Each antibody binds only one specific antigen.

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),[1] 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.[4]

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

Monoclonal antibodies for cancer. ADEPT: antibody directed enzyme prodrug therapy; ADCC: antibody-dependent cell-mediated cytotoxicity; CDC: complement-dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain Fv fragment.[5]

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.[6][7] 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.[8][9] 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.[10] Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications.[11] 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.[10] Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display.[11]

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.[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 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.[12][13] Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity 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-prone PCR, E. coli mutator strains and site-specific mutagenesis.[15]

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.[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 IgG allotype is one of the many factors that can contribute to immunogenicity.[16][17]

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.[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]

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.[22] Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help preventing acute rejection of kidney transplants.[22] 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.[23] According to the Amyloid hypothesis, the accumulation of extracellular amyloid betapeptides (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, such as AD, by inhibiting Aβ-oligomerization thereby preventing neurotoxicity. However, mAbs are large for passive protein channels and are therefore inefficient due to the blood–brain barrier preventing mAb passage into the brain. 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.[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,[26] in this case by introducing Aβ into transgenic animal models, known as active immunization. They can also introduce antibodies into animal models, known as passive immunization. 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 no approved monoclonal antibody therapies for Alzheimer's disease, but several clinical trials using passive and active immunization approaches by development of certain drugs approved by the FDA are currently underway, and are expected to yield results in a couple of years.[24] The implementation of these drugs is during the onset of AD. Other research and drug development for early intervention and AD prevention is ongoing. Various drugs that are under research to treat AD include Bapineuzumab, Solanezumab, Gautenerumab, and BAN2401.

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 treatment is associated with reduced rate of accumulation of Aβ in the brain in APOE e4 patients, and no significant reduction of Aβ concentration in APOE e4 patients and non-APOE e4 patients. Therefore, Aβ plaque concentration was not reduced, and there is no significant clinical benefits in cognitive functioning. Bapineuzumab was discontinued after failing in Phase III clinical trial.[28]

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 are currently ongoing.[25]

BAN2401

BAN2401, is a humanized mAb that selectively targets toxic soluble Aβ protofibrils,[29] and the therapy is currently undergoing a phase 3 clinical trial which is expected to be completed in 2022.[30]

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.[25] 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.[25] 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.[25]

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.[31]

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. As of 2016 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.[32]

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.[20]

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.[33]

FDA-approved therapeutic 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.[34] Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

