AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use—improves psoriasis in a human xenograft transplantation model

Targeting more than one molecule in multifactorial diseases involving several disease mediators may provide improved therapeutic efficacy. Psoriasis is a multifactorial disease in which interleukin (IL)-6 and IL-23 are important disease mediators because they facilitate development of Th17 cells; wi...

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Published in:	Protein engineering, design and selection Vol. 28; no. 10; pp. 467 - 480
Main Authors:	Stenderup, Karin, Rosada, Cecilia, Shanebeck, Kurt, Brady, William, Van Brunt, Michael P., King, Gordon, Marelli, Marcello, Slagle, Paul, Xu, Hengyu, Nairn, Natalie W., Johnson, Jeffrey, Wang, Aijun A., Li, Gary, Thornton, Kenneth C., Dam, Tomas N., Grabstein, Kenneth H.
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-10-2015
Subjects:	Animals Antibodies, Bispecific - immunology Antibodies, Bispecific - pharmacokinetics Antibodies, Bispecific - therapeutic use Antibody Specificity Disease Models, Animal Female Humans Interleukin-23 - immunology Interleukin-6 - immunology Mice Molecular Targeted Therapy Psoriasis - drug therapy Psoriasis - immunology Rats Transplantation, Heterologous bispecific antibody xenograft model IL-23 psoriasis IL-6
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Summary:	Targeting more than one molecule in multifactorial diseases involving several disease mediators may provide improved therapeutic efficacy. Psoriasis is a multifactorial disease in which interleukin (IL)-6 and IL-23 are important disease mediators because they facilitate development of Th17 cells; widely accepted to be associated with psoriasis. To meet the need for new therapeutics, we aimed to create a clinically relevant bispecific drug, by combining the inhibitory properties of anti-IL-6 and anti-IL-23 antibodies, exhibiting high affinity, high stability and the ability to be produced in high yield. The bispecific molecule AZ17 was created by combining high affinity binding domains originating from monoclonal antibodies targeting human IL-6 and IL-23. To allow for high and efficient production, AZ17 was assembled by site-specific bioconjugation from two individual single chain fragment variables that were synthesized separately in Escherichia coli. To improve stability and extend pharmacokinetics, a flexible poly-ethylene glycol molecule was used as linker. In preclinical psoriasis models, AZ17 reduced IL-23-induced ear inflammation and improved psoriasis in a xenograft transplantation model where psoriasis skin is transplanted onto immune-deficient mice. The data presented here suggest AZ17 to be a promising drug candidate in psoriasis and other inflammatory diseases associated with Th17 cell development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1741-0126 1741-0134
DOI:	10.1093/protein/gzv034