鼠抗人纤维蛋白抗体单链Fv片段的人源化分子设计  

Fv Fragment of Murine Antibody Against Human Fibrin

作　　者：刘士辉[1] 王国力[1] 黄君健 俞炜源[1] 黄培堂[1] 黄翠芬[1] 

机构地区：[1]北京生物工程研究所

出　　处：《生物化学杂志》1997年第6期677-685,共9页

摘　　要：产生免疫原性的残基主要是位于蛋白表面的暴露残基，为了消除鼠抗体对人的免疫原性，利用表面再塑的方法对本室克隆的鼠抗人纤维蛋白抗体单链Ｆｖ片段进行了人源化分子设计．首先确定了鼠及人Ｆｖ片段的表面残基，在此基础上分析了鼠与人抗体Ｆｖ片段表面残基的差异，将存在差异的鼠抗体的表面残基换成人的，从而实现鼠抗体的人源化．提出了残基最高频率人源化及最相似链人源化两种分子设计方案．人源化的鼠抗人纤维蛋白抗体单链Ｆｖ片段的结构经Ｐｒｏｆｉｌｅｓ－３Ｄ检测证明合理，替换的表面残基的溶剂可及性未变，而且未对ＣＤＲｓ的空间构象产生明显影响，应不会影响与纤维蛋白的亲和力，为鼠抗体人源化实验研究奠定了基础．Immunogenicity of murine antibody variable regions originates with the surface residues.In order to eliminating the immunogenicity in human,humanization of the single chain Fv fragment of murine antibody against human fibrin which cloned by the phage display in the lab,was designed by resurfacing the molecule.First,the surface residues of the Fv which may induced the immunogenicity were determined.Then the differences between the surface residues of murine and human antibody Fv fragments were analyzed,and the different surface residues of the murine antibody Fv against human fibrin studied in the paper were replaced by those from human.In the study,two humanization strategies,the most similar chain surface humanization and the most frequent surface humanization,were reported.Both of the three dimensional structures of the humanized murine Fv fragment designed by the two strategies were proved reasonable by Profiles 3D program.The analyses showed that the solution accessible propertises of the mutated surface residues of the humanized Fv fragment were not changed.In addition,the CDRs structures of the two humanized Fv were not affected by the residue change,so the affinity for fibrin of them may not be declined.

关 键 词：单链抗体 人源化 分子设计 纤维蛋白抗体 研制 

分 类 号：R392－33[医药卫生—免疫学]