title: Incomplete target neutralization by the anti-cancer antibody rilotumumab.
abstract: 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.
authors.affiliation: a Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, Hudson Institute of Medical Research , 27-31 Wright Street, Clayton , VIC 3168 , Australia.|b Monash University, Wellington Parade , Clayton , VIC 3800 , Australia.|c Biomedical Manufacturing Program, Commonwealth Scientific and Industrial Research Organisation , 343 Royal Parade, Parkville , VIC 3052 , Australia.
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Greenall
authors.affiliation: c Biomedical Manufacturing Program, Commonwealth Scientific and Industrial Research Organisation , 343 Royal Parade, Parkville , VIC 3052 , Australia.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Adams
authors.affiliation: a Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, Hudson Institute of Medical Research , 27-31 Wright Street, Clayton , VIC 3168 , Australia.|b Monash University, Wellington Parade , Clayton , VIC 3800 , Australia.
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006025:Glycosaminoglycans / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D006025:Glycosaminoglycans; C066855:HGF protein, human; C020341:glucosaminoglycans; C524459:rilotumumab; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt
keywords: Cancer; EGFR; HGF; MET; targeted therapy