Homogeneous antibody-angiopep 2 conjugates for effective brain targeting.
Homogeneous antibody-angiopep 2 conjugates for effective brain targeting.
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DOI：
10.1039/d1ra08131d
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发表时间：
2022-01-24
期刊：
影响因子：
3.9
通讯作者：
Tsuchikama K
中科院分区：
文献类型：
--
作者：
Anami Y;Xiong W;Yamaguchi A;Yamazaki CM;Zhang N;An Z;Tsuchikama K
基于抗体的疗法在治疗包括癌症在内的许多疾病方面取得了巨大成功。虽然抗体和抗体-药物缀合物（ADC）也已经针对中枢神经系统（CNS）病症以及脑肿瘤进行了评估，但是由于穿过血脑屏障（BBB）的低渗透性，它们的治疗功效可能基本上受到限制。因此，改善治疗性抗体的BBB渗透性对于将该药物类别确立为CNS疾病的可靠临床选择至关重要。在这里，我们报告说，与传统的异质性缀合相比，合成的血脑屏障穿梭肽血管肽-2（Ang 2）的单克隆抗体（mAb）的同质性缀合提供了改善的体外脑微血管内皮细胞的结合亲和力和体内正常脑组织的积累。在小鼠模型中，我们还证明了静脉内施用的均质抗EGFR mAb-Ang 2缀合物在颅内肿瘤中有效蓄积。这些发现表明，BBB穿梭肽如Ang 2的均质缀合是增强抗体药剂对CNS疾病的治疗功效的有前景的方法。血管肽素-2与单克隆抗体的均匀缀合改善了对脑微血管内皮细胞的结合亲和力，并通过BBB累积到脑组织和肿瘤中。
Antibody-based therapy has shown great success in the treatment of many diseases, including cancers. While antibodies and antibody–drug conjugates (ADCs) have also been evaluated for central nervous system (CNS) disorders as well as brain tumors, their therapeutic efficacy can be substantially limited due to low permeability across the blood–brain barrier (BBB). Thus, improving BBB permeability of therapeutic antibodies is critical in establishing this drug class as a reliable clinical option for CNS diseases. Here, we report that, compared with a conventional heterogeneous conjugation, homogeneous conjugation of the synthetic BBB shuttle peptide angiopep-2 (Ang2) to a monoclonal antibody (mAb) provides improved binding affinity for brain microvascular endothelial cells in vitro and accumulation into normal brain tissues in vivo. In a mouse model, we also demonstrate that the homogeneous anti-EGFR mAb–Ang2 conjugate administered intravenously efficiently accumulates in intracranial tumors. These findings suggest that homogeneous conjugation of BBB shuttle peptides such as Ang2 is a promising approach to enhancing the therapeutic efficacy of antibody agents for CNS diseases. Homogeneous conjugation of angiopep-2 to a monoclonal antibody improves binding affinity for brain microvascular endothelial cells and accumulation into brain tissues and tumors across the BBB.
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影响因子：
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通讯作者：
Tsuchikama K