From tool to therapy: a timeline of monoclonal antibody technology
They started out as a useful tool for studying the immune system in the lab and now they’re a family of drugs treating millions of patients, with global revenues of nearly $75 billion in 2013. MRC funding and researchers have been entwined with the monoclonal antibodies story from the very beginning. Forty years ago this month, Nature published a paper by César Milstein and Georges Köhler which described how they’d made mouse monoclonal antibodies. Here we look at the landmarks on the 40-year journey.
They can fight disease, determine blood types, and diagnose pregnancy in minutes. Such varied uses, but the usefulness of monoclonal antibodies actually lies in their uniformity.
Antibodies are proteins that recognise and fight foreign invaders, such as bacteria or viruses. Monoclonal antibodies are tailored in the lab to recognise specific desirable targets, such as a marker on a cancer cell or a pregnancy hormone. They are then churned out in their identical multitudes, ready to become a drug, a diagnostic test, or a probe to study disease in the lab.
Since that first paper in Nature 40 years ago, monoclonal antibodies have been created to harness the power of the immune system against a range of diseases such as breast cancer, leukaemia, multiple sclerosis, asthma, arthritis, melanoma, psoriasis and transplant rejection.
Mouse monoclonal antibodies are isolated by César Milstein and Georges Köhler at the MRC Laboratory of Molecular Biology (MRC LMB). They identified a way to produce antibodies by fusing antibody-producing cells with tumour cells, meaning they could produce large numbers of identical antibodies for their lab work.
Milstein and Köhler publish a Nature paper describing their technique.
Milstein and Köhler win a Nobel Prize for monoclonal antibody work.
The first mouse monoclonal antibody, orthoclone, is approved for preventing kidney transplant rejection in acute cases.
Greg Winter, a researcher also at the MRC LMB, discovers that the rodent monoclonal antibodies can be ‘humanised’ by transplanting their antigen-binding loops into human antibodies. This makes them less likely to be rejected by the human immune system.
The first humanised antibody, Campath-1H, a human antibody that had been fused with parts of a rat antibody to attack cancerous lymphocytes, is tested in a lymphoma patient. The original mouse version of Campath had been developed by MRC-funded Herman Waldmann.
Home pregnancy tests using monoclonal antibody technology are introduced.
MRC LMB scientists Michael Neuberger and colleague Marianne Brüggemann produce transgenic mice which can produce fully human monoclonal antibodies in response to immunisation.
Greg Winter invents another approach to making fully human monoclonal antibodies. This ‘phage display’ method involves creating large libraries of antibody genes, expressing the antibody fragments in bacteria and identifying those with binding activities to the desired target.
The MRC, Winter and others establish Cambridge Antibody Technology, a spin-out company focusing on the identification of fully human monoclonal antibodies using phage display.
The MRC-supported Therapeutic Antibody Centre opens in Cambridge to produce small amounts of humanised monoclonal antibodies for clinical trials.
Campath-1H, now known as alemtuzumab, is approved by the FDA for the treatment of B-cell chronic lymphocytic leukaemia.
The first fully human monoclonal antibody, adalimumab, is approved for rheumatoid arthritis. Found using CAT’s phage display technology and marketed as Humira, it is the world’s top selling medicine, with sales reaching almost £12 billion in 2014.
AstraZeneca buys CAT for £700 million.
Alemtuzumab is licensed in Europe for the treatment of relapsing-remitting multiple sclerosis.
There are around 47 monoclonal antibodies on the market and 300 in clinical trials.
Dawn M Ecker, Susan Dana Jones & Howard L Levine (2015) The therapeutic monoclonal antibody market, mAbs, 7:1, 9-14, DOI: 10.4161/19420862.2015.989042
What is biotechnology? The Story of César Milstein and Monoclonal Antibodies