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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 26 weeks. 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 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/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 knownmore » 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. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. • Lung changes observed reflect role of GM-CSF in alveolar macrophage function. • High safety margins support continued clinical development of mavrilimumab.« less

Authors:
 [1];  [2];  [1]; ;  [3];  [4];  [3]; ;  [1];  [2]; ;  [1]
  1. MedImmune, LLC, Gaithersburg, MD (United States)
  2. MedImmune, LLC, Cambridge (United Kingdom)
  3. MedImmune, LLC, Moutain View, CA (United States)
  4. Novartis, East Hanover, NJ (United States)
Publication Date:
OSTI Identifier:
22439821
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 279; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CHOLESTEROL; DOSES; INFLAMMATION; LUNGS; MACROPHAGES; MONKEYS; MONOCLONAL ANTIBODIES; NEUTROPHILS; PATHOGENESIS; PATIENTS; RHEUMATIC DISEASES; RISK ASSESSMENT; SAFETY MARGINS; TOXICITY

Citation Formats

Ryan, Patricia C., E-mail: ryanp@medimmune.com, Sleeman, Matthew A., Rebelatto, Marlon, Wang, Bing, Lu, Hong, Chen, Xiaomin, Wu, Chi-Yuan, Hinrichs, Mary Jane, Roskos, Lorin, Towers, Heidi, McKeever, Kathleen, and Dixit, Rakesh. Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.06.002.
Ryan, Patricia C., E-mail: ryanp@medimmune.com, Sleeman, Matthew A., Rebelatto, Marlon, Wang, Bing, Lu, Hong, Chen, Xiaomin, Wu, Chi-Yuan, Hinrichs, Mary Jane, Roskos, Lorin, Towers, Heidi, McKeever, Kathleen, & Dixit, Rakesh. Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety. United States. doi:10.1016/J.TAAP.2014.06.002.
Ryan, Patricia C., E-mail: ryanp@medimmune.com, Sleeman, Matthew A., Rebelatto, Marlon, Wang, Bing, Lu, Hong, Chen, Xiaomin, Wu, Chi-Yuan, Hinrichs, Mary Jane, Roskos, Lorin, Towers, Heidi, McKeever, Kathleen, and Dixit, Rakesh. Mon . "Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety". United States. doi:10.1016/J.TAAP.2014.06.002.
@article{osti_22439821,
title = {Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety},
author = {Ryan, Patricia C., E-mail: ryanp@medimmune.com and Sleeman, Matthew A. and Rebelatto, Marlon and Wang, Bing and Lu, Hong and Chen, Xiaomin and Wu, Chi-Yuan and Hinrichs, Mary Jane and Roskos, Lorin and Towers, Heidi and McKeever, Kathleen and Dixit, Rakesh},
abstractNote = {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 26 weeks. 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 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/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. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. • Lung changes observed reflect role of GM-CSF in alveolar macrophage function. • High safety margins support continued clinical development of mavrilimumab.},
doi = {10.1016/J.TAAP.2014.06.002},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 279,
place = {United States},
year = {Mon Sep 01 00:00:00 EDT 2014},
month = {Mon Sep 01 00:00:00 EDT 2014}
}
  • The effect of an anti-human transferrin receptor (anti-TFR) monoclonal antibody (MoAb), designated B3/25, and an anti-melanoma antibody, designated 96.5, on the uptake of gallium-67 (/sup 67/Ga) by tumor was studied. Three groups of six athymic mice bearing a human melanoma were injected via tail vein with (a) 0.55 mg human serum albumin (HSA) (control group), (b) 0.5 mg MoAb B3/25 + 0.55 mg HSA, and (c) 0.5 mg MoAb 96.5 + 0.55 mg HSA, respectively. Twenty-four hours later, each mouse was given an intravenous dose of 5 microCi (/sup 67/Ga) citrate. Biodistribution of activity (percent injected dose per gram) determinedmore » 48 hr after injection of /sup 67/Ga showed a 75% decrease in tumor uptake in the group of mice that received B3/25 (anti-TFR MoAb) compared with the control group. In contrast, MoAb 96.5 did not show any effect on melanoma uptake of /sup 67/Ga. Histologic findings suggest that the decreased uptake was not due to cellular damage resulting from binding of B3/25 to TFR. The results of this study strongly suggest the involvement of TFR in the in vivo tumor uptake of /sup 67/Ga.« less
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