Bispecific antibodies (bsAbs) are engineered monoclonal antibodies (mAbs) that possess two distinct binding sites, allowing them to noncovalently bind two different antigens. Representing one of the fastest-growing classes of investigational therapeutics, bsAbs currently exist in more than a hundred different formats in development pipelines. Meanwhile, antibody-drug conjugates (ADCs) have emerged as a novel and effective cancer therapeutic modality, leveraging the target specificity of monoclonal antibodies to deliver cytotoxic agents directly to cancer cells. To date, eight ADCs have received regulatory approval for cancer treatment. Recent studies have demonstrated that combining bsAbs and ADCs to create bispecific ADCs may offer enhanced therapeutic efficacy in oncology.

Creative Biolabs, a global leader in delivering customer-centric ADC development solutions, offers comprehensive services supported by world-class facilities and a highly experienced scientific team. The company provides integrated support ranging from conjugation development to clinical and commercial GMP batch manufacturing of ADCs. Building on this expertise, Creative Biolabs now offers full-service development of bispecific biparatopic ADCs targeting a variety of biomarkers, including the c-MET receptor.

Overview of c-MET

c-MET, also known as tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a membrane receptor encoded by the MET gene in humans. Structurally, it is a single-pass heterodimer consisting of an extracellular alpha subunit—comprising semaphorin, plexin-semaphorin-integrin, and immunoglobulin-plexin-transcription domains—linked to a transmembrane beta subunit via a disulfide bond. The transmembrane and intracellular domains regulate its kinase activity. Hepatocyte growth factor (HGF), primarily secreted by mesenchymal cells, binds to c-MET and is critical for regulating epithelial growth and tissue morphogenesis.

Aberrant activation of the HGF/MET signaling pathway has been implicated in tumorigenesis across multiple human cancers. Normally, c-MET is expressed by epithelial cells to support tissue generation during embryogenesis or tissue repair in adults. However, in cancer, tumor stem cells may exploit c-MET signaling to promote tumor growth, survival, and metastasis. c-MET is highly expressed in a range of malignancies, including gastric, lung, breast, ovarian, colon, kidney, thyroid, and liver cancers, as well as hepatocellular carcinoma (HCC). Consequently, c-MET has become a prominent therapeutic target under active clinical investigation.

Biparatopic c-MET-Targeted Bispecific Antibodies

Biparatopic bispecific antibodies enhance internalization and trafficking to lysosomes by simultaneously binding two distinct epitopes on the same antigen, in this case, c-MET. This dual engagement induces receptor clustering and cross-linking, which increases selectivity toward cancer cells and promotes efficient internalization—an advantage for ADC payload delivery.

A biparatopic IgG1 antibody targeting two non-overlapping, HGF-competing epitopes on c-MET’s extracellular domain has been developed. Preclinical studies demonstrated that this biparatopic antibody could simultaneously engage both epitopes recognized by the original parental monoclonal antibodies. Moreover, it exhibited superior inhibitory activity against MET signaling compared to the parental antibodies in tumor xenograft models.

Given the enhanced anti-tumor activity observed with bispecific biparatopic antibodies against c-MET, the development of bispecific biparatopic ADCs utilizing such targeting strategies represents a promising therapeutic avenue for cancer treatment.

Source: https://www.creative-biolabs.com/adc/development-of-biparatopic-c-met-targeted-bispecific-adcs.htm