Novel Antibody for the Treatment of Transthyretin Amyloidosis
Novel Antibody for the Treatment of Transthyretin Amyloidosis
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DOI：
10.1074/jbc.m116.738138
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发表时间：
2016-11-25
影响因子：
4.8
通讯作者：
Ando, Yukio
中科院分区：
文献类型：
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作者：
Hosoi, Akihiko;Su, Yu;Ando, Yukio
家族性淀粉样变性多神经病变（FAP）是一种主要由淀粉样变性甲状腺素（ATTR）引起的系统性淀粉样变性。这种不治之症在发病后10年左右会导致死亡。虽然人们普遍认为转甲状腺素（TTR）单体形式的构象变化对淀粉样蛋白在器官中的形成和沉积非常重要，但目前尚无针对这一步骤的有效治疗方法。在这项研究中，我们产生了一种小鼠单克隆抗体T24，它可以识别构象改变的TTR的隐表位。T24抑制FAP模型大鼠的TTR积累，使其在各组织中表达人ATTR V30M，并在胃肠道中表现出非纤原性的ATTR沉积。此外，人源化T24 （RT24）抑制TTR纤颤，促进巨噬细胞吞噬聚集的TTR。该抗体不能识别正常血清中TTR在血液中的正常功能。这些结果表明RT24可能是一种有效的新型FAP治疗抗体。
Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death similar to 10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very important for amyloid formation and deposition in the organs, no effective therapy targeting this step is available. In this study, we generated a mouse monoclonal antibody, T24, that recognized the cryptic epitope of conformationally changed TTR. T24 inhibited TTR accumulation in FAP model rats, which expressed human ATTR V30M in various tissues and exhibited non-fibrillar deposits of ATTR in the gastrointestinal tracts. Additionally, humanized T24 (RT24) inhibited TTR fibrillation and promoted macrophage phagocytosis of aggregated TTR. This antibody did not recognize normal serum TTR functioning properly in the blood. These results demonstrate that RT24 would be an effective novel therapeutic antibody for FAP.