Disguising a molecule to get it past the body’s immune system could greatly enhance the success of a groundbreaking new therapy, Cancer Research UK scientists report in the British Journal of Cancer1 this week.
In clinical trials, scientists are using a therapy known as ADEPT2 to send cancer killing drugs directly to tumours. But because the therapy uses an enzyme3 not naturally found in humans, a patient’s immune system can recognise and reject the enzyme before it can do its job.
Researchers in the Cancer Research UK Targeting and Imaging Group disguised a distinctive feature of the enzyme to enable it to repeatedly elude the immune system. The advance could allow patients to safely receive multiple courses of ADEPT to treat their cancer.
ADEPT uses the ability of an enzyme to turn otherwise harmless molecules, or ‘prodrugs’, into cell killing drugs.
The enzyme is given first and is designed to only attach to cancerous cells. When the prodrug is given, it passes harmlessly through healthy tissue, but in tumours is activated by the enzyme and kills the cancer cells. Several such combinations of enzyme and prodrug are already being tested in clinical trials.
ADEPT is a promising system for delivering therapy targeted to tumours, but is often hampered by immune reactions to the enzyme.
The new research focussed on a bacterial enzyme called carboxypeptidase G2, or CP, that is used in several ADEPT combinations. Routinely, a molecular ‘tag’ was added to one end of the enzyme as part of the production process. But the tag itself reduced the immune system’s response.
Lead author Dr Astrid Mayer, based at the Royal Free and University College Medical School, says: “We were really surprised at the size of the effect. Adding a molecular tag is common practice in the laboratory, but is new for products given to patients. In this case it had a significant effect on the immune response.
“The tag masks a prominent feature of CP, hiding it from the immune system. Because the body can no longer recognise that identifying feature, the immune response to part of the enzyme is reduced.
“We hope to find ways to disguise more features on the enzyme. Minimising the immune response to carboxypeptidase will increase the potential of many forms of ADEPT for clinical use.”
The immune system uses molecules called antibodies to recognise foreign substances. Each antibody has a highly specific shape that closely fits a particular feature of a foreign molecule, like a lock and key.
Upon the first exposure to an unknown substance, antibodies are made that fit its physical features. On subsequent exposure the antibodies can lock onto the matching features and call in the body’s self-defences to destroy the intruder.
Patients who received normal CP responded by producing antibodies to it as expected, indicating that the immune system would reject further attempts to use the treatment.
But patients who received the ‘tagged’ CP had significantly less antibody in their system, proving the success of the disguise.
Professor Robert Souhami, Executive Director of Clinical and External Affairs at Cancer Research UK, which owns the British Journal of Cancer, says: “Novel cancer treatments such as ADEPT use molecules that our immune systems recognise as foreign. To be fully effective against cancer cells, these molecules first have to get past the body’s own defences.
“This study has identified a relatively simple method of reducing the body’s reaction against this enzyme. Finding ways of disguising the molecular features of certain cancer therapies could make them safer and more effective.”
- British Journal of Cancer90 (12)
- Antibody directed enzyme prodrug therapy
- Enzymes are proteins that catalyse chemical reactions in cells
ADEPT is a method for targeting cancer therapy to tumours. It uses an antibody to identify characteristic features of cancer cells.
Researchers attach the antibody to an enzyme: a molecule that acts like a switch. It turns a harmless drug (the pro-drug) into its active form. The antibody directs the enzyme to the tumour. When the harmless pro drug reaches the cancer cell, the enzyme switch activates it. The active form of the drug then kills the cancer cell.
The antibody-enzyme used in this study is a recombinant fusion protein called MFECP. This means it is a genetically engineered molecule that contains both the carboxypeptidase enzyme (CP) and an antibody fragment (MFE). Being recombinant makes it easier to modify.
The MFE fragment contains only the antibody’s highly selective binding region. This matches a protein (CEA) characteristically overproduced by some cancers, the key to the therapy only being activated in tumours. The antibody fragment binds the enzyme to the CEA on cancer cells.
The molecular ‘tag’ was hexahistidine, commonly known as a “His-tag”. It is routinely added during the production of recombinant molecules to help in their purification in the laboratory.