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

It is difficult to overstate the extent to which monoclonal antibodies have transformed healthcare since their introduction in 1975. One of their key advantages is that they are very precise in their target and have a very high degree of sensitivity. This has makes them 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 Kitasato Shibasaburo 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

The production of monoclonal antibodies involves several steps. In the first instance a laboratory animal is injected with a desired target to stimulate their immune system. Following this, antibody producing cells, B lymphocytes, are harvested from the animal's spleen 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 (monoclonal) and has the capacity to bind to a specific receptor found on the surface of a cell.

One of the major advantages of monoclonal antibodies is that they can be produced very cheaply and on a large-scale. They are now routinely used as probes in laboratories to unravel the pathways of numerous diseases, whether it be cancer, Alzheimer’s disease or autoimmune disorders. Monoclonal antibodies are also vital to the typing of tissue for organ transplants and blood for transplants. Everyday they are also used to analyse bodily fluids for diagnosis and to monitor hospital infections. They are also instrumental in the detection of heart attacks. Beyond the clinic, monoclonal antibodies are important components in home-testing kits for determining ovulation, pregnancy, menopause and many other conditions.

In addition to their use in diagnostics, monoclonal antibodies have proven useful as drugs. 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, osteoporosis and ophthalmic problems. They have also been shown to help with migraines and reduce high cholesterol.

