Monoclonal antibody

from Wikipedia, the free encyclopedia

Monoclonal antibodies are antibodies , i.e. immunologically active proteins that are produced by a cell line (cell clone), which can be traced back to a single B lymphocyte and which are directed against a single epitope . A physiologically (naturally) occurring immune response against an antigen that has penetrated the body is, however, always polyclonal and is directed e.g. B. against many different epitopes on a bacterium.

Monoclonal antibodies play an important role in diagnostics and research, as they can bind a number of molecules with a high degree of specificity . The binding of the antibodies can then be detected using different techniques. This antigen-antibody reaction forms the basis for numerous experimental and diagnostic procedures (e.g. immunophenotyping , FACS , immunohistology , ELISA , ELISPOT , radioimmunoassay and Western blot ).

Many of the human cell surface antigens recognized by monoclonal antibodies are classified in the CD nomenclature .

Production of monoclonal antibodies

Production of monoclonal antibodies by hybridoma technology

The principle of the production of monoclonal antibodies was published in 1975 by César Milstein , Georges Köhler and Niels Jerne , who received the Nobel Prize in Medicine for it in 1984 . The technique is based on the fusion of antibody-producing B cells with cells of a myeloma - cell line , whereby hybrid cells are formed, the unlimited antibodies of a particular specificity produce ( hybridoma technique ).

When producing monoclonal antibodies against a specific antigen , a mouse is first infected with this antigen (1, see figure). The immune response leads to the formation of B lymphocytes , which form antibodies which react with the antigen and which accumulate in the spleen . The B lymphocytes are isolated from the removed spleen (2) and fused with cells ( plasma cells ) of a cell line (3) obtained from a myeloma ( plasmacytoma ) (4), so-called hybridoma cell lines (5) are formed. These hybridoma cells combine properties of their original cells: the B lymphocyte has the ability to produce a specific antibody, the myeloma cell the ability to grow indefinitely in vitro (“in a test tube”). The hybridoma cell line that best binds the desired epitope on the antigen is selected to obtain the monoclonal antibody (6). The immortal cell line is preserved and the cell supernatant is harvested regularly as needed. The monoclonal antibodies can be produced in vitro (7a) or in vivo (7b). The antibodies (8) are called monoclonal because they come from a single B-cell of origin and are therefore all identical.

The hybrid cells are selected using a so-called HAT medium. This nutrient medium contains hypoxanthine (a naturally occurring purine derivative), thymidine and aminopterin ( cell poison that inhibits the biosynthesis of purine and pyrimidine bases ). The B lymphocytes and thus also the hybrid cells can metabolize hypoxanthine and thymidine and thus bypass the blockage caused by the aminopterin. The myeloma cells used are deficiency mutants with regard to the alternative metabolic pathway and die in the HAT medium.
The non-fused B-lymphocytes only have a limited lifespan, so that after a few passages only the hybrid cells can be found in the culture.

The technology of phage display represents a major step forward, particularly in the cloning of human antibodies .

Therapeutic Monoclonal Antibodies

Derivatives of monoclonal antibodies
Modified antibodies for therapeutic use

Attempts to use monoclonal antibodies in therapy were initially not very successful. The mouse antibodies used (murine antibodies, ending: -omab) act as antigens in the human organism and can trigger an immune response directed against them. The interaction with cells of the recipient's immune system, which is important for their desired effect, was also not optimal due to the different species.

Significant advances have only been made after the development of modified monoclonal antibodies better adapted to human antibodies in recent years.

In addition, antibody conjugates , such as immunocytokines , are also used for therapeutic and diagnostic applications, especially in cancer immunotherapy .

Monoclonal Antibody Terminology

The Free Trade names of all therapeutic monoclonal antibodies carry the suffix "... mab " what for " m onoclonal a nti b is ody". According to the similarity to human antibodies, a distinction is made (in ascending order):

  • murine antibodies (from the mouse): ending - omab
  • Antibodies from primate: ending - imab
  • chimeric antibodies: ending - ximab (only the variable part of the AK is mouse protein.)
  • humanized antibodies: ending - zumab (only the antigen binding sites are mouse protein)
  • fully human, recombinant antibodies: ending - umab

Lists of antibodies developed

Therapeutic monoclonal antibodies approved or in clinical trials (phase III)

