Muromonab-CD3

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic kidney, heart, and liver transplants.{{cite web|url=https://www.drugs.com/mmx/orthoclone-okt3.html|title=Orthoclone OKT3|work=Professional Drug Information|publisher=Drugs.com|access-date=3 January 2010|archive-date=3 March 2016|archive-url=https://web.archive.org/web/20160303193952/http://www.drugs.com/mmx/orthoclone-okt3.html|url-status=dead}} 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.

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.

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,{{cite journal | vauthors = Abramowicz D, Schandene L, Goldman M, Crusiaux A, Vereerstraeten P, De Pauw L, Wybran J, Kinnaert P, Dupont E, Toussaint C | title = Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients | journal = Transplantation | volume = 47 | issue = 4 | pages = 606–608 | date = April 1989 | pmid = 2523100 | doi = 10.1097/00007890-198904000-00008 | s2cid = 22740065 | doi-access = free }} and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema. 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.

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.

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, which may be difficult to distinguish from a CRS.

T cells recognise antigens primarily via the T cell receptor (TCR).{{Cite book | vauthors = Rich R |url=https://www.sciencedirect.com/book/9780723436911/clinical-immunology |title=Clinical immunology : principles and practice |publisher=Elsevier |year=2013 |isbn=978-0-7234-3710-9 |edition=4th |location=London |oclc=823736017}}{{rp|160}} CD3 is one of the proteins that make up the TCR complex.{{rp|166}} The TCR transduces the signal for the T cell to proliferate and attack the antigen.{{rp|160}}

Muromonab-CD3 is a murine (mouse) monoclonal IgG2a antibody which was created using hybridoma technology.{{cite journal | vauthors = Sgro C | title = Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review | journal = Toxicology | volume = 105 | issue = 1 | pages = 23–29 | date = December 1995 | pmid = 8638282 | doi = 10.1016/0300-483X(95)03123-W | series = Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology | bibcode = 1995Toxgy.105...23S }} 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,{{cite journal | vauthors = Bhorade SM, Stern E | title = Immunosuppression for lung transplantation | journal = Proceedings of the American Thoracic Society | volume = 6 | issue = 1 | pages = 47–53 | date = January 2009 | pmid = 19131530 | doi = 10.1513/pats.200808-096go }} but subsequently inducing the clearance of TCR complex from cell surface and apoptosis of the T cells.{{cite journal | vauthors = Benekli M, Hahn T, Williams BT, Cooper M, Roy HN, Wallace P, Stewart C, Bambach B, McCarthy PL | title = Muromonab-CD3 (Orthoclone OKT3), methylprednisolone and cyclosporine for acute graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation | journal = Bone Marrow Transplantation | volume = 38 | issue = 5 | pages = 365–370 | date = September 2006 | pmid = 16862164 | doi = 10.1038/sj.bmt.1705450 | s2cid = 31056997 | doi-access = free }} This protects the transplant against the T cells. When administered for transplant induction, the drug is administered daily thereafter for up to 7 days.

Newer monoclonal antibodies in development with the same mechanism of action include otelixizumab (also known as TRX4), teplizumab (also known as hOKT3γ1(Ala-Ala) ), visilizumab and foralumab. They are being investigated for the treatment of other conditions like Crohn's disease, ulcerative colitis, and type 1 diabetes.

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986,{{cite journal | vauthors = Smith SL | title = Ten years of Orthoclone OKT3 (muromonab-CD3): a review | journal = Journal of Transplant Coordination | volume = 6 | issue = 3 | pages = 109–119; quiz 119–1 | date = September 1996 | pmid = 9188368 | doi = 10.7182/prtr.1.6.3.8145l3u185493182 | doi-broken-date = 9 February 2025 }} 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 (EMA) 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{{cite journal| vauthors = Abdi R, Martin S, Gabardi S |title=Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy|journal=Nephrology Rounds|year=2009|volume=7|issue=4|url=http://www.nephrologyrounds.org/crus/304-072.pdf|access-date=11 November 2012}}{{Dead link|date=October 2019 |bot=InternetArchiveBot |fix-attempted=yes }} it from the United States market in 2010 due to numerous side-effects, better-tolerated alternatives and declining usage.{{cite journal | vauthors = Mahmud N, Klipa D, Ahsan N | title = Antibody immunosuppressive therapy in solid-organ transplant: Part I | journal = mAbs | volume = 2 | issue = 2 | pages = 148–156 | year = 2010 | pmid = 20150766 | pmc = 2840233 | doi = 10.4161/mabs.2.2.11159 }}

Orthoclone OKT3 was withdrawn from the US market in 2010.{{cite book | title = Livertox: Clinical and Research Information on Drug-Induced Liver Injury | chapter = Drug Record: Muromonab-CD3 | publisher = National Institute of Diabetes and Digestive and Kidney Diseases | year = 2012 | pmid = 31643905 | url = https://www.ncbi.nlm.nih.gov/books/NBK547852/ | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK548590/ }}

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".

It has also been investigated for use in treating T-cell acute lymphoblastic leukemia.{{cite journal | vauthors = Gramatzki M, Burger R, Strobel G, Trautmann U, Bartram CR, Helm G, Horneff G, Alsalameh S, Jonker M, Gebhart E | title = Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness | journal = Leukemia | volume = 9 | issue = 3 | pages = 382–390 | date = March 1995 | pmid = 7885036 }}

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• {{cite journal | vauthors = Todd PA, Brogden RN | title = Muromonab CD3. A review of its pharmacology and therapeutic potential | journal = Drugs | volume = 37 | issue = 6 | pages = 871–99 | date = June 1989 | pmid = 2503348 | doi = 10.2165/00003495-198937060-00004 | s2cid = 30478429 }}

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Category:Immunology

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