FDA approved therapeutic monoclonal antibodies
AntibodyBrand nameCompanyApproval dateRouteTypeTargetIndication
(Targeted disease)
BLA STNDrug Label
abciximabReoProCentocor12/22/1994intravenouschimeric FabGPIIb/IIIaPercutaneous coronary intervention103575Link
adalimumabHumiraAbbvie12/31/2002subcutaneousfully humanTNFRheumatoid arthritis125057Link
adalimumab-attoAmjevitaAmgen9/23/2016subcutaneousfully human, biosimilarTNFRheumatoid arthritis
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn's disease
Ulcerative colitis
Plaque psoriasis
761024Link
ado-trastuzumab emtansineKadcylaGenentech2/22/2013intravenoushumanized, antibody-drug conjugateHER2Metastatic breast cancer125427Link
alemtuzumabCampath, LemtradaGenzyme5/7/2001intravenoushumanizedCD52B-cell chronic lymphocytic leukemia103948Link
alirocumabPraluentSanofi Aventis7/24/2015subcutaneousfully humanPCSK9Heterozygous familial hypercholesterolemia
Refractory hypercholesterolemia
125559Link
atezolizumabTecentriqGenentech5/18/2016intravenoushumanizedPD-L1Urothelial carcinoma761034Link
atezolizumabTecentriqGenentech10/18/2016intravenoushumanizedPD-L1Urothelial carcinoma
Metastatic non-small cell lung cancer
761041Link
avelumabBavencioEMD Serono3/23/2017intravenousfully humanPD-L1Metastatic Merkel cell carcinoma761049Link
basiliximabSimulectNovartis5/12/1998intravenouschimericIL2RAProphylaxis of acute organ rejection in renal transplant103764Link
belimumabBenlystaHuman Genome Sciences3/9/2011intravenousfully humanBLySSystemic lupus erythematosus125370Link
bevacizumabAvastinGenentech2/26/2004intravenoushumanizedVEGFMetastatic colorectal cancer125085Link
bezlotoxumabZinplavaMerck10/21/2016intravenousfully humanClostridium difficile toxin BPrevent recurrence of Clostridium difficile infection761046Link
blinatumomabBlincytoAmgen12/3/2014intravenousmouse, bispecificCD19Precursor B-cell acute lymphoblastic leukemia125557Link
brentuximab vedotinAdcetrisSeattle Genetics9/19/2011intravenouschimeric, antibody-drug conjugateCD30Hodgkin lymphoma
Anaplastic large-cell lymphoma
125388Link
brodalumabSiliqValeant2/15/2017subcutaneouschimericIL17RAPlaque psoriasis761032Link
canakinumabIlarisNovartis6/17/2009subcutaneousfully humanIL1BCryopyrin-associated periodic syndrome125319Link
capromab pendetideProstaScintCytogen10/28/1996intravenousmurine, radiolabeledPSMADiagnostic imaging agent in newly diagnosed prostate cancer or post-prostatectomy103608Link
certolizumab pegolCimziaUCB (company)4/22/2008subcutaneoushumanizedTNFCrohn's disease125160Link
cetuximabErbituxImClone Systems2/12/2004intravenouschimericEGFRMetastatic colorectal carcinoma125084Link
daclizumabZenapaxRoche12/10/1997intravenoushumanizedIL2RAProphylaxis of acute organ rejection in renal transplant103749Link
daclizumabZinbrytaBiogen5/27/2016subcutaneoushumanizedIL2RMultiple sclerosis761029Link
daratumumabDarzalexJanssen Biotech11/16/2015intravenousfully humanCD38Multiple myeloma761036Link
denosumabProlia, XgevaAmgen6/1/2010subcutaneousfully humanRANKLPostmenopausal women with osteoporosis125320Link
dinutuximabUnituxinUnited Therapeutics3/10/2015intravenouschimericGD2Pediatric high-risk neuroblastoma125516Link
dupilumabDupixentRegeneron Pharmaceuticals3/28/2017subcutaneousfully humanIL4RAAtopic dermatitis, asthma761055Link
durvalumabImfinziAstraZeneca5/1/2017intravenousfully humanPD-L1Urothelial carcinoma761069Link
