77 Monoclonal antibodies | Summary

Monoclonal antibodies

Monoclonal antibodies are made from natural antibodies made by the body to fight foreign invaders. Their production involves several steps. In the first instance a laboratory animal is injected with a desired target to stimulate their immune system to produce antibodies. Following this, the antibodies are harvested from the spleen of the immunised animal and fused with an immortal myeloma cell line to create hybrid cells, or hybridomas. The hybrid cells are then screened to find those that secrete antibodies with the desired specificity for a particular target. Once identified the hybrid cell is cloned to establish a hybridoma colony. This colony is then maintained in a culture medium to provide a continual supply of monoclonal antibodies. Each of the antibodies secreted by the hybrid cell is identical and has the capacity to bind to a specific receptor found on the surface of a cell.

The blue and green Y-shaped forms in this picture represent monoclonal antibodies in the process of binding to receptors found on the surface of cells. Credit: Anna Tanczos, Wellcome Images.

Definition

Monoclonal antibodies are laboratory produced antibodies designed to recognise and bind to specific receptors found on the surface of cells. They are derived from natural antibodies, complex proteins derived from a single B cell made by the body's immunological defence system to recognise and fight foreign invaders such as bacteria and viruses.

Importance

The advantage of monoclonal antibodies is that they can be produced cheaply on a large-scale. Being very precise in their target and having a very high degree of sensitivity, monoclonal antibodies have proven highly versatile tools for basic research, diagnostics and therapeutics. In 2010 the combined global monoclonal antibody diagnostics and therapeutics market was valued at US$55 billion. In 2012 there were more than 30 monoclonal antibody drugs on the worldwide market. Of these ten were blockbuster drugs, each of them generating more than US$1 billion per year. Today monoclonal antibody drugs account for a third of all new treatments introduced.

Discovery

For many centuries keen observers of epidemic diseases, such as smallpox and plague, noted that individuals who suffered and survived one disease outbreak remained unscathed the next time the same disease passed their way. The knowledge that individuals could acquire immunity to a disease underpinned some of the earliest interventions against smallpox. This involved taking material from the pustules of infected individuals and injecting it into healthy individuals so as to confer immunity. Such measures were taken with very little understanding of how the immune system worked. In the 1890s Emil von Behring and Shibasabura Kitasato observed that blood taken from animals infected with diphtheria or tetanus could give immunity to other animals not previously exposed to such diseases. Following this Paul Ehrlich identified that the source of protection in blood came from antibodies and hypothesised that antibodies could be used one day as magic bullets for medicine. Thereafter, scientists began hunting for a means to isolate and purify individual antibodies from the billions produced by the body's defence system. This was finally achieved in 1975 by Georges Kohler and Cesar Milstein, based at the Laboratory of Molecular Biology in Cambridge, UK, with their development of a technique to produce monoclonal antibodies.

Application

Everyday monoclonal antibodies are used as probes to unravel the pathways of disease and to type tissue and blood. They are also vital tools for analysing bodily fluids for diagnosis and to monitor hospital infections. Away from the clinic, monoclonal antibodies are important components in home-testing kits for determining ovulation, pregnancy, menopause and many other conditions. Since their emergence, monoclonal antibodies have helped improve the treatment of over 50 major diseases. They are used, for example, to prevent the rejection of organ transplants and for the treatment of cancer, inflammatory and autoimmune disorders, cardiovascular disease, infectious diseases, allergies and ophthalmic problems. Monoclonal antibodies are also vital to public health, being used in tests to detect and monitor infectious agents like HIV, the cause of AIDS, or the influenza virus causing pandemic flu and for identifying diseases released by biological weapons such as smallpox and anthrax. In addition, monoclonal antibodies help in checks for salmonella and bacteria that cause food poisoning. They are also instrumental in detecting viruses in animal livestock or plants and monitoring environmental pollution.

