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Teplizumab

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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
 ☒NcheckY (what is this?)  (verify)

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]

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. ^ a b "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.
  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.
  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.
  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. 381 (7). Massachusetts Medical Society: 603–613. doi:10.1056/nejmoa1902226. ISSN 0028-4793. PMC 6776880. PMID 31180194. {{cite journal}}: Invalid |ref=harv (help)
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