Differential tumor-targeting abilities of three single-domain antibody formats
Differential tumor-targeting abilities of three single-domain antibody formats
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DOI：
10.1016/j.canlet.2009.08.003
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发表时间：
2010-03-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Jianbing
中科院分区：
文献类型：
--
作者：
Bell, Andrea;Wang, Zheng J.;Zhang, Jianbing
抗体药物的大分子尺寸被认为是阻止它们成为更有效的治疗剂的一个主要因素。重链抗体可变区（HCAb）或单域抗体（sdAb）由于其分子大小和增强的稳定性，是较小抗体的理想构建块。在寻找用于癌症的体内成像和/或治疗的更好的抗体形式中，构建、表征和测试了三种类型的针对表皮生长因子受体（埃格）的基于sdAb的分子。从用EGFR变体免疫的美洲驼的sdAb库构建的噬菌体展示文库中分离11种sdAb。通过将sdAb之一EG 2与五聚化蛋白结构域融合来构建五聚sdAb或五体V2 C-EG 2。通过将EG 2与人IgG 1的可结晶片段（Fc）融合，构建嵌合HCAb（cHCAb）EG 2-hFc。静脉注射后，EG 2和V2 C-EG 2主要定位于肾脏。注射后，EG 2-hFc表现出优异的肿瘤蓄积，这主要归因于其与IgG相当的长血清半衰期。中等大小（类似于80 kDa）和完整的人Fc使HCAb成为独特的抗体形式，其作为成像和治疗试剂的性能可能优于全IgG。皇冠版权所有（C）2009由爱思唯尔爱尔兰有限公司出版。保留所有权利。
The large molecular size of antibody drugs is considered one major factor preventing them from becoming more efficient therapeutics. Variable regions of heavy chain antibodies (HCAbs), or single-domain antibodies (sdAbs), are ideal building blocks for smaller antibodies due to their molecular size and enhanced stability. In the search for better antibody formats for in vivo imaging and/or therapy of cancer, three types of sdAb-based molecules directed against epidermal growth factor receptor (EGER) were constructed, characterized and tested. Eleven sdAbs were isolated from a phage display library constructed from the sdAb repertoire of a llama immunized with a variant of EGFR. A pentameric sdAb, or pentabody, V2C-EG2 was constructed by fusing one of the sdAbs, EG2, to a pentamerization protein domain. A chimeric HCAb (cHCAb), EG2-hFc, was constructed by fusing EG2 to the fragment crystallizable (Fc) of human IgG1. Whereas EG2 and V2C-EG2 localized mainly in the kidneys after iv. injection, EG2-hFc exhibited excellent tumor accumulation, and this was largely attributed to its long serum half life, which is comparable to that of IgGs. The moderate size (similar to 80 kDa) and intact human Fc make HCAbs a unique antibody format which may outperform whole IgGs as imaging and therapeutic reagents. Crown Copyright (C) 2009 Published by Elsevier Ireland Ltd. All rights reserved.