Data Sheet 1_Hereditary angioedema plasma proteomics following specific plasma kallikrein inhibition with lanadelumab.docx

IntroductionPlasma proteomics analyses were performed to identify novel disease state biomarkers of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) and investigate the biological consequences of specific plasma kallikrein inhibition with lanadelumab.
MethodsAffinity proteomic analyses were performed using plasma from healthy controls (n=30) and patients with HAE-C1INH before (baseline, n=125) and after 6 months of treatment with lanadelumab (300 mg every 2 weeks, n=112) using the SomaScan platform.
ResultsRelative plasma levels for several proteins differed significantly between controls and patients with HAE-C1INH, and between matched baseline and post-treatment samples from patients with HAE-C1INH. As expected, C1 inhibitor and complement C4 were significantly lower (P<1.10e-39 false discovery rate [fdr], P<6.6e-25 fdr, respectively) in HAE-C1INH baseline plasma versus controls. Cleaved high-molecular-weight kininogen, a biomarker of excess kallikrein-kinin system (KKS) activation, was higher in HAE-C1INH baseline plasma versus controls (P<6.7e-6 fdr) and was reduced in HAE-C1INH plasma after lanadelumab treatment. Of 1041 identified proteins that differed significantly (P<0.05) from controls and HAE-C1INH baseline plasma, 120 proteins were no longer different between controls and patients with HAE-C1INH after 6 months of lanadelumab treatment. Canonical pathway and local network analyses of HAE-C1INH plasma proteomics suggest dysregulation in KKS, coagulation, cell adhesion, and connective tissue degradation that approach that of healthy controls following treatment with lanadelumab.
ConclusionProteomic analyses of plasma from patients with HAE-C1INH before and after treatment with lanadelumab compared with healthy controls confirmed known HAE-C1INH biomarkers and identified additional potential biomarkers of plasma kallikrein dysregulation for further investigation.

【引言】本研究开展血浆蛋白质组学分析，旨在鉴定C1抑制物缺陷型遗传性血管性水肿（hereditary angioedema due to C1 inhibitor deficiency, HAE-C1INH）新型疾病状态生物标志物，并探究拉奈芦单抗（lanadelumab）特异性抑制血浆激肽释放酶的生物学效应。
【方法】本研究采用SomaScan检测平台，以健康对照者（n=30）、HAE-C1INH患者基线状态（未接受治疗，n=125）及接受拉奈芦单抗（lanadelumab）治疗6个月后（每2周给药300mg，n=112）的血浆样本为研究对象，开展亲和蛋白质组学分析。
【结果】健康对照者与HAE-C1INH患者之间，以及HAE-C1INH患者配对的基线与治疗后血浆样本之间，多种蛋白质的相对血浆水平均存在显著差异。正如预期，HAE-C1INH患者基线血浆中的C1抑制物与补体C4水平显著低于健康对照者（错误发现率[false discovery rate, fdr]分别为P<1.10×10^-39、P<6.6×10^-25）。裂解型高分子量激肽原——激肽释放酶-激肽系统（kallikrein-kinin system, KKS）过度激活的生物标志物——在HAE-C1INH患者基线血浆中的水平高于健康对照者（P<6.7×10^-6 fdr），且经拉奈芦单抗治疗后该蛋白水平有所降低。在1041种与健康对照者及HAE-C1INH患者基线血浆存在显著差异（P<0.05）的已鉴定蛋白质中，有120种蛋白质在接受6个月拉奈芦单抗治疗后，其在HAE-C1INH患者血浆与健康对照者之间的差异不再显著。对HAE-C1INH患者血浆蛋白质组进行的经典通路与局部网络分析显示，激肽释放酶-激肽系统、凝血、细胞黏附及结缔组织降解相关通路的失调状态，经拉奈芦单抗治疗后可接近健康对照者水平。
【结论】本研究通过对比健康对照者、HAE-C1INH患者接受拉奈芦单抗治疗前后的血浆蛋白质组，验证了已知的HAE-C1INH生物标志物，并鉴定出额外的血浆激肽释放酶失调潜在生物标志物，以供后续研究。