Download The History of Antibodies

The History of Antibodies
quantities outside of the body; these ‘monoclonal antibodies’ paved the way for
the widespread use of antibodies as a research tool. More recently, monoclonal
antibodies are proving themselves to be remarkably effective in the clinic,
particularly for the treatment of certain types of cancer and autoimmune disease.
As of 2015, the global monoclonal antibody market is estimated at US $75 billion,
and this figure is projected to increase substantially over the coming years. This
poster provides an overview of important historical milestones in the discovery of
antibodies and their development as therapeutics.
Enabling Legendary Discovery™
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Antibodies are large, characteristic Y-shaped molecules and arguably one of the
most iconic structures in all of science. They are produced by plasma cells of the
immune system and have the ability to specifically bind an almost limitless variety
of target molecules, which enables them to neutralize toxins and pathogens like
bacteria or viruses. Antibodies were originally described in the late 1800s as the
active component of antiserum and as such are a key component of most types of
immune response. In ground-breaking work in the 1970s, scientists developed
techniques to produce antibodies of a defined specificity artificially and in vast
/Alamy
Library
First checkpoint inhibitors in cancer:
Jim Allison and colleagues show that
an antibody against CTLA-4 enables
mice to reject solid tumor grafts28.
icture
Mary E
Radioimmunoassay: Rosalyn Yalow and Solomon
Berson develop an antibody-based system to
quantify insulin present in blood plasma9.
Use of antibodies as an analytical tool:
Robin Coombs, Arthur Mourant and Robert
Race develop the Coombs test, which detects
antibodies to rhesus factor in the blood5.
Leonard Herzenberg and
colleagues use fluorescently
conjugated antibodies to sort
B cells with a flow cytometer17.
Gerald Edelman and colleagues
describe the covalent structure
of an entire antibody molecule13.
1945
1947
Astrid Fagraeus shows
that plasma cells
produce antibodies6.
1957
1958
1960
1965
1966
1969
1970
1971
1972
1975
1976
Greg Winter and colleagues develop
the first fully humanized antibody25.
1977
1982
1983
1984
1985
Tasuku Honjo and colleagues identify
activation induced cytidine deaminase
(AID) as a key enzyme in class switching29.
David Schatz, Majorie Oettinger
and David Baltimore isolate
recombination-activating gene 1
(RAG-1) and show that it
activates V(D)J recombination26.
Sherie Morrison et al. and
Michael Neuberger et al.
generate chimeric antibodies23,24.
Georges Köhler and César Milstein fuse
myeloma cells with B cells, thereby
generating immortal hybridomas that
secrete antibodies of a single specificity18.
Max Cooper and colleagues identify the
bursa of Fabricius (a unique lymphoid organ
in birds) as the organ producing B cells10.
Paul Ehrlich presents the ‘side chain model’,
proposing that cells can express a wide variety
of side-chains that can be shed into the blood
and act as antitoxins or ‘antibodies’3,4.
Ronald Levy and colleagues use
an anti-idiotype monoclonal
antibody to successfully treat
B cell lymphoma21.
Nobumichi Hozumi and
Susumu Tonegawa demonstrate
the somatic rearrangement of
immunoglobulin genes19.
Gustav Nossal and Joshua Lederberg
demonstrate that plasma cells produce
antibodies of a single specificity8.
1900
edical Med
ia/Nature
Enid W. Silverton, Manuel A. Navia
and David R. Davies present the first
three-dimensional structure of an
immunoglobulin20.
Tai Te Wu and Elvin Kabat discover the
complementarity-determining regions
of antibodies14.
vans P
Diphtheria anti-serum: Emil von Behring
and Shibasaburo Kitasato demonstrate
that serum from infected animals can be
used to treat and prevent infection in
other animals1,2.
1890
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1986
1989
1993
First antibody–drug conjugate: gemtuzumab
ozogamicin receives FDA approval for the
treatment of acute myelogenous leukemia.
It is later withdrawn from market.
1996
First monoclonal antibody in inflammatory disease:
Marc Feldmann and Ravinder Maini show that the
anti-TNF antibody cA2 (later registered as infliximab)
is effective in patients with rheumatoid arthritis27.
Eva Engvall and Peter Perlman
develop the enzyme-linked
immunosorbent assay (ELISA)16.
