Antibody-drug Conjugate PCMC1D3-Duocarmycin SA as a Novel Therapeutic Entity for Targeted Treatment of Cancers Aberrantly Expressing MET Receptor Tyrosine Kinase

Abstract

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.

Keywords: MET receptor tyrosine kinase; antibody-drug conjugate; drug delivery; duocarmycin; in vitro cytotoxicity; mouse monoclonal antibody; therapeutic efficacy; tumor xenograft model.