title: The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells.
abstract: The association of fibroblast growth factor receptor 3 (FGFR3) expression with t(4;14) multiple myeloma (MM) and the demonstration of the transforming potential of this receptor tyrosine kinase (RTK) make it a particularly attractive target for drug development. We report here a novel and highly specific anti-FGFR3-neutralizing antibody (PRO-001). PRO-001 binds to FGFR3 expressed on transformed cells and inhibits FGFR3 autophosphorylation and downstream signaling. The antibody inhibited the growth of FGFR3-expressing FDCP cells (IC(50) of 0.5 microg/mL) but not that of cells expressing FGFR1 or FGFR2, and potently inhibited FGFR3-dependent solid tumor growth in a mouse xenograft model. Furthermore, PRO-001 inhibited the growth of the FGFR3-expressing, human myeloma cell line, UTMC2. Inhibition of viability was still observed when cells were cocultured with stroma or in the presence of IL-6 or IGF-1. PRO-001 did not inhibit constitutive activation of K650E, G384D, and Y373C FGFR3 in myeloma cell lines and failed to inhibit the growth of these cells. Most importantly, however, PRO-001 induced cytotoxic responses in primary t(4;14)(+) MM samples with an increase in apoptotic index of 20% to 80% as determined by annexin V staining. The data demonstrate that PRO-001 is a potent and specific inhibitor of FGFR3 and deserves further study for the treatment of FGFR3-expressing myeloma.
authors.affiliation: University Health Network, Princess Margaret Hospital, McLaughlin Centre of Molecular Medicine, 620 University Avenue, Rm 8204, Toronto, Ontario, Canada M5G 2C1. strudel@uhnres.utoronto.ca
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Eran
authors.initials: E
authors.lastname: Rom
authors.forename: Ellen
authors.initials: E
authors.lastname: Wei
authors.forename: Zhi Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Sarit
authors.initials: S
authors.lastname: Kotzer
authors.forename: Irina
authors.initials: I
authors.lastname: Chumakov
authors.forename: Yossi
authors.initials: Y
authors.lastname: Singer
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Sheng-Ben
authors.initials: SB
authors.lastname: Liang
authors.forename: Avner
authors.initials: A
authors.lastname: Yayon
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3