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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/06 16:14:49」(JST)

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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]

History

Muromonab-CD3 (OKT3) was approved by the U.S. Food and Drug Administration (FDA) in 1985,^[3] 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 However, the manufacturer of Muromonab-CD3 has voluntarily withdrawn^[4] it from the United States market due to decreased utilization; current OKT3 supplies are expected to be exhausted by mid-2010.

Indications

Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants.^[5] 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.^[6]

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 created 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]^[5] After application of muromonab-CD3, normal T cell function is said to be restored within a week. 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 (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".^[8]

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,^[9] and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.^[5] 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.^[10]

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.^[5]

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]^[5]

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

^ 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. doi:10.1034/j.1399-0012.2003.02105.x. PMID 12588325.
^ ^a ^b ^c ^d ^e ^f Mutschler, Ernst; Gerd Geisslinger; Heyo K. Kroemer; Monika Schäfer-Korting (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 937. ISBN 3-8047-1763-2.
^ ^a ^b Smith, S. L. (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): 109–119; quiz 119–1. PMID 9188368. edit
^ Abdi, Reza; Spencer Martin; Steven Gabardi (2009). "Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy" (PDF). Nephrology Rounds 7 (4). Retrieved 11 November 2012.
^ ^a ^b ^c ^d ^e "Orthoclone OKT3". Professional Drug Information. Drugs.com. Retrieved 3 January 2010.
^ 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.
^ Bhorade, S. M., Stern, E. (2009). Immunosuppression for Lung Transplantation. Proc Am Thorac Soc 6: 47-53
^ "MacroGenics and Lilly Ponder Future of Diabetes mAb after Phase III Flop". 21 Oct 2010.
^ Abramowicz, D.; Schandene, L.; Goldman, M.; Crusiaux, A.; Vereerstraeten, P.; De Pauw, L.; Wybran, J.; Kinnaert, P.; Dupont, E.; Toussaint, C. (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. edit
^ Bhorade, S. M., Stern, E. (2009). Immunosuppression for Lung Transplantation. Proc Am Thorac Soc 6: 47-53

UpToDate Contents

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1. 成人の腎移植における免疫抑制誘導療法 induction immunosuppressive therapy in renal transplantation in adults
2. 移植片対宿主病の予防および治療に使用される免疫抑制剤の概要 overview of immunosuppressive agents used for prevention and treatment of graft versus host disease
3. 成人肝移植における免疫抑制の概要 overview of immunosuppression in adult liver transplantation
4. 臨床的腎移植における研究中の免疫抑制剤およびそのアプローチ investigational immunosuppressive drugs and approaches in clinical kidney transplantation
5. 急性心臓同種移植拒絶反応：治療 acute cardiac allograft rejection treatment

English Journal

OKT3 antibody pre-treatment prevents xenogeneic GVHD and allows for reliable initiation of xenografts from unfractionated human hematopoietic tissues.

Wunderlich M1, Brooks RA, Panchal R, Rhyasen GW, Danet-Desnoyers G, Mulloy JC.
Blood.Blood.2014 Apr 28. [Epub ahead of print]
Immunodeficient mice are now readily engrafted with human hematopoietic cells. However, these mice are susceptible to graft versus host disease (GVHD) induced by the engraftment and rapid expansion of co-injected human T cells. Therefore, highly purified sample populations must be used, adding signi
PMID 24778156

Induction immunosuppressive therapy in kidney transplantation.

Bakr MA1, Nagib AM, Donia AF.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation.Exp Clin Transplant.2014 Mar;12 Suppl 1:60-9.
Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first contact with donor antigens. Initial intensive immunosuppression may be required to prevent acute rejection and graft loss, and sub
PMID 24635795

A comparison of outcomes between OKT3 and antithymocyte globulin for treatment of steroid-resistant rejection in hepatitis C liver transplant recipients.

