CN109415706A - 假型化的溶瘤弹状病毒及其在组合治疗中的应用 - Google Patents
假型化的溶瘤弹状病毒及其在组合治疗中的应用 Download PDFInfo
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Abstract
本发明的实施方案包括与用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒相关的组合物和方法,以及它们特别是与补体抑制剂组合而作为抗癌治疗剂的用途。
Description
相关申请的交叉引用
本申请要求2016年5月19日提交的美国临时专利申请系列号62/338,940的权益,其全部内容通过引用并入本文。
以文本文件提供的序列表通过引用并入
序列表以文本文件提供,文本于2017年5月17日创建,名称为“PAT 104044W-90Sequence Listing.txt”,大小为12.6 KB。该文本文件的内容通过引用整体并入本文。
发明领域
本发明总体上涉及病毒学和医学。在某些方面,本发明涉及溶瘤病毒,特别是嵌合的溶瘤弹状病毒及其与补体抑制剂组合用于治疗癌症的用途。
背景
溶瘤病毒特异性地感染恶性细胞,在其中复制并杀死恶性细胞,而正常组织不受影响。几种用于治疗各种肿瘤的溶瘤病毒已经达到临床评估的最后阶段。
弹状病毒(Rhabdoviruses),包括水疱性口炎病毒(vesicular stomatitisvirus, VSV)和Maraba病毒(MRB),是已进行广泛临床前研究的溶瘤弹状病毒的两个例子。弹状病毒是具有前景的临床候选药物,因为该病毒没有遗传重配、整合到宿主基因组或恶性转化的潜力。这些病毒可溶解多种肿瘤细胞,对1型干扰素高度敏感,使得治疗指数非常大。此外,人类感染很罕见并且通常无症状,所以人类几乎没有预先存在的免疫力。目前溶瘤VSV和MRB在I期人体临床试验中进行临床评估。
一些研究已经使用小鼠模型证明,在用溶瘤弹状病毒进行初始体内治疗后,发生强烈的中和抗体反应,这极大地降低了后续病毒给药的功效。克服循环溶瘤弹状病毒的抗体中和作用的治疗方法将带来本领域的显著进步。
发明概述
在几个实施方案中,本发明提供一种假型化的复制型溶瘤弹状病毒,其包含代替弹状病毒糖蛋白的沙粒病毒包膜糖蛋白,还提供了一种药物组合物,其包含用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒和药学上可接受的载体。在一些实施方案中,该假型化的复制型溶瘤弹状病毒是野生型或重组水疱病毒,特别是野生型或重组的水疱性口炎病毒(VSV)或Maraba病毒(MRB),其中沙粒病毒糖蛋白取代了VSV或MRB糖蛋白。在一些实施方案中,假型化的溶瘤弹状病毒是包含一种或多种增加肿瘤选择性和/或病毒溶瘤作用的遗传修饰的VSV或MRB。在其它优选的实施方案中,沙粒病毒糖蛋白是淋巴细胞脉络丛脑膜炎病毒(LCMV)糖蛋白、Lassa病毒糖蛋白、Junin病毒糖蛋白或其变体(variant)。在特别优选的实施方案中,本发明提供了用Lassa或Junin糖蛋白替代VSV或Maraba糖蛋白的假型溶瘤VSV或Maraba病毒。在一些实施方案中,与具有相同遗传背景的非假型化的复制型溶瘤性弹状病毒相比,假型化的复制型溶瘤弹状病毒表现出降低的嗜神经性。在其他实施方案中,假型化的复制型溶瘤弹状病毒包含编码一种或多种肿瘤抗原的异源核酸序列(例如WIPO公开号WO2014/127478的第[0071]-[0082]段和美国专利申请公开号2012/0014990的第[0042]段中提到的那些,其内容通过引用并入本文)和/或包含编码一种或多种细胞因子的异源核酸序列和/或包含编码一种或多种免疫检查点抑制剂的异源核酸序列。
在其他实施方案中,本发明提供了一种治疗和/或预防癌症和/或治疗和/或预防转移癌的方法,该方法包含向有此需要的哺乳动物施用有效量的包含沙粒病毒糖蛋白的假型化的复制型溶瘤弹状病毒。在优选的实施方案中,该溶瘤弹状病毒是用Lassa病毒或Junin病毒糖蛋白假型化的VSV或Maraba病毒,并且该哺乳动物是人。优选地,通过全身(例如血管内)和/或肿瘤内施用途径给哺乳动物施用多剂量(2、3、4、5、6或更多剂量)假型化的复制型溶瘤弹状病毒。在其他优选的实施方案中,待治疗和/或预防的癌症选自肝癌、脑癌(例如神经胶质瘤)、黑素瘤、前列腺癌、乳腺癌、结肠癌、结肠直肠癌、肺癌、肾癌、胰腺癌、食道癌和膀胱癌。
在相关的实施方案中,本发明提供一种药物组合,其包括(i)包含沙粒病毒糖蛋白的假型化的复制型溶瘤弹状病毒和(ii)补体抑制剂。在优选的实施方案中,本发明提供一种治疗和/或预防癌症和/或治疗和/或预防转移癌的方法,其包括向被诊断患有癌症或有发展成癌症或转移癌的风险的哺乳动物共同施用(i)有效治疗和/或预防癌症和/或转移癌的量的包含沙粒病毒糖蛋白的假型化的复制型溶瘤弹状病毒,和(ii)有效抑制补体活性的量的补体抑制剂。优选地,该组合的假型化的复制型溶瘤弹状病毒通过肿瘤内、全身的、特别是血管内(静脉内和/或动脉内)或颅内施用,并且多次施用。在一些实施方案中,与单独施用(即不存在补体抑制剂)相同的假型化的复制型溶瘤弹状病毒相比,假型化的复制型溶瘤弹状病毒的治疗浓度在哺乳动物中维持的时间增加。
在相关的实施方案中,本发明提供了一种用于预防或降低哺乳动物中抗体对用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒的中和作用的方法,该方法包含向该哺乳动物共同施用一种或多种补体抑制剂及该假型化的复制型溶瘤弹状病毒。优选地,该哺乳动物是人。
在其他相关的实施方案中,本发明提供了一种在向哺乳动物施用一次或多次所述病毒之后,增加用沙粒病毒糖蛋白假型化的假型复制型溶瘤弹状病毒在所述哺乳动物中的持久性的方法,所述方法包含向该哺乳动物共同施用一种或多种补体抑制剂和该假型化的复制型溶瘤弹状病毒。优选地,该哺乳动物是人。
该组合中的补体抑制剂抑制、防止或减少导致产生C3a或通过C3a受体的信号传导或导致产生C5a或通过C5a受体的信号传导的补体级联(cascade)的激活和/或传播。可用于该组合的补体抑制剂包括在经典、替代(alternative)或凝集素途径中的一种或多种上起作用的补体抑制剂。在一些实施方案中,该组合中的补体抑制剂抑制经典途径。在其他实施方案中,该组合中的补体抑制剂抑制替代途径。在其他实施方案中,该组合中的补体抑制剂抑制经典途径和替代途径,在这种情况下,该补体抑制剂优选靶向终末途径的组分,例如C3或C5。
该组合中的弹状病毒包括但不限于野生型或基因修饰的Arajas病毒、Chandipura病毒、Cocal病毒、Isfahan病毒、Maraba病毒、Piry病毒、水泡性口炎Alagoas病毒、BeAn157575病毒、Boteke病毒、Calchaqui病毒、美洲鳗病毒(Eel virus American)、Grey Lodge病毒、Jurona病毒、Klamath病毒、Kwatta病毒、 La Joya病毒、Malpais Spring病毒、MountElgon蝙蝠病毒、Perinet病毒、Tupaia病毒、Farmington病毒、Bahia Grande病毒、MuirSprings病毒、Reed Ranch病毒、Hart Park病毒、Flanders病毒、Kamese病毒、Mosqueiro病毒、Mossuril病毒、Barur病毒、福冈(Fukuoka)病毒、克恩峡谷(Kern Canyon)病毒、Nkolbisson病毒、Le Dantec病毒、Keuraliba病毒、Connecticut病毒、New Minto病毒、Sawgrass病毒、Chaco病毒、Sena Madureira病毒、Timbo病毒、Almpiwar病毒、Aruac病毒、Bangoran病毒、Bimbo病毒、Bivens Arm病毒、Blue crab病毒、Charleville病毒、CoastalPlains病毒、DakArK 7292病毒、Entamoeba病毒、Garba病毒、Gossas病毒、Humpty Doo病毒、Joinjakaka病毒、Kannamangalam病毒、Kolongo病毒、Koolpinyah病毒、Kotonkon病毒、Landjia病毒、Manitoba病毒、Marco病毒、Nasoule病毒、Navarro病毒、Ngaingan病毒、Oak-Vale病毒、Obodhiang病毒、Oita病毒、Ouango病毒、Parry Creek病毒、Rio Grande cichlid病毒、Sandjimba病毒、Sigma病毒、Sripur病毒、 Sweetwater Branch病毒、Tibrogargan病毒、Xiburema病毒、Yata病毒、Rhode Island病毒、Adelaide River病毒、Berrimah病毒、Kimberley病毒或牛流行热病毒。在一些优选的实施方案中,假型化的溶瘤弹状病毒是假型野生型或重组水泡病毒。在其他优选的实施方案中,该组合中的假型化的溶瘤弹状病毒是基于野生型或重组VSV、Farmington、Maraba、Carajas、Muir Springs或Bahia grande病毒背景株(background strain)(包括其变体)而获得的。在特别优选的实施方案中,该组合中的假型化的溶瘤弹状病毒是基于VSV或Maraba弹状病毒的背景株而获得的。在其他特别优选的实施方案中,该溶瘤弹状病毒是VSV或Maraba弹状病毒,其包含一种或多种增加病毒的肿瘤选择性和/或溶瘤作用的基因修饰。
在相关的实施方案中,根据该组合疗法的假型化的溶瘤弹状病毒被改造已表达一种或多种肿瘤抗原,例如在WIPO公开号WO 2014/127478的第[0071]-[0082]段和美国专利申请公开号2012/0014990的第[0042]段中提到的那些。在优选的实施方案中,该假型化的溶瘤弹状病毒(例如VSV或Maraba株)表达MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺蛋白的六跨膜上皮抗原、或癌睾丸抗原1或其变体。在特别优选的实施方案中,溶瘤病毒是溶瘤弹状病毒,其选自表达MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺蛋白的六跨膜上皮抗原、或癌睾丸抗原1或其变体的Maraba和VSVdelta51。
在其他实施方案中,根据该组合疗法的假型化的溶瘤弹状病毒被工程化以表达一种或多种细胞因子。
在其他实施方案中,一种或多种免疫检查点抑制剂与补体抑制剂和假型化的溶瘤弹状病毒的药物组合共同施用,以治疗和/或预防癌症或转移癌,优选在有此需要的人类对象中施用。
该组合中的假型化的溶瘤弹状病毒可以以一个或多个剂量的10、100、103、104、105、106、107、108、109、1010、1011、1012、1013、1014或更多的病毒颗粒(vp)或噬斑形成单位(pfu)施用。在优选的实施方案中,该假型化的溶瘤弹状病毒是野生型或基因修饰的VSV或Maraba,其中LCMV、Lassa或Junin糖蛋白替代了VSV或Maraba糖蛋白,并且任选地表达一种或多种肿瘤抗原和/或细胞因子,并以一个或多个剂量的106-1014 pfu、106-1012 pfu、108-1014 pfu或108-1012施用至患有癌症的人。施用可以通过肿瘤内、腹膜内、静脉内、动脉内、肌肉内、皮内、颅内、皮下或鼻内施用。在优选的实施方案中,该假型化的溶瘤弹状病毒被全身施用,特别是通过血管内(静脉内和/或动脉内)施用,包括注射、灌注等。
该假型化的溶瘤弹状病毒和补体抑制剂同时或依序地施用至有需要的哺乳动物,并且可以作为同一个制剂的一部分施用或以不同制剂施用。在一些实施方案中,补体抑制剂的第一剂量在假型化的溶瘤弹状病毒的第一剂量之后、但在随后的(例如,第二)剂量之前施用。在其他实施方案中,在假型化的溶瘤弹状病毒的第一剂量之前施用一个剂量的补体抑制剂,并且任选地,在假型化的溶瘤弹状病毒的每个随后剂量之前都施用一个剂量的补体抑制剂。因此,在一些实施方案中,补体抑制剂的第一剂量在假型化的溶瘤弹状病毒的第一剂量之前施用,并且补体抑制剂的第二剂量在假型化的溶瘤弹状病毒的第二剂量之前施用,以此类推。
根据本文所述的组合治疗的癌症包括但不限于白血病、急性淋巴细胞白血病、急性髓细胞白血病、成髓细胞早幼粒细胞、髓单核细胞红细胞白血病、慢性白血病、慢性粒细胞(粒细胞)白血病、慢性淋巴细胞白血病、套细胞淋巴瘤、原发性中枢神经系统淋巴瘤、伯基特淋巴瘤和边缘区B细胞淋巴瘤、真性红细胞增多症淋巴瘤、霍奇金病、非霍奇金病、多发性骨髓瘤、Waldenstrom氏巨球蛋白血症、重链疾病、实体瘤、肉瘤、以及癌、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮细胞瘤、滑膜瘤、间皮瘤、尤因氏(Ewing)肿瘤、平滑肌肉瘤、横纹肌肉瘤、结肠肉瘤、结肠直肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管肺癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、Wilm氏肿瘤、宫颈癌、子宫癌、睾丸肿瘤、肺癌、小细胞肺癌、非小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、血管瘤、神经母细胞瘤、视网膜母细胞瘤、鼻咽癌、食管癌、基底细胞癌、胆道癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌症、宫颈癌、绒毛膜癌、结肠直肠癌、结缔组织癌、消化系统癌、子宫内膜癌、食道癌、眼癌、头颈癌、胃癌、上皮内瘤、肾癌、喉癌、肝癌、肺癌(包括小细胞肺癌、鳞状非小细胞肺癌和非鳞状非小细胞肺癌))、黑色素瘤(包括转移性黑色素瘤)、神经母细胞瘤;口腔癌(例如唇、舌、口和咽)、卵巢癌、胰腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌;呼吸系统癌、肉瘤、皮肤癌、胃癌、睾丸癌、甲状腺癌、子宫癌和泌尿系统癌症。在一些优选的实施方案中,待治疗的癌症选自非小细胞肺癌(NSCLC)、乳腺癌(例如激素难治性转移性乳腺癌)、头颈癌(例如头颈部鳞状细胞癌)、转移性结直肠癌、激素敏感或激素难治性前列腺癌、结肠直肠癌、卵巢癌、肝细胞癌、肾细胞癌、软组织肉瘤和小细胞肺癌。
在一个方面,用该组合治疗的对象是患有癌症的人,所述癌症难以用一种或多种化学治疗剂治疗和/或难以用一种或多种抗体治疗。
在另一方面,所述方法进一步包括:在用所述组合疗法治疗之前、同时或之后,向所述对象施用化学治疗剂、靶向疗法、放射疗法、冷冻疗法或热疗疗法。
本发明的相关实施方案提供一种用于在哺乳动物中治疗癌症或用于制备治疗癌症的药物的药物组合,其中所述组合包含假型化的溶瘤弹状病毒(优选假型野生型或减毒(attenuated)VSV或Maraba,其具有LCMV、Lassa或Junin糖蛋白)和补体抑制剂。在一些实施方案中,该药物组合包含C3抑制剂和/或C5抑制剂和具有LCMV、Lassa或Junin糖蛋白的假型VSVdelta51或Maraba病毒。
在另一方面,本发明提供了用于治疗哺乳动物的癌症的试剂盒,其包括假型化的溶瘤弹状病毒(优选假型野生型或减毒Maraba或VSV)和补体抑制剂。在一些实施方案中,所述试剂盒包含VSVdelta51或Maraba株弹状病毒和检查点抑制剂,所述弹状病毒表达MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺蛋白的六跨膜上皮抗原、癌睾丸抗原1或其变体。该试剂盒可以进一步包含使用该组合治疗癌症的说明。
本发明的方法和组合物能够包括第二种治疗性病毒,例如溶瘤病毒或复制缺陷型病毒。溶瘤通常是指能够杀死、裂解或停止癌细胞生长的药剂。就溶瘤病毒而言,该术语是指在癌细胞中某种程度上能够复制,导致癌细胞死亡、裂解或生长停止并且通常对非癌细胞具有最小毒性作用的病毒。第二种病毒包括但不限于腺病毒、痘苗病毒、新城疫病毒、甲病毒、细小病毒、疱疹病毒、弹状病毒、非VSV弹状病毒等。在其他方面,该组合物是药学上可接受的组合物。该组合物还可以包括第二种抗癌剂,例如化学治疗剂、放射治疗剂或免疫治疗剂。
