteins of Immunological Interest"National Institutes of Health,Bethesda,Md。这些表述包括插入抗体轻链和重链的可变区内的CDR之间的那些氨基酸序列区。
如本文所用,“异源”泛指核酸的多个部分,其表明该核酸包含两个或更多个在性质上相互不以相同关系存在的子序列。例如,通常以重组方式产生核酸,使其具有两个或更多个来自不相关基因、被布置成产生新的功能性核酸的序列(例如启动子来自一个来源而编码区来自另一来源)。类似地,异源蛋白表明该蛋白质包含两个或更多个在性质上相互不以相同关系存在的子序列(例如,融合蛋白)。
如本文所用,“高亲和力”泛指抗体对靶抗原的KD为至少10-8M、更优选地至少10-9M并且甚至更优选地至少10-10M。然而,“高亲和力”结合可针对其他抗体同种型而变化。例如,对IgM同种型的“高亲和力”结合是指抗体的KD为至少10-7M,更优选地至少10-8M。
如本文所用,“同源性”泛指在核酸序列与参考核酸序列之间或在多肽序列与参考多肽序列之间的相似性程度。同源性可以为部分的或完全的。完全同源性表示核酸或氨基酸序列是相同的。部分同源的核酸或氨基酸序列是与参考核酸或氨基酸序列不相同的核酸或氨基酸序列。同源性程度可通过序列比较来确定。术语“序列同一性”可与“同源性”互换使用。
如本文所用,“宿主细胞”泛指已引入了本发明的核酸分子诸如本发明的重组表达载体的细胞。宿主细胞可以是原核细胞(例如大肠杆菌),或真核细胞诸如酵母、昆虫(例如SF9)、两栖动物或哺乳动物细胞诸如CHO、HeLa、HEK-293,例如培养的细胞、外植体和体内细胞。术语“宿主细胞”和“重组宿主细胞”可在本文中互换使用。应当了解,这些术语不仅是指特定的受试者细胞,而且还指这种细胞的子代或可能的子代。因为后代中可能因突变或环境影响而出现某些改变,所以子代实际上可能不与亲本细胞相同,但是仍包括在如本文所用的该术语的范围内。
如本文所用,“人源化抗体”泛指包括通过具有可变区和恒定区的非人细胞产生的抗体,所述可变区和恒定区已发生改变从而与将通过人细胞产生的抗体更加密切相似。例如,通过改变非人抗体氨基酸序列以并入见于人种系免疫球蛋白序列中的氨基酸。本发明的人源化抗体可以包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如通过体外随机或位点特异性诱变或通过体内体细胞突变所引入的突变),例如在CDR中。如本文所用,术语“人源化抗体”还包括这样的抗体,其中已将来源于另一种哺乳动物物种诸如小鼠的种系的CDR序列移植到人框架序列上。
如本文所用,“杂交”泛指互补的(包括部分互补的)多核苷酸链当各链相互反平行布置时通过在互补核苷酸之间形成氢键而产生的物理相互作用。
如本文所用,“IgV结构域”和“IgC结构域”泛指Ig超家族成员结构域。这些结构域对应于具有不同折叠模式(称为Ig折叠)的结构单元。Ig折叠包含两个β折叠的夹心结构,每个β折叠由5-10个氨基酸的反平行β链与大多数但非全部结构域中的两个折叠之间的保守二硫键组成。Ig、TCR和MHC分子的IgC结构域共有相同类型的序列模式并称为Ig超家族内的C1组。其他IgC结构域落在其他组内。IgV结构域也共有序列模式并称为V组结构域。IgV结构域长于C结构域并形成另外一对β链。
如本文所用,“免疫细胞”泛指具有造血来源并在免疫反应中起作用的细胞。免疫细胞包括淋巴细胞,诸如B细胞和T细胞;自然杀伤细胞;以及骨髓细胞,诸如单核细胞、巨噬细胞、嗜酸性粒细胞、肥大细胞、嗜碱性粒细胞和粒细胞。
如本文所用,“免疫分析”泛指使用抗体来特异性结合抗原的分析法。免疫分析可通过使用特定抗体的特异性结合性质以分离、靶向和/或定量抗原来表征。
如本文所用,“免疫反应”泛指T细胞介导的和/或B细胞介导的免疫反应,其受T细胞共刺激的调节的影响。示例性免疫反应包括B细胞反应(例如抗体产生)、T细胞反应(例如细胞因子产生,以及细胞毒性)和细胞因子反应性细胞例如巨噬细胞的活化。如本文所用,关于免疫反应的术语“下调”包括任何一种或多种免疫反应的降低,而关于免疫反应的术语“上调”则包括任何一种或多种免疫反应的提高。应当了解,一种类型的免疫反应的上调可导致另一类型的免疫反应的相应下调。例如,某些细胞因子(例如IL-10)的产生的上调可导致细胞免疫反应的下调。
如本文所用,“炎性病症或炎性疾病”泛指慢性或急性的炎性疾病。
如本文所用,术语“抑制信号”泛指通过免疫细胞上的抑制性受体分子传送的信号。信号通过活化受体(例如通过TCR、CD3、BCR或Fc分子)拮抗信号并可导致例如以下方面的抑制:第二信使生成;增殖;或免疫细胞中的效应功能,例如减少的吞噬作用、减少的抗体产生或降低的细胞毒性,或使免疫细胞无法产生介体(例如细胞因子(如IL-2)和/或变应性反应介体);或发生无变应性。
如本文所用,“分离的”泛指物质从其天然存在的原始环境移除,因此从其天然环境经人手而改变。分离的物质可以为例如载体系统中包括的外源性核酸、宿主细胞内所含的外源性核酸,或已经从其原始环境移除并因此经人手而改变的任何物质(例如“分离的抗体”)。例如,如本文所用,“分离的”或“纯化的”泛指蛋白质、DNA、抗体、RNA或其生物活性部分,它们基本上不含生物物质所来源的细胞或组织源中的细胞物质或其他污染性蛋白,或当通过化学方法合成时基本上不含化学前体或其他化学物质。用语“基本上不含细胞物质”包括以下VISTA(PD-L3)蛋白制备物:其中该蛋白质与其从中分离的细胞的细胞组分分离或重组产生。
如本文所用,“分离的抗体”意指基本上不含具有不同抗原特异性的其他抗体的抗体(例如,特异性结合PD-L3或VISTA的分离的抗体基本上不含特异性结合除PD-L3或VISTA以外的抗原的抗体)。此外,分离的抗体可以基本上不含其他细胞物质和/或化学物质。
如本文所用,“K-assoc”或“Ka”泛指特定抗体-抗原相互作用的缔合速率,而如本文所用,术语“Kdiss”或“Kd”是指特定抗体-抗原相互作用的解离速率。如本文所用,术语“KD”意指解离常数,其得自Kd与Ka的比率(即Kd/Ka)并且表示为摩尔浓度(M)。可使用本领域中公认的方法测定抗体的KD值。
如本文所用,“标记”或“可检测部分”泛指可通过分光光度法、光化学、生化、免疫化学、化学或其他物理手段检测的组合物。
如本文所用,“低严格度”、“中等严格度”、“高严格度”或“极高严格度条件”泛指核酸杂交和洗涤的条件。进行杂交反应的指导可见于Ausubel等(2002)Short Protocols inMolecular Biology(第5版)John Wiley&Sons,NY。示例性的特异性杂交条件包括但不限于:(1)低严格度杂交条件:在6×氯化钠/柠檬酸钠(SSC)中在约45℃下,接着在0.2×SSC、0.1%SDS中至少在50℃下洗涤两次(对于低严格度条件,洗涤温度可提高至55℃);(2)中等严格度杂交条件:在6×SSC中在约45℃下,接着在0.2×SSC、0.1%SDS中在60℃下洗涤一次或多次;(3)高严格度杂交条件:在6×SSC中在约45℃下,接着在0.2×SSC、0.1%SDS中在65℃下洗涤一次或多次;以及(4)极高严格度杂交条件:0.5M磷酸钠、7%SDS,在65℃下,接着在0.2×SSC、1%SDS中在65℃下洗涤一次或多次。
如本文所用,“哺乳动物”泛指哺乳纲的任何及所有温血脊椎动物(包括人),其特征在于皮肤上覆有毛发,并且雌性有滋养幼儿的产乳乳腺。哺乳动物的实例包括但不限于羊驼、犰狳、水豚、猫、骆驼、黑猩猩、灰鼠、牛、狗、山羊、大猩猩、仓鼠、马、人、狐猴、美洲驼、小鼠、非人灵长类动物、猪、大鼠、绵羊、駒鼯、松鼠、貘和田鼠。哺乳动物包括但不限于牛科动物、犬科动物、马科动物、猫科动物、鼠科动物、绵羊(ovine)、猪科动物、灵长类动物和啮齿动物物种。哺乳动物还包括任何及所有由华盛顿哥伦比亚特区国家自然历史博物馆史密森学会(National Museum of Natural History,Smithsonian Institution inWashington DC)列在世界哺乳动物物种(Mammal Species of the World)上的那些动物。
如本文所用,“天然存在的核酸分子”泛指具有存在于自然界中的核苷酸序列的RNA或DNA分子(例如编码天然蛋白)。
如本文所用,“核酸”或“核酸序列”泛指呈单链或双链形式的脱氧核糖核苷酸或核糖核苷酸寡核苷酸。该术语涵盖核酸,即寡核苷酸,其含有天然核苷酸的已知类似物。该术语还涵盖具有合成主链的核酸样结构。除非另外指明,否则特定核酸序列还含蓄地涵盖其保守修饰的变体(例如简并密码子取代)和互补序列,以及明确指示的序列。术语核酸为可与基因、cDNA、mRNA、寡核苷酸和多核苷酸互换使用。
如本文所用,“寡聚化结构域”泛指当连接于VISTA胞外结构域或其片段时有助于寡聚化的结构域。所述寡聚结构化域包含自缔合α-螺旋,例如亮氨酸拉链结构,其可通过另外的二硫键进一步稳定。将所述结构域设计为与跨膜的矢量折叠(vectorial folding)相容,这一过程被认为有助于多肽体内折叠成功能性结合蛋白。其实例在本领域中是已知的,并且包括例如卷曲GCN4和COMP。
