Integrin αvβ3-targeted therapy for Kaposi's sarcoma with an in vitro-evolved antibody
Integrin αvβ3-targeted therapy for Kaposi's sarcoma with an in vitro-evolved antibody
复制标题
DOI：
10.1096/fj.02-0281fje
复制
发表时间：
2002-10-01
期刊：
影响因子：
4.8
通讯作者：
Barbas, CF
中科院分区：
文献类型：
--
作者：
Rader, C;Popkov, M;Barbas, CF
在这里，我们将整合素α β 3定义为卡波西肉瘤（KS）抗体治疗的分子靶点。我们之前报道，利用一种新的噬菌体展示策略，基于设计的组合V基因文库，人源化了针对人整合素alphavbeta3的小鼠单克隆抗体LM609。在本研究中，我们利用噬菌体展示策略对抗体分子的三个互补决定区域进行顺序和平行优化，描述了人源化LM609的体外亲和力成熟。进化的Fab具有150 pM的亲和力，并通过使用新的哺乳动物表达载体转化为IgG1。由此产生的全抗体，命名为JC-7U IgG1，在裸鼠模型中被发现选择性地靶向人类KS，并在治疗相关剂量下抑制肿瘤生长。由于其高亲和力和高度的人源化，JC-7U IgG1是整合素α β 3作为分子靶点的治疗应用的优秀候选药物。特别令人感兴趣的是治疗KS、乳腺癌、黑色素瘤和其他癌症，其中整合素alphavbeta3在血管生成内皮细胞和肿瘤细胞上都表达，这将允许用一种药物双重抗血管生成和抗肿瘤。
Here, we define integrin alphavbeta3 as a molecular target for antibody therapy for Kaposi's sarcoma (KS). We previously reported, using a new phage display strategy based on designed combinatorial V gene libraries, the humanization of mouse monoclonal antibody LM609 directed to human integrin alphavbeta3. In the present study, we describe the in vitro affinity maturation of humanized LM609 by using a phage display strategy for the sequential and parallel optimization of three complementarity determining regions of the antibody molecule. The evolved Fab had an affinity of 150 pM and was converted into IgG1 by use of a new mammalian expression vector. The resulting whole antibody, designated JC-7U IgG1, was found to selectively target human KS in a nude mouse model and inhibit tumor growth at a therapeutically relevant dose. Because of its high affinity and its high degree of humanization, JC-7U IgG1 is an excellent drug candidate for therapeutic applications that involve integrin alphavbeta3 as the molecular target. Of particular interest is therapy for KS, breast cancer, melanoma, and other cancers in which integrin alphavbeta3 is expressed on both angiogenic endothelial cells and tumor cells, which would allow a dual antiangiogenic and antitumor strike with a single drug.