SBIR Phase I: Highly Specific Flex-Hinge Antibody-Like Checkpoint Inhibitors for Safer and More Effective Cancer Therapy

这个SBIR第一阶段项目介绍了一种基于抗体的治疗分子的新设计。Y型常规抗体中通常刚性的手臂被附着在比常规抗体中发现的更小的结合域上的柔性和可延伸的连接物所取代。这种新的设计允许一次绑定多个治疗靶点，具有比以前可能的更大的绑定强度和更少的脱靶效应。该项目将重新制造过去十年中最成功的两种抗癌药物，创造出每种药物的改进版本。此外，还将生产一种结合了这两种功能的新分子。如果该项目成功，可能会改善多种晚期转移性癌症的治疗方法，特别是黑色素瘤和肺癌。虽然目前的重点是癌症，但这里描述的方法可能会改善或结合许多治疗性抗体的性能；这个项目只是第一个演示。这个SBIR第一阶段项目的潜在长期影响可能会延伸到整个制药行业，代表着一个重要的商业机会和应用生物学研究的里程碑。该项目介绍了一种改进单抗的新药设计。它使用一种化学组装方法，通过灵活的、可扩展的非肽基连接物将免疫球蛋白Fc结构域与小的单链纤维连接蛋白结合结构域连接起来。由此产生的灵活的药物分子受益于双手合作结合，在这种结合中，两个结构域都能够同时结合一个或多个疾病靶点。因此，它们获得了比单抗更高的结合亲和力和靶向选择性，同时它们也更小，更容易制造。根据需要，这些分子也可以是单特异性或双特异性的。该项目将针对目前癌症免疫治疗中最成功的两种检查点抑制剂的靶标生产灵活的单特异性和双特异性分子。该项目包括化学合成，结合化学计量学的验证，对纯化蛋白和靶细胞的结合亲和力的体外测量，以及检查点抑制和双特异性结合的细胞分析。它为这些抗癌药物的临床前动物研究奠定了基础，并展示了一种可用于改进更广泛制药市场中的大多数抗体疗法的分子设计。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This SBIR Phase I project introduces a new design for antibody-based therapeutic molecules. The generally rigid arms in Y-shaped conventional antibodies are replaced with flexible and extendible linkers attached to binding domains that are smaller than those found in conventional antibodies. This new design allows multiple therapeutic targets to be bound at once, with greater binding strength and fewer off-target effects than was previously possible. This project will remake two of the most successful cancer drugs of the last decade, creating improved versions of each. In addition, a new molecule combining the functionality of both will be produced. If this project is successful, it may improve the treatments available for many kinds of advanced metastatic cancer, especially melanoma and lung cancer. Though the current focus is on cancer, the method described here may improve or combine the performance of many therapeutic antibodies; this project is just the first demonstration. The potential long-term impact of this SBIR Phase I project may extend throughout the pharmaceutical industry, representing a significant commercial opportunity and a milestone of applied biological research.This project introduces a novel drug design that improves on monoclonal antibodies (mAbs). It uses a chemical assembly method that joins immunoglobulin Fc domains to small, single-chain fibronectin binding domains through flexible, extendible, non-peptidyl linkers. The resulting flexible drug molecules benefit from two-handed cooperative binding, in which both domains are able to bind a disease target or targets simultaneously. They thus achieve higher binding affinity and target selectivity than mAbs, while also being smaller and easier to manufacture. These molecules can also be mono- or bispecific as needed. This project will produce flexible monospecific and bispecific molecules against the targets of the two most successful checkpoint inhibitors in current cancer immunotherapy. This project encompasses chemical synthesis, verification of binding stoichiometry, in vitro measurements of binding affinity to both purified protein and target cells, and cellular assays of both checkpoint inhibition and bispecific binding. It sets the stage for pre-clinical animal studies of these cancer drugs, and showcases a molecular design that could be used to improve most antibody therapies in the broader pharmaceutical market.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.