Cesar Milstein: Timeline of key events

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Koprowski 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+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 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+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+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+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+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+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+0000
Date Event People Places Sciences
Sep 1976Cesar Milstein supplies myeloma cells to Hilary Koprowski at the Wistar Institute for producing monoclonal antibodiesKoprowski, MilsteinLaboratory of Molecular Biology, Wistar InstituteMonoclonal antibodies
Oct 1976British government declines to patent monoclonal antibodiesMilsteinLaboratory of Molecular BiologyMonoclonal antibodies
1977Monoclonal antibodies developed for automatic fluorescence-activated cell sorter Milstein, Herzenberg, OiLaboratory of Molecular Biology, Stanford University Medical School, University of TorontoMonoclonal antibodies
Feb 1977Partnership begun for first commercial distribution of cells for producing monoclonal antibodiesMilstein, Murray Monoclonal antibodies
1977Monoclonals produced against histocompatibility antigensMilstein, Galfre, HowardLaboratory of Molecular Biology, Brabraham InstituteMonoclonal antibodies
Jun 1977First US patent application filed for monoclonal antibodiesCroce, Koprowski, MilsteinWistar InstituteMonoclonal antibodies
1977Monoclonal antibodies made to unknown cell surface antigensMilstein, Galfre, WilliamsLaboratory of Molecular Biology, Sir William Dunn School of PathologyMonoclonal antibodies
1978First monoclonal antibodies generated to human T-cellsMilstein, McMichaelLaboratory of Molecular Biology, Oxford UniversityMonoclonal antibodies
1978First monoclonal antibody generated for blood typingMilsteinLaboratory of Molecular Biology, Oxford UniversityMonoclonal antibodies
Feb 1978First commercialisation of monoclonal antibodies as laboratory reagentsMilstein, MurrayLaboratory of Molecular Biology, Sera-LabMonoclonal antibodies
Oct 1979First US patent for monoclonal antibodies grantedKoprowski, MilsteinWistar InstituteMonoclonal antibodies
Jan 1980First monoclonal antibody created to purify a human therapeutic protein.Burke, Milstein, SecherLaboratory of Molecular Biology, Warwick UniversityMonoclonal antibodies
1980Cesar Milstein proposed the use of recombinant DNA to improve monoclonal antibodiesMilsteinLaboratory of Molecular BiologyMonoclonal antibodies, Recombinant DNA
1980British government report criticised non-patenting of monoclonal antibody technologyMilstein Monoclonal antibodies
1982Monoclonal antibodies generated for routine use in ABO blood typingLennox, Milstein, Sacks, VoakLaboratory of Molecular Biology, Addenbrookes HospitalMonoclonal antibodies
1983First bispecific monoclonal antibody producedCuello, MilsteinLaboratory of Molecular Biology, Oxford UniversityMonoclonal antibodies
Feb 1992Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, CentoxinSchoemaker, Koprowski, MilsteinCentocor, WistarMonoclonal antibodies
Mar 2002Cesar Milstein diedMilsteinLaboratory of Molecular BiologyAntibodies, Monoclonal antibodies, Immunology

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

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

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

British government report criticised non-patenting of monoclonal antibody technology

1982

Monoclonal antibodies generated for routine use in ABO blood typing

1983

First bispecific monoclonal antibody produced

Feb 1992

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

Mar 2002

Cesar Milstein died