Monoclonal antibody therapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses.[1] More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.[2]

Each antibody binds only one specific antigen.

It is possible to create a mAb that is specific to almost any extracellular/cell surface target. Research and development is underway to create antibodies for diseases (such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Ebola[3] and different types of cancers).

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 constant) 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.[4] 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.[5] 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.[6] 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.[6]

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.[7]

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.[8][9] 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.[10][11] 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.[12] Chimeric and humanized antibodies have generally replaced them in therapeutic antibody applications.[13] 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 complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock.[12] Hybridoma technology has been replaced by recombinant DNA technology, transgenic mice and phage display.[13]

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.[12] 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.[14][15] Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR),[16] 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.[1]

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.[13] Murine antibodies in vitro are thereby transformed into fully human antibodies.[5]

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.[17][18]

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.[19] In childhood lymphoma, phase I and II studies have found a positive effect of using antibody therapy.[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 betapeptides (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, 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.[24] Therefore, many research studies are being conducted from failed attempts to treat AD in the past.[23]

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.[22] Vaccines can stimulate the immune system to produce its own antibodies,[25] 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.[23]. Therefore, 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.[23] 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, and Gautenerumab.

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,[26] 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.[27] 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[27]

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.[24]

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.[24] 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.[24] 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.[24]

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.[28]

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.[29]

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.[2]

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, ET_BR, 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 T_reg 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.[30]

FDA-approved therapeutic antibodies

For a more comprehensive list, see 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.[31] Hundreds of therapies are undergoing clinical trials. Most are concerned with immunological and oncological targets.