α-螺旋型卷曲螺旋可能是见于蛋白中的最广泛的亚单位寡聚化基序。因此,卷曲螺旋发挥许多不同的功能。在转录激活物的多个家族中,例如,短亮氨酸拉链结构在DNA上定位DNA结合区中发挥着重要作用。Ellenberger等(1992)Cell 71:1223-1237。卷曲螺旋还用于形成中间丝蛋白的寡聚物。卷曲螺旋蛋白此外似乎还在囊泡和病毒膜融合中都发挥着重要作用。Skehel和Wiley(1998)Cell 95:871-874。在两种情况中,嵌入待融合的膜中的疏水序列位于由一束长α螺旋组成的杆状复合体的同一端。这种分子排列据信会在组装复合体以进行膜融合时导致亲密的膜并置。经常将卷曲螺旋用于控制寡聚化。其见于许多类型的蛋白质中,包括转录因子,包括但不限于GCN4、病毒融合肽、SNARE复合体以及某些tRNA合成酶等等。极长的卷曲螺旋见于蛋白质诸如原肌球蛋白、中间丝蛋白和纺锤极体组分中。卷曲螺旋涉及许多α-螺旋,它们围绕彼此以高度组织化的形式(以平行或反平行取向缔合)形成超螺旋。但二聚体和三聚体是最常见的。螺旋可以来自相同的或来自不同的蛋白质。卷曲螺旋由汇合在一起以埋藏它们的疏水缝的组分螺旋形成。由于疏水缝围绕每个螺旋扭曲,因此螺旋也绕彼此扭曲成圈,从而埋藏疏水缝并形成超螺旋。它是相邻螺旋之间侧链的特征性交错接合,称为结节入洞堆积(knobs-into-holes packing),其将该结构定义为卷曲螺旋。对于发生这种类型的相互作用,螺旋不必以相同的方向行进,但平行构象更常见反平行构象在三聚体中非常罕见,并且在五聚体中未知,但在分子内二聚体中较常见,其中两个螺旋通常通过短环连接。在细胞外间隙中,异源三聚卷曲螺旋蛋白层粘蛋白在基底膜的形成中起着重要作用。其他实例为血小板反应蛋白和软骨寡聚基质蛋白(COMP),其中连接了三条(血小板反应蛋白1和2)或五条(血小板反应蛋白3、4和COMP)链。所述分子具有花束样外观,并且其寡聚结构的原因可能是C端结构域与细胞受体的多价相互作用。酵母转录激活物GCN4是超过30种已鉴定的含碱性区亮氨酸拉链(bZIP)DNA结合基序的真核蛋白中的1种。Ellenberger等(1992)Cell 71:1223-1237。bZIP二聚体是一对连续的α螺旋,该螺旋在其羧基末端的34个残基上方形成平行的卷曲螺旋并朝其氨基末端逐渐分开以通过DNA结合位点的大沟。卷曲螺旋二聚化接口几乎垂直于DNA轴线取向,从而使复合体具有字母T的外观。bZIP含有疏水非极性残基的4-3七肽重复区域(heptad repeat),这些残基以平行的α螺旋型卷曲螺旋堆叠在一起。Ellenberger等(1992)Cell71:1223-1237。二聚体的稳定性由以下方面产生:亮氨酸以及七肽重复区域a和d位的非极性残基的并列堆积(side-by-sidepacking)以及有限数量的螺旋内和螺旋间盐桥,如在GCN4亮氨酸拉链肽的晶体结构中所示。Ellenberger等(1992)Cell 71:1223-1237。另一实例为从牛气管软骨中而分离的作为Mr 52,000亚单位的同源三聚体的CMP(母系蛋白-1)(Paulsson&Heinegard(1981)BiochemJ.197:367-375),其中每个亚单位由vWFAl模块、单个EGF结构域、vWFA2模块以及跨五个七肽的卷曲螺旋结构域组成。Kiss等(1989)J.Biol.Chem.264:8126-8134;Hauser和Paulsson(1994)J.Biol.Chem.269:25747-25753。经过纯化的CMP的电子显微镜分析显示出花束样三聚体结构,其中每个亚单位形成从对应于卷曲螺旋的公共点显露出来的椭圆体。Hauser和Paulsson(1994)J.Biol.Chem.269:25747-25753。母系蛋白-1中的卷曲螺旋域已得到了广泛的研究。三聚体结构在非变性条件下完全还原链间二硫键后得以保留。Hauser和Paulsson(1994)J.Biol.Chem.269:25747-25753。又一个实例为软骨寡聚基质蛋白(COMP)。非胶原性糖蛋白COMP最初在软骨中鉴定出。Hedbom等(1992)J.Biol.Chem.267:6132-6136。所述蛋白为524kDa的五个亚单位的同源五聚体,其由N端七肽重复区(cc)接着四个表皮生长因子(EGF)样结构域(EF)、七个钙结合结构域(T3)和C端球状结构域(TC)组成。根据这种结构域组织,COMP属于血小板反应蛋白家族。在位置a和d具有优先疏水性残基的七肽重复区(abcdefg)n形成螺旋型卷曲螺旋结构域。Cohen和Parry(1994)Science 263:488-489。最近,将COMP的重组五链卷曲螺旋结构域(COMPcc)结晶,并以0.2nm的分辨率对其结构进行了解析。Malashkevich等(1996)Science 274:761-765。
如本文所用,“可操作地连接”泛指当两个DNA片段接合时使由两个DNA片段编码的氨基酸序列保持同框。
如本文所用,“互补位”(paratope)泛指识别抗原的抗体部分(例如抗体的抗原结合位点)。互补位可为抗体Fv区的小区域(例如15-22个氨基酸)并且可以含有抗体重链和轻链的部分。参见Goldsby等Antigens(第3章)Immunology(第5版)New York:W.H.Freemanand Company,第57-75页。
如本文所用,“患者”泛指需要治疗以减轻疾病状态或防止疾病状态出现或复发的任何动物。另外,如本文所用,“患者”泛指具有风险因素、疾病史、易感性、症状、体征、先前已诊断、处于疾病风险中或是疾病患者群体的成员的任何动物。患者可为临床患者,诸如人或兽医学患者,诸如伴侣动物、驯化动物、家畜动物、外来动物或动物园动物。术语“受试者”可与术语“患者”互换使用。
“多肽”、“肽”和“蛋白质”可互换使用并且泛指氨基酸残基的聚合物。该术语适用于以下氨基酸聚合物:其中一个或多个氨基酸残基是相应天然存在的氨基酸的类似物或模拟物;以及适用于天然存在的氨基酸聚合物。该术语适用于以下氨基酸聚合物: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;以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。可例如通过添加碳水化合物残基以形成糖蛋白来修饰多肽。术语“多肽”、“肽”和“蛋白质”包括糖蛋白以及非糖蛋白。
如本文所用,“启动子”泛指引导核酸转录的一系列核酸序列。如本文所用,启动子包括在起始转录位点附近的必要的核酸序列,诸如在聚合酶II型启动子的情况下是TATA元件。启动子还任选地包括远端增强子或阻遏子元件,其可位于距离转录起始位点几千个碱基对之处。“组成型”启动子是在大多数环境和发育条件下具有活性的启动子。“诱导型”启动子是在环境或发育调节下具有活性的启动子。
如本文所用,“预防有效量”泛指化合物当施用于患者以预防疾病或防止疾病复发时足以对疾病或复发实现这种预防的量。预防有效量可为有效防止体征和/或症状出现的量。“预防有效量”可根据待治疗患者的疾病及其严重性以及年龄、体重、病史、病症倾向性和先前存在的病症而变化。
如本文所用,“预防”泛指这样一个疗程,其中体征和/或症状不存在于患者中、处于缓解中或先前存在于患者中。预防包括防止在治疗患者的疾病之后出现疾病。此外,防止包括治疗可能会发生疾病的患者,尤其是对疾病易感的患者(例如,患者群体的成员、具有风险因素的那些患者、或处于发生疾病的风险中的那些)。
如本文所用,“重组”关于产品时例如泛指细胞或核酸、蛋白质或载体,其表示所述细胞、核酸、蛋白质或载体已经通过引入异源核酸或蛋白质或改变初始核酸或蛋白质而得到修饰,或所述细胞来源于如此修饰的细胞。因此,例如,重组细胞表达该细胞的初始(非重组)形式中未见的基因,或者表达原本异常表达、表达不足或根本不表达的初始基因。
如本文所用,“信号序列”或“信号肽”泛指如下肽:其含有约15个或更多个出现在分泌性和膜结合多肽的N端处并且含有大量的疏水性氨基酸残基的氨基酸。例如,信号序列含有至少约10-30个氨基酸残基、优选地约15-25个氨基酸残基、更优选地约18-20个氨基酸残基并且甚至更优选地约19个氨基酸残基,且具有至少约35-65%、优选地约38-50%、更优选地约40-45%的疏水性氨基酸残基(如缬氨酸、亮氨酸、异亮氨酸或苯丙氨酸)。“信号序列”在本领域中也称为“信号肽”,其用以将含有这种序列的多肽引导至脂质双层,并在分泌性和膜结合多肽中裂解。
如本文所用,“特异性(或选择性)结合”至抗体或者“对...具有特异性(或选择性)免疫活性”或“与...特异性相互作用或结合”泛指蛋白质或肽(或其他表位),在一些实施方案中是指决定蛋白质和其他生物制品的异源群体中所述蛋白质的存在的结合反应。例如,在规定的免疫分析条件下,指定的抗体结合至特定蛋白质,结合量要比背景(非特异性信号)大至少两倍,并且基本上不会与样品中存在的其他蛋白质大量结合。典型地,特异性或选择性反应将为背景信号或噪音的至少两倍,并且更典型地,为背景的约10至100倍以上。
如本文所用,“可特异性杂交的”和“互补的”泛指核酸可通过传统的沃森-克里克(Watson-Crick)或其他非传统类型与另一核酸序列形成氢键。核酸分子与其互补序列的结合自由能足以使核酸的有关功能得到发挥,例如RNAi活性。本领域熟知核酸分子的结合自由能的测定。参见例如Turner等(1987)CSH Symp.Quant.Biol.LII:123-33;Frier等(1986)PNAS 83:9373-77;Turner等(1987)J.Am.Chem.Soc.109:3783-85。互补性百分比表示核酸分子中可与第二核酸序列形成氢键(例如沃森-克里克碱基配对)的连续残基的百分比(例如,10个中约至少5、6、7、8、9、10个,即有约至少50%、60%、70%、80%、90%和100%的互补性(包括所述数值))。“完美互补”或100%互补性泛指核酸序列的所有连续残基都与第二核酸序列中相同数目的连续残基氢键合。“基本互补性”(substantial complementarity)是指排除被选择为具有非互补性的多核苷酸链区域,诸如突出(overhang),多核苷酸链表现出约至少90%的互补性。特异性结合需要足够程度的互补性以避免寡聚化合物与非目标序列在需要特异性结合的条件下,即在体内分析或治疗性治疗的情况下在生理条件下,或在体外分析的情况下在进行分析的条件下发生非特异性结合。非目标序列通常可相差至少5个核苷酸。
如本文所用,疾病的“体征”泛指指示疾病、在检查患者后可发现的任何异常;与症状相反的客观的疾病指示,而症状是主观的疾病指示。
