Antibodies: Timeline of key events

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S. Brenner, C. Milstein, 'Origin of antibody variation', Nature, 211 (1966), 242-3.1966-07-16T00:00:00+0000BA Askonas, AR Williamson, Nature, 216 (1967), 264–67; ZL Awdeh, et al., Nature, 219 (1968), 66–67; BA Askonas et al., PNAS USA, 67 (1970), 1398–1403; ZL Awdeh et al, Biochemestry Journal, 116 (1970), 241–48; BA Askonas et al., Bull. Soc. Chim. Biol, 50 (1968), 1113–28.1967-01-01T00:00:00+0000Funded by the multinational pharmaceutical company F. Hoffman La Roche, the Basel Institute of Immunology was designed to keep the pharmaceutical company keep ahead of developments in biology, cell biology and biochemistry. It rapidly became the world's largest centres for immunological research and antibody investigation.1969-01-01T00:00:00+0000Joseph Sinkovics, a Hungarian clinical pathologist and laboratory clinical virologist, successfully develops a cell line of antibodies with known specificity that could be grown indefinitely by fusing antibody-producing plasma cells with lymphoma cells.1969-01-01T00:00:00+0000Norman Klinman, an American immunologist, devises a splenic fragments culture technique for growing antibodies.1969-01-01T00:00:00+0000The FACS instrument automatically separates cells. Its sorting mechanism relies on antibodies coupled with fluorescent tags. The FACS was first outlined in HR Hulett, WA Bonner, J Barrett, LA Herzenberg, 'Cell sorting: automated separation of mammalian cells as a function of intracellular fluorescence' Science, 166 (1969), 747–49. By 1971 the FACS could sort 5,000 cells per second. The performance of the instrument was greatly improved by the development of monoclonal antibodies which provided a standardised reagent for the machine. Between 1971 and the early 1980s the number of FACS being used in laboratories increased from half a dozen to over 500. FACS provided a critical tool for investigating cellular structures and functions, measuring processes in cells and determining how viruses infect cells. On the clinical front they provided a means of counting white blood cells, a routine test for assessing the efficacy of chemotherapy in diseases like leukaemia. 1969-11-07T00:00:00+0000Milstein working with his doctoral student, David Secher, and post-doctoral researcher Dick Cotton, start their hunt for somatic mutants among antibodies. Reported in R.G.H. Cotton, D.S. Secher, C. Milstein, 'Somatic mutation and the origin of antibody diversity, Clonal variability of the immunoglobulin produced by MOPC21 cells in culture', European Journal Immunology, 3 (1973), 135-40. 1970-07-01T00:00:00+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+0000The technique uses antibodies to detect antibodies. It was first conceived by two Swedish scientists, Peter Perlman and Eva Engvall at Stockholm University. They published their method in 1971 as 'Enzyme-linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G', Immunochemistry, 8/9, 871-4. 1971-09-01T00:00:00+00001972-01-01T00:00:00+0000Niels Jerne, Danish immunologist, electrifies research into antibodies with his proposition that within the body there are a vast number of immune responses going on all the time and that antibodies form not only to external antigens but also in response to internal antigens within the body. 1973-01-01T00:00:00+0000Kohler hears Milstein present work on myeloma cellular fusions and asks to join Milstein's team in Cambridge1973-01-01T00:00:00+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+0000The marker was found by George and Freda Stevenson, a husband and wife team at the Tenovus Research Laboratory, Southampton University. This they found during investigations of leukaemia in guinea-pigs. They called the marker 'idiotype' because it was identical on every tumour cells but different for every other normal B lymphocytes. Their findings paved the way to development of cancer immunotherapy. The work was published in G T Stevenson, F K Stevenson, 'Antibody to a molecularly-defined antigen confined to a tumour cell surface', Nature, 254 (1975), 714-16. 1975-04-25T00:00:00+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+0000