FDA approved therapeutic monoclonal antibodies

Antibody	Brand name	Company	Approval date	Route	Type	Target	Indication (Targeted disease)	BLA STN	Drug Label
abciximab	ReoPro	Centocor	12/22/1994	intravenous	chimeric Fab	GPIIb/IIIa	Percutaneous coronary intervention	103575	Link
adalimumab	Humira	Abbvie	12/31/2002	subcutaneous	fully human	TNF	Rheumatoid arthritis	125057	Link
adalimumab-atto	Amjevita	Amgen	9/23/2016	subcutaneous	fully human, biosimilar	TNF	Rheumatoid arthritis Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Crohn's disease Ulcerative colitis Plaque psoriasis	761024	Link
ado-trastuzumab emtansine	Kadcyla	Genentech	2/22/2013	intravenous	humanized, antibody-drug conjugate	HER2	Metastatic breast cancer	125427	Link
alemtuzumab	Campath, Lemtrada	Genzyme	5/7/2001	intravenous	humanized	CD52	B-cell chronic lymphocytic leukemia	103948	Link
alirocumab	Praluent	Sanofi Aventis	7/24/2015	subcutaneous	fully human	PCSK9	Heterozygous familial hypercholesterolemia Refractory hypercholesterolemia	125559	Link
atezolizumab	Tecentriq	Genentech	5/18/2016	intravenous	humanized	PD-L1	Urothelial carcinoma	761034	Link
atezolizumab	Tecentriq	Genentech	10/18/2016	intravenous	humanized	PD-L1	Urothelial carcinoma Metastatic non-small cell lung cancer	761041	Link
avelumab	Bavencio	EMD Serono	3/23/2017	intravenous	fully human	PD-L1	Metastatic Merkel cell carcinoma	761049	Link
basiliximab	Simulect	Novartis	5/12/1998	intravenous	chimeric	IL2RA	Prophylaxis of acute organ rejection in renal transplant	103764	Link
belimumab	Benlysta	Human Genome Sciences	3/9/2011	intravenous	fully human	BLyS	Systemic lupus erythematosus	125370	Link
bevacizumab	Avastin	Genentech	2/26/2004	intravenous	humanized	VEGF	Metastatic colorectal cancer	125085	Link
bezlotoxumab	Zinplava	Merck	10/21/2016	intravenous	fully human	Clostridium difficile toxin B	Prevent recurrence of Clostridium difficile infection	761046	Link
blinatumomab	Blincyto	Amgen	12/3/2014	intravenous	mouse, bispecific	CD19	Precursor B-cell acute lymphoblastic leukemia	125557	Link
brentuximab vedotin	Adcetris	Seattle Genetics	9/19/2011	intravenous	chimeric, antibody-drug conjugate	CD30	Hodgkin lymphoma Anaplastic large-cell lymphoma	125388	Link
brodalumab	Siliq	Valeant	2/15/2017	subcutaneous	chimeric	IL17RA	Plaque psoriasis	761032	Link
canakinumab	Ilaris	Novartis	6/17/2009	subcutaneous	fully human	IL1B	Cryopyrin-associated periodic syndrome	125319	Link
capromab pendetide	ProstaScint	Cytogen	10/28/1996	intravenous	murine, radiolabeled	PSMA	Diagnostic imaging agent in newly diagnosed prostate cancer or post-prostatectomy	103608	Link
certolizumab pegol	Cimzia	UCB (company)	4/22/2008	subcutaneous	humanized	TNF	Crohn's disease	125160	Link
cetuximab	Erbitux	ImClone Systems	2/12/2004	intravenous	chimeric	EGFR	Metastatic colorectal carcinoma	125084	Link
daclizumab	Zenapax	Roche	12/10/1997	intravenous	humanized	IL2RA	Prophylaxis of acute organ rejection in renal transplant	103749	Link
daclizumab	Zinbryta	Biogen	5/27/2016	subcutaneous	humanized	IL2R	Multiple sclerosis	761029	Link
daratumumab	Darzalex	Janssen Biotech	11/16/2015	intravenous	fully human	CD38	Multiple myeloma	761036	Link
denosumab	Prolia, Xgeva	Amgen	6/1/2010	subcutaneous	fully human	RANKL	Postmenopausal women with osteoporosis	125320	Link
dinutuximab	Unituxin	United Therapeutics	3/10/2015	intravenous	chimeric	GD2	Pediatric high-risk neuroblastoma	125516	Link
dupilumab	Dupixent	Regeneron Pharmaceuticals	3/28/2017	subcutaneous	fully human	IL4RA	Atopic dermatitis, asthma	761055	Link
durvalumab	Imfinzi	AstraZeneca	5/1/2017	intravenous	fully human	PD-L1	Urothelial carcinoma	761069	Link
eculizumab	Soliris	Alexion	3/16/2007	intravenous	humanized	Complement component 5	Paroxysmal nocturnal hemoglobinuria	125166	Link
elotuzumab	Empliciti	Bristol-Myers Squibb	11/30/2015	intravenous	humanized	SLAMF7	Multiple myeloma	761035	Link
evolocumab	Repatha	Amgen	8/27/2015	subcutaneous	fully human	PCSK9	Heterozygous familial hypercholesterolemia Refractory hypercholesterolemia	125522	Link
golimumab	Simponi	Centocor	4/24/2009	subcutaneous	fully human	TNF	Rheumatoid arthritis Psoriatic arthritis Ankylosing spondylitis	125289	Link
golimumab	Simponi Aria	Janssen Biotech	7/18/2013	intravenous	fully human	TNF	Rheumatoid arthritis	125433	Link
ibritumomab tiuxetan	Zevalin	Spectrum Pharmaceuticals	2/19/2002	intravenous	murine, radioimmunotherapy	CD20	Relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma	125019	Link
idarucizumab	Praxbind	Boehringer Ingelheim	10/16/2015	intravenous	humanized Fab	dabigatran	Emergency reversal of anticoagulant dabigatran	761025	Link
infliximab	Remicade	Centocor	8/24/1998	intravenous	chimeric	TNF alpha	Crohn's disease	103772	Link
infliximab-abda	Renflexis	Samsung Bioepis	4/21/2017	intravenous	chimeric, biosimilar	TNF	Crohn's disease Ulcerative colitis Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis	761054	Link
infliximab-dyyb	Inflectra	Celltrion Healthcare	4/5/2016	intravenous	chimeric, biosimilar	TNF	Crohn's disease Ulcerative colitis Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis	125544	Link
ipilimumab	Yervoy	Bristol-Myers Squibb	3/25/2011	intravenous	fully human	CTLA-4	Metastatic melanoma	125377	Link
ixekizumab	Taltz	Eli Lilly	3/22/2016	subcutaneous	humanized	IL17A	Plaque psoriasis	125521	Link
mepolizumab	Nucala	GlaxoSmithKline	11/4/2015	subcutaneous	humanized	IL5	Severe asthma	125526	Link
