Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to monospectively bind to certain cells or proteins. The goal is that this treatment will stimulate the patient's immune system to attack the cells. Alternatively, in radioimmunotherapy, the radioactive dose localizes the target cell, resulting in a lethal chemical dose. Recently antibodies have been used to bind molecules involved in T-cell regulation to eliminate inhibitory pathways that block T-cell responses. This is known as immune-control therapy.
It is possible to make mAbs specific to almost all extracellular cell surface targets/cells. Research and development is underway to create antibodies to the disease (such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Ebola and various types of cancer).
Video Monoclonal antibody therapy
Structure and function of antibody
Immunoglobulin G (IgG) antibody is a large heterodimeric molecule, about 150 kDa and consists of two types of polypeptide chains, called weight (~ 50kDa) and light chains (~ 25kDa). The two types of light chains are kappa (?) And lambda (?). By cleavage with papain enzymes, the Fab ( fragment-antigen binding ) section can be separated from the Fc ( fragment constant ) part of the molecule. Fragment Fab contains a variable domain, consisting of three domains of the amino acid hypervariable antibody that is responsible for the specificity of antibodies that are embedded into the constant region. The four subgroups of IgG are known to be involved in the cellular cytotoxicity of antibodies. Antibodies are a key component of the adaptive immune response, playing a central role in both the recognition of foreign antigens and the stimulation of the immune response against them. The advent of monoclonal antibody technology has made it possible to increase antibodies against specific antigens presented at the surface of the tumor. Monoclonal antibodies can be obtained in the immune system through passive immunity or active immunity. The advantage of active monoclonal antibody therapy is the fact that the immune system will produce long-term antibodies, with only short-term drug delivery to induce this response. However, the immune response to certain antigens may be inadequate, especially in the elderly. In addition, adverse reactions of these antibodies may occur due to long lasting antigenic response. Passive monoclonal antibody therapy ensures consistent antibody concentrations, and can control adverse reactions by discontinuing administration. However, repeated administration and consequently a higher cost for this therapy is a big disadvantage.
Monoclonal antibody therapy may prove useful for cancer, autoimmune disease, and neurological disorders that result in degeneration of body cells, such as Alzheimer's Disease. Monoclonal antibody therapy can help the immune system because the innate immune system responds to the environmental factors it encounters by distinguishing foreign cells from the body's cells. Therefore, tumor cells that multiply at high levels, or dying body cells that then cause physiological problems are generally not specifically targeted by the immune system, because tumor cells are the patient's own cells. The tumor cells, however, are very abnormal, and many feature unusual antigens. Some such tumor antigens are not suitable for cell type or environment. Monoclonal antibodies can target tumor cells or abnormal cells in the body known as body cells, but weaken for one's health.
Maps Monoclonal antibody therapy
History
Immunotherapy was developed in the 1970s after the discovery of antibody structures and the development of hybridoma technology, which provided the first reliable source of monoclonal antibodies. This progress allows for specific targeting of tumors both in vitro and in vivo. Early studies of malignant neoplasms found limited and generally short-lived mAb therapy successful with blood malignancy. Treatment should also be tailored for each patient, which is not practical in a routine clinical setting.
The four main types of antibodies that have been developed are murine, chimeric, humanised and human. Antibodies of each type are distinguished by suffixes in their names.
Murine
Early therapeutic antibodies are murine analogs (suffix -omab ). This antibody has: a short half-life in vivo (due to immune complex formation), limited penetration to tumor sites and insufficient recruiting host effector function. Chimeric and human antibodies generally replace them in the application of therapeutic antibodies. Understanding of proteomics has proven important in identifying new tumor targets.
Initially, murine antibodies were obtained with hybridoma technology, which Jerne, KÃÆ'¶hler and Milstein received the Nobel Prize. But the inequalities between murine and the human immune system lead to clinical failure of these antibodies, except in some circumstances. The major problems associated with murine antibodies include reducing cytotoxicity stimulation and complex formation after repeated administration, resulting in mild allergic reactions and occasionally anaphylactic shock. Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage look. Chimeric and humanized
Chimeric and humanized
To reduce the immunogenicity of murine antibodies (attacks by the immune system against antibodies), murine molecules are engineered to eliminate immunogenic content and improve immunological efficiency. This is initially achieved by the production of chimeric (suffix -ximab) and human antibodies (suffix -zumab ). The chimeric antibody comprises a murine variable region fused into a constant region of humans. Taking the sequence of human genes from lightweight chains of kappa and heavy chain IgG1 produces antibodies that are about 65% human. This reduces immunogenicity, and thus increases the serum half-life.
