Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that bindsspecifically to almost anyextracellular target, such ascell surface proteins andcytokines. They can be used to render their target ineffective (e.g. by preventing receptor binding),^[1] to induce a specific cell signal (by activating receptors),^[1] to cause theimmune system to attack specific cells, or to bring a drug to a specific cell type (such as withradioimmunotherapy which deliverscytotoxic radiation).

Major applications includecancer,autoimmune diseases,asthma,organ transplants,blood clot prevention, and certain infections.

Immunoglobulin G (IgG) antibodies are largeheterodimeric molecules, approximately 150kDa and are composed of two kinds ofpolypeptide chain, called the heavy (~50kDa) and the light chain (~25kDa). The two types of light chains are kappa (κ) and lambda (λ). By cleavage with enzymepapain, theFab (fragment-antigen binding) part can be separated from theFc (fragment crystallizable region) part of the molecule. The Fab fragments contain the variable domains, which consist of three antibodyhypervariable amino acid domains responsible for the antibody specificity embedded into constant regions. The four known IgG subclasses are involved inantibody-dependent cellular cytotoxicity.^[2]Antibodies are a key component of theadaptive immune response, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. The advent ofmonoclonal antibody technology has made it possible to raise antibodies against specific antigens presented on the surfaces of tumors.^[3]Monoclonal antibodies can be acquired in the immune system viapassive immunity oractive immunity. The advantage of active monoclonal antibody therapy is the fact that the immune system will produce antibodies long-term, with only a short-term drug administration to induce this response. However, the immune response to certain antigens may be inadequate, especially in the elderly. Additionally, adverse reactions from these antibodies may occur because of long-lasting response to antigens.^[4] Passive monoclonal antibody therapy can ensure consistent antibody concentration, and can control for adverse reactions by stopping administration. However, the repeated administration and consequent higher cost for this therapy are major disadvantages.^[4]

Monoclonal antibody therapy may prove to be beneficial forcancer,autoimmune diseases, and neurological disorders that result in the degeneration of body cells, such asAlzheimer's disease. Monoclonal antibody therapy can aid the immune system because the innate immune system responds to the environmental factors it encounters by discriminating against foreign cells from cells of the body. Therefore, tumorcells that are proliferating at high rates, or body cells that are dying which subsequently cause physiological problems are generally not specifically targeted by the immune system, since tumor cells are the patient's own cells. Tumor cells, however are highly abnormal, and many display unusualantigens. Some suchtumor antigens are inappropriate for the cell type or its environment. Monoclonal antibodies can target tumor cells or abnormal cells in the body that are recognized as body cells, but are debilitating to one's health.^{[citation needed]}

Immunotherapy developed in the 1970s following the discovery of the structure ofantibodies and the development ofhybridoma technology, which provided the first reliable source ofmonoclonal antibodies.^[6][7] These advances allowed for the specific targeting of tumors bothin vitro andin vivo. Initial research onmalignantneoplasms found mAb therapy of limited and generally short-lived success with blood malignancies.^[8][9] Treatment also had to be tailored to each individual patient, which was impracticable in routine clinical settings.^{[citation needed]}

Four major antibody types that have been developed aremurine,chimeric,humanised and human. Antibodies of each type are distinguished by suffixes on their name.^{[citation needed]}

Initial therapeutic antibodies were murineanalogues (suffix-omab). These antibodies have: a short half-life in vivo (due toimmune complex formation), limited penetration into tumour sites and inadequately recruit host effector functions.^[10] Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications.^[11] Understanding ofproteomics has proven essential in identifying novel tumour targets.^{[citation needed]}

Initially, murine antibodies were obtained by hybridoma technology, for which Jerne, Köhler and Milstein received a Nobel prize. However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances. Major problems associated with murine antibodies included reduced stimulation ofcytotoxicity and the formation of complexes after repeated administration, which resulted in mildallergic reactions and sometimesanaphylactic shock.^[10]Hybridoma technology has been replaced byrecombinant DNA technology,transgenic mice andphage display.^[11]

