A high-affinity antibody-drug conjugates Actuximab-MMAE for potent and selective targeting of CEACAM5-Positive tumors

Abstract

Antibody-drug conjugates (ADCs) represent a promising class of anti-cancer therapy with an increasingly critical role in treating various tumors. They broaden the range of therapeutic targets, enabling the consideration of tumor-associated proteins that are overexpressed but lack well-defined mechanisms. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a clinically relevant screening marker due to its tumor-specific overexpression, making it an attractive target for ADC development. However, the therapeutic potential of earlier anti-CEACAM5 ADCs has been limited by side effects and suboptimal drug-to-antibody ratios (DARs), restricting their clinical utility. In this study, we developed a novel anti-CEACAM5 ADC (named Actuximab-MMAE), characterized by high affinity, an optimized DAR, and potent tumor-selective cytotoxicity. Actuximab-MMAE demonstrated rapid and effective elimination of CEACAM5-positive tumors in vivo at low doses, while maintaining a favorable safety profile. These findings highlight Actuximab-MMAE as a promising therapeutic option for CEACAM5-overexpressing tumors, offering a new therapeutic method for targeted cancer therapy.

Keywords: Antibody-drug conjugate; Carcinoembryonic antigen-related cell adhesion molecules 5; Colorectal carcinoma; Drug-antibody ratio; Solid tumor.