Background::Aberrant expression of the MET receptor tyrosine kinase is an oncogenic
determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting
MET are under clinical trials.
Objective::Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody-
drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy.
Methods::The monoclonal antibody PCMC1D3 (IgG1a/κ), generated by a hybridoma technique
and specific to one of the MET extracellular domains, was selected based on its high specificity to
human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable
valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody
ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization
efficacy ranging from 6.5 to 17.2h dependent on individual cell lines.
Results::Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted
the cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation.
The calculated IC50 values for cell viability reduction were 1.5 to 15.3 nM. Results from
mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10
mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of
tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor
growth and inhibition, was around 2 mg/kg body weight. Taken together, PCMC1D3-DCM
was effective in targeting the inhibition of tumor growth in xenograft models.
Conclusion::This work provides the basis for the development of humanized PCMC1D3-DCM for
MET-targeted cancer therapy in the future.