Governments are also reliant on monoclonal antibodies for protecting public health. The antibodies are used, for example, 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+0000A virologist and physician, Burnet is best known for his discovery of acquired immunological tolerance and demonstrating how the body recognises the difference between self and non-self. Burnet shared the Nobel Prize in Physiology or Medicine in 1960 for this work. His research helped advance the development of vaccines, tissue transplantation, monoclonal antibodies and associated therapies. In addition, Burnett made significant contributions to the development of techniques to grow and study the influenza virus, including hemagglutination assays. Based on his study of the genetics of the virus he showed that the influenza virus recombined at a high frequency. 1899-09-03T00:00:00+0000Jerne shared the 1984 Nobel Prize for Medicine for 'theories concerning the specificity in development and control of the immune system'. He developed three important theories for immunology. Firstly, that antibodies are formed during fetal development and are present in the body from birth. Secondly, that white blood cells, lymphocytes, teach themselves to recognise the body's own substances in the thymus gland. Thirdly, he proposed the network theory which depicts the immune system as a complex self-regulating network that can turn itself on and off when needed. Jerne's work paved the way to development of monoclonal antibodies. He was the founder and director of the Basel Institute of Immunology.1911-12-23T00:00:00+0000A virologist, Koprowski invented the world's first effective live polio vaccine while at Lederle Laboratories. He developed the vaccine by attenuating the virus in brain cells of a cotton rat. In January 1948 he injected the vaccine into himself. The vaccine had the advantage that it directly entered the intestinal tract and provided long-lasting immunity. Within a decade the vaccine had been adopted on four continents. Koprowski went on to become the director of the Wistar Institute where in the 1960s he led efforts to improve the rabies vaccine. He subsequently became the first scientist, together with colleagues, to hold a patent for monoclonal antibodies. Born to Jewish parents, Koprowski was forced to flee Poland in 1939 after Germany invaded the country. 1916-12-05T00:00:00+0000Porter was a biochemist who won the Nobel Prize in Physiology or Medicine in 1972 for helping to determine the chemical structure of antibodies. This was based on some experiments he carried out between 1949 and 1960 while based at St Mary's Medical School in London. He showed that antibodies have a Y-shaped structure, consisting of a large component that has no antigen-combining capacity, at the bottom, and two smaller fragments at the top which have active sites that bind to the antigen. Porter's understanding of the antibody structure and its implications for function opened up the way to the potential use of antibodies as therapeutics and vaccines.1917-10-08T00:00:00+0000Askonas was a leading figure in immunology whose work helped to establish the basic mechanisms and components of immune system. Together with colleagues she developed one of the first systems for the cloning of antibody-forming B cells in vivo, some of the earliest monoclonal antibodies. She was also one of the first scientists to isolate and clone virus specific T lymphocytes, laying the foundation for defining different influenza sub-sets and improving vaccines.1923-04-01T00:00:00+0000Milstein was an Argentinian biochemist. Together with Georges Kohler, Milstein developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 1927-10-08T00:00:00+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. He developed the method, known as site-directed mutagenesis, in the 1970s, in collaboration with Fred Sanger and Clyde A Hutchinson III. The advantage of the technique was that it allowed comparisons to be made of different protein molecules and provided a means to deliberately alter a specific gene thereby making it possible to modify the characteristics of an organism. His work opened up a new chapter for studying and treating genetic diseases. Site-directed mutagenesis is a pivotal tool today in genetic and protein research and engineering and at the forefront of the development of monoclonal antibody drugs. 1932-04-26T00:00:00+0000Klinman was an immunologist who developed the splenic focus assay, a tool that allowed analysis of antibody production derived from single clones of B cells. He used the tool to analyse immune tolerance and immune responses to influenza. In addition he invented the splenic fragment system, a technique that helped generate some of earliest monoclonal antibodies against viral antigens and cancer. 1937-03-23T00:00:00+0000Levy is an oncologist who in 1981 made history by successfully using monoclonal antibodies to treat the first patient with lymphoma. This work laid the foundation for the development of Rituxan, the first monoclonal antibody drug approved by the FDA for the treatment of cancer. Levy is now focused on the development of cancer vaccines. 1941-12-06T00:00:00+0000Feldmann is an immunologist who in the early 1980s developed the hypothesis that cytokines like the tumour necrosis factor (TNF) played an important role in the induction of autoimmune disease like rheumatoid arthritis. Together with Ravinder Maini, he demonstrated that an antibody targeting TNF could block inflammation in the joints of rheumatoid arthritis patients. Feldmann's pioneering work on cytokines also laid the foundation for the successful treatment of other autoimmune disorders like Crohn's disease and anklosing spondylitis. Feldmann left Ukraine with his Jewish parents for France immediately after World War II and then went to Australia at the age of eight. 1944-12-02T00:00:00+0000An oncologist, researcher and venture capitalist, Royston, together with Howard Birndorf and Ted Greene co-founded Hybritech, America's first monoclonal antibody biotechnology company. Hybritech helped kick-start the biotechnology industry in San Diego. Royston also co-founded Idec Pharmaceuticals,the company that developed Rituxan, the first monoclonal antibody drug approved by the FDA for cancer. 1944-11-30T00:00:00+0000Waldmann is an immunologist who demonstrated how monoclonal antibodies could induce tolerance to foreign proteins and transplanted tissues. He and his team developed the first humanised monoclonal antibody (alemtuzumab) which is now used for combating leukaemia, preventing transplant rejection and treating autoimmune disorders such as multiple sclerosis and vasculitis. 