title: Rat-specific decreases in platelet count caused by a humanized monoclonal antibody against sclerostin.
abstract: LY2541546 is a humanized monoclonal antibody (IgG(4)) 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.
authors: Lilly Research Laboratories, Translational Sciences, Molecular Pathology and Imaging and Development Center of Excellence, Toxicology and Pathology, Indianapolis, IN 46285, USA. rudmanndg@lilly.com
authors: Daniel G
authors: DG
authors: Rudmann
authors: Todd J
authors: TJ
authors: Page
authors: John L
authors: JL
authors: Vahle
authors: Luc
authors: L
authors: Chouinard
authors: Solomon
authors: S
authors: Haile
authors: Florence
authors: F
authors: Poitout
authors: Gary
authors: G
authors: Baskin
authors: André-Jean
authors: AJ
authors: Lambert
authors: Pamela
authors: P
authors: Walker
authors: Genevieve
authors: G
authors: Glazier
authors: Malaika
authors: M
authors: Awori
authors: Lise
authors: L
authors: Bernier
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000633:toxicity*; D000918:Antibody Specificity; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D003429:Cross Reactions; D004305:Dose-Response Relationship, Drug; D005260:Female; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D015576:Hyperostosis / Q000139:chemically induced; D008252:Macaca fascicularis; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects* / Q000473:pathology; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019485:Bone Morphogenetic Proteins