Monoclonal antibody targeting CD3 receptor preserves insulin secretion in early type 1 diabetes

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• Teplizumab (TZIELD), an anti-CD3 monoclonal antibody, was found to preserve the function of pancreatic β cells in newly diagnosed type 1 diabetes mellitus. Earlier, the drug has received FDA approval in the prevention of type 1 diabetes in high-risk individuals, in whom it extended the time to diagnosis by almost 3 years.
• Type 1 diabetes is a chronic autoimmune disease caused by the progressive destruction of insulin-secreting β cells in pancreas, which makes patient completely dependent on exogenous insulin. Prevention with teplizumab could delay this process and prevent long-term complications.
• Teplizumab was derived from OKT3, the first approved therapeutic monoclonal antibody, which contained fully murine sequences and showed high reactogenicity upon administration to humans. Grafting of the complementarity determining regions onto human IgG1 backbone and modification of the Fc portion, reduced T-cell activating properties and paved the way for clinical use in autoimmune disorders.

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Modern medicine is now capable of preventing and treating the diseases that were once thought unconquerable. Biologic drugs play a large, if not the largest, role in this amazing scientific advancement. Yet another “magic bullet” has recently stepped into the clinics, this time aiming at type 1 diabetes mellitus – a highly prevalent autoimmune disease that results in lifetime insulin dependence.

This magic bullet is teplizumab (TZIELD), a chimeric monoclonal antibody targeting the CD3 receptor abundantly expressed on the surface of T-cells. In the latest study performed in newly diagnosed diabetics, teplizumab was shown to protect the pancreatic β-cells from destruction, allowing them to maintain insulin secretion for a much longer period than without treatment. The primary endpoint was change from baseline in stimulated C-peptide levels. C-peptide is a by-product of insulin synthesis, released from pancreas into the blood at the same time and amounts as the produced hormone. Because C-peptide has a longer half-life than insulin, it serves as the most reliable marker of β-cells function.

The conducted trial was of course double-blind, randomized and placebo-controlled with 217 children and adolescents receiving two 12-day course of teplizumab and 111 receiving an inert solution. After 78 weeks, 94.9% of patients in the active group had a clinically meaningful peak level of C-peptide, while the same percentage in the control group was 79.2%. Unfortunately, none of the secondary endpoints were met, possibly due to the short observation time, enrolment of slowly progressing patients or insufficient sample size. These endpoints were more clinically-oriented and included glucose and glycated hemoglobin levels.

Prior to the current study, teplizumab was tested in Phase 2 trial that enrolled patients at high risk of developing type 1 diabetes, who had no symptoms at the time of trial initiation. The results were truly spectacular – the progression to clinically apparent disease was over twice longer in subjects randomized to teplizumab than placebo. Diagnosis of type 1 diabetes was made in 50% of patients receiving the active drug after a median of 59.6 months. In the placebo group, 78% developed diabetes and the median time to diagnosis was almost three years shorter (27.1 months). In light of these results, the researchers remain confident that in spite of no significant differences in secondary endpoints in the more recent study, teplizumab can slow the progression of already diagnosed type 1 diabetes.

Teplizumab has a long and interesting history of development. It was derived from OKT3 (Ortho Kung CD3), a murine anti-CD3 antibody with immunosuppressive properties, generated in the late 70. OKT-3, approved by the FDA in 1985 for the prevention of acute transplant rejection, was the first therapeutic monoclonal antibody in history. However, its wider use was stalled by frequent infusion reactions including potentially fatal cytokine release syndrome, as well as high level of immunogenicity. Adverse reactions induced by OKT-3 were attributed to excessive T-cell activation and allergic reaction to mouse Fc part. To counter these unwanted effects, researchers modified the constant regions to resemble human sequences by merging the CD3-binding regions (complementarity determining regions) from mouse antibody with the human IgG backbone. Further modifications resulted in obtaining teplizumab, a chimeric mAb with potential use in autoimmune disorders such as type 1 diabetes.

The development of teplizumab took around 40 years, but it finally paid off. Now people with early type 1 diabetes, or at high risk of developing diabetes, have a chance to delay the onset of this debilitating condition for many years. Additional research will be needed to establish if complete abrogation of the disease is possible. So far, 10 of 13 subjects followed for more than 5 years in the Phase 2 trial were not diagnosed with diabetes and of these, eight received teplizumab.

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References

1. Ramos, Eleanor L., et al. “Teplizumab and β-cell function in newly diagnosed type 1 diabetes.” New England Journal of Medicine 389.23 (2023): 2151-2161.
2. Herold, Kevan C., et al. “An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes.” New England Journal of Medicine 381.7 (2019): 603-613C) 8-11 January 2024” (January 12, 2024).
3. Sims, Emily K., et al. “Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.” Science translational medicine 13.583 (2021): eabc8980.
4. Keam, Susan J. “Teplizumab: first approval.” Drugs 83.5 (2023): 439-445.
5. Gaglia, Jason, and Stephan Kissler. “Anti-CD3 antibody for the prevention of type 1 diabetes: a story of perseverance.” Biochemistry 58.40 (2019): 4107-4111.