如本文所用,“固体支撑物”、“支撑物”和“衬底”泛指提供固体或半固体结构的借此可连接另一材料的任何材料,其包括但不限于光滑支撑物(例如金属、玻璃、塑料、硅和陶瓷表面)以及纹理化和多孔的材料。
如本文所用,“受试者”泛指适于根据本发明进行治疗的任一个,包括但不限于鸟类和哺乳动物受试者,并且优选地为哺乳动物。需要根据本发明进行治疗的任何哺乳动物受试者都是合适的。两种性别和在任何发育阶段(即新生儿、婴儿、幼儿、青少年、成年)的人受试者都可根据本发明进行治疗。也可以对动物受试者,特别是哺乳动物受试者如小鼠、大鼠、狗、猫、牛、山羊、绵羊和马实施本发明以用于兽医学目的,以及用于药物筛选和药物开发目的。“受试者”可与“患者”互换使用。
如本文所用,“基本上不含化学前体或其他化学物质”泛指如下VISTA蛋白制备物:其中所述蛋白质与合成所述蛋白质中所涉及的化学前体或其他化学物质分离。在一个实施方案中,用语“基本上不含化学前体或其他化学物质”包括具有少于约30%(按干重计)化学前体或非VISTA化学物质、更优选地少于约20%化学前体或非VISTA化学物质、还更优选地少于约10%化学前体或非VISTA化学物质以及最优选地少于约5%化学前体或非VISTA(PD-L3)化学物质的VISTA蛋白制备物。
如本文所用,疾病的“症状”泛指患者所经历并且指示疾病的任何病态的现象或与结构、功能或感觉的正常状态相背离。
如本文所用,“T细胞”泛指CD4+ T细胞和CD8+ T细胞。术语T细胞还包括T辅助1型T细胞和T辅助2型T细胞两者。
如本文所用,“Treg细胞”(有时还称为抑制T细胞)是指T细胞亚群,其调节免疫系统并且维持对自身抗原的耐受性并且可消除自身免疫疾病。Foxp3+CD4+CD25+调节T细胞(Treg)在正常生理条件下维持外周耐受性方面是关键性的,并在癌症中抑制抗肿瘤免疫反应。
如本文所用,“疗法”、“治疗性”或“治疗”泛指治疗疾病,停滞或减轻疾病或其临床症状的发展,和/或缓解疾病、使疾病或其临床症状消退。疗法涵盖预防、治疗、补救、减少、减轻和/或使得疾病、疾病的体征和/或症状缓解。疗法涵盖减轻具有进行中疾病体征和/或症状(例如炎症、疼痛)的患者的体征和/或症状。疗法还涵盖“预防”。对于疗法的目的,术语“减少”泛指体征和/或症状的临床显著的减少。疗法包括治疗复发或复发体征和/或症状(例如炎症、疼痛)。疗法涵盖但不限于阻止任何时候出现体征和/或症状以及减轻现有体征和/或症状以及消除现有体征和/或症状。疗法包括治疗慢性疾病(“维持”)和急性疾病。例如,治疗包括治疗或预防体征和/或症状(例如炎症、疼痛)的复发。
如本文所用,“跨膜结构域”泛指长度为约15个氨基酸残基的跨越质膜的氨基酸序列。更优选地,跨膜结构域包含约至少20、25、30、35、40或45个氨基酸残基并跨越质膜。跨膜结构域富含疏水性残基,并且通常具有α-螺旋结构。在一个实施方案中,跨膜结构域的氨基酸中的至少50%、60%、70%、80%、90%、95%或更多具有疏水性,例如亮氨酸、异亮氨酸、酪氨酸或色氨酸。跨膜结构域描述于例如Zagotta等(1996)Annu.Rev.Neurosci.19:235-263。
如本文所用,“转基因动物”泛指非人动物,优选地为哺乳动物,更优选地为小鼠,其中动物细胞的一个或多个包括“转基因”。术语“转基因”是指整合到发育成转基因动物的细胞的基因组中并保留在成熟动物基因组中,从而例如指导转基因动物的一种或多种细胞类型或组织中编码基因产物的表达的外源性DNA。
如本文所用,术语“肿瘤”泛指至少一个细胞或呈组织新生物(neoformation)形式的细胞团块,尤其是内源性组织的自发、自主和不可逆的或多或少脱抑制的过度生长形式,所述生长通常与或多或少的特定细胞和组织功能的明显丧失相关。这种细胞或细胞团块通过自身或通过宿主生物体(例如结直肠癌、黑素瘤或癌)的调节性机理在其生长方面无有效抑制。肿瘤抗原不仅包括存在于恶性肿瘤细胞本身中或其上的抗原,而且还包括存在于肿瘤的基质支持组织(包括内皮细胞和其他血管组分)上的抗原。
如本文所用,术语“无响应性”泛指免疫细胞对刺激(例如,通过活化性受体或细胞因子的刺激)的折射性。无响应性可例如由于暴露于免疫抑制剂或高剂量的抗原而发生。
如本文所用,“可变区”或“VR”泛指在抗体结合至抗原中直接涉及的抗体中每对轻链和重链内的结构域。每条重链在一端都具有可变结构域(VH),随后是许多恒定结构域。每条轻链在一端都有可变结构域(VL)并且在另一端有恒定结构域;轻链的恒定结构域与重链的第一恒定结构域对准,并且轻链可变结构域与重链的可变结构域对准。
如本文所用,“载体”泛指能够转运其已经连接的另一核酸分子的核酸分子。一种类型的载体为“质粒”,它是指可向其中连接另外的DNA片段的环状双链DNA环。另一种类型的载体为病毒载体,其中可将另外的DNA片段连接到病毒基因组中。某些载体能够在它们所引入的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和游离型哺乳动物载体)。其他载体(例如非游离型哺乳动物载体)在引入宿主细胞中时整合到宿主细胞的基因组,并因而随宿主基因组一起复制。此外,某些载体能够引导其所可操作地连接的基因的表达。在本文将载体称为“重组表达载体”或简称为“表达载体”。一般来说,在重组DNA技术中有用的表达载体经常为质粒形式。在本说明书中,“质粒”和“载体”可互换使用,因为质粒是最常用的载体形式。然而,本发明旨在包括这些发挥等效功能的其他形式的表达载体,诸如病毒载体(例如复制缺陷型逆转录病毒、腺病毒和腺相关病毒)。所述技术和程序通常根据本领域熟知的常规方法并且如本说明书通篇所引用和讨论的多个一般且较特定的参考文献中所述来进行。参见例如Sambrook等(2001)Molec.Cloning:Lab.Manual[第3版]ColdSpring Harbor Laboratory Press。可以将标准技术用于重组DNA、寡核苷酸合成和组织培养,以及转化(例如电穿孔、脂转染)。酶促反应和纯化技术可以根据制造商的说明书或如本领域中通常所实现或如本文所述来进行。
与本文所述的分析化学、合成有机化学以及医药和药物化学结合所用的命名,以及本文所述的分析化学、合成有机化学以及医药和药物化学的实验程序和技术为熟知的并且常用于本领域中。可以将标准技术用于化学合成、化学分析、药物制备、配制和递送以及患者治疗。
“VISTA激动剂”在本文包括直接或间接促进VISTA的表达或活性尤其是其对B细胞增殖和B细胞反应例如抗原性特异性抗体反应的抑制作用的任何化合物。这包括激动性抗VISTA抗体和抗体片段、抗体或其抗体片段、肽、糖苷生物碱(glycoalkoid)、反义核酸、核酶、类视黄素、高亲和性多聚体(avemir)、小分子或其任意组合。优选的VISTA激动剂包括VISTA-Ig多肽,例如,其中VISTA多肽或其片段连接至抗体的整个Fc区或Fc区的片段,例如,人IgG1、IgG2、IgG3或IgG4。其他示例性VISTA激动剂包括VISTA的多聚形式,即,其包含多于一个VISTA多肽或其片段,例如,通常经由低聚或多聚结构域或序列连接的2、3、4、5或6个VISTA多肽。此类序列是已知的并且可以得到的。另外,VISTA激动剂包括在其表面上表达VISTA的转染细胞,和促进VISTA表达的核酸。在大多数情况下,此类激动剂将是对人VISTA特异的。
“VISTA拮抗剂”在本文包括直接或间接抑制或阻断VISTA的表达或活性尤其是其对B细胞增殖和B细胞反应例如抗原性特异性抗体反应的抑制作用的任何化合物。这包括拮抗性抗VISTA抗体和抗体片段、抗体或其抗体片段、肽、糖苷生物碱(glycoalkoid)、反义核酸、核酶、类视黄素、高亲和性多聚体(avemir)、小分子或其任意组合。优选的VISTA拮抗剂包括阻断或抑制MSDC对B细胞增殖或B细胞反应(例如,抗原特异性抗体反应)的抑制作用的抗人VISTA抗体和抗体片段。其他优选的VISTA拮抗剂包括阻断或抑制VISTA的表达的核酸,诸如反义核酸,以及干扰RNA或siRNA或肽核酸(“PNA”)。其他示例性VISTA拮抗剂包括阻断VISTA与细胞的结合的VISTA片段,所述细胞诸如为免疫细胞,和表达阻断VISTA与免疫细胞结合的VISTA多肽的细胞。
发病的程度的宿主控制清楚地反映了免疫调节反应,包括例如在肿瘤微环境的情况下导致过度的负免疫调节的控制机理。在病毒感染中,虽然在大多数情况下,免疫调节细胞和分子的病毒劫持仅通过降低宿主反应而间接促进发病的增加,但可能的是,被误导的免疫调节系统可直接充当近端病因的效应细胞/分子。
在过去十年间得到充分研究的免疫调节细胞类型是髓源性抑制细胞(MDSC)(综述见于Ostrand-Rosenberg,2010;Youn和Gabrilovich,2010)。就像CD4+FoxP3+Treg细胞,MDSC被视作关于保护性T细胞反应主要以负作用方式发挥作用,尤其是在各种肿瘤系统中。此外,有少量但越来越多的文献证实MDSC调节性控制可限制自身免疫疾病进程(Bowen和Olson,2009)。虽然MDSC的最终定义基于其(未成熟的)骨髓来源及其抑制功能,但是MDSC在鼠系统中具有针对Gr-1和CD11b的普遍接受的表面阳性表型。虽然MDSC群体通常是异质的,但是存在两个可在表型上加以区分的细胞表面表型鼠MDSC亚组。使用mAb来分离抗Gr-1识别的特异性:粒细胞/PMN样MDSC亚组是Ly6G+/hi Ly6C+/lo的,而单核细胞MDSC亚组是Ly6G+/lo Ly6C+/hi(综述见于Ostrand-Rosenberg,2010;Peranzoni等,2010;Youn和Gabrilovich,2010)。主要基于对广泛的肿瘤微环境的研究,MDSC还通过它们导致反应T细胞抑制所依赖的机理而差异化表征,这些机理包括:精氨酸酶、iNOS/NO、其他氧和氮反应性物质、以及其他机理(综述见于LaFace和Talmadge)。虽然一些MDSC综述表明B细胞反应可能对MDSC调节敏感,并且MDSC可表现出对多克隆激活物和有丝分裂原宽泛的、非MHC限制性的反应,但关于MDSC对B细胞的靶向作用的主要文献显然有限。