To reduce murine antibodyimmunogenicity (attacks by the immune system against the antibody), murine molecules were engineered to remove immunogenic content and to increase immunologic efficiency.^[10] This was initially achieved by the production of chimeric (suffix-ximab) and humanized antibodies (suffix-zumab). Chimeric antibodies are composed of murine variable regions fused onto human constant regions. Taking human gene sequences from the kappa light chain and the IgG1 heavy chain results in antibodies that are approximately 65% human. This reduces immunogenicity, and thus increasesserumhalf-life.^{[citation needed]}

Humanised antibodies are produced by grafting murine hypervariable regions on amino acid domains into human antibodies. This results in a molecule of approximately 95% human origin. Humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold.^[12][13] Increases in antibody-antigen binding strength have been achieved by introducingmutations into thecomplementarity determining regions (CDR),^[14] using techniques such as chain-shuffling, randomization of complementarity-determining regions and antibodies with mutations within the variable regions induced by error-pronePCR,E. coli mutator strains andsite-specific mutagenesis.^[15]

Human monoclonal antibodies (suffix-umab) are produced usingtransgenic mice orphage display libraries by transferring humanimmunoglobulin genes into the murine genome and vaccinating the transgenic mouse against the desired antigen, leading to the production of appropriate monoclonal antibodies.^[11] Murine antibodies in vitro are thereby transformed into fully human antibodies.^[3]

The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms. Human IgGallotype is one of the many factors that can contribute to immunogenicity.^[16][17]

Anti-cancer monoclonal antibodies can be targeted against malignant cells by several mechanisms.Ramucirumab is a recombinant human monoclonal antibody and is used in the treatment of advanced malignancies.^[18] In childhood lymphoma, phase I and II studies have found a positive effect of using antibody therapy.^[19]

Monoclonal antibodies used to boost an anticancer immune response is another strategy to fight cancer where cancer cells are not targeted directly. Strategies include antibodies engineered to block mechanisms which downregulate anticancer immune responses, checkpoints such as PD-1 and CTLA-4 (checkpoint therapy),^[20] and antibodies modified to stimulate activation of immune cells.^[21]

Monoclonal antibodies used forautoimmune diseases includeinfliximab andadalimumab, which are effective inrheumatoid arthritis,Crohn's disease andulcerative colitis by their ability to bind to and inhibitTNF-α.^[22]Basiliximab anddaclizumab inhibitIL-2 on activatedT cells and thereby help preventing acuterejection of kidney transplants.^[22]Omalizumab inhibits humanimmunoglobulin E (IgE) and is useful in moderate-to-severe allergicasthma.^{[citation needed]}

Alzheimer's disease (AD) is a multi-faceted, age-dependent, progressive neurodegenerative disorder, and is a major cause of dementia.^[23] According to theAmyloid hypothesis, the accumulation of extracellularamyloid beta peptides (Aβ) into plaques via oligomerization leads to hallmark symptomatic conditions of AD through synaptic dysfunction and neurodegeneration.^[24] Immunotherapy via exogenous monoclonal antibody (mAb) administration has been known to treat various central nervous disorders. In the case of AD, immunotherapy is believed to inhibit Aβ-oligomerization or clearing of Aβ from the brain and thereby preventneurotoxicity.^[25]

However, mAbs are large molecules and due to theblood–brain barrier, uptake of mAb into the brain is extremely limited, only approximately 1 of 1000 mAb molecules is estimated to pass.^[25] However, thePeripheral Sink hypothesis proposes a mechanism where mAbs may not need to cross the blood–brain barrier.^[26] Therefore, many research studies are being conducted from failed attempts to treat AD in the past.^[24]

However, anti-Aβ vaccines can promote antibody-mediated clearance of Aβ plaques in transgenic mice models with amyloid precursor proteins (APP), and can reduce cognitive impairments.^[23]Vaccines can stimulate the immune system to produce its own antibodies, in the case of Alzheimer's disease by administration of the antigen Aβ.^[27] This is also known asactive immunotherapy. Another strategy is so calledpassive immunotherapy. In this case the antibodies is produced externally in cultured cells and are delivered to the patient in the form of a drug. In mice expressing APP, both active and passive immunization of anti-Aβ antibodies has been shown to be effective in clearing plaques, and can improve cognitive function.^[24]

