Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification

Abstract

Backgroundc-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity.MethodWe generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH).ResultsABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH.ConclusionsThe preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2138-z) contains supplementary material, which is available to authorized users.

A novel antagonist anti‐cMet antibody with antitumor activities targeting both ligand‐dependent and ligand‐independent c‐Met receptors

“…Note that hz224G11 also inhibits the Akt and Erk pathways, as reported elsewhere. 49 The results reported here highlight the therapeutic potential of hz224G11 for patients with HGF-driven tumors and/ or c-Met ligand-independent cancer. This is the only full antagonist IgG1 antibody reported to date with both blocking activities and ADCC functions, making it arguably the best molecule in its class.…”

A “Prozone-Like” Effect Influences the Efficacy of the Monoclonal Antibody ABT-700 against the Hepatocyte Growth Factor Receptor

“…Since gastric cancer [30,31] is a primary clinical indication for ABT-700 [18,21,29], the ability to improve outcome upon combination with the SoC agent CPt was evaluated. The combination of ABT-700 and CPt was evaluated using the same progressively increasing initial tumor burden scheme as described previously.…”

“…The primary clinical indication for ABT-700 is gastric carcinoma [18,21,29] and hence the majority of mechanistic studies were performed using the gastric cancer model Hs 746T. To determine the degree of antibody-receptor engagement necessary for activity, Fab and F(ab') 2 fragments of ABT-700 were generated and evaluated using proliferation assays as a readout.…”

“…ABT-700 is a first-in-class antagonistic humanized bivalent monoclonal antibody that binds MET and inhibits the proliferation of multiple MET expressing cancer cell lines in vitro [18,19,20]. ABT-700 prevents ligand binding, MET dimerization, and consequent receptor-phosphorylation.…”

ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both MET–Amplified and c-Met–Overexpressing Tumors, Irrespective of MET Pathway Dependence

“…Instead patient selection strategies to identify those tumors in which MET is constitutively activated through gene amplification, mutation, or ligand-dependent activation may be necessary to predict sensitivity to many of these inhibitors (14,15). Consistent with reliance on MET activation for activity, ABT-700, a c-Met-targeting antibody without the agonist activity associated with many c-Met antibodies, was well tolerated in a phase I trial and demonstrated antitumor activity in select patients with MET-amplified solid tumors (16,17). Although increased frequencies of MET amplification may be associated with relapsed/refractory tumors including those with EGFR-activating mutation in non-small cell lung cancer (NSCLC), primary MET genomic amplification is a low frequency event in most tumors (1%-5%), thereby limiting the patient population where inhibitors that block MET signaling may be effective (18)(19)(20)(21).…”