MDSC已在以下各种感染性疾病中进行了不太充分的研究:细菌(Gabrilovich和Nagaraj,2009)、酵母/真菌(Mencacci等,2002)、原生动物寄生虫(Voisin等,2004)、肠虫(Brys等,2005)和病毒感染例如甲型流感病毒(Jeisy-Scott等,2011)、慢性鼠乙型肝炎病毒(Chen等,2011);以及水泡性口炎病毒(Willmon等,2011)和单纯疱疹病毒1型工程株(Walker等,2011)。但是,仅有少量关于在逆转录病毒感染的情况下MDSC群体的存在或功能及接着发生的疾病诸如获得性免疫缺陷的最近报道(Vollbrecht等,2012,commentMacantangay等2012;Green等,2013;Qin等,2013;Garg和Spector,2014)。
逆转录病毒善于收编各种免疫调节机理。HIV-1和SIV已被证实可导致效应T细胞上PD-1的过早表达,这可推动抗病毒CD8+细胞毒性T淋巴细胞(CTL)效应细胞不当地早期下调,类似于在病毒清除的后期阶段发生的正常T细胞收缩阶段(Day等,2006;Velu等,2009)。对于鼠Friend逆转录病毒(FV),已报道PD-1和Tim-3的改变的表达对逆转录病毒负载和发病具有不同的作用(Takamura等,2010;Zelinsky等,2011),包括“耗竭”(exhaustion),或在其他病毒系统中观察到的“无功能”T细胞表型(Day等,2006;Velu等,2009)。病毒感染还可改变免疫调节细胞,诸如CD4+FoxP3+ T调节(Treg)细胞,这是抗肿瘤免疫和自身免疫的主要控制点(综述见于Sakaguchi,2004;Piccirillo和Shevach,2004)。在这里研究的LP-BM5鼠逆转录病毒系统中,早期报道提供证据支持CD25+CD4+ T细胞(基于其他评估的标志物但不包括FoxP3,被视为Treg)在介导LP-BM5发病中的直接作用(Beilharz等,2004)。然而,后续报道支持真实的CD4+FoxP3+ Treg细胞在LP-BM5感染/发病中的间接作用,从而限制了(与PD-1/PD-L1一起)保护性CD8+CTL反应的发生(Li和Green,2006;Li和Green 2011)。
在被LP-BM5逆转录病毒分离株感染后,小鼠的某些近交品系诸如高度敏感的C57BL/6(B6)品系产生了包括免疫缺陷的疾病综合征。始于感染后大约5周,极大的免疫缺陷非常明显,包括严重受到抑制的T细胞和B细胞反应,从而导致全面的疾病特征(Simard等,1997)。因此,当暴露于通常导致有限感染的环境病原体时,更易于发生疾病进展,有时死亡。在之后的时间点,LP-BM5感染的B6小鼠发生B细胞淋巴瘤。因为LP-BM5诱导的疾病的这些特征与在HIV感染的个体中所见的那些特征中的许多相似,所以该综合征被称为鼠AIDS(MAIDS)。
对LP-BM5逆转录病毒的发病机理尚未完全了解。将LP-BM5接种到CD4+ T细胞或B细胞遗传缺陷的或接受了CD4+ T细胞或B细胞的在先体内抗体耗尽的B6小鼠体内导致了感染,但未导致病毒诱导的疾病(Yetter等,1988)。相对于病原性CD4+ T效应细胞的这种需要,我们确定了CD154/CD40相互作用对于LP-BM5发病的诱导和进展均是必需的。在B6小鼠感染开始时或3-4周后,用□-CD 154(CD40配体)单克隆抗体(mAb)进行体内处理导致了标准MAIDS参数的实质性抑制,这些参数包括:脾肿大、高丙种球蛋白血症、免疫细胞亚组表型变化以及B细胞和T细胞免疫缺陷(Green等,1996;Green等,1998)。LP-BM5诱导的疾病的程度还受PD-1/PD-L1和IL-10控制,PD-1/PD-L1和IL-10起到下调病原性CD4+ T细胞的作用,从而导致疾病减弱(Li和Green,2006)。PD-1连接和CD4+ Treg细胞还组合抑制B6小鼠中保护性CD8+ CTL反应的产生(Li和Green,2011)。CD11b+ FCRγIII/II+骨髓细胞群的扩增也是LP-BM5诱导的发病的主要特征。基于该细胞表面表型,我们最近在该系统中评估了逆转录病毒诱导的MDSC的可能牵涉。事实上,我们鉴定了具有单核细胞表面表型(Gr-1+,Ly6C+,Ly6G-,CD11b+)的LP-BM5诱导的MDSC群,针对对于标准地用来测量LP-BM5诱导的免疫缺陷的刺激所产生的免疫反应,该细胞群具有有效的强离体抑制活性。通过使用若干提供大量信息的我们在之前已证实表现出不同水平的对LP-BM5发病的敏感性的B6k.o.品系,我们确立了体内LP-BM5诱导的疾病严重性与离体MDSC抑制活性之间的直接关系(Green等,2013)。
也在最近,已经确定了属于关键免疫负调节配体亚组的新免疫球蛋白(Ig)超家族成员VISTA(T细胞活化的V结构域Ig阻遏子)(Wang等,2011;LeMercier等,2014;Lines等,2014)。VISTA具有与B7家族配体PD-L1的同源性,尤其是对于其胞外结构域而言。因为VISTA主要在造血细胞上表达,所以VISTA可在骨髓抗原呈递细胞(APC)和T细胞上高度上调。多条证据表明VISTA在自身免疫和抗肿瘤免疫中起到抑制T细胞反应的作用。第一,VISTA特异性mAb在体外干扰VISTA诱导的VISTA表达APC对T细胞反应的抑制。第二,抗VISTA处理加剧了小鼠中T细胞介导的实验性自身免疫性脑脊髓炎的发生。第三,可溶性VISTA-Ig融合蛋白或APC上的VISTA表达在体外抑制T细胞增殖和细胞因子产生。第四,肿瘤细胞上的VISTA过表达在小鼠体内直接干扰保护性抗肿瘤免疫。这些早期报道一起表明了VISTA充当新的免疫调节分子,其具有与其他Ig超家族成员诸如PD-L1不重复的功能活性,并因此在针对肿瘤细胞的自身免疫和T细胞免疫监督的发生和调节中都发挥着可能关键性的作用,尽管对于疾病严重性而言具有基本上相反的结果。
在本申请中,我们相对于VISTA在这些MDSC的抑制机理中的可能牵涉,进一步评估了刚才描述(Green等,2013)的LP-BM5逆转录病毒诱导的单核MDSC群。具体地讲,鉴于MDSC对T细胞增殖和IFN-γ生成反应的抑制几乎完全依赖于iNOS/NO(Green等,2013),我们针对MDSC的T细胞靶标与B细胞靶标比较了VISTA牵涉,其中我们之前仅能将大约50%的MDSC抑制机理解释为是由于iNOS/NO。我们的结果表明了MDSC表达的VISTA在抑制T细胞反应与B细胞反应中的差异作用,从而强调了MDSC功能的异质性和不同MDSC亚群的可能性。
实验性实施例
实施例中所用的材料和方法
小鼠。七周龄的雄性C57BL/6(B6)小鼠购自National Institutes of Health(Bethesda,MD),关在达特茅斯医学院动物房(Dartmouth Medical School Animalfacility),并在大约8-10周龄时使用。完全回交到B6的iNOS k.o.小鼠繁殖对得自JacksonLabs(Bar Harbor,ME),并且最初来源如先前所述(Laubach等,1995)。也回交到B6的VISTAk.o.繁殖对(来源如报道的那样)得自
细胞纯化。对于实验性抑制细胞群,合并来自三只或四只LP-BM5感染小鼠(5w.p.i.)的脾细胞悬液,用□-Ly6G偶合的顺磁性珠粒标记,然后根据制造商方案进行柱纯化(MACS,Miltenyi Biotec,Auburn,CA)。将得自第一次分离的穿柱液(flow-through)用□-CD11b偶合的顺磁性珠粒标记,然后接受柱纯化,得到阳性选择的>75%CD11b+Ly6C+的细胞群。
LP-BM5病毒接种。如先前所述(Klinken等,1988)在我们的实验室中制备了LP-BM5。为了产生LP-BM5病毒储备液,最初由Janet Hartley和Herbert Morse博士(NIH)慷概提供的G6细胞(作为得自用LP-BM5病毒制备物感染的SC-1细胞的克隆细胞系)用于与未感染的SC-1细胞共同培养。将小鼠经腹膜内用5×104个嗜亲性噬斑形成单位感染,如通过标准逆转录病毒XC噬斑分析所确定(Rowe等,1970)。
3H胸苷掺入增殖分析。对于反应细胞,将5×105个未感染的脾细胞(为未分级的或CD 19+纯化的)连同1.6×105个(除非另外指明)CD11b+Ly6G+或CD11b+Ly6C+富集的抑制细胞(得自指定w.t.B6或B6敲除品系的5-w.p.i.LP-BM5小鼠的脾)平铺到96孔平底板中。将所有孔一式三分地平铺上培养基,该培养基含有5%FCS、L谷氨酰胺、抗生素和最终浓度为10.ig/ml的LPS、50.ig/ml的ct-CD40加10ng/ml的IL-4、或2.ig/ml的Con A。对于对增殖抑制的抑制分析,将未分级的或CD11b+Ly6C+富集的抑制细胞在开始共同培养前用0.8mM NOS抑制剂NG-单乙基-L-精氨酸(L-NMMA)、阴性对照对映体NG-单乙基-D-精氨酸(D-NMMA)(A.G.Scientific,San Diego,CA)、或80ug/ml纯化的ct-VISTA(13F3)或对照HIg预处理一小时。在66小时后,将所有孔用1mCi 3H胸苷(Perkin Elmer,Waltham,MA)脉冲处理,并6小时后收获,以用于通过闪烁计数法(Perkin Elmer,Waltham,MA)评估胸苷掺入。将B细胞和T细胞反应细胞刺激的数据表示为抑制百分比。对于抑制百分比的计算,首先,如下计算残余反应百分比:R=(共同培养的反应细胞和实验性抑制细胞的cpm)÷(共同培养的反应细胞和对照、未感染的抑制细胞的cpm)×100%。确定一式三份孔的平均值的标准偏差,并通过双尾、双样本等方差学生T检验进行统计比较。
