Preclinical profile of BYON3521 predicts an effective and safe c-MET-antibody-drug conjugate.

c-MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor (HGF/SF), which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. BYON3521 is a novel site-specifically conjugated duocarmycin-based ADC, comprising a humanized cysteine-engineered IgG1 monoclonal antibody with low pM binding affinity towards both human and cynomolgus c-MET. In vitro studies showed that BYON3521 internalizes efficiently upon c-MET binding and induces both target- and bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high c-MET-expressing cancer cell lines; in moderate and low c-MET-expressing cancer cell lines good potencies and partial efficacy were observed. In mouse xenograft models, BYON3521 showed significant anti-tumor activity upon single dose administration in multiple non-MET-amplified tumor types with low, moderate and high c-Met expression, including complete tumor remissions in models with moderate c-MET expression. In the repeat-dose GLP safety assessment in cynomolgus monkeys, BYON3521 was well tolerated and based on the observed toxicities and their reversibility, the highest non-severely toxic dose (HNSTD) was set at 15 mg/kg. A human pharmacokinetics (PK) model was derived from the PK data from the cynomolgus safety assessments, and the minimal efficacious dose in humans is estimated to be in the range of 3-4 mg/kg. In all, our nonclinical data suggests that BYON3521 is a safe ADC with potential for clinical benefit in patients. A first-in-human dose escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045).