IL-23 as a therapeutic target

The Interleukin 23 (IL-23) cytokine is a heterodimeric cytokine consisting of the two subunits p19 and p40. It is an inducer of the Th17 cell population and a component of the IL-23/IL-17 immune pathway which is an orchestrator of many pathological conditions, including psoriasis. 

Due to its crucial role in pathogenesis, the two IL-23 subunits are promising therapeutic targets for inflammatory conditions. The first approved biologic agent targeting IL-23 was ustekinumab (Stelara), a fully human monoclonal antibody against the shared IL-12/IL23 p40 subunit that was approved for the indication of psoriasis and Chron’s disease. Guselkumab (Tremfya), a monoclonal antibody targeting the IL23p19 subunit was recently approved for the treatment of psoriasis, while tildrakizumab (Ilumya), also targeting IL23p19, and other therapeutics are currently under development.

We have developed and characterized transgenic mice expressing in a dysregulated manner either the human IL23p19 (TghIL23p19) or the human IL12p40 (TgK14hIL12p40).  In both transgenic lines, dysregulation is the result of the replacement of the gene’s 3’UTR with that of beta globin that is not subject to posttranscriptional regulation. Expression pattern is determined by the promoters used, that is the gene’s  own promoter for TghIL23p19 and the human keratin 14 promoter for TghIl12p40. Both transgenic lines develop lupus-like autoimmune pathologies and are available for testing therapeutics.

Model Disease Treatment Pathology Read outs
TghIL23p19 Lupus-like Guselkumab -Dermatits
-Splenomegaly
-Renal pathology
-Weight
-Skin clinical scoring
-Histology
-Circulating IgG levels
-Urine protein
TgK14hIL12p40 Lupus-like Ustekinumab -Dermatits
-Splenomegaly
-Renal pathology
-Weight
-Skin clinical scoring
-Histology
-Circulating IgG levels
-Urine protein