| 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 |
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| Identifiers | |
| CAS Number | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C6460H9946N1720O2043S56 |
| Molar mass | 146189.98 g·mol−1 |
 N Y (what is this?) (verify) | |
Muromonab-CD3 (brand nameOrthoclone OKT3, marketed byJanssen-Cilag) is animmunosuppressant medication given to reduceacute rejection in people withorgan transplants.[1][2] It is amonoclonal antibody targeted at theCD3 receptor,[3] amembrane protein on the surface ofT cells. It is the first monoclonal antibody to beapproved for clinical use in humans.[2]
Muromonab-CD3 is approved for the therapy of acute,glucocorticoid-resistant rejection ofallogeneickidney,heart, andliver transplants.[4] Unlike the monoclonal antibodiesbasiliximab anddaclizumab, it is not approved forprophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.[5]
Except under special circumstances, the drug is contraindicated for patients with an allergy against mouse proteins, as well as patients with uncompensatedheart failure, uncontrolledarterial hypertension orepilepsy. It should not be used duringpregnancy orlactation.[2][4]
Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to releasecytokines liketumor necrosis factor andinterferon gamma. Thiscytokine release syndrome, or CRS, includes side effects like skin reactions,fatigue,fever,chills,myalgia,headaches,nausea anddiarrhea,[6] and could lead to life-threatening conditions likeapnoea,cardiac arrest, andflash pulmonary edema.[4] To minimize the risk of CRS and to offset some of the minor side effects patient experience,glucocorticoids (such asmethylprednisolone),acetaminophen, anddiphenhydramine are given before the infusion.[7]
Other adverse effects includeleucopenia, as well as an increased risk for severe infections andmalignancies typical of immunosuppressive therapies.Neurological side effects likeaseptic meningitis andencephalopathy have been observed. Possibly, they are also caused by the T cell activation.[4]
Repeated application can result intachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to ananaphylactic reaction against the mouse protein,[2] which may be difficult to distinguish from a CRS.
T cells recogniseantigens primarily via theT 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 toproliferate and attack the antigen.[8]: 160
Muromonab-CD3 is amurine (mouse) monoclonalIgG2a antibody which was created usinghybridoma 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 andapoptosis 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 includeotelixizumab (also known as TRX4),teplizumab (also known as hOKT3γ1(Ala-Ala) ),visilizumab andforalumab. They are being investigated for the treatment of other conditions likeCrohn's disease,ulcerative colitis, andtype 1 diabetes.
Muromonab-CD3 was approved by theU.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 theEuropean Communities, it is the first drug to be approved under thedirective 87/22/EWG, a precursor of theEuropean Medicines Agency (EMA) centralised approval system in the European Union. This process included an assessment by theCommittee 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 inFrankfurt. However, the manufacturer of muromonab-CD3 has voluntarily withdrawn[11] it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage.[12]
Orthoclone OKT3 was withdrawn from the US market in 2010.[13]
Muromonab-CD3 was developed before theWHOnomenclature of monoclonal antibodies took effect, and consequently its name does not follow this convention. Instead, it is a contraction from "murinemonoclonalantibody targetingCD3".[2]
It has also been investigated for use in treatingT-cell acute lymphoblastic leukemia.[14]
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