alefacept

Alefacept
Systematic (IUPAC) name
	1-92-LFA-3 (Antigen) (human) fusion protein with immunoglobin G1 (human hinge CH2-CH3γ1-chain) dimer
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a603011
Pregnancy cat.	C (AU) B (US)
Legal status	℞-only (US)
Routes	Intravenous, intramuscular
Pharmacokinetic data
Bioavailability	63% (IM)
Half-life	~270 hours
Identifiers
CAS number	222535-22-0
ATC code	L04AA15
DrugBank	DB00092
UNII	ELK3V90G6C
KEGG	D02800
ChEMBL	CHEMBL1201571
Chemical data
Formula	C2306H3594N610O694S26
Mol. mass	51801.1 g/mol
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/18 20:08:42」(JST)

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Alefacept is a genetically engineered immunosuppressive drug. It was sold under the brand name Amevive in Canada, the United States, Israel, Switzerland and Australia. In 2011, the manufacturers made a decision to cease promotion, manufacturing, distribution and sales of Amevive during a supply disruption. According to Astellas Pharma US, Inc. (http://www.amevive.com/Patient%20letter.pdf), the decision to cease Amevive sales was neither the result of any specific safety concern nor the result of any FDA-mandated or voluntary product recall. On the other hand, usage of Amevive was associated with a certain risk of development systemic diseases such as malignancies. This drug was never approved for the European drug market.

Alefacept is used to control inflammation in moderate to severe psoriasis with plaque formation, where it interferes with lymphocyte activation.^[1] It is also being studied in the treatment of cutaneous T-cell lymphoma and T-cell non-Hodgkin lymphoma.

Alefacept is a fusion protein: it combines part of an antibody with a protein that blocks the growth of some types of T cells.

Mechanism of action[edit]

The mechanism of action involves dual mechanisms. Alefacept inhibits the activation of CD4⁺ and CD8⁺ T cells by interfering with CD2 on the T cell membrane thereby blocking the costimulatory molecule LFA-3/CD2 interaction. Another mechanism is inducing apoptosis of memory-effector T lymphocytes. If the T cells were to become activated they would stimulate proliferation of keratinocytes resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions. Combinations of therapeutic modalities have been utilized to meet the challenge of difficult to treat psoriasis.^[2]

Indications[edit]

Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical corticosteroids was permitted during the treatment phase with alefacept and does not seem to pose any additional risks.

The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment.

Contraindications and precautions[edit]

Alefacept reduces CD4⁺ T cell counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections.
Pretreatment CD4⁺ and/or CD8⁺ cell counts below the accepted lower limit
History of systemic malignancy
Caution: Patients at high risk to develop a systemic malignancy
Known hypersensitivity to alefacept or to any other ingredient of the preparation
Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted.

Pregnancy and lactation[edit]

Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia.
Lactation : It is not known if the drug is excreted into human milk. Either the drug or breastfeeding should be terminated, taking into account the importance of treatment to the mother.

Pediatric patients[edit]

No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients.

Side effects[edit]

Lymphopenia : Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below).
Malignancies : In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas.
Infections : In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such as sepsis, pneumonia, abscesses, wound infections and toxic shock syndrome.
Sensitivity reactions: Urticaria and angioedema were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once.
Forming of antibodies to alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Long-term immune effects have not been well explored.
Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT and/or AST), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver failure. It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops.
Different Common Side Effects : side effects such as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently.

Interactions[edit]

Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate are conducted, but no results have been published so far.
Live vaccines: The efficiency of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in clinical trials.

Necessary laboratory examinations[edit]

CD4⁺ cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks.
It may be desirable to monitor liver function studies (AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol).

Dosage regimes[edit]

The standard dosage regime is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents.

Notes[edit]

^ "New drugs". Australian Prescriber 27 (101): 5. 2004. Retrieved 2006-08-20.
^ Scheinfeld N. Therapy-resistant psoriasis treated with alefacept and subsequent narrow band ultraviolet B phototherapy with total clearing of psoriasis. Dermatol Online J. 2005;11(2)7. PMID 16150215

This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms".

External links[edit]

Koo J, Bagel J, Sweetser M, Ticho B (2006). "Alefacept in combination with ultraviolet B phototherapy for the treatment of chronic plaque psoriasis: results from an open-label, multicenter study.". J Drugs Dermatol 5 (7): 623–8. PMID 16865867.
Krell J (2006). "Use of alefacept and etanercept in 3 patients whose psoriasis failed to respond to etanercept.". J Am Acad Dermatol 54 (6): 1099–101. doi:10.1016/j.jaad.2005.08.032. PMID 16713481.
Parrish C, Sobera J, Robbins C, Cantrell W, Desmond R, Elewski B (2006). "Alefacept in the treatment of psoriatic nail disease: a proof of concept study.". J Drugs Dermatol 5 (4): 339–40. PMID 16673801.
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UpToDate Contents

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1. 乾癬の治療 treatment of psoriasis
2. 重症難治性アトピー性皮膚炎（湿疹）のマネージメント management of severe refractory atopic dermatitis eczema
3. 乾癬性関節炎の治療 treatment of psoriatic arthritis
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. 円形脱毛症のマネージメント management of alopecia areata

English Journal

Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

Kim EJ, Kwun J, Gibby AC, Hong JJ, Farris AB 3rd, Iwakoshi NN, Villinger F, Kirk AD, Knechtle SJ.Author information Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA.AbstractDe novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+) ) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.Am J Transplant.2014 Jan;14(1):59-69. doi: 10.1111/ajt.12526.
De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production wi
PMID 24354871

Novel immunosuppressive agents in kidney transplantation.

Hardinger KL, Brennan DC.Author information Karen L Hardinger, Department of Pharmacy Practice and Administration, University of Missouri-Kansas City, Kansas City, MO 64108, United States.AbstractExcellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.
World journal of transplantation.World J Transplant.2013 Dec 24;3(4):68-77.
Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus
PMID 24392311

Japanese Journal

Quantification of Alefacept, an immunosuppressive fusion protein in human plasma using a protein analogue internal standard, trypsin cleaved signature peptides and liquid chromatography tandem mass spectrometry

HALQUIST Matthew S.,KARNES H. Thomas
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 879(11), 789-798, 2011-04-01
NAID 10029518752