Incomplete target neutralization by the anti-cancer antibody rilotumumab.
The antibody rilotumumab, which has been tested in multiple Phase 2 and Phase 3 trials, has been reported to neutralize hepatocyte growth factor (HGF), the ligand for the oncogene MET. However, we report that rilotumumab does not prevent HGF from directly binding to MET on conventional and primary patient-derived human gliomasphere lines, a trait driven by the HGF α-chain, which remains free to engage cell-surface glycosaminoglycans and the receptor MET. This binding induces MET phosphorylation, initiates robust AKT and ERK signaling and potentiates biological effects such as cell scattering. This partial antagonism was highly exacerbated in the presence of activated epidermal growth factor receptor, which is common in several cancers. Hence, we confirm that rilotumumab is only a partial antagonist of HGF activity, a finding that has considerable implications for the therapeutic use of rilotumumab.
['Greenall|Sameer A|SA|', 'Adams|Timothy E|TE|', 'Johns|Terrance G|TG|']
D000911:Antibodies, Monoclonal D061067:Antibodies, Monoclonal, Humanized D057134:Antibodies, Neutralizing D045744:Cell Line, Tumor D017322:Clinical Trials, Phase II as Topic D017326:Clinical Trials, Phase III as Topic D006025:Glycosaminoglycans D017228:Hepatocyte Growth Factor D006801:Humans D020935:MAP Kinase Signaling System D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D019859:Proto-Oncogene Proteins c-met
HGF MET Cancer EGFR targeted therapy