Abstract 1203: Preclinical development of ADU-1805, a highly selective pan-allele anti-SIRPα antibody that blocks the SIRPα-CD47 innate immune checkpoint
Authors: Erik Voets, Joost Kreijtz, Paul Vink, David Lutje Hulsik, Mark Parade, Sanne Spijkers, Inge Reinieren-Beeren, Joost Rens, Wout Janssen, Peter van Zandvoort, Brian Francica, Meredith Leong, Andrea van Elsas, Hans van Eenennaam
Journal: Cancer Research (2019)

Abstract Background: SIRPα signaling dependent immunoregulatory activity on myeloid cells is activated by binding of its ligand CD47, and blockade of the pathway may enhance anti-tumor immunity. Hence the pathway is thought to represent a novel immune checkpoint. CD47 has been extensively studied in the context of “don’t-eat-me” signaling. Since CD47 is ubiquitously expressed on normal cells, upregulated on many cancer cells, and also has SIRPα-independent functions, the safety of a CD47-targeted antibody has been a concern. Alternative strategies therefore are focusing on directly targeting SIRPα because of its more restricted expression to cells of the myeloid lineage. Methods: Using Aduro Biotech’s B-select platform, we have identified and characterized ADU-1805: a highly selective pan-allele anti-SIRPα antibody (EC50 SIRPαV1/SIRPαV2 ≤ 3nM) that lacks appreciable SIRPβ binding (EC50 &amp;gt; 120nM) but cross-reacts with SIRPγ (EC50 ≤ 5nM). We also demonstrate that ADU-1805 is cross-reactive with SIRP family members in non-human primates (NHPs) including cynomolgus monkeys. Results: ADU-1805 potently blocks CD47 binding (IC50 ≤ 1.5nM) to SIRPα in all known human SIRPA genotypes (including homozygous and heterozygous genotypes) and antagonizes SIRPα-CD47 interactions on primary SIRPα+ myeloid cells (IC50 ≤ 4nM). In line with its antagonistic properties, ADU-1805 enhances tumor cell clearance by human granulocytes and macrophages. Interestingly, anti-CD47 antibodies but not ADU-1805 inhibit T cell activation in an allogeneic mixed lymphocyte reaction. In addition, anti-SIRPα combines in a synergistic manner with PD-1 blockade to reduce tumor burden in several syngeneic mouse tumor models. Unlike CD47-targeting antibodies, ADU-1805 does not trigger hemagglutination or platelet binding in vitro, suggesting a reduced risk of red blood cell and platelet depletion in vivo. ADU-1805 is tested in a NHP study in cynomolgus monkeys at increasing dose levels to assess safety of the antibody. Conclusions: We have identified ADU-1805 as a potentially best-in-class antagonistic anti-SIRPα antibody with a unique binding profile as it binds all reported human SIRPα alleles but does not appreciably bind to the activating SIRPβ receptor. Blocking the SIRPα-CD47 innate immune checkpoint with ADU-1805 modulates myeloid cells in the tumor microenvironment and promotes antigen presentation and cross-priming of dendritic cells. We are currently advancing ADU-1805 through preclinical studies to address the safety, pharmacokinetics, and pharmacodynamics profile of this anti-human SIRPα antibody in vivo. Citation Format: Erik Voets, Joost Kreijtz, Paul Vink, David Lutje Hulsik, Mark Parade, Sanne Spijkers, Inge Reinieren-Beeren, Joost Rens, Wout Janssen, Peter van Zandvoort, Brian Francica, Meredith Leong, Andrea van Elsas, Hans van Eenennaam. Preclinical development of ADU-1805, a highly selective pan-allele anti-SIRPα antibody that blocks the SIRPα-CD47 innate immune checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1203.