Next-generation of Transforming Growth Factor ß inhibitors

转化生长因子β（transforminggrowthfactorbeta，TGF-β）是一种多效性细胞因子，在正常胚胎发育和组织稳态中起重要作用.过度的TGF-β作用在纤维化中的作用是有据可查的，因此，开发阻断TGF-β信号传导的药物以获得治疗益处是有意义的。这一治疗领域目前正由FormationBiologics公司进行探索，该公司是一家专注于开发TGF-β抑制剂的加拿大公司。Formation有一个成功的药物开发记录，一个产品在I期临床试验中，另一个在IND开发中。为了继续开发特异性TGF-β抑制剂（即对TGF-β超家族中的每种亚型都具有特异性），Formation Biologics现在致力于探索基于抗体的治疗方法的有前景的替代品。因此，拟议的研究集中在利用TGF-β受体胞外结构域的TGF-β中和潜力来开发有效的TGF-β拮抗剂。更具体地说，该建议是物理上联合收割机结合各种受体胞外结构域，以提高它们的TGF-β结合和螯合效率，同时利用它们的结合特异性.如果用经典的实验方法（即，设计与两种不同受体的融合相对应的嵌合蛋白，它们的纯化和相关的测定），如果考虑到TGF-β同种型的数量、它们结合的受体的数量以及产生的受体组合的数量，这样的研究将是非常耗时的。使用De Crescenzo实验室先前工作中产生的独特分子适配器策略，通过设置创新的混合匹配策略，将更快地测试不同TGF-β受体组合对TGF-β信号传导的抑制。预期的结果是一个有竞争力的和新的策略来抑制TGF-β信号转导。该项目的成功完成为Formation Biologics提供了抑制TGF-β信号传导的新治疗途径，从而促进新药的开发，从而直接造福加拿大患者群体和经济。

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.