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

基本信息

  • 批准号:
    10689216
  • 负责人:
  • 金额:
    $ 15.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Juan C Osorio其他文献

1114-199 A comparison of postnatal changes in fetal phenotype between the left and right ventricles
  • DOI:
    10.1016/s0735-1097(04)91632-4
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Ana M Duque Gonzalez;Juan C Osorio;Susan Vannucci;Seema Mital
  • 通讯作者:
    Seema Mital
1114-198 Genomic profiles of left ventricular and right ventricular hypertrophy in congenital heart disease
  • DOI:
    10.1016/s0735-1097(04)91631-2
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Beth D Kaufman;Juan C Osorio;Manisha Desai;Jonathan Chen;Ralph S Mosca;Jan M Quaegebeur;Anthony W Ferrante;Seema Mital
  • 通讯作者:
    Seema Mital

Juan C Osorio的其他文献

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{{ truncateString('Juan C Osorio', 18)}}的其他基金

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:
    10526066
  • 财政年份:
    2022
  • 资助金额:
    $ 15.13万
  • 项目类别:

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