Benjamin MM1, Dasher KJ, Trotter JF.
Transplantation.Transplantation.2014 Feb 27;97(4):470-3. doi: 10.1097/01.TP.0000435701.54019.98.
BACKGROUND: The treatment of steroid-resistant rejection (SRR) is associated with severe recurrent hepatitis C virus (HCV) infection after liver transplantation (LTx). After OKT3 was recently withdrawn from the market, thymoglobulin (TG) became the principal treatment for SRR.METHODS: A retrospectiv
PMID 24142032

Japanese Journal

Muromonab-CD3 for the Successful Treatment of Early Chronic Rejection After Pediatric Liver Transplantation : Report of a Case

HORI TOMOHIDE,NGUYEN JUSTIN H.,UEMOTO SHINJI
Surgery today : the Japanese journal of surgery 41(4), 585-590, 2011-04-01
NAID 10029046956

Muromonab-CD3 therapy for refractory rejections after liver transplantation : a single-center experience during two decades in Japan

UEDA Daisuke,HORI Tomohide,NGUYEN Justin H.,UEMOTO Shinji
Journal of hepato-biliary-pancreatic sciences 17(6), 885-891, 2010-11-01
NAID 10027664313

Related Pictures

Major Competitors in the Transplantation okt3 Orthoclone OKT3 , (after and before mondeo-okt3 Structure and function Skin and Appendages:

★リンクテーブル★

リンク元	「超急性拒絶反応」「慢性拒絶反応」「急性拒絶反応」「ムロモナブ-CD3」「muromonab-CD3」
拡張検索	「OKT3 monoclonal antibody」「OKT3モノクローナル抗体」

「超急性拒絶反応」

Muromonab-CD3^?
Monoclonal antibody
Type	Whole antibody
Source	Mouse
Target	CD3ε
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a605011
Pregnancy; category	US: C (Risk not ruled out);
Legal status	℞ (Prescription only);
Routes of; administration	intravenous
Pharmacokinetic data
Bioavailability	N/A
Identifiers
CAS Registry Number	140608-64-6
ATC code	L04AA02
DrugBank	DB00075
UNII	JGA39ICE2V
ChEMBL	CHEMBL1201608
Chemical data
Formula	C6460H9946N1720O2043S56
Molecular mass	146.091 kDa
(what is this?) (verify)

　　[★]

英: hyperacute rejection
関: 移植免疫、拒絶反応

移植直後から24時間以内に起こる激しい拒絶反応。
腎移植の時は、ドナーの血清とレシピエントのT細胞を使って抗体抗原反応が起きないか調べる。抗原はHLA class Iである。(HIM.1777)
移植腎で超急性拒絶反応が起こったときは次の病理像が見られる：neutrophils, immunoglobulin, and complement in vessel walls

反応機序：液性免疫。レシピエントの抗HLA抗体の存在による
治療法：臓器摘出

hyperacute rejection	Antibody mediated due to the presence of preformed antidonor antibodies in the transplant recipient. Occurs within minutes after transplantation.
acute rejection	Cell mediated due to cytotoxic T lymphocytes reacting against foreign MHCs. Occurs weeks after transplantation. Reversible with immunosuppressants such as cyclosporin and OKT3.
chronic rejection	Antibody-mediated vascular damage (fibrinoid necrosis); Occurs months to years after transplantation. Irreversible.

「慢性拒絶反応」

　　[★]

英: chronic rejection
同: 慢性拒否反応
関: 拒絶反応

hyperacute rejection	Antibody mediated due to the presence of preformed antidonor antibodies in the transplant recipient. Occurs within minutes after transplantation.
acute rejection	Cell mediated due to cytotoxic T lymphocytes reacting against foreign MHCs. Occurs weeks after transplantation. Reversible with immunosuppressants such as cyclosporin and OKT3.
chronic rejection	Antibody-mediated vascular damage (fibrinoid necrosis); Occurs months to years after transplantation. Irreversible.

「急性拒絶反応」

　　[★]

英: acute rejection

hyperacute rejection	Antibody mediated due to the presence of preformed antidonor antibodies in the transplant recipient. Occurs within minutes after transplantation.
acute rejection	Cell mediated due to cytotoxic T lymphocytes reacting against foreign MHCs. Occurs weeks after transplantation. Reversible with immunosuppressants such as cyclosporin and OKT3.
chronic rejection	Antibody-mediated vascular damage (fibrinoid necrosis); Occurs months to years after transplantation. Irreversible.