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

Autor: Kuo TC; ALX Oncology, Burlingame, CA, USA. tracy@tallactx.com.; Tallac Therapeutics, Burlingame, CA, USA. tracy@tallactx.com., Chen A; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Harrabi O; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Sockolosky JT; ALX Oncology, Burlingame, CA, USA.; Genentech, South San Francisco, CA, USA., Zhang A; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Sangalang E; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Doyle LV; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Kauder SE; ALX Oncology, Burlingame, CA, USA.; Coherus BioSciences, Redwood City, CA, USA., Fontaine D; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Bollini S; ALX Oncology, Burlingame, CA, USA., Han B; ALX Oncology, Burlingame, CA, USA.; ProLynx Inc., San Francisco, CA, USA., Fu YX; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Sim J; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA., Pons J; ALX Oncology, Burlingame, CA, USA., Wan HI; ALX Oncology, Burlingame, CA, USA.; Tallac Therapeutics, Burlingame, CA, USA.
Jazyk: angličtina
Zdroj: Journal of hematology & oncology [J Hematol Oncol] 2020 Nov 30; Vol. 13 (1), pp. 160. Date of Electronic Publication: 2020 Nov 30.
DOI: 10.1186/s13045-020-00989-w
Abstrakt: Background: Signal regulatory protein α (SIRPα) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRPα 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-SIRPα interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPα, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPα polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPα. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPα antibody that binds human, cynomolgus monkey, and mouse SIRPα alleles with high affinity and blocks the interaction with CD47.
Methods: Human macrophages derived from donors with various SIRPα 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: SIRPα 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-SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.
Databáze: MEDLINE
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