Hao Xiaohu, Liu Dongping, Fan Long
Production and R&D Center I of LSS (Life Science Service), GenScript Biotech Corporation, No. 28, Yongxi Rd., Nanjing, 211100, Jiangsu, China.
Production and R&D Center I of LSS (Life Science Service), GenScript (Shanghai) Biotech Corporation, No. 186, Hedan Rd., Shanghai, 200100, China.
Comput Struct Biotechnol J. 2024 Aug 22;23:3222-3231. doi: 10.1016/j.csbj.2024.08.013. eCollection 2024 Dec.
The application of antibody therapeutics is promising in the field of immunotherapy. While, heterologization should be done in most cases before applying the therapeutic antibodies into bodies, e.g., humanization, caninization and felinization for human beings, canine and feline, respectively. Here we report YabXnization, the platform which realizes antibody heterologization on the basis of rational design and artificial intelligence (AI)-assisted computation. YabXnization provides two ways for heterologization: traditional CDR-grafting and backmutation-based rational design; and AI-assisted fusion computational design. Taking humanization as example, both of the two ways first find the proper template for heavy and light chains with CDR-grafting followed. For rational design, bioinformatics analysis-based backmutation is then conducted. For AI-assisted computational design, the backmutation and humanness evaluation are implemented through evolutionary computation framework with DeepForest-based humanness evaluation model and the distance to the previously found human template as objective functions. Finally, the top heterologized antibodies can be provided by YabXnization platform. We examined the platform with 18 antibodies to be heterologized, in which 10 for humanization, 6 for caninization and 2 for felinization, respectively. The heterologized antibodies were measured by indirect ELISA and BLI(Octet)/SPR(Biacore) binding affinity measurement methods. Test results show a 90% success rate with the binding affinity loss of heterologized antibodies within an order of magnitude compared to the corresponding chimeric antibodies. It even shows an increase in the binding affinity on some of the heterologized antibodies. The platform can be reached through https://www.genscript.com/tools/yabxnization-service.
抗体疗法在免疫治疗领域具有广阔的应用前景。然而，在将治疗性抗体应用于人体之前，大多数情况下需要进行异源化，例如，分别针对人类、犬类和猫类进行人源化、犬源化和猫源化。在此，我们报告了YabXnization平台，该平台基于合理设计和人工智能（AI）辅助计算实现抗体异源化。YabXnization提供了两种异源化方法：传统的互补决定区（CDR）移植和基于回复突变的合理设计；以及AI辅助融合计算设计。以人源化为例，两种方法首先通过CDR移植找到重链和轻链的合适模板。对于合理设计，随后进行基于生物信息学分析的回复突变。对于AI辅助计算设计，通过具有基于DeepForest的人源化评估模型的进化计算框架以及与先前找到的人类模板的距离作为目标函数来实现回复突变和人源化评估。最后，YabXnization平台可以提供排名靠前的异源化抗体。我们用18种待异源化的抗体检测了该平台，其中分别有10种用于人源化、6种用于犬源化和2种用于猫源化。通过间接酶联免疫吸附测定（ELISA）和生物层干涉（BLI，Octet）/表面等离子体共振（SPR，Biacore）结合亲和力测量方法对异源化抗体进行检测。测试结果显示成功率为90%，异源化抗体的结合亲和力损失与相应的嵌合抗体相比在一个数量级以内。甚至在一些异源化抗体上显示出结合亲和力的增加。可通过https://www.genscript.com/tools/yabxnization-service访问该平台。
