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Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
mAbs ( IF 5.3 ) Pub Date : 2020-10-25 , DOI: 10.1080/19420862.2020.1829335
Michael R Dyson 1 , Edward Masters 1 , Deividas Pazeraitis 1 , Rajika L Perera 2 , Johanna L Syrjanen 3 , Sachin Surade 1 , Nels Thorsteinson 4 , Kothai Parthiban 1 , Philip C Jones 1 , Maheen Sattar 1 , Gordana Wozniak-Knopp 5 , Florian Rueker 5 , Rachael Leah 1 , John McCafferty 1
Affiliation  

ABSTRACT

The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularly as proteins are formulated at high concentrations, causing aggregation or polyreactivity. Such late-stage “developability” problems can lead to delay or failure in traversing the development process. Aggregation propensity is also correlated with increased immunogenicity, resulting in expensive, late-stage clinical failures. Using nucleases-directed integration, we have constructed large mammalian display libraries where each cell contains a single antibody gene/cell inserted at a single locus, thereby achieving transcriptional normalization. We show a strong correlation between poor biophysical properties and display level achieved in mammalian cells, which is not replicated by yeast display. Using two well-documented examples of antibodies with poor biophysical characteristics (MEDI-1912 and bococizumab), a library of variants was created based on surface hydrophobic and positive charge patches. Mammalian display was used to select for antibodies that retained target binding and permitted increased display level. The resultant variants exhibited reduced polyreactivity and reduced aggregation propensity. Furthermore, we show in the case of bococizumab that biophysically improved variants are less immunogenic than the parental molecule. Thus, mammalian display helps to address multiple developability issues during the earliest stages of lead discovery, thereby significantly de-risking the future development of protein drugs.



中文翻译:

超越亲和力:从哺乳动物展示文库中选择具有最佳生物物理特性和降低免疫原性的抗体变体

摘要

蛋白质药物开发的早期阶段传统上侧重于导致所需治疗作用模式的目标结合特性。随着越来越多的蛋白质疗法通过开发管道;然而,很明显,可能会出现非最佳生物物理特性,特别是当蛋白质以高浓度配制时,会导致聚集或多反应性。这种后期的“可开发性”问题会导致开发过程的延迟或失败。聚集倾向也与增加的免疫原性相关,导致昂贵的后期临床失败。使用核酸酶指导的整合,我们构建了大型哺乳动物展示文库,其中每个细胞都包含插入单个基因座的单个抗体基因/细胞,从而实现转录正常化。我们显示了较差的生物物理特性与在哺乳动物细胞中实现的展示水平之间存在很强的相关性,而酵母展示无法复制这一点。使用两个有据可查的生物物理特性较差的抗体示例(MEDI-1912 和 bococizumab),基于表面疏水性和正电荷补丁创建了一个变体库。哺乳动物展示用于选择保留目标结合并允许增加展示水平的抗体。所得变体表现出降低的多反应性和降低的聚集倾向。此外,我们在 bococizumab 的情况下表明,生物物理改进的变体的免疫原性低于亲本分子。因此,哺乳动物展示有助于在铅发现的最早阶段解决多个可开发性问题,

更新日期:2020-10-30
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