Light-activation targets cancer with cytotoxic T-cells
Antibody technique may offer specificity for cancer treatment.
Cancer treatment has long posed challenges for physicians because it must be aggressive enough to defeat the cancer, yet not so aggressive that it kills the patient. Thus, researchers are looking for new ways to target cancerous tissue without targeting healthy tissue. Scientists at the University of Newcastle Upon Tyne in the UK have coupled light activation with antibody targeting and have shown that the method can eradicate cancer in mouse studies. They hope that will hold true for human trials.
Researchers have developed a method for using light-activated antibodies to target cancer. They built bispecific antibodies that target a tumor and that can be activated using UV light to prompt the immune system to kill the targeted cancer cells. Courtesy of BioTransformations Ltd.
The development of specific antibodies that target only cancer cells has been elusive — despite their great promise for cancer treatment — because even antibodies specific for a particular kind of tumor often have specific or nonspecific reactions in other tissues. In fact, some researchers have abandoned work on cancer antibodies because they were not specific enough.
The researchers, led by Colin H. Self and Stephen Thompson, are creating a bispecific antibody consisting of a tumor-binding antibody coupled to a second antibody that can bind a T-cell. The key, however, is that the T-cell antibody is coated with 2-nitrophenylethanol (NPE), which effectively deactivates it. This new method creates the possibility that previously discarded antibodies could be coupled with coated T-cell ones to create a bispecific antibody that could be activated in the tumor in much the same way as photodynamic therapy works, but with the added advantage that it would actively stimulate the patient’s own immune system.
The researchers published two papers on the method in the Nov. 12 issue of ChemMedChem, detailing the construction of a photoactivatable bispecific antibody, the ability to use NPE to deactivate an anti-T-cell antibody and then reactivate it with UV light, and the ability of the NPE-coated antibody to destroy ovarian cancer in a mouse model when reactivated in vivo.
In the initial phases of their research, the investigators built a bispecific antibody consisting of carcinoembryonic antigen (CEA) coupled with an antibody that binds alkaline phosphatase, which is easy to detect and may itself have applications for cancer treatment. The anti-alkaline phosphatase antibody end was deactivated with NPE. They then conducted a series of experiments to test the antibody conjugates to determine whether coupling them changed their ability to bind to cancer cells, and whether the alkaline phosphatase antibodies could be reactivated by UV light. For this, they used a Spectroline handheld mercury vapor UV lamp operating with a wavelength peak at 365 nm.
With the success of the initial research into creating a bispecific antibody that could be activated with light, they moved on to testing the new method. This time, instead of developing a bispecific antibody, they simply coated an antibody that binds to human T-cells. Using a Becton-Dickinson flow cytometer, the group demonstrated that the UV irradiation does not damage the uncoated antibodies. They also demonstrated that antibodies that were coated and then reactivated had similar abilities to bind T-cells.
In one of the papers, the group demonstrated some exciting results — that the technique can be used to attack ovarian cancer in a C57BL6 mouse model. Using NPE, they coated the mouse T-cell antibody to deactivate it. Then, they conducted toxicology studies to determine whether the NPE-coated antibody would have ill effects on the mice, either from the substance itself or from any byproducts created with UV illumination.
They studied the compound’s effectiveness by implanting an aggressive ovarian tumor, an M5076 variety, into the mice in two experiments. In one experiment, the group injected the tumor-bearing mice with the uncoated T-cell antibody, and the tumors shrank to about 10 percent of their original size. “This was an interesting finding in itself, as it demonstrated that if an anti-CD3 antibody was present in the area next to a tumor, it would stimulate the immune response, even though it was not being specifically targeted to the tumor by a bi-specific antibody,” the paper explains. However, when the coated antibody was activated in the tumor region using UV light, there was no trace of the tumor detectable in five of six mice after 25 days.
For this work, the researchers activated the antibody with a UVA lamp, although Thompson said that the antibody also can be reactivated using 360-nm (single-wavelength) light from a dental probe. The light was delivered via a glass probe 10 cm long and 1 cm in diameter, which could allow light delivery to more deep-seated tumors.
The work opens up many possible applications — for example, after the surgeon has removed the bulk of a tumor, a light could be shone on the affected area, activating previously injected antibodies, which would activate the patient’s own immune system to destroy the residual tumor.
Self said that the researchers are waiting for funding to prepare for clinical trials in humans. “There are numerous applications of this technology, within and outside of oncology,” he explained. “The light-activatable anti-CD3 antibody alone offers not only a therapeutic agent in its own right for a wide variety of tumors, but it also can be used in a bispecific form in combination with a tumor-targeting agent.”
He added that the group intends to proceed with clinical trials with the light-activatable anti-CD3 (T-cell) antibody while also developing bispecific configurations of it.
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