Surname Trade name Type Target structure field of use
Hematology , oncology
Alemtuzumab 5 MabCampath humanized CD52 antigen on lymphocytes Chronic lymphocytic leukemia , T-cell lymphoma 2 , acute lymphocytic leukemia 2
Apolizumab 1.2 Remitogenic humanized HLA-DR antigen on B lymphocytes Solid tumors, acute lymphocytic leukemia , chronic lymphocytic leukemia , non-Hodgkin lymphomas
(MPDL3280A) 1,2
Tecentriq ( Roche ) humanized PD-L1 Bladder cancer (approved in USA) CHMP recommendation positive in EU .
(MSB0010718C) 2
Bavencio ( Merck / Pfizer ) humane PD-L1 Bladder cancer , non-small cell lung cancer (NSCLC), Merkel cell carcinoma
Bevacizumab Avastin ( Roche ) humanized VEGF (Vascular Endothelial Growth Factor) Colon cancer , breast cancer , non-small cell lung cancer , wet, age-related macular degeneration ( off-label use ) 2
Blinatumomab Blincyto ( Amgen ) murine, bispecific CD-19 ALLES
Catumaxomab Removab ( Neovii Biotech ) murine (rat / mouse), trifunctional EpCAM antigen on tumor cells, CD3 receptor on T lymphocytes malignant ascites due to EpCAM -positive carcinoma
Cemiplimab 1.2
NN, ( Sanofi / Regeneron Pharmaceuticals ) from primate PD-1 Squamous cell carcinoma
Cetuximab Erbitux ( BMS / Merck ) chimeric EGF receptor (Epidermal Growth Factor Receptor) Colon cancer , head and neck tumors
Daratumumab 1.2 Darzalex ( Genmab / Janssen Biotech) humane CD38 Multiple myeloma , already approved in the US and EU
Durvalumab 1.2 Imfinzi ( AstraZeneca / Medimmune ) humane PD-L1 Lung cancer 1,2
Eculizumab Soliris ( Alexion ) humanized C5 complement factor Paroxysmal nocturnal hemoglobinuria (PNH)
Elotuzumab 1.2 Empliciti ( BMS ) humanized Signaling Lymphocyte Activation Molecule (SLAMF7; CS1) Multiple myeloma , already approved in the USA
Emicizumab 1.2
Hemlibra ( Roche ) humanized, bispecific Factors IXa and X Inhibitor hemophilia
Epratuzumab 1.2 LymphoCide ( UCB ) humanized CD22 antigen Non-Hodgkin lymphomas , autoimmune diseases , acute lymphoblastic leukemia
Gemtuzumab ozogamicin 1 Mylotarg ( Wyeth ) humanized, calicheamicin loaded CD33 antigen Acute myeloid leukemia
Ibritumomab-Tiuxetan Zevalin ( Bayer ) murine, 90 Y -labeled CD20 antigen on B lymphocytes Non-Hodgkin lymphoma ( radioimmunotherapy )
Inotuzumab ozogamicin (as conjugate ) 1,2 Besponsa ( Pfizer ) humanized CD22 antigen Acute lymphoblastic leukemia
Ipilimumab Yervoy ( BMS ) humane CTLA-4 Malignant melanoma
Mogamulizumab Poteligeo ( Kyowa Hakko Kirin ) humanized CCR4 Adult T-cell leukemia , various non-Hodgkin lymphomas
Moxetumomab pasudotox-tdfk 1,2 Lumoxiti ( AstraZeneca ) murine CD22 antigen Hairy cell leukemia
Necitumumab 1.2 Portrazza
( Eli Lilly )
humane EGF receptor (Epidermal Growth Factor Receptor) Lung cancer , gastric cancer , already approved in NSCLC in the US
Nivolumab BMS) humane PD-1 Approved in Europe for malignant melanoma and non-small cell lung cancer
Obinutuzumab Gazyva humanized CD20 antigen on B lymphocytes Chronic lymphocytic leukemia , follicular lymphoma
Ofatumumab Arzerra ( GSK ) humane CD20 antigen on B lymphocytes Chronic lymphocytic leukemia
Olaratum from 1.2 Lartruvo
