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

• 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
• ISSN: 1741-0126; 1741-0134
• DOI: 10.1093/protein/gzv034

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.