Investigational therapies targeting CD3 for prevention and treatment of type 1 diabetes

ABSTRACT

Introduction

Immunotherapies for type 1 diabetes mellitus (T1D) have been the focus of intense research over the past few decades. Nevertheless, the results of clinical trials have not matched expectations. However, thanks to the recent and promising results on T1D prevention, among all the different immune-intervention strategies, clinical evidence on anti-CD3 monoclonal antibodies (mAb) deserves particular attention and in-depth evaluation.

Areas covered

In this narrative review, we introduce the role of T-cells and their co-receptor CD3 in the pathogenesis of T1D and examine the potential of anti-CD3 mAbs as a treatment for preventing or curing T1D. We discuss pre-clinical studies and phase II/III clinical trials testing the anti-CD3 mAb teplizumab in subjects at T1D high risk, and testing teplizumab and otelixizumab in T1D recent onset patients. In this work, we discuss the current evidence gathered on anti-CD3 therapy to offer insights on the treatment strengths, limitations, and unmet needs.

Expert opinion

Recent phase II clinical trials with teplizumab in individuals at high-risk of developing T1D seem encouraging, but benefits associated with the use of anti-CD3 mAb in recent-onset T1D are still controversial. A better patient selection, based on immunological profiles and specific biomarkers, is crucial to improve clinical outcomes in T1D immunotherapies.

KEYWORDS:

• Anti-CD3
• high-risk type 1 diabetes
• monoclonal antibodies
• otelixizumab
• prevention
• teplizumab
• type 1 diabetes

Article highlights

• The signaling hexamer CD3 is a T-cell co-receptor indispensable for the activity of the T-cell receptor. Anti-CD3 monoclonal antibodies bind to CD3 inducing tolerance of Tregs in autoimmune disease.

• Several investigations conducted to detect efficacy and safety of anti-CD3 in murine models of autoimmune diabetes demonstrated that intravenous anti-CD3 mAb therapy in animal models is more efficient to reversing than preventing autoimmune diabetes.

• Otelixizumab and teplizumab are the new-generation anti-CD3 mAb used in phase II and III clinical trials for the prevention and cure of T1D.

• In a phase II prevention trial, treating people at high-risk of T1D with teplizumab delayed the onset of the disease and was associated with lower incidence rate of T1D compared to placebo.

• Even though people with recent-onset T1D treated with anti-CD3 mAb had improved their beta-cell function in the short term (as demonstrated for teplizumab by Herold et al. in 2002 and for otelixizumab by Keymeulen et al. in 2005), phase III clinical trials did not show clinically meaning benefits in the long-term associated with anti-CD3 therapy.

• In future, combination therapies with anti-CD3 mAb and immunosuppressive agents or incretin mimetics (i.e. GLP1-RA) should be investigated to improve safety and efficacy.

This box summarizes key points contained in the article.

Declaration of interest

Raffaella Buzzetti disclosures: Novo Nordisk A/S, Eli Lilly S.p.A., Sanofi S.p.A., Abbott S.r.l., and Astrazeneca.Ernesto Maddaloni disclosure: Abbott S.r.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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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