( Eli Lilly )
humane IgG1 on PDGF Receptor-α (platelet-derived growth factor receptor α) Sarcoma ; Revoke admission
Oregovomab 1.2 OvaRex ( United Therapeutics ) murine CA-125 Ovarian cancer
Panitumumab Vectibix ( Amgen ) humane EGF receptor (Epidermal Growth Factor Receptor) EGF receptor expressing tumors, especially metastatic colorectal carcinoma
Pembrolizumab (MK-3475) Keytruda ( MSD ) humanized PD-1 Melanoma , mesothelioma , NSCLC
Pertuzumab Perjeta ( Roche ) humanized HER2 / neu , HER2 / neu receptor ; Pertuzumab inhibits the dimerization of the target structure and its heterodimerization with other HER receptors (e.g. EGF receptor (EGFR)), which is said to slow down tumor growth Breast cancer , clinical studies, etc. a. in ovarian carcinoma , bronchial carcinoma and prostate carcinoma
Ramucirumab Cyramza ( Eli Lilly ) humane VEGF receptor 2 Bronchial carcinoma , gastric carcinoma
Rituximab MabThera ( Roche / Biogen ) chimeric CD20 antigen on B lymphocytes Non-Hodgkin lymphoma
Rovalpituzumab tesirine 1,2 NN ( Stemcentrx ) humanized delta-like protein 3 (DLL3) Small cell lung cancer (SCLC)
Siltuximab Sylvant ( Janssen ) chimeric binds human IL-6 Castleman's disease (MCD), multiple myeloma
Tremelimumab 1.2 NN ( AstraZeneca / Medimmune ) humane CTLA-4 Bronchial carcinoma 1,2 mesothelioma 1,2
Tositumomab 1 Bexxar ( GSK ) murine, 131 I -labeled CD20 antigen on B lymphocytes Non-Hodgkin lymphoma ( radioimmunotherapy )
Trastuzumab Herceptin ( Roche ) humanized HER2 / neu receptor Breast cancer , gastric cancer
Zanolimumab 1.2 HuMax-CD4 ( Genmab ) humane CD4 antigen on T lymphocytes T-cell lymphomas
Autoimmune diseases , transplant rejection , pain
Adalimumab Humira humane TNF-α (Tumor Necrosis Factor α) Rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis , Crohn's disease
Alemtuzumab 5 Lemtrada humanized CD52 antigen on lymphocytes multiple sclerosis
Anifrolumab 1.2
NN humane anti-type-I IFN Lupus erythematosus
Basiliximab Simulect chimeric CD25 antigen ( interleukin-2 receptor) Prophylaxis of acute rejection reactions in kidney transplantation
Belimumab Benlysta humane BLys (B-lymphocyte stimulator, a cytokine of the TNF superfamily) Lupus erythematosus
Brodalumab 1.2 Kyntheum ( LEO Pharma ) humane Interleukin-17 receptor Psoriasis , psoriatic arthritis , asthma
Canakinumab Ilaris humane Interleukin-1 beta receptor Periodic fever syndromes (CAPS, TRAPS, HIDS / MKD, FMF), systemic juvenile idiopathic arthritis (SJIA) , gouty arthritis
Certolizumab Cimzia humanized TNF-α (Tumor Necrosis Factor α) Rheumatoid arthritis , axial spondolyarthritis , psoriatic arthritis , psoriasis , Crohn's disease (not in Germany)
Clazakizumab 1.2 NN ( BMS ) humanized Interleukin-6 receptor Rheumatoid arthritis
Daclizumab Zenapax (aH); Zinbryta (aH) humanized CD25 antigen ( interleukin-2 receptor) Multiple sclerosis , but taken off the market (aH)
Epratuzumab 1.2 LymphoCide humanized CD22 antigen Autoimmune diseases , non-Hodgkin lymphomas ,
Fasinum from 1.2 NN ( Regeneron Pharmaceuticals ) humane Nerve Growth Factor (NGF) Osteoarthritis pain
Guselkumab 1.2 Tremfya

