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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Humanization of murine monoclonal antibodies through variable domain resurfacing.
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Humanization of murine monoclonal antibodies through variable domain resurfacing.

机译：通过可变结构域表面修饰使鼠类单克隆抗体人源化。

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摘要

Two murine monoclonal antibodies, N901 (anti-CD56) and anti-B4 (anti-CD19), were humanized by a process we call "resurfacing." A systematic analysis of known antibody structures has been used to determine the relative solvent accessibility distributions of amino acid residues in murine and human antibody variable (Fv) regions and has shown that the sequence alignment positions of surface amino acids for human and murine variable region heavy (VH) and light (VL) chains are conserved with 98% fidelity across species. While the amino acid usage at these surface positions creates surface residue patterns that are conserved within species, there are no identical patterns across species. However, surprisingly few amino acid changes need to be made to convert a murine Fv surface pattern to that characteristic of a human surface. Resurfacing was used to change the patterns of surface accessible residues in the Fv regions of the N901 and anti-B4 antibodies to resemble those found on the Fv regions of human antibody sequences. Two different procedures for selecting a human sequence were compared. For anti-B4, a data base of clonally derived human VL-VH sequence pairs was used, while for N901, sequences for VL and VH were independently selected from the Kabat et al. data base [Kabat, E. A., Wu, T. T., Reid-Miller, M., Perry, H. M. & Gottesman, K. S. (1991) Sequences of Proteins of Immunological Interest (DHHS, Washington, DC), 5th Ed.]. Resurfaced N901 and anti-B4 antibodies had apparent affinities for their cell surface ligands that were identical to those of their respective parent murine antibodies. These data provide evidence that, despite the differences in the surfaces of mouse and human Fv regions, it is possible to substitute one for the other while retaining full antigen binding affinity.
机译：两种鼠类单克隆抗体N901（抗CD56）和抗B4（抗CD19）通过我们称为“重铺表面”的过程被人源化。对已知抗体结构的系统分析已用于确定鼠和人抗体可变区（Fv）区域中氨基酸残基的相对溶剂可及性分布，并表明人和鼠可变区重链的表面氨基酸序列比对位置（VH）和轻（VL）链在物种间的保真度为98％。虽然在这些表面位置使用氨基酸会产生物种内保守的表面残基模式，但物种间没有相同的模式。然而，出乎意料的是，几乎不需要进行氨基酸改变就可以将鼠的Fv表面图案转化为人的表面特征。重铺表面用于改变N901和抗B4抗体Fv区表面可及残基的模式，类似于在人抗体序列Fv区发现的残基。比较了选择人序列的两种不同方法。对于抗B4，使用克隆来源的人VL-VH序列对的数据库，而对于N901，VL和VH的序列独立地选自Kabat等。数据库[Kabat，E. A.，Wu，T. T.，Reid-Miller，M.，Perry，H.M.＆Gottesman，K.S.（1991）Immunological Interest of Proteins of Immunological Interest（DHHS，Washington，DC），第5版。]。重现的N901和抗B4抗体对其细胞表面配体的表观亲和力与其各自亲本鼠抗体的亲和力相同。这些数据提供了证据，尽管小鼠和人Fv区的表面有所不同，但有可能在保持完整的抗原结合亲和力的同时用另一种替代。

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