基于单域抗体的全人源长效基因工程抗体的构建及其功能研究

The large size of monoclonal antibodies results in poor penetration into tissues, poor or absent binding to sterically restricted regions of some antigens, and high production cost, which has largely limited their clinical applications. A variety of antibody fragments of smaller size such as single-domain antibodies are promising to replace monoclonal antibodies and serve as the next-generation therapeutic antibodies. However, to date, these antibody fragments have been of limited therapeutic applications because they usually display very short in vivo half-life. We have recently found that high affinity single-domain antibodies can be identified from a very large fully human single-domain antibody library which was generated based on a specific human VH subfamily. We have also recently generated a panel of small monomers with long in vivo half-life based on human IgG1 Fc. In this project, we aim to further identify fully human single-domain antibodies against various targets, and then fuse the single-domain antibodies with the Fc-derived small monomers to generate some novel antibody constructs with small size, fully human origin, high binding affinity and long half-life. Their mechanism of action will also be investigated in this project. This research could provide an important contribution to overcome the bottlenecks in the clinical applications of antibody therapeutics.

全长单克隆抗体药物的分子量过大，从而导致其在临床应用时存在渗透性差、无法靶向有空间位阻的靶点、成本过高等显著缺陷。单域抗体等一些保留了单克隆抗体抗原结合性能的小分子抗体片段有潜力替代单克隆抗体，成为新一代抗体药物。然而这些抗体片段体内半衰期过短，目前难以用于临床治疗。最近，我们发现利用基于人的一特定重链可变区亚家族构建的超大型全人源单域抗体库，可有效筛选到针对不同靶点的高亲和力单域抗体。另一方面，我们还基于人抗体恒定区构建了一系列小分子量长效单体模块。本研究拟在这些研究基础上，进一步筛选针对不同疾病靶点的全人源单域抗体，并将全人源单域抗体与源于人抗体恒定区的小分子量长效单体模块进行融合，构建一类兼具全人源、分子量小、靶向性好、半衰期长等性质的新型基因工程抗体，以及对其作用机制进行深入研究，以期为突破抗体药物的发展瓶颈提供重要的理论依据和解决方案。

全长单克隆抗体药物的分子量过大，从而导致其在临床应用时存在渗透性差、无法靶向有空间位阻的靶点、成本过高等显著缺陷。单域抗体等一些保留了单克隆抗体抗原结合性能的小分子抗体片段有潜力替代单克隆抗体，成为新一代抗体药物。然而这些抗体片段体内半衰期过短，目前难以用于临床治疗。我们前期发现利用基于人的一特定重链可变区亚家族构建的超大型全人源单域抗体库，可有效筛选到针对不同靶点的高亲和力单域抗体。另一方面，我们还基于人抗体恒定区构建了一系列小分子量长效单体模块。本研究在这些研究基础上，进一步筛选了针对寨卡病毒、癌胚抗原等不同疾病靶点的全人源单域抗体，并将全人源单域抗体与源于人抗体恒定区的小分子量长效单体模块进行融合，构建了一类兼具全人源、分子量小、靶向性好、半衰期长等性质的新型基因工程抗体，并对其作用机制进行了深入研究。在整个课题实施过程中，课题进展顺利，均能按时或提前完成每年度的研究工作，并发表SCI论文20篇，申报专利11项。该工作为突破抗体药物的发展瓶颈提供了重要的理论依据和解决方案。