MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6 % of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named METΔ7−8. METΔ7−8 is located predominantly in the cytosol and is constitutively active. The auto-activating nature of METΔ7−8, in combination with a lack of transmembrane localization, renders METΔ7−8 not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an ongoing global human health crisis and will likely become endemic, requiring novel sustainable therapeutic strategies. We report on the discovery of a fully human multi-antibody cocktail (TATX-03) targeting diversified non-overlapping epitopes on the SARS-CoV-2 spike protein that suppressed replication-competent viral titers to undetectable levels in the lungs of SARS-CoV-2 challenged hamsters upon both prophylactic and therapeutic administration. While monotherapy with two of the individual cocktail components also showed clear in vivo protection, neither recapitulated the efficacy of TATX-03. This synergistic effect was further supported by examining in vivo efficacy of these individual antibodies and corresponding combination therapy at a lower dose. Furthermore, in vitro screenings using VSV-particles pseudo-typed with spike proteins representing the SARS-CoV-2 variants of concern Alpha, Beta, and Delta showed that TATX-03 maintained its neutralization potency. These results merit further development of TATX-03 as a potential therapy for SARS-CoV-2 infection with resistance to mutagenic escape.
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