Monoclonal antibodies

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.

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.

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

Antiserum preparted against human oesteogenic sarcoma in an ass and 2 dogs. Reported successful in treating 50 patients suffering from cancer of the stomach and chest wall. J Hericourt, C Richet, 'Traitement d'un cas de sarcome par la sarcome par la serotherapie', Seances Acad Sci, 120 (1895), 948-50.1895-01-01T00:00:00+0000Jerne shared the 1984 Nobel Prize for Medicine for 'theories concerning the specificity in development and control of the immune system' and laying the foundation for the production of monoclonal antibodies.1911-12-23T00:00:00+0000E Witebsky, 'Disponibilitiit und Spezifitat alkoholloslicher Strukturen von Organen und bosartigen Geschwulsten', Zeitschrift fur Imrnunitaetsforschung, Allergie und Klinische Immunologie' 62 (1929), 35-73. 1929-01-01T00:00:00+0000Michael Smith shared the 1993 Nobel Prize for Chemistry for a technique that enables researchers to introduce specific mutations into genes and, thus, to the proteins that they encode.1932-04-26T00:00:00+0000Kohler co-pioneered the first monoclonal antibodies which today are a major component in diagnostics and blockbuster drugs.1946-04-17T00:00:00+0000Georges Barski, Serge Sorieul and Francine Cornefert, French scientists at the Institut Gustave Roussy, spot cellular fusion occurs when two different tumour cell lines, taken from two different inbred strains of mice, are grown as a cell mixture in tissue cultures. This observation lays the basis for the development of new techniques for cellular fusion. 1960-01-01T00:00:00+0000Milstein is awarded a three-year MRC contract, arranged by Fred Sanger, to work at the Laboratory of Molecular Biology.1963-01-01T00:00:00+0000Norman Klinman, an American immunologist, devises a splenic fragments culture technique for growing antibodies.1969-01-01T00:00:00+0000Brigette Askonas, a Canadian biochemist, Alan Williamson, a British immunologist, and Brian Wright clone B cells in vivo using spleen cells from mice immunised with haptenated carrier antigen.1970-01-01T00:00:00+0000Sera-Lab is established in Crawley-Down, UK, to commercially supply serum reagents to the scientific community. Sera-Lab was to become the first company to commercialise monoclonal antibodies. 1971-01-01T00:00:00+0000Milstein and Cotton's create hybrid cell to study allelenic exclusion in antibodies. Reported in R.G.H. Cotton, C. Milstein, 'Fusion of two immunoglobulin-producing myeloma cells', Nature 244 (1973), 42-3. This work lays the foundation for the later development of monoclonal antibodies.1973-07-06T00:00:00+0000The investigation into somatic mutation lays the basis for the hunt for an antibody which has known specificity for particular antigens.1974-06-01T00:00:00+0000Cesar Milstein, an Argentinian scientist, and Georges Kohler, a German scientist, develop the first long-lasting monoclonal antibodies as part of their basic research project to investigate the mechanism behind the diversity of antibodies. 1975-01-01T00:00:00+0000Swiss-born immunologist Walter Gerhard cultivates single antibodies with known specificity against influenza viruses using Klinman's splenic fragment technique.1975-01-01T00:00:00+0000The Argentinian born scientists Claudio Cuello and Cesar Milstein generate a monoclonal antibody against substance P, a peptide involved in the neurotransmission of pain. This marks the first application of monoclonal antibodies to neuroscience paving the way to an explosion of research into the brain the central nervous system bringing with it better understandings of neurological disease and neuropharmacological intervention. The work is published in A.C. Cuello, G. Galfre, C. Milstein, 'Detection of substance P in the central nervous system by a monoclonal antibody', Proceedings of the National Academy Science, USA, 76 (1979), 3532-6. 1975-01-01T00:00:00+0000Cesar Milstein, with the help of Tony Vickers, submits the monoclonal antibody technique to the British National Development Corporation for patenting,1975-08-07T00:00:00+0000G. Kohler, C. Milstein, 'Continuous cultures of fused cells secreting antibody of predefined specificity', Nature 256 (1975), 495-7. Article highlighted that monoclonal antibodies could be invaluable for medical and industrial purposes. By 1993 the paper had been cited in more than 6,905 publications.1975-08-07T00:00:00+0000EA Carswell, LJ Old, RL Kassel, S Green, N Fiore, B Williamson, 'An endotoxin-induced serum factor that causes necrosis of tumors', Proc Natl Acad Sci USA, 72/9 (1975), 3666-70.1975-09-01T00:00:00+0000Koprowski uses myeloma cells from Milstein's laboratory to generate monoclonal antibodies against tumour antigens. This work forms the basis of the first patent later awarded for monoclonal antibodies.1976-09-01T00:00:00+0000The British National Research Development Corporation executives indicate that they will not pursue a patent the technique for producing monoclonal antibodies because they cannot see what diagnostic application it can be used for or any industrial end-products.1976-10-01T00:00:00+0000American geneticist and biochemist, Leonard Herzenberg and Argentinian biochemist, Cesar Milstein, devise monoclonal antibodies for use on an automatic fluorescence-activated cell sorter, FACS. This improves the reliability of the FACS allowing the instrument to go on to become a major tool not only for cell sorting and cellular biology but the diagnosis of disease. The work is done in collaboration with the American geneticist and immunologist Leonore Herzenberg and Vernon Oi, then a graduate student in genetics at Stanford University. 