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.
OBJECTIVE
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.
Department of Pharmacokinetics and Pharmacodynamics, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA. kamath.amrita@gene.com
Amrita V
AV
Kamath
Dan
D
Lu
Priyanka
P
Gupta
Denise
D
Jin
Yan
Y
Xin
Ann
A
Brady
Jean-Philippe
JP
Stephan
Hao
H
Li
Janet
J
Tien
Jing
J
Qing
Lisa A
LA
Damico-Beyer
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D017711:Nonlinear Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D051498:Receptor, Fibroblast Growth Factor, Type 3; C573866:vofatamab