Targeting the myeloid checkpoint receptor SIRP? potentiates innate and adaptive immune responses to promote anti-tumor activity.

ABSTRACT: BACKGROUND:Signal regulatory protein ? (SIRP?) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRP? interaction synergizes with tumor-specific antibodies and T-cell checkpoint inhibitors by promoting myeloid-mediated antitumor functions leading to the induction of adaptive immunity. Inhibition of the CD47-SIRP? interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRP?, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRP? polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRP?. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRP? antibody that binds human, cynomolgus monkey, and mouse SIRP? alleles with high affinity and blocks the interaction with CD47. METHODS:Human macrophages derived from donors with various SIRP? v1 and v2 allelic status were used to assess the ability of hAB21 to enhance phagocytosis. HAB21_IgG subclasses were evaluated for targeted depletion of peripheral blood mononuclear cells, phagocytosis and in vivo efficacy in xenograft models. Combination therapy with anti-PD1/anti-PD-L1 in several syngeneic models was performed. Immunophenotyping of tissues from MC38 tumor-bearing mice treated with AB21 and anti-PD-1 was evaluated. PK, PD and tolerability of hAB21 were evaluated in cynomolgus monkeys. RESULTS:SIRP? blockade with hAB21 promoted macrophage-mediated antibody-dependent phagocytosis of tumor cells in vitro and improved responses to rituximab in the Raji human tumor xenograft mouse model. Combined with PD-1/PD-L1 blockade, AB21 improved response rates by facilitating monocyte activation, dendritic cell activation, and T cell effector functions resulting in long term, durable antitumor immunity. In cynomolgus monkeys, hAB21 has a half-life of 5.3 days at 10 mg/kg and complete target occupancy with no hematological toxicity or adverse findings at doses up to 30 mg/kg. CONCLUSIONS:The in vitro and in vivo antitumor activity of hAB21 broadly recapitulates that of CD47 targeted therapies despite differences in ligand expression, binding partners, and function, validating the CD47-SIRP? axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.

SUBMITTER: Kuo TC 

PROVIDER: S-EPMC7706287 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature