Monoclonal antibody therapy explained

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. 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), to cause the immune system to attack specific cells, or to bring a drug to a specific cell type (such as with radioimmunotherapy which delivers cytotoxic radiation).

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

Antibody structure and function

Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, approximately 150 kDa and are composed of two kinds of polypeptide 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 enzyme papain, the Fab (fragment-antigen binding) part can be separated from the Fc (fragment crystallizable region) part of the molecule. The Fab fragments contain the variable domains, which consist of three antibody hypervariable amino acid domains responsible for the antibody specificity embedded into constant regions. The four known IgG subclasses are involved in antibody-dependent cellular cytotoxicity.[2] Antibodies are a key component of the adaptive 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 of monoclonal 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 via passive immunity or active 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.

Monoclonal antibody therapy may prove to be beneficial for cancer, autoimmune diseases, and neurological disorders that result in the degeneration of body cells, such as Alzheimer'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, tumor cells 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 unusual antigens. Some such tumor 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.

History

Immunotherapy developed in the 1970s following the discovery of the structure of antibodies and the development of hybridoma technology, which provided the first reliable source of monoclonal antibodies.[5] [6] These advances allowed for the specific targeting of tumors both in vitro and in vivo. Initial research on malignant neoplasms found mAb therapy of limited and generally short-lived success with blood malignancies.[7] [8] Treatment also had to be tailored to each individual patient, which was impracticable in routine clinical settings.

Four major antibody types that have been developed are murine, chimeric, humanised and human. Antibodies of each type are distinguished by suffixes on their name.

Murine

Initial therapeutic antibodies were murine analogues (suffix -omab). These antibodies have: a short half-life in vivo (due to immune complex formation), limited penetration into tumour sites and inadequately recruit host effector functions.[9] Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications.[10] Understanding of proteomics has proven essential in identifying novel tumour targets.

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 of cytotoxicity and the formation of complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock. Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display.[10]

Chimeric and humanized

To reduce murine antibody immunogenicity (attacks by the immune system against the antibody), murine molecules were engineered to remove immunogenic content and to increase immunologic efficiency. 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 increases serum half-life.

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.[11] [12] Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR),[13] using techniques such as chain-shuffling, randomization of complementarity-determining regions and antibodies with mutations within the variable regions induced by error-prone PCR, E. coli mutator strains and site-specific mutagenesis.[14]

Human monoclonal antibodies

Human monoclonal antibodies (suffix -umab) are produced using transgenic mice or phage display libraries by transferring human immunoglobulin genes into the murine genome and vaccinating the transgenic mouse against the desired antigen, leading to the production of appropriate monoclonal antibodies. Murine antibodies in vitro are thereby transformed into fully human antibodies.

The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms. Human IgG allotype is one of the many factors that can contribute to immunogenicity.[15] [16]

Targeted conditions

Cancer

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.[17] In childhood lymphoma, phase I and II studies have found a positive effect of using antibody therapy.[18]

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),[19] and antibodies modified to stimulate activation of immune cells.[20]

Autoimmune diseases

Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn's disease and ulcerative colitis by their ability to bind to and inhibit TNF-α.[21] Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help preventing acute rejection of kidney transplants.[21] Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-to-severe allergic asthma.

Alzheimer's disease

Alzheimer's disease (AD) is a multi-faceted, age-dependent, progressive neurodegenerative disorder, and is a major cause of dementia.[22] According to the Amyloid hypothesis, the accumulation of extracellular amyloid beta peptides (Aβ) into plaques via oligomerization leads to hallmark symptomatic conditions of AD through synaptic dysfunction and neurodegeneration.[23] 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 prevent neurotoxicity.[24]

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

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. Vaccines can stimulate the immune system to produce its own antibodies, in the case of Alzheimer's disease by administration of the antigen Aβ. [26] This is also known as active immunotherapy. Another strategy is so called passive 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.

Currently, there are two FDA approved antibody therapies for Alzheimer's disease, Aducanemab and Lecanemab. Aducanemab has received accelerated approval while Lecanemab has received full approval. 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. The implementation of these drugs is often during the early onset of AD. 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 include Bapineuzumab, Solanezumab, Gautenerumab, Crenezumab, Aducanemab, Lecanemab and Donanemab.

Bapineuzumab

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 increased apolipoprotein (APOE) e4 carriers, Bapineuzumab treatment is also accompanied by vasogenic edema,[27] 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.[28]

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.

