Teplizumab

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Teplizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD3
Names
Trade namesTzield
Other namesteplizumab-mzwv, PRV-031,[1] MGA031
Clinical data
Main usesEarly type 1 diabetes[2][3]
Side effectsHeadache, rash, low white blood cells[2]
Routes of
use		Intravenous
Legal
License data
Legal status
Chemical and physical data
FormulaC6462H9938N1738O2022S46
Molar mass145801.49 g·mol−1

Teplizumab, sold under the brand name Tzield, is a medication used in early type 1 diabetes (antibodies present to islet cells, abnormal blood sugar levels, but no symptoms) to decrease progression symptomatic disease.[2][3] It is used in those who are at least 8 years old.[2] It is given by gradual injection into a vein.[2]

Common side effects include headache, rash, and low white blood cells.[2] Other side effects may include cytokine release syndrome, infection, and allergic reactions.[2] Use in pregnancy may harm the baby.[2] It is a monoclonal antibody that blocks CD3 found on T lymphocytes.[2] It is believed that this decreases their attacking pancreatic beta cells.[2]

Teplizumab was approved for medical use in the United States in 2022.[2] As of 2022 it is not approved in Europe or the United Kingdom.[5] The two week course of treatment costs about 200,000 USD in the United States as of 2022.[6]

Medical uses

Teplizumab is indicated to delay the onset of stage 3 type 1 diabetes (T1D) people aged eight years of age and older with stage 2 T1D.[2][4]

Dosage

It is given once per day for 14 days.[2] Doses are increased over the first 5 days from 65 mcg/m[7] to 1,030 mcg/m2.[2]

Mechanism of action

The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties.[8] The mechanisms of action of teplizumab appear to involve weak agonistic activity on signaling via the T cell receptor-CD3 complex associated with the development of anergy, unresponsiveness, and/or apoptosis, particularly of unwanted activated Teff cells. In addition, regulatory cytokines are released and regulatory T cells are expanded that may lead to the reestablishment of immune tolerance [9][10]

History

Teplizumab was developed at the University of Chicago in partnership with Ortho Pharmaceuticals, and was then further developed at MacroGenics, Inc.,[11][12] including a collaboration with Eli Lilly to conduct the first Phase 3 clinical trial in early-onset type 1 diabetes.[13] After the initial Phase 3 trial conducted by Macrogenics failed to meet the primary endpoint,[14] the drug was acquired by Provention Bio, which restarted development based on subset analysis of the original trials.[15][16]

Research

Teplizumab has been used in clinical trials with the aim of protecting the remaining β-cells in newly diagnosed type 1 diabetes patients.[17] Immunomodulatory agents such as anti-CD3-antibodies may restore normal glucose control if provided in very early stages of the disease, such as stage 2 T1DM, when there are still enough beta cells to maintain euglycemia.[18]

Teplizumab has been evaluated for treatment of renal allograft rejection, for induction therapy in islet transplant recipients, and for psoriatic arthritis.[19]

A phase II study showed that teplizumab could delay the development of diabetes in family members of type 1 diabetics showing signs of progression towards diabetes by about two years after a single treatment, renewing interest in its use as a preventive rather than therapeutic treatment in high-risk patients.[20]

