From the CRNH Ouest, INRA UMR 1280 PhAN (A.T., V.B., M.C., G.L.) and L'institut du thorax, INSERM UMR 1087, CNRS UMR 6291 (A.T., M.P., B.C.), Université de Nantes, France; L'institut du thorax, CHU de Nantes, CIC Endocrino-Nutrition, France (A.T., M.P., B.C.); Lipidology Division of Internal Medicine, University of Cape Town, South Africa (D.J.B.); INSERM UMR 1188 DéTROI, Université de La Réunion, Sainte Clotilde, France (S.R.-M., V.B., K.C., B.N., S.B., G.L.); Amgen, Thousand Oaks, CA (L.T.); CHU Dijon Bourgogne, Point Médical, France (M.F.); and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R.).
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):592-598. doi: 10.1161/ATVBAHA.117.310217. Epub 2017 Dec 28.
Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9)-neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low-density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition.
Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment.
Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab.
依洛尤单抗是一种 PCSK9（脯氨酰羧肽酶枯草溶菌素 9）中和抗体，可降低 LDLR（低密度脂蛋白受体）功能降低的纯合子家族性高胆固醇血症（HoFH）患者的 LDL-C（低密度脂蛋白胆固醇）。然而，即使是 LDLR 遗传缺陷相同的携带者，他们的个体反应也存在很大差异。我们旨在阐明为什么 HoFH 患者对 PCSK9 抑制的反应存在差异。
从参加 TAUSSIG 试验（评估基因 LDL 紊乱患者长期使用 PCSK9 抑制剂的试验）的 22 名 HoFH 患者中分离淋巴细胞。10 名患者为真正的纯合子（FH1/FH1），5 名相同的复合杂合子（FH1/FH2）。将淋巴细胞与或不与美伐他汀、重组 PCSK9（rPCSK9）或 PCSK9 中和抗体一起铺板。通过流式细胞术分析细胞表面 LDLR 的表达。对于每种治疗方式，所有 HoFH 淋巴细胞的细胞表面 LDLR 表达均低于非-FH 淋巴细胞。FH1/FH2 患者（LDLR 缺陷/阴性）的淋巴细胞显示出最低的 LDLR 表达水平，其次是 FH1/FH1 患者（缺陷/缺陷）的淋巴细胞。美伐他汀增加，而 rPCSK9 降低 LDLR 表达。PCSK9 中和抗体恢复 LDLR 表达。细胞表面 LDLR 表达水平较高的淋巴细胞来自 LDL-C 和载脂蛋白 B 水平最低的患者，分别在接受依洛尤单抗治疗 24 周之前和之后。这些负相关在 FH1/FH1 患者中仍然显著，并且当单独分析载脂蛋白 E3/E3 基因型的患者时，似乎更加明显。在依洛尤单抗治疗时，LDLR 表达水平与 LDL-C 降低百分比之间存在显著正相关。
HoFH 中残留的 LDLR 表达是 LDL-C 水平的主要决定因素，似乎决定了他们对依洛尤单抗的个体反应。