CFSE稀释增殖分析。将初始反应脾细胞用5.iM于PBS/0.5%BSA中的CFSE(Celltrace,CFSE增殖试剂盒,Molecular Probes,Eugene,OR)在37℃下标记10分钟,然后添加冷的10%于RPMI中的FBS,在冰上保持5分钟。在三次冷10%FCS/RPMI洗涤后,以与上文所述的3H胸苷掺入增殖分析相同的方式建立细胞培养。在培养的第4天,将孔用单克隆抗体(mAb):ct-CD19-PerCP(Biolegend,San Diego,CA)染色,然后在FACSCalibur流式细胞仪(BDbioscience,San Jose,CA)上分析。
流式细胞术。将5×105个脾细胞与未标记的针对FcγIII/II受体的mAb(2.4G2,Biolegend,San Jose,CA)在冰上温育10分钟,然后在冰上用FITC-、PE-、APC-或PerCP-偶联的抗体进行表面染色持续25分钟。将染色后的细胞在FACSCalibur流式细胞仪上使用CellQuest软件(BD Bioscience,San Jose,CA)进行分析,如通过对数扩增所定量。为了检测以下鼠抗原的表达,采用了指定的mAb:VISTA(13F4)纯化的/PE链霉亲和素、CD4(RM4-5)、CD19(6D5)、CD11b(M1/70)、Ly6G(1A8)、Ly6C(HK1.4)。将适当的具有不相关特异性的FITC-、PE-、PerCP-或APC-偶联的Ig同种型用于每个实验性mAb的对照。
实施例1:脾细胞的VISTA表达
该实施例涉及图1中的实验。在这些实验中,显示了脾细胞的VISTA表达因体内LP-BM5感染而增加。图1(A)包括流式细胞分析,该分析显示了得自未感染的或5或8.5周被感染的W.t.B6小鼠的脾细胞的VISTA表达模式。百分比表示VISTA表达阳性的细胞;斜体的值表示VISTA阳性细胞的MFI。图1(B)显示了以下组的CD11b+细胞的脾细胞表面VISTA表达VISTA:得自指示的未感染或感染小鼠品系的细胞(无后续纯化);和得自5wpi-LP-BM5小鼠的纯化的Ly6C+CD11b+脾细胞。所展示的结果模式代表两项另外的实验。
实施例2:Ly6C+CD11b+纯化的脾细胞对于抑制体外B和T细胞增殖具有不同的机理要求
该实施例涉及图2中的实验。这些实验证明了Ly6C+CD11b+纯化的脾细胞对于抑制体外B和T细胞增殖具有不同的机理要求。图2(A和B)显示了实验的结果,其中将初始B6反应脾细胞与a-VISTA和LNMMA预处理的Ly6C+CD11b+MDSC以3:1的反应细胞与抑制细胞(R:S)比率混合,并用(A)a-CD40和IL-4或(B)Con A刺激三天。
在图中,将3H胸苷掺入转化成抑制%(参见材料和方法)。所展示的结果模式代表每个刺激的三项另外的实验。图2C显示了4项独立实验的平均值+标准偏差,这些值显示了在与初始W.t.B6反应细胞培养三天前,通过对Ly6C+CD11b+MDSC进行a-VISTA预处理,而对抑制产生的阻断%。显著性水平:*,P<0.05;**,P<0.01,***,P<0.001。
实施例3:VISTA拮抗剂对MDSC介导的脾细胞增殖抑制的作用
该实施例涉及图3中的实验。在这些实验中,将初始VISTA-/-反应脾细胞与a-VISTA预处理的Ly6C+CD11b+MDSC以3:1的反应细胞与抑制细胞(R:S)比率混合,并用a-CD40和IL-4刺激三天。所展示的结果模式代表三项另外的实验。*,P<0.05;**,P<0.01;***,P<0.001;ns.,P>0.05。
实施例4:脾细胞增殖的MDSC抑制
该实施例涉及图4中的实验。在这些实验中,得自指定品系的5周LP-BM5感染小鼠的纯化的单核MDSC(Ly6C+CD11b+)显示了初始VISTA-/-脾细胞增殖的差异抑制模式,如通过流式细胞术所评估。将CFSE标记的VISTA-/-反应细胞在存在(+)或不存在(-)ct-CD40+IL-4并且具有或不具有MDSC(a)(-);(b)(+)(灰色阴影曲线);(c)(+),W.t.MDSC(黑色开放曲线);(d)(+),DNMMA处理的W.t.MDSC(黑色开放曲线);(e)(+),LNMMA处理的W.t.MDSC;(f)(+),INOS-/-MDSC(虚线曲线);(g)(+),(h)(+),VISTA-/-MDSC与w.t.MDSC的情况下培养三天;将得自所有培养的细胞在四天温育结束时用ct-CD19荧光染料偶联的mAb染色,并且还通过FACS评估了CFSE稀释。CFSE标记的VISTA-/-反应细胞:%=在第一个增殖峰中的细胞百分比;斜体的数值=CFSE+细胞的MFI。所展示的结果模式代表一项另外的实验。
实施例5:B细胞增殖的MDSC抑制
该实施例涉及图5中的实验。在这些实验中,显示了B细胞增殖的单核细胞抑制取决于两大机理iNOS/NO和VISTA。在5A的实验中,将得自5w.p.LP-BM5感染的W.t.或VISTA-/-小鼠的纯化Ly6C+CD11b+MDSC用ct-VISTA阻断抗体或对照HIg、LNMMA或对照DNMMA预处理,并用VISTA-/-反应细胞以及ct-CD40和IL-4培养三天。在5(B)的实验中将W.t.Ly6C+CD11b+MDSC用如图(A)所示的相同处理方案预处理,包括既含ct-VISTA也含LNMMA的组合方案。通过cpm反应3H胸苷掺入,计算(A)和(B)的抑制%。所展示的结果模式代表两项另外的实验(A)和一项另外的实验(B)。*,P<0.05;**,P<0.01;ns.,P>0.05。
结果与结论
因为MDSC在LP-BM5逆转录病毒感染后扩增,所以首先p.i.评估了VISTA细胞表面表达。虽然在5w.p.i.下,未扩大VISTA+脾细胞的百分比,但是VISTA MFI增加,并且阳性峰的形状发生变化(图1A)。这种变化既与所报道的未感染B6小鼠中VISTA的CD4T细胞表达的优势地位一致(Wang等,2011),也与在体内刺激后扩增的另外的细胞类型诸如CD11b+VISTA+细胞一致,所述体内刺激在这里是我们已报道的扩增MDSC的LP-BM5感染(我们的参考文献)。在8.5w.p.i.下,增加的VISTA表达更加明显(图1A)。对得自未感染的小鼠相比5w.p.i.、W.t.、VISTA-/-和INOS-/-B6小鼠的细胞的VISTA和CD11b共表达进行的进一步染色确认了抗VISTAmAb的特异性,并证实了在高度富集的单核MDSC群中扩增的VISTA表达(图1B)(之前已表明还表达Ly6C(我们的参考文献和数据未在这里示出)。同样,如由Wang等(2011)开展的研究所预测,其他主要的VISTA+群为CD4T细胞区室(数据未示出)。
接下来在阻断实验中评估了单核MDSC的VISTA表达的功能。首先,将可能的VISTA机理参与和已知的iNOS/NO在MDSC抑制中的差异作用进行了比较(图2A/B)。然而,T细胞反应的MDSC抑制基本上完全依赖于iNOS/NO,如通过iNOS抑制剂LNMMA(相比对照DNMMA)所揭露;对于B细胞反应,LNMMA将MDSC抑制阻断了大约50%(如之前所示,Green等,2013)。形成鲜明的对比,抗VISTA mAb将B细胞反应的MDSC抑制也阻断了大约50%,而T细胞反应的MDSC抑制基本上不受影响。事实上,在多项独立的实验中,抗VISTA的阻断范围集中于约65%,但是如果考虑到对照仓鼠免疫球蛋白(HIg)的小非特异性作用,则更靠近大约55%的δ。因此,对于B细胞反应的抑制而言,VISTA似乎以相对于iNOS/NO可区分的方式发挥作用。
为了明确地证明抗VISTA的阻断作用具体针对MDSC,通过使用VISTA-/-反应细胞重复了抗VISTA阻断实验(图3)。同样,观察到了非常显著的(p=0.0001)但部分的被VISTA(但非HIg)产生的阻断。这些结果确认了对于阻断而言对MDSC VISTA的依赖性,并且为了简单和清楚起见,所有以下实验均采用了VISTA-/-反应细胞。
为了独立地证实这些发现并对这两种分子机理进行比较,将预负载CFSE的反应细胞在存在各种野生型与k.o.B6起源的单核MDSC的情况下进行刺激,并通过鉴定CD19+B细胞执行流式细胞分析(图4)。在图4A中,清楚地观察到了经刺激的B细胞的MDSC抑制(图a、b相比c),并且通过包括LNMMA(不是DNMMA),将增殖曲线向不存在MDSC的情况下刺激的对照B细胞的曲线部分地恢复(图d、e)。同样,通过在第一个增殖峰中显示的细胞百分比以及由第一个和所有后续增殖峰一起得到的CFSE MFI值,揭露了这种对iNOS/NO的部分依赖性。替代性使用iNOS-/-MDSC(在不存在抑制剂的情况下)通过图4B中iNOS-/-MDSC对比w.t.MDSC+LNMMA曲线(图e对比f)的叠合强调了这种CFSE增殖特征。然而,重要的是,当采用VISTA-/-MDSC时,得到两个突出的结果:1)由于MDSC VISTA表达的丧失而对MDSC抑制的部分阻断(图4的图g);和2)通过移除MDSC VISTA产生的增殖曲线相比iNOS/NO的LNMMA阻断大不相同的阻断特征,每一者与不存在抑制剂的w.t.MDSC抑制进行比较(图4的图h)。这些发现确认了VISTA相比iNOS/NO可区别的性质B细胞反应的MDSC抑制的依赖性组分,并且暗示了这两种机理的独立性。
