Muromonab-CD3

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Muromonab-CD3
Monoclonal antibody
Type Whole antibody
Source Mouse
Target CD3
Clinical data
Trade names Orthoclone OKT3
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a605011
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C6460H9946N1720O2043S56
Molar mass 146189.98 g·mol−1
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Muromonab-CD3 (brand name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant medication given to reduce acute rejection in people with organ transplants. [1] [2] It is a monoclonal antibody targeted at the CD3 receptor, [3] a membrane protein on the surface of T cells. It is the first monoclonal antibody to be approved for clinical use in humans. [2]

Contents

Medical uses

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic kidney, heart, and liver transplants. [4] Unlike the monoclonal antibodies basiliximab and daclizumab, it is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose. [5]

Contraindications

Except under special circumstances, the drug is contraindicated for patients with an allergy against mouse proteins, as well as patients with uncompensated heart failure, uncontrolled arterial hypertension or epilepsy. It should not be used during pregnancy or lactation. [2] [4]

Adverse effects

Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines like tumor necrosis factor and interferon gamma. This cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea, [6] and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema. [4] To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion. [7]

Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation. [4]

Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, [2] which may be difficult to distinguish from a CRS.

Pharmacology

T cells recognise antigens primarily via the T cell receptor (TCR). [8] :160 CD3 is one of the proteins that make up the TCR complex. [8] :166 The TCR transduces the signal for the T cell to proliferate and attack the antigen. [8] :160

Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology. [9] It binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, initially leading to an activation, [7] but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells. [10] This protects the transplant against the T cells. [2] [4] When administered for transplant induction, the drug is administered daily thereafter for up to 7 days. [7]

Newer monoclonal antibodies in development with the same mechanism of action include otelixizumab (also known as TRX4), teplizumab (also known as hOKT3γ1(Ala-Ala) ), and visilizumab. They are being investigated for the treatment of other conditions like Crohn's disease, ulcerative colitis, and type 1 diabetes. Further development of teplizumab is uncertain, due to one-year data from a recent Phase III trial being "disappointing". [11]

History

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986, [5] making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European Communities, it is the first drug to be approved under the directive 87/22/EWG, a precursor of the European Medicines Agency (EMEA) centralised approval system in the European Union. This process included an assessment by the Committee for Proprietary Medicinal Products (CPMP, now CHMP), and a subsequent approval by the national health agencies; in Germany, for example, in 1988 by the Paul Ehrlich Institute in Frankfurt. However, the manufacturer of muromonab-CD3 has voluntarily withdrawn [12] it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage. [13]

Society and culture

Orthoclone OKT3 was withdrawn from the US market in 2010. [14]

Etymology

Muromonab-CD3 was developed before the WHO nomenclature of monoclonal antibodies took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murine monoclonal antibody targeting CD3". [2]

Research

It has also been investigated for use in treating T-cell acute lymphoblastic leukemia. [15]

Related Research Articles

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Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

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

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).

<span class="mw-page-title-main">Transplant rejection</span> Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

Basiliximab, sold under the brand name Simulect, is a monoclonal antibody used to prevent rejection in kidney transplants. It is a chimeric mouse-human monoclonal antibody to the α chain (CD25) of the IL-2 receptor of T cells. It is used in combination with other medicines used to prevent organ rejection.

Daclizumab is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells.

In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

<span class="mw-page-title-main">Acute lymphoblastic leukemia</span> Blood cancer characterised by overproduction of lymphoblasts

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

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<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

Odulimomab is an investigational drug for the prevention of transplant rejection and for the treatment of various immunological diseases.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.

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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.

<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.

Thymoglobulin is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses.

References

  1. Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, et al. (February 2003). "Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection". Clinical Transplantation. 17 (1): 69–74. doi:10.1034/j.1399-0012.2003.02105.x. PMID   12588325. S2CID   8677441.{{cite journal}}: CS1 maint: overridden setting (link)
  2. 1 2 3 4 5 6 Mutschler E, Geisslinger G, Kroemer HK, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 937. ISBN   3-8047-1763-2.
  3. "muromonab-CD3". Guide to Pharmacology. IUPHAR/BPS. Retrieved 21 August 2015.
  4. 1 2 3 4 5 "Orthoclone OKT3". Professional Drug Information. Drugs.com. Archived from the original on 3 March 2016. Retrieved 3 January 2010.
  5. 1 2 Smith SL (September 1996). "Ten years of Orthoclone OKT3 (muromonab-CD3): a review". Journal of Transplant Coordination. 6 (3): 109–119, quiz 119–1. doi:10.7182/prtr.1.6.3.8145l3u185493182. PMID   9188368.
  6. Abramowicz D, Schandene L, Goldman M, Crusiaux A, Vereerstraeten P, De Pauw L, et al. (April 1989). "Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients". Transplantation. 47 (4): 606–608. doi: 10.1097/00007890-198904000-00008 . PMID   2523100. S2CID   22740065.{{cite journal}}: CS1 maint: overridden setting (link)
  7. 1 2 3 Bhorade SM, Stern E (January 2009). "Immunosuppression for lung transplantation". Proceedings of the American Thoracic Society. 6 (1): 47–53. doi:10.1513/pats.200808-096go. PMID   19131530.
  8. 1 2 3 Rich R (2013). Clinical immunology : principles and practice (4th ed.). London: Elsevier. ISBN   978-0-7234-3710-9. OCLC   823736017.
  9. Sgro C (December 1995). "Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review". Toxicology. Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology. 105 (1): 23–29. doi:10.1016/0300-483X(95)03123-W. PMID   8638282.
  10. Benekli M, Hahn T, Williams BT, Cooper M, Roy HN, Wallace P, et al. (September 2006). "Muromonab-CD3 (Orthoclone OKT3), methylprednisolone and cyclosporine for acute graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation". Bone Marrow Transplantation. 38 (5): 365–370. doi: 10.1038/sj.bmt.1705450 . PMID   16862164. S2CID   31056997.{{cite journal}}: CS1 maint: overridden setting (link)
  11. "MacroGenics and Lilly Ponder Future of Diabetes mAb after Phase III Flop". Genetic Engineering & Biotechnology News. 21 October 2010.
  12. Abdi R, Martin S, Gabardi S (2009). "Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy" (PDF). Nephrology Rounds. 7 (4). Retrieved 11 November 2012.[ permanent dead link ]
  13. Mahmud N, Klipa D, Ahsan N (2010). "Antibody immunosuppressive therapy in solid-organ transplant: Part I". mAbs. 2 (2): 148–156. doi:10.4161/mabs.2.2.11159. PMC   2840233 . PMID   20150766.
  14. "Drug Record: Muromonab-CD3". Livertox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID   31643905.
  15. Gramatzki M, Burger R, Strobel G, Trautmann U, Bartram CR, Helm G, et al. (March 1995). "Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness". Leukemia. 9 (3): 382–390. PMID   7885036.{{cite journal}}: CS1 maint: overridden setting (link)

Further reading