同: OKT3, Orthoclone OKT3

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the 3rd letter of the Roman alphabet (同)c
(music) the keynote of the scale of C major
a general-purpose programing language closely associated with the UNIX operating system

PrepTutorEJDIC

carbonの化学記号
certificate of deposit / (また『C.D.』)Civil Defense民間防衛

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/12 00:40:06」(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,^[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]

History

Muromonab-CD3 (OKT3) was approved by the U.S. Food and Drug Administration (FDA) in 1985,^[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 However, the manufacturer of Muromonab-CD3 has voluntarily withdrawn^[5] it from the United States market due to decreased utilization; current OKT3 supplies are expected to be exhausted by mid-2010.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.^[6] 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.^[7]

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]^[6] 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.^[8]

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".^[9]

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,^[10] and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.^[6] 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.^[6]

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]^[6]

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.
^ "muromonab-CD3". Guide to Pharmacology. IUPHAR/BPS. Retrieved 21 August 2015.
^ ^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. doi:10.7182/prtr.1.6.3.8145l3u185493182. PMID 9188368.
^ 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.
^ Bhorade, S. M., Stern, E. (2009). Immunosuppression for Lung Transplantation. Proc Am Thorac Soc 6: 47-53

UpToDate Contents

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1. 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
2. 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
3. 成人における肝移植：免疫抑制の概要 liver transplantation in adults overview of immunosuppression
4. 急性移植片対宿主病の治療 treatment of acute graft versus host disease
5. Secondary immunodeficiency induced by biologic therapies

English Journal

Anti-CD3 antibodies for type 1 diabetes: beyond expectations.

Bach JF.SourceUniversite Paris Descartes, Paris, France. jean-francois.bach@academie-sciences.fr
Lancet.Lancet.2011 Aug 6;378(9790):459-60. Epub 2011 Jun 28.
PMID 21719098

Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial.

Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ Jr, Bode B, Aronoff S, Holland C, Carlin D, King KL, Wilder RL, Pillemer S, Bonvini E, Johnson S, Stein KE, Koenig S, Herold KC, Daifotis AG; Protege Trial Investigators.Collaborators (85)Lenhard J, Aronoff S, Bode B, Berg J, Brenner D, Allen H, Sherry N, Cengiz E, Rendell M, Ovalle F, Hart C, Guthrie R, Liljenquist D, Hays R, Ganong K, Wahlen J, Luidens M, Izquierdo R, Moore W, Tsalikian E, Huffman DM, Reiner B, Gottlieb P, Hagopian W, Nebesio T, Christensen R, Ferry RJ Jr, Pacaud D, Taback S, Escalante M, Rivera JR, Prieto IM, Perez HE, Sumnik Z, Skvor J, Neumann D, Michalek J, Vavrinec J, Mankovsky B, Karachentsev Y, Zelinskaya N, Lezhenko G, Mykhaylychenko T, Khyzhnyak O, Vlasenko M, Rudofsky G, Kumar P, Chaturvedi R, Phadke U, Lodha S, Sahay R, Modi KD, Shah S, Rao PV, Gandhi P, Shah P, Subrahmanyam KA, Pathak S, Kalra S, Jain S, Mukhopadyay M, Chandratreya S, Hanukoglu A, Jaffe A, Phillip M, Pinchas-Hamiel O, Shehadeh N, Gorska M, Mlynarski W, Noczynska A, Pregiel M, Szalecki M, Buszkowskiego W, Mysliwiec M, Dumitrescu A, Hancu ND, Nafornita V, Szilagyi I, Farcasiu E, Jakovlev U, Rajasalu T, Pirags V, Engel WR, Serrano MB, Ludvigsson J.
Lancet.Lancet.2011 Aug 6;378(9790):487-97. Epub 2011 Jun 28.
BACKGROUND: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the saf
PMID 21719095

Japanese Journal

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

小児における生体肝移植後の早期慢性拒絶に対してOKT3投与が効果を示した1例

上田大輔,米川幸秀,宮川文,岡本晋弥
日本小児外科学会雑誌 46(2), 254-259, 2010-04-20
患者は4歳6か月男児.進行性家族性肝内胆汁うっ滞症2型の診断で当科にて生体肝移植を施行.術後7日目に肝酵素の上昇を認め急性細胞性拒絶と診断し,ステロイドパルスを3日間施行し肝酵素の改善が得られた.その後再度肝酵素の上昇を認めたため,mycophenolate mofetilの併用や2回目のステロイドパルスを施行したが治療反応性は極めて乏しくグラフト不全に陥った.肝生検所見では門脈域のリンパ球を主体 …
NAID 110007593923

Related Pictures

★リンクテーブル★

リンク元	「免疫抑制薬」「ムロモナブ-CD3」「OKT3」
関連記事	「C」「CD3」「CD」

「免疫抑制薬」

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 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: immunosuppressive drug, immunosuppressant
関

免疫抑制薬

作用機序

シクロスポリン、タクロリムス

56kDa immunophilinに結合 (GOO.1596)

56kDa immunophilinはHSP70, HSP90と共にglucocorticoid receptosに結合している。

再生不良性貧血に対する治療薬として

抗ヒト胸腺細胞抗体

副作用

感染症

リスクの上がる病原微生物

https://www.jpn-geriat-soc.or.jp/publications/other/pdf/clinical_practice_of_geriatrics_48_5_461.pdf

	量と投与期間	病原微生物	予防薬
ステロイド	プレドニン10mgで8週間以上投与予定	Pneumocystis jirovecii	ST合剤
	リンデロン1mg以上を1カ月以上投与	Pneumocystis jirovecii	ST合剤
	プレドニン15mg以上を2～3週間以上	結核	感染予防はなし，潜在結核治療としてはイソニアジド
	ステロイド全般	ノカルジア？	ST合剤？（ただし，投与下での発症あり）
TNFα阻害薬	インフリキシマブ、エタネルセプト	Pneumocystis jirovecii	ST合剤
TNFα阻害薬	インフリキシマブ、エタネルセプト	結核	新規感染予防はなし，潜在結核治療としてはイソニアジド