本申请讨论了本发明的其他实施方案。关于本发明的一个方面讨论的任何实施方案也适用于本发明的其他方面,反之亦然。具体实施方式和实施例部分中的实施方案应理解为适用于本发明所有方面的本发明的非限制性实施方案。
当在权利要求和/或说明书中使用时,术语“抑制”、“减少”或“防止”或这些术语的任何变化包括任何可测量的减少或完全抑制以实现期望的结果。期望的结果包括但不限于缓解、减少、减缓或根除癌性或过度增殖性病症,以及改善生活质量或延长寿命。
“补体抑制剂”是防止或减少三种活化途径或终末途径中的任何一种的活化的任何一种药剂。这可以最终防止C3或C5的分裂以及随后在细胞膜或病原体膜表面上相关分子的沉积以及释放关键信号分子。补体抑制剂能够在一种或多种补体途径上起作用,即经典途径、替代途径或凝集素途径。“C3抑制剂”是防止或减少C3分裂成C3a和C3b的分子或物质。“C5a抑制剂”是防止或减少C5a活性的分子或物质。“C5aR抑制剂”是防止或减少C5a与C5a受体结合的分子或物质。“C3aR抑制剂”是防止或减少C3a与C3a受体结合的分子或物质。“因子D抑制剂”是防止或减少因子D活性的分子或物质。“因子B抑制剂”是防止或减少因子B活性的分子或物质。“C4抑制剂”是防止或减少C4分裂成C4b和C4a的分子或物质。“C1q抑制剂”是防止或减少C1q与抗体-抗原复合物、病毒粒子、感染的细胞或其他与C1q结合以启动补体激活的分子结合的分子或物质。如本领域技术人员所理解的,本文所述的任何补体抑制剂可以包含抗体或抗体片段。
当与权利要求和/或说明书中的术语“包括”结合使用时,使用词语“一”或“一个”可以表示“一个”,但它也与“一个或多个”、“至少一个”和“一个或多于一个”的含义一致。
在整个本申请中,术语“约”用于表示一个值包括由于测定该值的装置或方法的误差导致的标准偏差。
权利要求中术语“或”用于表示“和/或”,除非明确指出仅指替代方案或替代方案是相互排斥的,尽管本公开支持仅指替代方案和“和/或”的定义。
如在本说明书和权利要求中所使用的,词语“包含”(以及任何形式的包含)、“具有”(以及任何形式的具有),“包括”(以及任何形式的包括)或“含有”(以及任何形式的含有)都是包容性的或开放式的并且不排除其他未列举的元素或方法步骤。
应理解,“组合疗法”设想了所述组合的组分的同时的、依序的或分开的施用。在本发明的一个方面,“组合疗法”设想了同时施用假型化的溶瘤弹状病毒和补体抑制剂。在本发明的另一方面,“组合疗法”设想了依序施用假型化的溶瘤弹状病毒和补体抑制剂。在本发明的另一个方面,“联合疗法”设想了分开施用假型化的溶瘤弹状病毒和补体抑制剂。当依序或分开施用假型化的溶瘤弹状病毒和补体抑制剂时,在允许治疗剂显示出协作性(例如协同)作用的时间间隔之内施用假型化的溶瘤弹状病毒和补体抑制剂。在优选的实施方案中,假型化的溶瘤弹状病毒和补体抑制剂在相对彼此来说1、2、3、6、12、24、48、72小时之内,或4、5、6或7天之内或8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之内施用。
从以下详细描述中,本发明的其他目的、特征和优点将变得显而易见。然而,应该理解,详细描述和具体实施例虽然表明了本发明的具体实施方案,但是仅以说明的方式给出,因为对于本领域的技术人员来说,从这些详细的描述获得本发明的精神和范围内的各种变化和修改是显而易见的。
附图说明
以下附图形成本说明书的一部分,并且被包括来进一步说明本发明的某些方面。通过参考这些附图中的一个或多个并结合本文给出的具体实施方案的详细描述,可以更好地理解本发明。
图1A-C. MRB LCMV G抗体(但不是MG1抗体)仅在补体存在下诱导病毒中和。图1A:体内和体外治疗方案。在第0天,用107个噬斑形成单位(pfu)的MG1(含有G蛋白Q242R和M蛋白L123W点突变的Maraba)或MRB LCMV G(用LCMV糖蛋白假型化的Maraba病毒)静脉内(IV)接种大鼠。在第15天,每组的一半大鼠用35U眼镜蛇毒因子(CVF)处理以消耗补体。在第16天,从大鼠收集血液。图1B-C:用大鼠血液、血浆或热灭活血浆体外中和MG1(图1B)或MRBLCMV G(图1C)。比较了MG1或MRB LCMV G与来自补体耗尽或补体未耗尽的未接种(初始(naïve))大鼠的血液、血浆或热灭活血浆的中和作用。每个免疫/补体状态使用一只大鼠,数据表示为技术重复±SD。
图2A-B. 由LCMV糖蛋白导致的病毒的补体依赖性抗体中和与弹状病毒骨架无关。图2A:用108 pfu的MG1或MRB LCMV G或107 pfu的野生型Maraba(Maraba wt)、VSVd51或VSVLCMV G(用LCMV糖蛋白假型化的VSV)接种大鼠。在接种后14天取血清。在将大约5×105 pfu的相应病毒与混合了右旋葡萄糖明胶veronal缓冲液(GVB对照缓冲液)的热灭活免疫血清、初始大鼠血清(补体的来源)或用眼镜蛇毒因子(CVF)预处理以耗尽C3的初始大鼠血清温育(1h;37oC)后,通过体外噬斑测定评估病毒中和。图1B:显示了每个组的输入病毒的相对回收率。N=2只大鼠/组,数据表示为组平均值±SD。
图3A-C. LCMV G假型弹状病毒抗体中和的补体依赖性质不是啮齿动物特异性现 象。图3A:两只食蟹猴静脉内接受1010 pfu(动物1)或颅内接受109 pfu(动物2)。在将热灭活的免疫血清与对照缓冲液、食蟹猴血清(补体的来源)或用CP40处理的食蟹猴血清(补体抑制)离体温育(1h;37oC)后,评估中和。图3B:显示了接种后在不同时间点来自动物1免疫血清的MRB LCMV G病毒的相对回收率。图3C:显示了接种后在不同时间点来自动物2免疫血清的MRB LCMV G病毒的相对回收率。数据表示为技术重复±SD。
图4A-D. 消除补体依赖性MRB LCMV G病毒中和可以通过经典途径或终末途径实 现。图4A:在MRB LCMV G接种后18或21天收集免疫大鼠血清。在抽血前一天从用35 U CVF处理的动物收集C3研究中使用的免疫血清。将免疫大鼠血清(抗体的来源)与对照缓冲液GVB、正常人血清(NHS)、C1q免疫耗尽的NHS、C3免疫耗尽的NHS或C5免疫耗尽的NHS(补体的来源)混合。在指出的情况下,分别以70或75 ug/mL的浓度回添C1q或C5。另外,以25μM的浓度添加CP40以抑制人C3或C5单克隆抗体,使用100μg/mL的浓度的Eculizumab来抑制C5。将MRBLCMV G与这些抗体的和补体的来源在37℃温育1小时,并通过噬斑测定定量感染的病毒。图4B:来自C1q耗尽的血清的MRB LCMV G病毒的相对回收率。显示了来自C1q耗尽的血清(图4B)、来自C3耗尽的血清(图4C)和C5耗尽的血清(图4D)的MRB LCMV G病毒的相对回收率。
图5A-C. 针对表面糖蛋白产生的抗体的补体依赖性是泛-沙粒病毒(pan- arenavirus)现象。图5A:用107个噬斑形成单位(pfu)的MRB Lassa G(用Lassa糖蛋白假型化的Maraba病毒)或MRB Junin G(用Junin糖蛋白假型化的Maraba病毒)静脉内接种大鼠,并在接种后14天取血清。在将大约5x105 pfu的相应病毒与混有右旋葡萄糖明胶veronal缓冲液(GVB++)的热灭活免疫血清、大鼠血清(补体的来源)或用CVF预处理以耗尽C3(补体耗尽的)的大鼠血清离体温育(1h;37oC)后评估中和。通过噬斑测定评估病毒的回收率。图5B:MRB Junin G病毒的相对回收率。图5C:MRB Lassa G病毒的相对回收率。N=3只鼠/组,数据表示为组平均值±SD。
图6A-C. 补体耗尽改善了MRB LCMV G(但非MG1)在免疫动物中的稳定性和递送。图6A:Fisher大鼠静脉内接种MRB LCMV G或MG1,或保持不接触病毒(virus-naïve)。接种后6天,给大鼠植入双侧13762 MATBIII肿瘤。在实验第14天,一半动物用35 U CVF耗尽补体。在实验第20天,大鼠静脉内给予指定剂量的同源病毒。在病毒处理后10分钟处死大鼠,并通过噬斑测定定量来自血液和肿瘤的感染的病毒。图6B:对于MRB LCMV G处理的动物,定量血液和肿瘤中感染的病毒。图6C:对于MG1处理的动物,定量血液和肿瘤中感染的病毒。每组N=3只鼠。数据表示为组平均值±SD,每个点代表一只大鼠。ND=未检测到。单因素方差分析(One way ANOVA)(*** p <0.001、** p <0.01、* p <0.05、ns p> 0.05)。
图7A-C. 在免疫大鼠中局部施用MRGB LCMV G而不是MG1后,补体耗尽改善了肿瘤 的感染。图7A:Fisher大鼠静脉内接种MRB LCMV G(图7B)或MG1(图7C),或保持不接触病毒。接种后9天,给大鼠植入双侧13762 MATBIII肿瘤。在实验第19天,一半动物用35 U CVF耗尽补体。在实验第20天,给大鼠肿瘤内注射指定剂量的同源病毒。在病毒处理后24小时处死大鼠,并通过噬斑测定定量来自肿瘤的感染的病毒。显示了皮下肿瘤滴度(每组n = 4)。数据表示为组平均值±SD。每个点代表一只鼠。ND=未检测到。单因素方差分析(* p <0.05、ns p>0.05)。
图8. 野生型Maraba (Maraba WT)、LCMV糖蛋白假型化的Maraba病毒(MRB LCMVG)、Junin糖蛋白假型化的Maraba病毒(MRB LCMV G)和Lassa糖蛋白假型化的Maraba病毒(MRB Lassa G)的基因组图谱。
具体实施方式
已经发现,用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒引起抗体应答,其需要补体来中和病毒颗粒。此外,通过使用补体抑制剂或耗尽补体能够防止这种中和,这导致感染性病毒在血液中的持久性增加。
本申请证明补体抑制显著增加假型化的复制型溶瘤弹状病毒在血液中的稳定性,并且在局部和全身施用病毒后显著增加病毒向肿瘤的递送。本发明提供了用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒及其用于在哺乳动物中治疗和/或预防癌症和/或治疗和/或预防转移癌的用途,以及包含(i)有效量的用沙粒病毒糖蛋白假型化的复制型溶瘤性弹状病毒,和(ii)有效抑制哺乳动物中补体活性的量的补体抑制剂的药物组合用于在哺乳动物中治疗和/或预防癌症和/或治疗和/或预防转移癌的用途。
本发明的实施方案包括与假型弹状病毒有关的组合物和方法及其作为抗癌治疗剂的用途。特别地,本发明提供了基于弹状病毒背景株(或骨架)的假型弹状病毒,其中糖蛋白基因被异源的沙粒病毒糖蛋白取代。
I. 弹状病毒科(弹状病毒)
任何复制型溶瘤弹状病毒株都能够被修饰以用异源的沙粒病毒糖蛋白代替天然的弹状病毒糖蛋白。
典型的弹状病毒是狂犬病病毒和水疱性口炎病毒(VSV),这是该病毒家族中研究最多的病毒。弹状病毒是一类具有非分段(-)义RNA基因组的子弹形病毒。弹状病毒家族包括但不限于:Arajas病毒、Chandipura病毒(AF128868/gi:4583436、AJ810083/gi:57833891、AY871800/gi:62861470、AY871799/gi:62861468、AY871798/gi:62861466、AY871797/gi:62861464、AY871796/gi:62861462、AY871795/gi:62861460、AY871794/gi:62861459、AY871793/gi:62861457、AY871792/gi:62861455、AY871791/gi:62861453)、Cocal病毒(AF045556/gi:2865658)、Isfahan病毒(AJ810084/gi:57834038)、Maraba病毒(美国专利号8,481,023的SEQ ID ON:1-6,通过引用并入本文,HQ660076.1)、Carajas病毒(美国专利号8,481,023的SEQ ID ON:7-12,通过引用并入本文,AY335185/gi:33578037)、Piry病毒(D26175/gi:442480、Z15093/gi:61405)、水泡性口炎Alagoas病毒、BeAn 157575病毒、Boteke病毒、Calchaqui病毒、美洲鳗病毒、Gray Lodge病毒、Jurona病毒、Klamath病毒、Kwatta病毒、La Joya病毒、Malpais Spring病毒、Mount Elgon蝙蝠病毒(DQ457103/gi|91984805)、Perinet病毒(AY854652/gi:71842381)、Tupaia病毒(NC_007020/gi:66508427)、Farmington、Bahia Grande病毒(美国专利号8,481,023的SEQ ID ON:13-18,通过引用并入本文,KM205018.1)、Muir Springs病毒(KM204990.1)、Reed Ranch病毒、HartPark病毒、Flanders病毒(AF523199/gi:25140635、AF523197/gi:25140634、AF523196/gi:25140633、AF523195/gi:25140632、AF523194/gi:25140631、AH012179/gi:25140630)、Kamese病毒、Mosqueiro病毒、Mossuril病毒、Barur病毒、福冈(Fukuoka)病毒(AY854651/gi:71842379)、克恩峡谷(Kern Canyon)病毒、Nkolbisson病毒、Le Dantec病毒(AY854650/gi:71842377)、Keuraliba病毒、Connecticut病毒、New Minto病毒、Sawgrass病毒、Chaco病毒、Sena Madureira病毒、Timbo病毒、Almpiwar病毒(AY854645/gi:71842367)、Aruac病毒、Bangoran病毒、Bimbo病毒、Bivens Arm病毒、Blue crab病毒、Charleville病毒、CoastalPlains病毒、DakArK 7292病毒、Entamoeba病毒、Garba病毒、Gossas病毒、Humpty Doo病毒(AY854643/gi:71842363)、Joinjakaka病毒、Kannamangalam病毒、Kolongo病毒(DQ457100/gi|91984799核蛋白(N)mRNA,部分cds)、Koolpinyah病毒、Kotonkon病毒(DQ457099/gi|91984797、AY854638/gi:71842354)、Landjia病毒、Manitoba病毒、Marco病毒、Nasoule病毒、Navarro病毒、Ngaingan病毒(AY85464/gi:71842375)、Oak-Vale病毒(AY854670/gi:71842417)、Obodhiang病毒(DQ457098/gi|91984795)、Oita病毒(AB116386/gi:46020027)、Ouango病毒、Parry Creek病毒(AY854647/gi:71842371)、Rio Grande cichlid病毒、Sandjimba病毒(DQ457102/gi|91984803)、Sigma病毒(AH004209/gi:1680545、AH004208/gi:1680544、AH004206/gi:1680542)、Sripur病毒、Sweetwater Branch病毒、Tibrogargan病毒(AY854646/gi:71842369)、Xiburema病毒、Yata病毒、Rhode Island、Adelaide River病毒(U10363/gi:600151、AF234998/gi:10443747、AF234534/gi:9971785、AY854635/gi:71842348)、Berrimah病毒(AY854636/gi:71842350)、Kimberley病毒(AY854637/gi:71842352)、或牛流行热病毒(NC_002526/gi:10086561)。
