BioWorld International Correspondent
LONDON - A promising new cancer therapy now might be more effective with the discovery that a "molecular patch" can hide part of the therapeutic agent from the patient's immune system.
The therapy, known as antibody-directed enzyme prodrug therapy, or ADEPT, involves giving the patient an enzyme linked to an antibody which homes in on cancer cells. After a while, the antibody-directed enzyme is cleared from the circulation but remains in the tumor. The patient then is given a harmless prodrug, which, when it encounters the enzyme in the tumor, is converted into an active drug.
Initial trials of the therapy have been positive. However, patient immune responses to the antibody and enzyme have made it difficult to give second or subsequent doses because those are cleared from the body before reaching the tumor.
Astrid Mayer, clinical research fellow at the Cancer Research UK Targeting and Imaging Group at University College London, and her colleagues have discovered a way around that problem.
Mayer told BioWorld International, "For any type of protein therapeutic, the immune response is a potential problem, so it is obviously good to find ways of reducing immunogenicity."
The group has published an account of their study in the June issue of the British Journal of Cancer. Their paper is titled "Modifying an immunogenic epitope on a therapeutic protein: a step toward an improved system for antibody-directed enzyme prodrug therapy (ADEPT)."
Mayer and her colleagues had been working with an antibody-enzyme construct comprising an antibody fragment called MFE and a bacterial enzyme called carboxypeptidase, or CP. That construct was produced by genetic engineering, and, as part of the purification process, it had a molecular "tag" attached to it. The tag, hexahistidine, made it easy to isolate the construct by chromatography.
When the team tested MFECP in patients, they found that it was less immunogenic than previous constructs they had used. Mayer said: "We hypothesized that the tag might cover an immunogenic epitope on the enzyme. In the [study], we looked at whether this hypothesis was true, and we found that those patients who received the tagged protein had no antibody response to this epitope."
Patients who received the tagged CP had significantly less antibody in their system, proving the success of the disguise, while patients who received normal CP responded by producing antibodies as expected.
Mayer noted: "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 group hopes to find other ways of disguising more features on the enzyme. Mayer said: "We will explore whether we can change more epitopes on the enzyme, and try to work out the best strategy for giving the protein repeatedly. We will look at whether we need to alternate treatment with different forms of the molecule - for example, whether we should have different epitopes covered each time we give the patient treatment."
Robert Souhami, executive director of clinical and external affairs at Cancer Research UK, which owns the British Journal of Cancer, said: "Novel cancer treatments such as ADEPT use molecules that our immune systems recognize as foreign. To be fully effective against cancer cells, these molecules first have to get past the body's own defenses.
"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."
Writing in the British Journal of Cancer, Mayer and colleagues concluded: "Modification of [immunogenic] epitopes appears to be a useful strategy for the reduction of immunogenicity to foreign proteins and may have generic application, in particular for recombinant cancer therapeutics, which are not intended for protracted use."