What question did this study set out to answer?

This research aims to characterize the novel antibody IMC-002 against CD47, assessing its safety and efficacy in cancer treatment.

April 5, 2026

Abstract 4355: Cryo EM-based structural characterization of IMC-002, a next-generation anti-CD47 antibody with a unique binding site and biomarker candidates, supporting evidence of enhanced safety and efficacy

Key Points

This research aims to characterize the novel antibody IMC-002 against CD47, assessing its safety and efficacy in cancer treatment.
Cryogenic electron microscopy (cryo-EM) was used to analyze IMC-002's binding site.
De-glycosylation studies evaluated the effect on binding selectivity.
Clinical trials, including Phase 1a and Phase 1b, tested IMC-002 in hepatocellular carcinoma and triple-negative breast cancer populations.
Proteomic and AI-assisted immunohistochemistry (IHC) analyses identified potential biomarkers for efficacy.
IMC-002 demonstrates enhanced tumor-cell selectivity with minimal red blood cell binding compared to other antibodies.
Phase 1a trials report a favorable safety profile for IMC-002.
In vitro studies show IMC-002 increases macrophage-mediated phagocytosis and T-cell activation.
Biomarker candidates linked to IMC-002 efficacy were identified, aiding in patient selection for treatment.

Abstract

Abstract CD47 is a ubiquitously expressed transmembrane glycoprotein that interacts with SIRPα on macrophages to deliver a “don’t eat me” signal, thereby inhibiting phagocytosis. Tumor cells upregulate CD47 to evade immune surveillance, which correlates with poor clinical outcomes. Consequently, the CD47-SIRPα axis has emerged as a promising target for cancer immunotherapy. However, clinical development of CD47 blockade has been hampered by hematologic toxicities and rapid drug clearance due to high CD47 expression on normal cells, particularly red blood cells (RBCs). IMC-002 is a fully human IgG4 monoclonal antibody against CD47, developed to achieve an optimized affinity that balances therapeutic efficacy with safety. IMC-002 shows markedly enhanced tumor-cell selectivity with minimal RBC binding, compared with Hu5F9 and 13H3. Moreover, unlike Hu5F9, IMC-002 did not induce RBC phagocytosis and hemagglutination. The tumor selectivity and lack of RBC binding by IMC-002 appear to result from differences in its binding site. Cryo-electron microscopy (cryo-EM) revealed a unique binding interface near residues containing a predicted O-glycosylation site, which is distinct from the binding modes of competitive antibodies. De-glycosylation study also supported this glycosylation-dependent binding selectivity, as reported at AACR 2025. The results from biochemical and structural studies explaining IMC-002’s reduced hematologic toxicity and enhanced tumor selectivity in its clinical trials. Phase 1a data confirmed a favorable safety profile, and a hepatocellular carcinoma (HCC) cohort in phase 1b has been completed. An ongoing Phase 1b trial is evaluating its efficacy in triple-negative breast cancer (TNBC) and biliary tract cancer (BTC) cohorts in combination with standard of care (SoC). IMC-002 in combination with standard-of-care agents enhanced macrophage-mediated phagocytosis and T-cell activation in vitro and showed potent anti-tumor activity in HCC xenograft model, correlating with tumor CD47 expression. In a Phase 1b (NCT05276310), aptamer-based proteomic and AI-assisted IHC analyses of HCC patient samples identified candidate biomarkers associated with IMC-002 efficacy and macrophage-related signatures, suggesting their use in patient selection. In conclusion, the cancer-selective binding of IMC-002 is characterized by binding sites located proximal to a predicted O-glycosylation region, as supported by biochemical and structural studies. Several factors identified through proteomics and AI-based IHC studies showed potential possibilities as predictive biomarker candidates. IMC-002 demonstrated excellent efficacy and safety in clinical trials through its unique binding mechanism, supporting its continued clinical development as a promising cancer therapy. Citation Format: Hyesun Lee, Jiyea Choi, HyeHyeon Jang, Heewook Shin, Jiyoung Yoon, Woochan Hwang, Sung Ho Kim, Heung Tae Kim. Cryo EM-based structural characterization of IMC-002, a next-generation anti-CD47 antibody with a unique binding site and biomarker candidates, supporting evidence of enhanced safety and efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4355.

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