Coiled-coil assisted control of antibody quality, delivery and binding

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The market of therapeutic recombinant proteins is now dominated by monoclonal antibodies (mAbs). With more than 60 mAbs approved and more than 350 undergoing clinical trials, this market now exceeds 50 billion dollars. Due to the complexity of mAb mode of production, mAb manufacturing still represent a significant economic burden to the public health care system. On the one hand, in the biopharmaceutical industry, the lack of cost-effective and high-throughput engineering solutions to assess mAb critical quality attributes severely impedes the improvement of current manufacturing processes relying on cell culture. First and foremost, the assessment of mAb glycosylation, a post translational modification performed by the cells, is crucial as glycosylation directly influences mAb stability and therapeutic efficacy. On the other hand, in the clinic, the mode of administration of mAbs via intravenous route, also needs improvement (more likely via materials engineering) to achieve maximal therapeutic efficacy. Indeed, intravenous administration forces the use of huge doses, in turn leading to patient inconvenience and high medical treatment costs. The lack of an efficient and versatile approach to promote the sustained local delivery of mAbs, alone or in combination with other drugs, severely impedes the development and implementation of the next-generation therapeutics. The focus of my ongoing research program is to develop versatile and efficient engineering strategies to control recombinant protein quality and delivery. Over the past years, my team has made significant progress on addressing these issues: we spearheaded the use of a grafting strategy relying on two distinct peptides, i.e., the E and K coils, to design better biosensing assays and control the capture of bioactive proteins into hydrogels. Because of the importance of mAbs, we will focus the next 5 years specifically on this class of biomolecules. Our short-term objectives for this Discovery Grant are to: 1) Develop the biosensing and numerical tools to characterize mAb glycosylation, and thus create an enhanced process analytical technology for mAb biomanufacturing 2) Design tunable, self-assembled hydrogels for the controlled release of mAbs and other entities, hence addressing the needs of the industry for platforms delivering combined therapies. 3) Further refine our grafting and delivery technological platform by fine-tuning the E and K coil peptide sequences, extending the characterization of their interactions to support the short and long-term objectives of this program. Overall, this Discovery Grant Program will contribute to the training of 10 undergraduate and 4 PhD students. Attaining our research objectives will not only yield insight into the fundamentals of mAb glycosylation and controlled release but facilitate technology transfer to our Canadian industrial partners, ultimately leading to more efficient and cost- effective treatment to Canadians.