Targeting the SIRPα-CD47 Pathway: Unveiling the Potential of ADU-1805 in Cancer Immunotherapy

The study explores the role of SIRPα in immune regulation and its potential as a novel immune checkpoint. The research focuses on the interaction between SIRPα and CD47, which is known to be involved in "don't-eat-me" signaling and is overexpressed in many cancers. Given the widespread presence of CD47 on normal cells and its functions beyond SIRPα binding, targeting CD47 directly has raised safety concerns. Therefore, the strategy shifts to targeting SIRPα, which is more specifically expressed in myeloid cells.

Aduro Biotech's B-select platform facilitated the discovery and characterization of ADU-1805, a highly selective anti-SIRPα antibody. This antibody shows minimal binding to SIRPβ but has cross-reactivity with SIRPγ and is effective across all known human SIRPA genotypes. It also demonstrates cross-reactivity with SIRP family members in non-human primates.

ADU-1805 effectively blocks CD47 binding to SIRPα and antagonizes their interactions on primary myeloid cells, leading to enhanced clearance of tumor cells by human granulocytes and macrophages. Unlike anti-CD47 antibodies, ADU-1805 does not inhibit T cell activation. Furthermore, it synergizes with PD-1 blockade to reduce tumor burden in mouse models. Importantly, ADU-1805 does not induce hemagglutination or platelet binding, suggesting a lower risk of red blood cell and platelet depletion.

The study concludes that ADU-1805 is a promising candidate with a unique binding profile, binding all reported human SIRPα alleles without significant binding to the activating SIRPβ receptor. It modulates myeloid cells in the tumor microenvironment, promoting antigen presentation and dendritic cell cross-priming. The research is progressing with preclinical studies to evaluate the safety, pharmacokinetics, and pharmacodynamics of ADU-1805.

The research was presented by Erik Voets and colleagues at the American Association for Cancer Research Annual Meeting in 2019, with the abstract published in Cancer Research.