Currently, there are twoFDA approved antibody therapies for Alzheimer's disease,Aducanemab andLecanemab. Aducanemab has receivedaccelerated approval while Lecanemab has received full approval.^[25] Several clinical trials using passive and active immunization have been performed and some are on the way with expected results in a couple of years.^[24][25] The implementation of these drugs is often during the early onset of AD. One trial testingForalumab seeks to determine if there is benefit in later stages of AD by reduction of brain inflammation.^[28] Other research and drug development for early intervention and AD prevention is ongoing. Examples of important mAb drugs that have been or are under evaluation for treatment of AD includeBapineuzumab,Solanezumab,Gautenerumab,Crenezumab,Aducanemab,Lecanemab andDonanemab.^[25]

Bapineuzumab, a humanized anti-Aβ mAb, is directed against the N-terminus of Aβ. Phase II clinical trials of Bapineuzumab in mild to moderate AD patients resulted in reduced Aβ concentration in the brain. However, in patients with increasedapolipoprotein (APOE) e4 carriers, Bapineuzumab treatment is also accompanied byvasogenic edema,^[29] a cytotoxic condition where the blood brain barrier has been disrupted thereby affecting white matter from excess accumulation of fluid from capillaries in intracellular and extracellular spaces of the brain.^[30]

In Phase III clinical trials, Bapineuzumab showed promising positive effect on biomarkers of AD but failed to show effect on cognitive decline. Therefore, Bapineuzumab was discontinued after failing in the Phase III clinical trial.^[30]

Solanezumab, an anti-Aβ mAb, targets the N-terminus of Aβ. In Phase I and Phase II of clinical trials, Solanezumab treatment resulted incerebrospinal fluid elevation of Aβ, thereby showing a reduced concentration of Aβ plaques. Additionally, there are no associated adverse side effects. Phase III clinical trials of Solanezumab brought about significant reduction in cognitive impairment in patients with mild AD, but not in patients with severe AD. However, Aβ concentration did not significantly change, along with other AD biomarkers, includingphospho-tau expression, and hippocampal volume. Phase III clinical trials of Solanezumab failed as it did not show effect on cognitive decline in comparison to placebo.^[31]

Lecanemab (BAN2401), is a humanized mAb that selectively targets toxic soluble Aβ protofibrils,^[32] In phase 3 clinical trials,^[33] Lecanemab showed a 27% slower cognitive decline after 18 months of treatment in comparison to placebo.^[34][35] The phase 3 clinical trials also reported infusion related reactions,amyloid-related imaging abnormalities and headaches as the most common side effects of Lecanemab. In July 2023 the FDA gave Lecanemab full approval for the treatment of Alzheimer's Disease^[36] and it was given the commercial name Leqembi.

Failure of several drugs in Phase III clinical trials has led to AD prevention and early intervention for onset AD treatment endeavours. Passive anti-Aβ mAb treatment can be used for preventive attempts to modify AD progression before it causes extensive brain damage and symptoms. Trials using mAb treatment for patients positive for genetic risk factors, and elderly patients positive for indicators of AD are underway. This includes anti-AB treatment in Asymptomatic Alzheimer's Disease (A4), the Alzheimer's Prevention Initiative (API), and DIAN-TU.^[26]The A4 study on older individuals who are positive for indicators of AD but are negative for genetic risk factors will test Solanezumab in Phase III Clinical Trials, as a follow-up of previous Solanezumab studies.^[26]DIAN-TU, launched in December 2012, focuses on young patients positive for genetic mutations that are risks for AD. This study uses Solanezumab and Gautenerumab. Gautenerumab, the first fully human MAB that preferentially interacts with oligomerized Aβ plaques in the brain, caused significant reduction in Aβ concentration in Phase I clinical trials, preventing plaque formation and concentration without altering plasma concentration of the brain. Phase II and III clinical trials are currently being conducted.^[26]

