AL008 Enhances Myeloid Antitumor Function by Inhibiting SIRPα Signaling and Activating Fc Receptors

Author:

Yang Jingping1,Deresa Isaiah1,Ho Wei-Hsien1,Long Hua1,Maslyar Daniel1ORCID,Rosenthal Arnon1,Liang Spencer C.1,Pincetic Andrew1ORCID

Affiliation:

1. Alector, Inc., South San Francisco, CA

Abstract

Abstract Antagonizing the CD47–signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promoted human monocyte-derived dendritic cell–mediated T cell proliferation. In humanized mouse models, AL008 induced internalization of SIRPα and increased expression of CD86 and HLA-DR on human tumor-associated macrophages, confirming that the mechanism of action is retained in vivo. Monotherapy treatment with AL008 significantly reduced tumor growth in humanized mice implanted with human MDA-MB-231 tumor cells. AL008 also significantly potentiated the effects of T cell checkpoint blockade with anti–programmed death ligand-1 in syngeneic tumor models. This dual and specific mechanism of AL008, to our knowledge, provides a novel therapeutic strategy for targeting myeloid cells for immune activation.

Funder

Alector, Inc

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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