A Novel Anti-CD47 Antibody TJH2201: Efficacious Tumor Suppression with Reduced RBC Toxicity via a SIRPα-Independent Mechanism

Abstract The CD47/SIRPα axis serves as a “don’t eat me” signal, protecting normal cells from phagocytosis, but in the meantime, enabling immune evasion by tumor cells. While substantial progress has been made in developing CD47 antagonists, achieving a balance between hematotoxicity and anti-tumor efficacy remains a critical challenge. Here, we demonstrated that the bivalent anti-CD47 antibody, Hu5F9, caused severe anemia in both human CD47 knock-in mice lacking the CD47/SIRPα signal and human CD47/SIRPα double knock-in mice with complete signal, suggesting the CD47/SIRPα signal is not essential. Moreover, the single-arm CD47 antibody Hu5F9/gp120 exhibited only mild red blood cell (RBC) destruction in vitro and in vivo. These findings reveal that RBC toxicity induced by anti-CD47 antibodies is determined by the bivalency of the antibody rather than the CD47/SIRPα signal engagement. Based on this, we engineered TJH2201, a novel anti-CD47 antibody that avoids RBC agglutination while retaining high-affinity CD47 binding, robust signaling blockade, and enhanced pro-phagocytosis activity in vitro. In xenograft models with Raji and MV-4-11 cells, TJH2201 demonstrated potent anti-tumor activity without inducing body weight loss. These results suggest that TJH2201 is a promising CD47 antagonist that balances anti-tumor efficacy and hematological safety, providing a new therapeutic approach for CD47-expressing malignancies.