Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments

Kathryn E. Gropp, Cathy S. Carlson, Mark G. Evans, Cedo M. Bagi, William J. Reagan, Susan I. Hurst, David L. Shelton, Mark A. Zorbas

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article–related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Original languageEnglish (US)
Pages (from-to)408-420
Number of pages13
JournalToxicologic Pathology
Volume46
Issue number4
DOIs
StatePublished - Jun 1 2018

Bibliographical note

Funding Information:
The authors would like to thank Shana Dalton (Covance study director), Sato Oneda (SNBL [Everett, WA] study director), Thomas Cummings (Pfizer), Edwin Berryman (Pfizer), and Colleen Huddleston (Pfizer). The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Medical writing support was provided by Joseph Oleynek at Engage Scientific Solutions and was funded by Eli Lilly & Co. and Pfizer. These studies were funded by Pfizer.

Keywords

  • bone safety
  • joint safety
  • nerve growth factor
  • osteoarthritis
  • tanezumab

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