Exploring How Antibody Format Drives Clearance from the Brain

• Published in: Molecular pharmaceutics Vol. 21; no. 9; pp. 4416 - 4429
• Main Authors: Schwinghamer, Kelly, Kopec, Brian M., Ayewoh, Ebehiremen, Tao, Xun, Sadekar, Shraddha, Sreedhara, Alavattam, Kelley, Robert F., Tesar, Devin B., Siahaan, Teruna J.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02-09-2024
• Subjects: blood-brain barrier; antibody clearance; and hyaluronic binding; FcRn; pharmacokinetics; intracerebroventricular; antibody brain delivery; blood-brain barrier modulator; central nervous system
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.4c00354

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.