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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries
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Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries

机译：从细胞内组合抗体库中选择调节表型的抗体

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摘要

A method is presented that uses combinatorial antibody libraries to endow cells with new binding energy landscapes for the purpose of regulating their phenotypes. Antibodies that are expressed in cells infected with a lentiviral combinatorial antibody library are selected directly for function rather than only for binding. The potential diversity space can be very large because more than one lentivirus can infect a single cell. Thus, the initial combinatorial diversity of ~1.0 x 1011 members generated by the random association of antibody heavy and light chains is greatly increased by the reassortment of the antibody Fv domains themselves inside cells. The power of the system is illustrated by its ability to select unusual antibodies. Here, the selected antibodies are potent eryth-ropoietin agonists whose ontogeny depends on recombination at the protein level of pairs of antibodies expressed in the same cell to generate heterodimeric bispecific antibodies. The obligate synergy between the different binding specificities of the antibody's monomeric subunits appears to replicate the asymmetric binding mechanism of authentic erythropoietin.
机译：提出了一种使用组合抗体文库为细胞赋予新的结合能格局以调节其表型的方法。直接选择受慢病毒组合抗体文库感染的细胞中表达的抗体是为了发挥功能，而不仅仅是为了结合。潜在的多样性空间可能非常大，因为一个以上的慢病毒可以感染单个细胞。因此，通过抗体重链和轻链自身在细胞内的重配，由抗体重链和轻链的随机缔合产生的约1.0 x 1011个成员的初始组合多样性大大提高了。该系统的强大能力来自其选择异常抗体的能力。在此，所选择的抗体是有效的促红细胞生成素激动剂，其个体发育取决于在同一细胞中表达的成对抗体对的蛋白质水平上的重组以产生异二聚体双特异性抗体。抗体的单体亚基的不同结合特异性之间的专职协同作用似乎复制了真实的促红细胞生成素的不对称结合机制。

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