Integrin-specific binding macrocyclic RGD peptides functionalized with dinitrophenol as multivalent...

The diverse expression of antigenic subtypes on tumor cells can substantially influence the specific binding and tumor cytotoxicity of antibody-recruiting molecules (ARMs). Therefore, the development of multivalent ARMs with high selectivity and affinity for binding to different subtypes on tumor cells can be expected to improve clinical performance. In this study, multivalent ARMs incorporated with multivalent dinitrophenyl (DNP) haptens and an integrin-specific arginine-glycine-aspartic acid (RGD) macrocyclic peptide were synthesized using a chemoenzymatic approach. The molecules specifically recognized integrin α_vβ₃-positive tumor cells and exhibited robust antibody recruitment capacity and tumor-killing effects depending on the multivalent effects. Notably, the D3 molecule showed excellent anti-DNP antibody recruitment capacity in the α_vβ₃-positive tumor cells and antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)-mediated tumor cytotoxicity. Given the variable expression of integrin receptor subtypes among individuals, the multivalent ARMs developed in this study that specifically target α_vβ₃-positive tumor cells to enhance cancer cytotoxicity represent a promising strategy for tumor immunotherapy.