Anti-MET VHH Pool Overcomes MET-Targeted Cancer Therapeutic Resistance

Receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) play crucial roles in many human malignancies. Numerous drugs have been developed against kinase center of MET or HGF-mediated activation; however, the outcomes in patients are not so promising. Increasing evidence show that MET has kinase-independent effects on tumorigenesis and dissemination, which explains the low efficacy in kinase inhibition-based strategy. VHH is the recombinant variable region of Camelid heavy-chain antibody. As a nanoscale antigen-binding unit, VHH has become an appealing drug candidate in cancer therapy. In our study, we choose a novel strategy to construct an anti-MET VHH pool against the whole ecto-domain of MET. Comparing to monoclonal antibody or single VHH, the anti-MET VHH pool strongly promotes MET degradation through Clathrin-dependent endo-lysosomal pathway. Thus, the anti-MET VHH pool not only blocks kinase activity of MET, but also reduces protein level of MET. As a consequence, anti-MET VHH pool dramatically suppresses cancer cell proliferation, viability, and colony formation in vitro, and inhibits tumorigenesis and growth in mice. Taken together, VHH pool-based strategy greatly improves MET-targeted therapeutic effects on cancer.