title: Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody.
abstract: Activating mutations in fibroblast growth factor receptor 3 (FGFR3) have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9), a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small cell lung cancer (NSCLC) specimens. Furthermore, in a mouse model where FGF9 can be induced in lung epithelial cells, epithelial proliferation and ensuing tumorigenesis is dependent on FGFR3. To develop new customized therapies for cancers that are dependent on FGFR3 activation, we have used this mouse model to evaluate a human monoclonal antibody (D11) with specificity for the extracellular ligand-binding domain of FGFR3, that recognizes both human and mouse forms of the receptor. Here, we show that D11 effectively inhibits signaling through FGFR3 in vitro, inhibits the growth of FGFR3-dependent FGF9-induced lung adenocarcinoma in mice, and reduces tumor-associated morbidity. Given the potency of FGF9 in this mouse model and the absolute requirement for signaling through FGFR3, this study validates the D11 antibody as a potentially useful and effective reagent for treating human cancers or other pathologies that are dependent on activation of FGFR3.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Quantitative Biology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Cancer Angiogenesis, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Qianxu
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Immunology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Malabunga
authors.affiliation: Department of Immunology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Ilhem
authors.initials: I
authors.lastname: Guernah
authors.affiliation: Department of Antibody Technology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Antibody Technology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Juqun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Bioprocess Sciences, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Immunology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Nabil
authors.initials: N
authors.lastname: Chehab
authors.affiliation: Department of Immunology, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Loizos
authors.affiliation: Department of Bioprocess Sciences, Eli Lilly and Company, New York, NY 10016, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA dornitz@wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D055745:Bronchioles / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011650:Pulmonary Alveoli / Q000473:pathology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D008024:Ligands; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: Adenocarcinoma; FGFR3; Fibroblast growth factor receptor 3; Inhibitory monoclonal antibody; Lung cancer; NSCLC