College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
Biochem Biophys Res Commun. 2010 May 28;396(2):231-7. doi: 10.1016/j.bbrc.2010.04.071. Epub 2010 Apr 23.
We previously constructed a humanized antibody, HuS10, by grafting the complementarity-determining regions (CDRs) of a parental murine monoclonal antibody into the homologous human antibody sequences. This process is termed CDR grafting. Some residues that were thought to affect the CDR loops and stabilize the structure of the variable regions were retained in the framework region. HuS10 exhibited in vivo virus-neutralizing activity, but its murine content had the potential to elicit immune responses in patients. In this study, to minimize the immunogenic potential of HuS10, we replaced 17 mouse residues in HuS10 with the comparable human residues using specificity-determining residue (SDR)-grafting and de-immunization methods. The resultant humanized antibody, HzS-III, had the same affinity and epitope specificity as HuS10 and had reduced immunogenic potential, as assessed by T-cell epitope analysis. Thus, SDR grafting in combination with de-immunization may be a useful strategy for minimizing the immunogenicity of humanized antibodies. In addition, HzS-III may be a good candidate for immunoprophylaxis of HBV infection.
我们先前通过将亲本鼠单克隆抗体的互补决定区（CDR）移植到同源人抗体序列中构建了一种人源化抗体 HuS10。这个过程被称为 CDR 移植。一些被认为会影响 CDR 环并稳定可变区结构的残基被保留在框架区中。HuS10 表现出体内病毒中和活性，但它的鼠源成分有可能在患者中引发免疫反应。在这项研究中，为了最大限度地降低 HuS10 的免疫原性，我们使用特异性决定残基（SDR）移植和去免疫化方法将 HuS10 中的 17 个鼠残基替换为相应的人残基。所得的人源化抗体 HzS-III 与人源化抗体 HuS10 具有相同的亲和力和表位特异性，并且通过 T 细胞表位分析评估，其免疫原性降低。因此，SDR 移植结合去免疫化可能是降低人源化抗体免疫原性的有效策略。此外，HzS-III 可能是预防乙型肝炎病毒感染的良好候选物。
