title: Carcinogenicity risk assessment of romosozumab: A review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study.
abstract: Romosozumab is a humanized immunoglobulin G2monoclonal 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.
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Luc
authors: L
authors: Chouinard
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Melanie
authors: M
authors: Felx
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Nacera
authors: N
authors: Mellal
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Aurora
authors: A
authors: Varela
authors: EPL NorthWest, 600 North 36th Street, Suite 220, Seattle, WA, 98103, USA.
authors: Peter
authors: P
authors: Mann
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Jacquelin
authors: J
authors: Jolette
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Rana
authors: R
authors: Samadfam
authors: Charles River Laboratories, Montreal ULC, 22022 Transcanadienne, Senneville, Quebec, H9X 3R3, Canada.
authors: Susan Y
authors: SY
authors: Smith
authors: One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
authors: Kathrin
authors: K
authors: Locher
authors: One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
authors: Sabina
authors: S
authors: Buntich
authors: One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
authors: Michael S
authors: MS
authors: Ominsky
authors: One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
authors: Ian
authors: I
authors: Pyrah
authors: One Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA, 91320, USA. Electronic address: rboyce@amgen.com.
authors: Rogely Waite
authors: RW
authors: Boyce
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D018570:Risk Assessment
chemical_list: D000911:Antibodies, Monoclonal; C557282:romosozumab
keywords: Carcinogenicity; Chronic toxicity; Null antibody; Romosozumab; Sclerostin antibody