Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, 27100 Pavia, Italy.
Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK.
Sci Rep. 2017 Apr 21;7:46711. doi: 10.1038/srep46711.
Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β-microglobulin knock out mice, the D76N β-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis.
系统性淀粉样变性是由体内球蛋白蛋白的错误折叠和聚集引起的，迫切需要有效的治疗方法。抑制蛋白质自聚集代表了一种有吸引力的治疗策略。对引起遗传性系统性淀粉样变性的β-微球蛋白 D76N 变异体的研究变得尤为重要，因为在生理相关条件下体外形成了纤维。在这里，我们比较了两种先前描述的野生型β-微球蛋白纤维形成抑制剂强力霉素和单域抗体（纳米抗体）的效力。β-微球蛋白结合纳米抗体 Nb24 比强力霉素更有效地抑制 D76N β-微球蛋白纤维形成，完全阻止了纤维的形成。在β-微球蛋白敲除小鼠中，D76N β-微球蛋白/Nb24 预先形成的复合物以与未复合蛋白相同的速度从循环中清除; 然而，组织分布的分析表明，与抗体的相互作用降低了心脏中变异蛋白的浓度，但不改变野生型β-微球蛋白的组织分布。这些发现强烈支持该抗体在系统性淀粉样变性治疗中的潜在治疗用途。
