Anti-CD3 Monoclonal Antibody for Treating New-onset Type 1 Diabetes Mellitus

Immune-mediated destruction of insulin-producing beta islet cells in the pancreas causes type 1 diabetes mellitus (T1DM). Anti-CD3 monoclonal antibodies (CD3-MAbs) are a new class of drugs intended to help preserve beta-cell function if used early in the onset of T1DM. Preserving beta-cell function may delay the need for exogenous insulin treatment and thereby reduce the risks of hypoglycemic (low blood sugar) events associated with insulin treatment.

CD3-MAbs bind to and inactivate special immune-system components called cytotoxic T-lymphocytes (CTLs), the cells responsible for destroying pancreatic beta cells in T1DM. In addition, CD3-MAbs may activate T-regulatory cells, which help control CTL action. Activation of T-regulatory cells has been shown to cause sustainable immunomodulation for at least one to two years in clinical trials. Researchers suggest that longer studies will be needed to determine whether the effects will last longer than two years.

Two companies were developing CD3-MAb therapies, but one temporarily stopped its phase III development program in late 2010.1  Tolerx, Inc. (Cambridge, MA, USA) is conducting phase II clinical trials on otelixizumab (TRX4, formerly ChAglyCD3). Otelixizumab has shown the ability to preserve beta-cell function and reduce the amount of exogenous insulin required by patients with T1DM for longer than a year.2 MacroGenics, Inc. (Rockville, MD, USA) conducted phase III trials on teplizumab (MGA031, formerly hOKT3g1 Ala-Ala) but halted trials in October 2010 after they did not meet its endpoints to determine how to proceed.3

CD3-MAbs are administered through once-daily intravenous infusion for 14 days in an inpatient or outpatient setting. Treatment follow-up requires careful monitoring of blood glucose levels and residual beta-cell function.4 CD3-MAb manufacturers hope that a single course of treatment will delay the onset of T1DM for patients with newly diagnosed conditions for one to two years. In addition, they propose that CD3-MAbs may also help...