Mechanistic Studies Of Av370, A Potent Fgfr3 Antagonistic Antibody

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO The t(4;14)(p16.3;q32) translocation found in approximately 15% of patients with multiple myeloma leads to aberrant expression of 2 putative oncogenes, MMSET (a histone methyltransferase) and FGFR3 (a receptor tyrosine kinase). Patients carrying the t(4:14) translocation have a poor prognosis. Previous studies have demonstrated the oncogenic potential of FGFR3 in t(4:14) multiple myeloma, therefore targeting this receptor tyrosine kinase represents an attractive therapeutic opportunity in this patient population. Monoclonal antibodies have been developed to specifically block FGFR3 signaling in response to ligand stimulation. However, some of the tumors that harbor the t(4;14) translocation also carry mutations in FGFR3 that render the receptor constitutively active or hypersensitive to ligand stimulation. Whether antibody treatment is effective on tumors expressing mutant FGFR3 needs to be evaluated in preclinical models. The antagonistic anti-FGFR3 antibody, AV370 potently inhibits ligand-induced proliferation of FDCP cells expressing wild type FGFR3. AV370 also binds to mutant FGFR3 receptor with high affinity and inhibits the proliferation of FDCP cells driven by some mutant variants of the receptor. When tested in xenograft models using multiple myeloma cell lines, AV370 also significantly inhibited the growth of the OPM-2 xenograft that carries the K650E mutation in FGFR3. Although K650E mutation is thought to constitutively activate the receptor, we demonstrated that the tyrosine phosphorylation of this mutant receptor can be further stimulated by its ligands and AV370 could inhibit its tyrosine phosphorylation both in vitro and in vivo. Both cell surface and total FGFR3 level in OPM-2 cells were markedly reduced upon incubation with AV370. A profound receptor dowregulation in OPM-2 xenografts was also observed within 8 hours and the receptor downregulation sustained for at least 72 hours following a single dose of AV370 treatment. Similar receptor downregulation was also observed in another multiple myeloma cell line that carries a different activating mutation. Inhibition of receptor phosphorylation and induction of receptor downregulation by AV370 could bring therapeutic benefits to multiple meyloma patients with t(4:14) translocation. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3775.