Since drug candidates that often effectively shrink tumor bulk in murine xenograft models are unable to eliminate the disease in the humans, it has become absolutely critical to develop novel and more predictive pre-clinical models. The goal of this proposal is to develop a novel in vivo test system consisting of (1) a molecular platform allowing the """"""""caninization"""""""" or engineering of therapeutic antibody drug candidates with sequences compatible with the dog immune system to allow repeated administration in dogs, and (2) their testing for efficacy and safety in a dog model of spontaneous cancer. For this feasibility study, Vet Therapeutics Inc. (VTI) has selected to """"""""caninize"""""""" Campath, a monoclonal antibody to human CD52 target present on lymphocytes. Campath is utilized for the treatment of lymphoproliferative diseases. In preliminary studies conducted by VTI, Campath was shown to cross-react with canine CD52. In addition, Campath exerted its effects on canine cells by similar mechanisms than on human cells. VTI has already successfully engineered a caninized form of Campath. Experiments to be funded by the grant include (1) production, purification and characterization of 8-10 g of the caninized form of Campath, and (2) studies in dogs to evaluate the activity of the caninized antibody in dog models of spontaneous T-cell lymphoma and studies to clearly define the mechanism of action of the caninized antibody. This model provides a unique opportunity to examine the role of T-cell lymphocyte in the context of relevant factors with impact on survival of tumor cells even after therapeutic intervention. Also, studies that otherwise would be very difficult and would take years to perform in humans, are feasible in dogs with lymphoma over a short period of time considering that time from diagnosis to death is only of a few months with over 100,000 cases per year. Lymphoma is also very relevant with a reported number of cases on the rise with 66,000 new cases of NHL in humans in the United States per year. Furthermore, T-cell-based lymphoma has poor prognosis and often poorly responsive to conventional chemotherapy. At the completion of this work, we anticipate that the data (1) will validate this novel in vivo test system and (2) will extend our knowledge on the role of T-lymphocyte cells in lymphoma progression. Besides creating a significant source of information on cancer biology, efforts devoted to this program will create reagents urgently needed that will be shared with the scientific community at large for translational research studies using dogs as models of cancer.
A recognized problem in target validation and early drug development of novel human cancer therapeutics is the translation of safety and efficacy data observed in most commonly used preclinical models (i.e. mouse-based models) to clinic. This is particularly the case when biologics such as antibodies are used as therapeutics and tested in models sharing minimal biology/clinical features with humans. As monoclonal antibodies are becoming a central component of many cancer treatment regimens, it is becoming imperative that novel models are developed to assess their therapeutic potential and safety in models other than current pre-clinical models with serious limitations such as mice xenografts. The goal of this proposal is to develop a comprehensive and robust platform to re-engineer antibodies against human targets with dog specific sequences so that they can be rapidly tested for safety and efficacy in dog models of spontaneous cancer. Indeed, dogs shares similar tumor biology (histology, heterogeneity, etc.) and clinical features (tumor behavior, metastasis, response to therapy, etc.) with human cancer. This novel in vivo system will be tested in a dog model of T-cell based lymphoma with a """"""""caninized"""""""" form of Campath, an anti-human CD52 monoclonal antibody developed for the treatment of lymphoproliferative diseases. This novel test system will enable: (1) Translational research in dogs to characterize and validate novel targets discovered in humans or other species. (2) Early drug development in dogs defining the pharmacokinetic and pharmacodynamic of the different antibody drug candidates. (3) Therapeutic index assessment in relevant diseased dogs that is highly translatable to man in the form of dose regimen with assessment of the potential effects on the tumors, tumor microenvironment, tumor heterogeneity and development of any resistant patterns. (4) Assessment of the full spectrum and nature of any adverse events occurring in dogs that would be highly translatable and relevant to human patients. (5) Ultimately, this approach can also be leveraged to develop a comprehensive pre-clinical data package and to provide solid guidance about its clinical potential in humans.
