Teplizumab (also known as MGA031 and hOKT3γ1(Ala-Ala)) is a humanized anti-CD3 monoclonal antibody (mAb) developed at Columbia University, and was then further developed at MacroGenics, Inc. The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties. This antibody has been used in clinical trials with the aim of protecting the remaining β-cells in newly diagnosed type 1 diabetes mellitus patients, but "these agents [i. e. anti-CD3-antibodies] alone do not restore normal glucose control". Eli Lilly licensed the drug back in 2007 from MacroGenics. It is in Phase-3 clinical trials for Type 1 Diabetes (T1D). One-year data from one phase III trial was disappointing.
Type 1 diabetes (T1D) is a T cell mediated autoimmune disease with selective destruction of β-cells by auto reactive CD4+ and CD8+ T lymphocytes. Other immune cells apart from CD4+ and CD8+ T cells may also play a role in development of T1D. Teplizumab is a humanized Fc-mutated anti-CD3 mAb. Teplizumab contains the binding region of the transplant rejection preventative agent OKT3, but amino acids 234 and 235 have been changed to alanine residues. As a result, this diminishes the binding to complement and Fc receptors, reducing toxicities that may be associated with murine mAb. In a mechanism that is not well understood, teplizumab reduces autoimmune destruction of pancreatic β-cells by increasing Foxp 3+, CD8+, CD25+ T-cells while maintaining CD4+ T-cells, thus leading to a reduction in the ratio of CD4+ to CD8+ cells. This shift may be the result of transforming growth factor-β and tumor necrosis factor-α mediated apoptosis of activated T-cells, immunomodulation of the T-cell receptor complex, altered trafficking, and resetting of the T-cell tolerogenic mechanisms. Furthermore, T-cells that produce interleukin-2 or interferon-γ become unresponsive, whereas T-cells that produce interleukin-4 or interleukin-10 may be stimulated. Augmentations of interleukin-2 may reverse the course of T1D and increased interferon-γ concentrations may be associated with worsened disease; therefore, reduced responsiveness of T-cells producing these mediators may improve T1D.
Fig.1 Mechanism of action of Teplizumab
Table 1. Clinical Projects of teplizumab*
|NCT ID||Status||Conditions||Lead Sponsor||Update Time|
|NCT01030861||Active, not recruiting||Autoantibody Positive, Non-diabetic Relatives at Risk for Type 1 Diabetes; High Risk, Impaired Glucose Tolerance||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)||December 14, 2009|
* The table was excerpted from the following website
For research use only. Not intended for any clinical use.