Carcinogenicity risk assessment of romosozumab: A review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study.

Autor: Chouinard L; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Felx M; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Mellal N; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Varela A; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Mann P; EPL NorthWest, 600 North 36th Street, Suite 220, Seattle, WA, 98103, USA., Jolette J; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Samadfam R; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Smith SY; Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada., Locher K; One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA., Buntich S; One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA., Ominsky MS; One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA., Pyrah I; One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA., Boyce RW; One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA. Electronic address: rboyce@amgen.com.
Jazyk: angličtina
Zdroj: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2016 Nov; Vol. 81, pp. 212-222. Date of Electronic Publication: 2016 Aug 26.
DOI: 10.1016/j.yrtph.2016.08.010
Abstrakt: Romosozumab is a humanized immunoglobulin G 2 monoclonal antibody that binds and blocks the action of sclerostin, a protein secreted by the osteocyte and an extracellular inhibitor of canonical Wnt signaling. Blockade of sclerostin binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) allows Wnt ligands to activate canonical Wnt signaling in bone, increasing bone formation and decreasing bone resorption, making sclerostin an attractive target for osteoporosis therapy. Because romosozumab is a bone-forming agent and an activator of canonical Wnt signaling, questions have arisen regarding a potential carcinogenic risk. Weight-of-evidence factors used in the assessment of human carcinogenic risk of romosozumab included features of canonical Wnt signaling, expression pattern of sclerostin, phenotype of loss-of-function mutations in humans and mice, mode and mechanism of action of romosozumab, and findings from romosozumab chronic toxicity studies in rats and monkeys. Although the weight-of-evidence factors supported that romosozumab would pose a low carcinogenic risk to humans, the carcinogenic potential of romosozumab was assessed in a rat lifetime study. There were no romosozumab-related effects on tumor incidence in rats. The findings of the lifetime study and the weight-of-evidence factors collectively indicate that romosozumab administration would not pose a carcinogenic risk to humans.
(Copyright © 2016 Amgen Inc. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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