Development of c-Met-based Bispecific ADCs

Bispecific antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in several preclinical studies, showing improved drug selectivity and efficacy. As a professional service provider in ADC production for years, Creative Biolabs has successfully completed a significant number of ADC development projects. Our customers, ranging from research institutions to large biotech companies, have taken full advantage of our ADC platforms. Creative Biolabs now offers a comprehensive set of c-Met-based bispecific ADCs development services for our worldwide clients.

The Overview of c-Met

c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR). The ligand of c-Met, hepatocyte growth factor (HGF) was identified as a potent mitogen/morphogen. The HGF/c-Met signaling pathway has been demonstrated to play important roles in the development and progression of various cancers. HGF/c-Met signaling through downstream effectors stimulates diverse cellular processes such as cell proliferation, differentiation, migration, invasion, and survival. c-Met has become a promising therapeutic target in the treatment of cancer.

c-Met is produced as a single-chain precursor and processed to yield a mature receptor composed of a glycosylated, extracellular alpha subunit disulfide-bonded to a transmembrane beta subunit. The extracellular portion of c-Met is composed of a Sema domain, a cysteine-rich, Met-related-sequence domain, and four immunoglobulin (Ig)-like modules responsible for binding HGF. The intracellular portion of c-Met is composed of a juxtamembrane domain, a tyrosine kinase domain, and a C-terminal regulatory tail responsible for signal transduction. Tyrosine residues in the tyrosine kinase domain regulate the kinase activity of c-Met, and tyrosine residues in the C-terminal regulatory tail are important for the recruitment of downstream adapters.

Fig.1 Structure of c-Met and binding sites for c-Met monoclonal antibody. (Zhang, 2018)

Antibodies-based Therapeutics Targeting c-Met

Multiple therapeutic antibodies targeting c-Met are currently in preclinical and clinical development. Onartuzumab, the one-armed humanized antibody against c-Met, blocks the interaction between the HGF-α chain and the Sema domain of the c-Met receptor. Clinical trials are also ongoing for two bivalent antibodies against c-Met (emibetuzumab and ARGX-111). More important aspects to consider for the development of c-Met therapeutics include the identification of effective combinations of inhibitors targeting the HGF/c-Met pathway along with other interacting signaling pathways such as the EGFR (epidermal growth factor receptor) pathway. ME22S, a bispecific antibody that targets EGFR and c-Met, was generated to induce an efficient EGFR internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR-targeted therapies.

What Can We Do for You?

c-Met × EGFR bispecific ADCs have emerged recently, which seek to enhance internalization and trafficking to the lysosome, thus maximizing the amount of drug effectively delivered to tumor cells at a given dose. It has been demonstrated that selecting the appropriate combination of affinity optimized c-Met × tumor target bispecific ADC variants could lead to higher selectivity for tumor versus normal tissue, which could broaden the therapeutic index.

Creative Biolabs is a long-term expert who focuses on the discovery and development of novel ADCs. We have constructed different epitope combinations for c-Met-based bispecific ADCs development, including cMet × EGFR, cMet × HER2, cMet × HER3, cMet × PD-L1, and cMet × VEGF. We are confident in providing the best service and the most suitable solution to satisfy your specific demands. If you are interested in our services, please do not hesitate to contact us for more details.

Reference

1. Zhang Y.; et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Molecular Cancer, 2018, 17(1):45.

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