Teplizumab 2mg/2ml solution for infusion vials

Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β 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 T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions.[A241495]

The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response.[A241480] Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 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 β 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 not yet progressed to Stage 3 and who have an active immune response.[A241490]