BioWorld International Correspondent

LONDON - The long-awaited goal of being able to selectively treat tumors by putting a light-activated anticancer agent into the bloodstream and then zapping the tumor with laser light to activate the drug is coming closer.

To date, this type of photodynamic therapy (PDT) has been available only for a limited range of cancers because of side effects.

Now, however, researchers at Imperial College London and the university's spinout biotechnology company, Photobiotics, of London, believe they have made a breakthrough that eventually will allow clinicians to offer PDT as a treatment for a much wider range of cancers.

Mahendra Deonarain, senior lecturer in biochemistry at Imperial College London and co-founder of Photobiotics, told BioWorld International: "We believe that we have refined PDT to make it applicable to many more cancers, bringing benefits such as low scarring, fewer side effects and a low risk of resistance to the drugs used."

Deonarain and his collaborators have shown that they can achieve complete tumor regression in animal models of human tumors, using their new approach to PDT. The team expects to embark on clinical trials within the next three years.

A report of the work appears in The International Journal of Cancer (online publication, Oct. 31, 2007), in a paper titled "Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments."

During PDT, the patient receives a light-activated anti-cancer drug, which spreads throughout the body. When the tumor or other diseased tissue is illuminated with cold laser light, a chemical chain reaction begins, which converts normal oxygen into highly reactive oxygen species.

Those chemical entities kill the cells where they are generated, thereby localizing the damage to the immediate vicinity of the tumor.

That type of PDT currently is used to treat some head and neck cancers, and to remove the growth of new blood vessels from the retina of the eye in age-related macular degeneration.

One problem with PDT is that the light-activated drugs can end up in the patient's skin, so that for some weeks after the treatment, patients must avoid strong light or they will suffer unpleasant burns.

During the 1990s, Lionel Milgrom, a chemist, tried to tackle that problem by attaching the photosensitive drugs to monoclonal antibodies specific for the tumor. He theorized that if the antibody drug combination could localize the drug to the tumor, then the side effects would be reduced.

Unfortunately, he was unable to get many drug molecules to stick onto the monoclonal antibodies before the combination became ineffective.

He then met Deonarain, who suggested that he try attaching the drug molecules to just the variable part of the antibody - the part known as the single-chain Fv fragment.

The pair of researchers thought the smaller combination of antibody fragment with drug would clear more quickly from patients' bodies, addressing one of the important side effects of PDT.

Along with two other colleagues from Imperial, the pair went on to found Photobiotics and have since filed patents on the use of antibody fragments to target PDT drugs in a range of diseases.

"We discovered that you have to engineer the antibody fragments in a certain way in order to attach the drug molecules," Deonarain said.

"You have to attach the drugs to lysine residues, so the number of these is important, but they also have to be in the right positions," he added.

Experiments showed that they could attach about 10 molecules of a general photosensitizing drug called pyropheophorbide-a (PPA) onto an antibody fragment that is about a fifth of the size of a whole antibody molecule, while retaining the function of both the drug and the antibody fragment.

Earlier this year, the team reported in Photochemical and Photobiological Sciences that PPA, when attached to antibody fragments, entered tumor cells in culture much more quickly than PPA on its own; the combination also stayed within the cells much longer than free PPA.

The work reported more recently in The International Journal of Cancer described the use of an antibody fragment specific for a type of ovarian cancer.

"We showed that our antibody fragment carrying drug molecules killed an ovarian cancer cell line that had the target for the antibody, but did not kill a colorectal cell line that did not have the target," Deonarain said.

Finally, the team injected their drug-antibody fragment into mice that provided an animal model of ovarian cancer. Tests showed that the drug-antibody fragment localized to the tumors; after treating the tumors three times with a cold laser, they completely regressed.

Next, the researchers want to engineer other antibody fragments that could target the drugs to other cancers, such as prostate cancer.

They also want to improve on PPA before going ahead with clinical trials.