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Therapeutic antibodies

MRC research stemming from the 1970s has led to the development of monoclonal antibodies – which now make up a third of all new drug treatments for a variety of major diseases. The invention of methods for producing therapeutic monoclonal antibodies has revolutionised biomedical research and sparked an international multi-billion pound biotechnology industry. It has given rise to a new class of drugs for treating a variety of diseases, including cancer, arthritis and asthma.

In 1975, Drs César Milstein and Georges Köhler of the MRC Laboratory of Molecular Biology devised a way to isolate and reproduce individual, or monoclonal, antibodies from among the multitude of different antibody proteins that the immune system makes to seek and destroy foreign invaders attacking the body1. They won the 1984 Nobel Prize in Physiology or Medicine in recognition of this ground-breaking work.

Monoclonal antibodies were initially developed from mice as a tool for studying the immune system. The method allowed the production of large amounts of highly specific antibodies, enabling reproducible research measurements and results.

The early applications of monoclonal antibodies included grouping blood types, identifying viruses, purifying drugs and testing for pregnancy, cancers, blood clots and heart disease. However, applications in human medicine were limited because mouse monoclonal antibodies are rapidly inactivated by the human immune response, which prevents them from providing long-term benefits.

Humanisation – the breakthrough

Monoclonal antibodies began to reveal their full therapeutic potential in 1986, when MRC researcher Sir Gregory Winter, also at the Laboratory of Molecular Biology, pioneered a technique to ‘humanise’ mouse monoclonal antibodies2. This made them better suited to human medical use as they were much less likely to elicit an inappropriate immune response in patients. Sir Gregory’s technology has since been licensed to around 50 companies, which have each paid a one-off licence fee and agreed to pay royalties on any resulting drugs that reach the market.

Sir Gregory’s colleague Dr Michael Neuberger invented the ‘Neuberger technique’ for producing humanised monoclonal antibodies. This technology has been licensed to two companies.

Further patented research by Sir Gregory along with scientists at the Scripps Research Institute in California led to development of the ‘phage display’ method of producing monoclonal antibodies. The technique was used in the development of Humira® by Cambridge Antibody Technologies, an MRC spin-out company. Humira®, the first fully human monoclonal antibody drug, was launched in 2003 as a treatment for rheumatoid arthritis.

Wonder drugs

Today, monoclonal antibodies account for a third of all new treatments. These include therapeutic products for breast cancer, leukaemia, asthma, arthritis, psoriasis and transplant rejection, and dozens more that are in late-stage clinical trials. The size of the therapeutic antibody market is projected to more than double to around £16 billion per year by 2010.

Monoclonal antibody technology has not only benefited human health. The UK economy also stands to gain: in 2005, US pharmaceutical company Abbott paid the MRC over £100 million in lieu of future licensing royalties for Humira®. And Cambridge Antibody Technology, of which the MRC is a shareholder, has been sold to pharma giant AstraZeneca.

In 2006, the MRC received more than £7m as part of GlaxoSmithKline’s £230m acquisition of the antibody company Domantis Ltd – which was founded in 2000 by Sir Gregory Winter and Dr Ian Tomlinson at the LMB. Domantis has pioneered methods for the production of the fundamental building blocks of the immune system known as antibody single domains (dAbs). All the income the MRC receives from commercial activities is ploughed back into further research to improve human health.

Therapeutic antibodies timeline

  • 1975 - Method devised to isolate and reproduce monoclonal antibodies.
  • 1986 - Techniques pioneered to ‘humanise’ mouse monoclonal antibodies.
  • 1990 - Test-tube production of highly specific human monoclonal antibodies.
  • 2003 - First fully human monoclonal antibody – Humira® – launched in the UK.
  • 2005 - MRC signs deal with Abbott for rights to Humira®, worth over £100 million.
  • 2006 - MRC spin-out company Cambridge Antibody Technology sold to AstraZeneca for £702 million.
  • 2006 - MRC-founded Domantis sold to GSK.

References

1. Kohler & Milstein (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 256, 495

2. Jones et al. (1986). Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature, 321, 522

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