natalizumab	Tysabri	Biogen Idec	11/23/2004	intravenous	humanized	alpha-4 integrin	Multiple sclerosis	125104	Link
necitumumab	Portrazza	Eli Lilly	11/24/2015	intravenous	fully human	EGFR	Metastatic squamous non-small cell lung carcinoma	125547	Link
nivolumab	Opdivo	Bristol-Myers Squibb	12/22/2014	intravenous	fully human	PD-1	Metastatic melanoma	125554	Link
nivolumab	Opdivo	Bristol-Myers Squibb	3/4/2015	intravenous	fully human	PD-1	Metastatic squamous non-small cell lung carcinoma	125527	Link
obiltoxaximab	Anthem	Elusys Therapeutics	3/18/2016	intravenous	chimeric	Protective antigen of the Anthrax toxin	Inhalational anthrax	125509	Link
obinutuzumab	Gazyva	Genentech	11/1/2013	intravenous	humanized	CD20	Chronic lymphocytic leukemia	125486	Link
ocrelizumab	Ocrevus	Genentech	3/28/2017	intravenous	humanized	CD20	Multiple sclerosis	761053	Link
ofatumumab	Arzerra	Glaxo Grp	10/26/2009	intravenous	fully human	CD20	Chronic lymphocytic leukemia	125326	Link
olaratumab	Lartruvo	Eli Lilly	10/19/2016	intravenous	fully human	PDGFRA	Soft tissue sarcoma	761038	Link
omalizumab	Xolair	Genentech	6/20/2003	subcutaneous	humanized	IgE	Moderate to severe persistent asthma	103976	Link
palivizumab	Synagis	MedImmune	6/19/1998	intramuscular	humanized	F protein of RSV	Respiratory syncytial virus	103770	Link
panitumumab	Vectibix	Amgen	9/27/2006	intravenous	fully human	EGFR	Metastatic colorectal cancer	125147	Link
pembrolizumab	Keytruda	Merck	9/4/2014	intravenous	humanized	PD-1	Metastatic melanoma	125514	Link
pertuzumab	Perjeta	Genentech	6/8/2012	intravenous	humanized	HER2	Metastatic breast cancer	125409	Link
ramucirumab	Cyramza	Eli Lilly	4/21/2014	intravenous	fully human	VEGFR2	Gastric cancer	125477	Link
ranibizumab	Lucentis	Genentech	6/30/2006	intravitreal injection	humanized	VEGFR1 VEGFR2	Wet age-related macular degeneration	125156	Link
raxibacumab	Raxibacumab	Human Genome Sciences	12/24/2012	intravenous	fully human	Protective antigen of Bacillus anthracis	Inhalational anthrax	125349	Link
reslizumab	Cinqair	Teva	3/23/2016	intravenous	humanized	IL5	Severe asthma	761033	Link
rituximab	Rituxan	Genentech	11/26/1997	intravenous	chimeric	CD20	B-cell non-Hodgkin's lymphoma	103705	Link
secukinumab	Cosentyx	Novartis	1/21/2015	subcutaneous	fully human	IL17A	Plaque psoriasis	125504	Link
siltuximab	Sylvant	Janssen Biotech	4/23/2014	intravenous	chimeric	IL6	Multicentric Castleman's disease	125496	Link
tocilizumab	Actemra	Genentech	1/8/2010	intravenous	humanized	IL6R	Rheumatoid arthritis	125276	Link
tocilizumab	Actemra	Genentech	10/21/2013	intravenous subcutaneous	humanized	IL6R	Rheumatoid arthritis Polyarticular juvenile idiopathic arthritis Systemic juvenile idiopathic arthritis	125472	Link
trastuzumab	Herceptin	Genentech	9/25/1998	intravenous	humanized	HER2	Metastatic breast cancer	103792	Link
ustekinumab	Stelara	Centocor	9/25/2009	subcutaneous	fully human	IL12 IL23	Plaque psoriasis	125261	Link
ustekinumab	Stelara	Janssen Biotech	9/23/2016	subcutaneous intravenous	fully human	IL12 IL23	Plaque psoriasis Psoriatic arthritis Crohn's disease	761044	Link
vedolizumab	Entyvio	Takeda	5/20/2014	intravenous	humanized	integrin receptor	Ulcerative colitis Crohn's disease	125476	Link
sarilumab	Kevzara	Sanofi Aventis	5/22/17	subcutaneous	fully human	IL6R	Rheumatoid arthritis	761037	Link
rituximab and hyaluronidase	Rituxan Hycela	Genentech	6/22/17	subcutaneous	chimeric, co-formulated	CD20	Follicular lymphoma Diffuse large B-cell lymphoma Chronic lymphocytic leukemia	761064	Link
guselkumab	Tremfya	Janssen Biotech	7/13/17	subcutaneous	fully human	IL23	Plaque psoriasis	761061	Link
inotuzumab ozogamicin	Besponsa	Wyeth	8/17/17	intravenous	humanized, antibody-drug conjugate	CD22	Precursor B-cell acute lymphoblastic leukemia	761040	Link
adalimumab-adbm	Cyltezo	Boehringer Ingelheim	8/25/17	subcutaneous	fully human, biosimilar	TNF	Rheumatoid arthritis Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Crohn's disease Ulcerative colitis Plaque psoriasis	761058	Link
gemtuzumab ozogamicin	Mylotarg	Wyeth	9/1/17	intravenous	humanized, antibody-drug conjugate	CD33	Acute myeloid leukemia	761060	Link
bevacizumab-awwb	Mvasi	Amgen	9/14/17	intravenous	humanized, biosimilar	VEGF	Metastatic colorectal cancer Non-squamous Non-small-cell lung carcinoma Glioblastoma Metastatic renal cell carcinoma Cervical cancer	761028	Link
benralizumab	Fasenra	Astrazeneca	11/14/17	subcutaneous	humanized	interleukin-5 receptor alpha subunit	Severe asthma, eosinophilic phenotype	761070	Link
emicizumab-kxwh	Hemlibra	Genentech	11/16/17	subcutaneous	humanized, bispecific	Factor IXa, Factor X	Hemophilia A (congenital Factor VIII deficiency) with Factor VIII inhibitors.	761083	Link
trastuzumab-dkst	Ogivri	Mylan	12/1/17	intravenous	humanized, biosimilar	HER2	HER2-overexpressing breast cancer, metaststic gastric or gastroesophageal junction adenocarcinoma	761074	Link
infliximab-qbtx	Ixifi	Pfizer	12/13/17	intravenous	chimeric, biosimilar	TNF	Crohn's disease Ulcerative colitis Rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis	761072	Link
ibalizumab-uiyk	Trogarzo	TaiMed Biologics	3/6/18	intravenous	humanized	CD4	HIV	761065	Link
tildrakizumab-asmn	Ilumya	Merck	3/20/18	subcutaneous	humanized	IL23	Plaque psoriasis	761067	Link
burosumab-twza	Crysvita	Ultragenyx	4/17/18	subcutaneous	fully human	FGF23	X-linked hypophosphatemia	761068	Link
erenumab-aooe	Aimovig	Amgen	5/17/18	subcutaneous	fully human	CGRP receptor	Migraine headache prevention	761077	Link