还进行了另外的组合“处理”实验,以评估这两种途径在B细胞的MDSC抑制中的作用。首先,我们在存在iNOS/NO抑制剂LNMMA的情况下采用了w.t.相比VISTA-/-起源的MDSC。对于w.t.MDSC(作为对照),它们的B细胞反应抑制部分地被抗VISTA mAb或LNMMA阻断(图5A),与我们上文的结果相符。相比之下,在使用相同的反应细胞和试剂的相同实验中,VISTA-/-起源的MDSC以仅能被LNMMA阻断的方式抑制了B细胞反应(图5A)。并且阻断程度现在基本上为100%,从而表明了仅iNOS/NO途径的保留。这些数据还与MDSC抑制的仅两大机理途径一致。在第二种方法中,将w.t.MDSC用抗VISTA、LNMMA或这两种阻断试剂的组合处理(图5B)。仅组合处理(其中VISTA和iNOS/NO牵涉均被干扰)实现了基本上完全的对抑制的阻断。总的来说(图5A/B),对MDSC抑制的这种相加(如果不是协同的话)阻断重申了iNOS/NO和VISTA依赖性是得自LP-BM5感染小鼠的单核MDSC对B细胞反应的抑制的两大明确的机理。
总之,我们在这里就我们所知首次描述了新型负检查点调节剂VISTA在尤其是对B细胞反应的MDSC抑制中的牵涉。我们对这种VISTA依赖性抑制机理仅在B细胞而非T细胞反应的MDSC抑制中发挥作用的观察有助于我们的发现的新颖性。因此,B细胞反应性的MDSC抑制已经是正大力研究的领域。我们之前已公布了(Green等,2013)LP-BM5逆转录病毒诱导的MDSC抑制既不依赖于PD-L1也不依赖于PD-1(也不依赖于IL-10)。因此,当前关于VISTA依赖性途径的参与的结果连同iNOS/NO机理强调了VISTA相关功能相比其序列同源性上的近亲PD-L1(Wang等,2011)的独特性。与VISTA在得自LP-BM5逆转录病毒感染小鼠的相同单核MDSC群体对B细胞相比T细胞的抑制中的差异牵涉合在一起,这些结果提出了进一步的重要问题,这些问题的范围从具有不同机理和抑制靶标的功能性/表型MDSC亚群的存在可能性,到MDSC亚组在LP-BM5诱导的MAIDS所特有的T细胞和B细胞反应的极大且广泛的免疫缺陷中的作用。
本发明的治疗性应用
基于VISTA对B细胞反应的作用,尤其是其对MSDC介导的B细胞反应的抑制作用,VISTA拮抗剂可单独地或与其他免疫激活剂或激动剂尤其是增强体液免疫的那些(诸如CD40激动剂,诸如激动性抗CD40抗体或CD40L多肽)相结合使用,以便治疗或预防其中在治疗上期望增加B细胞反应的病症。此类病症尤其包括其中疾病病理学中或引发预防性或治疗性免疫时涉及到B细胞反应(例如,抗体反应)的癌症。此类癌症病症的实例包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤(包括脂肪肉瘤)、神经内分泌瘤、间皮瘤、神经鞘瘤、脑膜瘤、腺癌、黑素瘤、卵巢癌、乳腺癌、肺癌、脑癌、消化器官癌症和白血病或淋巴样恶性肿瘤。
此类癌症的更具体实例包括恶性血液病,诸如非霍奇金氏淋巴瘤(NHL)。NHL癌症包括但不限于:伯基特淋巴瘤(Burkitt's lymphoma,BL)、小淋巴细胞性淋巴瘤/慢性淋巴细胞性白血病(SLL/CLL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、弥漫性大B细胞淋巴瘤(DLCL)、边缘区淋巴瘤(MZL)、毛细胞白血病(HCL)和淋巴浆细胞样白血病(LPL)、粘膜相关淋巴组织(MALT)结外边缘区B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、纵隔大细胞淋巴瘤、血管内大细胞淋巴瘤、原发性渗出性淋巴瘤、前体B成淋巴细胞性白血病/淋巴瘤、前体T和NK细胞淋巴瘤(前体T成淋巴细胞性淋巴瘤、母细胞性NK细胞淋巴瘤)、成熟T和NK细胞肿瘤(包括外周T细胞淋巴瘤和白血病(PTL))、成人T细胞白血病/T细胞淋巴瘤和大颗粒淋巴细胞性白血病、T-细胞慢性淋巴细胞性白血病/幼淋巴细胞性白血病、T细胞大颗粒淋巴细胞性白血病、侵袭性NK细胞白血病、结外T-/NK细胞淋巴瘤、肠病型T细胞淋巴瘤、肝脾型T细胞淋巴瘤、间变性大细胞淋巴瘤(ALCL)、血管中心性和血管成免疫细胞性T细胞淋巴瘤、蕈样真菌病/塞扎里综合征(Sézary syndrome)和皮肤T细胞淋巴瘤(CTCL)。可通过VISTA拮抗剂治疗的其他癌症包括但不限于:霍奇金氏淋巴瘤、淋巴细胞前体细胞的肿瘤(包括B细胞急性成淋巴细胞性白血病/淋巴瘤(B-ALL)和T细胞急性成淋巴细胞性白血病/淋巴瘤(T-ALL)),胸腺瘤、朗格汉斯(Langerhans)细胞组织细胞增多症、多发性骨髓瘤(MM),骨髓瘤形成(诸如急性骨髓性白血病(AML),包括伴有成熟的AML、没有分化的AML、急性前髓细胞性白血病、急性骨髓单核细胞性白血病和急性单核细胞性白血病)、脊髓发育不良综合征、和慢性骨髓增生障碍(MDS)(包括慢性髓细胞性白血病(CML))。可通过VISTA拮抗剂治疗的其他癌症包括但不限于中枢神经系统的肿瘤,诸如神经胶质瘤、成胶质细胞瘤、成神经细胞瘤、星形细胞瘤、成神经管细胞瘤、室管膜瘤和视网膜母细胞瘤;以下器官的实体瘤:头和颈(如鼻咽癌、唾液腺癌和食管癌)、肺(如小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状细胞癌)、消化系统(如胃癌,包括胃肠癌、胆管或胆道癌、结肠癌、直肠癌、结直肠癌和肛门癌)、生殖系统(如睾丸癌、阴茎或前列腺癌、子宫癌、阴道癌、外阴癌、宫颈癌、卵巢癌和子宫内膜癌)、皮肤(如黑素瘤、基底细胞癌、鳞状细胞癌、光线性角化病)、肝(如肝癌、肝肿瘤、肝细胞癌和肝细胞瘤)、骨骼(如破骨细胞瘤和溶骨性骨癌)、其他组织或器官(如胰腺癌、膀胱癌、肾癌、甲状腺癌、乳腺癌、腹膜癌和卡波济氏肉瘤(Kaposi's sarcoma));以及血管系统的肿瘤(如血管肉瘤和血管外皮细胞瘤)。
可以治疗的其他具体的癌症适应症包括但不限于所有非霍奇金氏淋巴瘤(NHL),特别是难治性/耐药性NHL、慢性淋巴细胞性白血病(CLL)、急性B细胞淋巴细胞性白血病/淋巴瘤(B-ALL)、套细胞淋巴瘤(MCL)和多发性骨髓瘤(MM)。
还基于VISTA对B细胞反应的作用,尤其是其对MSDC介导的B细胞反应的抑制作用,VISTA拮抗剂可用于治疗或预防其中在治疗上期望增加B细胞反应的感染性病症。此类病症尤其包括由诸如病毒、细菌、真菌、原生动物和寄生虫的病原体引起的疾病。感染性疾病可由病毒引起,包括腺病毒、巨细胞病毒、登革热病毒、EB病毒、汉坦病毒(hanta)、甲肝病毒、乙肝病毒、丙肝病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人免疫缺陷病毒(HIV)、人乳头瘤病毒(HPV)、流感病毒、麻疹病毒、腮腺炎病毒、乳多泡病毒、脊髓灰质炎病毒、呼吸道合胞病毒(RSV)、牛瘟病毒、鼻病毒、轮状病毒、风疹病毒、SARS病毒、天花病毒、病毒性脑膜炎病毒等。感染性疾病也可由细菌引起,包括炭疽杆菌(Bacillus antracis)、布氏疏螺旋体(Borrelia burgdorferi)、空肠弯曲杆菌(Campylobacter jejuni)、砂眼衣原体(Chlamydia trachomatis)、肉毒梭菌(Clostridium botulinum)、破伤风梭菌(Clostridium tetani)、白喉(Diphtheria)、大肠杆菌(E.coli)、军团菌(Legionella)、幽门螺杆菌(Helicobacter pylori)、分枝杆菌(Mycobacterium)立克次氏体(rickettsia)、支原体(Mycoplasma)奈瑟氏菌(nesisseria)、百日咳(Pertussis)、铜绿假单胞菌(Pseudomonas aeruginosa)、肺炎链球菌(S.pneumonia)、链球菌(Streptococcus)、葡萄球菌(Staphylococcus)、霍乱弧菌(Vibrio cholerae)、鼠疫耶尔森氏菌(Yersinia pestis)等。感染性疾病还可由真菌引起,诸如烟曲霉(Aspergillus fumigatus)、皮炎芽生酵母(Blastomyces dermatitidis)、白色假丝酵母(Candida albicans)、粗球孢子菌(Coccidioides immitis)、新型隐球酵母(Cryptococcus neoformans)、夹膜组织胞浆菌(Histoplasma capsulatum)、马尼弗氏青霉(Penicillium marneffei)等。感染性疾病还可由原生动物和寄生虫引起,诸如衣原体、kokzidioa、利什曼原虫、疟原虫、立克次氏体、锥虫等。
还基于VISTA对B细胞反应的作用,尤其是其对MSDC介导的B细胞反应的抑制作用,VISTA拮抗剂可用于“增强”治疗性疫苗的效果。在本发明的该应用中,受试者将通过施用一种或多种抗原或一种或多种抗体(通常为抗原特异性的人抗体或人源化抗体)连同至少一种VISTA拮抗剂(例如,抗VISTA抗体、或拮抗性VISTA多肽、或包含此类肽的缀合物、或拮抗VISTA活性或表达的核酸诸如反义核酸)而针对特定的抗原主动或被动免疫。
VISTA拮抗剂可在施用包含所需抗原或抗体的疫苗之前、同时或之后施用。此类抗原或抗体以及VISTA拮抗剂可以在相同或不同的制剂中。最通常的是,它们包含在不同的制剂中。VISTA拮抗剂按一定的量并在一定的给药条件下施用,以使得其促进将针对所需抗原或由治疗性抗体引起的B细胞免疫反应。该抗原可包括肿瘤抗原、感染因子抗原(例如,细菌、病毒、酵母、真菌或寄生虫抗原)或可包括过敏原或自身抗原。类似地,所施用的抗体可以为肿瘤抗原、感染因子抗原(例如,细菌、病毒、酵母、真菌或寄生虫抗原)、过敏原或自身抗原特异性的。
还基于VISTA对B细胞反应的作用,尤其是其对MSDC介导的B细胞反应的抑制作用,VISTA激动剂可用于治疗或预防其中在治疗上期望降低B细胞反应的病症。此类病症尤其包括其中疾病病理学中涉及到B细胞反应的病症、其中疾病病理学中涉及到B细胞反应的炎性病症以及其中疾病病理学中涉及到B细胞反应的过敏性病症。
