CD3 Monoclonal Antibodies in Type 1 Diabetes: A First Step Towards Operational Immune Tolerance in the Clinic

Lucienne Chatenoud and Herman Waldman

INSERM U1013, Necker Hospital, Paris, France
University of Oxford, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK

Abstract

Type 1 diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting β-cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive CD4+ and CD8+ T lymphocytes which infiltrate pancreatic islets (insulitis). Current treatment is substitutive i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycemia) and insufficient over the long term to prevent severe degenerative complications. Finding a cure for type 1 diabetes represents a real medical health challenge, the more so since the incidence of the disease is steadily increasing in industrialized countries. Importantly, since type 1 diabetes mainly affects children and young adults, any candidate immune therapy must be safe and avoid a sustained depression of immune responses with all its attendant problems of recurrent infection and drug toxicity. In this context, inducing or, in the case of established Type 1 diabetes, restoring immune tolerance to target autoantigens would be the ideal approach. We refer to immune tolerance here as the selective damping of the damaging autoimmune response following a short treatment, while keeping intact the capacity of the host to respond normally to exogenous antigens. The therapeutic approach we discuss herein stemmed from an interesting avenue based on empirical yet successful attempts to induce tolerance both to soluble antigens as well as tissue antigens (i.e. alloantigens and autoantigens) with biological agents that selectively interfere with lymphocyte activation, namely polyclonal and monoclonal anti-T cell antibodies. The challenged dogma was that in an adult primed immune system it would not be possible to restore self-tolerance therapeutically without use of exogenous autoantigen(s) administration. The reality has been that in diabetes endogenous host autoantigen can fulfill that role because, even at the time of established hyperglycemia, a significant amount of functioning β-cells remain. Based on experimental results we obtained back in the 1990s showing that a short-term CD3 antibody treatment (five consecutive days) in recently diagnosed diabetic Non Obese Diabetic (NOD) mice induced permanent remission of the disease by restoring self-tolerance, therapeutic trials were launched both in Europe and the USA. Phase I, II and III trials were conducted using two distinct humanised Fc-mutated antibodies to human CD3 namely, ChAglyCD3 (Otelixizumab) and OKT3γ1 Ala-Ala (Teplizumab). Overall, where dosing was adequate, the results demonstrate that CD3 antibodies very efficiently preserve b-cell function, maintaining significantly high levels of endogenous insulin secretion in treated patients for up to approximately 24 months after treatment. These data provide the first proof of concept that it is possible to obtain a long-term therapeutic effect in Type I diabetes, following a short course administration of a therapeutic agent. Our aim is to review these data and to discuss them in the context of the pitfalls linked to pharmaceutical development especially when, as in autoimmune diabetes, one deals with a substantial cohort of pediatric patients.