( Janssen )

humane Anti-interleukin-23 Psoriasis , rheumatoid arthritis
Golimumab Simponi humane TNF-α (Tumor Necrosis Factor α) Ulcerative colitis , rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis
Infliximab Remicade chimeric TNF-α (Tumor Necrosis Factor α) Crohn's disease , rheumatoid arthritis , ankylosing spondylitis , psoriatic arthritis , ulcerative colitis
Ixekizumab Taltz humanized Interleukin-17 A receptor (IL-17A) Psoriasis , psoriatic arthritis
Mavrilimumab (CAM-3001) 1.2 NN ( AstraZeneca ) humane Rheumatoid arthritis
Muromonab CD3 Orthoclone OKT3 murine CD3 receptor on T lymphocytes Treatment of acute rejection reactions in kidney, heart and liver transplants
Natalizumab 3 Tysabri humanized CD49d4 integrin) multiple sclerosis
Risankizumab 1.2 Skyrizi ( AbbVie ) humanized Interleukin-23 receptor Psoriasis , psoriatic arthritis , Crohn's disease
Rituximab MabThera chimeric CD20 antigen on B lymphocytes Rheumatoid arthritis
Sarilumab Kevzara humane Interleukin-6 receptor (IL-6R) Rheumatoid arthritis
Secukinumab Cosentyx ( Novartis ) humane Interleukin-17 A receptor Psoriasis , psoriatic arthritis , ankylosing spondylitis
Sifalimumab (MEDI-545) 1.2 NN ( AstraZeneca ) humane Lupus erythematosus
Sirukumab 1.2 Plivensia ( Janssen Pharmaceutica / GlaxoSmithKline ) humane Interleukin-6 receptor Rheumatoid arthritis , but negative recommendation from the FDA
Tocilizumab RoActemra humanized Interleukin-6 receptor Rheumatoid arthritis , cytokine storm after treatment with CART cells, giant cell arteritis
Ustekinumab Stelara humane Interleukin 12/23 Plaque psoriasis
Vedolizumab 1.2 Entyvio humanized IgG1 Crohn's disease and ulcerative colitis
Alirocumab Praluent ( Sanofi ) humane PCSK9 (indirect: LDL receptor ) Hypercholesterolemia (prevention of cardiovascular events including stroke )
(REGN1500) 1.2
NN (Regeneron / Sanofi) humane PCSK9 Homozygous familial hypercholesterolemia
Repatha ( Amgen ) humane PCSK9 (indirect: LDL receptor ) Hypercholesterolemia (prevention of cardiovascular events including stroke )
Cardiovascular diseases
Abciximab ReoPro chimeric, Fab fragment GPIIb / IIIa on platelets Prevention of vascular occlusion after PTCA , discontinued
Special forms of therapy
Idarucizumab Praxbind humanized Antibody fragment (Fab) that binds to dabigatran with a very high affinity . Antidote for the rapid and specific abolition of the anticoagulant caused by dabigatran
Infectious diseases
Bezlotoxumab 1.2 Zinplava ( MSD ) humane Clostridium difficile toxin B. Clostridium difficile infection (CDI)
Motavizumab 4 Numax chimeric Part of the respiratory syncytial virus (RSV) Prophylaxis of RSV (respiratory syncytial virus) pneumonia in premature babies , ELBW (Extremely Low Birth Weight Preterm) and VLBW (Very Low Birth Weight Preterm)
Palivizumab Synagis humanized Part of the respiratory syncytial virus (RSV) Prophylaxis of RSV pneumonia in premature infants
Ibalizumab-uiyk Trogarzo humanized CD4 T cell receptor AIDS
Neurological diseases
Aducanumab 1.2 NN
( Biogen )
humane tbd. Alzheimer
Eptinezumab NN humanized Calcitonin Gene-Related Peptide (CGRP) migraine
Erenumab Aimovig
( Amgen )
humane Calcitonin Gene-Related Peptide (CGRP) receptor migraine
Fremanezumab 1.2 NN
( Teva )
humanized Calcitonin Gene-Related Peptide (CGRP) Migraine
cluster headache
Galcanezumab 1.2 Emgality
( Eli Lilly )
humanized Calcitonin Gene-Related Peptide (CGRP) Migraine
cluster headache
Ocrelizumab 1.2 Ocrevus
( Roche )
humanized CD20 antigen multiple sclerosis
Solanezumab 1.2 NN
( Eli Lilly )
humanized tbd. Alzheimer's disease
Ublituximab NN ( TG Therapeutics ) chimeric (mouse / human) CD20 antigen on B lymphocytes multiple sclerosis
Ranibizumab Lucentis humanized, Fab fragment VEGF-A (Vascular Endothelial Growth Factor A) Wet macular degeneration
Adalimumab Humira humane TNF-α (Tumor Necrosis Factor α) psoriasis
Dupilumab Dupixent ( Sanofi ) humane Interleukin 4/13 Atopic eczema sinusitis
Efalizumab Raptiva humanized CD11a antigen psoriasis
Infliximab Remicade chimeric TNF-α (Tumor Necrosis Factor α) psoriasis
Nemolizumab 1.2 NN ( Chugai ) humanized Interleukin 31 Atopic eczema
Tildrakizumab Ilumetri humane Interleukin 23 Moderate to severe plaque psoriasis
Ustekinumab Stelara humane Interleukin 12/23 Plaque psoriasis
Allergic diseases
Benralizumab Fasenra (AstraZeneca) humanized Alpha subunit of the IL-5 receptor (IL-5Rα) Asthma ; So far tested in COPD , but not successful
Mepolizumab Nucala ( GSK ) humanized Interleukin-5 Asthma , COPD , hypereosinophilia syndrome , eosinophilic granulomatosis with polyangiitis
Omalizumab Xolair humanized IgE (F c part) Severe bronchial asthma , chronic idiopathic urticaria ( hives )
Reslizumab Cinqaero ( Teva ) humanized Interleukin-5 asthma
Tralokinumab 1.2 NN ( AstraZeneca / Medimmune) humanized IL-13 Severe bronchial asthma, atopic eczema
( plantibody ) 1,2 CaroRx produced recombinantly in plants ("plantibody") specific binding to Streptococcus mutans (key germ of dental caries) as a mouth rinse against dental caries ; Elimination of S. mutans from the oral flora
Denosumab Prolia, XGEVA humane RANK ligand (receptor activator of the NF-κB ligand, RANKL ) Osteoporosis ; Bone metastases
Romosozumab Evenity ( Amgen / UCB ) humanized Sclerostin postmenopausal osteoporosis

