SBIR Phase II: Bioinformatics knowledge-based, universal library design for a non-immunoglobulin, protein-scaffold

这个小企业创新研究第二阶段项目旨在完全建立ProtElix基于支架的人纤维连接蛋白文库(人纤维连接蛋白的第14个纤维连接蛋白III型模块)作为平台技术，以发现用于广泛治疗应用的新型抗体模拟药物候选药物。这一发现的社会和商业意义可能包括开发第二代蛋白质药物拮抗剂，这种药物比目前基于单抗的药物更便宜、更有效、更安全。总体而言，这一二期工程将分为两个阶段：研究计划，在此期间将执行不同的结合和稳定性优化策略。此外，ProtElix技术将用几种蛋白质靶标(CD20、EGFR、VEGFR2、VLA-4)进行测试，以全面评估平台本身的普遍性。该项目的第二阶段将侧重于药物开发活动。候选铅将在体外和体内进行全面的动力学表征，并将在小动物模型中进行PK/PD测试。随着第二阶段的完成，基于14FN3的人类专有抗体模拟库的全面发现平台将得到全面开发，并对主要候选抗体的“药效性”进行评估。应用蛋白质支架开发新的疗法正成为一个具有巨大商业潜力的领域，具有很高的社会影响，因为它涉及到降低成本和增加对几种危及生命的疾病的治疗的可及性。特别是，使用抗体模拟物选择性地阻断具有治疗意义的重要蛋白质靶点，可能是克服目前基于抗体的治疗方法的临床局限性和潜在毒性和缺乏疗效的关键。ProtElix支架平台技术的灵活格式与其专有的突变技术相结合，可以产生“智能”文库多样性，这将为制药和生物技术公司发现和开发下一代生物疗法提供一个有吸引力的替代方案。此外，与基于免疫球蛋白的抗体相比，纤维连接蛋白III型结构域的固有特性(即小尺寸，无二硫键)将导致更低的制造成本，以及潜在更有效和更安全的药物(更高的组织渗透率和更快的清除速度)。如果成功，该项目将把基于支架的治疗的潜在应用提升到比第一代抗体更高的水平，包括癌症、自身免疫性疾病、心血管疾病和传染病。

This Small Business Innovation Research Phase II project seeks to fully establish ProtElix' scaffold-based human fibronectin libraries (14th fibronectin type III module of Human Fibronectin) as platform technology to discover novel antibody-mimics drug candidates for a wide range of therapeutic applications. The social and commercial implications of this discovery may include developing second generation protein drug antagonists which are less expensive, more efficacious and safer than current monoclonal antibody-based drugs. Overall, this Phase II Project will be divided in two stages: a research plan during which different binding and stability optimization strategies will be executed. Moreover, ProtElix technology will be tested with several protein targets (CD20, EGFR, VEGFR2, VLA-4) in order to fully assess the universality of the platform itself. The second stage of the project will be focused upon drug development activities. Lead candidates will undergo full kinetic characterization in vitro and in vivo and will be tested for PK/PD in small animal models. By the completion of phase II, a comprehensive discovery platform for proprietary human 14FN3-based antibody mimics libraries will be fully developed and the "drugability" of lead candidates assessed.The application of protein scaffold to develop new therapeutics is becoming an area of great commercial potential with high social implications as it relates to lower the cost and increase the accessibility of therapy to several life-threatening diseases. In particular the use of antibody-mimics to selectively block therapeutically important protein targets could be the key to overcome the clinical limitations and potential toxicity and lack of efficacy of current antibody-based therapeutics. The flexible format of ProtElix scaffold platform technology together with its proprietary mutagenesis technology for producing "intelligent" library diversity will provide an attractive alternative to pharmaceutical and biotech companies for the discovery and development of next-generation biotherapeutics. In addition, the intrinsic characteristics of the Fibronectin Type III domain (i.e. small size, no disulfide bonds) would lead to cheaper cost of manufacturing and potentially more effective and safe drugs (higher tissue penetration and faster clearance) compared to immunoglobulin-based antibodies. If successful, this project will take the potential applications of scaffold-based therapeutics to a higher level than first generation antibodies, including cancer, autoimmune diseases, cardiovascular and infectious diseases.