Targeting CD47 in Cancer: A Safe and Effective Therapeutic Approach with IMC-002

Immune checkpoint inhibitors are a cornerstone of cancer therapy, yet some cancers are resistant to these treatments. As a result, there is a drive to identify new targets to alter the tumor microenvironment (TME) and enhance anti-cancer immunity. Macrophages, known for their functional flexibility, are key players in TME, and CD47 is a significant target on macrophages that cancer cells often overexpress to avoid phagocytosis.

IMC-002 is a human IgG4 monoclonal antibody designed to target CD47 with an optimized safety and efficacy profile. It lacks hemagglutination activity and includes a hinge-stabilizing mutation to prevent Fab arm exchange. In vitro assays were conducted to evaluate ligand binding, cell surface binding, and phagocytosis. IMC-002 was found to bind strongly to CD47 on various cancer cells and to some T cells, but not to NK or B cells. Notably, it did not bind to red blood cells (RBCs), avoiding RBC agglutination.

In vivo studies in human breast cancer models demonstrated IMC-002's ability to induce phagocytosis of cancer cells and suppress tumor growth in a dose-dependent manner. The antibody showed enhanced phagocytosis when combined with tumor antigen-targeting IgG1 therapeutics. Epitope mapping indicated that IMC-002 binds to distinct parts of the CD47 antigen, which may account for its cell-selective binding.

Pharmacokinetic and toxicity assessments in mice and cynomolgus monkeys showed that IMC-002 was well-tolerated, with no hematologic toxicity observed at doses up to 100 mg/kg and a typical therapeutic antibody half-life of 5–10 days. The preclinical data supported the simulation of human pharmacokinetics and the determination of an optimal first-in-human dose.

The preclinical efficacy and safety profiles of IMC-002 support its potential therapeutic value, particularly for hematologic cancer patients due to its engineered minimization of hematological toxicities. The first-in-human study of IMC-002 is currently underway to assess safety, tolerability, and to establish the recommended Phase 2 dose in subjects with advanced solid tumors and lymphomas.

All experimental procedures were conducted in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines. This research contributes to the understanding of CD47 as a target for cancer therapy and the development of antibodies like IMC-002 that may offer new treatment options for patients with resistant cancers.