The Cloning, Optimization, and Validation of Caninized-Phage Monoclonal Antibody Library For Regulation of Cancer Responses in Canus lupus

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Cancer has emerged as a major cause of morbidity and mortality in the dog, with an estimated incidence of 1 in 4. Despite advances in conventional chemotherapy and radiation, complete cures for most cancer types remains elusive, the challenge being to develop highly targeted therapies that kill cancer cells but leave normal cells healthy. The same seemingly insurmountable problem holds true for the treatment of human cancer and a big advance in oncology in the past 20 years has been the discovery and application of monoclonal antibodies as novel therapeutic tools to improve cancer treatments in patients. In fact, one of the biggest areas of R and D in the pharmaceutical industry is now in the development of monoclonal antibodies. What are monoclonal antibodies (MAb's)? These are proteins made by our bodies that form a normal part of a healthy immune system and is the way nature helps to rid our bodies of foreign viruses, pathogenic bacteria, and also minimize disease development. Indeed, one reason why disease develops when we age or why we are more sensitive to viruses when we are older is essentially due to a "broken" immune system. However, scientists have discovered spectacular ways to harness the power of the immune system, by first cloning MAb's and then turning the MAb's on to treat particular diseases. The MAb's then act essentially like "magic bullets" as they can specifically hone in on rogue cells and cure disease. However, a major obstacle in this strategy of using MABs as magic bullets is that the immune system can recognize as foreign any particle that looks in any way different from normal proteins in the body; even a MAb given to patients with disease can paradoxically look foreign and be eliminated from the body before the MAb has a chance to act and elicit a cure. To overcome this obstacle, scientists in turn have pioneered a way to "tailor" the MAb so that it appears invisible to the body's immune system and can circulate and target disease cells. This tailoring of a MAb to treat humans is called "human-izing" the MAb and this approach provides further hope that complex diseases can be treated in the future. Despite these advances, the treatment of dog cancer, though in principle could be carried out like that in humans, has not been attempted in any significant way using MAb's. The main reason is that "dog-ized" MAb's would have to be used that are not recognized as invaders by the dog's immune system and dog-ized MAb's have not been developed that would greatly facilitate this process. In our research programme, we have developed novel methods to capture and clone the large majority of MAb's that can be made by the dog's immune system. Our application aims to optimize our dog-ized MAb library and validate it by isolating potential dog-ized "magic bullets" that can be used to inhibit specific receptor proteins that are implicated in causing dog cancers. The successful validation of these dog-ized MAb's will lead to clinical trials that would hopefully improve the health and longevity of dogs with cancer, but also produce a road map on how to develop dog-ized MAb's to treat other age related diseases in the dog.