Development of a Novel Bifunctional Anti-CD47 Fusion Protein with Improved Efficacy and a Favorable Safety Profile

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Anti-CD47 monoclonal antibodies (mAbs) target the CD47-SIRPα checkpoint to eliminate cancer cells.
• Current anti-CD47 mAbs face challenges like off-tumor toxicity and limited efficacy in advanced cancers.
• CD47 also acts as a death receptor, mediating programmed cancer cell death (PCCD), a mechanism underexplored in therapies.

Purpose of the Study:

• Introduce CO-001 and its optimized variant CO-005, a novel bifunctional antibody.
• Evaluate CO-005's potential to overcome safety limitations and enhance therapeutic efficacy.
• Investigate CO-005's dual mechanism of action: enhancing phagocytosis and inducing PCCD.

Main Methods:

• Developed CO-001 (chimeric IgG4 mAb) and CO-005 (humanized single-chain fragment variable-fragment crystallizable fusion protein).
• Assessed phagocytosis and PCCD induction in vitro and ex vivo.
• Evaluated hematologic safety profile, including red blood cell and white blood cell binding, and hemagglutination activity.
• Tested antitumor activity in preclinical B-cell precursor acute lymphoblastic leukemia and Raji lymphoma xenograft models.

Main Results:

• Both CO-001 and CO-005 promoted phagocytosis and PCCD.
• CO-005 demonstrated a superior hematologic safety profile compared to benchmark anti-CD47 antibodies, with no red blood cell binding and limited white blood cell binding.
• CO-005 exhibited potent antitumor activity in preclinical models via dual PCCD induction and enhanced phagocytosis.

Conclusions:

• CO-005 effectively induces programmed cancer cell death (PCCD) while preserving immune responses.
• CO-005 presents a promising, safer alternative to existing anti-CD47 therapies for cancer treatment.
• The dual mechanism and favorable safety profile position CO-005 as a potential therapeutic advantage.