Development of a novel bifunctional anti-CD47 fusion protein with improved efficacy and a favorable safety profile.

in Molecular cancer therapeutics by Sittana Matar, Seham Skah, Liza E Diomande, Tim Buss, Hanne R Hagland, Ajay Yadav, Rune J Forstrøm, Bjørn Dalhus, Kjetil Hestdal, Rolf D Pettersen, Nina Richartz

TLDR

  • The study introduces CO-005, a bivalent humanized anti-CD47 antibody that demonstrates a superior safety profile and potent antitumor activity in pre-clinical models through dual action of PCCD induction and phagocytosis.
  • CO-005 may offer therapeutic advantages over existing anti-CD47 treatments, warranting further investigation in clinical trials.

Abstract

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 (scFv-Fc) 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 to benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells (RBCs), limited binding to white blood cells (WBCs), and showed no hemagglutination activity. In pre-clinical models, CO-005 demonstrated potent antitumor activity in BCP-ALL 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.

Overview

  • The study introduces CO-001 and CO-005, therapeutic anti-CD47 monoclonal antibodies designed to overcome limitations of current anti-CD47 treatments.
  • CO-005 is a bivalent humanized single-chain fragment variable-fragment crystallizable (scFv-Fc) fusion protein engineered to overcome safety limitations and demonstrate a superior hematologic safety profile.
  • The study aims to investigate the efficacy and safety of CO-005 in pre-clinical models and its potential as a novel and promising approach for CD47-targeted cancer therapy.

Comparative Analysis & Findings

  • CO-005 demonstrated a superior hematologic safety profile compared to benchmark anti-CD47 antibodies, showing no binding to red blood cells and limited binding to white blood cells.
  • CO-005 exhibited potent antitumor activity in BCP-ALL and Raji lymphoma xenograft models through the dual action of programmed cancer cell death (PCCD) induction and enhancement of phagocytosis.
  • CO-005 triggered strong PCCD while preserving conventional immune responses, providing a novel and promising approach for CD47-targeted cancer therapy.

Implications and Future Directions

  • The findings of this study position CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments, including its favorable safety profile and antitumor activity.
  • Future studies should investigate the efficacy and safety of CO-005 in clinical trials to further assess its potential as a therapeutic option for cancer treatment.
  • The ability of CO-005 to trigger PCCD while preserving immune responses suggests that this mechanism may be a valuable addition to current cancer therapies, warranting further exploration.
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