The Compelling Case for Anti-CD3 in Type 1 Diabetes

Abstract

Immunotherapy trials in recent-onset type 1 diabetes (T1D) have had mixed results, with some therapies—anti-CD3 monoclonal antibodies targeting T cells (1–7), anti-CD20 monoclonal antibodies targeting B cells (8), and costimulation blockade (9)—showing promise, with at least transient improvement in β-cell function compared with randomized control groups. In the current issue, Herold et al. (10) from the Immune Tolerance Network (ITN) report the results of the Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes (AbATE) trial. This is the fifth trial with anti-CD3, the fourth with the monoclonal antibody teplizumab, demonstrating preservation of β-cell function. The article describes a group of “responders” to treatment, identified by the label “responders” for those who maintained C-peptide better than the randomized but untreated comparison group at 24 months. Responders, defined in this way, constituted 45% of the subjects treated with anti-CD3. When examining β-cell function over time in the trial, it was evident that the responders had maintained β-cell function for 2 years, whereas the nonresponders had lost β-cell function at a rate similar to the control group. This is a crucial observation, because in an analysis that includes both responders and nonresponders, the profound retention of C-peptide in nearly half of subjects can be missed. The fundamental question is why some subjects failed to respond. It could be that the immunotherapy was …