Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase

Highlights

• Cancerous MET overexpression is a common pathological feature manifested by genetic, molecular, and cellular abnormalities.

• Conventional therapeutic antibodies targeting MET, under clinical trials for almost 10 years, have made little progress with various setbacks.

• Novel biotherapeutics, such as bispecific antibodies, antibody-drug conjugates, and their combination, are under anti-MET clinical trials.

• Amivantamab, a MET/EGFR bispecific antibody, has been granted the Breakthrough Therapy Designation status for treatment of advanced NSCLC.

• An emerging era of antibody-based biotherapeutics for treatment of cancer overexpressing MET is in the horizon.

Aberrant expression of the MET receptor, defined by immunohistochemical (IHC) staining and manifested through amplification, mutation, alternative exon splicing, and abnormal protein metabolism, has led to the development of small-molecule kinase inhibitors (SMKIs) and conventional therapeutic monoclonal antibodies (TmAbs) for targeted cancer therapy. SMKIs have been approved for clinical application. However, conventional anti-MET TmAbs, although under clinical trials for 10 years, have made little progress, with various setbacks, raising uncertainty about their usefulness. In this review, we discuss the relevance of MET overexpression and the latest development of bispecific antibodies, antibody–drug conjugates (ADCs), and their combined products for clinical development. Evidence from preclinical and clinical studies highlights the potential of these novel MET-targeted biotherapeutics for cancer therapy in the future.