Abatacept

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Abatacept
Clinical data
Trade names Orencia
AHFS/Drugs.com Monograph
MedlinePlus a606016
License data
Pregnancy
category
  • AU:C
Routes of
administration 		Intravenous, subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 13.1 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C3498H5458N922O1090S32
Molar mass 78895.43 g·mol−1
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Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. [1] [3] It is a modified antibody. [1] [3]

Contents

Abatacept is a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. In order for a T cell to be activated and produce an immune response, an antigen-presenting cell must present two signals to the T cell. One of those signals is the major histocompatibility complex (MHC), combined with the antigen, and the other signal is the CD80 or CD86 molecule (also known as B7-1 and B7-2). Abatacept binds to the CD80 and CD86 molecule, and prevents the second signal. Without the second signal, the T cell can't be activated.

Abatacept was developed by Bristol-Myers Squibb and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFα therapy. Abatacept received approval from the FDA in 2005. [4]

Medical uses

Abatacept is used to treat adults with moderate to severe rheumatoid arthritis (RA) as a second-line agent, and as a first-line agent for people whose RA is severe and rapidly progressing. It also used to treat psoriatic arthritis and juvenile idiopathic arthritis. [1] [5] [6] [3]

Contraindications

Abatacept has not been tested in pregnant women and it is not known if it is secreted in breast milk; it causes birth defects in rodents when given in very high doses, and is transmitted in rodent breast milk. [5]

Abatacept will likely interfere with any vaccine given while people are taking it. [5]

It should not be used in combination with anakinra or TNF antagonists. [7] Because abatacept, anakinra, and TNF antagonists suppress the immune system, using them in combination may significantly increase the risk for severe infections. [1]

Adverse effects

People have experienced serious infections due to abatacept's suppression of the immune system; some of these infections have been fatal. People with COPD are likely to get lung infections more often than usual. Some people have had anaphylactic reactions to the drug. Abatacept may cause otherwise slow-growing cancers to proliferate and spread, due to suppression of the immune system. [5]

Very common adverse effects (occurring in more than 10% of people) include upper respiratory tract infections. Common adverse effects (occurring in between 1% and 10% of people) include lower respiratory tract infections, urinary tract infections, herpes infections, pneumonia, flu, cough, high blood pressure, stomach pain, diarrhea, nausea, vomiting, upset stomach, mouth sores, elevated transaminases, rashes, fatigue, weakness, local injection site reactions, and systemic injection reactions. [5]

Chemistry

Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the hinge, CH2, and CH3 domains of IgG1. [7]

Mechanism of action

Abatacept is a soluble CTLA-4 analog that prevents antigen-presenting cells (APCs) from delivering the co-stimulatory signal. This prevents the T cells from being fully activated, and even downregulates them. Simple signaling without co-stimulation allows the cell to recognize the primary signal as "self" and not ramp-up responses for future responses as well.

In order for T cells to be activated and attack an antigen, that antigen must be presented to the T cell by an APC.

That activation requires two signals (one of which is called co-stimulatory signal or signal 2):

For signal 1, the APC must bind the antigen to a major histocompatibility complex (MHC) molecule, bring that complex to its surface, and present it to the T cell receptor on the surface of the T cell.

For signal 2, the APC must present a B7 protein (CD80 or CD86) on its cell surface to a CD28 protein on the surface of the T cell. These two signals activate the T cell. Without signal 2, the T cell will not be activated, and will become anergic.

Abatacept, which consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG1, binds to the B7 protein on the APC and prevents it from delivering the co-stimulatory signal to the T cell. [8] [9]

Related Research Articles

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">Anakinra</span> Pharmaceutical drug

Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.

<span class="mw-page-title-main">Cytotoxic T-lymphocyte associated protein 4</span> Mammalian protein found in humans

Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.

B7 is a type of integral membrane protein found on activated antigen-presenting cells (APC) that, when paired with either a CD28 or CD152 (CTLA-4) surface protein on a T cell, can produce a costimulatory signal or a coinhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively. Binding of the B7 of APC to CTLA-4 of T-cells causes inhibition of the activity of T-cells.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">CD28</span> Mammalian protein found in humans

CD28 is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins.

Belatacept, sold under the brand name Nulojix, is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial in the regulation of T cell costimulation, selectively blocking the process of T-cell activation. It is intended to provide extended graft and transplant survival while limiting the toxicity generated by standard immune suppressing regimens, such as calcineurin inhibitors. It differs from abatacept (Orencia) by only two amino acids.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in Homo sapiens

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">Tremelimumab</span> Monoclonal antibody

Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma. Tremelimumab is designed to attach to and block CTLA-4, a protein that controls the activity of T cells, which are part of the immune system.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in humans

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

The following outline is provided as an overview of and topical guide to immunology:

Artificial antigen presenting cells (aAPCs) are engineered platforms for T-cell activation. aAPCs are used as a new technology and approach to cancer immunotherapy. Immunotherapy aims to utilize the body's own defense mechanism—the immune system—to recognize mutated cancer cells and to kill them the way the immune system would recognize and kill a virus or other micro-organisms causing infectious diseases. Antigen presenting cells are the sentinels of the immune system and patrol the body for pathogens. When they encounter foreign pathogens, the antigen presenting cells activate the T cells—"the soldiers of the immune system"— by delivering stimulatory signals that alert there is foreign material in the body with specific cell surface molecules (epitopes). aAPCs are synthetic versions of these sentinel cells and are made by attaching the specific T-cell stimulating signals to various macro and micro biocompatible surfaces like micron-sized beads. This can potentially reduce the cost while allowing control over generating large numbers of functional pathogen-specific T cells for therapy. Activated and stimulated T cells can be studied in this biomimetic contex and used for adoptive transfer as an immunotherapy.

An immune checkpoint regulator is a modulator of the immune system, that allows initiation of a productive immune response and prevents the onset of autoimmunity. Examples of such a molecule are cytotoxic T-lymphocyte antigen 4, which is an inhibitory receptor found on immune cells and programmed cell death 1 (CD279), which has an important role in down-regulating the immune system by preventing the activation of T-cells.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

References

  1. 1 2 3 4 5 "Orencia- abatacept injection, powder, lyophilized, for solution Orencia- abatacept injection, solution". DailyMed. 15 December 2021. Retrieved 16 March 2022.
  2. ↑ "FDA approves abatacept for prophylaxis of acute graft". U.S. Food and Drug Administration (FDA). 15 December 2021. Archived from the original on 24 January 2022. Retrieved 16 March 2022.
  3. 1 2 3 4 "Orencia EPAR". European Medicines Agency (EMA). Retrieved 6 October 2020.
  4. ↑ "Drug Approval Package: Orencia (Abatacept) NDA #125118". U.S. Food and Drug Administration (FDA). Retrieved 29 December 2020.
  5. 1 2 3 4 5 "UK label prefilled pen". UK Electronic Medicines Compendium. 25 July 2017.
  6. ↑ "UK label powder". UK Electronic Medicines Compendium. 25 July 2017.
  7. 1 2 Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery. 5 (3): 185–186. doi:10.1038/nrd1989. PMID   16557658. S2CID   266176720.
  8. ↑ "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Archived from the original on 5 December 2008. Retrieved 25 May 2007.
  9. ↑ Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus. 13 (5): 372–376. doi:10.1191/0961203303lu1029oa. PMID   15230295. S2CID   32235606.
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