Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease
Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease
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DOI：
10.1021/acs.molpharmaceut.9b00396
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发表时间：
2019-09-01
影响因子：
4.9
通讯作者：
Gentry, Matthew S.
中科院分区：
文献类型：
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作者：
Austin, Grant L.;Simmons, Zoe R.;Gentry, Matthew S.
拉福拉病(LD)是一种致命的青少年癫痫，其特征是聚集了称为拉福拉小体(Lbs)的异常葡聚糖聚集体。将基于蛋白质的疗法输送到中枢神经系统(CNS)以清除LBS在该领域仍然是一个独特的挑战。最近，来源于小鼠系统性红斑狼疮DNA自身抗体(3E10)的人源化抗原结合片段(HFab)被证明可以介导细胞穿透，并被认为是一种广泛适用的载体来介导细胞靶向和摄取。我们报道了由3E10hFab和人胰腺α-淀粉酶组成的抗体-酶融合蛋白Val-0417在LD小鼠模型中的疗效和中枢神经系统递送的研究。已经建立了一种酶联免疫吸附试验来检测治疗后的Val-0417，作为一种传递有效性的衡量标准。我们展示了融合蛋白在多种组织类型中的稳健和灵敏的检测。利用这种方法，我们测量了不同给药方式下的生物分布。我们发现，与鞘内给药相比，脑室内给药提供了强大的中枢神经系统递送。这些数据定义了治疗LD的VAL-0417翻译管道中的关键步骤。
Lafora disease (LD) is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called Lafora bodies (LBs). Delivery of protein-based therapeutics to the central nervous system (CNS) for the clearance of LBs remains a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on the efficacy and CNS delivery of VAL- 0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic a-amylase, in a mouse model of LD. An enzyme-linked immunosorbent assay has been developed to detect VAL-0417 post-treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using this method, we measured biodistribution in different methods of delivery. We found that intracerebroventricular administration provided robust CNS delivery when compared to intrathecal administration. These data define critical steps in the translational pipeline of VAL-0417 for the treatment of LD.