Background: Accumulating preclinical data indicate that targeting the SIRPα/CD47 axis alone or in combination with existing targeted therapies or immune checkpoint inhibitors enhances tumor rejection. Although several CD47-targeting agents are currently in phase I clinical trials and demonstrate activity in combination therapy, high and frequent dosing was required and safety signals (acute anemia, thrombocytopenia) were recorded frequently as adverse events. Based on the restricted expression pattern of SIRPα we hypothesized that antibodies targeting SIRPα might avoid some of the concerns noted for CD47-targeting agents. Methods: SIRPα-targeting antibodies were generated and characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. Functional activity was established in vitro using human macrophages or neutrophils co-cultured with human Burkitt's lymphoma cell lines. The effect of SIRPα versus CD47 targeting on human T-cell activation was studied using an allogeneic mixed lymphocyte reaction and a Staphylococcus enterotoxin B-induced T-cell proliferation assay. Potential safety concerns of the selected SIRPα-targeting antibody were addressed in vitro using a hemagglutination assay and a whole blood cytokine release assay, and in vivo in a single-dose toxicity study in cynomolgus monkeys. Results: The humanized monoclonal IgG2 antibody ADU-1805 binds to all known human SIRPα alleles, showing minimal binding to SIRPβ1, while cross-reacting with SIRPγ, and potently blocking the interaction of SIRPα with CD47. Reduced FcγR binding proved critical to retaining its function towards phagocyte activation. In vitro characterization demonstrated that ADU-1805 promotes macrophage phagocytosis, with similar potency to anti-CD47 antibodies, and enhances neutrophil trogocytosis. Unlike CD47-targeting agents, ADU-1805 does not interfere with T-cell activation and is not expected to require frequent and extensive dosing due to the restricted expression of SIRPα to cells of the myeloid lineage. ADU-1805 is cross-reactive to cynomolgus monkey SIRPα and upon singledose intravenous administration in these non-human primates (NHPs) did not show any signs of anemia, thrombocytopenia or other toxicities. Conclusions: Blocking the SIRPα-CD47 interaction via SIRPα, while similarly efficacious in vitro, differentiates ADU-1805 from CD47-targeting agents with respect to safety and absence of inhibition of T-cell activation. The data presented herein support further advancement of ADU-1805 towards clinical development.
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 > 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.
CONCLUSION • ADU-1604 binds to a unique epitope on hCTLA4 • ADU-1604 was well tolerated when given weekly for 5 dosages at doses up to 30 mg/kg to cynomolgus monkeys • ADU-1604 enhanced T cell responses in a non-humane primate HBsAg immunization model and induced tumor growth inhibition in humanized NSCLC PDX models • Anti-CTLA-4 therapy enhanced anti-tumor activity of STING agonist ADU-S100 in a syngeneic mouse model • Intratumoral administration of anti-CTLA-4 induced tumor growth inhibition and T cell modulation in a syngeneic mouse model • The recommended starting dose in humans of 0.3 mg/kg ADU-1604 has a 100-fold safety factor based on the HNSTD • ADU-1604 will be clinically evaluated in a phase I study in advanced melanoma patients Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evaluation of local anti-CTLA-4 application
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