title: 89Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection.
abstract: The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a89Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated89Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors.Methods:The chelatorp-SCN-Bn-DFO was conjugated to AMG102, radiolabeling with89Zr was performed in high radiochemical yields and purity (>99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown).Results:Tumor uptake of89Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 ± 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 ± 1.3 %ID/g and a control of nonspecific human IgG89Zr-DFO-IgG in U87MG tumors was 11.5 ± 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of89Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that89Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors.Conclusion:The new immuno-PET imaging agent89Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that89Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Price
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carnazza
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cho
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Edwards
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kuntal K
authors.initials: KK
authors.lastname: Sevak
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Glaser
authors.affiliation: Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; and.
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York lewisj2@mskcc.org.|Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003676:Deferoxamine / Q000737:chemistry*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D018579:Patient Selection; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D014018:Tissue Distribution; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C066855:HGF protein, human; D018796:Immunoconjugates; D011868:Radioisotopes; C524459:rilotumumab; D017228:Hepatocyte Growth Factor; D015040:Zirconium; D003676:Deferoxamine
keywords: AMG102; HGF; MET; PET; hepatocyte growth factor; patient-derived xenograft; rilotumumab; scatter factor