Role of anti-Fc Gamma RIIB antibody in tumor clearance

抗 Fc Gamma RIIB 抗体在肿瘤清除中的作用

• 批准号: 6791780
• 负责人: CHRISTOPHER T RANKIN
• 金额: $ 10万
• 依托单位: MACROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791780
• 关键词: CD antigens; antibody receptor; antireceptor antibody; antitumor antibody; athymic mouse; breast neoplasms; cell line; cell mediated cytotoxicity; clinical research; disease /disorder model; drug design /synthesis /production; human genetic material tag; human tissue; immunocytochemistry; macrophage; monoclonal antibody; monocyte; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; ovary neoplasms; protooncogene

DESCRIPTION (provided by applicant): One of the main mechanisms by which clinically approved anti-cancer antibodies, Herceptin and Rituxan, mediate their anti-tumor effect is by antibody-dependent cell-mediated cytotoxicity (ADCC) 1,2,3. In a xenograft model in mice deficient in the inhibitory Fc-gammaRIIB4, Herceptin demonstrated substantially increased tumor clearance compared to wild-type mice. Furthermore, in a syngeneic Fc-gammaRIIB4-deficient mouse tumor model, an anti-melanoma antibody resulted in 100-fold greater reduction of tumor load than in wild type mice, indicating that engagement of Fc-gammaRIIB by therapeutic antibodies may limit their effectiveness. The observation that deletion of Fc-gammaRIIB increases protection in nude mice implicates involvement of effector cells other than NK cells, which lack Fc-gammaRIIB. Monocytes and macrophages, which express Fc-gammaRIIB, are the likely effector populations whose recruitment and anti-tumor effect may be limited by the engagement of the inhibitory Fc-gammaRIIB. An agent aimed at blocking Fc-gammaRllB can be envisioned to have tremendous value in the elimination of tumor cells by lowering their triggering threshold through the activating Fc receptors and enhancing ADCC activity of tumor-specific antibodies. In this proposal, it is hypothesized that the therapeutic effect, of approved tumor-specific antibodies and those under development, may be enhanced by concomitant administration of a blocking antibody to the inhibitory Fc receptor, Fc-gammaRIIB. MacroGenics, Inc., has selected 2B6, a murine monoclonal antibody specifically directed against the human Fc-gammaRIIB receptor, from a panel of antibodies to evaluate its role in enhancing tumor clearance. Of note, these are the first set of monoclonal antibodies directed specifically against the human inhibitory receptor, Fc-gammaRIIB. It is hypothesized here that blocking the inhibitory pathway with this Fc-gammaRIIB-specific antibody will lower the threshold for the activation signal, augmenting ADCC, and hence enhance tumor clearance. The role of 2B6 will be tested along with an anti-Her2neu antibody, 4D5 (the parent molecule of Herceptin) in xenograft nude mouse models of ovarian and breast cancer with adoptively transferred human monocytes. These studies are proposed as proof-of-concept for the use of anti-Fc-gammaRIIB antibodies in enhancing the effectiveness of anti-tumor therapeutics whose in vivo mechanism of action is mediated by ADCC. A successful study could therefore impact on and benefit a large numbers of cancer patients in the future.

描述（由申请人提供）： 临床批准的抗癌抗体Herceptin和Rituxan介导其抗肿瘤作用的主要机制之一是抗体依赖性细胞介导的细胞毒性（ADCC）1,2,3。 在缺乏抑制性FC-Gammariib4的小鼠中的异种移植模型中，与野生型小鼠相比，赫斯蒂汀在肿瘤清除率显着增加。此外，在一种缺陷的抗甲基抗体抗体中，抗甲烷瘤抗体的肿瘤负荷降低了100倍以比野生型小鼠大100倍，这表明通过治疗抗体接合FC-Gammariib可能会限制其有效性。 FC-GammariiB缺失增加裸鼠的保护的观察结果暗示了缺乏FC-Gammariib的NK细胞以外的其他效应细胞的参与。表达FC-Gammariib的单核细胞和巨噬细胞是可能的效应人群，其募集和抗肿瘤效应可能受到抑制性FC-Gammariib的参与而受到限制。旨在阻止FC-GammarllB的代理可以设想通过通过激活FC受体降低其触发阈值并增强肿瘤特异性抗体的ADCC活性，从而在消除肿瘤细胞中具有巨大的价值。 在该提案中，假设批准的肿瘤特异性抗体的治疗作用和正在开发的抗体可以通过同时施用对抑制性FC受体FC-Gammariib的封闭抗体来增强。 Macogenics，Inc。从一组抗体中选择了针对人FC-Gammariib受体的鼠单克隆抗体2B6，以评估其在增强肿瘤清除率中的作用。值得注意的是，这些是针对人抑制受体FC-Gammariib的第一组单克隆抗体。在这里假设，使用该FC-Gammariib特异性抗体阻止抑制途径将降低激活信号的阈值，增强ADCC，从而增强肿瘤清除率。 2B6的作用将与抗HER2NEU抗体，4D5（赫斯蒂汀的亲本分子）一起进行测试，并在带有人类单核细胞的卵巢和乳腺癌的异种移植小鼠模型中。这些研究被提出为使用抗FC-Gammariib抗体在增强抗肿瘤疗法的有效性的概念验证，其在体内作用机理的有效性是由ADCC介导的。因此，一项成功的研究可能会影响并受益于许多癌症患者。