可用VISTA激动剂治疗的此类自身免疫疾病的实例包括以下:同种异体胰岛移植排斥、斑秃、强直性脊柱炎、抗磷脂综合征、自身免疫性爱迪生氏病(autoimmune Addison'sdisease)、抗中性白细胞胞质自身抗体(ANCA)、肾上腺自身免疫病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性心肌炎、自身免疫性嗜中性白细胞减少症、自身免疫性卵巢炎和睾丸炎、自身免疫性血小板减少症、自身免疫性荨麻疹、贝切特氏病(disease)、大疱性类天疱疮、心肌病、卡斯尔曼氏综合征(Castleman's syndrome)、口炎性腹泻-皮炎、慢性疲劳免疫机能异常综合征、慢性炎性脱髓鞘性多神经病、丘-施二氏(Churg-Strauss)综合征、疤痕性类天疱疮、CREST综合征、冷凝集素病、克罗恩氏病(Crohn's disease)、皮肌炎、盘状狼疮、特发性混合型冷球蛋白血症、因子VIII缺乏症、纤维肌痛-纤维肌炎、肾小球肾炎、格雷夫斯氏病(Grave's disease)、格-巴二氏(Guillain-Barre)病、古德帕斯丘综合征(Goodpasture's syndrome)、移植物抗宿主病(GVHD)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、血友病A、特发性肺纤维化、特发性血小板减少性紫瘢(ITP)、IgA神经病、IgM多神经病、免疫介导的血小板减少症、幼年型关节炎、川崎氏病(Kawasaki's disease)、扁平苔藓(Iichen plantus)、红斑狼疮、美尼尔氏病(Meniere'sdisease)、混合性结缔组织病、多发性硬化症、1型糖尿病、重症肌无力、寻常天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、多腺性综合征、风湿性多肌痛、多肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬变、银屑病、银屑病性关节炎、雷诺氏现象(Reynaud’sphenomenon)、莱特尔氏综合征(Reiter's syndrome)、类风湿性关节炎、结节病、硬皮病、斯耶格伦氏综合征(syndrome)、实体器官移植排斥、僵人综合征、系统性红斑狼疮、大动脉炎、颞动脉炎/巨细胞动脉炎、血栓性血小板减少性紫瘢、溃疡性结肠炎、葡萄膜炎、血管炎诸如疱疹样皮炎血管炎、白癜风和韦格纳氏肉芽肿病(Wegner's granulomatosis)。
可用VISTA激动剂治疗的此类自身免疫病症的实例包括以下:急性呼吸窘迫综合征(ARDS)、急性脓毒性关节炎、佐剂性关节炎、幼年型特发性关节炎、变应性脑脊髓炎、变应性鼻炎、变应性脉管炎、过敏症、哮喘、动脉粥样硬化、由于慢性细菌或病毒感染引起的慢性炎症、慢性阻塞性肺病(COPD)、冠状动脉疾病、脑炎、炎性肠病、炎性骨质溶解、与急性和迟发性超敏反应有关的炎症、与肿瘤有关的炎症、外周神经损伤或脱髓鞘性疾病、与组织创伤诸如烧伤和局部缺血有关的炎症、由脑膜炎引起的炎症、多器官损伤综合征、肺纤维化、脓毒症和败血性休克、斯-约二氏(Stevens-Johnson)综合征、未分化的关节化脓以及未分化的脊椎关节病。
可用VISTA激动剂治疗的此类过敏性病症的实例包括例如可用VISTA激动剂治疗的优选的过敏性病症包括:过敏性接触性皮炎、普秃、哮喘、过敏性紫癜性哮喘、特应性皮炎、疱疹样皮炎、持久隆起性红斑、边缘性红斑、多形性红斑、结节性红斑、过敏性肉芽肿、环状肉芽肿、粒细胞减少症、过敏性肺炎、角膜炎、肾病综合征、重叠综合征(overlapsyndrome)、养鸽人疾病(pigeon-breeder’s disease)、特发性多神经炎、荨麻疹、葡萄膜炎、青少年皮肌炎和白癜风。
其中可能期望降低B细胞反应的病症的其他实例包括:变应性支气管肺曲霉病;自身免疫性溶血性贫血;黑棘皮病;变应性接触性皮炎;爱迪生氏病(Addison's disease);特应性皮炎;斑秃;普秃;淀粉样变性;过敏性样紫癜;过敏性样反应;再生障碍性贫血;遗传性血管性水肿;特发性血管性水肿;强直性脊柱炎;颅动脉炎;巨细胞动脉炎;高安动脉炎(Arteritis,Takayasu's);颞动脉炎;哮喘;共济失调-毛细血管扩张症;自身免疫性卵巢炎;自身免疫性睾丸炎;自身免疫性多内分泌腺衰竭;贝切特氏病(disease);伯杰氏病(Berger's disease);伯格病(Buerger's disease);大疱性天疱疮;慢性粘膜皮肤型念珠菌病;卡普兰综合征(Caplan's syndrome);心肌梗死后综合征;心包切开后综合征;心炎;乳糜泻(celiac sprue);查加斯病(Chagas's disease);谢-希综合征(Chediak-Higashi syndrome);丘-斯病(Churg-Strauss disease);科根综合征(Cogan'ssyndrome);冷凝集素病;肢端硬皮综合征;克罗恩氏病(Crohn's disease);冷球蛋白血症;原因不明的纤维化肺泡炎;疱疹样皮炎;皮肌炎;糖尿病;戴-布综合征(Diamond-Blackfansyndrome);迪乔治综合征(DiGeorge syndrome);盘形红斑狼疮;嗜酸性粒细胞增多性肌膜炎;巩膜外层炎;持久隆起性红斑;边缘性红斑;多形性红斑;结节性红斑;家族性地中海热;费尔蒂综合征(Felty's syndrome);肺纤维化;过敏性样肾小球肾炎;自身免疫性肾小球肾炎;链球菌感染后肾小球肾炎;移植后肾小球肾炎;膜性肾小球病;古德帕斯丘综合征(Goodpasture's syndrome);移植物抗宿主病;免疫介导型粒细胞减少;环形肉芽肿;变应性肉芽肿病;肉芽肿肌炎;格雷夫斯病(Grave's disease);桥本氏甲状腺炎(Hashimoto'sthyroiditis);新生儿溶血病;特发性血色素沉着病;亨-舍紫癜(purpura);慢性活动型和慢性进行性肝炎;组织细胞增多症X;嗜酸性粒细胞增多综合征;特发性血小板减少性紫癜;乔布综合征(Job's syndrome);幼年型皮肌炎;幼年型类风湿性关节炎(幼年型慢性关节炎);川畸病(Kawasaki's disease);角膜炎;干燥性角结膜炎;兰-格-巴-斯四氏综合征(Landry-Guillain-Barre-Strohl syndrome);瘤型麻风;勒夫勒综合征(Loeffler's syndrome);莱尔综合征(Lyell's syndrome);莱姆病(Lyme disease);淋巴瘤样肉芽肿病;全身性肥大细胞病;混合性结缔组织病;多发性单神经炎;穆-韦综合征(Muckle-Wells syndrome);粘膜皮肤淋巴结综合征;多中心性网状组织细胞增多症;多发性硬化;重症肌无力;蕈样肉芽肿病;系统性坏死性血管炎;肾病综合征;重叠综合征;脂膜炎;阵发性寒冷性血红蛋白尿;阵发性睡眠性血红蛋白尿;类天疱疮;天疱疮;红斑性天疱疮;落叶性天疱疮;寻常性天疱疮;养鸽人疾病(Pigeon breeder's disease);过敏性肺炎;结节性多动脉炎;风湿性多肌痛;多肌炎;特发性多神经炎;葡萄牙家族性多发性神经病;先兆子痫/子痫;原发性胆汁性肝硬化;进行性系统性硬化症(硬皮病);银屑病;银屑病关节炎;肺泡蛋白沉着症;肺纤维化;雷诺氏现象/综合征(Raynaud's phenomenon/syndrome);里德尔甲状腺炎(Reidel's thyroiditis);赖特尔综合征(Reiter's syndrome);复发性多软骨炎;风湿热;类风湿性关节炎;结节病;巩膜炎;硬化性胆管炎;血清病;塞泽里综合征(Sézary syndrome);干燥综合征(syndrome);斯-约综合征(Stevens-Johnsonsyndrome);斯蒂尔病(Still's disease);亚急性硬化性全脑炎;交感性眼炎;系统性红斑狼疮;移植物排斥反应;溃疡性结肠炎;未分化型结缔组织病;慢性荨麻疹;寒冷性荨麻疹;眼色素层炎;白癜风;韦-克病(Weber-Christian disease);韦格纳氏肉芽肿病(Wegener'sgranulomatosis);维-奥综合征(Wiskott-Aldrich syndrome)。可用VISTA激动剂或拮抗剂治疗的其他B细胞相关病症包括B细胞相关病症,包括特征在于具有过多的B细胞、过少的B细胞、过度活跃的B细胞、不活跃的B细胞(或活动实质性降低的B细胞)或功能障碍的B细胞的病状。已知涉及B细胞的示例性人疾病包括但不限于:自身免疫疾病(例如,类风湿性关节炎、系统性红斑狼疮、干燥综合征(syndrome)、ANCA相关血管炎、抗磷脂综合征\特发性血小板减少性紫癜(ITP)、自身免疫性溶血性贫血、吉兰巴雷综合征(Guillain-Barrésyndrome)、慢性免疫多发性神经病、自身免疫性甲状腺炎、I型(自身免疫性)糖尿病、膜性肾小球肾炎、古德帕斯彻病(Goodpasture's disease)、自身免疫性胃炎、恶性贫血、寻常性天疱疮(pemphigus vulgarus)、原发性胆汁性肝硬化、皮肌炎-多发性肌炎、重症肌无力、系统性硬化症(硬皮病)、多发性硬化、间质性肺病、慢性疲劳综合征、由于孕期抗中性粒细胞胞浆抗体(ANCA)导致的自身免疫性甲状腺炎和乳糜泻);炎性疾病(例如,免疫球蛋白A神经病、亨-舍恩莱因紫癜(purpura)、慢性移植物排斥、特应性皮炎、桥本甲状腺炎(Hashimoto's thyroiditis)、格雷夫斯病(Grave's disease)、萎缩性甲状腺炎、立得氏甲状腺炎(Riedel's thyroiditis)、哮喘、神经莱姆病(lyme neuroborreliosis)、溃疡性结肠炎、克罗恩氏病(Crohn’s disease)和过敏症);以及癌症(例如,淋巴瘤、非霍奇金氏淋巴瘤(NHL)、侵袭性NHL、复发侵袭性NHL、复发惰性NHL、难治性NHL、难治性惰性NHL、慢性淋巴细胞性白血病(CLL)包括免疫球蛋白突变CLL和免疫球蛋白非突变CLL、小淋巴细胞性淋巴瘤、白血病、毛细胞白血病(HCL)、急性淋巴细胞性白血病(ALL)、套细胞淋巴瘤、中级/滤泡性NHL、中级弥散性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小无核裂细胞性NH、肿块性疾病NHL(bulky disease NHL)、伯基特淋巴瘤(Burkitt's lymphoma)、多发性骨髓瘤、前体B细胞成淋巴细胞性白血病和其他源自早期B细胞前体的恶性肿瘤、毛细胞白血病、裸细胞型急性成淋巴细胞性白血病、瓦尔登斯特伦氏巨球蛋白血症(macroglobulinemia)、弥散性大B细胞淋巴瘤(DLBCL)包括生发中心B细胞样(GCB)DLBCL、活化的B细胞样(ABC)DLBCL和3型DLBCL、幼淋巴细胞性白血病、轻链疾病、浆细胞瘤、骨硬化性骨髓瘤、浆细胞白血病、意义未明的单克隆丙种球蛋白病(MGUS)、郁积型多发性骨髓瘤(SMM)、无痛性多发性骨髓瘤(IMM)、霍奇金氏淋巴瘤包括经典和结节状淋巴细胞优势型、淋巴浆细胞增多型淋巴瘤(LPL)、以及边缘区淋巴瘤包括胃粘膜相关淋巴组织(MALT)淋巴瘤。
