Therapeutic anti-CD47 monoclonal antibodies (mAbs) are designed to block the CD47-SIRPα checkpoint and promote immune-mediated recognition and elimination of cancer cells. However, current anti-CD47 mAbs have limitations, including off-tumor toxicity and reduced effectiveness in advanced cancers. Additionally, CD47 serves as a death receptor that mediates programmed cancer cell death (PCCD), a mechanism that has not been fully explored in current therapies. In this study, we introduce CO-001, a chimeric bifunctional IgG4 mAb, and its optimized variant CO-005, a bivalent humanized single-chain fragment variable-fragment crystallizable fusion protein. Both CO-001 and CO-005 promoted phagocytosis and PCCD. CO-005, specifically engineered to overcome the safety limitations associated with anti-CD47 antibodies, demonstrates a superior hematologic safety profile in vitro and ex vivo compared with benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells, limited binding to white blood cells, and showed no hemagglutination activity. In preclinical models, CO-005 demonstrated potent antitumor activity in B-cell precursor acute lymphoblastic leukemia and Raji lymphoma xenograft models through the dual action of PCCD induction and enhancement of phagocytosis. The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.
©2025 The Authors; Published by the American Association for Cancer Research.