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Muromonab-CD3 ?
Monoclonal antibody
Source mouse
Target CD3ε
Identifiers
CAS number 140608-64-6
ATC code L04AA02
PubChem  ?
Chemical data
Formula C 6460H9946N1720O2043S56  
Mol. mass 146.091 kDa
Pharmacokinetic data
Bioavailability N/A
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Prescription only
Routes intravenous

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, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans.[2]

Contents

History

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986,[3] making it the first monoclonal antibody to be used as a drug for humans worldwide. 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.

Indications

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid resistant rejection of allogeneic renal, 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.[3]

It has also been investigated for use in treating T-cell acute lymphoblastic leukemia.[5]

Pharmacodynamics and chemistry

T cells recognise antigens primarily via the T cell receptor. This receptor needs various co-receptors to function, one of which is CD3. The T cell receptor-CD3 complex transduces the signal for the T cell to proliferate and attack the antigen.

Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was identified using hybridoma technology. 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, but subsequently inducing blockage and apoptosis of the T cells. This protects the transplant against the T cells.[2][4] After application of muromonab-CD3, normal T cell function is said to be restored within a week.

Newer monoclonal antibodies with the same mechanism of action include otelixizumab, teplizumab and visilizumab. They are being investigated for the treatment of other conditions like Crohn's disease, colitis ulcerosa and type 1 diabetes.

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 (cytokine release syndrome, CRS). This results in a number of side effects, including skin reactions, fatigue, fever, myalgia, nausea and diarrhoea,[6] and could lead to life-threatening conditions like apnoea and cardiac arrest.[4] To minimize the risk of CRS, glucocorticoids are given before the infusion.

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 antigens 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][4]

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, 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. PMID 12588325. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0902-0063&date=2003&volume=17&issue=1&spage=69.  
  2. ^ a b c d e f Mutschler, Ernst; Gerd Geisslinger, Heyo K. Kroemer, Monika Schäfer-Korting (2001) (in German). Arzneimittelwirkungen (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 937. ISBN 3-8047-1763-2.  
  3. ^ a b Smith, SL (1996). "Ten years of Orthoclone OKT3 (muromonab-CD3): a review". Journal of transplant coordination : official publication of the North American Transplant Coordinators Organization (NATCO) 6 (3): 109–19; quiz 120–1. PMID 9188368.   edit
  4. ^ a b c d e "Orthoclone OKT3". Professional Drug Information. Drugs.com. http://www.drugs.com/mmx/orthoclone-okt3.html. Retrieved 3 January 2010.  
  5. ^ Gramatzki M, Burger R, Strobel G, et al. (March 1995). "Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness". Leukemia 9 (3): 382–90. PMID 7885036.  
  6. ^ Abramowicz; Schandene, L; Goldman, M; Crusiaux, A; Vereerstraeten, P; De Pauw, L; Wybran, J; Kinnaert, P et al. (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): 606–8. PMID 2523100.   edit







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