Targeting galectin-3 to overcome insulin resistance in type 2 diabetes

项目摘要/摘要 肥胖介导的胰岛素抵抗是2型糖尿病(T2D)的一个标志，约占所有2型糖尿病的90% 糖尿病。尽管有许多药物可用于治疗T2D，但没有FDA批准的直接治疗T2D的药物 作用于胰岛素受体(IR)以克服胰岛素抵抗。最近的研究表明，Galectin-3(Gal3) 可以直接与IR结合，抑制IR下游信号，导致胰岛素抵抗和血糖受损 肥胖诱导的T2D的耐受性。我们的科学前提是我们已经开发出一种非常强大的Gal3 拮抗剂TFD100，来自天然饮食来源。此第二阶段提案的主要目标是 完成我们向FDA提交IND所需的临床前研究，以启动首例- 人类第一阶段临床试验。成功完成我们提出的目标将产生重大价值 这对公司来说是一个转折点，为我们的合作或融资做好了准备。 拟议的研究体现了两个领域的技术创新：1)这将是首个FDA- 批准的基于天然碳水化合物的生物疗法；2)TFD100‘S皮摩尔亲和力 TO Gal3具有许多优点，包括克服了常见的与抗原性相关的饱和问题。一个 拟议研究的预期必然收益包括阐明新的凝集素介导的分子。 T2D中调节IR信号的细胞-细胞或细胞-细胞外基质(ECM)相互作用的机制。这 知识将是开辟以碳水化合物为基础的T2D治疗新方法的基础。 我们已成功完成第一阶段的研究。在细胞研究中，Gal3抑制IR/IRS-1的激活， 这被TFD100逆转了。在高脂饮食(HFD)动物模型中，TFD100治疗显著改善 糖耐量和胰岛素耐量与赋形剂处理的动物进行比较。在分析了我们的结果之后， 我们很高兴能继续我们的药物开发。TFD100是一种生物药物，我们相信TFD100将 可能作为溶液分发在预填充盒中，供T2D患者在家中服用，类似于非 侵入性SC注射胰岛素或Ozempic。为了加强科学的严谨性，我们计划确定SC 给予TFD100‘S对HFD模型T2D的治疗作用，并完成相关的IND使能实验 具体目标：1)测定TFD100的PK/PD；2)确定给药的疗效 TFD100用于治疗HFD引起的肥胖、胰岛素抵抗和T2D，以及3)生产TFD100的GLP用于 未来的毒理学研究。拟议的活动将由专家合同合作者执行 或将由在生物制品方面具有专业行业专业知识的杰出顾问团队指导 发展、调节和临床发展。这些研究的结果将导致提交 IND提交给FDA，随后进行一期临床试验。

Project Summary/Abstract Obesity-mediated insulin resistance is a hallmark of type 2 diabetes (T2D), which accounts for ~90% of all diabetes. Despite many drugs that are available to treat T2D, there is no FDA-approved drug that directly works on the insulin receptor (IR) to overcome insulin resistance. Recent studies show that galectin-3 (Gal3) can bind directly to the IR and inhibit downstream IR signaling causing insulin resistance and impaired glucose tolerance in obesity-induced T2D. Our scientific premise is that we have developed a very potent Gal3 antagonist, TFD100, from a natural dietary source. The primary objective of this Phase II proposal is to complete the preclinical studies required for our IND submission to the FDA to enable the initiation of a first–in– human Phase 1 clinical trial. Successful completion of our proposed aims will achieve a significant value inflection point for the company, positioning us well for either partnering or a capital raise. The proposed research embodies technological innovation in two areas: 1) This will be the first FDA- approved biologic therapeutics based on a natural carbohydrate compound; 2) TFD100’s picomolar affinity to Gal3 has many advantages including overcoming the common saturation issue related to antigenicity. An anticipated corollary benefit of the proposed studies includes the elucidation of novel lectin-mediated molecular mechanisms of cell-cell or cell-extracellular matrix (ECM) interactions that modulate IR signaling in T2D. This knowledge will be fundamental to opening-up new carbohydrate-based approaches to T2D treatments. We have successfully completed Phase 1 studies. In studies with cells, Gal3 inhibited IR/IRS-1 activation, which was reversed by TFD100. In high fat diet (HFD) animal model, TFD100 treatment significantly improved glucose tolerance and insulin tolerance compared to the vehicle-treated animals. After analyzing our results, we are excited to continue our drug development. TFD100 is a biologic drug and we believe that TFD100 will likely be distributed as a solution in the prefilled cartridge to be taken by T2D patients at home similar to non- invasive SC injection of insulin or Ozempic. To enhance the scientific rigor, we plan to ascertain SC administered TFD100’s ability to treat T2D in HFD model, and to complete relevant IND-enabling experiments in the following specific aims: 1) Determine PK/PD of TFD100; 2) Ascertain efficacy of SC administered TFD100 to treat HFD induced obesity, insulin resistance and T2D, and 3) GLP production of TFD100 for future toxicology studies. The proposed activities will be either performed by expert contractual collaborators or will be guided by an exceptional consultant team with specialized industry expertise in biologics product development, regulation, and clinical development. The outcomes of these studies will lead to the submission of IND to the FDA followed by a Phase 1 clinical trial.