1977-01-01T00:00:00+0000Cesar Milstein and David Murray from Sera-Lab agree partner to commercially distribute cells for producing monoclonal antibodies to meet the worldwide requests flooding into Milstein's laboratory for access to such cells. 1977-02-01T00:00:00+0000Together with Australian immunologist, the Argentinian biochemist Cesar Milstein and Italian biochemist Giovanni Galfre develop monoclonal antibodies against rat histocompatibility antigens. This research demonstrates the practical applications of monoclonal antibodies for the first time, opening the way to their use for tissue typing for organ transplants. he work is published as A. F. Williams, G. Galfre, C. Milstein, 'Analysis of Cell Surfaces by Xenogeneic Myeloma-Hybrid Antibodies Differentiation Antigens of Rat Lymphocytes', Cell 12 (Nov 1977), 663-73. This paper would go on to cited in more than 1,490 publications by 1993. 1977-04-01T00:00:00+0000Hilary Koprowski, Polish born virologist and Carlo Croce, Italian born geneticist, both based at the Wistar Institute, file for the first US patent for monoclonal antibodies. The antibodies are made against viral antigens using cells supplied from Milstein's laboratory in September 1976. 1977-06-01T00:00:00+0000Argentinian biochemist Cesar Milstein, Italian biochemist Giovanni Galfre, and Australian scientist Alan Williams publish technique for the development of monoclonal antibodies against unknown rat cell surface antigens, predicting it will be possible to make monoclonals against any sort of cell surface molecule. The publication marks the beginning of the major use of monoclonals for understanding cellular function and disease. The article is published as A.F. Williams, G. Galfre and C. Milstein, 'Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: Differentiation antigens of rat lymphocytes', Cell, 12/3 (1 Nov 1977), 663-73.1977-11-01T00:00:00+0000Ivor Royston, British-American onclologist together with American scientist Howard Birndorf set up Hybritech in San Diego. Hybritech is the first American company established to commercialise monoclonal antibodies for medical diagnostics and therapeutics. 1978-01-01T00:00:00+0000Argentinian biochemist Cesar Milstein and British immunologist Andrew McMichael produce the first monoclonal antibodies that target human T-cells. This lays the foundation for new understandings of the immune responses and disease. While initially rejected for publication, this work is published in A.J. McMichael, J.R. Pitch, J.W. Fabre, David Y. Mason, G. Galfre, 'A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody', European Journal of Immunology, 9/3 (March 1979), 205-210. 1978-01-01T00:00:00+0000Cesar Milstein and Alan Williams generate a monoclonal antibody that targets blood group A cells. 1978-01-01T00:00:00+0000Sera-Lab, a British company specialising in antiserum, issues its first catalogue advertising monoclonal antibody cells from Milstein's laboratory. It represents the first commercialisation of monoclonal antibodies. 1978-02-01T00:00:00+0000Hilary Koprowski, Polish-born virologist and director of the Wistar Institute, together with American entrepreneur Michael Wall establish Centocor with Dutch-born biochemist Hubert Schoemaker and American scientist Ted Allen. Located in Philadelphia, Centocor is the second American company established to commercialise monoclonal antibodies for medical diagnostics and therapeutics.1979-05-01T00:00:00+0000Hilary Koprowski, Polish-born virologist, and colleagues granted US patent for monoclonal antibodies against tumour antigens (US Patent 4,172,124). The patent helps in the building of Centocor, the second American biotechnology set up to commercialise monoclonal antibodies. It also causes a major political controversy in Britain as the patent makes broad claims, essentially patenting the technique first developed by Cesar Milstein and George Kohler in 1975.1979-10-01T00:00:00+0000The British scientist, David Secher, based at the Laboratory of Molecular Biology in Cambridge, together with Derek Burke, a British scientist at Warwick University, create the first monoclonal antibody suitable for purifying interferon. This lays the foundation for the use of monoclonal antibodies as tools for the purification of human therapeutic proteins and other natural compounds.1980-01-01T00:00:00+0000Milstein suggests at a Wellcome Foundation lecture that by using genetic engineering scientists might be able to design tailor-made monoclonal antibodies that mimic antibodies made by the human body. This would free them up from a dependence on rodents for producing monoclonal antibodies. He publishes the idea in C. Milstein, 'Monoclonal antibodies from hybrid myelomas: Wellcome Foundation Lecture 1980', Proceedings Royal Society of London, 211 (1981), 393-412.1980-01-01T00:00:00+0000Referred to as Campath-1 (CAMbridge Pathology) family of antibodies, these are the first set of monoclonal antibodies against human lymphocytes derived from a rat. 1980-01-01T00:00:00+0000Spinks Report on Biotechnology points finger at Cesar Milstein and his colleagues for not attempting to patent the technique for producing monoclonal antibodies.1980-07-03T00:00:00+0000Tests begin with 17-1A, also known as edrecolomab, a monoclonal antibody developed at the Wistar Institute. 