All authors, except FK, ECM and RW were employed by MedImmune when this work was undertaken.
Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma
Version of Record online: 10 APR 2012
© 2011 MedImmune Ltd. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Secretin Family (Class B) G Protein-Coupled Receptors - from Molecular to Clinical Perspectives. Guest Editors: David R Poyner and Debbie L Hay
Volume 166, Issue 1, pages 177–193, May 2012
How to Cite
May, R., Monk, P., Cohen, E., Manuel, D., Dempsey, F., Davis, N., Dodd, A., Corkill, D., Woods, J., Joberty-Candotti, C., Conroy, L., Koentgen, F., Martin, E., Wilson, R., Brennan, N., Powell, J. and Anderson, I. (2012), Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma. British Journal of Pharmacology, 166: 177–193. doi: 10.1111/j.1476-5381.2011.01659.x
Re-use of this paper is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
- Issue online: 10 APR 2012
- Version of Record online: 10 APR 2012
- Accepted manuscript online: 6 SEP 2011 08:38AM EST
- Received; 4 November 2010; Revised; 24 May 2011; Accepted; 18 June 2011
- preclinical development for asthma;
- uncontrolled asthma;
- therapeutic antibody;
- asthma treatment
BACKGROUND AND PURPOSE IL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development.
EXPERIMENTAL APPROACH In vitro the potency, specificity and species selectivity of CAT-354 was assayed in TF-1 cells, human umbilical vein endothelial cells and HDLM-2 cells. The ability of CAT-354 to modulate disease-relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT-354 was tested on human IL-13-induced air pouch inflammation in mice, ovalbumin-sensitization and challenge in IL-13 humanized mice and antigen challenge in cynomolgus monkeys.
KEY RESULTS CAT-354 has a 165 pM affinity for human IL-13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL-13. CAT-354 did not neutralize human IL-4. In vitro CAT-354 functionally inhibited IL-13-induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT-354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia.
CONCLUSIONS AND IMPLICATIONS CAT-354 is a potent and selective IL-13-neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.