[show abstract][hide abstract] ABSTRACT: MFGR1877A is a human IgG1 monoclonal antibody that binds to fibroblast growth factor receptor 3 (FGFR3) and is being investigated as a potential therapy for relapsed/refractory FGFR3+ multiple myeloma. The purpose of these studies was to characterize the pharmacokinetics (PK) of MFGR1877A in mouse, rat, and monkey and predict its human PK and efficacious dose.
PK of MFGR1877A was determined in athymic nude mice, Sprague-Dawley rats and cynomolgus monkeys after administration of single intravenous doses. Human PK profiles were projected from monkey PK profiles using a species-invariant time method, and human population PK parameters were estimated using a non-linear, two-compartment model comprising specific (target-mediated) and non-specific clearance pathways. The anti-tumor efficacy in mice bearing human tumor xenografts was used in conjunction with inhibitory activity in cell proliferation assays and human PK projections to estimate clinical efficacious dose.
The PK of MFGR1877A in mice was non-linear in the dose range of 1-50 mg/kg, while in rats and monkeys, PK was non-linear in the dose range of 1-10 mg/kg and linear at doses ≥ 10 mg/kg. The predicted non-specific clearance range in humans was 2.6-4.4 mL/day/kg. Doses ranging from 2 to 3 mg/kg weekly to 6-10 mg/kg every 4 weeks were predicted to achieve the target exposure in ≥ 90% of multiple myeloma patients.
The predicted non-specific clearance of MFGR1877A in humans is similar to typical human IgG1 antibodies and will be verified in a Phase 1 study. The projected human efficacious dose and regimen appear to be achievable in patients.
Cancer Chemotherapy and Pharmacology 12/2011; 69(4):1071-8. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
The Journal of clinical investigation 05/2009; 119(5):1216-29. · 15.39 Impact Factor