1980-12-01T00:00:00+0000Argentinian scientists Cesar Milstein and Claudio Cuello demonstrate the feasibility of monoclonal antibodies for use in radioimmunoassay.1981-01-01T00:00:00+0000Philip Karr, a patient with lymphoma, is treated by Ron Levy at Stanford University with a customised monoclonal antibody. It marks the first time a monoclonal antibody successfully treats cancer in a patient.1981-01-01T00:00:00+0000Held in Paris, the international workshop on human differentiation helped formulate a system for classifying monoclonals and bring out standardisation. Importantly it established a system based on identifying monoclonals found clustered around specific antigens. This laid the foundation for the CD nomeclature which has become a univeral tool for scientists to share and exchange knowledge about immune responses and disease. 1982-01-01T00:00:00+0000Encouraged by Cesar Milstein, collaborative research undertaken by Steven Sacks, Edwin Lennox and Douglas Voak produces monoclonal antibodies suitable for patenting and commercialisation for routine blood typing. 1982-01-01T00:00:00+0000JP Allison, BW McIntyre, D Bloch, 'Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody', Journal Immunology, 129 (1982), 2293.1982-11-01T00:00:00+0000Argentinian scientists Cesar Milstein and Claudio Cuello demonstrate the feasibility of creating bispecific monoclonal antibodies for use in immunohistochemistry, but application for patent, filed in 1983, is abandoned as result of prior patent promoting theory of such a technique. 1983-01-01T00:00:00+0000Two teams of scientists publish methods for the generation of chimeric monoclonal antibodies, that is antibodies possessing genes that are half-human and half mouse. Each team had developed their techniques separate from each other. The first team was lead by Michael Neuberger together with Terence Rabbitts and other colleagues at the Laboratory of Molecular Biology, Cambridge. The second team consisted of Sherie Morrison and colleagues at Stanford University together with Gabrielle Boulianne and others at the University of Toronto. 1984-12-01T00:00:00+0000Susumu Tonegawa, Japanese scientist, identifies immunoglobulin genes1985-01-01T00:00:00+0000The suggestion involves the insertion of gene segments from a human antibody into the DNA of early mouse embryos. It is put forward by scientists at Columbia University, this idea is published in FW. Alt, TK. Blackwell, GD. Yancopoulos, 'Immunoglobulin genes in transgenic mice', Trends Genetics, 1 (1985), 231–6.1985-01-01T00:00:00+0000These are created with the objective of studying self-tolerance. 1985-01-01T00:00:00+0000Greg Winter together with other colleagues from the Laboratory Molecular Biology demonstrate the feasibility of building a new more human-like monoclonal antibody by grafting on to the humab antibody portions of a variable region from a mouse antibody. This reduced the mouse component of the monoclonal antibody to just 5%, making the monoclonal antibody safer and more effective for use in humans. The technique was published in PT Jones, PH Dear, J Foote, MS Neuberger, G Winter, 'Replacing the complementarity-determining regions in a mouse antibody with those from a mouse', Nature, 321 (29 May 1986), 522-5.1986-05-01T00:00:00+0000Hoffmann-LaRoche and Schering-Plough gain FDA permission to market genetically engineered alpha interferon for use as treatment hairy cell leukaemia. The development of interferon rested on the application of both genetic cloning and monoclonal antibodies. 1986-06-04T00:00:00+0000Orthoclone OKT3, developed by Ortho Pharm, was approved as an immunosuppressant drug to reduce acute rejection in patients with kidney transplants. It is a mouse-derived (murine) monoclonal antibody (Muromonab-CD3) that targets a membrane protein on the surface of T cells.1986-06-19T00:00:00+0000Campath-1G is humanised, resulting in Campath-1H. It is accomplished with technology developed by Greg Winter.1988-01-01T00:00:00+0000This patent is filed on the basis of work reported in M Brüggeman, HM Caskey, C Teale, H Waldmann, Williams, Surani, and MS Neuberger, A repertoire of monoclonal antibodies with human heavy chains from transgenic mice, Proc Natl Acad Sci USA, 86 (Sept 1989), 6709-13. 