Monoclonal antibodies: timeline of key events

Date Event People Places
1895Humans treated with antiserum prepared against human cancer. This established the principle of using serotherapy to fight cancerHericourt, RichetCollege de France
December 23, 1911Niels K Jerne was born in London, United KingdomJerneBasel Institute for Immunology
1929First molecular marker, antigen, identified on a tumour, laying foundation for use of antibodies to diagnose and treat cancerWitebsky University of Heidelberg
April 26, 1932Michael Smith was born in Blackpool, United KingdomSmithUniversity of British Columbia
April 17, 1946Georges Kohler was bornKohlerLaboratory of Molecular Biology
1960Cellular fusion technique formulatedBarski, Sorieul, CarnefertInstitut Gustave Roussy
1963Cesar Milstein returns to Cambridge and begins researching the structure and diversity of antibodiesMilstein, SangerLaboratory of Molecular Biology
1969Splenic fragment technique devised for growing antibodiesKlinmanWistar Institute
1970 - 1972Means developed for cloning B cells that produce single antibodies with known specificityAskonas, Williamson, WrightNational Institute for Medical Research
1971Sera-Lab foundedMurray
July 1973Cesar Milstein and Dick Cotton report the successful fusion of two different myeloma cell lines, one from a mouse and the other from a ratCotton, MilsteinLaboratory of Molecular Biology
June 1974Georges Kohler joins Cesar Milstein's research team to investigate somatic mutation and antibody diversityKohler, MilsteinLaboratory of Molecular Biology
January 1975Unlimited long-surviving monoclonal antibodies createdMilstein, KohlerLaboratory of Molecular Biology
1975Short-lasting antibodies against influenza virus devisedGerhardWistar Institute
1975 - 1979First monoclonal antibody created to target a neurotransmitter peptideMilstein, CuelloLaboratory of Molecular Biology, MRC Neurochemical Pharmacology Unit, Oxford University
August 1975First step taken to patent Kohler and Milstein's monoclonal antibodiesMilsteinLaboratory of Molecular Biology
August 7, 1975Cesar Milstein and Georges Kohler publish a paper outlining a technique for producing limitless monoclonal antibodiesKohler, MilsteinLaboratory of Molecular Biology
September 1975Tumour necrosis factor (TNF) was discovered. It was the first immune molecule shown to kill cancer cellsCarswell, Old, Kassel, Green, Fiore, WilliamsonMemorial Sloan Kettering Cancer Center
September 1976Cesar Milstein supplies myeloma cells to Hilary Koprowski at the Wistar Institute for producing monoclonal antibodiesKoprowski, MilsteinLaboratory of Molecular Biology, Wistar Institute
October 1976British government declines to patent monoclonal antibodiesMilsteinLaboratory of Molecular Biology
1977Monoclonal antibodies developed for automatic fluorescence-activated cell sorter Milstein, Herzenberg, OiLaboratory of Molecular Biology, Stanford University Medical School, University of Toronto
February 1977Partnership begun for first commercial distribution of cells for producing monoclonal antibodiesMilstein, Murray
1977Monoclonals produced against histocompatibility antigensMilstein, Galfre, HowardLaboratory of Molecular Biology, Brabraham Institute
June 1977First US patent application filed for monoclonal antibodiesCroce, Koprowski, MilsteinWistar Institute
1977Monoclonal antibodies made to unknown cell surface antigensMilstein, Galfre, WilliamsLaboratory of Molecular Biology, Sir William Dunn School of Pathology
1978Hybritech foundedRoyston, Birndoff, GreeneSan Diego
1978First monoclonal antibodies generated to human T-cellsMilstein, McMichaelLaboratory of Molecular Biology, Oxford University
1978First monoclonal antibody generated for blood typingMilsteinLaboratory of Molecular Biology, Oxford University
February 1978First commercialisation of monoclonal antibodies as laboratory reagentsMilstein, MurrayLaboratory of Molecular Biology, Sera-Lab
May 1979Centocor foundedKoprowski, Schoemaker, WallWistar Institute
October 1979First US patent for monoclonal antibodies grantedKoprowski, MilsteinWistar Institute
January 1980First monoclonal antibody created to purify a human therapeutic protein.Burke, Milstein, SecherLaboratory of Molecular Biology, Warwick University
1980Cesar Milstein proposed the use of recombinant DNA to improve monoclonal antibodiesMilsteinLaboratory of Molecular Biology
1980First monoclonal antibodies developed against T-cells which can also activate human complement.Waldmann, Cobbold, Hale, Metcalfe. Watt, TrangCambridge University
1980British government commissioned report publically criticises non-patenting of technique for producing monoclonal antibodiesMilstein
December 1980Clinical tials begin with a monoclonal antibody for the treatment of gastrointestinal cancerKoprowskiWistar Institute
1981First monoclonal antibodies generated for use in radioimmunoassaysCuello, MilsteinLaboratory of Molecular Biology, Oxford University
1981First patient successfully treated with anti-idiotype monoclonal antibodyLevyStanford University Medical School
