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Home , Gerald Edelman, Robin Coombs

The History of

Antibodies are large, characteristic Y-shaped molecules and arguably one of the quantities outside of the body; these ‘monoclonal antibodies’ paved the way for most iconic structures in all of science. They are produced by plasma cells of the the widespread use of antibodies as a research tool. More recently, monoclonal Enabling Legendary Discovery™ and have the ability to specifically bind an almost limitless variety antibodies are proving themselves to be remarkably effective in the clinic, of target molecules, which enables them to neutralize toxins and pathogens like particularly for the treatment of certain types of cancer and autoimmune disease. bacteria or viruses. Antibodies were originally described in the late 1800s as the As of 2015, the global monoclonal market is estimated at US $75 billion, active component of antiserum and as such are a key component of most types of and this figure is projected to increase substantially over the coming years. This immune response. In ground-breaking work in the 1970s, scientists developed poster provides an overview of important historical milestones in the discovery of techniques to produce antibodies of a defined specificity artificially and in vast antibodies and their development as therapeutics.

l a n io at Genetic basis of class switching: Alfred Nisonhoff Pr N . oc he A Ac eedings of t S and colleagues identify identical variable regions ad es U emy o cienc in IgM and IgG antibodies in a patient with f S multiple myeloma, indicating that a genetic switch event must have happened15. Enid W. Silverton, Manuel A. Navia and David R. Davies present the first Tai Te Wu and Elvin Kabat discover the three-dimensional structure of an complementarity-determining regions immunoglobulin20. of antibodies14. First checkpoint inhibitors in cancer: Diphtheria anti-serum: Jim Allison and colleagues show that and Shibasaburo Kitasato demonstrate an antibody against CTLA-4 enables Nucleus Medical Media/Nature Publishing Group that serum from infected animals can be Radioimmunoassay: Rosalyn Yalow and Solomon Leonard Herzenberg and mice to reject solid tumor grafts28. used to treat and prevent infection in Berson develop an antibody-based system to colleagues use fluorescently Mary Evans Picture Library/Alamy Stock Photo 9 Ronald Levy and colleagues use Greg Winter and colleagues develop other animals1,2. quantify insulin present in blood plasma . conjugated antibodies to sort B cells with a flow cytometer17. an anti-idiotype monoclonal the first fully humanized antibody25. antibody to successfully treat and colleagues identify B lymphoma21. Use of antibodies as an analytical tool: activation induced cytidine deaminase , and Robert (AID) as a key enzyme in class switching29. Race develop the , which detects Gerald Edelman and colleagues David Schatz, Majorie Oettinger 5 describe the covalent structure Nobumichi Hozumi and and isolate antibodies to rhesus factor in the blood . 13 of an entire antibody molecule . demonstrate Sherie Morrison et al. and recombination-activating 1 the somatic rearrangement of Michael Neuberger et al. (RAG-1) and show that it First antibody–drug conjugate: gemtuzumab Gustav Nossal and 26 immunoglobulin genes19. generate chimeric antibodies23,24. activates V(D)J recombination . ozogamicin receives FDA approval for the demonstrate that plasma cells produce treatment of acute myelogenous leukemia. 8 antibodies of a single specificity . It is later withdrawn from market.

1890 1900 1945 1947 1957 1958 1960 1965 1966 1969 1970 1971 1972 1975 1976 1977 1982 1983 1984 1985 1986 1989 1993 1996 1998 2000 2001 2011

Astrid Fagraeus shows Max Cooper and colleagues identify the Georges Köhler and César Milstein fuse First approval of a monoclonal antibody First clinical checkpoint inhibitor: that plasma cells bursa of Fabricius (a unique lymphoid organ myeloma cells with B cells, thereby for use in humans: the anti-CD3 Ipilimumab (anti-CTLA-4) receives U.S. FDA produce antibodies6. in birds) as the organ producing B cells10. generating immortal hybridomas that antibody muromonab-CD3 receives approval for the treatment of melanoma. secrete antibodies of a single specificity18. U.S. FDA approval for use in preventing transplant rejection. presents the ‘side chain model’, Husband-and-wife team Kimishige Approval of first monoclonal antibody for proposing that cells can express a wide variety and Teruko Ishizaka discover IgE11,12. of side-chains that can be shed into the blood the targeted treatment of a solid tumor: and act as antitoxins or ‘antibodies’3,4. The anti-Her2 monoclonal antibody trastuzumab gains U.S. FDA approval for First monoclonal antibody in inflammatory disease: the treatment of metastatic breast cancer. Eva Engvall and Peter Perlman Marc Feldmann and Ravinder Maini show that the Clonal selection theory: Sir Frank Macfarlane develop the enzyme-linked anti-TNF antibody cA2 (later registered as infliximab) Burnet extends the idea that antibody-producing immunosorbent assay (ELISA)16. is effective in patients with rheumatoid arthritis27. cells make antibodies of a single specificity by predicting that these cells proliferate in response to , thus creating ‘clones’7. Photo reproduced courtesy of Celia Milstein and the MRC Laboratory of Molecular , Cambridge, UK