1945-02-27T00:00:00+0000Together with Cesar Milstein, Kohler developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 1946-04-17T00:00:00+0000In 1978 Birndorf, along with Ivor Royston, helped found Hybritech, America's first biotechnology company dedicated to monoclonal antibodies. Birndorf went on to found other companies including: Gen-Probe, IDEC Pharmaceuticals (which merged with Biogen to form Biogen-Idec), Ligand, Gensia (Sicor), Neurocrine Biosciences, FastTraQ and Nanogen. 1950-02-21T00:00:00+0000Schoemaker was co-founder and first Chief Executive Officer of Centocor, an American biotechnology company that pioneered the commercialisation of monoclonal antibody diagnostics and therapeutics. After Centocor was sold to Johnson & Johnson for $5.2 billion in 1999, Schoemaker founded Neuronyx to develop cellular therapies. One of the treatments pioneered by Neuronyx was the use of stem cells from bone marrow to help regenerate heart tissue damaged by heart attacks. 1950-03-23T00:00:00+0000A pioneer of protein engineering, Winter invented techniques to both humanise and later to make fully human antibodies for therapeutic uses. Today his technology is used in over two-thirds of antibody drugs on the market, including Humira, a treatment for rheumatoid arthritis and other autoimmune conditions, which in 2012 was listed as the top selling drug in the world. He is also the founder of three biotechnology companies: Cambridge Antibody Technology, Domantis and Bicycle Therapeutics. 1951-03-31T00:00:00+0000A pioneer of antibody engineering, Neuberger developed some of the first techniques for the generation of chimeric and humanised antibodies. He also helped create the first transgenic mice for the production of human monoclonal antibodies. His work paved the way for the generation of safer and more effective monoclonal antibody drugs. 1953-11-02T00:00:00+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+0000The medium was first described by John Littlefield in work he did to characterise four cell lines. He published this in JW Littlefield, 'Selection of hybrids from matings of fibroblasts in vitro and their presumed recombinants,' Science 145 (1964), 709–10.The HAT meidum has the advantage that it can inhibit unfused myeloma cell proliferation. This is particularly important for the growth of monoclonal antibodies. 1964-08-14T00:00:00+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 cloned B cells in vivo using spleen cells from mice immunised with haptenated carrier antigen. BA Askonas, AR Williamson, BEG Wright, 'Selection of a single antibody-forming cell clone and its propagation in syngeneic mice', PNAS, 67/3 (1970), 1398-14031970-11-01T00:00:00+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+0000Providing a means to produce limitless quantities of antibodies for the first time, Milstein and Kohler's technique was a major breakthrough. It provided a major tool for unravelling disease pathways, and brought major changes to diagnosis and the treatment of over 50 major diseases. The technique was published in G. 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+0000Chaired by Alfred Spinks, the report which examined Britain's state of biotechnology, unfairly singled out Cesar Milstein and his colleagues for the failure. Milstein, however, had approached the National Research Development Corporation to patent the monoclonal antibody technology, but the Corporation failed to take the appropriate action. 1980-02-07T00:00:00+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+0000An English biochemist, Porter won the Nobel Prize in Physiology or Medicine in 1972 for helping to determine the chemical structure of antibodies. This was based on some experiments he carried out between 1949 and 1960 while based at St Mary's Medical School in London. He showed that antibodies have a Y-shaped structure, consisting of a large component that has no antigen-combining capacity, at the bottom, and two smaller fragments at the top which have active sites that bind to the antigen. Porter's understanding of the antibody structure and its implications for function opened up the way to the potential use of antibodies as therapeutics and vaccines. 1985-09-07T00:00:00+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 (muromonamb0CD3) was approved as an immunosuppressant drug to reduce patients' rejection of their kidney transplants. It is a mouse-derived (murine) monoclonal antibody (Muromonab-CD3) that targets a membrane protein on the surface of T cells. OKT3 was first developed in 1979 by Patrick Kung at Ortho Diagnostics as tool to identify different T-cell subsets in humans. It took Kung time to persuade his company to develop the monoclonal antibody as a drug. 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+0000Developed to treat Gram-negative sepsis, Centoxin originated from research conducted by Henry Kaplan and Nelson Teng based at Stanford University. It was licensed to Centocor, a small biotechnology company in Philadelphia. Following the FDA's request for more information, Centocor watched US$1.5 billion of its market capitalisation disappear. The news also had a devastating impact on other companies developing monoclonal antibody drugs. 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'. He developed three important theories for immunology. Firstly, that antibodies are formed during fetal development and are present in the body from birth. Secondly, that white blood cells, lymphocytes, teach themselves to recognise the body's own substances in the thymus gland. Thirdly, he proposed the network theory which depicts the immune system as a complex self-regulating network that can turn itself on and off when needed. Jerne's work paved the way to development of monoclonal antibodies. He was the founder and director of the Basel Institute of Immunology.1994-10-07T00:00:00+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. 