Title: Development and Delivery of Inhibitors for Viral Pathogenic Deubiquitinases
In human viral diseases, misbehaviour of the cellular machinery utilizing ubiquitin is frequently observed. Ubiquitin is a small protein that attaches to target proteins in human cells and signals for their destruction. Human deubiquitinases are enzymes that remove ubiquitin to keep protein levels in balance. Viral pathogens have evolved proteins that mimic human deubiquitinases to evade the immune system by interfering with host ubiquitin-dependent processes. Unfortunately, the lack of molecules that can block the activity of viral deubiquitinases has severely hampered attempts to manipulate them for therapeutic benefits. We have invented a new technology to develop synthetic protein modulators for any ubiquitin-interacting proteins. The goal of this project is to generate highly specific and potent inhibitors for viral pathogenic deubiquitinases and a platform to deliver these molecules into human cells. This will lead to effective antiviral therapy, expanding the existing therapeutic portfolio of CCAB.
Title: Development of Cell-Based Functional Assays to Accelerate Commercialization and Therapeutic Application of Recombinant Antibodies
Antibodies are the fastest growing segment of the pharmaceutical market, and with modern engineering technologies antibodies can be programmed to target devastating diseases. Within the immune system, antibodies fight invading bacteria and viruses. High-quality synthetic antibodies directed to disease-related targets have immense therapeutic potential. Development of cell-based assays to enable rapid identification of functionally active antibodies is a critical step in the commercialization process. The proposed research project will involve screening of binders against disease-associated targets; antibodies showing clinical relevancy will be considered for entry into the clinical trial pipeline. The newly formed Centre for the Commercialization of Antibodies and Biologics (CCAB) will bridge the research and discovery occurring at the Donnelly Centre with industry partners to enable accelerated delivery of new therapies to fight diseases such as cancer, arthritis, and Crohn’s disease. CCAB will facilitate commercialization of antibodies by leveraging a world-class technology platform and experienced product development professionals.
Title: Targeting clonal heterogeneity in treatment-refractory glioblastoma with novel and empiric immunotherapies
Glioblastoma (GBM) is the most common primary adult brain tumor, characterized by extensive cellular and genetic heterogeneity. Even with surgery, standard chemotherapy, and radiation, tumor recurrence and patient relapse are inevitable with a median survival rate of <15 months. The overall goal of this proposal is to identify new therapeutic targets that drive clonal evolution in treatment-refractory GBM, develop novel and empirical immunotherapies that harness the immune system and target specific cell surface receptors on GBM cells at the same time, and undertake preclinical evaluation of candidate therapeutic antibodies using our unique animal model of human GBM recurrence.
The interns in this proposed cluster will be involved in 1) tracking GBM cell populations to determine the intracellular pathways that drive relapse and 2) the development of novel biologics to target specific proteins in these pathways under the direction of Prof. Moffat (UofT) as well as 3) testing these in animal models in Prof. Singh’s lab (McMaster).
A promising lead panel of biotherapeutics will be translated into early clinical development at the partner organization, CCAB, and its network of clinicians and industry partners with the hope of generating targeted therapies.
Title: Development of specific inhibitors and activators to assess the role of human Ephrin Receptors in health and disease
Signaling through the Eph family of cell surface receptors is crucial for embryonic development and the maintenance of adult tissues. Given the central role of the 14 Eph receptors in controlling cell fate, it is not surprising that they also play a central role in oncogenesis and other pathological conditions. However, the signaling mechanisms of Eph receptors are extremely complex, and developing an effective therapeutic intervention for a particular disease requires a comprehensive understanding of Eph function. The goal of this project is to generate a collection of synthetic antibody molecules that block and activate every Eph receptor. This toolkit of antibody reagents will allow researchers to identify the best approach for targeting Eph receptors individually or in combination to counteract a particular disease state. This collection of Eph-modulating antibody reagents will expand the existing antibody portfolio of the Centre for the Commercialization of Antibodies and Biologics (CCAB).
Title: Design and advancement of Graft Enabled Antibody Therapies (GrEAT)
Membrane proteins such as ion channels, transporters or G-protein coupled receptors (GPCRs) are excellent but difficult drug targets involved in a large number of life-threatening diseases and conditions. These proteins, over-expressed and essential for disease onset and progression, are naturally targeted by toxins from venomous organisms. During evolution, these toxins have been optimized to efficiently target physiologically-relevant proteins involved in ion channel opening or closure, thus incapacitating the prey or defending against predators. We propose to generate synthetic antibody (Ab) libraries that integrate natural toxin-based polypeptides grafted in place of one of the complementarity determining regions as a scaffold. Such libraries will be a formidable resource for discovery and subsequent directed-evolution of graft-enabled antibodies against pharmacologically challenging or previously thought as “undruggable” targets, as well as be a starting point for further biological therapeutic lead development and commercialization, in line with the vision and mission of the partner organization, CCAB.
Title: Engineering Synthetic D-Proteins as Novel and Transformative Molecular Therapeutics Against Cancer Targets
Proteins can exist in two forms: left-handed (L) or right-handed (D); however, for indeterminate reasons life on this planet only uses the L-form. When studied in more detail, both protein forms possess identical physiochemical and biological properties. Yet, D-proteins show minimal proteolytic degradation and fail to elicit immune responses in animals, due to their unnatural arrangement for recognition in biological systems.
Accordingly, the proposed project seeks to develop synthetic D-proteins as biopharmaceutical molecules. We will utilize a method of high-throughput selection, previously established for selection of antibodies, to isolate D-proteins to target cellular receptors involved in cancer. In this regard, D-protein therapeutics will allow for longer circulation of peptide drugs in the body, and also render them less immunogenic and toxic. More exciting, is our collaboration with the CCAB, which will bridge the research and discovery with industry partners to enable the accelerated delivery of D-protein as therapies.
Title: Development of dual antibody therapies for cancer
Cancer is a devastating disease defined by genetic changes that result in the activation of proteins that encourage cell growth or prevent cell death. Modern oncology aims to specifically target these tumour-promoting proteins, which has the secondary benefit of leaving normal cells unharmed, unlike chemotherapy. Recently, a number of drugs that specifically block tumour-promoting proteins have been produced, yet the results are underwhelming: most targeted therapies show an initial benefit, followed by the development of resistance. To combat resistance, targeted therapies are often combined in multi-drug regimens, though these strategies are biased towards using existing drugs. Our approach aims to first identify new ‘helper’ drug targets that, when blocked, improve the efficacy of first generation targeted therapies being developed at the Centre for the Commercialization of Antibodies and Biologics (CCAB). Our second aim is to develop drugs that block the identified targets by engineering versions of naturally-occurring human proteins – antibodies – that bind the targets. These antibodies will be tested for their ability to increase targeted therapy efficacy, hopefully establishing novel approaches for cancer treatment and positively impacting the development of CCAB cancer drugs.