D. Samineni, C. Li, D. Nazzal, D. Maslyar, D. Li, S. Girish; Genentech, South San Francisco, CA

BACKGROUND: DMOT4039A ADC is a human IgG1 anti-MSLN monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E (MMAE) linked through a protease-labile linker. The MSLN tumor antigen is overexpressed in pancreatic and ovarian cancers.
METHODS: The phase I dose escalation study evaluated the safety, PK and efficacy of DMOT4039A administered every 3 weeks (q3w) (0.2-2.8 mg/kg) and weekly (qw) (0.8-1.2 mg/kg) to patients with pancreatic or ovarian cancers. A traditional 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D). Serum and plasma samples were obtained to characterize the PK of antibody conjugated MMAE (acMMAE), total antibody (Tab) and unconjugated MMAE. The cycle 1 PK parameters were estimated using non-compartmental analysis (NCA).
RESULTS: Following DMOT4039A administration, exposure of acMMAE and Tab increased proportionally with increase of dose for the q3w and qw schedules at the tested clinical dose range. Systemic exposure of unconjugated MMAE was low and also increased non-proportionally with dose. At the RP2D of 2.4 mg/kg q3w, the clearance (CL) was 26 mL/day/kg for acMMAE and 20 mL/day/kg for Tab; steady state volume of distribution (Vd,ss) was 59-78 mL/kg for acMMAE and Tab, suggesting limited extravascular distribution. For the unconjugated MMAE, the maximum concentration (Cmax) at RP2D was 4 ng/mL and was at a minimum of 100-fold lower than the acMMAE Cmax. The half-life (t1/2) of unconjugated MMAE was similar to acMMAE (3-4 days), suggesting formation-rate limited kinetics for unconjugated MMAE.
CONCLUSION: DMOT4039A showed linear PK at the tested dose range for the q3w and qw schedules for the acMMAE and Tab analytes. The unconjugated MMAE levels were >100-fold lower than those for acMMAE.