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

这项小型企业创新研究二期项目旨在全面建立ProtElix基于支架的人类纤维连接蛋白文库（人类纤维连接蛋白的第14个纤维连接蛋白III型模块），作为平台技术，发现新的抗体模拟候选药物，用于广泛的治疗应用。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克隆抗体的药物更便宜、更有效和更安全。总体而言，该二期项目将分为两个阶段：研究计划阶段，在此阶段将执行不同的绑定和稳定性优化策略。此外，ProtElix技术将在多个蛋白靶点（CD20、EGFR、VEGFR2、vla4）上进行测试，以充分评估平台本身的通用性。该项目的第二阶段将侧重于药物开发活动。主要候选药物将在体外和体内进行完整的动力学表征，并在小动物模型中进行PK/PD测试。II期完成后，将全面开发基于人类14fn3抗体模拟文库的综合发现平台，并评估主要候选药物的“可药物性”。利用蛋白质支架开发新的治疗方法正成为一个具有巨大商业潜力和高度社会意义的领域，因为它涉及到降低成本和增加治疗几种危及生命的疾病的可及性。特别是，使用抗体模拟物选择性地阻断治疗上重要的蛋白质靶点可能是克服当前基于抗体的治疗方法的临床局限性、潜在毒性和缺乏疗效的关键。ProtElix支架平台技术的灵活格式及其专有的突变技术可产生“智能”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型结构域的固有特征（即小尺寸，无二硫键）将导致更低的制造成本和潜在的更有效和更安全的药物（更高的组织穿透性和更快的清除）。如果成功，该项目将把基于支架的治疗方法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.