Solanezumab

Solanezumab, an anti-Aβ mAb, targets the N-terminus of Aβ. In Phase I and Phase II of clinical trials, Solanezumab treatment resulted in cerebrospinal 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, including phospho-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. [29]

Lecanemab

Lecanemab (BAN2401), is a humanized mAb that selectively targets toxic soluble Aβ protofibrils,[30] In phase 3 clinical trials,[31] Lecanemab showed a 27% slower cognitive decline after 18 months of treatment in comparison to placebo.[32] [33] 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 [34] and it was given the commercial name Leqembi.

Preventive trials

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.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.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.

Therapy types

Radioimmunotherapy

Radioimmunotherapy (RIT) involves the use of radioactively-conjugated murine antibodies against cellular antigens. Most research involves their application to lymphomas, 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.

Antibody-directed enzyme prodrug therapy

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.[35]

Antibody-drug conjugates

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. a few have been approved.

Immunoliposome therapy

Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides 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 human transferrin receptor. Tissue-specific gene delivery using immunoliposomes has been achieved in brain and breast cancer tissue.[36]

Checkpoint therapy

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 include CTLA-4 targeted by ipilimumab, PD-1 targeted by nivolumab and pembrolizumab and the tumor microenvironment.[19]

The tumor microenvironment (TME) features prevents the recruitment of T cells to the tumor. Ways include chemokine CCL2 nitration, which traps T cells in the stroma. Tumor vasculature helps tumors preferentially recruit other immune cells over T cells, in part through endothelial cell (EC)–specific expression of FasL, ETBR, and B7H3. Myelomonocytic and tumor cells can up-regulate expression of PD-L1, partly driven by hypoxic conditions and cytokine production, such as IFNβ. Aberrant metabolite production in the TME, such as the pathway regulation by IDO, can affect T cell functions directly and indirectly via cells such as Treg cells. CD8 cells can be suppressed by B cells regulation of TAM phenotypes. Cancer-associated fibroblasts (CAFs) have multiple TME functions, in part through extracellular matrix (ECM)–mediated T cell trapping and CXCL12-regulated T cell exclusion.[37]

FDA-approved therapeutic antibodies

See main article: List of therapeutic monoclonal antibodies.

The first FDA-approved therapeutic monoclonal antibody was a murine IgG2a CD3 specific transplant rejection drug, OKT3 (also called muromonab), in 1986. This drug found use in solid organ transplant recipients who became steroid resistant.[38] Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

