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

项目总结/摘要 肥胖介导的胰岛素抵抗是2型糖尿病（T2 D）的标志，占所有糖尿病的约90%。 糖尿病尽管有许多药物可用于治疗T2 D，但没有FDA批准的药物直接 作用于胰岛素受体（IR）以克服胰岛素抵抗。最近的研究表明，半乳糖凝集素-3（Gal 3） 可直接与IR结合并抑制下游IR信号传导，导致胰岛素抵抗和葡萄糖受损 肥胖诱导的T2 D的耐受性。我们的科学前提是，我们已经开发出一种非常有效的Gal 3 拮抗剂，TFD 100，来自天然膳食来源。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，以便启动首次临床试验。 人类1期临床试验。成功完成我们提出的目标将实现重大价值 公司的转折点，无论是合作还是融资，我们都处于有利地位。 拟议的研究体现了两个领域的技术创新：1）这将是第一个FDA- 基于天然碳水化合物的获批生物治疗剂; 2）TFD 100的皮摩尔亲和力 Gal 3具有许多优点，包括克服与抗原性相关的常见饱和问题。一个 所提出的研究的预期必然益处包括阐明新的凝集素介导的分子生物学特性。 细胞-细胞或细胞-细胞外基质（ECM）相互作用的机制，其调节T2 D中的IR信号传导。这 知识将是开辟新的基于碳水化合物的T2 D治疗方法的基础。 我们已经成功完成了第一阶段的研究。在细胞研究中，Gal 3抑制IR/IRS-1激活， TFD 100逆转了这一趋势。在高脂饮食（HFD）动物模型中，TFD 100治疗显著改善了 葡萄糖耐量和胰岛素耐量。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。TFD 100是一种生物药物，我们相信TFD 100将 可能作为预充式药筒中的溶液分发，供T2 D患者在家服用，类似于非 侵入性皮下注射胰岛素或Ozempic。为了提高科学严谨性，我们计划确定SC 在HFD模型中给予TFD 100治疗T2 D的能力，并完成相关的IND使能实验 具体目的如下：1）确定TFD 100的PK/PD; 2）确定SC给药的疗效 TFD 100治疗HFD诱导的肥胖、胰岛素抵抗和T2 D，和3）GLP产生TFD 100用于治疗HFD诱导的肥胖、胰岛素抵抗和T2 D， 未来的毒理学研究拟议的活动将由专家合同合作者执行 或将由具有生物制剂产品专业知识的杰出顾问团队指导 开发、监管和临床开发。这些研究的结果将导致提交 IND给FDA，然后进行1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.