Antibody-related Nobel prizes 1901 Emil von Behring for ‘the development of serum therapy’. . n io First description of a potently lytic therapeutic t 1908 Paul Ehrlich ‘in recognition of … work on immunity’. a d n monoclonal antibody: and colleagues u o 1972 Gerald Edelman and Rodney Porter ‘for their discoveries concerning the l F show that CAMPATH-1 (later registered as alemtuzumab) be No can fix human complement and eliminate lymphocytes22. chemical structure of antibodies’. © ® The 1977 Rosalyn Yalow ‘…for the development of radioimmunoassays of peptide hormones’. 1984 Niels K. Jerne, Georges J. F. Köhler and César Milstein ‘for theories concerning the

Walter and Eliza Hall Institute of Medical Research, specificity in development and control of the immune system and the discovery of Courtesy of Stefan H. E. Kaufmann. E. H. Stefan of Courtesy Melbourne, Australia. the principle for production of monoclonal antibodies’. 1987 Susumu Tonegawa ‘for his discovery of the genetic principle for generation of antibody diversity’.

BioLegend References 181, 1419–1420 (1958). 16. Engvall, E. & Perlmann, P. Enzyme-linked immunosorbent assay (ELISA) 23. Morrison et al. Chimeric human antibody molecules: mouse antigen-binding Advisors 9. Yalow, R. S. & Berson, S. A. Immunoassay of endogenous plasma insulin in quantitative assay of . Immunochemistry 8, 871–874 domains with human constant region domains. Proc. Natl Acad. Sci. USA 81, BioLegend develops and manufactures highly recognized, world-class antibodies and reagents 1., Behring E. & Kitasato, S. Über das Zustandekommen der Diphtherie- man. J. Clin. Invest. 39, 1157–1175 (1960). (1971). 6851–6855 (1984). Marc Feldmann, University of Oxford, UK | Andrew J. T. The poster content is peer reviewed, at an outstanding value to customers for biomedical research. Our broad product portfolio Immunität und der Tetanus-Immunität bei Thieren. Dtsch. Med. Wschr 16, 10. Cooper, M. D. et al. Delineation of the thymic and bursal lymphoid systems 17. Julius, M. H., Masuda, T. & Herzenberg, L. A. Demonstration that antigen- 24. Neuberger, M. S., Williams, G. T. & Fox, R. O. Recombinant George, Brunel University, UK | Philip D. Hodgkin, WEHI, editorially independent and the sole 1113–1114 (in German) (1890). in the chicken. Nature 205, 143–146 (1965). binding cells are precursors of antibody-producing cells after purification antibodies possessing novel effector functions. Nature 312, 604–608 responsibility of Macmillan Publishers includes flow cytometry, cell biology, and biofunctional molecules for research in , 2. Behring, E. Untersuchungen über das Zustandekommen der Diphtherie- 11. Ishizaka, K. et al. Physico-chemical properties of human reaginic antibody: with a fluorescence-activated cell sorter. Proc. Natl Acad. Sci. USA 69, (1984). Australia | Daniel H. Kaplan, University of Pittsburgh, Dtsch. Med. Wschr. J. Immunol. et al. Limited. , cancer, cell biology, stem cells, and more. Our aggressive product development Immunität bei Thieren. 16, IV. Presence unique immunoglobulin carrier reaginic antibody. 1934–1938 (1972). 25. Jones, P. T. Replacing the complementarity-determining regions in a USA | Stefan H. E. Kaufmann, Max Planck Institute for 1145–1147 (in German) (1890). 97, 75–85 (1966). 18. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting human antibody with those from a mouse. Nature 321, 522–525 (1986). Infection Biology, Germany | Toshiaki Kawakami, Edited by Zoltan Fehervari and Alexandra program, accomplished through technology licensing, collaborations, and internal research 3. Ehrlich, P. Die Seitenkettentheorie und ihre Gegner. Münch. Med. Wschr. 