AZD9773 is a novel selective anti-TNFa ovine polyclonal immune Fab
Abstract number: P1438
Objectives: TNF-a is thought to play a central role in the pathogenesis of sepsis and septic shock. AZD9773 is an ovine polyclonal anti-human TNF-a (rhTNF-a) immune Fab and comprises both TNF-a-directed and non-specific Fab populations. Here we describe the binding and functional potency of AZD9773 against rhTNF-a and TNF-a orthologues from a number of species and characterise the specificity of AZD9773 against a panel of human frozen tissues.
Methods: AZD9773 binding and functional potency (IC50) versus rhTNF-a and TNF-a orthologues was assessed using surface plasmon resonance (SPR) technology and TNF-a-mediated cytotoxicity in L929 and PK(15) cell lines, respectively. AZD9773 binding to a variety of fresh frozen tissues from three unrelated human donors was determined via detection of fluorescein isothiocyanate-(FITC-)conjugated AZD9773 by immunohistochemical (IHC) staining. FITC sheep anti-digoxigenin Fab was used as a control.
Results: SPR revealed that AZD9773 total Fabs binding to other species TNF-a was less than that obtained with rhTNF-a. AZD9773:TNF-a orthologue binding relative to AZD9773:rhTNF-a binding was approximately 5060% for canine, equine, feline and primate TNF-a, approximately 20% for porcine TNF-a and <20% for bovine, murine, cotton rat and rat TNF-a. In cytotoxicity assays, AZD9773 potently inhibited the bioactivity of human and primate TNF-a with limited or no inhibition of canine, porcine, mouse and rat TNF-a. IHC analysis revealed specific AZD9773 staining of occasional cells in the lung, thymus and lamina propria of the ileum, and in cells within the red and white pulp of the spleen.
Conclusion: AZD9773 has limited capacity to bind and neutralise common TNF-a orthologues; consistent with the conservation of key TNF-a receptor-binding epitopes and overall sequence-identity between species. Specific binding of AZD9773 to human tissues was consistent with the theoretical distribution of TNF-a producing cells, reflecting the intended pharmacological binding. The non-TNF-a-direct Fab populations of AZD9773 do not appear to bind human antigens. Thus, AZD9773 is a potent and selective human TNF-a-neutralising ovine immune Fab. #FB Currently at Novartis, Basel, Switzerland.
|Session name:||Abstracts of 21st ECCMID / 27th ICC|
|Location:||Milan, Italy, 7 - 10 May 2011|
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