1994-12-22T00:00:00+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+0000Together with Cesar Milstein, Kohler developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 1995-03-01T00:00:00+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 prevention 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+0000The company was set up by Perry Fell and Clay Siegall. The two scientists founded Seattle Genetics after their former employer, Bristol-Myers Squibb cuts its antibody cancer research programme.1998-01-01T00:00:00+00001998-01-01T00:00:00+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+0000Genentech agreed to help Seattle Genetics develop SGN-40, one of its drugs for CD40 positive cancers. Under the deal Genentech made an upfront payment of $60 million to Seattle Genetics and agreed to make milestone payments in excess of $800 million and double-digit royalties on any sales.1999-01-01T00:00:00+0000Launched by the biotechnology company Medarex in collaboration with Jim Allison. 2000-01-01T00:00:00+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. He developed the method, known as site-directed mutagenesis, in the 1970s, in collaboration with Fred Sanger and Clyde A Hutchinson III. The advantage of the technique was that it allowed comparisons to be made of different protein molecules and provide a means to deliberately alter a specific gene thereby making it possible to modify the characteristics of an organism. His work opened up a new chapter for studying and treating genetic diseases. Site-directed mutagenesis is a pivotal tool today in genetic and protein research and engineering and at the forefront of the development of monoclonal antibody drugs. 2000-10-04T00:00:00+0000The technology allowed for the development of antibody drug conjugates.2001-01-01T00:00:00+00002001-03-01T00:00:00+0000Milstein was an Argentinian biochemist. Together with Georges Kohler, Milstein developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 2002-03-24T00:00:00+0000The drug, adalimumab (Humira), was approved by the FDA for the treatment of rheumatoid arthritis. It was created using phage display, a technique first invented by Greg Winter in 1990. Cambridge Antibody Technology, BASF Bioresearch Corporation and Abbott Laboratories partnered to develop and market the drug. 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+0000Murray was the founder of Sera-Lab, the first biotechnology company to commercialise monoclonal antibodies. His entrepreneurial efforts paved the way to the wide-scale adoption of monoclonal antibodies in research and their clinical application. 2004-10-11T00:00:00+0000The two companies agreed to share the costs and responsibilities of research and product development up to the completion of a Phase 2 clinical study in each party's territory.2005-05-01T00:00:00+0000Schoemaker was a Dutch biochemist who was co-founder and first Chief Executive Officer of Centocor, an American biotechnology company that pioneered the commercialisation of monoclonal antibody diagnostics and therapeutics. After Centocor was sold to Johnson & Johnson for $5.2 billion in 1999, Schoemaker founded Neuronyx to develop cellular therapies. One of the treatments pioneered by Neuronyx was the use of stem cells from bone marrow to help regenerate heart tissue damaged by heart attacks. 2006-01-01T00:00:00+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+0000Drug, MSX-1106, to be assessed for malignant melanoma, renal cell cancer, castrate-resistant prostate cancer and non-small cell lung carcinoma2008-11-24T00:00:00+0000Seattle genetics had been developing the drug with Genentech. 2009-01-01T00:00:00+0000The partnership ended because of lack of progress with the drug SGN-40.2009-10-01T00:00:00+0000The partnership allowed for Takeda to obtain overseas approvals for brentuximab vedotin.2009-12-01T00:00:00+0000Klinman was an American immunologist who developed the splenic focus assay, a tool that allowed analysis of antibody production derived from single clones of B cells. He used the tool to analyse immune tolerance and immune responses to influenza. In addition he invented the splenic fragment system, a technique that helped generate some of earliest monoclonal antibodies against viral antigens and cancer.2010-05-04T00:00:00+00002011-02-01T00:00:00+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+00002011-07-01T00:00:00+00002011-08-01T00:00:00+0000Askonas was a leading figure in immunology whose work helped to establish the basic mechanisms and components of immune system. Together with colleagues she developed one of the first systems for the cloning of antibody-forming B cells in vivo, some of the earliest monoclonal antibodies. She was also one of the first scientists to isolate and clone virus specific T lymphocytes, laying the foundation for defining different influenza sub-sets and improving vaccines. 2013-01-09T00:00:00+0000A Polish-born virologist, Koprowski invented the world's first effective live polio vaccine while at Lederle Laboratories. He developed the vaccine by attenuating the virus in brain cells of a cotton rat. In January 1948 he injected the vaccine into himself. The vaccine had the advantage that it directly entered the intestinal tract and provided long-lasting immunity. Within a decade the vaccine had been adopted on four continents. Koprowski went on to become the director of the Wistar Institute where in the 1960s he led efforts to improve the rabies vaccine. He subsequently became the first scientist, together with colleagues, to hold a patent for monoclonal antibodies. Born to Jewish parents, Koprowski was forced to flee Poland in 1939 after Germany invaded the country. 2013-04-11T00:00:00+0000Alemtuzumab was originally developed by Herman Waldmann as a laboratory tool to investigate immune tolerance. It soon became the first humanised monoclonal antibody drug. Initially alemtuzumab proved effective for helping prevent graft-versus host disease in transplant patients. It subsequently went on to be approved as a treatment for leukaemia and then many years later it was shown to be effective against multiple sclerosis. 2013-09-17T00:00:00+0000A pioneer of antibody engineering, Neuberger developed some of the first techniques for the generation of chimeric and humanised antibodies. He also helped create the first transgenic mice for the production of human monoclonal antibodies. His work paved the way for the generation of safer and more effective monoclonal antibody drugs. 2013-10-26T00:00:00+0000Marketed as Lemtrada, the drug was the first ever ever humanised monoclonal antibody produced. It started life as a laboratory tool for investigating immune tolerance and was subsequently approved for the treatment of leukaemia. The drug has also proven useful for treating a number of other auto-immune conditions including vasculitis. 