Teplizumab

Teplizumab (also known as PRV-031;[1] formerly also known as MGA031 and hOKT3γ1(Ala-Ala)) is a humanized anti-CD3 monoclonal antibody that is being evaluated for treatment and prevention of type 1 diabetes mellitus (T1DM) by the biopharmaceutical company Provention Bio.[1] Teplizumab has also been evaluated for treatment of renal allograft rejection, for induction therapy in islet transplant recipients, and for psoriatic arthritis.[2]

Teplizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD3
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
Chemical and physical data
FormulaC6462H9938N1738O2022S46
Molar mass145801.49 g·mol−1
 NY (what is this?)  (verify)

The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties.[3] 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 [4][5]

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.[6] Immunomodulatory agents such as anti-CD3-antibodies may restore normal glucose control if provided in very early stages of the disease, when there are still beta cells .[7]

Teplizumab was originally developed at 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]

A subsequent phase 2 study showed that teplizumab could delay the development of diabetes in family members of type I 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.[14]

See also

References
  1. "PRV-031". Provention Bio.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  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, Kevan C.; Bundy, Brian N.; Long, S. Alice; Bluestone, Jeffrey A.; DiMeglio, Linda A.; Dufort, Matthew J.; Gitelman, Stephen E.; Gottlieb, Peter A.; Krischer, Jeffrey P.; Linsley, Peter S.; Marks, Jennifer B.; Moore, Wayne; Moran, Antoinette; Rodriguez, Henry; Russell, William E.; Schatz, Desmond; Skyler, Jay S.; Tsalikian, Eva; Wherrett, Diane K.; Ziegler, Anette-Gabriele; Greenbaum, Carla J. (2019-08-15). "An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes". New England Journal of Medicine. Massachusetts Medical Society. 381 (7): 603–613. doi:10.1056/nejmoa1902226. ISSN 0028-4793. PMC 6776880. PMID 31180194.


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