1988-01-01T00:00:00+0000Gregory Winter at the Laboratory of Molecular Biology develops the technique as part of his strategy to create an artificial immune system for generating monoclonal antibodies. The technique is published in R Olandi, DH, Gussow, PT Jones and G Winter, 'Cloning immunoglobulin variable domains for expression by polymerase chain reaction', Proc Natl Acad Sci USA, 86 (May 1989), 3833-7. 1988-11-01T00:00:00+0000Gregory Winter together with David Chiswell set up CAT to develop phage display technology for monoclonal antibodies1989-01-01T00:00:00+0000Gregory Winter together with CAT create the first phage monoclonal antibodies, laying the foundation for the generation of diverse libraries of randomly shaped human antibodies. With this scientists are no longer dependent on the natural immune system of animals or humans and the limitations this poses for the production of monoclonal antibodies. 1990-01-01T00:00:00+0000This is achieved by Richard Lerner and Carlos Barbas at the Scripps Research Institute with the backing of Stratagene, an American biotechnology specialising in antibody engineering.1991-01-01T00:00:00+0000European Committee for Proprietary Medicinal Products recommends the approval of Centoxin (Nebacumab) , a drug originally developed by Henry Kaplan and Nelson Tang at Stanford University and prepared for market by Centocor. Based on this recommendation the drug was subsequently approved for market in The Netherlands, Britain, Germany and France between March and December 1991.1991-03-01T00:00:00+0000US$1.5 billion of Centocor's market capitalisation disappears with news that the FDA requires more information before it will recommend approval of Centoxin.1992-02-20T00:00:00+0000Interim trial data from trials show unexpectedly high mortality from Centoxin, leading to withdrawal of the drug from the European market. Reinforces general pessimism about the future for monoclonal antibody drugs. 1993-02-01T00:00:00+0000Three groups of scientists separately report the successful generation of different strains of transgenic mice for the generation of human monoclonal antibodies. Two of the teams are based in biotechnology companies: GenPharm (led by Nils Lonsberg), Cell Gensys (led by Larry Green) , and the other involved a collaboration (led by Marian Bruggemann and Michael Neuberger) between scientists at the Laboratory of Molecular Biology, Braham Institute and the University of Cologne.1994-01-01T00:00:00+0000Jerne shared the 1984 Nobel Prize for Medicine for 'theories concerning the specificity in development and control of the immune system' and laying the foundation for the production of monoclonal antibodies.1994-10-07T00:00:00+0000ReoPro (abciximab), developed by Centocor, approved for use during and after coronary artery procedures like angioplasty. A chimeric antibody (Abciximab) created by Barry Koller to study platelet behaviour, the antibody was found to be more effective than aspirin in prevent platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery. Today the drug is the most commonly used treatment for angioplasty patients, making the procedure safer for use during heart attacks and as a preventative measure. 1994-12-01T00:00:00+0000Abciximab (ReoPro) approved by the FDA and European regulatory authorities to prevent blot clots during coronary artery procedures like angioplasty. The monoclonal antibody was originally developed by Barry Coller at State University of New York and commercially developed by Centocor. The drug showed for the first time that monoclonal antibodies could be used for the treatment of acute disease conditions. 1994-12-01T00:00:00+0000German regulatory authorities approve Panorex as an adjuvant therapy, that is a drug given in addition to primary or main treatment, for postoperative colorectal cancer. The drug originated from resesearch undertaken by Hilary Koprowski and his colleagues at the Wistar Institute. 1995-01-01T00:00:00+0000German regulatory authorities approve edrecolomab (Panorex) as an adjuvant treatment for post-operative colorectal cancer. The monoclonal antibody, originally known as 17-1A, was developed at the Wistar Institute and commercially developed for market by Centocor. 1995-01-01T00:00:00+0000Kohler co-pioneered the first monoclonal antibodies which today are a major component in diagnostics and blockbuster drugs.1995-03-01T00:00:00+0000Research showed that tumour growth can be stopped in mice using a monoclonal antibody that blocks CTLA-4. 1996-03-22T00:00:00+0000Ritxuan (rituiximab) is approved for the treatment of non-Hodgkin Lymphoma. The drug arose out of Ronald Levy's research for three decades to find a way of harnessing the power of the body's own immune system to fight cancer. 1997-01-01T00:00:00+0000Daclizumab was approved by the FDA for the preventition of acute rejection of kidney transplants. The monoclonal antibody was developed by Protein Design Labs using a humanising method devised by Cary Queen and marketed together with F. Hoffmann-La Roche. 