Abstract
Abstract Background The signaling networks perpetuating chronic inflammatory bowel disease remain unclear. Interleukin-7 (IL-7) has been previously reported to trigger the expansion of effector Th17 cells and anti-IL-7 receptor (IL-7R) antagonism to render IL23-differentiated Th17 cells susceptible to apoptosis1. We previously reported that IL-7R pathway is locally dysregulated and over-expressed in the colon mucosa of severe IBD patients and reproducibly associated with unresponsiveness to anti-TNF or anti-α4β7 integrin therapies2. We developed a humanized anti-IL7R lusvertikimab with a good PK/PD and tolerance profile in healthy volunteers3 and recently announced positive phase 2 efficacy results in ulcerative colitis after a 10 week-induction treatment period (randomized placebo-controlled CoTikiS study: NCT04882007). Methods Here, we investigated at preclinical level the additive effect of blocking IL-7R in combination with anti-IL12/23 antagonist antibody in an anti-TNF refractory adoptive T cell transfer chronic colitis mouse model as well as in-vitro on human Th17 cell differentiation in combination with anti-IL23 antibody. Results T cell-recipient mice developed a colitis characterised by the development of diarrhoea and body weight loss with post-mortem examination confirming epithelial hyperplasia and inflammatory cell infiltration into the mucosa. Anti-IL7R monotherapy at this dose was suboptimal in this model. Anti-IL-12/23 blockade in monotherapy was efficient but not enough alone to achieve complete remission at macroscopic and histological level. In contrast, administration of anti-IL-7R in combination with anti-IL12/23 mAb was associated with a strong and significant reduction in all measured colitis symptoms, macroscopic large bowel changes and all histopathological endpoints (hyperplasia, colitis severity, inflammation). When mice were treated in combination, the group was statistically different from the anti-IL12/23 monotherapy group and no statistical difference have been measured with the non-colitis group, illustrating this combination achieved complete remission including at histological mucosal healing. In vitro, we confirmed that IL-7 drives human Th17 differentiation despite IL23 blockade and that combining IL7R and IL23 blockade was efficient to prevent Th17 generation in the presence of both IL7 and IL23. Conclusion Our findings show that anti-IL-7R is well tolerated in combination with anti-IL12/23 mAb in mice and act in synergy to achieve a profound control of chronic colitis and complete histological normalization compared to monotherapy.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call