Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint

Background The CD47-SIRP alpha pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRP alpha axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRP alpha, targeting SIRP alpha is an alternative approach to block the CD47-SIRP alpha pathway, which may result in differential efficacy and safety profiles. Methods SIRP alpha-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRP alpha alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRP alpha-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated. Results BR105 shows broad binding activity across various SIRP alpha variants, and potently blocks the interaction of SIRP alpha and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRP gamma, it does not inhibit T cell activation, unlike other non-selective SIRP alpha-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted. Conclusions The novel and differentiated SIRP alpha-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints.

Automated summary

The CD47-SIRP alpha pathway is crucial in tumor immunity, and targeting CD47/SIRP alpha axis is a promising strategy. Targeting SIRP alpha may offer an alternative approach with potential differential efficacy and safety profiles.