硬皮病涵盖一组异质性疾病,包括但不限于:限制性皮肤病、弥散性皮肤病、无皮肤硬化的硬皮病、未分化的结缔组织病、重叠综合征、局限性硬皮病、硬斑病、线形硬皮病、类军刀伤(en coup de saber)、布施克成人硬化病(scleredema adultorum of Buschke)、硬化性粘液水肿、慢性移植物抗宿主病(GVHD)、嗜酸细胞性筋膜炎、糖尿病的指状硬化以及原发性淀粉样变性和与多发性骨髓瘤相关的淀粉样变性。(综述见于:Harrison'sPrinciples of Internal Medicine,第16版/编辑Dennis L.Kasper等The McGraw-HillCompanies,Inc.2005New York,N.Y.)。
序列
鼠VISTA SEQ ID NO:1
鼠VISTA SEQ ID NO:2
鼠VISTA SEQ ID NO:3
人VISTA SEQ ID NO:4
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Claims (40)
1.一种抑制或逆转有需要的受试者中的VISTA介导的体液免疫抑制的方法,所述方法包括施用VISTA拮抗剂。
2.根据权利要求1所述的方法,其用于治疗包括其中B细胞免疫受到抑制的癌症或感染性疾病病症的受试者。
3.一种促进或增加有需要的受试者中的VISTA介导的体液免疫抑制的方法,所述方法包括施用VISTA激动剂。
4.根据权利要求3所述的方法,其用于治疗包括其中疾病病理学中涉及到B细胞或抗体反应的自身免疫、过敏、炎性或感染性病症的受试者。
5.一种抑制有需要的受试者中的B细胞增殖或B细胞反应(包括但不限于抗原特异性抗体反应)的方法,所述方法包括施用VISTA激动剂。
6.根据权利要求5所述的方法,其用于治疗包括其中疾病病理学中涉及到B细胞或抗体反应的自身免疫、过敏、炎性或感染性病症的受试者。
7.一种增加有需要的受试者中的B细胞增殖或B细胞反应(包括但不限于抗原特异性抗体反应)的方法,所述方法包括施用VISTA拮抗剂。
8.根据权利要求7所述的方法,其用于治疗包括其中B细胞免疫受到抑制的癌症或感染性疾病病症的受试者。
9.一种促进针对抗原或治疗性抗体引起的体液免疫反应的方法,所述方法包括在包括使用VISTA拮抗剂的治疗性方案中施用此类抗原或抗体。
10.根据权利要求9所述的方法,其中所述抗原是肿瘤抗原、自身抗原、过敏原或感染因子抗原。
11.根据权利要求9所述的方法,其中所述抗体是肿瘤抗原、自身抗原、过敏原或感染因子抗原特异性的。
12.一种促进由治疗性或预防性疫苗引起的体液免疫反应的方法,所述方法包括在包括使用VISTA拮抗剂的治疗性方案中施用此类疫苗。
13.根据权利要求12所述的方法,其中所述疫苗含有肿瘤抗原、自身抗原、过敏原或感染因子抗原。
14.根据权利要求1-13中任一项所述的方法,其还包括施用iNOS/NO抑制剂。
15.根据权利要求1-13中任一项所述的方法,其还包括施用iNOS/NO促进剂或一氧化氮或包含一氧化氮的化合物。
16.根据权利要求14所述的方法,其中所述iNOS/NO抑制剂是抑制一氧化氮或一氧化氮合成的化合物。
17.根据权利要求14所述的方法,其中所述iNOS/NO抑制剂是促进一氧化氮或一氧化氮合成的化合物。
18.根据权利要求17所述的方法,其中所述化合物是精氨酸衍生物,任选地NG-硝基-L-精氨酸甲酯、NG-乙基-L-精氨酸、N-亚氨乙基-L-精氨酸、L-NG-甲基精氨酸和NG-硝基-L-精氨酸或所述抑制剂是NG-硝基-L-精氨酸甲酯。
19.根据权利要求17所述的方法,其中所述化合物是洛伐他汀、苯乙酸钠盐(NaPA)、FPT抑制剂II、N-乙酰半胱氨酸(NAC)和cAMP或US 6,586,474;6,545,170;6,593,372;6,787,668;6,809,117;6,591,889;7,196,118;7,049,058中所公开的任何iNOS/NO抑制剂;所有这些专利均以引用方式全文并入本文。
20.根据权利要求1-19中任一项所述的方法,其中所述VISTA拮抗剂是抗VISTA抗体或VISTA的片段。
21.根据前述权利要求中任一项所述的方法,其中所述iNOS/NO抑制剂是L-NMA或LNMMA。
22.根据前述权利要求中任一项所述的方法,其中所述VISTA激动剂是激动性抗人VISTA抗体或抗体片段或VISTA-Ig缀合物或VISTA的多聚形式。
23.根据权利要求22所述的方法,其中所述VISTA-Ig包含IgG1、IgG2、IgG3或IgG4Fc区或其片段,其可任选地进行修饰以便削弱或增强至少一种效应功能。
24.根据前述权利要求中任一项所述的方法,其中所述受试者患有癌症或感染性疾病。
25.根据前述权利要求中任一项所述的方法,其中所述受试者患有由诸如逆转录病毒的病毒、细菌或寄生虫导致的感染性疾病。
26.根据前述权利要求中任一项所述的方法,其中所述受试者患有晚期癌症或转移性癌症和/或包括实体瘤。
27.根据权利要求26所述的方案,其中所述癌症是肉瘤、黑素瘤、卵巢癌、肺癌、淋巴瘤、白血病或骨髓癌。
28.根据前述权利要求所述的方法,其中所述VISTA激动剂或拮抗剂是完整抗VISTA抗体或抗体片段。
29.根据权利要求28所述的方法,其中所述抗体是人的或人源化的。
30.根据权利要求28所述的方法,其中所述抗体包含人Fc区。
31.根据权利要求30所述的方法,其中所述Fc区为IgG1、IgG2、IgG3或IgG4。
32.根据权利要求28所述的方法,其中使所述Fc区经突变以抑制或增强补体结合、FcR结合、ADCC、糖基化或半衰期。
33.根据前述权利要求中任一项所述的方法,其还包括施用PD-1、或PD-L1激动剂或PD-1、或PD-L1拮抗剂。
34.根据权利要求33所述的方法,其中所述拮抗剂是抗PD-1抗体或抗PD-L1抗体或PD-1融合蛋白。
35.根据权利要求33所述的方法,其中所述激动剂是抗PD-1抗体或抗PD-L1抗体、或PD-1或PD-L1融合蛋白、或表达PD-1或PD-L1的细胞。
36.根据前述权利要求中任一项所述的方法,其中VISTA拮抗剂和iNOS/NO抑制剂一起施用。
37.根据前述权利要求中任一项所述的方法,其中VISTA激动剂和iNOS/NO促进剂一起施用。
38.根据前述权利要求中任一项所述的方法,其中VISTA拮抗剂和iNOS/NO抑制剂在治疗性方案中分开施用以促进B细胞免疫。
39.根据前述权利要求中任一项所述的方法,其中VISTA拮抗剂化合物和iNOS/NO抑制剂化合物以相对于单独施用的这些化合物中的任一种足以引起对体液免疫的协同作用的量施用。
40.根据前述权利要求中任一项所述的方法,其中VISTA激动剂化合物和iNOS/NO促进剂或一氧化氮以相对于单独施用的这些化合物中的任一种足以引起对体液免疫的协同作用的量施用。
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CN107073109B (zh) | 2021-08-06 |
JP7026169B2 (ja) | 2022-02-25 |
WO2015191881A2 (en) | 2015-12-17 |
MX2016016310A (es) | 2017-10-20 |
AU2015274504B2 (en) | 2021-02-04 |
WO2015191881A9 (en) | 2016-04-21 |
CA2951885C (en) | 2023-07-04 |
US20170119877A1 (en) | 2017-05-04 |
JP6997619B2 (ja) | 2022-01-17 |
EP3154585A2 (en) | 2017-04-19 |
JP2020169192A (ja) | 2020-10-15 |
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MX2022001143A (es) | 2022-02-16 |
EP3154585B1 (en) | 2022-02-23 |
US11123426B2 (en) | 2021-09-21 |
EP3154585A4 (en) | 2017-12-06 |
US20220040298A1 (en) | 2022-02-10 |
AU2015274504A1 (en) | 2017-01-12 |
WO2015191881A3 (en) | 2016-03-03 |
CA2951885A1 (en) | 2015-12-17 |
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