| Description | Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic ß cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin.[A241490] Targeting T cells can be achieved through antibodies against the T cell receptor (TCR) component CD3 e. However, if Fc binding is left intact, severe adverse effects related to cytokine release syndrome (CRS) are observed, and therefore Fc-nonbinding antibodies are the preferred method of choice.[A241480] Anti-CD3 therapy has traditionally been used to prevent graft-versus-host-disease in organ transplantation but more recently has been explored to prolong the onset of (T1D) in high-risk patients.[A241480, A241500] Teplizumab is a humanized IgG1 Fc-nonbinding anti-CD3 monoclonal antibody currently under development for use in T1D.[A241480, A241045, A241475] |
| Mechanism of Action | Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic ß cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms.[A241490] The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition.[A241490, A241495] Combined with other observations from animal and human studies, it is clear that the T-B axis plays a role in T1D; treatment has focussed on targeting B and T cells independently, as well as their interactions.[A241495] The T cell receptor (TCR) comprises TCR a and ß chains together with six CD3 molecules, including two CD3 e chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response.[A241480] Teplizumab, a humanized IgG1 Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3ala-ala), is specific for CD3 e and inhibits T cell activation through steric inhibition of antigen recognition.[A241480, A241045, A241475] Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D.[A241500] However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further ß cell destruction.[A241490, A241505] Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8+ central memory (CD8CM) T cells.[A241510] It is clear, however, that treatment is most effective in patients who have very recently or not yet progressed to Stage 3 and who have an active immune response.[A241490] |