在优选的实施方案中,将任选地经基因修饰以例如增强肿瘤选择性的野生型Maraba株弹状病毒或其变体作为假型化的溶瘤弹状病毒的背景株。在特别优选的实施方案中,假型化的溶瘤弹状病毒是Maraba株(例如MG1),其包含沙粒病毒糖蛋白,优选LCMV、Junin或Lassa株糖蛋白。
在其他优选的实施方案中,将任选地经基因修饰以例如增强肿瘤选择性的VSV菌株(例如VSV Indiana、VSV New Jersey)或其变体作为假型化的溶瘤弹状病毒的背景株。在特别优选的实施方案中,假型化的复制型溶瘤弹状病毒的背景株是如Stojdl等人在CancerCell., 4(4): 263-75(2003)(其内容通过引用并入本文)中所述的包含在M蛋白的51位甲硫氨酸的缺失的VSV(VSVd51)。该VSV毒株可以进一步或可选地被减毒,例如通过美国专利号8,282,917(其内容通过引用并入本文)中所述的从M蛋白突变和/或缺失一个或多个氨基酸的方式。在一些优选的实施方案中,假型化的溶瘤弹状病毒包含具有LCMV、Junin或Lassa株糖蛋白的VSV骨架(例如VSVd51)。
在其他实施方案中,假型化的复制型溶瘤弹状病毒的背景株包含来自两种或更多种毒株或血清型的基因。例如,背景株可以包含来自一种毒株或血清型的N、P、M和/或L基因以及来自不同毒株或血清型的其余基因。
沙粒病毒糖蛋白
任何沙粒病毒毒株的(异源)糖蛋白都能够被取代进入复制型溶瘤弹状病毒背景中,以产生如本文所述的假型化的复制型溶瘤病毒,例如Bowen等人在J. Virology, 6992-7004(2000)中描述的任何一种。沙粒病毒是是沙粒病毒科的成员,沙粒病毒科成员是基因组由两条单链双义RNA组成的包膜病毒。两个RNA分段被命名为小(S)和大(L),每个分段以相反方向编码两个(非重叠的)病毒蛋白。L分段约为3.5 kb,编码病毒核衣壳蛋白(NP)和糖蛋白前体(GPC)。L分段约为7.2 kb,编码病毒RNA依赖性RNA聚合酶(L)和含有小RING结构域的蛋白质(Z)。沙粒病毒糖蛋白(GP)是三聚体复合物,它是通过GPC翻译后分裂为包膜糖蛋白GP1和GP2以及稳定信号肽(SSP)而形成,三者非共价地相互作用而覆盖(stud)病毒颗粒表面。
沙粒病毒被分为两个血清群,它们在遗传和地理分布上不同,即新世界沙粒病毒(在东半球发现)和旧世界沙粒病毒(在西半球发现)。旧世界沙粒病毒包括LCMV、Lassa病毒、Mopeia病毒、Mobala病毒、Ippy病毒、Mariental病毒、Merino Walk病毒、Menekre病毒、Gairo病毒、Gbagroube病毒、Morogoro病毒、Kodoko病毒、Lunk病毒、Okahandja病毒、 Lujo病毒、Lemniscomys病毒、Mus minutoides病毒、温州(Wenzhou)病毒和Luna病毒。新世界沙粒病毒包括Tacaribe病毒、Junin病毒、马秋博(Machupo)病毒,Cupixi病毒、Amapari病毒、巴拉那(Parana)病毒、Patawa病毒、Tamiami病毒、Pichinde病毒、Latino病毒、Flexal病毒、Guanarito病毒、Sabia病毒、Oliveros病毒、Whitewater Arroyo病毒、Pirital病毒、Pampa病毒、Bear Canyone病毒、Ocozocoautla de Espinosa病毒、Allpahuayo病毒、Tonto Creek病毒、Big Brushy Tank病毒、Real de Catorce病毒、Catarina病毒、Skinner Tank病毒和Chapare病毒。在一些实施方案中,复制型溶瘤弹状病毒用来自旧世界复合体沙粒病毒的沙粒病毒糖蛋白假型化。在其他实施方案中,复制型溶瘤弹状病毒用来自新世界沙粒病毒的沙粒病毒糖蛋白假型化。
在一些优选的实施方案中,复制型溶瘤弹状病毒用LCMV糖蛋白假型化。LCMV WE株糖蛋白序列能够在GenBank登录号AJ297484中找到,示例性pHCMV表达载体序列能够在GenBank登录号AJ318512(pHCMV-LCMV-GP(WE))和AJ318513(pHCMV-LCMV-GP(WE-HPI))中找到。LCMV Armstrong株糖蛋白序列可再GenBank登录号M20869中找到。在其他优选的实施方案中,复制型溶瘤弹状病毒用Lassa糖蛋白假型化。Lassa株糖蛋白序列能够在GenBank登录号AAT49014、AAT49012、AAT49010中找到。编码Lassa糖蛋白的DNA序列的实例公开在GenBank登录号HQ688673(Josiah segment S,完整序列)、AY179173(36-1511位置)、AF246121(54-1529位置)、AF333969(52-1524位置)、AF181854(52-1524位置)和AF181853(52-1524位置)中。在其他优选的实施方案中,复制型溶瘤弹状病毒用Junin糖蛋白假型化。示例性的Junin株糖蛋白序列能够在GenBank登录号NC_005081中找到。在一些实施方案中,复制型溶瘤弹状病毒用与GenBank登录号AJ297484、AAT49014、AAT49012、AAT49010、HQ688673、AY179173、AF246121、AF333969、AF181854、AF181853或NC_005081.1公开的沙粒病毒糖蛋白序列至少约70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的沙粒病毒糖蛋白假型化。在一些实施方案中,复制型溶瘤弹状病毒用不是来自LCMV株的糖蛋白的沙粒病毒糖蛋白假型化。在其他实施方案中,复制型溶瘤弹状病毒用不是来自Lassa株的糖蛋白的沙粒病毒糖蛋白假型化。在其他实施方案中,复制型溶瘤弹状病毒用不是来自Lassa株或来自LCMV株的糖蛋白的沙粒病毒糖蛋白假型化。Ippy病毒株糖蛋白序列能够在GenBank登录号U80003中找到,Mopeia病毒菌株糖蛋白序列能够在GenBank登录号U80005(AN20410毒株)和M33879(AN21366毒株)中找到。Mobala病毒train糖蛋白序列能够在GenBank登录号AF012530(3076株)中找到。
在一些优选的实施方案中,假型化的溶瘤弹状病毒基因组包括下列编码Junin株糖蛋白、其开放阅读框或与其开放阅读框具有至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同一性的片段或变体的密码子优化的核酸序列:
GGTACCCAGTTATATTTGTTACAACAATGGGACAATTCATCTCCTTCATGCAGGAGATACCTACTTTCCTCCAAGAGGCTCTCAATATCGCTCTGGTGGCGGTTTCACTGATCGCTATCATAAAGGGCATTGTGAACTTGTACAAATCAGGCCTGTTCCAATTCTTTGTGTTCCTGGCTCTTGCAGGGAGATCTTGTACAGAAGAGGCTTTTAAAATCGGCCTCCACACTGAGTTTCAGACCGTGAGTTTCTCAATGGTCGGCCTGTTTTCAAATAATCCCCATGACCTGCCCCTGTTGTGTACCCTGAACAAGAGTCACCTGTACATCAAGGGCGGAAACGCATCATTCATGATCTCCTTTGACGATATTGAAGTGCTGCTGCCTCAATACGATGTGATAATACAGCACCCAGCCGACATGTCCTGGTGCAGCAAGTCCGATGACCAAATTTGGTTGTCCCAGTGGTTTATGAATGCAGTCGGACATGATTGGCACTTGGACCCACCCTTCCTTTGCCGCAATAGAACTAAGACCGAGGGTTTCATTTTTCAGGTCAACACAAGCAAGACTGGGGTCAACGAAAACTATGCAAAAAAGTTCAAGACAGGTATGCATCACCTCTACCGGGAGTACCCTGATTCTTGCCTGAACGGGAAGTTGTGCCTGATGAAGGCCCAGCCAACGTCCTGGCCTCTGCAGTGCCCTTTGGACCATGTGAACACTTTGCACTTTCTCACTAGAGGCAAAAACATCCAGCTCCCTAGGCGATCCCTTAAGGCGTTCTTTTCTTGGAGTCTGACGGATTCTTCCGGAAAGGACACCCCTGGGGGCTACTGTCTCGAAGAATGGATGCTGGTAGCTGCAAAGATGAAATGTTTTGGGAACACTGCCGTCGCGAAATGCAACCTGAACCATGATTCTGAATTTTGCGATATGCTCCGACTTTTCGACTATAATAAGAATGCTATCAAGACACTGAACGATGAAACTAAGAAACAGGTGAATCTCATGGGACAGACCATTAATGCTCTGATCAGTGACAATCTGCTGATGAAGAATAAAATCCGAGAGCTGATGTCAGTGCCCTATTGTAATTATACAAAATTTTGGTACGTGAATCACACACTGTCCGGCCAGCACTCTCTGCCGAGGTGCTGGCTGATTAAGAATAATAGCTACTTGAACATCAGCGACTTCAGAAACGACTGGATTCTCGAGTCCGATTTTCTGATCAGCGAAATGCTCAGTAAAGAGTATTCAGACAGACAGGGCAAGACACCCCTTACTCTCGTTGATATTTGTTTTTGGAGTACAGTTTTTTTTACGGCCTCCCTGTTCCTCCATCTGGTCGGTATTCCTACCCACCGACATATCCGCGGCGAGGCATGTCCACTGCCTCATCGCCTCAATTCACTGGGAGGCTGTCGATGTGGAAAGTATCCGAATCTCAAAAAACCTACCGTCTGGCGCAGAAGACATTAGGCGGCCGC (SEQ ID NO: 1)
在相关的实施方案中,假型化的溶瘤弹状病毒基因组包含编码Junin糖蛋白或与其具有至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同一性的功能片段或变体的核酸序列:
MGQFISFMQEIPTFLQEALNIALVAVSLIAIIKGIVNLYKSGLFQFFVFLALAGRSCTEEAFKIGLHTEFQTVSFSMVGLFSNNPHDLPLLCTLNKSHLYIKGGNASFMISFDDIEVLLPQYDVIIQHPADMSWCSKSDDQIWLSQWFMNAVGHDWHLDPPFLCRNRTKTEGFIFQVNTSKTGVNENYAKKFKTGMHHLYREYPDSCLNGKLCLMKAQPTSWPLQCPLDHVNTLHFLTRGKNIQLPRRSLKAFFSWSLTDSSGKDTPGGYCLEEWMLVAAKMKCFGNTAVAKCNLNHDSEFCDMLRLFDYNKNAIKTLNDETKKQVNLMGQTINALISDNLLMKNKIRELMSVPYCNYTKFWYVNHTLSGQHSLPRCWLIKNNSYLNISDFRNDWILESDFLISEMLSKEYSDRQGKTPLTLVDICFWSTVFFTASLFLHLVGIPTHRHIRGEACPLPHRLNSLGGCRCGKYPNLKKPTVWRRRH (SEQ ID NO: 2)
在一些优选的实施方案中,假型化的溶瘤弹状病毒基因组包括下列编码Lassa菌株糖蛋白、其开放阅读框或与其开放阅读框具有至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同一性的片段或变体的密码子优化的核酸序列:
GGTACCCAGTTATATTTGTTACAACAATGGGACAAATCATCACGTTTTTCCAGGAAGTGCCCCACGTCATAGAGGAGGTAATGAATATAGTGCTCATTGCCCTCAGTTTGCTGGCGATCCTGAAAGGGATCTACAACGTGGCGACTTGTGGTCTGTTTGGCTTGGTGTCTTTCCTGCTGTTGTGCGGTCGAAGCTGCAGTACCACCTATAAGGGAGTCTACGAGCTGCAGACACTGGAACTGGACATGGCTAGCTTGAACATGACTATGCCTCTCTCCTGCACAAAGAATAACAGTCACCATTACATAATGGTGGGGAATGAAACTGGTTTGGAACTCACACTTACCAACACATCCATCATAAATCACAAGTTTTGTAACCTCAGTGACGCCCACAAAAAAAACTTGTATGATCACGCTCTCATGTCCATAATCAGCACTTTTCACCTGTCTATCCCTAACTTCAATCAGTACGAGGCTATGTCTTGCGACTTTAACGGGGGCAAAATCAGCGTGCAATACAATCTGAGCCACGCATATGCCGTCGACGCCGCCAACCACTGCGGAACTATCGCTAACGGCGTCCTGCAGACATTCATGCGGATGGCTTGGGGCGGCTCCTATATCGCTCTGGATAGCGGAAAGGGCAGTTGGGACTGTATTATGACCTCATACCAGTACCTTATTATCCAGAACACCACCTGGGAGGATCACTGTCAATTTTCCCGGCCGTCCCCAATCGGCTATCTGGGCCTCCTGAGCCAAAGAACTCGGGACATTTACATATCTCGGCGACTCCTCGGGACATTCACATGGACCCTGTCCGACTCTGAAGGGAATGAAACGCCAGGCGGGTATTGCCTGACCCGATGGATGCTGATCGAAGCCGAGCTCAAGTGCTTTGGAAATACCGCAGTCGCCAAGTGTAATGAAAAGCATGATGAAGAATTTTGCGATATGCTGCGGCTGTTCGATTTCAATAAACAGGCCATTCGACGGCTGAAAACCGAGGCCCAAATGAGTATCCAGCTGATTAACAAGGCCGTTAATGCCCTGATTAATGACCAGCTCATTATGAAAAATCACCTGCGGGATATCATGGGCATTCCTTACTGTAACTATTCCAAGTATTGGTATCTGAACCACACCGTGACTGGCAAAACGTCACTGCCAAGGTGCTGGCTGGTCTCCAATGGAAGCTACCTGAACGAGACCCATTTTTCCGATGATATCGAGCAGCAGGCCGATAATATGATTACCGAACTGTTGCAGAAAGAATACATGGACCGCCAGGGCAAAACTCCACTTGGGTTGGTCGACCTGTTTGTGTTCTCTACCAGCTTCTACTTGATTAGCATTTTCCTGCACCTGGTGCGCATCCCCACGCACAGACATGTCATCGGTAAGCCATGCCCTAAGCCGCATAGACTCAACCATATGGGGATTTGCTCCTGTGGTCTCTATAAACACCCCGGCGTGCCTGTCAAATGGAAGAGGTGAGCGGCCGC (SEQ IDNO: 3)
在相关的实施方案中,假型化的溶瘤弹状病毒基因组包含编码下列Lassa糖蛋白或与其具有至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的同一性的功能片段或变体的核酸序列:
