Muromonab-CD3

Muromonab-CD3 (trade name Orthoclone OKT3, marketed by Janssen-Cilag) is an immunosuppressant drug given to reduce acute rejection in patients 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 was the first monoclonal antibody to be approved for clinical use in humans.[2]

Muromonab-CD3
Monoclonal antibody
TypeWhole antibody
SourceMouse
TargetCD3ε
Clinical data
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa605011
Routes of
administration		intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityN/A
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC6460H9946N1720O2043S56
Molar mass146189.98 g·mol−1
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History

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986,[4] making it the first monoclonal antibody to be approved anywhere as a drug for humans. In the European Communities, it was 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 However, the manufacturer of muromonab-CD3 has voluntarily withdrawn[5] it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage.[6]

Indications

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants.[7] 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.[4]

It has also been investigated for use in treating T-cell acute lymphoblastic leukemia.[8]

Pharmacodynamics and chemistry

T cells recognise antigens primarily via the T cell receptor (TCR).[9]: 160  CD3 is one of the proteins that make up the TCR complex.[9]: 166  The TCR transduces the signal for the T cell to proliferate and attack the antigen.[9]: 160 

Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology.[10] 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,[11] but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells.[12] This protects the transplant against the T cells.[2][7] When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.[11]

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 (with a tentative trade name of Nuvion). 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".[13]

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,[14] and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.[7] 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.[11]

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.[7]

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.

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][7]

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]

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.
  2. 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. 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.
  5. Abdi R, Martin S, Gabardi S (2009). "Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy" (PDF). Nephrology Rounds. 7 (4). Retrieved 11 November 2012.
  6. 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.
  7. "Orthoclone OKT3". Professional Drug Information. Drugs.com. Retrieved 3 January 2010.
  8. 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.
  9. Rich R (2013). Clinical immunology : principles and practice (4th ed.). London: Elsevier. ISBN 978-0-7234-3710-9. OCLC 823736017.
  10. 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.
  11. 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.
  12. 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.
  13. "MacroGenics and Lilly Ponder Future of Diabetes mAb after Phase III Flop". Genetic Engineering & Biotechnology News. 21 October 2010.
  14. 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.
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