1998
2000
2001
2011
First clinical checkpoint inhibitor: Ipilimumab (anti-CTLA-4) receives U.S. FDA
approval for the treatment of melanoma.
First approval of a monoclonal antibody
for use in humans: the anti-CD3
antibody muromonab-CD3 receives
U.S. FDA approval for use in preventing
transplant rejection.
Husband-and-wife team Kimishige
and Teruko Ishizaka discover IgE11,12.
Clonal selection theory: Sir Frank Macfarlane
Burnet extends the idea that antibody-producing
cells make antibodies of a single specificity by
predicting that these cells proliferate in response
to antigen, thus creating ‘clones’7.
Nucleus M
Stock
Photo
Genetic basis of class switching: Alfred Nisonhoff
and colleagues identify identical variable regions
in IgM and IgG antibodies in a patient with
multiple myeloma, indicating that a genetic
switch event must have happened15.
Approval of first monoclonal antibody for
the targeted treatment of a solid tumor:
The anti-Her2 monoclonal antibody
trastuzumab gains U.S. FDA approval for
the treatment of metastatic breast cancer.
Photo reproduced courtesy of Celia Milstein and the MRC Laboratory
of Molecular Biology, Cambridge, UK
Stefan
esy of
Court
H. E. K
n.
1901 Emil von Behring for ‘the development of serum therapy’.
tio
1908 Paul Ehrlich ‘in recognition of … work on immunity’.
da
aufma
First description of a potently lytic therapeutic
monoclonal antibody: Herman Waldmann and colleagues
show that CAMPATH-1 (later registered as alemtuzumab)
can fix human complement and eliminate lymphocytes22.
1972 Gerald Edelman and Rodney Porter ‘for their discoveries concerning the
chemical structure of antibodies’.
un
nn.
Antibody-related Nobel prizes
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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
specificity in development and control of the immune system and the discovery of
the principle for production of monoclonal antibodies’.
Walter an
Melbourn d Eliza Hall Institute
e, Australia
of Medical
.
Research
,
1987 Susumu Tonegawa ‘for his discovery of the genetic principle for generation of
antibody diversity’.
BioLegend
References
BioLegend develops and manufactures highly recognized, world-class antibodies and reagents
at an outstanding value to customers for biomedical research. Our broad product portfolio
includes flow cytometry, cell biology, and biofunctional molecules for research in immunology,
neuroscience, cancer, cell biology, stem cells, and more. Our aggressive product development
program, accomplished through technology licensing, collaborations, and internal research
and development, has produced a product offering of over 17,000 products, which have been
collectively cited in over 25,000 peer-reviewed journals. BioLegend also offers a wide range of
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www.biolegend.com
1. Behring, E. & Kitasato, S. Über das Zustandekommen der DiphtherieImmunität und der Tetanus-Immunität bei Thieren. Dtsch. Med. Wschr 16,
1113–1114 (in German) (1890).
2. Behring, E. Untersuchungen über das Zustandekommen der DiphtherieImmunität bei Thieren. Dtsch. Med. Wschr. 16,
1145–1147 (in German) (1890).
3. Ehrlich, P. Die Seitenkettentheorie und ihre Gegner. Münch. Med. Wschr. 18,
2123 (in German) (1901).
4. Ehrlich, P. Die Schutzstoffe des Blutes. Dtsch. Med. Wschr. 27, 865
(in German) (1901).
5. Coombs, R. R. A. et al. A new test for the detection of weak and
“incomplete” Rh agglutinins. Br. J. Exp. Pathol. 26, 255–266 (1945).
6. Fagraeus, A. Plasma cellular reaction and its relation to the formation of
antibodies in vitro. Nature 159, 499 (1947).
7. Burnet, F. M. A modification of Jerne's theory of antibody production using
the concept of clonal selection. Aust. J. Sci. 20, 67–69 (1957).
8. Nossal, G. J. V. & Lederberg, J. Antibody production by single cells. Nature
181, 1419–1420 (1958).
9. Yalow, R. S. & Berson, S. A. Immunoassay of endogenous plasma insulin in
man. J. Clin. Invest. 39, 1157–1175 (1960).
10.Cooper, M. D. et al. Delineation of the thymic and bursal lymphoid systems
in the chicken. Nature 205, 143–146 (1965).
11.Ishizaka, K. et al. Physico-chemical properties of human reaginic antibody:
IV. Presence unique immunoglobulin carrier reaginic antibody. J. Immunol.
97, 75–85 (1966).
