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

Fc 受体在靶向 CD47-SIRP-α 轴的抗体的治疗活性中的作用

• 批准号: 10689216
• 负责人: Juan C Osorio
• 金额: $ 15.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689216
• 关键词: Acceleration; Address; Advisory Committees; Anti-CD47; Antibodies; Antitumor Response; Binding; Biological Assay; Blocking Antibodies; CD47 gene; CD47-SIRPα; CD47-SIRPα blockade; CD8-Positive T-Lymphocytes; Cell Surface Receptors; Cells; Classification; Clinic; Clinical; Clinical Trials; Consensus; Cytoprotection; Data; Dendritic Cells; Development; Development Plans; Eating; Effector Cell; Engineering; Ensure; Environment; Epidermal Growth Factor Receptor; Fab Immunoglobulins; Fc Receptor; Fc(alpha) receptor; Flow Cytometry; Foundations; Funding; Future; Goals; Grant; Human; Immune; Immune Targeting; Immunocompetent; Immunocompromised Host; Immunoglobulin Fragments; Immunology; Immunotherapy; Infiltration; Institution; International; Investigation; Laboratories; Laboratory Research; Lead; Macrophage; Malignant Neoplasms; Mediating; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Minority; Modeling; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Outcome; PTPNS1 gene; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phenotype; Physicians; Prognosis; Qualifying; Research; Research Project Grants; Role; Scientist; Signal Transduction; Specimen; System; T cell response; T-Cell Activation; T-Lymphocyte Subsets; Testing; Therapeutic; Toxic effect; Toxicity Tests; Training; Treatment Efficacy; Tumor Antigens; Tumor Biology; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; Universities; Variant; anti-PD-1; antitumor effect; cancer cell; cancer immunotherapy; cancer therapy; cancer type; career; career development; clinical training; early phase clinical trial; efficacy testing; experience; human tissue; humanized mouse; immune cell infiltrate; immune checkpoint; mouse model; neoplastic cell; neutrophil; novel; overexpression; preclinical study; prevent; rational design; receptor; recruit; research study; response; skills; tumor; tumor microenvironment

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.

项目概要/摘要 候选人：PI 是纪念斯隆凯特琳癌症中心 (MSK) 的肿瘤内科研究员， 基于他在免疫学方面的科学背景和 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 和肿瘤生物学对他未来的职业生涯至关重要，重点是了解介导的机制 癌症免疫疗法的有效反应。 PI 已计划解决必要的培训和 他需要通过精选的课程和强大的指导来成功过渡到独立 辅导计划。 MSK、洛克菲勒大学的制度环境和咨询委员会 由该领域的领导者组成的团队不仅可以确保PI的研究项目按计划进行，而且 PI 也作为一名拥有自己的实验室和资助的医师科学家向独立过渡。这 研究项目也与导师的研究项目有很大不同，以避免竞争或重叠。 研究计划：针对免疫检查点的抗体可在多种疾病中产生持久的临床反应 恶性肿瘤。然而，许多患者对这些疗法和增强抗肿瘤作用的新靶标没有反应 免疫力正在积极研究中。 CD47 是一种“别吃我”的信号，在多种类型的动物中过度表达 癌症并与不良预后相关。它的表达通过以下方式保护肿瘤细胞免受吞噬： 与 SIRP-α (SIRPα) 相互作用，SIRPα 是骨髓细胞（即巨噬细胞和巨噬细胞）上表达的细胞表面受体 树突状细胞）。阻断 CD47/SIRPα 通路的抗体可实现骨髓介导的吞噬作用和肿瘤 细胞消除，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 重点了解针对 CD47/SIRPα 轴的抗体的作用机制， 特别是抗体 Fc 结构域及其与 FcR 结合对诱导有效抗肿瘤的贡献 回应。本提案中提供的初步数据表明：a) Fc 域对 FcR 的参与 调节抗 CD47 和抗 SIRPα 抗体的活性，以及​​ b) Fc 优化的抗 CD47 抗体 增加抗肿瘤免疫和肿瘤相关巨噬细胞、树突状细胞和其他细胞的浸润 免疫细胞。该提案的目标是了解特定 FcγR 在介导有效抗肿瘤中的作用 使用针对 CD47、SIRPα 和 FcR 的新型人源化小鼠模型进行反应。在此模型中，Fc 设计 人源化抗 CD47/SIRPα 抗体将单独进行测试或与其他免疫疗法联合测试 确定它们对浸润免疫细胞的影响。阐明 FcR 作为反应调节剂的作用 抗 CD47/SIRPα 抗体可能会建立一条新途径，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抗肿瘤反应中的作用的关键信息。