A Mucin 16 bispecific T cell–engaging antibody for the treatment of ovarian cancer

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2019-06-19 DOI:10.1126/scitranslmed.aau7534

Alison Crawford, Lauric Haber, Marcus P. Kelly, Kristin Vazzana, Lauren Canova, Priyanka Ram, Arpita Pawashe, Jennifer Finney, Sumreen Jalal, Danica Chiu, Curtis A. Colleton, Elena Garnova, Sosina Makonnen, Carlos Hickey, Pamela Krueger, Frank DelFino, Terra Potocky, Jessica Kuhnert, Stephen Godin, Marc W. Retter, Paurene Duramad, Douglas MacDonald, William C. Olson, Jeanette Fairhurst, Tammy Huang, Joel Martin, John C. Lin, Eric Smith, Gavin Thurston, Jessica R. Kirshner

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引用次数: 65

Abstract

Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, we describe a human bispecific antibody (REGN4018) that binds both Mucin 16 (MUC16), a glycoprotein that is highly expressed on ovarian cancer cells, and CD3, thus bridging MUC16-expressing cells with CD3⁺ T cells. REGN4018 induced T cell activation and killing of MUC16-expressing tumor cells in vitro. Binding and cytotoxicity of REGN4018 in vitro were minimally affected by high concentrations of CA-125, the shed form of MUC16, which is present in patients. In preclinical studies with human ovarian cancer cells and human T cells in immunodeficient mice, REGN4018 potently inhibited growth of intraperitoneal ovarian tumors. Moreover, in a genetically engineered immunocompetent mouse expressing human CD3 and human MUC16 [humanized target (HuT) mice], REGN4018 inhibited growth of murine tumors expressing human MUC16, and combination with an anti–PD-1 antibody enhanced this efficacy. Immuno-PET imaging demonstrated localization of REGN4018 in MUC16-expressing tumors and in T cell–rich organs such as the spleen and lymph nodes. Toxicology studies in cynomolgus monkeys showed minimal and transient increases in serum cytokines and C-reactive protein after REGN4018 administration, with no overt toxicity. Collectively, these data demonstrate potent antitumor activity and good tolerability of REGN4018, supporting clinical evaluation of REGN4018 in patients with MUC16-expressing advanced ovarian cancer.

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用于治疗卵巢癌的粘蛋白 16 双特异性 T 细胞诱导抗体

晚期卵巢癌通常采用联合化疗，但高复发率表明需要能产生持久反应并延长总生存期的疗法。与癌细胞上的肿瘤抗原和免疫细胞上的受体相互作用的双特异性抗体提供了一种创新的免疫疗法。在这里，我们描述了一种人类双特异性抗体（REGN4018），它能同时结合卵巢癌细胞上高表达的糖蛋白 Mucin 16（MUC16）和 CD3，从而将 MUC16 表达细胞与 CD3+ T 细胞连接起来。REGN4018 在体外诱导 T 细胞活化并杀死表达 MUC16 的肿瘤细胞。REGN4018在体外的结合力和细胞毒性受高浓度CA-125（患者体内存在的MUC16的脱落形式）的影响极小。在对免疫缺陷小鼠的人卵巢癌细胞和人 T 细胞进行的临床前研究中，REGN4018 能有效抑制腹膜内卵巢肿瘤的生长。此外，在表达人 CD3 和人 MUC16 的基因工程免疫功能正常小鼠[人源化靶标（HuT）小鼠]中，REGN4018 可抑制表达人 MUC16 的小鼠肿瘤的生长，与抗 PD-1 抗体联用可增强疗效。免疫 PET 成像显示 REGN4018 定位于表达 MUC16 的肿瘤以及脾脏和淋巴结等 T 细胞丰富的器官。对猕猴进行的毒理学研究显示，服用 REGN4018 后，血清细胞因子和 C 反应蛋白的增加微乎其微，而且是一过性的，没有明显毒性。总之，这些数据证明了 REGN4018 强大的抗肿瘤活性和良好的耐受性，支持对 MUC16 表达的晚期卵巢癌患者进行 REGN4018 临床评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.