Chemistry:Teplizumab

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Short description: Monoclonal antibody
Teplizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD3
Clinical data
Trade namesTzield
Other namesteplizumab-mzwv, PRV-031,[1] MGA031
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6462H9938N1738O2022S46
Molar mass145801.49 g·mol−1
 ☒N☑Y (what is this?)  (verify)

Teplizumab, sold under the brand name Tzield, is a humanized anti-CD3 monoclonal antibody that is the first approved treatment indicated to delay the onset of stage 3 type 1 diabetes (T1D) in people with stage 2 T1D.[3][4][5]

The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties.[6] 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 [7][8]

Teplizumab was approved for medical use in the United States in November 2022.[9] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[10][11]

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][3]

History

Teplizumab was developed at the University of Chicago in partnership with Ortho Pharmaceuticals, and was then further developed at MacroGenics, Inc.,[12][13] including a collaboration with Eli Lilly to conduct the first Phase 3 clinical trial in early-onset type 1 diabetes.[14] After the initial Phase 3 trial conducted by Macrogenics failed to meet the primary endpoint,[15] the drug was acquired by Provention Bio, which restarted development based on subset analysis of the original trials.[16][17]

Research

Teplizumab has been used in clinical trials with the aim of protecting the remaining β-cells in newly diagnosed type 1 diabetes patients.[18] 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.[19]

Teplizumab has been evaluated for treatment of renal allograft rejection, for induction therapy in islet transplant recipients, and for psoriatic arthritis.[20]

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.[21]

References

  1. ↑ "Provention Bio Announces PRV-031 (Teplizumab) Granted PRIME Designation by the European Medicines Agency" (Press release). Provention Bio. 24 October 2019. Retrieved 18 November 2022 – via PR Newswire.
  2. ↑ 2.0 2.1 "Tzield- teplizumab-mzwv injection". 17 November 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e8a39a5f-139c-4510-9777-71cbb00138fa. 
  3. ↑ 3.0 3.1 3.2 "FDA Approves First Drug That Can Delay Onset of Type 1 Diabetes". U.S. Food and Drug Administration (Press release). 17 November 2022. Retrieved 18 November 2022. This article incorporates text from this source, which is in the public domain.
  4. ↑ 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. https://diabetesjournals.org/care/article/45/Supplement_1/S17/138925/2-Classification-and-Diagnosis-of-Diabetes. Retrieved 17 November 2022. 
  5. ↑ "Tzield (teplizumab-mzwv) approved by FDA as the first and only treatment indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients aged 8 years and older with stage 2 T1D" (Press release).
  6. ↑ "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. August 1995. doi:10.4049/jimmunol.155.3.1544. PMID 7636216. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=7636216. 
  7. ↑ "TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes". Nature Medicine 9 (9): 1202–8. September 2003. doi:10.1038/nm924. PMID 12937416. 
  8. ↑ "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. October 2005. doi:10.1172/JCI23961. PMID 16167085. 
  9. ↑ "Drug Approval Package: Tzield". 5 January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761183Orig1s000TOC.cfm. 
  10. ↑ "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". 10 January 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022.  This article incorporates text from this source, which is in the public domain.
  11. ↑ (PDF) New Drug Therapy Approvals 2022 (Report). January 2024. https://www.fda.gov/media/164429/download. Retrieved 14 January 2024.  This article incorporates text from this source, which is in the public domain.
  12. ↑ "Humanized, nonmitogenic OKT3 antibody, huOKT3 gamma(Ala-Ala): initial clinical experience". Transplantation Proceedings 30 (4): 1369–70. June 1998. doi:10.1016/S0041-1345(98)00278-4. PMID 9636555. 
  13. ↑ "Anti-CD3 antibody MacroGenics Inc". Current Opinion in Investigational Drugs 7 (4): 381–8. April 2006. PMID 16625825. 
  14. ↑ "Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial". Lancet 378 (9790): 487–97. August 2011. doi:10.1016/S0140-6736(11)60931-8. PMID 21719095. 
  15. ↑ "MacroGenics, Lilly abandon diabetes drug". Washington Business Journal. 21 October 2010. https://www.bizjournals.com/washington/quick_news/2010/10/macrogenics-lilly-abandon-diabetes-drug.html. 
  16. ↑ "MacroGenics sells rights for two autoimmune disorder candidates". The Pharma Letter. https://www.thepharmaletter.com/article/macrogenics-sells-rights-for-two-autoimmune-disorder-candidates. 
  17. ↑ "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. November 2013. doi:10.2337/db13-0345. PMID 23835333. 
  18. ↑ "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. June 2005. doi:10.2337/diabetes.54.6.1763. PMID 15919798. 
  19. ↑ "Anti-CD3 mAbs for treatment of type 1 diabetes". Diabetes/Metabolism Research and Reviews 25 (4): 302–6. May 2009. doi:10.1002/dmrr.933. PMID 19319985. 
  20. ↑ "CD3-specific antibodies: a portal to the treatment of autoimmunity". Nature Reviews. Immunology 7 (8): 622–32. August 2007. doi:10.1038/nri2134. PMID 17641665. 
  21. ↑ "An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes". New England Journal of Medicine 381 (7): 603–613. August 2019. doi:10.1056/nejmoa1902226. PMID 31180194. 

External links



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