Anti-CD3 monoclonal antibody

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An anti-CD3 monoclonal antibody is one that binds to CD3 on the surface of T cells. They are immunosuppresive drugs.

Monoclonal antibody monospecific antibody that is made by identical immune cells that are all clones of a unique parent cell

Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity, in that they bind to the same epitope. In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one single monoclonal antibody to two epitopes.

CD3 (immunology) antigen, cluster of differentiation protein (immunology), part of the T cell receptor (TCR) complex on a mature T lymphocyte

In immunology, the CD3 T cell co-receptor helps to activate both the cytotoxic T cell and also T helper cells. It consists of a protein complex and is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the ζ-chain (zeta-chain) to generate an activation signal in T lymphocytes. The TCR, ζ-chain, and CD3 molecules together constitute the TCR complex.

T cell Type of lymphocyte.

A T cell, or T lymphocyte, is a type of lymphocyte that plays a central role in cell-mediated immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface. They are called T cells because they mature in the thymus from thymocytes. The several subsets of T cells each have a distinct function. The majority of human T cells, termed alpha beta T cells, rearrange their alpha and beta chains on the cell receptor and are part of the adaptive immune system. Specialized gamma delta T cells,, have invariant T-cell receptors with limited diversity, that can effectively present antigens to other T cells and are considered to be part of the innate immune system.

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The first to be approved was muromonab-CD3 in 1986, to treat transplant rejection.

Muromonab-CD3 is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. 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.

Transplant rejection

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

Newer monoclonal antibodies with the same mechanism of action include otelixizumab, teplizumab and visilizumab. They are being investigated for the treatment of other conditions like Crohn's disease, ulcerative colitis and type 1 diabetes, [1] and for inducing immune tolerance. [2] [3]

Otelixizumab, also known as TRX4, is a monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and is being manufactured by Abbott Laboratories.

Teplizumab is a humanized anti-CD3 monoclonal antibody that is being evaluated for treatment and prevention of type 1 diabetes mellitus (T1DM) by the biopharmaceutical company Provention Bio. Teplizumab has also been evaluated for treatment of renal allograft rejection, for induction therapy in islet transplant recipients, and for psoriatic arthritis.

Visilizumab is a humanized monoclonal antibody. It is being investigated for use as an immunosuppressive drug in patients with ulcerative colitis and Crohn's disease. Visilizumab binds to the CD3 receptor on certain activated T cells without affecting resting T cells. It is currently under clinical studies for the treatment of ulcerative colitis and Crohn's disease.

Mechanism of action

See muromonab-CD3.

See also

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Immunosuppressive drugs or immunosuppressive agents or antirejection medications are drugs that inhibit or prevent activity of the immune system.

Cancer immunotherapy The artificial stimulation of the immune system to treat cancer, improving on the systems natural ability to fight cancer

Cancer immunotherapy is the artificial stimulation of the immune system to treat cancer, improving on the system's natural ability to fight cancer. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology. It exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. The tumor antigens are often proteins or other macromolecules. Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill.

CD38 protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

Antibody-dependent cellular cytotoxicity

The antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans. Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system. The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients. There are other types of antibodies developed. The International Nonproprietary Names of humanized antibodies end in -zumab, as in omalizumab.

The nomenclature of monoclonal antibodies is a naming scheme for assigning generic, or nonproprietary, names to monoclonal antibodies. An antibody is a protein that is produced in B cells and used by the immune system of humans and other vertebrate animals to identify a specific foreign object like a bacterium or a virus. Monoclonal antibodies are those that were produced in identical cells, often artificially, and so share the same target object. They have a wide range of applications including medical uses.

Monoclonal antibody therapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Programmed cell death protein 1 protein-coding gene in the species Homo sapiens

Programmed cell death protein 1, also known as PD-1 and CD279, is a protein on the surface of 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.

LAG3 protein-coding gene in the species Homo sapiens

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

Tolerx

Tolerx, Inc. was a biopharmaceutical company headquartered in Cambridge, Massachusetts. The company was focused on discovering and developing new therapies designed to treat patients by reprogramming the immune system, allowing for long-term remission of immune-related diseases after a short course of therapy. Targeted diseases include type 1 diabetes, rheumatoid arthritis, Inflammatory bowel disease (IBD), cancer, chronic and viral diseases. In 2008, Tolerx was named one of Fierce Biotech’s Fierce 15. In October 2011, Tolerx was shut down due to an unsuccessful Phase III trial in patients recently diagnosed with Type 1 diabetes.

Trifunctional antibody

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.

Chemically linked Fab

Two chemically linked fragments antigen-binding form an artificial antibody that binds to two different antigens, making it a type of bispecific antibody. They are fragments antigen-binding of two different monoclonal antibodies and are linked by chemical means like a thioether. Typically, one of the Fabs binds to a tumour antigen and the other to a protein on the surface of an immune cell, for example an Fc receptor on a macrophage. In this way, tumour cells are attached to immune cells, which destroy them.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

TOL101, is a murine-monoclonal antibody specific for the human αβ T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately.

Infectious tolerance is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural in vivo process. A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy.

References

  1. Herold KC, Taylor L. (2003). "Treatment of Type 1 diabetes with anti-CD3 monoclonal antibody: induction of immune regulation?". Immunologic Research. 28 (2): 141–50. doi:10.1385/IR:28:2:141. PMID   14610290.
  2. Bisikirska; et al. (2005). "TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs".
  3. Bisikirska & Herold; Herold, Kevan C. (2004). "Use of Anti-CD3 Monoclonal Antibody to Induce Immune Regulation in Type 1 Diabetes". Annals of the New York Academy of Sciences. 1037: 1–9. Bibcode:2004NYASA1037....1B. doi:10.1196/annals.1337.001. PMID   15699486.