Treatment of Type 1 Diabetes with Anti-CD3 Monoclonal Antibody

In summary, a Pilot trial of hOKT3γ 1 (Ala-Ala) has shown that drug treatment is associated with improvement in the loss of insulin production even beyond 1 year after diagnosis, with improvement in clinical parameters including Hemoglobin A1c and insulin usage, without the need for continuous drug administration. The modified form of the anti-CD3 mAb has an acceptable side effect profile at the dosages used. The mechanism of action is not clear at this time, but preliminary evidence from patients and from murine studies raise the possibility that the anti-CD3 mAb may induce a population(s) of cells that either secrete immune modulatory cytokines and/or themselves can regulate immune responses. Because of the relationship between the strength of the TCR signal delivered by the antibody and the clinical response, data from other anti-CD3 trial(s) that use either different dosing and/or other antibodies will be very informative and may help to develop the hypothesis that the immune regulatory effect of the mAb is due to the TCR signal it imparts in vivo. Other questions have emerged that may be addressed in future trials. The total duration of the clinical response is still not clear, but clearly a lasting effect is needed, since data from transplant studies indicate that autoimmunity can persist and even re-occur when patients with Type 1 diabetes are challenged with islet antigen. Therefore, repeated treatment and/or combination of anti-CD3 mAb with antigen to develop a "vaccine" needs to be considered. In patients with severely impaired β cell function at diagnosis, as was a frequent finding in younger children, even a good clinical response to the drug may not restore β cell mass may result in a significant impairment in functional responses. Therefore an approach to restore β cell mass, either through transplantation or through induction/regeneration of new islet cells, is needed. The convergence of these two approaches to treat Type 1 diabetes may offer a meaningful way to treat the disease even after clinical presentation.