2014-04-04T00:00:00+0000The drug was developed by scientists at Medarex2014-09-01T00:00:00+0000The drug (nivolumab, Opdivo®), a monoclonal antibody, was approved by the FDA for the treatment of patients with melanoma. The foundation for the drug was laid by the discovery by of the PD-1 protein in 1992 and the work of Gordon Freeman and his team at Dana-Faber Institute which showed that cancer cells can hijack the protein to evade attack by the immune system. 2014-12-22T00:00:00+0000The drugs use a monoclonal antibody to block a protein known as PD-1, which functions as an immune checkpoint, being responsible for preventing the activation of T-cells. Promising results were presented to American Society for Clinical Conference from trials directed towards treating lung and skin cancer. 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+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+0000The drug was developed by Genentech using the antibody drug conjugate technology it licensed from Seattle Genetics. The drug was to be used in combination with bendamustine plus Rituxan for relapsed and refractory diffuse large B-cell lymphoma. 2017-02-01T00:00:00+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 was the first FDA approved product to treat metastatic Merckel cell carcinoma. Approval was given on the basis of basis of a clinical trial of 88 patient, 33% of whom experienced a complete or partial shrinkage of their tumours. In patients who responded, 86% had a response that last 6 months, and 45% had a response that lasted more than 12 months. The drug is being developed through an alliance between Merck KGaA and Pfizer. 2017-03-23T00:00:00+0000L. Xu, et al, 'Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques', Science, 20 September 2017, Science, 20 Sep 2017, eaan8630, DOI: 0.1126/science.aan86302017-09-20T00:00:00+0000The drug, a form of immunotherapy, is a PDL1 checkpoint inhibitor.2017-09-20T00:00:00+0000Treatment was given to Leopold Fotso, a 33 year old man at King's College London using natalizumab, a drug licensed for multiple sclerosis. The trial is being led by Oliver Howe. 2017-11-03T00:00:00+0000The drug was developed by Seattle Genetics with Astellas Pharma. 2018-03-01T00:00:00+00002018-07-01T00:00:00+00002019-06-01T00:00:00+00002019-07-01T00:00:00+0000Developed by Biogen, the drug, aducanumab, targets a protein called amyloid that forms abnormal deposits in the brains of people with Alzheimer's. The company originally discontinued work on the drug in March 2019 after disappointing trial results. 2019-10-22T00:00:00+0000The drug, crizanlizumab, specifically inhibits selectin, a substance that contributes to cells sticking together and causes vaso-occlusive crisis, an extremely painful condition that is frequently a reason for patients to visit emergency departments. 2019-11-15T00:00:00+0000The drug is enfortumab vedotin-ejfv, an antibody drug conjugate. It was given accelerated approval for adult patients with locally advanced or metastatic urothelial cancer who failed to respond to PD1 immune checkpoint therapy or platinum-containing chemotherapy. 2019-12-18T00:00:00+0000The treatment, developed by Regeneron Pharmaceuticals, contains two monoclonal antibodies: casirivimab and imdevimab. The treatment had been trialled in a a randomised, double-blind, placebo-controlled clinical trial in 799 non-hospitalised adults. 2020-11-21T00:00:00+0000The treatment contains tixagevimab with cilgavimab and is intended for individuals with moderate to severely compromised immune systems or severe adverse reactions to a COVID-19 vaccine. 2021-12-08T00:00:00+0000The drug, bebtelovimab, is a neturalising IgG1 monoclonal antibody that binds to the SARS-CoV-2 spike protein. It was developed by AbCellera and Eli Lilly using a high throughput B-cell screening pipeline. . 2022-02-11T00:00:00+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
3 Sep 1899Frank Macfarlane Burnet born in Traralgon, Victoria, Australia BurnetWalter and Eliza Hall Institute
23 Dec 1911Niels K Jerne was born in London, United KingdomJerneBasel Institute for Immunology
5 Dec 1916Hilary Koprowski was born in Warsaw, PolandKoprowskiLederle Laboratories, Wistar Institute
8 Oct 1917Rodney R Porter was born in Newton-le-Willows, United KingdomPorterOxford University
1 Apr 1923Brigitte Askonas was born in Vienna, AustriaAskonasVienna
8 Oct 1927Cesar Milstein was born in Bahia Blanca, ArgentinaMilsteinLaboratory of Molecular Biology
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 KingdomMichael SmithUniversity of British Columbia
23 Mar 1937Norman Klinman was born in Philadelphia, Pennsylvania, USAKlinmanWistar Institute, University of Pennsylvania
6 Dec 1941Ronald Levy was born in Carmel, California, United StatesLevyStanford University
2 Dec 1944Marc Feldmann was born in Lvov, UkraineFeldmannFrance
30 Nov 1944Ivor Royston was born in Retford, UKRoystonHybritech, Idec
27 Feb 1945Herman Waldmann was born in LebanonWaldmannCambridge University, Oxford University
17 Apr 1946Georges Kohler was born in Munich, GermanyKohlerLaboratory of Molecular Biology
21 Feb 1950Howard Birndorf was born in Detroit, Michigan, USABirndorfHybritech
23 Mar 1950Hubert Schoemaker was born in Deventer, The NetherlandsSchoemakerDeventer, The Netherlands
31 Mar 1951Gregory Winter was born in Leicester, UKWinterLaboratory of Molecular Biology
2 Nov 1953Michael Neuberger was born in London, United KingdomNeubergerLondon
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
14 Aug 1964HAT medium introduced for cell selectionLittlefieldHarvard University
1969Splenic fragment technique devised for growing antibodiesKlinmanWistar Institute
November 1970Means 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 technique for 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, S.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 report criticised non-patenting of monoclonal antibody technologyMilstein 
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, laying 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
7 Sep 1985Rodney R Porter diedPorterOxford University
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 approved as a drug for use in humansChang, Kung, Gringas, Schlossman, GoldsteinOrtho Diagnostics
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 1992Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, CentoxinSchoemaker, Koprowski, MilsteinCentocor, Wistar
February 1993Centoxin withdrawn from European marketCentocor
1994First transgenic mice strains reported for producing human monoclonal antibodiesBruggemann, S.Green, Lonsberg, NeubergerCell Genesys, GenPharm, Laboratory of Molecular Biology
