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Publication Abstract from PubMed

BACKGROUND: Signal regulatory protein alpha (SIRPalpha) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRPalpha 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-SIRPalpha interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPalpha, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPalpha polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPalpha. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPalpha antibody that binds human, cynomolgus monkey, and mouse SIRPalpha alleles with high affinity and blocks the interaction with CD47. METHODS: Human macrophages derived from donors with various SIRPalpha 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: SIRPalpha 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-SIRPalpha axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.

Targeting the myeloid checkpoint receptor SIRPalpha potentiates innate and adaptive immune responses to promote anti-tumor activity.,Kuo TC, Chen A, Harrabi O, Sockolosky JT, Zhang A, Sangalang E, Doyle LV, Kauder SE, Fontaine D, Bollini S, Han B, Fu YX, Sim J, Pons J, Wan HI J Hematol Oncol. 2020 Nov 30;13(1):160. doi: 10.1186/s13045-020-00989-w. PMID:33256806^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.