MGQIITFFQEVPHVIEEVMNIVLIALSLLAILKGIYNVATCGLFGLVSFLLLCGRSCSTTYKGVYELQTLELDMASLNMTMPLSCTKNNSHHYIMVGNETGLELTLTNTSIINHKFCNLSDAHKKNLYDHALMSIISTFHLSIPNFNQYEAMSCDFNGGKISVQYNLSHAYAVDAANHCGTIANGVLQTFMRMAWGGSYIALDSGKGSWDCIMTSYQYLIIQNTTWEDHCQFSRPSPIGYLGLLSQRTRDIYISRRLLGTFTWTLSDSEGNETPGGYCLTRWMLIEAELKCFGNTAVAKCNEKHDEEFCDMLRLFDFNKQAIRRLKTEAQMSIQLINKAVNALINDQLIMKNHLRDIMGIPYCNYSKYWYLNHTVTGKTSLPRCWLVSNGSYLNETHFSDDIEQQADNMITELLQKEYMDRQGKTPLGLVDLFVFSTSFYLISIFLHLVRIPTHRHVIGKPCPKPHRLNHMGICSCGLYKHPGVPVKWKR (SEQ ID NO: 4)
优选地,假型病毒的基因组或编码假型病毒的基因组的质粒编码整个沙粒病毒糖蛋白前体,使得GP1和GP2都被表达并有助于假型病毒的包膜的形成。在其他实施方案中,假型病毒的基因组或编码假型病毒的基因组的质粒编码少于整个沙粒病毒糖蛋白前体。例如,在实施方案中,假型病毒的基因组或编码重组病毒基因组的质粒编码截短的GPC或仅编码GP1或仅编码GP2。
另外的异源核酸序列
在其他优选的实施方案中,假型化的溶瘤弹状病毒表达一种或多种肿瘤抗原,例如:癌胚(oncofetal)抗原,例如甲胎蛋白(AFP)和癌胚抗原(carcinoembryonic antigen,CEA);表面糖蛋白,例如CA 125;癌基因,例如Her2;黑素瘤相关抗原,例如多巴色素互变异构酶(DCT)、GP100和MART1;癌-睾丸抗原,例如MAGE蛋白和NY-ESO1;病毒癌基因,例如HPV E6和E7;以及在通常局限于胚胎或胚外组织的肿瘤中异位表达的蛋白,例如PLAC或肿瘤相关抗原的变体。肿瘤相关抗原的“变体”是指(a)包括来自肿瘤相关抗原蛋白的至少一种肿瘤相关抗原表位的蛋白,和(b)与肿瘤相关抗原蛋白至少70%、优选至少80%、更优选至少90%或至少95%相同的蛋白。在"Database of T cell-defined human tumor antigens: the2013 update." Cancer Immun 2013 13:15和 www.cancerimmunity.org/peptide中,Vander Bruggen P、Stroobant V、Vigneron N、Van den Eynde B提供了总结了公认的抗原表位的数据库。在特别优选的实施方案中,溶瘤弹状病毒表达MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺蛋白的六跨膜上皮抗原、或癌睾丸抗原1。在相关方面,将表达肿瘤抗原的假型化的溶瘤弹状病毒与补体抑制剂共同施用于患有癌症的哺乳动物以治疗该癌症。所述哺乳动物可具有对该肿瘤抗原预先存在的免疫力,其天然存在或通过在施用表达该肿瘤抗原的假型化的溶瘤弹状病毒之前将该肿瘤抗原施用于该哺乳动物而建立。
在De Plaen et al., Immunogenetics 40:360-369 (1994)中讨论了编码肿瘤特异性抗原的MAGE基因家族。MAGEA3在多种肿瘤中表达,包括黑素瘤、非小细胞肺癌、头颈癌、结肠直肠癌和膀胱癌。已经鉴定了MAGEA3的肿瘤相关抗原表位,并且这些表位的任何一个都可以通过假型化的溶瘤弹状病毒表达。
人乳头瘤病毒(HPV)癌蛋白E6/E7在宫颈癌中组成型表达(Zur Hausen,H(1996)Biochem Biophys Acta 1288:F55-F78)。此外,HPV 16和18型是75%的宫颈癌的原因(Walboomers JM(1999)J Pathol 189:12-19)。
前列腺的六跨膜上皮抗原(huSTEAP)是最近发现的一种蛋白,其在前列腺癌症中过度表达,并且在多种癌细胞系中上调,包括胰腺癌、结肠癌、乳腺癌、睾丸癌、宫颈癌、膀胱癌、卵巢癌、急性淋巴细胞白血病和尤文肉瘤(Hubert RS et al.,(1999)Proc Natl AcadSci 96:14523-14528)。STEAP基因编码具有六个潜在的跨膜区域、侧翼为亲水性氨基和羧基末端结构域的蛋白。
癌睾丸抗原1(NYES01)是在正常成人组织(例如睾丸和卵巢)和各种癌症中表达的癌/睾丸抗原(Nicholaou T et al., (2006) Immunol Cell Biol 84:303-317)。癌睾丸抗原是一种独特的抗原家族,其在正常成人的睾丸生殖细胞具有限制的表达,但在各种实体肿瘤上异常表达,包括软组织肉瘤、黑素瘤和上皮癌。
在其他实施方案中,假型化的溶瘤弹状病毒表达一种或多种细胞因子,例如粒细胞巨噬细胞集落刺激因子(GM-CSF)、肿瘤坏死因子α(TNFα)、肿瘤坏死因子β(TNFα)、白细胞介素1(IL-1)、白细胞介素2(IL-2)、白细胞介素4(IL-4)、白细胞介素5(IL-5)、白细胞介素6(IL-6)、白细胞介素10(IL-10)、白细胞介素12(IL-12)、白细胞介素15(IL-15)、白细胞介素21(IL-21)、干扰素α(IFNα)、干扰素β(IFNβ)、干扰素γ(IFNγ)及其变体和片段。在相关方面,将表达细胞因子的假型化的溶瘤弹状病毒与补体抑制剂共同施用于患有癌症的哺乳动物以治疗该癌症。在其他实施方案中,假型化的溶瘤弹状病毒表达一种或多种免疫检查点抑制剂,免疫检查点抑制剂结合并拮抗免疫检查点蛋白的活性,例如细胞毒性T淋巴细胞抗原-4(CTLA4)、程序性细胞死亡蛋白1(PD-1)及其配体PD-L1和PD-L2、B7-H3、B7-H4、疱疹病毒侵入介导物(herpesvirus entry mediator,HVEM)、T细胞膜蛋白3(TIM3)、半乳糖凝集素9(galectin 9,GAL9)、淋巴细胞活化基因3(LAG3)、抑制T细胞活化的含有V-结构域免疫球蛋白(Ig)抑制子(V-domain immunoglobulin (Ig)-containing suppressor of T-cellactivation,VISTA)、杀伤细胞免疫球蛋白样受体(Killer-Cell Immunoglobulin-LikeReceptor,KIR)、B和T淋巴细胞衰减子(B and T lymphocyte attenuator,BTLA)、具有Ig和ITIM结构域的T细胞免疫受体(T cell immunoreceptor with Ig and ITIM domain,TIGIT)或其组合。在优选的实施方案中,免疫检查点抑制剂是抗PD-1、抗PD-L1或抗CLTA4抗体或其抗原结合片段或融合蛋白。在一些实施方案中,假型化的溶瘤弹状病毒表达针对CTLA4的单克隆抗体(例如Ipilimumab(Yervoy®;BMS)或Tremelimumab(AstraZeneca/MedImmune))和/或针对PD-1的单克隆抗体(例如Nivolumab(Opdivo®; Bristol-MyersSquibb;代号BMS-936558)、Pembrolizumab(Keytruda®)或Pidilizumab)。
根据本文所述的方法,假型化的溶瘤弹状病毒的施用途径会自然地随病变的位置和性质而变化,包括例如皮内、透皮、肠胃外、血管内(静脉内或动脉内)、肌肉内、鼻内、皮下、区域性、经皮、气管内、腹膜内、膀胱内、肿瘤内、吸入、灌注、灌洗、直接注射、营养、口服施用和制剂配方。在优选的实施方案中,包含该组合中的假型化的溶瘤弹状病毒和药学上可接受的载体的药物组合物通过瘤内注射和/或血管内施用而被施用至患有癌症的哺乳动物,尽管所述药物组合物可以如美国专利5,543,158、5,641,515和5,399,363(各自通过引用整体并入本文)中所述,替代地通过肿瘤内、肠胃外、静脉内、动脉内、皮内、肌肉内、透皮或甚至腹膜内施用。如本文所用,“载体”包括任何和所有溶剂、分散介质、载体、包衣、稀释剂、抗细菌和抗真菌剂、等渗和吸收延迟剂、缓冲剂、载体溶液、悬浮液、胶体等。这些介质和药剂用于药物活性物质的用途是本领域熟知的。除非任何常规介质或试剂与活性成分不相容,否则都考虑其在治疗组合物中的用途。补充的活性成分也可以掺入组合物中。
在某些实施方案中,待治疗的肿瘤至少最初可能不是可切除的。使用治疗性病毒构建体进行的治疗可以增加肿瘤的可切除性,这是由于边缘处的收缩或通过消除某些特别侵入性部分而导致的。在治疗后,可能可以进行切除术。切除后的其他治疗将用于消除肿瘤部位的微观残留疾病。
对于原发性肿瘤或切除后肿瘤床,典型的治疗过程将涉及多个剂量。典型的原发性肿瘤治疗包括在1、2、3、4、5、6周或更长时间内施用1、2、3、4、5、6或更多个剂量。一个为期两周的方案可以重复一次、两次、三次、四次、五次、六次或更多次。在治疗过程中,可以重新评估完成计划的剂量的必要性。在一些实施方案中,当与补体抑制剂共同施用时,假型化的溶瘤弹状病毒的第二次、第三次、第四次、第五次、第六次或后续施用没有显著降低功效和/或相对于先前施用的剂量未显著增加剂量。
治疗可以包括各种“单位剂量”。单位剂量定义为含有预定量的治疗组合物。待施用的量、以及特定的途径和制剂,都属于临床技术人员的技术范围内。单位剂量不需要作为单次注射施用,而可以包括在设定的一段时间内的连续输注。本发明的单位剂量可方便地以噬斑形成单位(pfu)或病毒颗粒(对于病毒构建体来说)来描述。单位剂量的范围为103、104、105、106、107、108、109、1010、1011、1012、1013 pfu或vp及更高。或者,根据病毒的种类和可达到的滴度,可以将1到100、10到50、100-1000、或高达约1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、×1012、1×1013、1×1014或1×1015或更高的感染性病毒颗粒(vp)递送至患者或患者的细胞。
短语“药学上可接受的”或“药理学上可接受的”是指当施用至人时不产生过敏或类似的不良反应的分子实体和组合物。含有蛋白作为活性成分的含水组合物的制备在本领域中是已知的。通常,将这种组合物制成注射剂,可以是液体溶液或悬浮液,也可以制备为适于在注射前溶解或悬浮在液体中的固体形式。
II. 补体抑制剂
在多个方面,本发明提供了用于治疗和/或预防癌症和/或治疗和/或预防转移癌的组合疗法,其包含以有效治疗和/或预防癌症的组合量向有需要的哺乳动物共同施用(i)用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒和(ii)一种或多种补体抑制剂。
补体系统是先天免疫的关键组成部分。补体系统能够通过三种不同途径(经典途径、替代途径和凝集素途径)中的任何一种被激活,所有所述途径的识别模式都不同,但会聚在将中心组分C3裂解成C3a和C3b的C3转化酶的产生上。随后,通过将另一个C3b分子包含在C3转化酶中,C3转化酶转变为C5转化酶。所述C5转化酶裂解C5,导致C5a的释放和C5b-9复合物的形成。补体抑制剂防止或减少导致产生C3a或通过C3a受体的信号传导或导致产生C5a或通过C5a受体的信号传导的补体级联的激活和/或传播。该组合中有用的补体抑制剂包括在经典、替代或凝集素途径的一种或多种上或在共有的终末途径上起作用的抑制剂。
靶向C3的抑制剂能够抑制所有三种(经典、替代和凝集素)途径,这是由于在补体激活过程中C3处于中心位置。在一些实施方案中,该组合中的补体抑制剂抑制C3。抑制C3的补体抑制剂包括但不限于人源化单克隆抗体H17(EluSys Therapeutics);环肽compstatin及类似物;肽模拟物(peptidomimetics)及其衍生物,如4(1MeW)/POT-4(Potentia)、4(1MeW)/APL-1、APL-2(Apellis)、Cp40/AMY-101、PEG-Cp40(Amyndas);以及美国专利号6,319,897和7,888,323以及WIPO公开号WO2013/036778A2中描述的那些(其中每个的内容通过引用并入本文);基于CFH的蛋白质,如TT30(CR2/CFH; Alexion)、MiniCFH(Amyndas);基于CR1的蛋白质,如sCR1(CDX-1135; Celldex/Avant Immunotherapeutics)、Microcept(APT070)和TT32(CR2/CR1; Alexion Pharmaceuticals)。在优选的实施方案中,补体抑制剂是compstatin或类似物、肽模拟物或其衍生物。
靶向C5的抑制剂也能够抑制所有三种途径。因此,在其他实施方案中,该组合中的补体抑制剂抑制补体组分5(C5)。靶向C5的补体抑制剂包括但不限于单克隆抗体,例如Eculizumab(Soliris; Alexion Pharmaceuticals)和LFG316(Novartis/Morphosys);人微抗体,如Mubodina(Adienne);人源化单链可变片段(scFV),如Pexelizumab(AlexionPharmaceuticals);重组蛋白,如Coversin(OmCl; Volution Immuno-Pharmaceuticals);适体,如ARC1005(NovoNordisk)、ARC1905(Ophthotech)和SOMAmers(SomaLogic);亲和体(affibodies),如SOB1002(与白蛋白结合结构域融合,Swedish Orpahn Biovitrum);siRNA,如抗C5 siRNA(Alnylam)。在一个优选的实施方案中,补体抑制剂是依库丽单抗,一种与C5结合并抑制其分裂成C5a和C5b的人源化单克隆抗体。
经典途径通过形成抗原-抗体复合物而激活。C1是级联中的第一个酶复合物,由C1q、2个C1r分子和2个C1s分子组成。该复合物通过C1q结构域与抗原-抗体复合物结合以启动级联。一旦被激活,C1s切割C4从而产生C4b,C4b又结合C2。C2被C1切割,从而产生活化形式C2a,与C4b(C4b2a)结合并形成经典途径C3转化酶。随后C4b2a通过与另外的C3b分子结合而转化为C5转化酶。经典途径能够被特异性地抑制,例如通过靶向C2a和/或C2的C2a部分实现。在一个方面,经典途径的抑制剂是干扰C2和C4之间相互作用的单克隆抗C2a抗体。经典途径能够特异性地被抑制,例如通过靶向C2a和/或C2的C2a部分实现。在一个方面,经典途径的抑制剂是干扰C2和C4之间相互作用的单克隆抗C2a抗体。经典途径能够特异性地被抑制,例如通过靶向C2a和/或C2的C2a部分实现。在一个方面,经典途径的抑制剂是干扰C2和C4之间相互作用的单克隆抗C2a抗体。在其他实施方案中,补体抑制剂抑制C1。抑制C1(例如C1s)的补体抑制剂包括但不限于纯化或重组C1酯酶抑制剂(例如Cinryze(ViroPharma/Baxter))和单克隆抗体(如TNT003、TNT009和TNT010(True North Therapeutics))。在优选的实施方案中,补体抑制剂是Cinryze、TNT009或TNT010。因子I还通过抑制经典C3转化酶来抑制经典途径。
替代途径(AP)缺乏特异性识别分子。在该途径中,C3转化酶的组装通过C3b与激活蛋白表面的共价连接而启动。在下一步中,补体因子B(CFB)与表面结合的C3b结合,随后被补体因子D(CFD)切割,产生C3bBb。随后通过与另外的C3b分子的结合,C3bBb转化为C5转化酶。在一些实施方案中,补体抑制剂抑制CFB和/或CFD。抑制CFB的补体抑制剂包括单克隆抗体(如TA106(Alexion Pharmaceuticals))和siRNA(如抗FB siRNA(Alnylam))。抑制CFD的补体抑制剂包括单克隆抗体(如FCFD4514S(Genentech/Roche))和抗原结合抗体片段(如lampalizumab(Genetech))。抑制CFD和CFB的补体抑制剂包括适体(如SOMAmers(SomaLogic))和小分子抑制剂(如可从Novartis获得的那些)。因子H(无活性C3b)是一种可溶性糖蛋白,也通过与因子B竞争结合C3b来抑制C3转化酶的形成,从而抑制替代途径。
抑制补体生物活性的药剂的其他实施例包括但不限于:C5a受体拮抗剂,例如NGD2000-1(Neurogen, Corp., Branford, Conn.)、CCX168(ChemoCentryx)、PMX53(Promics/Cephalon)和AcPhe [Orn-Pro-D-环己基丙氨酸-Trp-Arg](AcF-[OPdChaWR],参见例如Strachan, A. J. et al., Br. J. Pharmacol. 134(8):1778-1786 (2001));因子I(无活性C4b);可溶性补体受体1型(sCR1,参见例如美国专利号5,856,297)和sCR1-sLe(X)(参见例如美国专利号5,856,300,膜辅因子蛋白(MCP)、衰变加速因子(DAF))和CD59及其可溶性重组形式(Ashgar, S. S. et al., Front Biosci. 5:E63-E81 (2000)和Sohn, J. H. etal., Invest. Opthamol. Vis. Sci. 41(13):4195-4202 (2000));具有至少两个互补抑制结构域的嵌合的补体抑制蛋白(参见例如美国专利号5,679,546、5,851,528和5,627,264);以及小分子拮抗剂(参见例如PCT公开号WO 02/49993、美国专利号5,656,659、5,652,237、4,510,158、4,599,203和4,231,958)。其他已知的补体抑制剂是本领域已知的,并且包括在本文所述的方法中。此外,测量补体活性的方法(例如,鉴定抑制补体活性的药剂)是本领域已知的。例如,此类方法包括使用50%溶血补体(CH50)测定法(参见例如Kabat etal., Experimental Immunochemistry, 2nd Ed. (Charles C. Thomas, Publisher,Springfield, Ill.), p. 133-239 (1961))、使用酶免疫测定(EIA)、使用脂质体免疫测定(LIA)(参见例如Jaskowski et al., Clin. Diagn. Lab. Immunol. 6(1):137-139(1999))。
根据该组合的补体抑制剂能够通过任何合适的施用途径施用于患有癌症的哺乳动物,包括血管内(静脉内和/或动脉内)、肌肉内、皮下、玻璃体腔内和口服。
根据该组合的补体抑制剂与假型化的复制型溶瘤弹状病毒以有效治疗和/或预防哺乳动物的癌症的组合量共同施用于哺乳动物。通常,补体抑制剂以有效抑制哺乳动物补体活性的量施用。合适的剂量是本领域已知的并且取决于所施用的抑制剂。对于抗体,合适的剂量通常为患者体重的0.1 mg/kg至20 mg/kg,优选为患者体重的1 mg/kg至10 mg/kg。例如,依库丽单抗能够以每7天600或900 mg的剂量通过静脉输注被施用1、2、3、4或更多周,之后剂量能够增加至900或1200 mg施用一次(7天后),之后每两周施用900或1200 mg。Pexelizumab能够通过单次2.0 mg/kg快速灌注(bolus)被施用,任选地随后以0.05 mg/kg/hr输注20至24小时。Cinryze能够以1000 U每3或4天静脉内施用。肽compstatin及其类似物(例如CP40)能够以一个(例如,快速灌注方式)或多个剂量(例如,约0.5 mg/kg至25 mg/kg)被施用。例如,compstatin或其类似物可以以例如2-10 mg/kg的快速灌注方式被施用,任选地随后进行连续输注。
在一些实施方案中,单一补体抑制剂与假型化的复制型溶瘤弹状病毒共同施用于哺乳动物以治疗和/或预防癌症。在其他实施方案中,两种或更多种补体抑制剂的组合与假型化的复制型溶瘤弹状病毒共同施用以治疗和/或预防癌症。例如,经典途径的抑制剂和替代途径的抑制剂的组合能够与假型化的复制型溶瘤弹状病毒共同施用于哺乳动物,以治疗和/或预防哺乳动物的癌症。
另外的疗法
本发明的化合物和方法可以被用于癌症。为了增加本文所述治疗方法的有效性,可能需要将如本文所述的组合物与其他有效预防/治疗癌症的药剂组合。例如,癌症的治疗可以用本发明的治疗化合物和其他抗癌疗法实施,例如抗癌剂或手术。
“抗癌”剂能够负面影响对象的癌症,例如,通过杀死癌细胞、诱导癌细胞中的凋亡、降低癌细胞的生长速度、降低转移的发生率或次数、减小肿瘤大小、抑制肿瘤生长、减少对肿瘤或癌细胞的血液供应、促进针对癌细胞或肿瘤的免疫应答、预防或抑制癌症的进展、或增加患癌对象的寿命。抗癌剂包括生物药物(生物疗法)、化疗药物和放射治疗药物。更普遍地,这些其他成分将以有效杀死或抑制细胞增殖的组合量被提供。该过程可以涉及将细胞与病毒或病毒构建体和药剂或多种因子同时接触。这可以通过使细胞与包括两种药剂的单一组合物或药学制剂接触来实现,或通过使细胞与两种不同的组合物或制剂同时接触来实现,其中一种组合物包括病毒而另一种包括第二种药剂。
肿瘤细胞对化学疗法和放射疗法药物的耐药性是临床肿瘤学的主要问题。目前癌症研究的一个目标是通过将其与基因疗法相结合,找到提高化疗和放疗功效的方法。例如,当通过逆转录病毒载体系统递送至脑肿瘤时,单纯疱疹胸苷激酶(HS-tK)基因成功诱导对抗病毒剂更昔洛韦(ganciclovir)的易感性(Culver et al., 1992)。在本发明中,预计除了其他促凋亡或细胞周期调节剂之外,痘病毒疗法可以类似地与化学疗法、放射疗法、免疫疗法或其他生物干预共同使用。
或者,病毒疗法可以在其他治疗之前或之后,间隔为数分钟至数周。在其他药剂和病毒分开应用于细胞的实施方案中,人们通常会确保每次递送时间之间不超过相当长的一段时间,使得药剂和病毒仍然能够对细胞发挥有利的组合作用。在这种情况下,预计可以在相对彼此约12-24小时内将细胞与两种疗法接触,更优选地,相对彼此约6-12小时内进行接触。但是,在某些情况下,可能需要显著地延长治疗的时期,各个施用之间超过几天(2、3、4、5、6或7)到几周(1、2、3、4、5、6、7或8)。
癌症疗法还包括各种基于化学和辐射的治疗的组合疗法。组合化学疗法包括:例如顺铂(cisplatin)(CDDP)、卡铂(carboplatin)、丙卡巴肼(procarbazine)、二氯甲基二乙胺(mechlorethamine)、环磷酰胺(cyclophosphamide)、喜树碱(camptothecin)、异环磷酰胺(ifosfamide)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、亚硝基脲(nitrosurea)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)、博来霉素(bleomycin)、plicomycin、丝裂霉素(mitomycin)、依托泊苷(etoposide)(VP16)、它莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、雌激素受体结合剂、紫杉酚(taxol)、吉西他滨(gemcitabien)、诺维本(navelbine)、法呢基蛋白转移酶抑制剂、transplatinum、5-氟尿嘧啶、长春新碱(vincristine)、长春碱(vinblastine)和甲氨蝶呤(methotrexate)、与替马唑胺(Temazolomide)(DTIC的水性形式),或前述的任何类似物或衍生变体。化学疗法与生物疗法的组合被称为生物化学疗法。
引起DNA损伤并且已广泛使用的其他因素包括γ射线、X射线、质子束和/或向肿瘤细胞的定向递送的放射性同位素。还考虑了其他形式的DNA损伤因素,例如微波和紫外线照射。所有这些因素很可能都会对DNA、DNA的前体、DNA的复制和修复以及染色体的组装和维持产生广泛的损害。X射线的剂量范围为从50至200伦琴每天,持续长时间段(3至4周),到单剂量的2000至6000伦琴。放射性同位素的剂量范围变化很大,取决于同位素的半衰期、发射的辐射强度和类型以及肿瘤细胞的摄取。
当应用于细胞时,术语“接触”和“暴露”在本文中用于描述将治疗构建体和化学治疗剂或放射治疗剂递送至靶细胞或与靶细胞直接并置的过程。为了实现细胞杀伤或停滞,将两种药剂以有效杀死细胞或防止其分裂的组合量递送至细胞。
诱导细胞增殖的蛋白质根据功能进一步分为各种类别。所有这些蛋白质的共性是它们调节细胞增殖的能力。例如,PDGF的一种形式,即sis癌基因,是分泌的生长因子。癌基因很少来自编码生长因子的基因,并且目前,sis癌基因是唯一已知的天然存在的致癌生长因子。在本发明的一个实施方案中,预计指向特定细胞增殖诱导物的反义mRNA被用于预防细胞增殖诱导物的表达。
肿瘤抑制癌基因具有抑制过度细胞增殖的作用。这些基因的失活破坏了它们的抑制活性,导致不受调节的增殖。肿瘤抑制因子包括p53、p16和C-CAM。根据本发明可使用的其他基因包括Rb、APC、DCC、NF-1、NF-2、WT-1、MEN-1、MEN-II、zac1、p73、VHL、MMAC1/PTEN、DBCCR-1、FCC、rsk-3、p27、p27/p16融合、p21/p27融合体、抗血栓形成基因(如COX-1、TFPI)、PGS、Dp、E2F、ras、myc、neu、raf、erb、fms、trk、ret、gsp、hst、abl、E1A、p300、参与血管生成的基因(例如,VEGF、FGF、血小板反应蛋白、BAI-1、GDAIF或其受体)和MCC。
细胞凋亡,或程序性细胞死亡,是正常胚胎发育、维持成体组织稳态和抑制癌发生的重要过程(Kerr et al., 1972)。Bcl-2蛋白质家族和ICE样蛋白酶已被证明是其他系统中细胞凋亡的重要调节因子和效应物。与滤泡性淋巴瘤相关的Bcl2蛋白在响应不同的凋亡刺激中控制细胞凋亡和增强细胞存活方面发挥着重要作用(Bakhshi et al., 1985;Cleary and Sklar, 1985; Cleary et al., 1986; Tsujimoto et al., 1985;Tsujimoto and Croce, 1986)。现在认识到进化上保守的Bcl-2蛋白是相关蛋白家族的成员,其可以被归类为死亡激动剂或死亡拮抗剂。
在其发现之后,显示Bcl2用于抑制由各种刺激引发的细胞死亡。此外,现在显而易见的是,存在一系列Bcl-2细胞死亡调节蛋白,其享有共同的结构和序列同源性。已显示这些不同的家族成员具有与Bcl2相似的功能(例如,BclXL、BclW、BclS、Mcl-1、A1,Bfl-1)或抵消Bcl2功能并促进细胞死亡(例如,Bax、Bak、Bik、Bim、Bid、Bad、Harakiri)。
大约60%的癌症患者将接受某种类型的手术,包括预防性、诊断性或分期、治愈性和姑息性手术。治愈性手术是可以与其他疗法结合使用的癌症治疗,例如本发明的治疗、化学疗法、放射疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法。
治愈性手术包括切除,其中全部或部分癌组织被物理移除、切除和/或破坏。肿瘤切除是指至少部分肿瘤的物理移除。除肿瘤切除外,手术治疗包括激光手术、冷冻手术、电外科手术和显微镜下控制手术(莫氏(Mohs’)手术)。进一步预计本发明可以与去除表面癌、癌前病变或附带量的正常组织结合使用。
在切除所有癌细胞、组织或肿瘤的一部分后,可在体内形成腔。可以通过用另外的抗癌疗法对该区域灌注、直接注射或局部施用来完成治疗。这种治疗可以例如每1、2、3、4、5、6或7天重复一次,或每1、2、3、4和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月重复一次。这些治疗也可以是不同的剂量。
预期其他药剂可以与本文所述的组合物和方法组合使用以改善治疗的功效。这些另外的药剂包括免疫调节剂(如上述免疫检查点抑制剂)、影响细胞表面受体和GAP连接上调的药剂、细胞抑制剂和分化剂、细胞粘附抑制剂、增加过度增殖细胞对凋亡诱导剂敏感性的药剂、或其他生物制剂。免疫调节剂包括肿瘤坏死因子;干扰素α、β和γ;IL-2和其他细胞因子;F42K和其他细胞因子类似物;或MIP-1、MIP-1β、MCP-1、RANTES和其他趋化因子。进一步预计细胞表面受体或其配体(如Fas/Fas配体、DR4或DR5/TRAIL(Apo-2配体))的上调将通过对过度增殖细胞建立自分泌或旁分泌作用来增强本发明的细胞凋亡诱导能力。通过提高GAP连接的数量来增加细胞间信号传导将增加对邻近的过度增殖细胞群的抗过度增殖作用。在其他实施方案中,细胞抑制剂或分化剂可以与本发明组合使用以改善治疗的抗过度增殖功效。预计细胞粘附抑制剂可以改善本发明的功效。细胞粘附抑制剂的实例是粘着斑激酶(FAK)抑制剂和洛伐他汀(Lovastatin)。进一步预计增加过度增殖细胞对细胞凋亡的敏感性的其他试剂(例如抗体c225)可以与本发明组合使用以改善治疗功效。
在引入细胞毒性化学治疗药物后,在癌症治疗方面取得了许多进展。然而,化疗的后果之一是耐药表型的发展/获得和多重耐药性的发展。耐药性的发展仍然是治疗这种肿瘤的主要障碍,因此,显然需要替代方法,例如病毒治疗。
与化学疗法、放射疗法或生物疗法结合使用的另一种形式的疗法包括热疗,其是患者组织暴露于高温(高达106°F)的过程。外部或内部加热装置可能涉及局部、区域或全身热疗的应用。局部热疗涉及将热量应用到小区域,例如肿瘤。可以利用来自身体外部的装置的靶向肿瘤的高频波在外部产生热量。内部热量可能涉及使用无菌探头,包括薄的加热电线或充满温水的空心管、植入式微波天线或射频电极。
对于区域治疗,患者的器官或肢体被加热,这是使用产生高能量的装置(例如磁体)来完成的。或者,一些患者的血液可以被移出并加热,然后灌注到将被内部加热的区域。在癌症扩散到全身的情况下也可以实施全身加热。为此目的,可以使用温水毯、热蜡,感应线圈和热室。
激素疗法也可以与本发明结合使用或与之前描述的任何其他癌症疗法组合使用。激素的使用可以被用于治疗某些癌症,例如乳腺癌、前列腺癌、卵巢癌或宫颈癌,以降低某些激素(如睾酮或雌激素)的水平或阻断某些激素(如睾酮或雌激素)的作用。该治疗通常与至少一种其他癌症疗法组合用作治疗。
III. 实施例
给出以下实施例是为了说明本发明的各种实施方案,并不意味着以任何方式限制本发明。本领域技术人员将容易理解,本发明非常适合于实现本文所述目的并获得所提到的目的和优点,以及本文固有的那些目的、目标和优点。本发明的实施例以及本文所述的方法目前是优选实施方案的代表,是示例性的,并不意图作为对本发明范围的限制。领域技术人员将想到其中的变化和包含在由权利要求的范围限定的本发明的精神内的其他用途。
实施例1
方法