7 Oct 1994Niels Kaj Jerne diedJerneBasel Institute for Immunology
22 Dec 1994First chimeric monoclonal antibody therapeutic approved for marketColler, SchoemakerCentocor, 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
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  
January 1998Seattle Genetics founded Fell, SiegallSeattle Genetics
1998Seattle Genetics licensed patents from Bristol-Myers SquibbSeattle Genetics
August 1998FDA and European regulatory authorities approved the first monoclonal antibody drug for an autoimmune diseaseVilcek, Le, Feldmann, Maini, SchoemakerNew York University, Centocor, Kennedy Institute of Rheumatology
1999Seattle Genetics and Genentech partnership signedSeattle Genetics, Genentech
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 diedMichael SmithUniversity of British Columbia
2001Seattle Genetics began licensing out its technology to other companiesSeattle Genetics
March 2001Seattle Genetics raised approximately $51 million through its Initial Public OfferingSeattle Genetics
March 2002Cesar Milstein diedMilsteinLaboratory of Molecular Biology
31 Dec 2002First fully human monoclonal antibody drug approved for market WinterCAT, BASF, Abbott
April 2004US FDA approved new imaging agent for detecting difficult to diagnose cases of appendicitisWistar Institute, Palatin Technologies
11 Oct 2004David Murray died in La Garde-Freinet, FranceMurraySera-Lab
May 2005Medarex and Ono Pharmaceuticals entered research alliance to develop a fully human anti-PD-1 antibody for the treatment of cancerMedarex, Ono Pharmaceutical
1 Jan 2006Hubert Schoemaker died in Philadelphia, USASchoemaker 
September 2006First fully human monoclonal antibody drug approvedAgensys, Amgen
24 Nov 2008First anti-PD-1 antibody entered phase 1 clinical trial for cancerMedarex, Ono Pharmaceutical
2009First drug developed by Seattle Genetics, SG40, failed phase IIb trialSeattle Genetics, Genentech
October 2009Genentech ended its drug development partnership with Seattle GeneticsSeattle Genetics, Genentech
December 2009Seattle Genetics partnered with Takeda Oncology Company Seattle Genetics, Takeda
4 May 2010Norman Klinman died in San Diego, California, USAKlinmanWistar Institute, University of Pennsylvania
February 2011Seattle Genetics submitted a Biologics License Application to the FDA for the approval of brentuximab vedotinSeattle Genetics
25 Mar 2011First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDAAllisonMedarex, University of California Berkley
July 2011Phase I clinical trials launched for enfortumab vedotin by Seattle Genetics with Agenys/Asterllas PharmaSeattle Genetics, Astellas Pharma
August 2011Seattle Genetics won FDA approval for its first drug - brentuximab vedotin (Adecetris)Seattle Genetics
9 Jan 2013Brigitte Askonas diedAskonasNational Institute for Medical Research
11 Apr 2013Hilary Koprowski diedKoprowskiLederle Laboratories, Wistar Institute
17 Sep 2013European Commission approved Alemtuzumab (Lemtrada) for MS treatmentCompston, Coles, WaldmannCambridge University, Sanofi
26 Oct 2013Michael Neuberger diedNeubergerLaboratory of Molecular Biology
4 Apr 2014British NICE recommends alemtuzumab as cost effective multiple sclerosis treatmentCompston, Coles, Waldmann, WinterCambridge University, Sanofi
September 2014FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma 
22 Dec 2014First immune checkpoint inhibitor drug targeting PD-1 approved in US Honko, Freeman, LonbergMedarex, Bristol-Myers Squibb, Ono Pharmaceutical, Kyoto University
5 Jun 2015Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system Allison 
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
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
February 2017FDA granted Breakthrough Therapy designation and Priority Review for polatuzumab vedotin Seattle Genetics, Genentech
17 Mar 2017Monoclonal antibody shown to effectively cut cholesterol levels, thereby preventing heart attacks and strokesSabatine
23 Mar 2017FDA granted accelerated approval to avelumab, a PD-L1 checkpoint inhibitor, to treat Merkel cell carcinoma, a rare form of skin cancer treatment, in patients 12 years and older with metastatic Merkel cell carcinoma, a rare form of skin disorderEMD Serono, Merck KGaA, Pfizer
20 Sep 2017Combination of three monoclonal antibodies reported to protect monkeys from HIV Xu, Pegu, Rao, Doria-Rose, Beninga, McKee, Lord, Wei, Deng, Louder, Schmidt, Mankoff, Wu, Asokan, Beil, Lange, Leuschner, Kruip, Sendak, Kwon, Zhou, Chen, Bailer, Wang, Choe, Tartaglia, Barouch, O’Dell, Todd, Burton, Roederer, Connors, Koup, Kwong, YangSanhofi, National Institute of Allergy and Infectious Disease, Harvard University, Massachusetts Institute of Technology, Scripps Research Institute,
20 Sep 2017Nivolumab (Opdivo®) made available for NHS patients with advanced lung cancer Honko, FreemanMedarex, Bristol-Myers Squibb, Ono Pharmaceutical
3 Nov 2017First patient treated in first clinical trial using monoclonal antibody drug to treat schizophreniaHoweKing's College London
March 2018FDA granted drug breakthrough therapy designation to enfortumab vedotin for treating metastatic urothelial cancerSeattle Genetics, Astellas Pharma
July 2018Seattle Genetics and Astellas Pharma launched global phase III trials for enfortumab vedotin for treating bladder cancerSeattle Genetics, Astellas Pharma
June 2019Genentech granted FDA approval for polatuzumab vedotin, an antibody drug conjugate developed using Seattle Genetics' technologySeattle Genetics, Genentech
July 2019Seattle Genetics and Astellas Pharma submitted application to FDA for accelerated approval of enfortumab vedotin Seattle Genetics, Astellas Pharma
22 Oct 2019Monoclonal drug originally dismissed for treating Alzheimers got new green light from FDA for testing for the diseaseBiogen
15 Nov 2019FDA approved first monoclonal antibody drug to help treat painful complications associated with sickle-cell diseaseNovartis
18 Dec 2019FDA granted accelerated approval for Seattle Genetics drug for advanced urothelial cancerSeattle Genetics
21 Nov 2020FDA issued emergency authorisation for the first monoclonal antibody treatment for patients with mild to moderate COVID-19Regeneron Pharmaceuticals
8 Dec 2021FDA issued emergency authorisation for long-acting monoclonal antibodies for pre-exposure prevention of COVID-19 in certain patientsAstraZeneca
11 Feb 2022FDA issued emergency use authorisation for a new monoclonal antibody treatment for COVID-19 that is active against the omicron variant. AbCellera, Eli Lilly

