Antibody therapeutics discovery: Focus on bispecifics and immune checkpoint modulators
Targeting the CD47-signal-regulatory protein α (SIRPα) pathway represents a novel therapeutic approach to enhance anti-cancer immunity by promoting both innate and adaptive immune responses. Ongoing clinical trials to inhibit this pathway through targeting CD47 have shown promising results in reducing tumor burden (Chow et al., ASCO 2019). Unlike CD47 which is expressed ubiquitously, SIRPα expression is mainly restricted to myeloid cells and neurons. Therefore, compared to CD47-targeted therapies, targeting SIRPα may result in differential safety and efficacy profiles, potentially enabling lower effective doses and improved pharmacokinetics and pharmacodynamics. In this talk, we will present our strategies of using wildtype/human antibody transgenic chickens for immunization and describe our screening approaches to identify SIRPα antibodies suitable for clinical translation. A total of 200 antibodies were isolated and approximately 70 antibodies with diverse SIRPα binding profiles, sequence families, and epitopes were characterized. A subset of antibodies was shown to bind both human SIRPα v1 and v2 alleles with high affinity (nM-pM), potently antagonize the CD47/SIRPα interaction and potentiate antibody-dependent cellular phagocytosis in vitro. The anti-SIRPα antibodies also enhanced anti-tumor activity in both xenograft and syngeneic tumor models, and were well tolerated in cynomolgus monkeys with favorable PK and extended receptor occupancy. These properties provide an attractive rationale to advance the development of these anti-SIRPα antibodies as a novel therapy for advanced malignancies.