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
| Autor: | Susan Hurst, Cedo M. Bagi, Mark Zorbas, William J. Reagan, Mark G. Evans, Kathryn E. Gropp, Cathy S. Carlson, David L. Shelton |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty medicine.medical_treatment Tanezumab Osteoarthritis Antibodies Monoclonal Humanized Toxicology Bone and Bones Pathology and Forensic Medicine Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Nerve Growth Factor medicine Animals Molecular Biology biology business.industry Growth factor Antibodies Monoclonal Histology Cell Biology medicine.disease Rats Mice Inbred C57BL Macaca fascicularis 030104 developmental biology Nerve growth factor chemistry Osteocalcin biology.protein Immunohistochemistry Biomarker (medicine) Joints Tomography X-Ray Computed business 030217 neurology & neurosurgery |
| Zdroj: | Toxicologic Pathology. 46:408-420 |
| ISSN: | 1533-1601 0192-6233 |
| DOI: | 10.1177/0192623318772501 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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