病毒和细胞。Vero、13762 MAT B III和9L/LacZ细胞购自American Type CultureCollection(Manassas, VA)。将13762 MAT B III细胞维持在补充有10%胎牛血清(HyClone, Logan, UT)的McCoy's 5A(ATCC, Manassas, VA)中。将9L/LacZ和Vero细胞维持在补充有10%胎牛血清(HyClone,Logan,UT)的Dulbecco's Modified Eagle's培养基(HyClone, Logan, UT)中。按之前所述使用Maraba MG1(含有G蛋白Q242R点突变和M蛋白L123W点突变的Maraba)和Maraba野生型。按之前所述使用VSVd51(在M蛋白的第51位含有甲硫氨酸缺失的VSV)和VSV LCMV G(包含编码LCMV的糖蛋白(G)的基因并且缺少编码VSV的包膜蛋白G的功能基因的VSV)。MRB LCMV G(或MV-LCMVg)通过用编码LCMV的糖蛋白(G)的基因取代Maraba的G蛋白而产生。MRB Lassa G(或MV-Lg)是通过用编码Lassa病毒糖蛋白(G)的基因取代Maraba的G蛋白而产生的。MRB Junin G(或MV-Jg)是通过用编码Junin病毒糖蛋白(G)的基因取代Maraba的G蛋白而产生的。参见图8。在每种假型病毒中,缺失天然VSV或Maraba G蛋白,在VSV或Maraba G蛋白基因被缺失的相同位置用编码LCMV、Junin或Lassa病毒糖蛋白的密码子优化基因取代。简言之,合成出编码Junin糖蛋白和Lassa糖蛋白的密码子优化的基因,并在上游插入KpnI限制性位点,在下游插入NotI限制性位点。将KpnI/NotIJunin糖蛋白和Lassa糖蛋白片段克隆到NotI-糖蛋白Maraba病毒载体(经改造的Maraba病毒载体,其被改造以具有在糖蛋白编码序列下游的NotI限制性位点)替换天然Maraba糖蛋白。
全血体外中和。在终末抽血前两周静脉内给大鼠接种1x107 pfu的病毒。在抽血前一天,一半大鼠用35U CVF耗尽补体。使用血清收集真空管(BD Bioscience, San Jose,CA)从大鼠收集血液,并立即用抗凝血剂Refludan(50μg/ mL)处理。将血液以800×g离心10分钟以获得血浆。将血浆等分试样在56℃温育30分钟以灭活补体。将200μL血液或其部分在37℃下与2 x 106 pfu的MRB LCMV G或MG1一起温育1小时。通过Vero细胞上的噬斑测定来定量剩余的感染性病毒。
血清体外中和。通过静脉注射,用1x108 pfu的MRB LCMV G或MG1、1x107 pfu的野生型(wt)Maraba、VSVd51、VSV LCMV G、MRB Lassa G或MRB Junin G给雌性F344 Fischer大鼠接种。接种疫苗后14天通过心脏穿刺从大鼠收集血清。将血清(25μL)加热灭活(56℃,30分钟)并用作抗体来源。补体补充有等体积(25μL)的大鼠血清(CompTech, Tyler, TX)。或者,使用25μL右旋葡萄糖明胶veronal缓冲液(GVB++; Lonza, Allendale, NJ)。将血清稀释到GVB++中,并在与病毒以5x105 pfu的浓度每个反应在37℃一起温育1小时后评估中和作用。通过Vero细胞上的噬斑测定来定量剩余的感染性病毒。还使用用10 U/mL眼镜蛇毒因子(CVF; Quidel, San Diego, CA) 在37℃下预处理1小时的大鼠血清(CompTech, Tyler,TX)评估中和作用。
根据加拿大多伦多大学健康网络动物资源中心批准的方案,用病毒处理食蟹猴(1x1010 pfu静脉内(动物1)或1x109 pfu颅内(动物2))。在不同时间点(给药前、给药后8天、14天或36天)收集血清。如大鼠和小鼠免疫血清部分所述,在用GVB++或食蟹猴血清(Innovative Research, Novi, MI)孵育热灭活的免疫血清(1小时; 37℃)后评估中和作用。数据表示为技术重复±标准偏差。
MRB LCMV G的中和用补充有人血清(NHS)或免疫耗竭了关键补体成分的血清的大鼠免疫血清评估。将C1q耗尽、C3耗尽、C5耗尽的血清以及NHS(ComTech, Tyler TX)或与Compstatin类似物、CP40(25μM)或Eculizumab(100μg/ mL)预孵育(在37℃下15分钟)的NHS与25μL热灭活的大鼠免疫血清和5 x 105 pfu在37℃下混合1小时。与人C3免疫耗尽的血清组合的免疫大鼠血清源自抽血前两天用CVF处理的动物。
体内动物研究。体重100-150g的雌性F344 Fischer大鼠购自Charles River(Wilmington, MA)。将所有动物饲养在无病原体环境下,并且所有进行的研究均符合渥太华大学动物护理兽医服务设施的指南。通过在左右单侧或双侧皮下注射1x106 13762MATBIII细胞来建立肿瘤。在病毒处理前两周,用1x107 pfu的MG1或MRB LCMV G静脉注射动物。对于补体的消耗,在病毒前24小时腹膜内施用35U的眼镜蛇毒因子(CVF) (Quidel, SanDiego, CA)。为了在给药后早期检查病毒的稳定性,用1x108 pfu的MG1或MRB LCMV G静脉内处理动物,并在处理后10分钟处死动物。通过心脏穿刺将血液收集到EDTA真空管(BDBioscience, Mississauga ON)中并切除肿瘤。在Vero细胞上滴定血液以定量剩余的病毒,并将肿瘤快速冷冻,匀浆,然后在Vero细胞上滴定以定量感染性病毒。
未用病毒处理的大鼠(Virus naïve rat)或病毒接种了的大鼠也用1x107 pfu的MG1或MRB LCMV G进行瘤内处理。在病毒处理后24小时收集肿瘤并立即冷冻。通过Vero细胞上的噬斑测定来定量感染性病毒。
结果
为了研究抗体和补体对MG1(非假型)和LCMV糖蛋白假型Maraba病毒(MRB LCMV G)的影响,在对未用病毒处理的大鼠或抽血前两周接种了病毒的大鼠的血液中离体评估病毒中和作用(图1A-C)。在抽血前一天,使用眼镜蛇毒因子(CVF)使一半动物耗尽补体。从动物中分离血液,用Refludan抗凝血,并在全血、血浆和热灭活血浆(补体破坏)中体外评估病毒中和。对于从MG1组中动物收集的血液,将感染性MG1体外添加至每个血液级分。对于从MRBLCMV G组中动物收集的血液,将感染性MRB LCMV G体外添加至每个血液级分。将血液病毒混合物在37℃下孵育1小时,之后通过病毒噬斑测定评估样品中剩余的感染性病毒。
在未用MG1处理的血液和血浆中,MG1对补体介导的中和敏感。然而,当通过热灭活破坏补体时,未观察到MG1的中和(图1B)。在从MG1接种的动物收集的血液中,由于抗MG1抗体的存在,失去了近5个对数的病毒。通过比较补体补充与补体耗尽,观察到全血和血浆中补体的存在导致病毒滴度的额外降低,但是这种差异非常小。当比较在热灭活的血浆中与血浆样品中回收的病毒时,观察到相同小的差异。因此,针对天然Maraba G的抗体仅通过补体中等程度地增强。数据表明,针对天然Maraba糖蛋白产生的抗体主要以补体非依赖性方式中和病毒,因为补体抑制仅提供感染性病毒滴度的中等程度增加。
MRB LCMV G对未用病毒处理的血液中的补体中和也具有中等敏感性(图1C)。然而,与MG1相反,从用MRB LCMV G病毒处理的大鼠收集的血液引发仅在补体存在下才中和的抗体。在补体存在下(血液和血浆样品),中和了近4个对数的MRB LCMV G病毒。如果血浆被热灭活,或者如果大鼠用补体抑制剂预处理,则该效果被消除。这些数据表明,针对MRBLCMV G产生的抗体仅在补体存在下中和MRB LCMV G。
为了确定由MRB LCMV G病毒引发的抗体的补体依赖性表型实际上与弹状病毒骨架无关,我们进行了离体大鼠研究。为了产生抗体来源,将大鼠用野生型Maraba病毒(Maraba wt)、MG1、MRB LCMV G以及减毒VSV(VSVd51)和用LCMV糖蛋白(VSV LCMV G)假型化的VSV接种。接种后2周,从大鼠收集血液,通过加热灭活收集的血清制备病毒特异性抗体。将血清(抗体来源)与活性补体来源(初始大鼠血清)或无活性补体来源(用CVF体外处理的初始大鼠血清)或对照缓冲液组合。向抗体:补体混合物中加入同源病毒,并在37℃温育1小时后通过噬斑测定评估中和作用。见图2A。
对于具有天然糖蛋白的病毒(Maraba wt, MG1, VSVd51),从接种动物的血液中收集的抗体导致病毒滴度的显著降低,证实天然弹状病毒糖蛋白引发的抗体能够中和至少99%的输入病毒。在补体存在(大鼠血清)下,病毒中和仅中等增强,表明大多数抗体以非补体依赖性方式中和。相反,对于LCMV G假型弹状病毒(MRB LCMV G和VSV LCMV G),从接种动物的血液中收集的抗体仅在补体存在(大鼠血清)下导致病毒滴度降低。这些数据如图2B所示,其证明靶向LCMV糖蛋白的抗体在没有补体的情况下是非中和性的,但在补体存在下可介导大于99%的中和作用。此外,这些数据表明这种现象与弹状病毒骨架无关。
使用食蟹猴模型确定抗体中和的补体依赖性不是啮齿动物特异性现象。两只动物用MRB LCMV G静脉内或颅内处理。在治疗后的不同时间点收集它们的血清。将血清热灭活以除去补体,并与两种补体来源或对照缓冲液组合:初始猕猴血清(活性补体),用补体抑制剂CP40处理的初始猕猴血清(无活性补体)。向每种抗体:补体混合物中加入等量的MRBLCMV G,并在37℃温育1小时后通过噬斑测定评估中和作用。见图3A。
在两只猕猴中,在接种疫苗之前,初始猴血清导致由于补体存在而导致可恢复病毒的少量减少。早在接种MRB LCMV G后8天,观察到抗体介导的补体依赖性中和,导致超过99%的输入病毒去除。在两种动物中,CP40的补体抑制能够极大地减弱抗体的作用。在一只动物中,这种减弱在处理后30天的过程中持续存在。这些数据图示于图3B和3C中,并证明LCMV G假型化抗体中和的补体依赖性质不是啮齿动物特异性现象。
使用人/大鼠离体系统,评估人补体抑制剂以确定其消除补体依赖性MRB LCMV G病毒中和的功效。尽管可用于大鼠的试剂的选择仅限于CVF,但在部分人离体体系中评估了人补体抑制剂。从MRB LCMV G接种的大鼠收集血清。将血清热灭活以除去补体,并与对照缓冲液(右旋葡萄糖明胶veronal缓冲液(GVB))、作为活性补体来源的正常人血清(NHS)、用各种补体抑制剂处理的NHS或耗尽了关键补体成分(C1q、C3或C5)的NHS组合。对于后一种混合物,C1q和C5包括额外的反向添加(add-back)对照,其中将这些组分加入到耗尽的NHS中以确认观察结果被逆转。向抗体:补体混合物中加入MRB LCMV G,并在37℃温育1小时后评估中和作用。见图4A。
当与对照缓冲液GVB组合时,针对从大鼠血清中分离的MRB LCMV G病毒的抗体不会导致病毒的中和。然而,当与NHS(作为补体来源)组合时,可恢复病毒的量减少至输入的约1%。如果关键的经典途径分子C1q从NHS免疫耗竭,则抗体和补体介导的病毒中和被消除。在添加C1q至生理浓度后,中和效果恢复。这些数据在图4B中描述,其证明病毒中和是通过C1q(经典途径的一部分)而补体介导的。类似地,当与耗尽C3的NHS组合时,从大鼠血清中分离的MRB LCMV G抗体不导致病毒中和。通过向NHS添加C3结合蛋白(CP40)来反映了这种效果。这些数据在图4C中描述,并证明病毒中和是通过C3而补体介导的。
为了评估终末补体途径是否也参与介导补体依赖性MRB LCMV G中和,使用了C5免疫耗竭血清和C5抑制性单克隆抗体(Eculizumab)。C5的消耗和抑制都能够阻止病毒中和。然而,对于C5耗尽的血清,添加生理水平的C5逆转了这种作用。这些数据图示于图4D,其证明病毒中和是经由C5(终末途径的一部分)而补体介导的。因此,可以通过抑制经典补体途径、中枢分子C3或终末补体途径来消除抗LCMV G抗体的功能活性。
为了测试对于LCMV G-假型弹状病毒所观察到的补体依赖性中和是否对LCMV糖蛋白具有特异性或者是泛纳病毒现象,构建了两种新的假型Maraba病毒:用Lassa病毒糖蛋白假型化的Maraba (MRB Lassa G),和用Junin病毒糖蛋白假型化的Maraba(MRB Junin G)。Lassa糖蛋白和Junin糖蛋白分别与LCMV糖蛋白具有75%和51%的同源性。在存在来自接种了这些病毒的大鼠的热灭活免疫血清下的条件下离体评估MRB Junin G和MRB Lassa G的中和作用。将血清(抗体来源)与两种补体来源中的一种组合:初始大鼠血清(活性补体)、用CVF体外处理的初始大鼠血清(无活性补体),或与对照缓冲液组合。向抗体:补体混合物中加入同源病毒,并在37℃温育1小时后通过噬斑测定评估中和作用。这些数据图示于图5A。
与热灭活的初始血清一起孵育的MRB Junin G与对照缓冲液(无补体)或大鼠血清(补体活性)组合时未被中和。从MRB Junin G疫苗接种的大鼠收集的含有抗体的免疫血清不会导致对照缓冲液中和;然而,当与初始大鼠血清(活性补体来源)组合时,导致将近4个对数的病毒被中和(相对回收率为输入病毒的0.0001,相当于0.01%)。如果将抗MRB JuninG抗体与用CVF耗尽了补体的血清组合,则中和消除。这些数据图示于图5B,其证明Junin糖蛋白引发需要补体活性以中和病毒的抗体。
在MRB Lassa G初始血清中,从含有大鼠血清(补体活性)的样品中回收的病毒与对照缓冲液(无补体)相比有少量减少。从MRB Lassa G接种的大鼠(抗体来源)收集的血清不会导致对照缓冲液中和,但是当与初始大鼠血清(活性补体来源)组合时,超过3个对数(3-log)的病毒被中和(相对汇率率为输入病毒的0.001,相当于0.1%)。如果大鼠血清用补体抑制剂CVF预处理,则该效果消除。这些数据图示于图5C,其证明Lassa糖蛋白也引发需要补体活性以中和病毒的抗体。
眼镜蛇毒因子(CVF)充当C3b模拟物并且结合产生C3转化酶,其激活并消耗C3分子。这种消耗类似于用诸如CP40的化合物靶向C3分子。使用与乳腺癌细胞系13762 MAT BIII同源的Fischer大鼠模型,评估补体消耗增加MG1和MRB LCMV G病毒在血液中的稳定性以及增加向肿瘤递送的能力。简而言之,病毒接种的或初始大鼠移植了双侧乳腺癌肿瘤(13762 MAT B III)。CVF用于消耗一部分动物中的补体,随后静脉内递送病毒(尾静脉注射)。在病毒施用后10分钟处死动物以通过噬斑测定来定量血液中的病毒和肿瘤。见图6A。
在MRB LCMV G初始大鼠中,与补体充足的大鼠相比,从补体耗尽的大鼠的血液中回收的感染性病毒显著增加。相对于初始动物,从接种了的动物的血液中回收的感染性病毒显著减少。相反,如果在静脉内给予MRB LCMV G之前用CVF补体抑制剂处理,则观察到MRBLCMV G免疫动物的血液中回收的感染性病毒的显著增加(平均97倍的增加)。这些发现转化为从MRB LCMV G免疫动物的皮下肿瘤中回收的感染性病毒的相应的显著增加,以及补体耗竭的初始动物肿瘤中回收病毒的增加趋势。这些数据图示于图6B,其证明体内补体抑制导致MRB LCMV G病毒在血液中的稳定性增强,这与从肿瘤中回收的病毒增加相关。
与用LCMV糖蛋白假型化的Maraba病毒相反,对于MG1,在初始或免疫动物中没有观察到补体耗尽对血液稳定性或向肿瘤递送有任何益处。对于MG1大鼠,当将从MG1初始大鼠分离的血液中回收的病毒与MG1接种的大鼠比较时,回收的病毒量急剧减少。在从MG1接种的大鼠分离的血液中,血液中没有可回收的病毒,并且未发现该抗体中和是补体介导的,因为用CVF处理(补体消耗)并未消除该作用。在肿瘤中观察到类似的观察结果。这些数据图示于图6C,其证明MRB LCMV G中观察到的补体依赖性抗体中和是糖蛋白特异性的。
还评估了局部病毒给药时补体耗尽的作用。用CVF或假手术处理初始和接种病毒的大鼠,然后根据图7中的时间表瘤内给予MG1病毒或MRB LCMV G病毒。补体耗尽增加了病毒给药24小时后从免疫大鼠肿瘤中回收的MRB LCMV G的滴度(平均增加135倍),但对于瘤内注射病毒后的初始大鼠未增加。与血液中病毒稳定性的研究一致,针对MG1的抗体独立于补体而中和病毒以预防肿瘤感染。补体耗尽也无助于初始动物皮下肿瘤中MG1的感染。因此,补体在血流和肿瘤微环境中起重要作用,以限制用沙粒病毒(arenavirus)糖蛋白假型化的弹状病毒的感染。尽管存在抗病毒抗体,组合补体抑制和假型化策略能够将感染性病毒局部和全身递送至肿瘤。
讨论
