Humanization of predicted T-cell epitopes reduces the immunogenicity of chimeric antibodies: new evidence supporting a simple method.
Humanization of predicted T-cell epitopes reduces the immunogenicity of chimeric antibodies: new evidence supporting a simple method.
复制标题
预测 T 细胞表位的人源化降低了嵌合抗体的免疫原性：支持简单方法的新证据。
DOI：
10.1089/153685903322328974
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
R. Pérez
中科院分区：
文献类型：
--
作者：
L. Roque;C. Mateo;J. Lombardero;G. Mustelier;A. Fernández;Katya Sosa;S. Morrison;R. Pérez
基因工程提供了几种降低鼠抗体免疫原性的方法。我们之前描述了一种基于呈递给 T 细胞的线性表位人源化的新方法。简而言之，鉴定了可变区中潜在的免疫原性表位，并对其进行点突变，使其成为人类和/或修饰两亲性基序。所得重组抗体保留了其抗原结合亲和力，并且在猴子中的免疫原性低于其鼠类或嵌合前体。本研究提供了这种T细胞表位人源化方法的两个新例子：识别人CD6分子的ior-t1A鼠单克隆抗体（mMAb）和识别恶性结直肠细胞表面表达的新型糖蛋白的ior-C5 mMAb。 ior-C5 中的 7 个氨基酸和 ior-t1A 中的 11 个残基被来自最高同源性人类序列的相应残基取代。令人惊讶的是，重塑的嵌合抗体可变区框架与人类序列之间的同源性为80-90%。猴子实验表明，T1AhT 和 C5hT“去位”抗体的免疫原性低于其嵌合类似物，同时保留了 30-50% 的抗原结合亲和力。所提出的方法可能具有普遍适用性，可降低具有治疗潜力的嵌合抗体的免疫原性。
Genetic engineering has provided several approaches to reduce immunogenicity of murine antibodies. We described previously a new method based on the humanization of the linear epitopes presented to T cells. In brief, potential immunogenic epitopes in the variable region were identified and subjected to point mutations to make them human and/or to modify amphipatic motifs. The resulting recombinant antibody retained its antigen binding affinity and was less immunogenic in monkeys than their murine or chimeric predecessors are. The present study provides two new examples of this T-cell epitope humanization approach: ior-t1A murine monoclonal antibody (mMAb), which recognizes the human-CD6 molecule, and ior-C5 mMAb, which recognizes a novel glycoprotein expressed on the surface of malignant colorectal cells. Seven amino acids were substituted in ior-C5 and eleven residues in ior-t1A, by the corresponding residues from the highest homologous human sequences. Surprisingly, the homology between re-shaped chimeric antibody variable region frameworks and human sequences was 80-90%. Experiments in monkeys showed that T1AhT and C5hT "detopes" antibodies were less immunogenic than their chimeric analogues while they retained 30-50% of antigen binding affinities. The proposed method might be of general applicability to reduce immunogenicity of chimeric antibodies with therapeutic potential.
登录
查看更多内容
DOI：
10.1073/pnas.81.21.6851
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
MORRISON, SL;JOHNSON, MJ;OI, VT
通讯作者：
OI, VT
用于选择 T 细胞呈递肽的疏水螺旋带算法。
影响因子：
3.6
作者：
Stille,CJ;Thomas,LJ;Reyes,VE;Humphreys,RE
通讯作者：
Humphreys,RE
影响因子：
2.2
作者：
COLOMA, MJ;HASTINGS, A;MORRISON, SL
通讯作者：
MORRISON, SL
亚组 II 和 III 的人免疫球蛋白 kappa 轻链基因。
影响因子：
14.9
作者：
Klobeck,HG;Meindl,A;Combriato,G;Solomon,A;Zachau,HG
通讯作者：
Zachau,HG
使用细胞 ELISA 检测细胞表面抗原。
影响因子：
2.7
作者：
Bishop,GA;Hwang,J
通讯作者：
Hwang,J