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

这项创新-技术转化伙伴关系（PFI-TT）项目的更广泛影响/商业潜力包括开发安全、有效和负担得起的动物疾病治疗方法，包括犬类癌症。强健的免疫系统对有效治疗癌症至关重要。除了手术、放疗和化疗，新的治疗方法还包括阻止肿瘤绕过人体免疫防御系统的药物。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药物一样，替代平台可以以更低的成本替代，使动物也能接受治疗，改善它们和照顾它们的人的生活。对医疗保健提出了更大的要求，需要新的灵活技术以快速和廉价的方式治疗疾病。每年有近600万只狗被诊断患有癌症，为宠物主人和兽医提供有效、经济、安全的治疗方法，这是一个商业机会。这些新原型疗法的制造过程将被用来证明项目成果的可行性，并有助于公众对这个平台的欣赏，以产生更便宜的基于生物的疗法。拟议中的项目旨在为治疗狗的癌症提供一种原型疗法。由于癌症是人类和狗的主要死亡原因，因此需要推出新技术。开发用于人类和动物的尖端治疗方法需要提供可预测结果的相关和强大的模型系统。抗体是一种经过验证的治疗平台，它是一种大型、复杂的蛋白质，开发和制造成本高昂。将研究几种专有亚基单域抗体的不同配置，这些抗体是更小的蛋白质，开发和生产成本更低。一个最佳的双表位结合原型，特定于同源犬的目标，将使用重组DNA方法构建和酵母表达系统生产。结合亲合力将通过生物层干涉法测量。将对大规模生产的可行性测试和优化进行审查，并对纯度和功能活性进行评估。预期的结果是，这些组合中的一种或多种将产生强大的结合原型，因此靶向同源犬分子可能为治疗犬癌症提供有效的治疗效果。该奖项反映了美国国家科学基金会的法定使命，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。

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.