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A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET

John O DaSilva1, Katie Yang2, Oliver Surriga2

  • 1Regeneron Pharmaceuticals, Inc., Tarrytown, New York. john.dasilva@regeneron.com.

Molecular Cancer Therapeutics
|July 28, 2021
PubMed

Insights

A novel antibody-drug conjugate (ADC), METxMET-M114, shows promise for treating MET-overexpressing lung cancers. This MET ADC offers a potential new therapy for patients resistant to current MET inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Lung cancers with specific MET genetic alterations respond to MET-selective tyrosine kinase inhibitors (TKIs).
  • Current TKIs benefit a small patient subset (4%-5%) and face acquired resistance.
  • MET-overexpressing tumors (approx. 25% of lung cancers) are often resistant to existing therapies.

Purpose of the Study:

  • To develop and evaluate a novel antibody-drug conjugate (ADC) targeting MET for treating MET-overexpressing tumors.
  • To assess the efficacy and safety of the MET ADC (METxMET-M114) in preclinical models.
  • To explore the potential of MET ADCs to overcome resistance to MET TKIs.

Main Methods:

  • Conjugation of a biparatopic METxMET antibody to a maytansinoid payload via a protease-cleavable linker to create METxMET-M114.
  • Evaluation of METxMET-M114 efficacy in xenograft models with moderate to high MET expression, including resistant models.
  • Assessment of tumor uptake of radiolabeled METxMET antibody using positron emission tomography (PET).
  • Toxicology study in cynomolgus monkeys.

Main Results:

  • METxMET-M114 demonstrated substantial and durable tumor regression in xenografts with MET overexpression.
  • Efficacy was observed in models with innate or acquired resistance to MET blockers.
  • PET studies showed correlation between radiolabeled antibody uptake, MET expression, and ADC efficacy.
  • The MET ADC was well tolerated in a monkey toxicology study at effective doses.

Conclusions:

  • METxMET-M114 is a promising candidate for treating MET-overexpressing tumors, including those resistant to current therapies.
  • The ADC leverages unique antibody trafficking properties for enhanced efficacy.
  • This approach may address limitations of current MET-targeted therapies, expanding treatment options for lung cancer patients.

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