Role of Fc Receptors in the Therapeutic Activity of Antibodies Targeting the CD47-SIRP-alpha axis

项目摘要/摘要 候选人：纪念斯隆·凯特琳癌症中心(MSK)的肿瘤学研究员PI 制定了一个为期5年的职业发展计划，该计划建立在他在免疫学和 肿瘤内科临床培训。他将在杰弗里博士的指导下进行拟议的研究 Ravetch是国际公认的Fc受体(FCR)专家。他还将开发抗体方面的新技能。 而肿瘤生物学对他未来的职业生涯至关重要，他们专注于了解 癌症免疫治疗的有效反应。PI已计划解决必要的培训和 通过精选课程和强健的课程成功过渡到独立所需的指导 指导计划。密歇根州立大学、洛克菲勒大学和咨询委员会的制度环境 由该领域的领导者组成的组织不仅将确保国际和平研究所的研究项目按计划进行，而且 此外，PI过渡到独立成为一名拥有自己的实验室和拨款的内科科学家。这 研究项目也与他导师的研究项目有很大的不同，以避免竞争或重叠。 研究计划：针对免疫检查点的抗体在多种疾病中导致长期临床反应 恶性肿瘤。然而，许多患者对这些疗法和增强抗肿瘤作用的新靶点没有反应。 豁免权正在积极调查中。CD47是一个“不要吃我”的信号，在几种类型的 癌症，并与预后不良有关。它的表达通过以下途径保护肿瘤细胞免受吞噬 与Sirp-α(Sirpα)相互作用，一种表达在髓系细胞(即巨噬细胞和 树突状细胞)。阻断CD47/Sirpα通路的抗体可促进髓系细胞吞噬和肿瘤 消除细胞，在临床前研究和早期临床试验中产生有效的抗肿瘤效果。圆周率研究 专注于了解针对CD47Sirpα轴的抗体的作用机制。 特别是抗体Fc结构域及其与FCR结合诱导有效抗肿瘤的作用 回应。本提案中提供的初步数据表明，a)FC域参与FCR 调节抗CD47和抗Sirpα抗体的活性，以及b)Fc优化的抗CD47抗体 增强抗肿瘤免疫和肿瘤相关巨噬细胞、树突状细胞和其他 免疫细胞。这项建议的目的是了解特定的Fcγ受体在介导有效的抗肿瘤中的作用 使用一种新的人源化小鼠模型对CD47、Sirpα和FCRs进行响应。在此模式中，FC工程 人源化抗CD47/Sirpα抗体将单独测试或与其他免疫疗法联合测试 确定它们对渗透的免疫细胞的影响。阐明FCR作为应答调节器的作用 抗CD47Sirpα抗体可能建立一条新的途径来最大化其治疗作用并提供 关于先天免疫细胞在促进有效抗肿瘤反应中的作用的关键信息。

PROJECT SUMMARY/ABSTRACT Candidate: The PI, a Medical Oncology Fellow at Memorial Sloan Kettering Cancer Center (MSK), has developed a 5-year career development plan that builds upon his scientific background in immunology and clinical training in medical oncology. He will conduct the proposed research under the mentorship of Dr. Jeffrey Ravetch, an internationally recognized expert in Fc receptors (FcRs). He will also develop new skills in antibody and tumor biology that are critical for his future career focused on understanding the mechanisms that mediate effective responses of cancer immunotherapies. The PI has planned to address the necessary training and mentoring required for his successful transition to independence through select coursework and a robust mentoring plan. The institutional environment of MSK, The Rockefeller University, and an Advisory Committee composed of leaders in the field will not only ensure that the PI’s research project progresses as planned, but also the PI’s transition to independence as a physician-scientist with his own laboratory and grant funding. This research project is also sufficiently different from his mentor’s to avoid competition or overlap. Research Plan: Antibodies targeting immune checkpoints lead to long-lasting clinical responses in a variety of malignancies. However, many patients fail to respond to these therapies and new targets that enhance antitumor immunity are under active investigation. CD47 is a “don’t eat me” signal overexpressed on several types of cancer and is associated with poor prognosis. Its expression protects tumor cells from phagocytosis by interacting with SIRP-alpha (SIRPα), a cell surface receptor expressed on myeloid cells (i.e., macrophages and dendritic cells). Antibodies blocking the CD47/SIRPα pathway enable myeloid-mediated phagocytosis and tumor cell elimination, leading to effective antitumor effects in preclinical studies and early clinical trials. The PI studies have focused on understanding the mechanism of action of antibodies targeting the CD47/SIRPα axis, in particular the contribution of the antibody Fc domain and its binding to FcRs to induce effective antitumor responses. Preliminary data presented in this proposal show that a) Engagement of FcRs by the Fc domain modulates the activity of anti-CD47 and anti-SIRPα antibodies, and b) Fc-optimized anti-CD47 antibodies increases antitumor immunity and infiltration and of tumor-associated macrophages, dendritic cells, and other immune cells. The goal of this proposal is to understand the role of specific FcγRs in mediating effective antitumor responses using a novel humanized mouse model for CD47, SIRPα and FcRs. In this model, Fc-engineered humanized anti-CD47/SIRPα antibodies will be tested alone or in combination with other immunotherapies to determine their effects on infiltrating immune cells. Elucidating the role of FcRs as modulators of response to anti-CD47/SIRPα antibodies may establish a new avenue to maximize their therapeutic actions and provide critical information on the role of innate immune cells in promoting effective antitumor responses.