JNJ-95437446: Discovery and preclinical characterization of an amivantamab-based EGFR/MET-ADC for solid tumor indications

JNJ-95437446 is a potential best-in-class EGFR/MET bispecific antibody drug conjugate designed to deliver a cytotoxic payload to tumor cells while leveraging the unique characteristics of amivantamab. EGFR and MET are frequently expressed in solid tumors and amivantamab has demonstrated clinical efficacy in multiple non-small cell lung cancer (NSCLC) indications and is being studied in colorectal and head & neck carcinomas. Therefore, to assess the unique characteristics of JNJ-95437446, the ADC was evaluated in preclinical models of these tumor types. JNJ-95437446 uses a dual-maleimide linker-payload CPT-113 (Hangzhou DAC Biotechnology Co., Ltd.) to retain antibody stability upon conjugation. Preclinical experiments demonstrated JNJ-95437446 retained amivantamab-like binding to EGFR and MET, induced rapid internalization, and produced potent, target-dependent cytotoxicity in vitro. Additionally, the released payload from the ADC was capable of bystander cytotoxicity. JNJ-95437446 resulted in potent efficacy, including complete tumor regressions, in preclinical cell line-derived NSCLC xenograft models of adenocarcinoma and squamous cell carcinoma, and in models resistant to amivantamab. In multi-dose GLP NHP safety assessment studies, JNJ-95437446 was well tolerated at all doses tested and pharmacokinetic analysis demonstrated favorable linker/payload stability. JNJ-95437446 is an EGFR/MET-ADC exhibiting potent in vitro cytotoxicity and in vivo anti-tumor activity while being well-tolerated in a GLP NHP toxicity study. In summary, these data support development of JNJ-95437446 in a first-in-human clinical study (NCT07107230).