Brand name Company Approval date Route Type Target Indication
(Targeted disease)
BLA STN Drug Label
ReoPro 12/22/1994 intravenous chimeric Fab 103575 Link
Humira 12/31/2002 subcutaneous fully human 125057 Link
Cyltezo 8/25/17 subcutaneous 761058 Link
Amjevita 9/23/2016 subcutaneous 761024 Link
Kadcyla 2/22/2013 intravenous 125427 Link
Campath, Lemtrada 5/7/2001 intravenous humanized 103948 Link
Praluent 7/24/2015 subcutaneous fully human 125559 Link
Tecentriq 5/18/2016 intravenous humanized 761034 Link
Tecentriq 10/18/2016 intravenous humanized 761041 Link
Bavencio 3/23/2017 intravenous fully human 761049 Link
Simulect 5/12/1998 intravenous chimeric 103764 Link
Benlysta 3/9/2011 intravenous fully human 125370 Link
Fasenra 11/14/17 subcutaneous humanized Severe asthma, eosinophilic phenotype 761070 Link
Avastin 2/26/2004 intravenous humanized 125085 Link
Mvasi 9/14/17 intravenous 761028 Link
Zinplava 10/21/2016 intravenous fully human 761046 Link
Blincyto 12/3/2014 intravenous mouse, bispecific 125557 Link
Adcetris 9/19/2011 intravenous 125388 Link
Siliq 2/15/2017 subcutaneous chimeric 761032 Link
Crysvita 4/17/18 subcutaneous fully human 761068 Link
Ilaris 6/17/2009 subcutaneous fully human 125319 Link
ProstaScint 10/28/1996 intravenous murine, radiolabeled 103608 Link
Cimzia 4/22/2008 subcutaneous humanized 125160 Link
Erbitux 2/12/2004 intravenous chimeric 125084 Link
Zenapax 12/10/1997 intravenous humanized 103749 Link
Zinbryta 5/27/2016 subcutaneous humanized 761029 Link
Darzalex 11/16/2015 intravenous fully human 761036 Link
Prolia, Xgeva 6/1/2010 subcutaneous fully human 125320 Link
Unituxin 3/10/2015 intravenous chimeric 125516 Link
Dupixent 3/28/2017 subcutaneous fully human 761055 Link
Imfinzi 5/1/2017 intravenous fully human 761069 Link
Soliris 3/16/2007 intravenous humanized 125166 Link
Empliciti 11/30/2015 intravenous humanized 761035 Link
Hemlibra 11/16/17 subcutaneous humanized, bispecific Hemophilia A (congenital Factor VIII deficiency) with Factor VIII inhibitors. 761083 Link
Aimovig 5/17/18 subcutaneous fully human CGRP receptor Migraine headache prevention 761077 Link
Repatha 8/27/2015 subcutaneous fully human 125522 Link
Mylotarg 9/1/17 intravenous 761060 Link
Simponi 4/24/2009 subcutaneous fully human 125289 Link
Simponi Aria 7/18/2013 intravenous fully human 125433 Link
Tremfya 7/13/17 subcutaneous fully human 761061 Link
Trogarzo 3/6/18 intravenous humanized 761065 Link
Zevalin 2/19/2002 intravenous murine, radioimmunotherapy 125019 Link
Praxbind 10/16/2015 intravenous humanized Fab 761025 Link
Remicade 8/24/1998 intravenous chimeric 103772 Link
Renflexis 4/21/2017 intravenous 761054 Link
Inflectra 4/5/2016 intravenous 125544 Link
Ixifi 12/13/17 intravenous 761072 Link
Besponsa 8/17/17 intravenous 761040 Link
Yervoy 3/25/2011 intravenous fully human 125377 Link
Taltz 3/22/2016 subcutaneous humanized125521 Link
Nucala 11/4/2015 subcutaneous humanized 125526 Link
Tysabri 11/23/2004 intravenous humanized 125104 Link
Portrazza 11/24/2015 intravenous fully human 125547 Link
Opdivo 3/4/2015intravenous fully human 125527 Link
Opdivo 12/22/2014 intravenous fully human 125554 Link
Anthem 3/18/2016 intravenous chimeric 125509 Link
Gazyva 11/1/2013 intravenous humanized 125486 Link
Ocrevus 3/28/2017 intravenous humanized761053 Link
Arzerra 10/26/2009 intravenous fully human 125326 Link
Lartruvo 10/19/2016 intravenous fully human 761038 Link
Xolair 6/20/2003 subcutaneous humanized 103976 Link
Synagis 6/19/1998intramuscular humanized 103770 Link
Vectibix 9/27/2006 intravenous fully human 125147 Link
Keytruda 9/4/2014 intravenous humanized 125514 Link
Perjeta 6/8/2012 intravenous humanized 125409 Link
Cyramza 4/21/2014 intravenous fully human 125477 Link
Lucentis 6/30/2006 intravitreal injection humanized 125156 Link
Raxibacumab 12/24/2012 intravenous fully human 125349 Link
Cinqair 3/23/2016 intravenous humanized 761033 Link
Rituxan 11/26/1997 intravenous chimeric 103705 Link
Rituxan Hycela 6/22/17 subcutaneous chimeric, co-formulated 761064 Link
Kevzara 5/22/17 subcutaneous fully human 761037 Link
Cosentyx 1/21/2015 subcutaneous (2015)
intravenous (2023)
fully human 125504 Link
Sylvant 4/23/2014 intravenous chimeric 125496 Link
Ilumya 3/20/18 subcutaneous humanized 761067 Link
Actemra 1/8/2010 intravenous humanized 125276 Link
Actemra 10/21/2013 intravenous
subcutaneous
humanized 125472 Link
Herceptin 9/25/1998 intravenous humanized 103792 Link
Ogivri 12/1/17 intravenous HER2-overexpressing breast cancer, metaststic gastric or gastroesophageal junction adenocarcinoma 761074 Link
Stelara 9/25/2009 subcutaneous fully human 125261 Link
Stelara 9/23/2016 subcutaneous
intravenous
fully human 761044 Link
Entyvio 5/20/2014 intravenous humanized integrin receptor 125476 Link

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

The bispecific antibodies have yielded promising results in clinical trials. In April 2009, the bispecific antibody catumaxomab was approved in the European Union.[39] [40]

Economics

Since 2000, the therapeutic market for monoclonal antibodies has grown exponentially. In 2006, the "big 5" therapeutic antibodies on 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 biotechnology drugs in the U.S. are therapeutic monoclonal antibodies.[41] This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.[42]

External links

Notes and References

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