Tositumomab - Bexxar - 2003 - CD20

Mogamulizumab - Poteligeo - August 2018 - CCR4

Moxetumomab pasudotox - Lumoxiti - Sept 2018 - CD22

Cemiplimab - Libtayo - Sept 2018 - PD-1

Polatuzumab vedotin - Polivy - June 2019 - CD79B

Recently, the bispecific antibodies, a novel class of therapeutic antibodies, have yielded promising results in clinical trials. In April 2009, the bispecific antibody catumaxomab was approved in the European Union.[32][33]

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.[34] This rapid growth in demand for monoclonal antibody production has been well accommodated by the industrialization of mAb manufacturing.[35]

See also

• Antigen 5T4
• Immunotherapy
• Immunoconjugate
• Nomenclature of monoclonal antibodies
• List of monoclonal antibodies, including investigational and withdrawn

References

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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.
3. Olinger GG, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly M, Whaley KJ, Lear CM, Biggins JE, Scully C, Hensley L, Zeitlin L (October 2012). "Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques". Proceedings of the National Academy of Sciences of the United States of America. 109 (44): 18030–5. Bibcode:2012PNAS..10918030O. doi:10.1073/pnas.1213709109. PMC 3497800. PMID 23071322.
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External links

• Cancer Management Handbook: Principles of Oncologic Pharmacotherapy (registration required)