Human-made antibodies are produced by grafting murine hypervariable regions in the amino acid domain into human antibodies. This produces about 95% of the human origin molecules. Antibodies bind to antigens are much weaker than murine mother monoclonal antibodies, with decreased affinities reported up to several hundred fold. Increased binding strengths of antibodies have been achieved by introducing mutations into the area that determines complementarity (CDR), using techniques such as chain-scrambling, randomization of complementary areas and antibodies with mutations in variable regions caused by error-prone PCR. , E. coli mutator strains and site-specific mutagenesis.
Human monoclonal antibody
Human monoclonal antibodies (suffix -umab ) are produced using transgenic mice or phag screening literature by transferring human immunoglobulin genes into the murine genome and vaccinating transgenic mice to the desired antigen, leading to appropriate monoclonal production. antibody. The murine antibodies in vitro are thus converted into complete human antibodies.
The heavy and lightweight chains of human IgG proteins are expressed in the form of structural (allotypic) polymorphisms. Human IgG allotype is one of many factors that can contribute to immunogenicity.
Target Condition
Cancer
Anti-cancer monoclonal antibodies can be targeted against malignant cells with several mechanisms. Ramucirumab is a recombinant human monoclonal antibody and is used in the treatment of advanced malignancies.
Autoimmune Disease
Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn's disease and Colitis ulcerativa by their ability to bind and block TNF-.. Basiliximab and daclizumab inhibit IL-2 in activated T cells and thus help prevent acute rejection of kidney transplant. Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-severe allergic asthma.
Alzheimer's Disease
Alzheimer's disease (AD) is a progressive, multi-dimensional, progressive neurodegenerative disorder, and is a major cause of dementia. According to the Amyloid hypothesis, the accumulation of the extracellular amyloid betapeptide (A?) Into the plaque through oligomerization leads to signs of AD condition symptoms through synaptic dysfunction and neurodegeneration. Immunotherapy through the administration of exogenous monoclonal antibodies (MAB) has been known to treat various central nervous disorders, such as AD, by inhibiting A? -oligomerization thus preventing neurotoxicity. However, MABs are great for passive protein channels and are therefore inefficient because the blood-brain barrier prevents MAB parts to the brain. However, the Peripheral Sink hypothesis proposes a mechanism in which MAB does not need to cross the blood-brain barrier. Therefore, many research studies are being conducted from failed attempts to treat AD in the past.
However, anti-A? vaccines can promote A-mediated antibody permission? plaque in a transgenic mouse model with amyloid precursor protein (APP), and can reduce cognitive impairment. Vaccines can stimulate the immune system to produce its own antibodies, in this case by introducing A? into a model of transgenic animals, known as active immunization. They can also introduce antibodies into animal models, known as passive immunizations. In mice expressing APP, both active and passive immunization against anti-A? antibodies have been shown to be effective in clearing plaque, and can improve cognitive function. Therefore, some clinical trials using passive and active immunization approaches with the development of certain drugs approved by the FDA are currently underway, and are expected to produce results within a few years. Implementation of these drugs is during AD onset. Research and development of other drugs for early intervention and prevention of AD is ongoing. Various drugs under investigation to treat AD include Bapineuzumab, Solanezumab, and Gautenerumab.
Bapineuzumab
Bapineuzumab, an anti-a human? MAB, directed against N-terminus A ?. Phase II Bapineuzumab clinical trials in mild to moderate AD patients result in A decrease? concentration in the brain. However, in patients with elevated apolipoprotein e4 (APOE) carriers, Bapineuzumab treatment is also accompanied by vasogenic edema, a cytotoxic condition in which the cerebral blood barrier has been impaired affecting the white matter from the accumulation of excess fluid from capillaries in the intracellular and extracellular spaces. brain. In Phase III clinical trials, Bapineuzumab treatment is associated with a decrease in the accumulation rate of A? in the brain in APOE e4 patients, and no significant A decrease? concentrations in APOE e4 patients and non-APOE patients e4. Therefore, A? the plaque concentration is not reduced, and there is no significant clinical benefit in cognitive function. Bapineuzumab was discontinued after failure in Phase III clinical trials.
Solanezumab
Solanezumab, anti-a? MAB, targeting N-terminus A ?. In Phase I and Phase II of clinical trials, Solanezumab treatment results in an increase in cerebrospinal fluid A ?, thus indicating a decrease in concentration A? plaque. In addition, no associated side effects. Clinical trials of Solanezumab III phase cause a significant reduction in cognitive impairment in patients with mild AD, but not in patients with severe DA. However, A? The concentration did not change significantly, along with other AD biomarkers, including phospho-tau expressions, and hippocampal volume. Phase III clinical trials are currently underway.