1997-12-01T00:00:00+0000The drug is a monoclonal antibody that targets cancer cells that overproduce the HER2/neu oncoprotein1998-01-01T00:00:00+0000Remicade (infliximab) is approved for the treatment of Crohn's disease. Soon after Remicade wins approval for other autoimmune and inflammatory conditions including rheumatoid arthritis and ulcerative colitis. The drug, a monoclonal antibody against TNF alpha, a powerful promoter of inflammation, was developed in 1989 by Jan Vilcek and Jumning Le and developed in collaboration with Centocor, Marc Feldmann and Maini1998-08-01T00:00:00+0000Launched by the biotechnology company Medarex in collaboration with Jim Allison. 2000-01-01T00:00:00+0000A Canadian biochemist, Michael Smith helped develop site-direct mutagenesis, a technique that allows for a mutation to be created at a specific defined site in a DNA molecule. This technique is pivotal to genetic and protein research and engineering. 2000-10-04T00:00:00+0000Adalimumab (Humira) approved by the FDA for the treatment of rheumatoid arthritis. The drug was developed and marketed by a collaboration between Cambridge Antibogy Technology, BASF Bioresearch Corporation and Abbott Laboratories.2002-12-31T00:00:00+0000The diagnostic, called NeutroSpectT, uses a monoclonal antibody, SSEA1, discovered at the Wistar Institute and developed by Palatin Technologies.2004-04-05T00:00:00+0000Panitumumab (Vectibix) was approved by the FDA for the treatment of patients with EGFR-expressing metatastic colorectal cancer. The drug is a fully human monoclonal antibody created with transgenic mice. It was developed by Agensys with Amgen. 2006-09-27T00:00:00+0000The drug was approved for the treatment of unresectable or metastatic melanoma. The drug uses a monoclonal that blocks CTLA-4 so as to activate an immune response against the cancer.2011-03-25T00:00:00+0000The drug was developed by scientists at Medarex2014-09-01T00:00:00+0000The drug, a monoclonal antibody, was approved by the FDA for the treatment of patients with melanoma. 2014-12-22T00:00:00+0000Results presented to American Society for Clinical Conference from trials involving monoclonal antibody drugs for lung and skin cancer. The drugs block a protein known as PD-1, which functions as an immune checkpoint, being responsible for preventing the activation of T-cells.2015-06-05T00:00:00+0000The drug was developed by Genetech/Roche2016-05-01T00:00:00+0000J. Sevigny et al, 'The antibody aducanumab reduces A-beta plaques in Alzheimer’s disease', 'Nature', 37 (2016), 50-56.2016-09-01T00:00:00+0000R.L. Ferris, 'Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck', NEJM (9 Oct 2016), DOI: 10.1056/NEJMoa1602252.2016-10-09T00:00:00+0000It was the first time tyhe FDA approved an immune checkpoint inhibitor for the treatment of lung cancer. The drug was developed by Merck & Co.2016-10-24T00:00:00+0000Evidence collected from randomised, doublice-blind, placebo controled study of 27,000 patients in 49 countries between Feb 2013 and June 2015. MS Sabatine, et al, 'Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease', NEJM, 2017, DOI: 10.1056/NEJMoa1615664.2017-03-17T00:00:00+0000Developed by EMD Serono avelumab is a PD-L1 blocking monoclonal antibody. It was the first FDA approved product to treat metastatic Merckel cell carcinoma.2017-03-23T00:00:00+0000
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
23 Dec 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
26 Apr 1932Michael Smith was born in Blackpool, United KingdomSmithUniversity of British Columbia
17 Apr 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 antibodiesMilsteinLaboratory 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
7 Aug 1975Cesar Milstein and Georges Kohler published their 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 monoclonal antibodiesBoumsell, 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
7 Oct 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
1 Mar 1995Georges Kohler diedKohlerLaboratory of Molecular Biology
March 1996Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4). 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
2000First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)AllisonMedarex, University of California Berkley
4 Oct 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
25 Mar 2011First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDAAllisonMedarex, University of California Berkley
September 2014FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma 
22 Dec 2014First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US AllisonMedarex, Bristol-Myers Squibb, University of California Berkley
5 Jun 2015Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system  
1 May 2016FDA approved atezolizumab (Tecentriq®), an immune checkpoint inhibitor targeted at PD1, for the treatment of urothelial carcinoma, the most common form of bladder cancerGenentech, Roche
1 Sep 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
9 Oct 2016Nivolumab (Opdivo®) shown to be promising treatment for head and neck cancer in randomised control trials with 351 patientsFerrisUniversity of Pittsburg, MD Anderson Cancer Center
24 Oct 2016FDA approved pembrolizumab (Keytruda®) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.Merck
17 Mar 2017Monoclonal antibody shown to effectively cut cholesterol levels, thereby preventing heart attacks and strokesSabatine
23 Mar 2017US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinomaEMD Serono