1895

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

3 Sep 1899

Frank Macfarlane Burnet born in Traralgon, Victoria, Australia

23 Dec 1911

Niels K Jerne was born in London, United Kingdom

5 Dec 1916

Hilary Koprowski was born in Warsaw, Poland

8 Oct 1917

Rodney R Porter was born in Newton-le-Willows, United Kingdom

1 Apr 1923

Brigitte Askonas was born in Vienna, Austria

8 Oct 1927

Cesar Milstein was born in Bahia Blanca, Argentina

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

23 Mar 1937

Norman Klinman was born in Philadelphia, Pennsylvania, USA

6 Dec 1941

Ronald Levy was born in Carmel, California, United States

2 Dec 1944

Marc Feldmann was born in Lvov, Ukraine

30 Nov 1944

Ivor Royston was born in Retford, UK

27 Feb 1945

Herman Waldmann was born in Lebanon

17 Apr 1946

Georges Kohler was born in Munich, Germany

21 Feb 1950

Howard Birndorf was born in Detroit, Michigan, USA

23 Mar 1950

Hubert Schoemaker was born in Deventer, The Netherlands

31 Mar 1951

Gregory Winter was born in Leicester, UK

2 Nov 1953

Michael Neuberger was born in London, United Kingdom

1960

Cellular fusion technique formulated

1963

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

14 Aug 1964

HAT medium introduced for cell selection

1969

Splenic fragment technique devised for growing antibodies

Nov 1970

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 technique for 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 report criticised non-patenting of monoclonal antibody technology

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, laying 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.