Preventative Trials
Failure of some drugs in Phase III clinical trials has led to AD prevention and early intervention to start AD treatment efforts. Anti-A passive? MAB treatment can be used for prevention efforts to modify the development of AD before causing extensive brain damage and symptoms. Experiments using MAB treatment for positive patients for genetic risk factors, and positive elderly patients for AD indicators are ongoing. These include anti-AB treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Prevention Initiative (API), and DIAN-TU. A4 studies in older individuals who are positive for AD indicators but negative for genetic risk factors will test Solanezumab in Phase III of Clinical Trial, as a follow up of previous Solanezumab research. DIAN-TU, launched in December 2012, focuses on young patients who are positive for risky genetic mutations for AD. This study used Solanezumab and Gautenerumab. Gautenerumab, the first fully human MAB that privately interacts with oligomerization A? plaque in the brain, causing a significant decrease in A? concentration in Phase I clinical trials. Therefore, this prevents the formation and concentration of plaque without altering the plasma plasma concentration. Phase II and III clinical trials are underway.
Type of therapy
Radioimmunotherapy
Radioimmunotherapy (RIT) involves the use of a conjugate radioactive murine antibody against cellular antigens. Most research involves its application to lymphoma, because it is a very radio sensitive malignancy. To limit radiation exposure, murine antibodies are selected, because their high immunogenicity promotes rapid tumor cleansing. Tositumomab is an example used for non-Hodgkins lymphoma.
Antivirus-directed antibody enzyme therapy
An antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer-associated monoclonal antibodies associated with drug-activating enzymes. Systemic administration of non-toxic agents results in the conversion of antibodies into toxic drugs, producing cytotoxic effects that can be targeted to malignant cells. The clinical success of ADEPT treatment is limited.
antibody-drug conjugate
Antibody-drug conjugates (ADCs) are antibodies associated with one or more drug molecules. Usually when the ADC meets the target cell (eg cancer cell) the drug is released to kill it. Many ADCs are in clinical development. By 2016 some have been approved.
Imunoliposome therapy
Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry therapeutic drugs or nucleotides and when conjugated with monoclonal antibodies, can be directed against malignant cells. Immunoliposomes have been successfully used in vivo to carry tumor suppressor genes into the tumor, using antibody fragments against human transferrin receptors. Delivery of tissue-specific genes using immunoliposomes has been achieved in the brain and breast cancer tissue.
Inspection point therapy
Checkpoint therapies use antibodies and other techniques to avoid the defenses that tumors use to suppress the immune system. Every defense is known as a checkpoint. Combined therapy combines antibodies to suppress multiple defensive layers. Known checkpoints include CTLA-4 targeted by ipilimumab, PD-1 targeted by nivolumab and pembrolizumab and micro-tumors.
The microenvironment tumor feature (TME) prevents the recruitment of T cells into tumors. His work includes chemokine nitrate CCL 2 , which traps T cells in the stroma. The vasculature tumor helps a special tumor recruit other immune cells above T cells, partially via cell endothelial (EC) expression of FasL, ET B R, and B7H3. Myelomonocytic cells and tumors can regulate PD-L1 expression, partially driven by hypoxic conditions and cytokine production, such as IFN ?. The production of abnormal metabolites in the TME, such as path arrangement by IDO, can affect the function of T cells directly and indirectly through cells such as T reg cells. CD8 cells can be suppressed by B cell regulation of the TAM phenotype. Cancer-related fibroblasts (CAFs) have several TME functions, partially via extracellular matrix (ECM) - T cell separation and regulated CXCL12 T cell exclusion.
FDA-approved therapeutic drugs
The first FDA-approved therapeutic monoclonal antibody is a murine-specific CD3 IgG2a transplantation drug, OKT3 (also called muromonab), in 1986. It was found to be used in solid-organ transplant recipients that become resistant to steroids. Hundreds of therapies are undergoing clinical trials. Most are concerned about immunological and oncologic targets.
Recently, bispecific antibodies, a new class of therapeutic antibodies, have produced promising results in clinical trials. In April 2009, specific antibody catumaxomab was approved in the European Union.
Economy
Since 2000, the therapeutic market for monoclonal antibodies has grown exponentially. In 2006, the "top 5" therapy antibodies in the market were bevacizumab, trastuzumab (both oncology), adalimumab, infliximab (both autoimmune and inflammatory disorders, 'AIID') and rituximab (oncology and AIID) accounted for 80% of revenues in 2006. In 2007, eight of the 20 best-selling biotech cures in the US were therapeutic monoclonal antibodies. Rapid demand growth for the production of monoclonal antibodies has been well accommodated by the industrialization of mAb manufacturing.
See also
- Antigen 5T4
- Immunotherapy
- Immunoconjugate
- Nomenclature of monoclonal antibodies
- List of monoclonal antibodies, including checks and withdrawals
References
External links
- Cancer Management Handbook: The Principles of Oncology Pharmacotherapy (required registration)
Source of the article : Wikipedia
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