Abstract 4817: Preclinical evaluation of a new, non-agonist ADC targeting MET -amplified tumors with a peptide-linked maytansinoid

With cancer among the leading causes of death worldwide, the search for better, personalized treatments is imperative. Novel techniques such as next generation sequencing have identified many assayable genetic biomarkers associated with cancer in patient samples. The tyrosine kinase receptor cMet is one such biomarker that is upregulated in various solid tumors and associated with poor prognosis, disease progression and metastasis. While most patients with elevated cMet show increased levels through protein upregulation, a small population harbors gene amplification. These patients face worse outcomes which could be improved with therapies specifically targeting MET-amplification. Antibody-drug conjugates (ADCs) are a modality designed to selectively deliver highly potent cytotoxic agents to tumors. cMet is an attractive target for ADCs which may address the unmet treatment need for patients with tumors harboring MET amplification. Since dimerization of cMet receptors by ligand HGF leads to agonistic proliferative events, a carefully selected antibody should be chosen to avoid triggering activation. As previously described, we identified and humanized an antibody with minimal agonism. Introducing an additional disulfide in the hinge region while maintaining the IgG1 isotype further reduced agonism as measured in vitro in both cell proliferation and phosphorylation signaling assays, while retaining high affinity to human and cynomolgus cMet, and acceptable expression and biophysical properties. To assess potential toxicity due to normal tissue expression, we measured binding of our antibody to normal hepatocytes from humans and cynos. Here we found very low expression and binding versus tumor cell lines. Next, we demonstrated that the cytotoxic activity of disulfide-cleavable maytansinoid ADCs prepared from the hinge-variant cMet antibody were equivalent to the parental form in in vivo models. In a MET-amplified xenograft model of gastric cancer, Hs746T, both parental and modified hucMet-sSPDB-DM4 ADCs demonstrated tumor eradication and comparable plasma clearance at 5 mg/kg. Similar results were found in the MET-amplified NSCLC model EBC-1 at 2.5 mg/kg. Conjugation to the newly-described dipeptide-linked maytansinoid DM21 further improved anti-tumor activity in both Hs746T and EBC-1 models, with a 2-fold decrease in minimally-efficacious dose. The activity of hucMet27Gv1.3Hinge-L-DM21 was durable, with a single dose yielding full regressions and tumor-free