PFI-TT: Increased affinity of cancer therapeutic via single-domain antibody and dimer targeting of canine PD-1

PFI-TT：通过犬 PD-1 的单域抗体和二聚体靶向提高癌症治疗的亲和力

• 批准号: 2213966
• 负责人: Christopher Cebra
• 金额: $ 25万
• 依托单位: Oregon State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2213966&HistoricalAwards=false
• 关键词: PFI; TT; Increased; affinity; cancer

The broader impact/commercial potential of this Partnerships for Innovation - Technology Translation (PFI-TT) project includes the development of safe, effective, and affordable treatments for animal diseases including cancer in dogs. A robust immune system is critical for effective treatment of cancer. Beyond surgery, radiation, and chemotherapeutics, new approaches include agents shown to block tumors from circumventing the body’s immune defenses. The societal outcomes of this work may include prototype and manufacturing optimization to produce biological molecules that bolster immune activity at comparatively low cost. Like the very expensive, though effective, human therapeutic counterparts, alternative platforms can be substituted at reduced cost, making the treatment accessible to animals, improving their lives and their caretakers’ lives. Greater demands have been placed on healthcare for new flexible technologies to treat disease in a rapid and inexpensive manner. A commercial opportunity resides in providing pet owners and veterinarians an effective, economical, and safe treatment for the nearly 6 million dogs diagnosed yearly with cancer. Creation of manufacturing processes of these new prototypic therapeutics will be utilized to demonstrate the feasibility of project outcomes and contribute to the general public's appreciation of this platform in generating less expensive biologics-based therapies. The proposed project seeks to produce a prototype therapeutic for the treatment of cancer in dogs. As cancer is a leading cause of death in people and dogs, new technologies need to be brought forth. Development of cutting-edge therapeutics for humans and animals requires relevant and robust model systems that provide predictable outcomes. Antibodies, a proven therapeutic platform, are large, complex proteins, that are expensive to develop and manufacture. Different configurations of several proprietary subunit single domain antibodies which are smaller proteins, cheaper to develop and produce will be examined. An optimal dual epitope-binding prototype, specific to an orthologous canine target, will be constructed using recombinant DNA methods and produced in Yeast expression systems. Binding affinity will be measured by bio-layer interferometry. Feasibility testing and optimization of large-scale production will be examined, and purity and functional activity assessed. The anticipated results are that one or more of these combinations will produce a robust binding protype and thus targeting the orthologous canine molecule could provide a potent therapeutic benefit in treatment of canine cancers.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.

这一创新-技术转化伙伴关系(PFI-TT)项目的更广泛影响/商业潜力包括为包括犬癌在内的动物疾病开发安全、有效和负担得起的治疗方法。强大的免疫系统对癌症的有效治疗至关重要。除了手术、放射和化疗外，新的方法还包括被证明可以阻止肿瘤绕过人体免疫防御的药物。这项工作的社会成果可能包括原型和制造优化，以相对较低的成本生产增强免疫活性的生物分子。就像非常昂贵但有效的人类治疗平台一样，可以以更低的成本替代替代平台，使动物能够获得治疗，改善它们的生活及其照顾者的生活。人们对医疗保健提出了更高的要求，要求采用灵活的新技术，以快速、廉价的方式治疗疾病。一个商业机会在于为宠物主人和兽医提供有效、经济和安全的治疗方法，治疗每年被诊断为癌症的近600万只狗。创建这些新的原型疗法的制造工艺将被用来展示项目成果的可行性，并有助于公众欣赏这一平台，以产生更便宜的基于生物的疗法。这项拟议的项目旨在生产一种治疗狗癌症的原型。由于癌症是人类和狗的主要死因，因此需要推出新的技术。开发用于人类和动物的尖端疗法需要相关和强大的模型系统，以提供可预测的结果。抗体是一种成熟的治疗平台，是一种大而复杂的蛋白质，开发和制造成本很高。将检查几种专有亚基单域抗体的不同配置，这些抗体是较小的蛋白质，开发和生产成本较低。将使用重组DNA方法构建针对同源犬类靶标的最佳双重表位结合原型，并在酵母表达系统中生产。结合亲和力将通过生物层干涉法测量。将审查大规模生产的可行性测试和优化，并评估纯度和功能活性。预期的结果是，这些组合中的一个或多个将产生强大的结合原型，因此针对直系犬类分子可以在治疗犬类癌症方面提供强大的治疗益处。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。