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COMBINING IL-23 BLOCKADE WITH ANTI-Ɑ4Β7 OR ANTI-TL1A FOR THE TREATMENT OF IBD IS SUPPORTED BY IN VITRO AND MOUSE IBD MODEL EXPERIMENTS

Daniel Rios 1, Murshid Alam 1, Joana Vidal 1, Joshua Friedman 2, Andy Spencer 2, Jason Oh 1, Hussam Shaheen 1

Affiliations

1 Paragon Therapeutics, Waltham, United States

2 Spyre Therapeutics, Waltham, United States

Summary

AI Generated

Pre-clinical study demonstrates that combining anti-IL-23 with anti-α4β7 or anti-TL1A antibodies enhances suppression of IL-17 and shows modest improvements in murine colitis models compared to monotherapy.

IL-23 and TL1A synergistically promote IL-17 production in human and mouse immune cells, and combined blockade of both targets suppresses IL-17 secretion more effectively than either antibody alone
In a mouse T-cell transfer colitis model, high-dose combination therapy with anti-IL-23 and anti-α4β7 improved body weight and reduced colonic IL-17 protein levels compared to monotherapy
The combination showed similar improvements to monotherapy in survival, disease activity index, and histology scores, with less obvious effects on these other disease measures
This pre-clinical work addresses the need to evaluate whether combining targeted biologics can improve efficacy by inhibiting multiple pathways while avoiding broad immunosuppression
This material is most relevant to researchers and clinicians interested in novel combination therapeutic strategies for inflammatory bowel disease

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Despite the discovery of advanced treatments for IBD, placebo-adjusted clinical remission rates during induction therapy are typically only 10%-25%, and loss of response is common even among those who initially benefit. Monoclonal antibodies targeting IL-23 or ɑ4β7 are both relatively safe and effective treatments for Crohn’s disease (CD) and ulcerative colitis (UC), while antibodies to the cytokine TL1A have shown promise in phase 2 clinical trials. The combined use of targeted biologic agents may improve efficacy by inhibiting multiple pathways while avoiding the risks associated with broad immunosuppression. Pre-clinical studies are needed to assess the potential benefit of combining IL-23 antagonism with ɑ4β7 or TL1A blockade.

Aims & Methods

IL-17 production in response to IL-23 and/or TL1A by human peripheral blood mononuclear cells (PBMC) and mouse splenocytes was assessed in the presence of anti-IL-23 and/or anti-TL1A. The ability of anti-IL-23 and anti-ɑ4β7 as monotherapies or in combination to prevent colitis was assessed by transferring CD4+ CD45RB^highT cells into Rag2^-/-mice. Survival, body weight, disease activity, histology, and colon IL-17 levels were measured.

Results

IL-23 and TL1A had a synergistic effect on IL-17 production by human PBMC and mouse splenocytes, extending previous findings in CD patient-derived lamina propria T cells¹. Both anti-IL-23 and anti-TL1A inhibited IL-17 production, with the greatest inhibition occurring with combined IL-23 and TL1A blockade.
In the mouse T-cell transfer colitis (TCT) model, the anti-IL-23 and anti-ɑ4β7 combination at high doses resulted in improved body weight relative to either monotherapy. The monotherapies and the combination of anti-IL-23 and anti-ɑ4β7 (both high and low doses) resulted in similar improvements in survival, disease activity index, and histology score. The combination resulted in greater reductions in colonic IL-17 protein than either monotherapy alone.

Conclusion

IL-23 and TL1A have a synergistic effect on promoting IL-17 secretion from human and mouse immune cells. The combination of anti-IL-23 and anti-TL1A suppresses IL-17 secretion more effectively than either agent alone. In the TCT model of IBD, combination therapy with anti-IL-23 and anti-ɑ4β7 improves body weight and reduces colonic IL-17 levels relative to monotherapy with less obvious effect on other disease measures.

References

Kamada, N. et al. TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn’s disease. Inflamm. Bowel Dis. 16, 568–575 (2010).

Disclosure

DR, MA, JV, JO, and HS are employees of Paragon Therapeutics.
JF, DN, and AS are employees of Sypre Therapeutics.

Conference

UEG Week Vienna 2024

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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