12.Ishizaka, K. et al. Physico-chemical properties of human reaginic antibody:
V. Correlation of reaginic activity with γ-E-globulin antibody. J. Immunol. 97,
840–853 (1966).
13.Edelman, G. M. et al. The covalent structure of an entire γG immunoglobulin
molecule. Proc. Natl Acad. Sci. USA 63, 78v85 (1969).
14.Wu, T. T. & Kabat, E. A. An analysis of the sequences of the variable regions
of Bence Jones proteins and myeloma light chains and their implications for
antibody complementarity. J. Exp. Med. 132, 211–250 (1970).
15.Wang, A. C. et al. Evidence for control of synthesis of the variable regions of
the heavy chains of immunoglobulins G and M by the same gene. Proc. Natl
Acad. Sci. USA 66, 337–343 (1970).
16.Engvall, E. & Perlmann, P. Enzyme-linked immunosorbent assay (ELISA)
quantitative assay of immunoglobulin G. Immunochemistry 8, 871–874
(1971).
17.Julius, M. H., Masuda, T. & Herzenberg, L. A. Demonstration that antigenbinding cells are precursors of antibody-producing cells after purification
with a fluorescence-activated cell sorter. Proc. Natl Acad. Sci. USA 69,
1934–1938 (1972).
18.Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting
antibody of predefined specificity. Nature 256, 495–497 (1975).
19.Hozumi, N. & Tonegawa, S. Evidence for somatic rearrangement of
immunoglobulin genes coding for variable and constant regions.
Proc. Natl Acad. Sci. USA 73, 3628–3632 (1976).
20.Silverton, E. W. et al. Three-dimensional structure of an intact human
immunoglobulin. Proc. Natl Acad. Sci. USA 74, 5140–5144 (1977).
21.Miller, R. A. et al. Treatment of B-cell lymphoma with monoclonal antiidiotype antibody. N. Engl. J. Med. 306, 517–522 (1982).
22.Hale, G. et al. Removal of T cells from bone marrow for transplantation: a
monoclonal antilymphocyte antibody that fixes human complement. Blood
62, 873–882 (1983).
23.Morrison et al. Chimeric human antibody molecules: mouse antigen-binding
domains with human constant region domains. Proc. Natl Acad. Sci. USA 81,
6851–6855 (1984).
24.Neuberger, M. S., Williams, G. T. & Fox, R. O. Recombinant
antibodies possessing novel effector functions. Nature 312, 604–608
(1984).
25.Jones, P. T. et al. Replacing the complementarity-determining regions in a
human antibody with those from a mouse. Nature 321, 522–525 (1986).
26.Schatz, D. G. et al. The V(D)J Recombination Activating Gene, RAG-1.
Cell 59, 1035–1048 (1989).
27.Elliott. M. J. et al. Treatment of rheumatoid arthritis with chimeric
monoclonal antibodies to tumor necrosis factor-α. Arthritis Rheum. 36,
1681–1690 (1993).
28.Leach, D. R. et al. Enhancement of antitumour immunity by CTLA-4
blockade. Science 271, 1734–1736 (1994).
29.Muramatsu, M. et al. Class switch recombination and hypermutation
require activation-induced cytidine deaminase (AID), a potent RNA editing
enzyme. Cell 102, 553–563 (2000).
Advisors
Marc Feldmann, University of Oxford, UK | Andrew J. T.
George, Brunel University, UK | Philip D. Hodgkin, WEHI,
Australia | Daniel H. Kaplan, University of Pittsburgh,
USA | Stefan H. E. Kaufmann, Max Planck Institute for
Infection Biology, Germany | Toshiaki Kawakami, La Jolla
Institute for Allergy and Immunology, USA | Michael G.
McHeyzer-Williams, Scripps Research Institute, USA |
Sergio A. Quezada, University College London, UK |
David G. Schatz, Yale University, USA | Herman
Waldmann, University of Oxford, UK | Ian A. Wilson,
Scripps Research Institute, USA
The poster content is peer reviewed,
editorially independent and the sole
responsibility of Macmillan Publishers
Limited.
Edited by Zoltan Fehervari and Alexandra
Flemming; copyedited by Jennifer Fosmire;
designed by Lauren Robinson.
© 2016 Macmillan Publishers Limited.
All rights reserved.
http://www.nature.com/posters/antibodies
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