eculizumabSolirisAlexion3/16/2007intravenoushumanizedComplement component 5Paroxysmal nocturnal hemoglobinuria125166Link
elotuzumabEmplicitiBristol-Myers Squibb11/30/2015intravenoushumanizedSLAMF7Multiple myeloma761035Link
evolocumabRepathaAmgen8/27/2015subcutaneousfully humanPCSK9Heterozygous familial hypercholesterolemia
Refractory hypercholesterolemia
125522Link
golimumabSimponiCentocor4/24/2009subcutaneousfully humanTNFRheumatoid arthritis
Psoriatic arthritis
Ankylosing spondylitis
125289Link
golimumabSimponi AriaJanssen Biotech7/18/2013intravenousfully humanTNFRheumatoid arthritis125433Link
ibritumomab tiuxetanZevalinSpectrum Pharmaceuticals2/19/2002intravenousmurine, radioimmunotherapyCD20Relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma125019Link
idarucizumabPraxbindBoehringer Ingelheim10/16/2015intravenoushumanized FabdabigatranEmergency reversal of anticoagulant dabigatran761025Link
infliximabRemicadeCentocor8/24/1998intravenouschimericTNF alphaCrohn's disease103772Link
infliximab-abdaRenflexisSamsung Bioepis4/21/2017intravenouschimeric, biosimilarTNFCrohn's disease
Ulcerative colitis
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
761054Link
infliximab-dyybInflectraCelltrion Healthcare4/5/2016intravenouschimeric, biosimilarTNFCrohn's disease
Ulcerative colitis
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
125544Link
ipilimumabYervoyBristol-Myers Squibb3/25/2011intravenousfully humanCTLA-4Metastatic melanoma125377Link
ixekizumabTaltzEli Lilly3/22/2016subcutaneoushumanizedIL17APlaque psoriasis125521Link
mepolizumabNucalaGlaxoSmithKline11/4/2015subcutaneoushumanizedIL5Severe asthma125526Link
natalizumabTysabriBiogen Idec11/23/2004intravenoushumanizedalpha-4 integrinMultiple sclerosis125104Link
necitumumabPortrazzaEli Lilly11/24/2015intravenousfully humanEGFRMetastatic squamous non-small cell lung carcinoma125547Link
nivolumabOpdivoBristol-Myers Squibb12/22/2014intravenousfully humanPD-1Metastatic melanoma125554Link
nivolumabOpdivoBristol-Myers Squibb3/4/2015intravenousfully humanPD-1Metastatic squamous non-small cell lung carcinoma125527Link
obiltoxaximabAnthemElusys Therapeutics3/18/2016intravenouschimericProtective antigen of the Anthrax toxinInhalational anthrax125509Link
obinutuzumabGazyvaGenentech11/1/2013intravenoushumanizedCD20Chronic lymphocytic leukemia125486Link
ocrelizumabOcrevusGenentech3/28/2017intravenoushumanizedCD20Multiple sclerosis761053Link
ofatumumabArzerraGlaxo Grp10/26/2009intravenousfully humanCD20Chronic lymphocytic leukemia125326Link
olaratumabLartruvoEli Lilly10/19/2016intravenousfully humanPDGFRASoft tissue sarcoma761038Link
omalizumabXolairGenentech6/20/2003subcutaneoushumanizedIgEModerate to severe persistent asthma103976Link
palivizumabSynagisMedImmune6/19/1998intramuscularhumanizedF protein of RSVRespiratory syncytial virus103770Link
panitumumabVectibixAmgen9/27/2006intravenousfully humanEGFRMetastatic colorectal cancer125147Link
pembrolizumabKeytrudaMerck9/4/2014intravenoushumanizedPD-1Metastatic melanoma125514Link
pertuzumabPerjetaGenentech6/8/2012intravenoushumanizedHER2Metastatic breast cancer125409Link
ramucirumabCyramzaEli Lilly4/21/2014intravenousfully humanVEGFR2Gastric cancer125477Link
ranibizumabLucentisGenentech6/30/2006intravitreal injectionhumanizedVEGFR1
VEGFR2
Wet age-related macular degeneration125156Link