7 Sep 1985

Rodney R Porter died

May 1986

First humanised monoclonal antibody created

Jun 1986

Interferon approved for treating hairy cell leukaemia

Jun 1986

First monoclonal antibody approved as a drug for use in humans

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

Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, 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

22 Dec 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

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

Jan 1998

Seattle Genetics founded

1998

Seattle Genetics licensed patents from Bristol-Myers Squibb

Aug 1998

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

1999

Seattle Genetics and Genentech partnership signed

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

2001

Seattle Genetics began licensing out its technology to other companies

Mar 2001

Seattle Genetics raised approximately $51 million through its Initial Public Offering

Mar 2002

Cesar Milstein died

31 Dec 2002

First fully human monoclonal antibody drug approved for market

Apr 2004

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

11 Oct 2004

David Murray died in La Garde-Freinet, France

May 2005

Medarex and Ono Pharmaceuticals entered research alliance to develop a fully human anti-PD-1 antibody for the treatment of cancer

1 Jan 2006

Hubert Schoemaker died in Philadelphia, USA

Sep 2006

First fully human monoclonal antibody drug approved

24 Nov 2008

First anti-PD-1 antibody entered phase 1 clinical trial for cancer

2009

First drug developed by Seattle Genetics, SG40, failed phase IIb trial

Oct 2009

Genentech ended its drug development partnership with Seattle Genetics

Dec 2009

Seattle Genetics partnered with Takeda Oncology Company

4 May 2010

Norman Klinman died in San Diego, California, USA

Feb 2011

Seattle Genetics submitted a Biologics License Application to the FDA for the approval of brentuximab vedotin

25 Mar 2011

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

Jul 2011

Phase I clinical trials launched for enfortumab vedotin by Seattle Genetics with Agenys/Asterllas Pharma

Aug 2011

Seattle Genetics won FDA approval for its first drug - brentuximab vedotin (Adecetris)

9 Jan 2013

Brigitte Askonas died

11 Apr 2013

Hilary Koprowski died

17 Sep 2013

European Commission approved Alemtuzumab (Lemtrada) for MS treatment

26 Oct 2013

Michael Neuberger died

4 Apr 2014

British NICE recommends alemtuzumab as cost effective multiple sclerosis treatment

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 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

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.

Feb 2017

FDA granted Breakthrough Therapy designation and Priority Review for polatuzumab vedotin

17 Mar 2017

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

23 Mar 2017

FDA granted accelerated approval to avelumab, a PD-L1 checkpoint inhibitor, to treat Merkel cell carcinoma, a rare form of skin cancer treatment, in patients 12 years and older with metastatic Merkel cell carcinoma, a rare form of skin disorder

20 Sep 2017

Combination of three monoclonal antibodies reported to protect monkeys from HIV

20 Sep 2017

Nivolumab (Opdivo®) made available for NHS patients with advanced lung cancer

3 Nov 2017

First patient treated in first clinical trial using monoclonal antibody drug to treat schizophrenia

Mar 2018

FDA granted drug breakthrough therapy designation to enfortumab vedotin for treating metastatic urothelial cancer

Jul 2018

Seattle Genetics and Astellas Pharma launched global phase III trials for enfortumab vedotin for treating bladder cancer

Jun 2019

Genentech granted FDA approval for polatuzumab vedotin, an antibody drug conjugate developed using Seattle Genetics' technology

Jul 2019

Seattle Genetics and Astellas Pharma submitted application to FDA for accelerated approval of enfortumab vedotin

22 Oct 2019

Monoclonal drug originally dismissed for treating Alzheimers got new green light from FDA for testing for the disease

15 Nov 2019

FDA approved first monoclonal antibody drug to help treat painful complications associated with sickle-cell disease

18 Dec 2019

FDA granted accelerated approval for Seattle Genetics drug for advanced urothelial cancer

21 Nov 2020

FDA issued emergency authorisation for the first monoclonal antibody treatment for patients with mild to moderate COVID-19

8 Dec 2021

FDA issued emergency authorisation for long-acting monoclonal antibodies for pre-exposure prevention of COVID-19 in certain patients

11 Feb 2022

FDA issued emergency use authorisation for a new monoclonal antibody treatment for COVID-19 that is active against the omicron variant.

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