Select animal models of colitis and their value in predicting clinical efficacy of biological therapies in ulcerative colitis

ABSTRACT

Introduction: Advancing new therapies from discovery to development usually requires proof-of-concept in animal models to justify the costs of continuing the program. While animal models are useful for understanding the mechanism of action (MOA) of a target, limitations of many published colitis models restrict their value to predict clinical efficacy.

Areas covered: The authors focused their literature search on published studies of chronic animal models used to evaluate the pre-clinical efficacy of therapeutic molecules subsequently evaluated in clinical trials for UC. The UC therapies evaluated were anti-α4β7, anti-IL13, anti-IL12p40, and anti-IL23p19. The models of chronic colitis evaluating these molecules were: mdra1a-/-, chronic dextran sulfate sodium (DSS), chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the T cell transfer model.

Expert opinion: While some models provide insight into target MOA in UC, none is consistently superior in predicting efficacy. Evaluation of multiple models, with varying mechanisms of colitis induction, is needed to understand potential drug efficacy. Additional models of greater complexity, reflecting the disease chronicity/heterogeneity seen in humans, are needed. Although helpful in prioritizing targets, animal models alone will likely not improve outcomes of UC clinical trials. Transformational changes to clinical efficacy will likely only occur when precision medicine approaches are employed.

KEYWORDS:

• α4β7
• chronic DSS colitis
• chronic TNBS colitis
• il12/IL23
• il13
• mdr1a-/-
• monoclonal antibodies
• murine models of colitis
• t cell transfer colitis
• ulcerative colitis

List of abbreviations

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Article highlights

• No single model of colitis can predict clinical efficacy in UC; however, some, like the mdr1a-/- and the chronic TNBS models have proven insightful in dissecting mechanism-of-action of potential therapeutic targets such as IL13, IL12/IL23, and IL-17.

• Murine models of colitis that are likely to be most relevant to UC are chronic models. Extending the duration of the traditional models may provide insight into the mechanism of action of targets in the chronic and resolution phases of disease.

• Multiple models with differing mechanisms of disease onset should be used to evaluate the efficacy of drug targets in vivo.

• Assessment of therapeutic efficacy in disease models requires a thorough analysis of both observational disease activity endpoints (i.e. body weight loss, blood in stool and stool consistency) and histological examination of tissues, across different locations in the intestine.

• Disease models of greater complexity are needed to adequately reflect the complexity associated with human disease.

• Even for the most effective therapeutic approved for the treatment of UC, a large proportion of patients are non-responsive. Developing more complex models may help prioritize targets that are most likely to have a clinical impact, but precision medicine approaches delivering the right drug to the right patient, will likely be key to the transformational changes we seek in the treatment of UC.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Dr S Targan of Cedars-Sinai Medical Center for their review of the content and L Karp of Cedars-Sinai Medical Center for their editorial assistance.

Declaration of interest

J Bilsborough is a consultant and shareholder for Prometheus Biosciences. Prometheus Biosciences holds a license to research results from Dr. Bilsborough’s studies supported by the MIRIAD Biobank. Cedars-Sinai has a financial interest in Prometheus Biosciences, which holds a license related to intellectual property developed from materials or data supplied by MIRIAD Biobank. Cedars-Sinai has an equity interest in and receives royalty and license payments from Prometheus Biosciences. M Fiorino and B Henkle are consultants and shareholders for Prometheus Biosciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.