The science behind immunotherapy drugs
Justin Bryans describes the development of cancer immunotherapies and their prospects for wider use.
Although vaccination and immunotherapy have been saving lives since Edward Jenner's pioneering work on smallpox over 200 years ago, it is only in the past 40 years that the theory of harnessing antibodies as cancer therapeutics has begun to gain ground. It has become increasingly apparent in recent times that an alternative solution to existing cancer treatments is needed. Cytotoxics (chemotherapy drugs) and radiation-based treatments are unable to discriminate between cancerous and healthy cells, killing both with side effects that often have a massive impact on patients' lives. Surgical intervention can be effective; however if only a few cells are left behind a patient can relapse.
The most recent cancer immunotherapy to hit the headlines is Merck's Keytruda. Initially approved for advanced melanoma, it is also the first drug to be approved through the UK's early access to medicines scheme (EAMS). Early development work on the antibody was carried out by MRC Technology (MRCT). Keytruda allows the body's own immune system to recognise cancer cells, which is particularly advantageous in melanoma as, although it can be treated with surgery at an early stage, once metastasised it becomes inoperable.
The basic theory behind cancer immunotherapy is to stimulate the body's immune system to attack the cancer cells. The discovery that some cancer cells evade the immune system by taking advantage of the PD-1 (programmed cell death-1) pathway has led to a raft of possible therapies. Cancer cells avoid being eliminated by T-cells by sending the PD-1 pathway of the immune system a signal that blocks/reduces the message to attack. Therefore an antibody that in turn blocks the PD-1 pathway should prevent this, enabling the immune system to continue finding and attacking cancerous cells.
"The next step is to develop an effective anti-PD-1 antibody that will work in humans"
Discovering the pathway was the first step; the next is to develop an effective anti-PD-1 antibody that will work in humans and can be generated in large enough quantities to be viable as a therapeutic. Although mouse monoclonal antibodies have been around since 1975 and can be manufactured in large quantities, the generation of clonal, fully human antibodies is not so successful. For this reason, mouse antibodies are usually the starting point when developing a new antibody drug. This presents a fresh problem, as mouse monoclonals elicit a human anti-mouse antibody response (HAMA) which causes the mouse antibodies to be destroyed before they can be effective.
A method for 'humanising' mouse monoclonal antibodies was invented at the UK's MRC (Medical Research Council) Laboratory of Molecular Biology in 1986 by Sir Greg Winter. He found that transplanting the complementarity determining region (CDR) – the region that interacts with the target protein or antigen – from the mouse antibody into an equivalent human framework effectively enabled the antibody to be recognised as 'human'. Using this method the HAMA response is virtually eliminated, and it is this technology that has underpinned almost all of the early therapeutic antibodies, and several blockbuster drugs.
"CDR grafting continues to deliver success – most recently with Keytruda"
The CDR grafting technology has been refined over the years but the basic principles remain. Competitor technologies do exist, such as transgenic mice where the mouse antibody genes are replaced by human, and the use of artificial proteins with potent binding properties. CDR grafting continues to deliver success, however, most recently with Keytruda, which was humanised in this way by MRCT in 2008. In fact one third of all the antibody treatments currently in phase III clinical trials have been humanised in this way, so it is clearly a powerful and effective technology.
Following the success of Keytruda, cancer researchers are now speculating that other tumour types could be effectively treated by immunotherapies. Data from multiple trials across a range of cancers that are challenging to treat with surgery, chemotherapy or radiotherapy, such as non-small cell lung cancer and mesothelioma, are due soon. When these are brought on to the market alongside more effective diagnostic tools, we could truly be heralding an exciting new era in cancer therapy.
About the author:
Justin Bryans is director of Drug Discovery at MRC Technology's (MRCT) Centre for Therapeutics Discovery (CTD) in London, UK. He gained a chemistry degree and a DPhil. at the University of York followed by a post-doc at the University of Oxford under Professor Sir Jack Baldwin.
He has since worked for over 20 years as a medicinal chemist in a number of biotechnology and pharma companies, including Pfizer, developing clinical candidates for a wide range of diseases. He joined MRCT in 2005 where he leads the drug discovery operation, working with some of the world's leading academics to translate cutting-edge biology into clinical benefit.
He teaches on drug discovery at Queen Mary Uuniversity of London, University College London and the Wellcome Trust and is a Fellow of the Royal Society of Chemistry.
MRCT helped to develop the drugs Tysabri, Actemra, Entyvio and Keytruda.
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