Nanomolecular HLA-DR10 Antibody Mimics: A Potent System for Molecular Targeted Therapy and Imaging
Nanomolecular HLA-DR10 Antibody Mimics: A Potent System for Molecular Targeted Therapy and Imaging
复制标题
DOI：
10.1089/cbr.2008.0589
复制
发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Balhorn, Rod
中科院分区：
文献类型：
--
作者：
DeNardo, Gerald L.;Natarajan, Arutselvan;Balhorn, Rod
为了模拟单克隆抗体（mAb）结合的分子特异性和细胞选择性，同时减小尺寸，基于计算机模拟，已经创建了纳米分子（选择性高亲和力配体; SHAL）以结合人白细胞抗原-DR（HLA-DR 10），这是一种在来自霍奇金淋巴瘤和慢性淋巴细胞白血病的恶性B淋巴细胞上上调的信号受体蛋白。用生物素或DOTA螯合物（1，4，7，10-四氮杂环十二烷-N，N ′，N ″，N ″-四乙酸）合成SHAL，使用固相赖氨酸-聚乙二醇骨架连接先前显示与HLA-DR 10结合的配体组。使用细胞结合和死亡测定和共聚焦显微镜，SHAL摄取，残留，和杀细胞活性进行了评估，在HLA-DR 10表达和非表达的活，人淋巴瘤细胞系。所有测试的SHAL对表达细胞都是选择性的，并且在表达细胞中积累。具有Ct配体（3-（2-（[3-氯-5-5-三氟甲基）-2-吡啶基]氧）-苯胺基）-3-氧代丙离子酸）的SHAL在表达细胞中的残留量比细胞表面膜HLA-DR 10的残留量高出179倍，反映了与细胞内HLA-DR 10的结合。共聚焦显微镜证实了这些SHAL的细胞内残留。重要的是，具有Ct配体的SHAL具有直接的杀细胞活性，与Lym-1 mAb和利妥昔单抗的效力相似，选择性地针对表达HLA-DR 10的淋巴瘤细胞和异种移植物。结果表明，含有Ct配体的SHAL在细胞内残留，并具有HLA-DR 10介导的细胞杀伤作用。这些SHAL具有非凡的潜力，作为新的分子选择性靶向淋巴瘤和白血病的分子治疗和成像。此外，这些SHAL可用于在这些恶性细胞内的关键部位附近转运和残留细胞毒性剂。
To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes from of Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesize with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N.N',N '',N'"-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3- oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show, that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.