title: Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: relevance for human safety.
abstract: Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥30mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress.
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA. Electronic address: ryanp@medimmune.com.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Ryan
authors.affiliation: MedImmune, LLC, Cambridge, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sleeman
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Marlon
authors.initials: M
authors.lastname: Rebelatto
authors.affiliation: MedImmune, LLC, Moutain View, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: MedImmune, LLC, Moutain View, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Novartis, East Hanover, NJ, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.affiliation: MedImmune, LLC, Moutain View, CA, USA.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Hinrichs
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Lorin
authors.initials: L
authors.lastname: Roskos
authors.affiliation: MedImmune, LLC, Cambridge, UK.
authors.forename: Heidi
authors.initials: H
authors.lastname: Towers
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McKeever
authors.affiliation: MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Dixit
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D008297:Male; D023421:Models, Animal; D019055:No-Observed-Adverse-Effect Level; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C561644:mavrilimumab
keywords: Alveolar macrophage; Biologics; GMCSF receptor; Mavrilimumab; Rheumatoid arthritis; Safety assessment