Teplizumab

Last updated
Teplizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target CD3
Clinical data
Trade names Tzield
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
Formula C6462H9938N1738O2022S46
Molar mass 145801.49 g·mol−1
 X mark.svgNYes check.svgY  (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]

Contents

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]

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., [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]

Related Research Articles

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D), and is sometimes referred to as type 1.5 diabetes. It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D. Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients. Since many people develop the disease later in life, it is often misdiagnosed as type 2 diabetes.

Muromonab-CD3 is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans.

<span class="mw-page-title-main">CD3 (immunology)</span> Protein complex and T cell co-receptor

CD3 is a protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells. It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) to generate an activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Visilizumab is a humanized monoclonal antibody. It is being investigated for use as an immunosuppressive drug in patients with ulcerative colitis and Crohn's disease. Visilizumab binds to the CD3 receptor on certain activated T cells without affecting resting T cells. It is currently under clinical studies for the treatment of ulcerative colitis and Crohn's disease.

Ibalizumab, sold under the brand name Trogarzo, is a non-immunosuppressive humanised monoclonal antibody that binds CD4, the primary receptor for HIV, and inhibits HIV from entering cells. It is a post-attachment inhibitor, blocking HIV from binding to the CCR5 and CXCR4 co-receptors after HIV binds to the CD4 receptor on the surface of a CD4 cell. Post-attachment inhibitors are a subclass of HIV drugs called entry inhibitors.

Otelixizumab, also known as TRX4, is a monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and is being manufactured by Abbott Laboratories.

Blinatumomab, sold under the brand name Blincyto, is a biopharmaceutical medication used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructed monoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells. In December 2014, it was approved by the US Food and Drug Administration under the accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.

<span class="mw-page-title-main">Bi-specific T-cell engager</span>

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.

Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seagen in the US.

<span class="mw-page-title-main">Trifunctional antibody</span> Monoclonal antibody

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.

An anti-CD3 monoclonal antibody is one that binds to CD3 on the surface of T cells. They are immunosuppresive drugs.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

TOL101, is a murine-monoclonal antibody specific for the human αβ T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.

<span class="mw-page-title-main">Nivolumab</span> Cancer drug

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is used by slow injection into a vein.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

<span class="mw-page-title-main">PD-1 and PD-L1 inhibitors</span> Class of anticancer drugs

PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as an anti-cancer medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.

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. 1 2 "Tzield- teplizumab-mzwv injection". DailyMed. 17 November 2022. Retrieved 4 December 2022.
  3. 1 2 3 "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.PD-icon.svg 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. S2CID   245451959 . 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. ↑ 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. doi: 10.4049/jimmunol.155.3.1544 . PMID   7636216. S2CID   38982992.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ "Drug Approval Package: Tzield". accessdata.fda.gov. 5 January 2023. Retrieved 23 January 2023.
  10. ↑ "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". U.S. Food and Drug Administration (FDA). 10 January 2023. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  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.
  15. ↑ "MacroGenics sells rights for two autoimmune disorder candidates". The Pharma Letter.
  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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.