Radioimmunotherapy (RIT) involves the use ofradioactively-conjugated murine antibodies against cellular antigens. Most research involves their application tolymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were chosen, as their high immunogenicity promotes rapid tumor clearance.Tositumomab is an example used for non-Hodgkin's lymphoma.^{[citation needed]}

Antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer-associated monoclonal antibodies that are linked to a drug-activating enzyme. Systemic administration of a non-toxic agent results in the antibody's conversion to a toxic drug, resulting in a cytotoxic effect that can be targeted at malignant cells. The clinical success of ADEPT treatments is limited.^[37]

Antibody-drug conjugates (ADCs) are antibodies linked to one or more drug molecules. Typically when the ADC meets the target cell (e.g. a cancerous cell) the drug is released to kill it. Many ADCs are in clinical development. As of 2016^[update] a few have been approved.^{[citation needed]}

Immunoliposomes are antibody-conjugatedliposomes. Liposomes can carry drugs or therapeuticnucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells. Immunoliposomes have been successfully used in vivo to convey tumour-suppressing genes into tumours, using an antibody fragment against the humantransferrin receptor. Tissue-specific gene delivery using immunoliposomes has been achieved in brain and breast cancer tissue.^[38]

Checkpoint therapy uses antibodies and other techniques to circumvent the defenses that tumors use to suppress the immune system. Each defense is known as a checkpoint. Compound therapies combine antibodies to suppress multiple defensive layers. Known checkpoints includeCTLA-4 targeted by ipilimumab,PD-1 targeted by nivolumab andpembrolizumab and the tumor microenvironment.^[20]

Thetumor microenvironment (TME) features prevents the recruitment of T cells to the tumor. Ways include chemokine CCL² nitration, which traps T cells in thestroma. Tumor vasculature helps tumors preferentially recruit other immune cells over T cells, in part through endothelial cell (EC)–specific expression ofFasL,ET_BR, and B7H3.Myelomonocytic and tumor cells can up-regulate expression ofPD-L1, partly driven by hypoxic conditions and cytokine production, such as IFNβ. Aberrantmetabolite production in the TME, such as the pathway regulation byIDO, can affect T cell functions directly and indirectly via cells such as T_reg cells. CD8 cells can be suppressed by B cells regulation of TAM phenotypes. Cancer-associatedfibroblasts (CAFs) have multiple TME functions, in part throughextracellular matrix (ECM)–mediated T cell trapping andCXCL12-regulated T cell exclusion.^[39]

This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(May 2021)

The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specifictransplant rejection drug,OKT3 (also called muromonab), in 1986. This drug found use in solidorgan transplant recipients who becamesteroid resistant.^[40] Hundreds of therapies are undergoingclinical trials. Most are concerned with immunological and oncological targets.

Tositumomab – Bexxar – 2003 –CD20

Mogamulizumab – Poteligeo – August 2018 –CCR4

Moxetumomab pasudotox – Lumoxiti – September 2018 –CD22

Cemiplimab – Libtayo – September 2018 –PD-1

Polatuzumab vedotin – Polivy – June 2019 –CD79B

Thebispecific antibodies have arrived in the clinic. In 2009, the bispecific antibodycatumaxomab was approved in the European Union^[41][42] and was later withdrawn for commercial reasons.^[43] Others includeamivantamab,blinatumomab,teclistamab, andemicizumab.^[44]

Since 2000, the therapeutic market for monoclonal antibodies has grown exponentially. In 2006, the "big 5" therapeutic antibodies on the market werebevacizumab,trastuzumab (both oncology),adalimumab,infliximab (bothautoimmune and inflammatory disorders, 'AIID') andrituximab (oncology and AIID) accounted for 80% of revenues in 2006. In 2007, eight of the 20 best-selling biotechnology drugs in the U.S. are therapeutic monoclonal antibodies.^[45] This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.^[46]

• Cancer Management Handbook: Principles of Oncologic Pharmacotherapy(registration required)Archived 2009-05-15 at theWayback Machine

• Immunology
• Monoclonal antibodies for tumors
• Monoclonal antibodies
• Antiviral drugs

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