1895

Humans treated with antiserum prepared against human cancer. This established the principle of using serotherapy to fight cancer

23 Dec 1911

Niels K Jerne was born in London, United Kingdom

1929

First molecular marker, antigen, identified on a tumour, laying foundation for use of antibodies to diagnose and treat cancer

26 Apr 1932

Michael Smith was born in Blackpool, United Kingdom

17 Apr 1946

Georges Kohler was born

1960

Cellular fusion technique formulated

1963

Cesar Milstein returns to Cambridge and begins researching the structure and diversity of antibodies

1969

Splenic fragment technique devised for growing antibodies

1970 - 1972

Means developed for cloning B cells that produce single antibodies with known specificity

1971

Sera-Lab founded

Jul 1973

Cesar Milstein and Dick Cotton report the successful fusion of two different myeloma cell lines, one from a mouse and the other from a rat

Jun 1974

Georges Kohler joins Cesar Milstein's research team to investigate somatic mutation and antibody diversity

Jan 1975

Unlimited long-surviving monoclonal antibodies created

1975

Short-lasting antibodies against influenza virus devised

1975 - 1979

First monoclonal antibody created to target a neurotransmitter peptide

Aug 1975

First step taken to patent Kohler and Milstein's monoclonal antibodies

7 Aug 1975

Cesar Milstein and Georges Kohler published their paper outlining a technique for producing limitless monoclonal antibodies

Sep 1975

Tumour necrosis factor (TNF) was discovered. It was the first immune molecule shown to kill cancer cells

Sep 1976

Cesar Milstein supplies myeloma cells to Hilary Koprowski at the Wistar Institute for producing monoclonal antibodies

Oct 1976

British government declines to patent monoclonal antibodies

1977

Monoclonal antibodies developed for automatic fluorescence-activated cell sorter

Feb 1977

Partnership begun for first commercial distribution of cells for producing monoclonal antibodies

1977

Monoclonals produced against histocompatibility antigens

Jun 1977

First US patent application filed for monoclonal antibodies

1977

Monoclonal antibodies made to unknown cell surface antigens

1978

Hybritech founded

1978

First monoclonal antibodies generated to human T-cells

1978

First monoclonal antibody generated for blood typing

Feb 1978

First commercialisation of monoclonal antibodies as laboratory reagents

May 1979

Centocor founded

Oct 1979

First US patent for monoclonal antibodies granted

Jan 1980

First monoclonal antibody created to purify a human therapeutic protein.

