Teplizumab

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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
  • None
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6462H9938N1738O2022S46
Molar mass145801.49 g·mol−1
 ☒NcheckY (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.[2][3][4]

The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties.[5] 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 [6][7]

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]

History

Teplizumab was developed at the University of Chicago in partnership with Ortho Pharmaceuticals, and was then further developed at MacroGenics, Inc.,[8][9] including a collaboration with Eli Lilly to conduct the first Phase 3 clinical trial in early-onset type 1 diabetes.[10] After the initial Phase 3 trial conducted by Macrogenics failed to meet the primary endpoint,[11] the drug was acquired by Provention Bio, which restarted development based on subset analysis of the original trials.[12][13]

Research

Teplizumab has been used in clinical trials with the aim of protecting the remaining β-cells in newly diagnosed type 1 diabetes patients.[14] 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.[15]

Teplizumab has been evaluated for treatment of renal allograft rejection, for induction therapy in islet transplant recipients, and for psoriatic arthritis.[16]

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.[17]

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. ^ a b c "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. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ 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. Retrieved 17 November 2022.
  4. ^ "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).
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ Brown WM (April 2006). "Anti-CD3 antibody MacroGenics Inc". Current Opinion in Investigational Drugs. 7 (4): 381–8. PMID 16625825.
  10. ^ 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.
  11. ^ "MacroGenics, Lilly abandon diabetes drug". Washington Business Journal. 21 October 2010.
  12. ^ "MacroGenics sells rights for two autoimmune disorder candidates". The Pharma Letter.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.

External links

  • "Teplizumab". Drug Information Portal. U.S. National Library of Medicine.