ArticleJournal of translational medicine2026
Tumor-associated protease-activated anti-CD47 antibody precisely maintains phagocytic ability of macrophages with minimal effect on healthy tissue.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
(BACKGROUND): CD47 is highly expressed on many cancer cells and acts as an innate immune checkpoint. Its binding to signal regulatory protein alpha (SIRPα) on macrophages enables cancer cells to evade phagocytosis. Although anti-CD47 antibody (αCD47 Ab) has been employed to restore phagocytic capacity, the ubiquitous expression of CD47 on normal cells results in significant toxicities during Ab treatment, such as anemia, thrombocytopenia, and sepsis.
methodsTo mitigate these side effects, we used an autologous hinge region as a spatial-hindrance-based Ab lock and connected it to the N-terminal of the light chain and heavy chain via matrix metalloprotease substrate peptides (i.e., MMP-2) to cover the complementarity-determining regions (CDR) of αCD47 Ab to generate Pro-αCD47 Ab. The Ab lock is selectively removed only in disease regions with overexpressed proteases, thereby reducing the non-selective on-target effect.
resultsOur results showed that Pro-αCD47 Ab exhibits a 225.9-fold weaker binding ability compared to parental αCD47 Ab but fully recovers its binding function following MMP-2 treatment. Significantly, Pro-αCD47 Ab exhibits a 100.2-fold and 83.7-fold reduction in binding affinity toward red blood cells and neutrophils, respectively, thereby minimizing the risk of hematological toxicities. Furthermore, in vivo xenograft studies confirmed that Pro-αCD47 Ab achieves dose-dependent and near-complete tumor suppression equivalent to the parental antibody, while maintaining a stable systemic safety profile as evidenced by consistent animal body weight. Besides, it was successfully demonstrated that Pro-αCD47 Ab can be activated by endogenous MMP-2 within clinical tumor specimens, specifically showing promising activation in triple-negative breast cancer (TNBC) samples, thereby restoring its ability to bind CD47.
conclusionIn summary, we developed a protease-activated Pro-αCD47 Ab that avoids the undesired interactions with normal tissues, thereby addressing the most challenging issue limiting clinical efficacy. This advancement may provide patients with better medical care by enhancing therapeutic efficacy and improving overall treatment quality.
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