Antibodies: Timeline of key events

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Two 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+0000Heidelberger was one of the founders of immunochemistrty, a branch of biochemistry that investigates the mammalian immune system at the molecular level. He first made his mark in 1923 when he found with Oswald Avery that that the immune system could target bacterial sugars. The two scientists made the discovery while investigating a capsular substance that envelops pneumococcus and other species of bacteria. Their work helped determine that antibodies were proteins. It also paved the way to improving the production of more effective serum therapies for the prevention of bacterial infectious like pneumonia and meningitis.1991-06-25T00:00:00+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'. His work laid the foundation for the production of monoclonal antibodies. He was the founder and director of the Basel Institute of Immunology. 1994-10-07T00:00:00+0000
Date Event People Places Sciences
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 SchoolMonoclonal antibodies, Recombinant DNA
1985Antibody genes identifiedTonegawaBasel Institute of ImmunologyMonoclonal antibodies
Jan 1985Idea put forward for the creation of transgenic mice to produce human antibodiesAlt, Blackwell, YancopoulosColumbia UniversityMonoclonal antibodies, gene cloning
1985First transgenic mice created with with genes coding for both the heavy and light chain domains in an antibody.Kohler, RusconiMax-Planck InstituteTransgenic animals, Monoclonal antibodies
7 Sep 1985Rodney R Porter diedPorterOxford UniversityAntibodies, Monoclonal antibodies
May 1986First humanised monoclonal antibody createdDear, Foote, Jones, Neuberger, WinterLaboratory of Molecular BiologyMonoclonal antibodies, Recombinant DNA
Jun 1986Interferon approved for treating hairy cell leukaemia  Recombinant DNA, Monoclonal antibodies
Jun 1986First monoclonal antibody approved as a drug for use in humansChang, Kung, Gringas, Schlossman, GoldsteinOrtho DiagnosticsMonoclonal antibodies, Transplantation
1988Campath-1H is created - the first clinically useful humanised monoclonal antibody.Winter, Waldmann, Reichmann, ClarkCambridge University, Laboratory of Molecular BiologyMonoclonal antibodies, Recombinant DNA, Campath
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 UniversityMonoclonal antibodies, gene cloning, transgenic animals
Nov 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 TumoriMonoclonal antibodies, PCR
1989Cambridge Antibody Technology (CAT) foundedWinter, ChiswellLaboratory of Molecular Biology, CATMonoclonal antibodies, Phage Display
1990Phage display monoclonal antibodies createdWinterLaboratory of Molecular Biology, CATMonoclonal antibodies, Phage Display
1991First display and selection of human antibodies phageBarbas, LernerScripps Research InstituteMonoclonal antibodies, Phage Display
Mar 1991Monoclonal antibody drug approved in Europe for the treatment of septic shockKaplan, TangStanford University Medical School, CentocorMonoclonal antibodies
25 Jun 1991Michael Heidelberger died in New York City, USAHeidelbergerRockefeller Institute, Columbia UniversityAntibodies, Immunology
Feb 1992Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, CentoxinSchoemaker, Koprowski, MilsteinCentocor, WistarMonoclonal antibodies
Feb 1993Centoxin withdrawn from European market CentocorMonoclonal antibodies
1994First transgenic mice strains reported for producing human monoclonal antibodiesBruggemann, S.Green, Lonsberg, NeubergerCell Genesys, GenPharm, Laboratory of Molecular BiologyMonoclonal antibodies, Transgenic animals, Gene cloning
7 Oct 1994Niels Kaj Jerne diedJerneBasel Institute for ImmunologyImmunology, Monoclonal antibodies

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

25 Jun 1991

Michael Heidelberger died in New York City, USA

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