Generation and characterization of 7DC-DM1: a non-cleavable CD47-targeting antibody-drug conjugates with antitumor effects

Abstract

Colorectal cancer is the second leading cause of cancer-related deaths following lung cancer in recent years. Therefore, lung or colorectal cancer therapy is very important for reducing mortality. In this study, we developed and characterized CD47-specific antibody-drug conjugates, namely 7DC-DM1 ADCs, to evaluate their therapeutic effects on lung and colorectal cancer. Both 7DC2-DM1 and 7DC4-DM1 demonstrated good binding affinities of 0.56 nM and 0.49 nM, respectively, and exhibited significant cytotoxicity, though they displayed different penetration effects. These findings suggest that the binding complexes of 7DC2-DM1 and 7DC4-DM1 with CD47 receptors adopt different conformations, leading to variations in their cellular internalized efficiencies. Molecular docking simulations revealed that 7DC2 and 7DC4 bind to CD47 molecules in distinct orientations and epitopes, differing between conserved and non-conserved regions. Furthermore, treatments with 7DC2-DM1 and 7DC4-DM1 displayed notable differences in antitumor effects in murine syngeneic tumor models derived from the MC38 cell line in C57BL/6 mice. In the tumor model treated with 7DC4-DM1, immunofluorescence staining analysis revealed a large area of necrosis in the tumor stroma, accompanied by a significant infiltration of CD11b-expressing immune cells. In summary, these results indicate that 7DC4-DM1 holds promise as a therapeutic agent for colorectal cancer treatment.