Br J Pharmacol 2011 Sep 6. doi: 10.1111/j.1476-5381.2011.01659.x. [Epub ahead of print]
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; Anderson, I.
MedImmune, Abington, Cambridge, UK.
Background and purpose: IL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. This paper describes the preclinical in vitro and in vivo characterisation of CAT-354, an IL-13-neutralising IgG4 mAb, which is currently in clinical development. Experimental approach: In vitro the potency, specificity, and species selectivity of CAT-354 was assessed in TF-1, HUVEC, and HDLM2 cell-based assays. The ability of CAT-354 to modulate disease relevant mechanisms was tested in bronchial smooth muscle calcium flux, NHLF eotaxin generation, PBMC CD23 upregulation, and B cell IgE production assay systems. In vivo CAT-354 was tested in huIL-13-induced air pouch inflammation, IL-13 humanised mouse ovalbumin-sensitisation and challenge, and cynomolgus monkey antigen challenge models. Key results: CAT-354 has a 165pM affinity for human IL-13 and functionally neutralises human, human variant associated with asthma and atopy (Q130R), and cynomolgus monkey, but not mouse IL-13. CAT-354 is selective for human IL-13 and does not neutralise IL-4. In vitro CAT-354 functionally inhibits IL-13-induced eotaxin production, an analogue of smooth muscle AHR, CD23 upregulation, and IgE production. In vivo, in humanised mouse and cynomolgus antigen challenge models, CAT-354 inhibits antigen-challenge induced AHR and BAL eosinophilia. Conclusions and implications: CAT-354 is a potent and selective IL-13-neutralising IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate-severe uncontrolled asthma.