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A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing
Ronald G Gill1, Philippe P Pagni2, Tinalyn Kupfer3
1Departments of Surgery and Immunology, University of Colorado Denver, Aurora, CO ronald.gill@ucdenver.edu.
Abstract:
There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet β-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti-IL-1β monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use.
Insights
Combining anti-CD3 therapy with IL-1 blockade did not improve outcomes for new-onset type 1 diabetes (T1D) in preclinical models. This highlights the need for robust, multicenter studies to validate therapies before clinical trials.
Area of Science:
- Immunology
- Endocrinology
- Diabetes Research
Background:
- Type 1 diabetes (T1D) requires novel therapeutic strategies to prevent disease or preserve beta-cell function.
- Reproducibility and clinical translation of preclinical findings in animal models are significant concerns for T1D drug development.
Purpose of the Study:
- To assess the efficacy and reproducibility of combined immunotherapy (anti-CD3 and IL-1 blockade) in reversing new-onset T1D using the NOD mouse model.
- To evaluate the added benefit of IL-1 blockade to anti-CD3 treatment in a standardized, multicenter preclinical setting.
Main Methods:
- A multicenter consortium utilized standardized protocols and reagents for coordinated studies.
- NOD mice with new-onset T1D were treated with anti-CD3 monoclonal antibody alone or in combination with IL-1 blockade (anti-IL-1β or IL-1trap).
- Efficacy was assessed by the ability to reverse new-onset disease.
Main Results:
- Anti-CD3 treatment alone showed no significant benefit in reversing new-onset T1D in NOD mice.
- The addition of IL-1 blockade (using anti-IL-1β or IL-1trap) did not provide additional therapeutic benefit compared to anti-CD3 treatment alone.
- The study demonstrated intergroup reproducibility in assessing therapeutic efficacy.
Conclusions:
- Combined anti-CD3 and IL-1 blockade is not effective in reversing new-onset T1D in the NOD mouse model.
- Large-scale, multicenter preclinical studies are crucial for validating and prioritizing potential T1D therapeutics for clinical translation.
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