raxibacumabRaxibacumabHuman Genome Sciences12/24/2012intravenousfully humanProtective antigen of Bacillus anthracisInhalational anthrax125349Link
reslizumabCinqairTeva3/23/2016intravenoushumanizedIL5Severe asthma761033Link
rituximabRituxanGenentech11/26/1997intravenouschimericCD20B-cell non-Hodgkin's lymphoma103705Link
secukinumabCosentyxNovartis1/21/2015subcutaneousfully humanIL17APlaque psoriasis125504Link
siltuximabSylvantJanssen Biotech4/23/2014intravenouschimericIL6Multicentric Castleman's disease125496Link
tocilizumabActemraGenentech1/8/2010intravenoushumanizedIL6RRheumatoid arthritis125276Link
tocilizumabActemraGenentech10/21/2013intravenous
subcutaneous
humanizedIL6RRheumatoid arthritis
Polyarticular juvenile idiopathic arthritis
Systemic juvenile idiopathic arthritis
125472Link
trastuzumabHerceptinGenentech9/25/1998intravenoushumanizedHER2Metastatic breast cancer103792Link
ustekinumabStelaraCentocor9/25/2009subcutaneousfully humanIL12
IL23
Plaque psoriasis125261Link
ustekinumabStelaraJanssen Biotech9/23/2016subcutaneous
intravenous
fully humanIL12
IL23
Plaque psoriasis
Psoriatic arthritis
Crohn's disease
761044Link
vedolizumabEntyvioTakeda5/20/2014intravenoushumanizedintegrin receptorUlcerative colitis
Crohn's disease
125476Link
sarilumabKevzaraSanofi Aventis5/22/17subcutaneousfully humanIL6RRheumatoid arthritis761037Link
rituximab and hyaluronidaseRituxan HycelaGenentech6/22/17subcutaneouschimeric, co-formulatedCD20Follicular lymphoma
Diffuse large B-cell lymphoma
Chronic lymphocytic leukemia
761064Link
guselkumabTremfyaJanssen Biotech7/13/17subcutaneousfully humanIL23Plaque psoriasis761061Link
inotuzumab ozogamicinBesponsaWyeth8/17/17intravenoushumanized, antibody-drug conjugateCD22Precursor B-cell acute lymphoblastic leukemia761040Link
adalimumab-adbmCyltezoBoehringer Ingelheim8/25/17subcutaneousfully human, biosimilarTNFRheumatoid arthritis
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn's disease
Ulcerative colitis
Plaque psoriasis
761058Link
gemtuzumab ozogamicinMylotargWyeth9/1/17intravenoushumanized, antibody-drug conjugateCD33Acute myeloid leukemia761060Link
bevacizumab-awwbMvasiAmgen9/14/17intravenoushumanized, biosimilarVEGFMetastatic colorectal cancer
Non-squamous Non-small-cell lung carcinoma
Glioblastoma
Metastatic renal cell carcinoma
Cervical cancer
761028Link
benralizumabFasenraAstrazeneca11/14/17subcutaneoushumanizedinterleukin-5 receptor alpha subunitSevere asthma, eosinophilic phenotype761070Link
emicizumab-kxwhHemlibraGenentech11/16/17subcutaneoushumanized, bispecificFactor IXa, Factor XHemophilia A (congenital Factor VIII deficiency) with Factor VIII inhibitors.761083Link
trastuzumab-dkstOgivriMylan12/1/17intravenoushumanized, biosimilarHER2HER2-overexpressing breast cancer, metaststic gastric or gastroesophageal junction adenocarcinoma761074Link
infliximab-qbtxIxifiPfizer12/13/17intravenouschimeric, biosimilarTNFCrohn's disease
Ulcerative colitis
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Plaque psoriasis
761072Link
ibalizumab-uiykTrogarzoTaiMed Biologics3/6/18intravenoushumanizedCD4HIV761065Link
tildrakizumab-asmnIlumyaMerck3/20/18subcutaneoushumanizedIL23Plaque psoriasis761067Link
burosumab-twzaCrysvitaUltragenyx4/17/18subcutaneousfully humanFGF23X-linked hypophosphatemia761068Link
erenumab-aooeAimovigAmgen5/17/18subcutaneousfully humanCGRP receptorMigraine headache prevention761077Link

