Using Humanized B-hSIRPa/hCD47 Mouse Model to Evaluate the Efficacy and Toxicity of CD47 and SIRPa Antibodies
CD47 is a transmembrane protein expressed the surface of many cells in the body. SIRPa, which is expressed on phagocytic cells, was identified as the receptor of CD47. Engagement of SIRPa by CD47 serves as “do not eat me” signal, thus inhibiting the phagocytic activity of macrophages. Antibodies blocking the CD47-SIRPa interaction will release such inhibition and promote tumor destruction. To evaluate the efficacy and toxicity of CD47 antibody, we generated a double humanized B- hSIRPa/hCD47 mouse. In homozygous mice, only human protein expression can be detected, while mouse SIRPa and CD47 were knocked out. Using B-hSIRPa/hCD47 mice, pairing with genetically modified MC38-hCD47 cancer cells, we can screen CD47 antibodies by balancing their efficacy and toxicity. Antibodies with less toxicity exhibited minimal weight loss, less blood cells and platelets reduction, and less ALT/AST elevation in mice. Besides CD47 antibody, humanized B-hSIRPa/hCD47 mouse model can be used for evaluating the efficacy of SIRPa antibody. We also generated triple humanized B-hPD-1/hSIRPa/hCD47 and B-hPD-L1/hSIRPa/hCD47 mice that would be useful for combination therapy of PD-1/PD-L1 with SIRPa/CD47 antibodies. Humanized B-hSIRPa/hCD47 mouse represents a promising in vivo efficacy model for the development of CD47 and SIRPa antibodies that can be advanced to human clinical trials.