SBIR Phase II: Design And Production Of IgG Fc Carrier Scaffolds With Increased Payload Capacity

这个小型企业创新研究(SBIR)II项目概述了半合成治疗性蛋白结合物的体内测试。低分子多肽药物由于清除速度快，治疗效果有限，因此必须非常频繁地注射。这些药物可以连接到载体蛋白上。附着在大的生物分子上，如载体蛋白，改善了这些多肽的半衰期。从历史上看，这些载体蛋白中的许多都是与感兴趣的多肽进行基因重组融合。通过融合，载体S与多肽的结合被限制在一个位置，即末端，而有限的放置可能会影响药物的功能，从而影响药物的效力。作为另一种选择，用小分子药物对载体蛋白进行化学修饰也可以使药物更有效和更持久。红木生物科学的科学家们已经开发出一种技术平台，可以以受控的、特定位置的方式普遍修改蛋白质。他们已经产生了载体蛋白支架，修饰的重组Fc结构域，这些结构域是均一的，很容易用治疗性多肽进行化学阐述。此外，优化的多肽与Fc蛋白的偶联提高了体外偶联活性。这项技术还需要通过初步的体内分析来进一步验证。这项研究的更广泛影响是开发出一流的治疗方法，并产生了一个强大的蛋白质修饰平台。这项工作将改变蛋白质疗法的效用，使原本不能用于疾病治疗的治疗性多肽得到优化。

This Small Business Innovation Research (SBIR) II project outlines in vivo testing of semi-synthetic therapeutic protein conjugates. Low molecular weight peptide drugs have had limited therapeutic utility due to rapid clearance and, consequently must be injected very frequently. These drugs could be conjugated to a carrier protein. Attachment to large biomolecules, such as carrier proteins, improves the half-life profile of these peptides. Historically, many of these carrier proteins are recombinant genetic fusions with the peptide of interest. With fusion, the carrier?s attachment to the peptide is limited to one site, the end terminus, and that limited placement can impact drug function and thus potency. As an alternative, chemical modification to carrier proteins with small molecule drugs can also render the drug more potent and longer lasting. The scientists at Redwood Bioscience have developed a technology platform that can universally modify proteins in a controlled, site-specific manner. They have generated carrier protein scaffolds, modified recombinant Fc domains that are homogeneous and easy to chemically elaborate with therapeutic peptides. Furthermore, optimized peptide conjugation to the Fc proteins improves conjugate activity in vitro. This technology is to be further validated through an initial in vivo analysis.The broader impacts of this research are the development of best in class therapeutics and the generation of a robust protein modification platform. This work will change the utility of protein therapeutics by enabling optimization of therapeutic peptides that otherwise would not be useful as treatment for disease.