Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.
Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-A resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.
Qing
Jing
J
Department of Molecular Oncology, Genentech Inc., South San Francisco, California, USA. jqing@gene.com
Du
Xiangnan
X
Chen
Yongmei
Y
Chan
Pamela
P
Li
Hao
H
Wu
Ping
P
Marsters
Scot
S
Stawicki
Scott
S
Tien
Janet
J
Totpal
Klara
K
Ross
Sarajane
S
Stinson
Susanna
S
Dornan
David
D
French
Dorothy
D
Wang
Qian-Rena
QR
Stephan
Jean-Philippe
JP
Wu
Yan
Y
Wiesmann
Christian
C
Ashkenazi
Avi
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000737:chemistry; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D034622:RNA Interference; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014178:Translocation, Genetic / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000939:Epitopes; C106534:FRS2 protein, human; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020928:Mitogen-Activated Protein Kinases