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.[35][36]

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.[37] This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.[38]

References

  1. 1 2 Yao, Sheng; Zhu, Yuwen; Chen, Lieping (2013). "Advances in targeting cell surface signalling molecules for immune modulation". Nature Reviews. Drug Discovery. 12 (2): 130–146. doi:10.1038/nrd3877. ISSN 1474-1776. PMC 3698571. PMID 23370250.
  2. Janeway, Charles; Paul Travers; Mark Walport; Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 978-0-8153-4101-7.
  3. 1 2 Janeway CA Jr.; et al. (2005). Immunobiology (6th ed.). Garland Science. ISBN 978-0-443-07310-6.
  4. 1 2 Baxter, David (December 2007). "Active and passive immunity, vaccine types, excipients and licensing". Occupational Medicine. 57 (8): 552–6. doi:10.1093/occmed/kqm110. PMID 18045976.
  5. Modified from Carter P (November 2001). "Improving the efficacy of antibody-based cancer therapies". Nature Reviews. Cancer. 1 (2): 118–29. doi:10.1038/35101072. PMID 11905803. S2CID 10169378.
  6. Prof FC Breedveld (2000). "Therapeutic monoclonal antibodies". Lancet. 355 (9205): 735–740. doi:10.1016/S0140-6736(00)01034-5. PMID 10703815. S2CID 43781004.
  7. Köhler G, Milstein C (August 1975). "Continuous cultures of fused cells secreting antibody of predefined specificity". Nature. 256 (5517): 495–7. Bibcode:1975Natur.256..495K. doi:10.1038/256495a0. PMID 1172191. S2CID 4161444.
  8. Nadler LM, Stashenko P, Hardy R, Kaplan WD, Button LN, Kufe DW, Antman KH, Schlossman SF (September 1980). "Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen". Cancer Research. 40 (9): 3147–54. PMID 7427932.
  9. Ritz J, Schlossman SF (January 1982). "Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma". Blood. 59 (1): 1–11. doi:10.1182/blood.V59.1.1.1. PMID 7032624.
  10. 1 2 3 Stern M, Herrmann R (April 2005). "Overview of monoclonal antibodies in cancer therapy: present and promise". Critical Reviews in Oncology/Hematology. 54 (1): 11–29. doi:10.1016/j.critrevonc.2004.10.011. PMID 15780905.
  11. 1 2 3 Hudson PJ, Souriau C (January 2003). "Engineered antibodies". Nature Medicine. 9 (1): 129–34. doi:10.1038/nm0103-129. PMID 12514726. S2CID 19243664.
  12. Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM (May 1992). "Humanization of an anti-p185HER2 antibody for human cancer therapy". Proceedings of the National Academy of Sciences of the United States of America. 89 (10): 4285–9. Bibcode:1992PNAS...89.4285C. doi:10.1073/pnas.89.10.4285. PMC 49066. PMID 1350088.
  13. Presta LG, Lahr SJ, Shields RL, Porter JP, Gorman CM, Fendly BM, Jardieu PM (September 1993). "Humanization of an antibody directed against IgE". Journal of Immunology. 151 (5): 2623–32. doi:10.4049/jimmunol.151.5.2623. PMID 8360482. S2CID 904440.
  14. Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S, Padlan EA, Davies D, Tulip WR (1989). "Conformations of immunoglobulin hypervariable regions". Nature. 342 (6252): 877–83. Bibcode:1989Natur.342..877C. doi:10.1038/342877a0. PMID 2687698. S2CID 4241051.
  15. Waldmann TA (March 2003). "Immunotherapy: past, present and future". Nature Medicine. 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576. S2CID 9745527.
  16. Jefferis R, Lefranc MP (July–August 2009). "Human immunoglobulin allotypes: possible implications for immunogenicity". mAbs. 1 (4): 332–8. doi:10.4161/mabs.1.4.9122. PMC 2726606. PMID 20073133.
  17. Chapman K, Pullen N, Coney L, Dempster M, Andrews L, Bajramovic J, Baldrick P, Buckley L, Jacobs A, Hale G, Green C, Ragan I, Robinson V (2009). "Preclinical development of monoclonal antibodies: considerations for the use of non-human primates". mAbs. 1 (5): 505–16. doi:10.4161/mabs.1.5.9676. PMC 2759500. PMID 20065651.
  18. Vennepureddy A, Singh P, Rastogi R, Atallah JP, Terjanian T (June 2016). "Evolution of ramucirumab in the treatment of cancer – A review of literature". Journal of Oncology Pharmacy Practice. 23 (7): 525–539. doi:10.1177/1078155216655474. PMID 27306885. S2CID 21298489.
  19. de Zwart, Verena; Gouw, Samantha C; Meyer-Wentrup, Friederike AG (2016-01-19). "Antibody therapies for lymphoma in children". Cochrane Database of Systematic Reviews. 2016 (1): CD011181. doi:10.1002/14651858.cd011181.pub2. ISSN 1465-1858. PMC 8719646. PMID 26784573.
