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

该SBIR I期项目引入了基于抗体的治疗分子的新设计。Y形常规抗体中的通常刚性的臂被与结合结构域连接的柔性且可延伸的接头替代，所述结合结构域小于常规抗体中发现的那些。这种新的设计允许同时结合多个治疗靶点，具有比以前更大的结合强度和更少的脱靶效应。该项目将改造过去十年中最成功的两种抗癌药物，创造每种药物的改进版本。此外，将产生结合两者功能的新分子。如果这个项目成功，它可能会改善许多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联合收割机许多治疗抗体的性能;这个项目只是第一个演示。该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克隆抗体（mAb）的新型药物设计。它使用化学组装方法，通过柔性、可延伸的非肽基接头将免疫球蛋白Fc结构域连接到小的单链纤连蛋白结合结构域。所得到的柔性药物分子受益于双手合作结合，其中两个结构域能够同时结合一个或多个疾病靶标。因此，它们实现了比mAb更高的结合亲和力和靶标选择性，同时也更小且更容易制造。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两种最成功的检查点抑制剂的靶标产生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测定。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善更广泛的制药市场中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知识价值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.