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：PI，纪念斯隆凯特琳癌症中心（MSK）的医学肿瘤学研究员， 制定了一个5年的职业发展计划，建立在他的免疫学科学背景， 医学肿瘤学的临床培训。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（FcRs）专家。他还将开发抗体方面的新技能 和肿瘤生物学对他未来的职业生涯至关重要， 癌症免疫疗法的有效反应。PI计划进行必要的培训， 通过精选的课程和强有力的培训， 指导计划。MSK、洛克菲勒大学和咨询委员会的制度环境 由该领域领导者组成的团队不仅将确保PI的研究项目按计划进行，而且 也是PI作为一个拥有自己的实验室和赠款资金的物理学家-科学家向独立的过渡。这 他的研究项目与导师的研究项目也有很大的不同，以避免竞争或重叠。 研究计划：靶向免疫检查点的抗体在多种疾病中导致持久的临床反应。 恶性肿瘤然而，许多患者对这些疗法和增强抗肿瘤活性的新靶点没有反应。 豁免权正在积极调查中。CD 47是一种“不要吃我”的信号，在几种类型的肿瘤细胞上过度表达。 癌症并与预后不良有关。它的表达可以保护肿瘤细胞免受吞噬作用， 与SIRP-α（SIRPα）相互作用，SIRP α是一种在骨髓细胞上表达的细胞表面受体（即，巨噬细胞和 树突细胞）。阻断CD 47/SIRPα通路的抗体使骨髓介导的吞噬作用和肿瘤 细胞消除，从而在临床前研究和早期临床试验中产生有效的抗肿瘤作用。PI研究 专注于了解靶向CD 47/SIRPα轴的抗体的作用机制， 特别是抗体Fc结构域及其与FcR的结合对诱导有效的抗肿瘤活性的贡献。 应答本提案中提供的初步数据显示：a）Fc结构域与FcR的结合 调节抗CD 47和抗SIRP α抗体的活性，和B）Fc优化的抗CD 47抗体 增加抗肿瘤免疫和浸润以及肿瘤相关巨噬细胞、树突状细胞和其他 免疫细胞。本研究的目的是了解特异性Fcγ R在介导有效的抗肿瘤作用中的作用， 使用新的人源化小鼠模型对CD 47、SIRPα和FcR的应答进行了研究。在该模型中，Fc工程化的 人源化抗CD 47/SIRPα抗体将单独或与其他免疫疗法组合进行测试， 确定它们对浸润免疫细胞的影响。阐明FcR作为对免疫应答的调节剂的作用 抗CD 47/SIRPα抗体可能建立一种新的途径，以最大限度地发挥其治疗作用，并提供 关于先天免疫细胞在促进有效的抗肿瘤反应中的作用的重要信息。

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.