Several antibodies and antibody fragments have been previously developed to treat various diseases, including cancer. These antibodies bind to cell surface receptors expressed at higher levels on cancer cells, addressing a major challenge of selective cell targeting in cancer therapy. Although full-length antibodies have shown promise for treating several cancers, limited success has been demonstrated in eliminating solid tumors.
Now, scientists at the University of East Anglia are a step closer to creating a new generation of light-activated cancer treatments. They introduced concurrent photoactivity and photoreactivity into an epidermal growth factor receptor (EGFR) targeting antibody fragment 7D12.
The treatment, which sounds futuristic, would work by turning on embedded LED lights adjacent to a tumor, activating biotherapeutic chemicals. These new treatments would be more precise and efficient than the most advanced cancer immunotherapies.
Scientists engineered antibody fragments, which not only ‘fuse’ with their target but are also light activated. These fragments bind to and form a covalent bond with its target — upon irradiation with U.V. light of a specific wavelength.
The principal scientist for this study, Dr. Amit Sachdeva, from UEA’s School of Chemistry, said: “Current cancer treatments like chemotherapy kill cancer cells, but they can also damage healthy cells in your body such as blood and skin cells.”
“This means that they can cause side effects including hair loss, feeling tired and sick, and they also put patients at increased risk of picking up infections.”
“There has therefore been a very big drive to create new treatments that are more targeted and don’t have these unwanted side-effects.”
“Several antibodies and antibody fragments have already been developed to treat cancer. These antibodies are much more selective than the cytotoxic drugs used in chemotherapy, but they can still cause severe side effects, as antibody targets are also present on healthy cells.”
“A covalent bond is like melting two pieces of plastic and fusing them. It means that drug molecules could, for example, be permanently fixed to a tumor.”
“We hope that our work will lead to developing a new class of highly targeted light-responsive biotherapeutics. This would mean that antibodies could be activated at the site of a tumor and covalently stick to their target upon light activation.”
“In other words, you could activate antibodies to attack tumor cells by shining light – either directly onto the skin, in the case of skin cancer, or using small LED lights that could be implanted at the site of a tumor inside the body.”
“This would allow cancer treatment to be more efficient and targeted because it means that only molecules in the vicinity of the tumor would be activated, and it wouldn’t affect other cells.”
“This would potentially reduce side effects for patients and improve antibody residence time in the body.”
“It would work for skin cancer, or where there is a solid tumor – but not for blood cancers like leukemia.”
“Development of these antibody fragments would not have been possible without pioneering work from several other research groups across the globe who developed and optimized methods for site-specific incorporation of non-natural amino acids into proteins expressed in live cells.”
“We employed some of these methods to site-specifically install unique light-sensitive amino acids into antibody fragments.”
- Bridge, T., Wegmann, U., Crack, J.C. et al. Site-specific encoding of photoactivity and photoreactivity into antibody fragments. Nat Chem Biol (2023). DOI: 10.1038/s41589-022-01251-9