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

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $151,339

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10526066
- **Project number:** 1K08CA266740-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Juan C Osorio
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $151,339
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526066

## Citation

> US National Institutes of Health, RePORTER application 10526066, Role of Fc Receptors in the Therapeutic Activity of Antibodies Targeting the CD47-SIRP-alpha axis (1K08CA266740-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10526066. Licensed CC0.

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