1 Not yet approved in Germany or in approval (may no longer be up-to-date)
2 In clinical studies
3 Approved again in the USA by the FDA under strict conditions despite possible rare serious side effects , European approval since 6/2006
4 Development discontinued.
5 Removed from the market by the manufacturer - as MabCampath - in order to bring the substance back onto the market under a new trade name and a different indication (MS). Criticized by the drug commission of the German medical profession (AkdÄ).

For in vivo diagnostic monoclonal antibody approved

Surname preparation Type Target structure field of use
Sulesomab LeukoScan ® murine, 99m Tc -labeled IMMU-MN3 Fab'-SH fragment against granulocytes Osteomyelitis
Arcitumomab CEA-Scan ® murine, 99m Tc -labeled IMMU-4 F (ab ') 2 versus CEA colorectal cancer

Withdrawn or discontinued diagnostic monoclonal antibodies

Surname preparation Type Target structure Planned areas of application Complications and comment
Igovomab Indimacis 125 murine, 111 labeled In CA 125 antigen ovarian serous adenocarcinomas Removed from the European market in 1999 at the request of the manufacturer. Reason?

Therapeutic monoclonal antibodies in preclinical or Phase I / II trials

Surname preparation Type Target structure field of use
Atrosab - humanized CD120a (TNFR1) Crohn's disease , multiple sclerosis , rheumatoid arthritis
Brentuximab - chimeric CD30 Lymphoma
Cantuzumab - humanized, mersantine conjugated CanAg ( MUC1 ), antibody conjugated with mersantin (toxin) Colon cancer , gastric cancer , pancreatic cancer , NSCLC
Labetuzumab - humanized Carcinoembryonic Antigen (CEA) Colon cancer , pancreatic cancer , ovarian cancer
Nimotuzumab TheraCim ® humanized EGF receptor (Epidermal Growth Factor Receptor) metastatic irinotecan refractory colorectal cancer
Mapatumumab - humane - Colon cancer
Matuzumab EMD72000 humanized EGF receptor (Epidermal Growth Factor Receptor) Gastric cancer , colon cancer , NSCLC
Pertuzumab Omnitarg ® humanized HER2 / new Breast cancer , prostate cancer , ovarian cancer , NSCLC
R1450 - humane Amyloid-β Alzheimer's disease
1D09C3 - humane MHC-II Non-Hodgkin lymphoma (NHL)

Withdrawn or discontinued therapeutic monoclonal antibodies

Surname preparation Type Target structure Planned areas of application Complications and comment
Bococizumab NN ( Pfizer ) humanized PCSK9 (indirect: LDL receptor ) Hypercholesterolemia Pfizer has stopped further development.
Briakinumab - p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23) psoriasis Abbott's application for approval withdrawn
Galiximab - chimeric CD80 antigen Non-Hodgkin lymphoma
Lumiliximab - chimeric (macaque / human) CD23 antigen on B lymphocytes Chronic lymphocytic leukemia
Nebacumab Centoxin ® humanized (IgM) Endotoxin sepsis Approval in Europe in 1991, withdrawn from the market in 1993 due to increased patient mortality after treatment with nebacumab compared to placebo.
Edrecolomab Panorex ® Mouse IgG2a EpCAM Colon cancer Approval in Germany in 1995, withdrawn from the market in 2000 because the previous standard therapy was more effective.
TGN1412 - humanized CD28 Leukemia and autoimmune diseases (such as multiple sclerosis and rheumatism ) Cytokine storm . In the public criticism were shortcomings in the test planning and execution, z. B. that the preparation was given to 6 subjects at the same time, and that the mechanisms of action were not understood.

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