在施用诸如VSV和Maraba病毒的弹状病毒后的第一周内,产生了针对这些病毒的中和抗体,从而限制了多轮给药。相反,已知诸如LCMV的沙粒病毒因不能产生早期中和性抗体。通过假型化而将这种性质赋予了弹状病毒,并且当在小鼠中测试时,用LCMV糖蛋白假型化的VSV病毒不会引起强烈的中和抗体应答,并且在多个治疗剂量后显示出增强的肿瘤递送。然而,这种策略未平移到其他动物模型。在大鼠和灵长类动物模型中使用用沙粒病毒糖蛋白假型化的弹状病毒,本申请首次令人惊讶地证明在三种不同物种中产生针对沙粒病毒糖蛋白的早期抗体,其虽然是非中和性的,但它们介导强大的补体依赖性病毒中和,限制这些病毒的治疗潜力。具体地,结合至用沙粒病毒糖蛋白假型化的病毒的抗体通过膜攻击复合物介导C1q结合和中和。本申请证明补体抑制改善了这种假型弹状病毒的稳定性和递送至肿瘤,无论是通过肿瘤内注射的局部给药还是通过静脉内注射的全身给药,都导致初始和免疫动物中肿瘤的溶瘤感染的持续增加。本申请支持使用补体抑制剂来躲避免疫动物或人中的病毒中和,当以单剂量施用时导致增加的治疗效果并且能够有效施用多轮治疗性假型病毒。
序列表
<110> Evgin, Laura
<120> 假型化的溶瘤弹状病毒及其在组合治疗中的应用
<130> PAT 104044W90
<150> US 62/338,940
<151> 2016-05-19
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 1492
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的Junin糖蛋白编码序列
<400> 1
ggtacccagt tatatttgtt acaacaatgg gacaattcat ctccttcatg caggagatac 60
ctactttcct ccaagaggct ctcaatatcg ctctggtggc ggtttcactg atcgctatca 120
taaagggcat tgtgaacttg tacaaatcag gcctgttcca attctttgtg ttcctggctc 180
ttgcagggag atcttgtaca gaagaggctt ttaaaatcgg cctccacact gagtttcaga 240
ccgtgagttt ctcaatggtc ggcctgtttt caaataatcc ccatgacctg cccctgttgt 300
gtaccctgaa caagagtcac ctgtacatca agggcggaaa cgcatcattc atgatctcct 360
ttgacgatat tgaagtgctg ctgcctcaat acgatgtgat aatacagcac ccagccgaca 420
tgtcctggtg cagcaagtcc gatgaccaaa tttggttgtc ccagtggttt atgaatgcag 480
tcggacatga ttggcacttg gacccaccct tcctttgccg caatagaact aagaccgagg 540
gtttcatttt tcaggtcaac acaagcaaga ctggggtcaa cgaaaactat gcaaaaaagt 600
tcaagacagg tatgcatcac ctctaccggg agtaccctga ttcttgcctg aacgggaagt 660
tgtgcctgat gaaggcccag ccaacgtcct ggcctctgca gtgccctttg gaccatgtga 720
acactttgca ctttctcact agaggcaaaa acatccagct ccctaggcga tcccttaagg 780
cgttcttttc ttggagtctg acggattctt ccggaaagga cacccctggg ggctactgtc 840
tcgaagaatg gatgctggta gctgcaaaga tgaaatgttt tgggaacact gccgtcgcga 900
aatgcaacct gaaccatgat tctgaatttt gcgatatgct ccgacttttc gactataata 960
agaatgctat caagacactg aacgatgaaa ctaagaaaca ggtgaatctc atgggacaga 1020
ccattaatgc tctgatcagt gacaatctgc tgatgaagaa taaaatccga gagctgatgt 1080
cagtgcccta ttgtaattat acaaaatttt ggtacgtgaa tcacacactg tccggccagc 1140
actctctgcc gaggtgctgg ctgattaaga ataatagcta cttgaacatc agcgacttca 1200
gaaacgactg gattctcgag tccgattttc tgatcagcga aatgctcagt aaagagtatt 1260
cagacagaca gggcaagaca ccccttactc tcgttgatat ttgtttttgg agtacagttt 1320
tttttacggc ctccctgttc ctccatctgg tcggtattcc tacccaccga catatccgcg 1380
gcgaggcatg tccactgcct catcgcctca attcactggg aggctgtcga tgtggaaagt 1440
atccgaatct caaaaaacct accgtctggc gcagaagaca ttaggcggcc gc 1492
<210> 2
<211> 485
<212> PRT
<213> 沙粒病毒 - Junin
<400> 2
Met Gly Gln Phe Ile Ser Phe Met Gln Glu Ile Pro Thr Phe Leu Gln
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Glu Ala Leu Asn Ile Ala Leu Val Ala Val Ser Leu Ile Ala Ile Ile
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Lys Gly Ile Val Asn Leu Tyr Lys Ser Gly Leu Phe Gln Phe Phe Val
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Phe Leu Ala Leu Ala Gly Arg Ser Cys Thr Glu Glu Ala Phe Lys Ile
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Gly Leu His Thr Glu Phe Gln Thr Val Ser Phe Ser Met Val Gly Leu
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Phe Ser Asn Asn Pro His Asp Leu Pro Leu Leu Cys Thr Leu Asn Lys
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Ser His Leu Tyr Ile Lys Gly Gly Asn Ala Ser Phe Met Ile Ser Phe
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Asp Asp Ile Glu Val Leu Leu Pro Gln Tyr Asp Val Ile Ile Gln His
115 120 125
Pro Ala Asp Met Ser Trp Cys Ser Lys Ser Asp Asp Gln Ile Trp Leu
130 135 140
Ser Gln Trp Phe Met Asn Ala Val Gly His Asp Trp His Leu Asp Pro
145 150 155 160
Pro Phe Leu Cys Arg Asn Arg Thr Lys Thr Glu Gly Phe Ile Phe Gln
165 170 175
Val Asn Thr Ser Lys Thr Gly Val Asn Glu Asn Tyr Ala Lys Lys Phe
180 185 190
Lys Thr Gly Met His His Leu Tyr Arg Glu Tyr Pro Asp Ser Cys Leu
195 200 205
Asn Gly Lys Leu Cys Leu Met Lys Ala Gln Pro Thr Ser Trp Pro Leu
210 215 220
Gln Cys Pro Leu Asp His Val Asn Thr Leu His Phe Leu Thr Arg Gly
225 230 235 240
Lys Asn Ile Gln Leu Pro Arg Arg Ser Leu Lys Ala Phe Phe Ser Trp
245 250 255
Ser Leu Thr Asp Ser Ser Gly Lys Asp Thr Pro Gly Gly Tyr Cys Leu
260 265 270
Glu Glu Trp Met Leu Val Ala Ala Lys Met Lys Cys Phe Gly Asn Thr
275 280 285
Ala Val Ala Lys Cys Asn Leu Asn His Asp Ser Glu Phe Cys Asp Met
290 295 300
Leu Arg Leu Phe Asp Tyr Asn Lys Asn Ala Ile Lys Thr Leu Asn Asp
305 310 315 320
Glu Thr Lys Lys Gln Val Asn Leu Met Gly Gln Thr Ile Asn Ala Leu
325 330 335
Ile Ser Asp Asn Leu Leu Met Lys Asn Lys Ile Arg Glu Leu Met Ser
340 345 350
Val Pro Tyr Cys Asn Tyr Thr Lys Phe Trp Tyr Val Asn His Thr Leu
355 360 365
Ser Gly Gln His Ser Leu Pro Arg Cys Trp Leu Ile Lys Asn Asn Ser
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Tyr Leu Asn Ile Ser Asp Phe Arg Asn Asp Trp Ile Leu Glu Ser Asp
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Phe Leu Ile Ser Glu Met Leu Ser Lys Glu Tyr Ser Asp Arg Gln Gly
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Lys Thr Pro Leu Thr Leu Val Asp Ile Cys Phe Trp Ser Thr Val Phe
420 425 430
Phe Thr Ala Ser Leu Phe Leu His Leu Val Gly Ile Pro Thr His Arg
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His Ile Arg Gly Glu Ala Cys Pro Leu Pro His Arg Leu Asn Ser Leu
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Gly Gly Cys Arg Cys Gly Lys Tyr Pro Asn Leu Lys Lys Pro Thr Val
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Trp Arg Arg Arg His
485
<210> 3
<211> 1507
<212> DNA
<213> 人工序列
<220>
<223> 密码子优化的Lassa糖蛋白编码序列
<400> 3
ggtacccagt tatatttgtt acaacaatgg gacaaatcat cacgtttttc caggaagtgc 60
cccacgtcat agaggaggta atgaatatag tgctcattgc cctcagtttg ctggcgatcc 120
tgaaagggat ctacaacgtg gcgacttgtg gtctgtttgg cttggtgtct ttcctgctgt 180
tgtgcggtcg aagctgcagt accacctata agggagtcta cgagctgcag acactggaac 240
tggacatggc tagcttgaac atgactatgc ctctctcctg cacaaagaat aacagtcacc 300
attacataat ggtggggaat gaaactggtt tggaactcac acttaccaac acatccatca 360
taaatcacaa gttttgtaac ctcagtgacg cccacaaaaa aaacttgtat gatcacgctc 420
tcatgtccat aatcagcact tttcacctgt ctatccctaa cttcaatcag tacgaggcta 480
tgtcttgcga ctttaacggg ggcaaaatca gcgtgcaata caatctgagc cacgcatatg 540
ccgtcgacgc cgccaaccac tgcggaacta tcgctaacgg cgtcctgcag acattcatgc 600
ggatggcttg gggcggctcc tatatcgctc tggatagcgg aaagggcagt tgggactgta 660
ttatgacctc ataccagtac cttattatcc agaacaccac ctgggaggat cactgtcaat 720
tttcccggcc gtccccaatc ggctatctgg gcctcctgag ccaaagaact cgggacattt 780
acatatctcg gcgactcctc gggacattca catggaccct gtccgactct gaagggaatg 840
aaacgccagg cgggtattgc ctgacccgat ggatgctgat cgaagccgag ctcaagtgct 900
ttggaaatac cgcagtcgcc aagtgtaatg aaaagcatga tgaagaattt tgcgatatgc 960
tgcggctgtt cgatttcaat aaacaggcca ttcgacggct gaaaaccgag gcccaaatga 1020
gtatccagct gattaacaag gccgttaatg ccctgattaa tgaccagctc attatgaaaa 1080
atcacctgcg ggatatcatg ggcattcctt actgtaacta ttccaagtat tggtatctga 1140
accacaccgt gactggcaaa acgtcactgc caaggtgctg gctggtctcc aatggaagct 1200
acctgaacga gacccatttt tccgatgata tcgagcagca ggccgataat atgattaccg 1260
aactgttgca gaaagaatac atggaccgcc agggcaaaac tccacttggg ttggtcgacc 1320