18, 12. Ishizaka, K. et al. Physico-chemical properties of human reaginic antibody: antibody of predefined specificity. Nature 256, 495–497 (1975). 26. Schatz, D. G. et al. The V(D)J Recombination Activating Gene, RAG-1. 2123 (in German) (1901). V. Correlation of reaginic activity with γ-E-globulin antibody. J. Immunol. 97, 19. Hozumi, N. & Tonegawa, S. Evidence for somatic rearrangement of Cell 59, 1035–1048 (1989). Institute for and Immunology, USA | Michael G. Flemming; copyedited by Jennifer Fosmire; and development, has produced a product offering of over 17,000 products, which have been 4. Ehrlich, P. Die Schutzstoffe des Blutes. Dtsch. Med. Wschr. 27, 865 840–853 (1966). immunoglobulin coding for variable and constant regions. 27. Elliott. M. J. et al. Treatment of rheumatoid arthritis with chimeric McHeyzer-Williams, Institute, USA | designed by Lauren Robinson. (in German) (1901). 13. Edelman, G. M. et al. The covalent structure of an entire γG immunoglobulin Proc. Natl Acad. Sci. USA 73, 3628–3632 (1976). monoclonal antibodies to tumor necrosis factor-α. Arthritis Rheum.36 , collectively cited in over 25,000 peer-reviewed journals. BioLegend also offers a wide range of 5. Coombs, R. R. A. et al. A new test for the detection of weak and molecule. Proc. Natl Acad. Sci. USA 63, 78v85 (1969). 20. Silverton, E. W. et al. Three-dimensional structure of an intact human 1681–1690 (1993). Sergio A. Quezada, University College London, UK | custom services including assay development, sample testing, and conjugation. BioLegend's “incomplete” Rh agglutinins. Br. J. Exp. Pathol. 26, 255–266 (1945). 14. Wu, T. T. & Kabat, E. A. An analysis of the sequences of the variable regions immunoglobulin. Proc. Natl Acad. Sci. USA 74, 5140–5144 (1977). 28. Leach, D. R. et al. Enhancement of antitumour immunity by CTLA-4 David G. Schatz, Yale University, USA | Herman © 2016 Macmillan Publishers Limited. 6. Fagraeus, A. Plasma cellular reaction and its relation to the formation of of Bence Jones proteins and myeloma light chains and their implications for 21. Miller, R. A. et al. Treatment of B-cell lymphoma with monoclonal anti- blockade. Science 271, 1734–1736 (1994). All rights reserved. reagents are supported by superior customer service and a quality management system antibodies in vitro. Nature 159, 499 (1947). antibody complementarity. J. Exp. Med. 132, 211–250 (1970). idiotype antibody. N. Engl. J. Med. 306, 517–522 (1982). 29. Muramatsu, M. et al. Class switch recombination and hypermutation Waldmann, University of Oxford, UK | Ian A. Wilson, dedicated to continuous improvement that is certified for ISO 9001:2008 and ISO 13485:2003. 7. Burnet, F. M. A modification of Jerne's theory of antibody production using 15. Wang, A. C. et al. Evidence for control of synthesis of the variable regions of 22. Hale, G. et al. Removal of T cells from bone marrow for transplantation: a require activation-induced cytidine deaminase (AID), a potent RNA editing Scripps Research Institute, USA http://www.nature.com/posters/antibodies the concept of clonal selection. Aust. J. Sci. 20, 67–69 (1957). the heavy chains of immunoglobulins G and M by the same gene. Proc. Natl monoclonal antilymphocyte antibody that fixes human complement. Blood enzyme. Cell 102, 553–563 (2000). www.biolegend.com 8. Nossal, G. J. V. & Lederberg, J. Antibody production by single cells. Nature Acad. Sci. USA 66, 337–343 (1970). 62, 873–882 (1983). ©2016 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved.