Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The c-Met proto-oncogene encodes a receptor tyrosine kinase activated by hepatocyte growth factor (HGF).
• Dysregulated c-Met signaling drives cancer progression, including tumor growth, metastasis, invasion, and angiogenesis.
• Targeting c-Met represents a potential therapeutic strategy for various cancers.

Purpose of the Study:

• To identify and characterize human monoclonal antibodies that inhibit c-Met activity.
• To evaluate the efficacy of these antibodies in blocking ligand-dependent c-Met activation and downstream signaling.
• To assess the anti-tumor potential of these antibodies in preclinical cancer models.

Main Methods:

• Identification of human monoclonal antibodies against the extracellular domain of c-Met.
• In vitro assays to assess antibody binding, inhibition of HGF binding, and c-Met activation in A549 cells.
• Phenotypic assays including soft agar growth and tubular morphogenesis.
• In vivo studies using xenograft tumor models to evaluate antibody efficacy and pharmacodynamics.

Main Results:

• Four distinct epitope classes of antibodies were identified, inhibiting HGF binding and c-Met activation.
• Antibodies induced c-Met receptor downregulation and antagonized its function in cell-based assays.
• In vivo, antibodies demonstrated sustained inhibition of c-Met activity (≥ 80% for 72-96 h) and significant tumor growth inhibition.
• Lead antibody CE-355621 achieved up to 98% inhibition in glioblastoma and gastric xenografts.

Conclusions:

• Human monoclonal antibodies targeting c-Met are effective inhibitors of ligand-dependent receptor activation.
• These antibodies demonstrate potent anti-tumor activity in preclinical models, including those overexpressing c-Met or HGF.
• Targeting c-Met with monoclonal antibodies is a promising therapeutic approach for cancer treatment.