SBIR Phase I: Stable prophylactic antibodies

这个小型企业创新研究（SBIR）第一阶段项目的更广泛的影响/商业潜力是解决各种没有足够预防或治疗的传染病，如艾滋病毒，流感，疟疾和普通感冒。事实证明，这些疾病的疫苗接种非常困难，通常是因为有无数的自然菌株。直接提供抗体代表了一种可能的解决方案，因为一些最广泛的抗体可以制服97%或更多的循环菌株。然而，抗体在体内不会持续超过几个月。该项目建议在抗体的恒定部分中收集突变，以使其稳定数十年甚至终生。这项小型企业创新研究（SBIR）I期项目将推进对模型抗体Fc区进行诱变的潜在应用，最终开发稳定的预防性抗体。首先，使Fc对所有细胞和所有主要微生物抗体蛋白酶具有抗性。已经实现了赋予抗体对某些蛋白酶的抗性的突变;这些突变将在模型系统中组合。对所有剩余蛋白酶的抗性将通过靶向突变（如果切割位点已知）和通过综合突变（如果切割位点未知）来工程化。全长免疫球蛋白G噬菌体展示将促进突变体的高通量筛选。第二，Fc在体内通过新生儿Fc受体（FcRn）稳定。 通过全长免疫球蛋白G噬菌体展示，对Fc中所有可能的单突变体和双突变体进行无偏倚筛选，将分离出进一步增强与FcRn结合的突变体。该奖项反映了NSF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 Small Business Innovation Research (SBIR) Phase I project is to solve a variety of infectious diseases for which there is no adequate prevention or therapy, such as HIV, flu, malaria, and the common cold. Vaccination has proven immensely difficult for these diseases, often because there are countless natural strains. Providing antibodies directly represents a possible solution because some of the broadest antibodies can subdue 97% or more of circulating strains. However, antibodies will not last beyond a few months in the body. This project proposes to make a collection of mutations in the constant part of antibodies to stabilize them potentially for decades or even a lifetime. This will improve public health.This Small Business Innovation Research (SBIR) Phase I project will advance the potential applications of mutagenizing the Fc region of a model antibody toward the eventual development of stable prophylactic antibodies. First, the Fc will be made resistant to all cellular and all major microbial antibody proteases. Mutations conferring resistance of antibodies to some proteases have already been achieved; these will be combined in the model system. Resistance to all remaining proteases will be engineered by targeted mutation, if the cleavage sites are known, and by comprehensive mutation, if the cleavage sites are unknown. High-throughput screening of mutants will be facilitated by full-length Immunoglobulin G phage display. Second, Fc is stabilized in vivo by the neonatal Fc receptor (FcRn). An unbiased screen of all possible single and double mutants in Fc, also by full-length Immunoglobulin G phage display, will isolate mutants that have still further enhanced binding to FcRn.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.