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.

项目总结/文摘