1980

Cesar Milstein proposed the use of recombinant DNA to improve monoclonal antibodies

1980

First monoclonal antibodies developed against T-cells which can also activate human complement.

1980

British government commissioned report publically criticises non-patenting of technique for producing monoclonal antibodies

Dec 1980

Clinical tials begin with a monoclonal antibody for the treatment of gastrointestinal cancer

1981

First monoclonal antibodies generated for use in radioimmunoassays

1981

First patient successfully treated with anti-idiotype monoclonal antibody

1982

First international workshop on human differentiation antigens establishes international code for classifying and coding monoclonal antibodies

1982

Monoclonal antibodies generated for routine use in ABO blood typing

Nov 1982

James Allison and collegues use monoclonal antibody to provide first biochemical description of tumour specific antigen of murine T-lymphoma

1983

First bispecific monoclonal antibody produced

1984

First chimeric monoclonal antibodies developed which lays foundation for safer and more effective monoclonal antibody therapeutics

1985

Antibody genes identified

Jan 1985

Idea put forward for the creation of transgenic mice to produce human antibodies

1985

First transgenic mice created with with genes coding for both the heavy and light chain domains in an antibody.

May 1986

First humanised monoclonal antibody created

Jun 1986

Interferon approved for treating hairy cell leukaemia

Jun 1986

First monoclonal antibody drug approved

1988

Campath-1H is created - the first clinically useful humanised monoclonal antibody.

1988

Patent application filed for a method to create transgenic mice for the production of human antibodies

Nov 1988

Patent application filed for the the use of PCR to create a library of antibody fragments

1989

Cambridge Antibody Technology (CAT) founded

1990

Phage display monoclonal antibodies created

1991

First display and selection of human antibodies phage

Mar 1991

Monoclonal antibody drug approved in Europe for the treatment of septic shock

Feb 1992

Market interest in monoclonal antibody drugs plummeted with news that the FDA needed more information before it would approve Centoxin

Feb 1993

Centoxin withdrawn from European market

1994

First transgenic mice strains reported for producing human monoclonal antibodies

7 Oct 1994

Niels Kaj Jerne died

Dec 1994

Second monoclonal antibody drug approved

1994

First chimeric monoclonal antibody therapeutic approved for market

1995

First monoclonal antibody drug for cancer approved in Europe

1995

First monoclonal antibody therapeutic for cancer approved for market

1 Mar 1995

Georges Kohler died

Mar 1996

Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4).

1997

FDA approved the first monoclonal antibody cancer drug for the American market

Dec 1997

First humanised monoclonal antibody approved for market

1998

FDA approved Trastuzumab (Herceptin) for the treatment of metastatic breast cancer

Aug 1998

FDA and European regulatory authorities approved the first monoclonal antibody drug for an autoimmune disease

2000

First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)

4 Oct 2000

Michael Smith died

Dec 2002

First monoclonal antibody made using phage display approved for market

Apr 2004

US FDA approved new imaging agent for detecting difficult to diagnose cases of appendicitis

Sep 2006

First fully human monoclonal antibody drug approved

25 Mar 2011

First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDA

Sep 2014

FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma

22 Dec 2014

First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US

5 Jun 2015

Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system

1 May 2016

FDA approved atezolizumab (Tecentriq®), an immune checkpoint inhibitor targeted at PD1, for the treatment of urothelial carcinoma, the most common form of bladder cancer

1 Sep 2016

Monoclonal antibody drug for Alzheimer's Disease shown to be promising in phase II clinical trials

9 Oct 2016

Nivolumab (Opdivo®) shown to be promising treatment for head and neck cancer in randomised control trials with 351 patients

24 Oct 2016

FDA approved pembrolizumab (Keytruda®) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.

17 Mar 2017

Monoclonal antibody shown to effectively cut cholesterol levels, thereby preventing heart attacks and strokes

23 Mar 2017

US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma