title: Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: MedImmune, Abington, Cambridge, UK. mayr@medimmune.com
authors: R D
authors: RD
authors: May
authors: P D
authors: PD
authors: Monk
authors: E S
authors: ES
authors: Cohen
authors: D
authors: D
authors: Manuel
authors: F
authors: F
authors: Dempsey
authors: N H E
authors: NH
authors: Davis
authors: A J
authors: AJ
authors: Dodd
authors: D J
authors: DJ
authors: Corkill
authors: J
authors: J
authors: Woods
authors: C
authors: C
authors: Joberty-Candotti
authors: L A
authors: LA
authors: Conroy
authors: F
authors: F
authors: Koentgen
authors: E C
authors: EC
authors: Martin
authors: R
authors: R
authors: Wilson
authors: N
authors: N
authors: Brennan
authors: J
authors: J
authors: Powell
authors: I K
authors: IK
authors: Anderson
mesh_terms: D000293:Adolescent; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology; D012720:Severity of Illness Index; D013045:Species Specificity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D018793:Interleukin-13; D017455:Receptors, IgE; D007073:Immunoglobulin E; D010047:Ovalbumin; C574065:tralokinumab