Toxicology and Applied Pharmacology. 355():147–155, SEP 2018

DOI: 10.1016/j.taap.2018.06.033

,  

PMID: 30008375

Issn Print: 0041-008X

Publication Date: 2018/09/01


Share this on facebook   Share this on Twitter   Share this on LinkedIn   Email this article  



Print

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats

Nicholas Buss;Jean-Martin Lapointe;Lolke de Haan;Sally Price;Andrea Ahnmark;Lorraine Irving;Andrew Buchanan;Feenagh Keyes;Pia Davidsson;Rakesh Dixit;Daniel Lindén;

+ Author Information


    loading  Checking for direct PDF access through Ovid

Abstract

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10mg/kg for up to 4weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.HIGHLIGHTSAssessed potential toxicity of three anti-FGFR1c mAbs in rats after repeated dosingAll three mAbs caused significant reductions in food intake and weight lossMicroscopically, thickening of the diaphyseal cortex of long bones observed.Endocardial myxomatous change affecting all valves also observedPresence of FGFR1 mRNA in the heart valves observed using in situ hybridization

Related Topics

        loading  Loading Related Articles