tgtttgtgtt ctctaccagc ttctacttga ttagcatttt cctgcacctg gtgcgcatcc 1380
ccacgcacag acatgtcatc ggtaagccat gccctaagcc gcatagactc aaccatatgg 1440
ggatttgctc ctgtggtctc tataaacacc ccggcgtgcc tgtcaaatgg aagaggtgag 1500
cggccgc 1507
<210> 4
<211> 490
<212> PRT
<213> 沙粒病毒 - Lassa
<400> 4
Met Gly Gln Ile Ile Thr Phe Phe Gln Glu Val Pro His Val Ile Glu
1 5 10 15
Glu Val Met Asn Ile Val Leu Ile Ala Leu Ser Leu Leu Ala Ile Leu
20 25 30
Lys Gly Ile Tyr Asn Val Ala Thr Cys Gly Leu Phe Gly Leu Val Ser
35 40 45
Phe Leu Leu Leu Cys Gly Arg Ser Cys Ser Thr Thr Tyr Lys Gly Val
50 55 60
Tyr Glu Leu Gln Thr Leu Glu Leu Asp Met Ala Ser Leu Asn Met Thr
65 70 75 80
Met Pro Leu Ser Cys Thr Lys Asn Asn Ser His His Tyr Ile Met Val
85 90 95
Gly Asn Glu Thr Gly Leu Glu Leu Thr Leu Thr Asn Thr Ser Ile Ile
100 105 110
Asn His Lys Phe Cys Asn Leu Ser Asp Ala His Lys Lys Asn Leu Tyr
115 120 125
Asp His Ala Leu Met Ser Ile Ile Ser Thr Phe His Leu Ser Ile Pro
130 135 140
Asn Phe Asn Gln Tyr Glu Ala Met Ser Cys Asp Phe Asn Gly Gly Lys
145 150 155 160
Ile Ser Val Gln Tyr Asn Leu Ser His Ala Tyr Ala Val Asp Ala Ala
165 170 175
Asn His Cys Gly Thr Ile Ala Asn Gly Val Leu Gln Thr Phe Met Arg
180 185 190
Met Ala Trp Gly Gly Ser Tyr Ile Ala Leu Asp Ser Gly Lys Gly Ser
195 200 205
Trp Asp Cys Ile Met Thr Ser Tyr Gln Tyr Leu Ile Ile Gln Asn Thr
210 215 220
Thr Trp Glu Asp His Cys Gln Phe Ser Arg Pro Ser Pro Ile Gly Tyr
225 230 235 240
Leu Gly Leu Leu Ser Gln Arg Thr Arg Asp Ile Tyr Ile Ser Arg Arg
245 250 255
Leu Leu Gly Thr Phe Thr Trp Thr Leu Ser Asp Ser Glu Gly Asn Glu
260 265 270
Thr Pro Gly Gly Tyr Cys Leu Thr Arg Trp Met Leu Ile Glu Ala Glu
275 280 285
Leu Lys Cys Phe Gly Asn Thr Ala Val Ala Lys Cys Asn Glu Lys His
290 295 300
Asp Glu Glu Phe Cys Asp Met Leu Arg Leu Phe Asp Phe Asn Lys Gln
305 310 315 320
Ala Ile Arg Arg Leu Lys Thr Glu Ala Gln Met Ser Ile Gln Leu Ile
325 330 335
Asn Lys Ala Val Asn Ala Leu Ile Asn Asp Gln Leu Ile Met Lys Asn
340 345 350
His Leu Arg Asp Ile Met Gly Ile Pro Tyr Cys Asn Tyr Ser Lys Tyr
355 360 365
Trp Tyr Leu Asn His Thr Val Thr Gly Lys Thr Ser Leu Pro Arg Cys
370 375 380
Trp Leu Val Ser Asn Gly Ser Tyr Leu Asn Glu Thr His Phe Ser Asp
385 390 395 400
Asp Ile Glu Gln Gln Ala Asp Asn Met Ile Thr Glu Leu Leu Gln Lys
405 410 415
Glu Tyr Met Asp Arg Gln Gly Lys Thr Pro Leu Gly Leu Val Asp Leu
420 425 430
Phe Val Phe Ser Thr Ser Phe Tyr Leu Ile Ser Ile Phe Leu His Leu
435 440 445
Val Arg Ile Pro Thr His Arg His Val Ile Gly Lys Pro Cys Pro Lys
450 455 460
Pro His Arg Leu Asn His Met Gly Ile Cys Ser Cys Gly Leu Tyr Lys
465 470 475 480
His Pro Gly Val Pro Val Lys Trp Lys Arg
485 490
Claims (42)
1.一种治疗和/或预防有此需要的哺乳动物的癌症或转移癌的方法,包括向所述哺乳动物施用有效量的组合,所述组合包含(a)用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒和(b)一种或多种补体抑制剂。
2.根据权利要求1所述的方法,其中所述假型化的复制型溶瘤弹状病毒具有野生型或遗传修饰的水疱病毒骨架。
3.根据权利要求2所述的方法,其中所述假型化的复制型溶瘤弹状病毒具有野生型或遗传修饰的VSV或Maraba病毒骨架。
4.根据权利要求3所述的方法,其中所述假型化的复制型溶瘤弹状病毒具有野生型或遗传修饰的Maraba病毒骨架。
5.根据权利要求1-4中任一项所述的方法,其中所述补体抑制剂是经典补体途径的抑制剂。
6.根据权利要求5所述的方法,其中所述补体抑制剂靶向C1,任选地选自C1酯酶抑制剂(Cinryze或Berinert)和抗C1s抗体,如TNT009或TNT010。
7.根据权利要求1-4中任一项所述的方法,其中所述补体抑制剂是替代补体途径的抑制剂。
8.根据权利要求7所述的方法,其中所述补体抑制剂靶向补体因子B(CFB)和/或补体因子D(CFD),任选地选自抗体或抗体片段,例如TA106、FCFD4514S和lampalizumab、抗CFBsiRNA、抗CFD siRNA和适体(aptamer)。
9.根据权利要求1-4中任一项所述的方法,其中所述补体抑制剂是经典途径和替代途径的抑制剂。
10.根据权利要求9所述的方法,其中所述补体抑制剂靶向C3,任选地选自TT30(CR2/CFH)、MiniCFH、sCR1(CDX-1135)、Microcept(APT070)、TT32(CR2/CR1)、例如 H17的抗体、compstatin或类似物、肽模拟物或其衍生物,例如4(1MeW)/POT-4、4(1MeW)/APL-1/2、Cp40/AMY-101和PEG-Cp40。
11.根据权利要求9所述的方法,其中所述补体抑制剂靶向C5,任选地选自抗体或其抗原结合片段,例如Eculizumab 、LFG316、Mubodina、CaCP29和Pexelizumab;重组蛋白质,如Coversin(OmCl);适体,例如 ARC1005和ARC1905;抗C5 siRNA,如ALN-CC5;以及C5a受体拮抗剂,如NGD 2000-1、CCX168、PMX53和AcPhe [Orn-Pro-D-环己基丙氨酸-Trp-Arg](AcF-[OpdChaWR])。
12.根据权利要求1-11中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒与至少两种补体抑制剂组合施用于哺乳动物,所述至少两种补体抑制剂优选包含经典补体途径的抑制剂和替代补体途径的抑制剂和/或终末途径的抑制剂。
13.根据权利要求1-12中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒与所述补体抑制剂同时施用。
14.根据权利要求1-13中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒和所述补体抑制剂按顺序施用,其中第一次施用假型化的溶瘤弹状病毒发生在第一次施用补体抑制剂之前,并且优选在第一次施用补体抑制剂的30天内发生。
15.根据权利要求14所述的方法,其中所述假型化的复制型溶瘤弹状病毒在至少8天的时期内多次给药,并且其中第一次给予补体抑制剂发生在第二次或之后的假型化的复制型溶瘤弹状病毒给药之前。
16.根据权利要求1-13中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒和所述补体抑制剂按顺序施用,并且其中第一次施用补体抑制剂发生在第一次施用假型化的复制型溶瘤病毒之前,并且优选发生在第一次施用假型化的复制型溶瘤病毒的30天内。
17.根据权利要求16所述的方法,其中所述假型化的复制型溶瘤弹状病毒被多次施用。
18.根据前述权利要求任一项所述的方法,其中所述假型化的溶瘤弹状病毒表达肿瘤抗原。
19.根据权利要求18所述的方法,其中所述肿瘤抗原是选自以下的肿瘤相关抗原:MAGEA3、人乳头瘤病毒E6/E7融合蛋白、人前列腺蛋白六跨膜上皮抗原、肿瘤睾丸抗原1以及它们的变体。
20.根据权利要求18或19所述的方法,其中所述哺乳动物对所述肿瘤相关抗原具有既存的免疫力。
21.根据权利要求20所述的方法,其中所述哺乳动物中既存的免疫力是通过在施用所述假型化的溶瘤弹状病毒之前将所述肿瘤相关抗原施用至哺乳动物来建立的。
22.根据前述权利要求任一项所述的方法,其中所述复制型溶瘤弹状病毒是用旧世界沙粒病毒糖蛋白假型化的。
23.根据权利要求22所述的方法,其中旧世界沙粒病毒糖蛋白选自LCMV、Lassa病毒糖蛋白、Mopeia病毒糖蛋白、Mobala病毒糖蛋白、Ippy病毒糖蛋白、Mariental病毒糖蛋白、Merino Walk病毒糖蛋白、Menekre病毒糖蛋白、Gairo病毒糖蛋白、Gbagroube 病毒糖蛋白、Morogoro病毒糖蛋白、Kodoko病毒糖蛋白、Lunk病毒糖蛋白、Okahandja病毒糖蛋白、Lujo病毒糖蛋白、Lemniscomys病毒糖蛋白、Mus minutoides病毒糖蛋白、Wenzhou病毒糖蛋白和Luna病毒糖蛋白。
24.根据权利要求23所述的方法,其中旧世界沙粒病毒糖蛋白是LCMV或Lassa病毒糖蛋白。
25.根据权利要求1至21任一项所述的方法,其中所述复制型溶瘤弹状病毒用新世界沙粒病毒糖蛋白假型化。
26.根据权利要求25所述的方法,其中新世界沙粒病毒糖蛋白选自Junin病毒糖蛋白、Tacaribe病毒糖蛋白、Machupo病毒糖蛋白、Cupixi病毒糖蛋白、Amapari病毒糖蛋白、Parana病毒糖蛋白、Patawa病毒糖蛋白、Tamiami病毒糖蛋白、Pichinde病毒糖蛋白、Latino病毒糖蛋白、Flexal病毒糖蛋白、Guanarito病毒糖蛋白、Sabia病毒糖蛋白、Oliveros病毒糖蛋白、Whitewater Arroyo病毒糖蛋白、Pirital病毒糖蛋白、Pampa病毒糖蛋白、BearCanyone病毒糖蛋白、Ocozocoautla de Espinosa病毒糖蛋白、Allpahuayo病毒糖蛋白、Tonto Creek病毒糖蛋白、Big Brushy Tank病毒糖蛋白、Real de Catorce病毒糖蛋白、Catarina病毒糖蛋白、Skinner Tank病毒糖蛋白和Chapare病毒糖蛋白。
27.根据权利要求26所述的方法,其中新世界沙粒病毒糖蛋白是Junin病毒糖蛋白。
28.根据前述权利要求中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒以一个或多个剂量的106-1014 pfu、106-1012 pfu、108-1014 pfu或108-1012 pfu施用。
29.根据权利要求28所述的方法,其中所述假型化的复制型溶瘤弹状病毒在至少8天的时间内以106-1014 pfu、106-1012 pfu、108-1014 pfu或108-1012 pfu的剂量多次施用。
30.根据前述权利要求中任一项所述的方法,其中所述假型化的复制型溶瘤弹状病毒通过血管内和/或肿瘤内方式施用。
31.根据前述权利要求中任一项所述的方法,其中所述癌是结直肠癌、肺癌、食道癌、黑素瘤、胰腺癌、卵巢癌、肾细胞癌、宫颈癌、肝癌、乳腺癌、头颈癌、前列腺癌、脑癌、膀胱癌和软组织肉瘤。
32.根据前述权利要求中任一项所述的方法,其中所述补体抑制剂是抗体或抗体片段,并以一个或多个剂量的.01-10 mg/kg、0.1-10 mg/kg、1-10 mg/kg、2-8 mg/kg、3-7 mg/kg、4-5 mg/kg 或至少10 mg/kg施用。
33.根据权利要求32所述的方法,其中所述补体抑制剂每周至少给药三次、每周至少四次、每周至少五次、每周一次、每两周一次、每隔一周一次或每三周一次。
34.根据任何前述权利要求所述的方法,其中所述哺乳动物是人。
35.根据权利要求34所述的方法,其中所述人患有对一种或多种先前治疗方案难以治愈的癌症。
36.一种治疗组合,其包含(a)用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒和(b)一种或多种补体抑制剂。
37.一种组合产品,其包含(a)用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒和(b)一种或多种补体抑制剂,以及药学上可接受的佐剂、稀释剂或载体。
38.一种包含以下组分的试剂盒:(a)用沙粒病毒糖蛋白假型化的复制型溶瘤弹状病毒,其与药学上可接受的佐剂、稀释剂或载体联合在一起,和(b)与药学上可接受的佐剂、稀释剂或载体联合在一起的一种或多种补体抑制剂,其中这些组分以适于按顺序、分开和/或同时给药的形式提供。
39.根据权利要求38所述的试剂盒,其中所述假型化的复制型溶瘤弹状病毒以有效治疗哺乳动物的癌的量存在,并且其中所述补体抑制剂以有效抑制哺乳动物的补体活性的量存在。
40.一种复制型溶瘤弹状病毒,优选野生型或减毒的VSV或Maraba病毒,其包含编码沙粒病毒糖蛋白的基因,其中所述沙粒病毒糖蛋白不是LCMV糖蛋白,并且缺少编码Maraba病毒或VSV的G蛋白的功能基因。
41.根据权利要求40所述的复制型溶瘤弹状病毒,其中所述弹状病毒是用Junin或Lassa病毒糖蛋白假型化的野生型或减毒的VSV,或者是用Junin或Lassa病毒糖蛋白假型化的野生型或减毒的Maraba病毒。
42.一种药物组合物,其包含有效量的权利要求40或41所述的假型化的复制型溶瘤弹状病毒和药学上可接受的佐剂、稀释剂或载体。
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