Department of Pharmaceutical Chemistry, The University of Kansas, 2093 Constant Ave., Lawrence, Kansas 66046, United States.
Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Mol Pharm. 2024 Sep 2;21(9):4416-4429. doi: 10.1021/acs.molpharmaceut.4c00354. Epub 2024 Jul 26.
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.
单克隆抗体（mAbs）具有高的结合特异性和亲和力，使其成为治疗脑部疾病的有吸引力的选择。然而，它们的效果受到血脑屏障（BBB）通透性差和中枢神经系统（CNS）清除速度快的限制。我们的研究小组发现了可以改善 mAb 通过血脑屏障进入大脑的通透性的血脑屏障调节剂（BBBM）肽。在这项研究中，我们研究了通过静脉（IV）给药后使用 BBBM 将 mAb 递送至大脑的药代动力学，并通过脑室内（ICV）注射直接注射到中枢神经系统（CNS）来探讨抗体形式（大小、新生儿 Fc 受体（FcRn）结合、透明质酸结合）对大脑清除的影响。IRDye800CW 标记的抗体通过 ICV 或 IV 注射给药到 C57BL/6 小鼠中，并在不同时间点测量器官浓度。当 mAb 与 BBBM 肽共同给药时，与单独使用 mAb 相比，mAb 穿过 BBB 的通透性在早期增加；然而，mAb 在 2 小时内从大脑中清除。ICV 实验表明，抗体 Fab 片段比 mAb 具有更高的大脑暴露量，并且与透明质酸结合域融合的 Fab（Fab-VG1）显示出显著改善的大脑暴露量。这些发现表明，BBBM 和抗体形式的优化可能是增强治疗性抗体在大脑中保留的有前途的策略。
