The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate’s stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.

IgE在变应性疾病中的关键作用已得到充分证明并已得到临床证明。人源化抗IgE抗体Omalizumab是第一个获批的用于治疗过敏性疾病的抗体。尽管如此，奥马珠单抗仍具有一些局限性，例如产品不稳定性和临床应用中的剂量限制。在这项研究中，我们试图开发一种具有克服其局限性的奥马珠单抗生物优势抗体。我们在奥马珠单抗的CDR中删除了两个天冬氨酸异构化热点，以提高候选抗体的稳定性。同时，奥马珠单抗框架区的几种鼠类氨基酸被人源替代，以降低潜在的免疫原性。然后将酵母展示技术应用于筛选对IgE具有高结合亲和力的候选抗体。此外，将Fc片段中的YTE突变引入候选物中以延长其血清半衰期。筛选出候选候选药物AB1904Am15，该药物显示出所需的生物物理特性，并具有改善的稳定性，高结合亲和力和增强的效能体外，延长人FcRn转基因小鼠的半衰期并增强 体内在食蟹猴哮喘模型中的功效。总体而言，我们的研究开发了一种奥马珠单抗的生物抗性抗体AB1904Am15，它有可能显示出改善的变应性疾病临床疗效。