References

  1. ↑ "Provention Bio Announces PRV-031 (Teplizumab) Granted PRIME Designation by the European Medicines Agency" (Press release). Provention Bio. 24 October 2019. Archived from the original on 18 November 2022. Retrieved 18 November 2022 – via PR Newswire.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 "Tzield- teplizumab-mzwv injection". DailyMed. 17 November 2022. Archived from the original on 4 December 2022. Retrieved 4 December 2022.
  3. ↑ 3.0 3.1 American Diabetes Association Professional Practice Committee (1 January 2022). "2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2022". Diabetes Care. 45 (45): S17–S38. doi:10.2337/dc22-S002. PMID 34964875. S2CID 245451959. Archived from the original on 18 November 2022. Retrieved 17 November 2022.
  4. ↑ 4.0 4.1 "FDA Approves First Drug That Can Delay Onset of Type 1 Diabetes". U.S. Food and Drug Administration (Press release). 17 November 2022. Archived from the original on 16 December 2022. Retrieved 18 November 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ↑ "Teplizumab". SPS - Specialist Pharmacy Service. 29 April 2019. Archived from the original on 30 November 2021. Retrieved 16 December 2022.
  6. ↑ "FDA approves 1st drug to delay the onset of Type 1 diabetes". NBC News. Archived from the original on 15 December 2022. Retrieved 16 December 2022.
  7. ↑ 2
  8. ↑ Alegre ML, Tso JY, Sattar HA, Smith J, Desalle F, Cole M, Bluestone JA (August 1995). "An anti-murine CD3 monoclonal antibody with a low affinity for Fc gamma receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity". Journal of Immunology. 155 (3): 1544–55. PMID 7636216. Archived from the original on 2022-12-16. Retrieved 2022-12-04.
  9. ↑ Belghith M, Bluestone JA, Barriot S, Mégret J, Bach JF, Chatenoud L (September 2003). "TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes". Nature Medicine. 9 (9): 1202–8. doi:10.1038/nm924. PMID 12937416. S2CID 26301557.
  10. ↑ Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC (October 2005). "TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs". The Journal of Clinical Investigation. 115 (10): 2904–13. doi:10.1172/JCI23961. PMC 1201661. PMID 16167085.
  11. ↑ Woodle ES, Bluestone JA, Zivin RA, Jolliffe LK, Auger J, Xu D, Thistlethwaite JR (June 1998). "Humanized, nonmitogenic OKT3 antibody, huOKT3 gamma(Ala-Ala): initial clinical experience". Transplantation Proceedings. 30 (4): 1369–70. doi:10.1016/S0041-1345(98)00278-4. PMID 9636555.
  12. ↑ Brown WM (April 2006). "Anti-CD3 antibody MacroGenics Inc". Current Opinion in Investigational Drugs. 7 (4): 381–8. PMID 16625825.
  13. ↑ Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ, et al. (August 2011). "Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial". Lancet. 378 (9790): 487–97. doi:10.1016/S0140-6736(11)60931-8. PMC 3191495. PMID 21719095.
  14. ↑ "MacroGenics, Lilly abandon diabetes drug". Washington Business Journal. 21 October 2010. Archived from the original on 17 June 2022. Retrieved 4 December 2022.
  15. ↑ "MacroGenics sells rights for two autoimmune disorder candidates". The Pharma Letter. Archived from the original on 2022-12-11. Retrieved 2022-12-04.
  16. ↑ Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, et al. (November 2013). "Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders". Diabetes. 62 (11): 3766–74. doi:10.2337/db13-0345. PMC 3806618. PMID 23835333.
  17. ↑ Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA (June 2005). "A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes". Diabetes. 54 (6): 1763–9. doi:10.2337/diabetes.54.6.1763. PMC 5315015. PMID 15919798.
  18. ↑ Kaufman A, Herold KC (May 2009). "Anti-CD3 mAbs for treatment of type 1 diabetes". Diabetes/Metabolism Research and Reviews. 25 (4): 302–6. doi:10.1002/dmrr.933. PMID 19319985. S2CID 36595661.
  19. ↑ Chatenoud L, Bluestone JA (August 2007). "CD3-specific antibodies: a portal to the treatment of autoimmunity". Nature Reviews. Immunology. 7 (8): 622–32. doi:10.1038/nri2134. PMID 17641665. S2CID 11868182.
  20. ↑ Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. (August 2019). "An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes". New England Journal of Medicine. 381 (7): 603–613. doi:10.1056/nejmoa1902226. PMC 6776880. PMID 31180194.

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