An AI-guided biparatopic DLL3-targeting ADC demonstrates enhanced preclinical efficacy

Purpose This study aimed to develop a novel biparatopic antibody-drug conjugate (ADC) targeting delta-like ligand 3 (DLL3) for small cell lung cancer (SCLC) and other neuroendocrine neoplasms, addressing limitations of previous DLL3-targeted therapies. Methods Leveraging our AI-guided antibody development platform, we engineered a biparatopic anti-DLL3 antibody with optimized binding and internalization properties. The antibody was conjugated with various linker-payload combinations. In vitro cytotoxicity of the ADCs were evaluated using DLL3-expressing cell lines and in vivo efficacy were assessed using CDX mice models. Safety was assessed in transgenic mice and non-human primates. Results The biparatopic antibody demonstrated higher internalization efficiency compared to the monoclonal antibody counterparts. The ADC showed potent cytotoxicity across multiple DLL3-expressing cell lines and achieved significant tumor suppression in CDX models. Toxicological studies revealed a favorable safety profile in both transgenic mice and non-human primates. Conclusion This biparatopic ADC represents a promising therapeutic candidate for DLL3-expressing tumors, demonstrating enhanced efficacy and favorable preclinical safety compared to previous approaches.