1982First international workshop on human differentiation antigens establishes international code for classifying and coding MabsBoumsell, BernardSaint-Louis Hospital
1982Monoclonal antibodies generated for routine use in ABO blood typingLennox, Milstein, Sacks, VoakLaboratory of Molecular Biology, Addenbrookes Hospital
November 1982James Allison and collegues use monoclonal antibody to provide first biochemical description of tumour specific antigen of murine T-lymphomaAllison, McIntyre, BlochUniversity of Texas System Cancer Center
1983First bispecific monoclonal antibody producedCuello, MilsteinLaboratory of Molecular Biology, Oxford University
1984First chimeric monoclonal antibodies developed which lays foundation for safer and more effective monoclonal antibody therapeuticsNeuberger, Rabbitts, Morrison, Oi, Herzenberg, Boulianne, Schulman, HozumiLaboratory of Molecular Biology, Stanford Univerity Medical School
1985Antibody genes identifiedTonegawaBasel Institute of Immunology
January 1985Idea put forward for the creation of transgenic mice to produce human antibodiesAlt, Blackwell, YancopoulosColumbia University
1985First transgenic mice created with with genes coding for both the heavy and light chain domains in an antibody.Kohler, RusconiMax-Planck Institute
May 1986First humanised monoclonal antibody createdDear, Foote, Jones, Neuberger, WinterLaboratory of Molecular Biology
June 1986Interferon approved for treating hairy cell leukaemia
June 1986First monoclonal antibody drug approvedChang, Kung, Gringas, Schlossman, Goldstein
1988Campath-1H is created - the first clinically useful humanised monoclonal antibody.Winter, Waldmann, Reichmann, ClarkCambridge University, Laboratory of Molecular Biology
1988Patent application filed for a method to create transgenic mice for the production of human antibodiesBruggeman, Caskey, Neuberger, Surani, Teale, Waldmann, WilliamsLaboratory of Molecular Biology, Babraham Institute, Cambridge University
November 1988Patent application filed for the the use of PCR to create a library of antibody fragmentsGussow, Jones, Olandi, WinterLaboratory of Molecular Biology, Istituto Nazionale dei Tumori
1989Cambridge Antibody Technology (CAT) foundedWinter, ChiswellLaboratory of Molecular Biology, CAT
1990Phage display monoclonal antibodies createdWinterLaboratory of Molecular Biology, CAT
1991First display and selection of human antibodies phageBarbas, LernerScripps Research Institute
March 1991Monoclonal antibody drug approved in Europe for the treatment of septic shockKaplan, TangStanford University Medical School, Centocor
February 1992Market interest in monoclonal antibody drugs plummeted with news that the FDA needed more information before it would approve CentoxinCentocor
February 1993Centoxin withdrawn from European marketCentocor
1994First transgenic mice strains reported for producing human monoclonal antibodiesBruggemann, Green, Lonsberg, NeubergerCell Genesys, GenPharm, Laboratory of Molecular Biology
October 7, 1994Niels Kaj Jerne diedJerneBasel Institute for Immunology
December 1994Second monoclonal antibody drug approvedCollerStony Brook University, Centocor
1994First chimeric monoclonal antibody therapeutic approved for marketCollerCentocor, State University of New York
1995First monoclonal antibody drug for cancer approved in EuropeKoprowski
1995First monoclonal antibody therapeutic for cancer approved for marketKoprowskiWistar Institute, Centocor
March 1, 1995Georges Kohler diedKohlerLaboratory of Molecular Biology
March 22, 1996Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxi T lymphocite-associated antigen (CTLA-4). Lays the foundation for a new concept in immunotherapy of 'checkpoint blockade'Leach, Krummel, AllisonUniversity California Berkeley
1997FDA approved the first monoclonal antibody cancer drug for the American marketLevy, RastetterStanford University Medical School, Idec Pharmaceuticals
December 1997First humanised monoclonal antibody approved for marketQueenProtein Design Labs, Roche
1998FDA approved Trastuzumab (Herceptin) for the treatment of metastatic breast cancer
August 1998FDA and European regulatory authorities approved the first monoclonal antibody drug for an autoimmune diseaseVilcek, Le, Feldmann, MainiNew York University, Centocor, Kennedy Institute of Rheumatology
October 4, 2000Michael Smith diedUniversity of British Columbia
December 2002First monoclonal antibody made using phage display approved for marketCAT, BASF, Abbott
April 2004US FDA approved new imaging agent for detecting difficult to diagnose cases of appendicitisWistar Institute, Palatin Technologies
September 2006First fully human monoclonal antibody drug approvedAgensys, Amgen
September 4, 2014First checkpoint inhibitor drug approved in US targeting PD-1, the protein responsible for preventing the activation of T-cells
June 5, 2015Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system
September 1, 2016Monoclonal antibody drug for Alzheimer's Disease shown to be promising in phase II clinical trialsSevigny, Chiao, Bussiere, WeinrebBiogen, Neuimmune, Butler Hospital, University of Zurch

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