  20. 1 2 Sharma P, Allison JP (April 2015). "The future of immune checkpoint therapy". Science. 348 (6230): 56–61. Bibcode:2015Sci...348...56S. doi:10.1126/science.aaa8172. PMID 25838373. S2CID 4608450.
  21. Dempke, Wolfram C.M.; Fenchel, Klaus; Uciechowski, Peter; Dale, Stephen P. (March 2017). "Second- and third-generation drugs for immuno-oncology treatment—The more the better?". European Journal of Cancer. 74: 55–72. doi:10.1016/j.ejca.2017.01.001. PMID 28335888.
  22. 1 2 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 241. ISBN 978-0-443-07145-4.
  23. 1 2 Pul, Refik; Dodel, Richard; Stangel, Martin (March 2011). "Antibody-based therapy in Alzheimer's disease". Expert Opinion on Biological Therapy. 11 (3): 343–357. doi:10.1517/14712598.2011.552884. PMID 21261567. S2CID 19375883.
  24. 1 2 3 4 van Dyck, Christopher (August 24, 2017). "Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise". Biological Psychiatry. 83 (4): 311–319. doi:10.1016/j.biopsych.2017.08.010. PMC 5767539. PMID 28967385.
  25. 1 2 3 4 5 Panza, F.; Imbimbo, B. P.; Logroscino, G. (2014). "Amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease: The point of no return?". Expert Opinion on Biological Therapy. 14 (10): 1465–76. doi:10.1517/14712598.2014.935332. PMID 24981190. S2CID 26323381.
  26. Hanan, Eilat; Solomon, Beka (January 1996). "Inhibitory effect of monoclonal antibodies on Alzheimer's P-amyloid peptide aggregation". Amyloid. 2 (3): 130–133. doi:10.3109/13506129609014365.
  27. Goel, Ayush (20 August 2013). "Vasogenic cerebral oedema". radiopaedia.org. Retrieved 2017-11-01.
  28. 1 2 Panza, F.; Imbimbo, B.P.; D'aOnofrio, G.; Pietrarossa, G.; Seripa, Davide; Frisardi, V. (November 2010). "Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease". Immunotherapy. 2 (6): 767–82. doi:10.2217/imt.10.80. PMID 21091109.
  29. Logovinsky, Veronika; Satlin, Andrew; Lai, Robert; Swanson, Chad; Kaplow, June; Osswald, Gunilla; Basun, Hans; Lannfelt, Lars (December 2016). "Safety and tolerability of BAN2401 – a clinical study in Alzheimer's disease with a protofibril selective Aβ antibody". Alzheimer's Research & Therapy. 8 (1): 14. doi:10.1186/s13195-016-0181-2. ISSN 1758-9193. PMC 4822297. PMID 27048170.
  30. "A Study to Confirm Safety and Efficacy of BAN2401 in Participants With Early Alzheimer's Disease". Case Medical Research. 2019-03-25. doi:10.31525/ct1-nct03887455. ISSN 2643-4652. S2CID 242999976.
  31. Francis RJ, Sharma SK, Springer C, Green AJ, Hope-Stone LD, Sena L, Martin J, Adamson KL, Robbins A, Gumbrell L, O'Malley D, Tsiompanou E, Shahbakhti H, Webley S, Hochhauser D, Hilson AJ, Blakey D, Begent RH (September 2002). "A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours". British Journal of Cancer. 87 (6): 600–7. doi:10.1038/sj.bjc.6600517. PMC 2364249. PMID 12237768.
  32. Krauss WC, Park JW, Kirpotin DB, Hong K, Benz CC (2000). "Emerging antibody-based HER2 (ErbB-2/neu) therapeutics". Breast Disease. 11: 113–24. doi:10.3233/bd-1999-11110. PMID 15687597.
  33. Joyce JA, Fearon DT (April 2015). "T cell exclusion, immune privilege, and the tumor microenvironment". Science. 348 (6230): 74–80. Bibcode:2015Sci...348...74J. doi:10.1126/science.aaa6204. PMID 25838376. S2CID 11603692.
  34. Hooks MA, Wade CS, Millikan WJ (1991). "Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation". Pharmacotherapy. 11 (1): 26–37. doi:10.1002/j.1875-9114.1991.tb03595.x. PMID 1902291. S2CID 25271222.
  35. Chames P, Baty D (2009). "Bispecific antibodies for cancer therapy: the light at the end of the tunnel?". mAbs. 1 (6): 539–47. doi:10.4161/mabs.1.6.10015. PMC 2791310. PMID 20073127.
  36. Linke, Rolf; Klein, Anke; Seimetz, Diane (2010). "Catumaxomab: Clinical development and future directions". mAbs. 2 (2): 129–136. doi:10.4161/mabs.2.2.11221. PMC 2840231. PMID 20190561.
  37. Scolnik PA (2009). "mAbs: a business perspective". mAbs. 1 (2): 179–84. doi:10.4161/mabs.1.2.7736. PMC 2725420. PMID 20061824.
  38. Kelley B (2009). "Industrialization of mAb production technology: the bioprocessing industry at a crossroads". mAbs. 1 (5): 443–52. doi:10.4161/mabs.1.5.9448. PMC 2759494. PMID 20065641.
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