![]() ![]() These findings provide the framework for potential clinical application of anti-FGFR3 antibodies in t(4 14) MM. We describe here a fully human anti-FGFR3–neutralizing antibody (PRO-001) that selectively inhibits the proliferation of FGFR3-transformed cells and induces apoptosis of FGFR3-expressing human myeloma cells. Neutralizing antibodies, on the other hand, are by their nature highly specific and have high binding affinity and thus present an attractive alternative for the development of FGFR3 inhibitors. 24 The inherent lack of specificity of these drugs might limit their dose to a level below that required to achieve maximal target inhibition. 19- 23 However, limitations of small-molecule inhibitors include substantial cross-inhibition of other kinases as well as acquired drug resistance based on selection of clones that no longer bind the drug as seen with imatinib for the treatment of chronic myelogenous leukemia (CML). ![]() To date, several small-molecule inhibitors have been reported to induce cytotoxic responses of FGFR3-expressing myeloma cells. 15, 17, 18 The data have spurred the development of selective FGFR3 tyrosine kinase inhibitors for the potential treatment of MM. ![]() 12, 13 In vitro studies suggest that FGFR3 can impart chemoresistance 14 consistent with clinical data that demonstrate poor responses to conventional chemotherapy 15, 16 and shortened median survival of t(4 14) MM patients. 11, 12 Subsequent acquisition of activating mutations of FGFR3 in some MMs is associated with disease progression and is strongly transforming in several experimental models. Activation of wild-type (WT) FGFR3 promotes proliferation of myeloma cells and is weakly transforming in a hematopoietic mouse model. Studies indicate that FGFR3 may play a significant, albeit not a singular, role in myeloma oncogenesis, thus making this receptor tyrosine kinase (RTK) an attractive target for therapeutic intervention. Activation of FGFRs transduces signals through mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K) pathways, among others that regulate multiple cellular processes, including cell growth, differentiation, migration, and survival depending on the cellular context. ![]() 9 Binding of fibroblast growth factor (FGF) ligand and heparin promotes receptor dimerization and activation of the kinase domain, resulting in autophosphorylation of specific tyrosines. The FGFRs are characterized by 2 to 3 immunoglobulin (Ig)–like extracellular domains that bind ligand, a hydrophobic transmembrane domain, and a cytoplasmic region that contains a split tyrosine kinase domain. 8 FGFR3 belongs to a family of 5 receptors, FGFR1-5, 4 of which harbor a functional tyrosine kinase. The t(4 14)(p16.3 q32) translocation, which occurs in approximately 15% to 20% of MM tumors, 6, 7 results in the dysregulated expression of 2 putative oncogenes, MMSET and fibroblast growth factor receptor 3 (FGFR3). 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. 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. 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. Inhibition of viability was still observed when cells were cocultured with stroma or in the presence of IL-6 or IGF-1. Furthermore, PRO-001 inhibited the growth of the FGFR3-expressing, human myeloma cell line, UTMC2. The antibody inhibited the growth of FGFR3-expressing FDCP cells (IC 50 of 0.5 μg/mL) but not that of cells expressing FGFR1 or FGFR2, and potently inhibited FGFR3-dependent solid tumor growth in a mouse xenograft model. PRO-001 binds to FGFR3 expressed on transformed cells and inhibits FGFR3 autophosphorylation and downstream signaling. We report here a novel and highly specific anti-FGFR3–neutralizing antibody (PRO-001). 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. ![]()
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