Date Event People Places Sciences
Jul 1966Cesar Milstein and Sydney Brenner publish theory attributing antibody diversity to somatic mutationBrenner, MilsteinLaboratory of Molecular BiologyAntibodies
1967 - 1970Brigitte Askonas and colleagues demonstrated that a single antibody-forming cell produces a single type of antibodyAskonas, Williamson, AwdehNational Institute for Medical ResearchAntibodies
1969Basel Institute of Immunology foundedJerneBasel Institute of ImmunologyAntibodies
1969First antibodies with known specificity grownSinokovicsMD Anderson Cancer CenterAntibodies
1969Splenic fragment technique devised for growing antibodiesKlinmanWistar InstituteMonoclonal antibodies
7 Nov 1969Fluorescence activated cell sorter (FACS) publishedHerzenberg, Hulett, Bonner, BarrettStanford UniversityAntibodies, Cell, Oncology
Jul 1970Cesar Milstein launches experiments to determine whether somatic mutation underlies antibody diversityCotton, Milstein, SecherLaboratory of Molecular BiologyAntibodies
Nov 1970Means developed for cloning B cells that produce single antibodies with known specificityAskonas, Williamson, WrightNational Institute for Medical ResearchMonoclonal antibodies
1971Sera-Lab foundedMurray Monoclonal antibodies
Sep 1971Enzyme-linked immunosorbent assay (ELISA) technique first publishedPerlmann, EngvallStockholm UniversityAntibodies, Diagnostics
1 Jan 1972Nobel Prize awarded to Gerald Edelman and Rodney Porter for discovery of antibody chain-like structureEdelman, Porter antibodies
1973Antibody network theoryJerneBasel Institute of ImmunologyAntibodies
1973Cesar Milstein meets Georges Kohler at the Basel Institute of ImmunologyKohler, MilsteinBasel Institute of ImmunologyAntibodies
Jul 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 BiologyMonoclonal antibodies
Jun 1974Georges Kohler joins Cesar Milstein's research team to investigate somatic mutation and antibody diversityKohler, MilsteinLaboratory of Molecular BiologyMonoclonal antibodies
Jan 1975Unlimited long-surviving monoclonal antibodies createdMilstein, KohlerLaboratory of Molecular BiologyMonoclonal antibodies
1975Short-lasting antibodies against influenza virus devisedGerhardWistar InstituteMonoclonal antibodies
1975 - 1979First monoclonal antibody created to target a neurotransmitter peptideMilstein, CuelloLaboratory of Molecular Biology, MRC Neurochemical Pharmacology Unit, Oxford UniversityMonoclonal antibodies
25 Apr 1975Unique 'idiotype' marker discovered on the surface of proteins in cancer cells, providing target for treating cancer with antibodiesStevensonSouthampton UniversityAntibodies, Oncology, Cancer immunotherapy
Aug 1975First step taken to patent Kohler and Milstein's monoclonal antibodiesMilsteinLaboratory of Molecular BiologyMonoclonal antibodies

Jul 1966

Cesar Milstein and Sydney Brenner publish theory attributing antibody diversity to somatic mutation

1967 - 1970

Brigitte Askonas and colleagues demonstrated that a single antibody-forming cell produces a single type of antibody

1969

Basel Institute of Immunology founded

1969

First antibodies with known specificity grown

1969

Splenic fragment technique devised for growing antibodies

7 Nov 1969

Fluorescence activated cell sorter (FACS) published

Jul 1970

Cesar Milstein launches experiments to determine whether somatic mutation underlies antibody diversity

Nov 1970

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

1971

Sera-Lab founded

Sep 1971

Enzyme-linked immunosorbent assay (ELISA) technique first published

1 Jan 1972

Nobel Prize awarded to Gerald Edelman and Rodney Porter for discovery of antibody chain-like structure

1973

Antibody network theory

1973

Cesar Milstein meets Georges Kohler at the Basel Institute of Immunology

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

25 Apr 1975

Unique 'idiotype' marker discovered on the surface of proteins in cancer cells, providing target for treating cancer with antibodies

Aug 1975

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

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