PT  - JOURNAL ARTICLE
AU  - Boyd Steere
AU  - Catherine Beidler
AU  - Andrea Martin
AU  - Stu Bright
AU  - Kristy Kikly
AU  - Robert J Benschop
TI  - <strong>Generation and characterization of mirikizumab, a humanized monoclonal antibody targeting the p19 subunit of IL-23</strong>
AID  - 10.1124/jpet.122.001512
DP  - 2023 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2022-001512
4099  - http://jpet.aspetjournals.org/content/early/2023/09/15/jpet.122.001512.short
4100  - http://jpet.aspetjournals.org/content/early/2023/09/15/jpet.122.001512.full
AB  - IL-23 exists as a heterodimer consisting of p19 and p40 and is a key cytokine for promoting inflammatory responses in a variety of target organs. IL-23 plays a key role in the differentiation and maintenance of T helper 17 cells, and deregulation of IL-23 can result in autoimmune pathologies of the skin, lungs, and gut. This study describes the generation and characterization of mirikizumab, a humanized IgG4 monoclonal antibody directed against the p19 subunit of IL-23. Mirikizumab binds human and cynomolgus monkey IL-23 with high affinity and binds rabbit IL-23 weakly but does not bind to rodent IL-23 or the other IL-23 family members IL-12, IL-27, or IL-35. Mirikizumab effectively inhibits the interaction of IL-23 with its receptor, and potently blocks IL-23-induced IL-17 production in cell-based assays while preserving the function of IL-12. In both local and systemic in vivo mouse models, mirikizumab blocked IL-23-induced keratin mRNA or IL-17 production, respectively. These data provide a comprehensive preclinical characterization of mirikizumab, for which efficacy and safety have been demonstrated in human clinical trials for psoriasis, ulcerative colitis, and Crohn's disease. Significance Statement This manuscript describes the generation and characterization of mirikizumab, a high affinity, neutralizing IgG4 variant monoclonal antibody which is under development for the treatment of ulcerative colitis and Crohn’s disease. Neutralization of IL-23 is achieved by preventing the binding of IL-23 p19 subunit to the IL-23 receptor and does not affect the IL-12 pathway.