单克隆抗体
间隙
血脑屏障
药代动力学
透明质酸
中枢神经系统
新生儿Fc受体
药理学
抗体
渗透(战争)
化学
医学
免疫球蛋白G
免疫学
内科学
泌尿科
解剖
运筹学
工程类
作者
Kelly Schwinghamer,Brian M. Kopec,Ebehiremen Ayewoh,Xun Tao,Shraddha Sadekar,Alavattam Sreedhara,Robert F. Kelley,Devin B. Tesar,Teruna J. Siahaan
标识
DOI:10.1021/acs.molpharmaceut.4c00354
摘要
Monoclonal antibodies (mAbs) have high binding specificity and affinity, making them attractive for treating brain diseases. However, their effectiveness is limited by poor blood-brain barrier (BBB) penetration and rapid central nervous system (CNS) clearance. Our group identified blood-brain barrier modulator (BBBM) peptides that improved mAb penetration across the BBB into the brain. In this study, we investigated the pharmacokinetics of a mAb delivered to the brain using BBBMs after intravenous (IV) administration and explored the impact of antibody format (size, neonatal Fc receptor (FcRn) binding, hyaluronic acid binding) on brain clearance following direct injection into the central nervous system (CNS) via intracerebroventricular (ICV) injection. IRDye800CW-labeled antibodies were administered into C57BL/6 mice via ICV or IV injection, and organ concentrations were measured after various time points. When a mAb was coadministered with a BBBM peptide, the permeation of mAb across the BBB was increased compared to mAb alone at early time points; however, the mAb was cleared within 2 h from the brain. ICV experiments revealed that an antibody Fab fragment had a higher brain exposure than a mAb, and that a Fab fused to a hyaluronic acid binding domain (Fab-VG1) showed remarkable improvement in brain exposure. These findings suggest that BBBMs and antibody format optimization may be promising strategies for enhancing brain retention of therapeutic antibodies.
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