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全面建立ProtElix基于支架的人纤连蛋白文库（人纤连蛋白的第14个纤连蛋白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，其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，在此期间将执行不同的结合和稳定性优化策略。此外，ProtElix技术将使用几种蛋白质靶点（CD 20，EGFR，VEGFR 2，VLA-4）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。先导候选药物将在体外和体内进行完整的动力学表征，并将在小动物模型中进行PK/PD检测。到第二阶段完成时，将全面开发基于14 FN 3的专有人类抗体模拟库的综合发现平台，并评估主要候选物的“可药用性”。蛋白质支架应用于开发新疗法正成为一个具有巨大商业潜力的领域，具有高度的社会意义，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。特别地，使用抗体模拟物选择性地阻断治疗上重要的蛋白质靶标可能是克服当前基于抗体的治疗剂的临床局限性和潜在毒性以及缺乏功效的关键。ProtElix支架平台技术的灵活形式及其用于产生“智能”文库多样性的专有诱变技术将为制药和生物技术公司发现和开发下一代生物治疗药物提供有吸引力的替代方案。此外，纤连蛋白III型结构域的固有特征（即小尺寸，无二硫键）与基于免疫球蛋白的抗体相比将导致更便宜的制造成本和潜在更有效和安全的药物（更高的组织渗透和更快的清除）。如果成功，该项目将使基于支架的治疗方法的潜在应用达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.