Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma

Cancer Chemother Pharmacol. 2012 Apr;69(4):1071-8. doi: 10.1007/s00280-011-1807-5. Epub 2011 Dec 28.


Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacokinetics*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Immunoglobulin G / pharmacology
  • Macaca fascicularis
  • Mice
  • Mice, Nude
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Nonlinear Dynamics
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Fibroblast Growth Factor, Type 3 / immunology*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin G
  • Receptor, Fibroblast Growth Factor, Type 3
  • vofatamab