Next-generation of Transforming Growth Factor ß inhibitors

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Transforming growth factor beta (TGF-ß) is a pleiotropic cytokine with essential roles in normal embryonicdevelopment and tissue homeostasis. The role of excessive TGF-ß action in fibrosis is well documented.Therefore, it is of interest to develop drugs that block TGF-ß signaling for therapeutic benefit. This therapeuticniche is now being explored by Formation Biologics, a Canadian company focusing on the development ofTGF-ß inhibitors. Formation has a successful drug development record with one product in phase I clinicaltrials, and a second in IND-enabling development. To continue its efforts in the development of specific TGF-ßinhibitors (i.e. specific to each isoform within the TGF-ß superfamily), Formation Biologics is now interestedin exploring promising alternatives to antibody-based therapeutics. The proposed research thus focuses onharnessing the TGF-ß-neutralizing potential of TGF-ß receptor extracellular domains to develop potent TGF-ßantagonists. More specifically, the proposal is to physically combine various receptor extracellular domains toimprove their TGF-ß binding and sequestration efficiency while taking advantage of their binding specificity. Ifperformed with a classical experimental approach (i.e., the design of chimeric proteins corresponding to thefusion of two distinct receptors, their purification and related assays), such a study would be extremelytime-consuming if one considers the number of TGF-ß isoforms, the number of receptors they bind to, as wellas the number of resulting receptor combinations. Using a unique molecular adaptor strategy emanating fromprevious work performed in De Crescenzo's lab, the inhibition of TGF-ß signaling by different TGF-ß receptorcombinations will be tested more rapidly by setting an innovative mix-and-match strategy. The expectedoutcome is a competitive and novel strategy to inhibit TGF-ß signaling. Successful completion of this projectwill provide Formation Biologics with a new therapeutic avenue to inhibit TGF-ß signaling, hence promotingthe development of new drugs, and thus directly benefiting the Canadian patient population and economy.