Crespi Gabriela A N, Hermans Stefan J, Parker Michael W, Miles Luke A
ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
1] ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia [2] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
Sci Rep. 2015 Apr 16;5:9649. doi: 10.1038/srep09649.
Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å(2) buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core. The conformation of Aβ captured is an intermediate between observed sheet and helical forms with intramolecular hydrogen bonds stabilising residues 20-26 in a helical conformation. Remarkably, Aβ-binding residues are almost perfectly conserved in crenezumab. The structure explains the observed shared cross reactivity of solanezumab and crenezumab with proteins abundant in plasma that exhibit this Phe-Phe dipeptide.
索拉珠单抗（礼来公司）和克奈珠单抗（基因泰克公司）是针对淀粉样β蛋白（Aβ）的主要临床抗体，正在多项III期临床试验中进行测试，用于预防有患病风险个体的阿尔茨海默病。本文通过首次报道的Aβ中部区域Aβ - 抗Aβ复合物晶体结构，对这些临床抗体捕获Aβ的机制进行了解释。索拉珠单抗可容纳一个较大的Aβ表位（16至26位残基上有960 Å(2)的掩埋界面），该表位与抗体形成广泛的接触和氢键，主要通过Aβ主链原子以及一个深埋的苯丙氨酸 - 苯丙氨酸二肽核心。捕获的Aβ构象是观察到的β折叠和螺旋形式之间的一种中间态，分子内氢键使20 - 26位残基稳定在螺旋构象中。值得注意的是，Aβ结合残基在克奈珠单抗中几乎完全保守。该结构解释了索拉珠单抗和克奈珠单抗与血浆中富含这种苯丙氨酸 - 苯丙氨酸二肽的蛋白质所观察到的共同交叉反应性。
