-
Views
-
Cite
Cite
Daniel G. Rudmann, Todd J. Page, John L. Vahle, Luc Chouinard, Solomon Haile, Florence Poitout, Gary Baskin, André-Jean Lambert, Pamela Walker, Genevieve Glazier, Malaika Awori, Lise Bernier, Rat-Specific Decreases in Platelet Count Caused by a Humanized Monoclonal Antibody Against Sclerostin, Toxicological Sciences, Volume 125, Issue 2, February 2012, Pages 586–594, https://doi.org/10.1093/toxsci/kfr318
- Share Icon Share
Abstract
LY2541546 is a humanized monoclonal antibody (IgG4) that has been optimized for neutralizing activity against sclerostin. In 5-week and 6-month nonclinical safety studies in rats, LY2541546 caused dose-dependent reversible decreases in platelet counts accompanied by accelerated platelet production, increased megakaryocytes, and altered megakaryocyte morphology. These treatment-related effects resulted in altered primary hemostasis as manifested by prolonged bleeding after phlebotomy or incidental toenail break. In some cases, the defects in hemostasis were sufficient to result in death of the affected rats. There was no evidence in rats of general bone marrow suppression or processes (e.g., disseminated intravascular coagulopathy) that may result in thrombocytopenia. Cynomolgus monkeys given LY2541546 for 5 weeks or 9 months had no changes in platelet count or megakaryocytes. In vitro cross-reactivity studies in rats, cynomolgus monkeys, and humans revealed LY2541546-bound rat but not cynomolgus monkey or human platelets and megakaryocytes. These data taken together demonstrated that the platelet and megakaryocyte effects in rats had a species-specific pathogenesis which likely involved LY2541546 binding of a rat-specific antigen on the surface of platelets and megakaryocytes resulting in the increased clearance of platelets and megakaryocyte hyperplasia. The species-specific nature of these reversible toxicological findings combined with the ease of clinical monitoring using standard hematology enabled the safe initiation of clinical studies in human volunteers.
Comments