Selective Uptake of Macromolecules to the Brain in Microfluidics and Animal Models Using the HAVN1 Peptide as a Blood-Brain Barrier Modulator.

Autor: Schwinghamer K; Department of Pharmaceutical Chemistry, The University of Kansas, 2093 Constant Avenue, Lawrence, Kansas 66047, United States., Line S; Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada., Tesar DB; Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States., Miller DW; Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada., Sreedhara A; Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States., Siahaan TJ; Department of Pharmaceutical Chemistry, The University of Kansas, 2093 Constant Avenue, Lawrence, Kansas 66047, United States.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2024 Apr 01; Vol. 21 (4), pp. 1639-1652. Date of Electronic Publication: 2024 Feb 23.
DOI: 10.1021/acs.molpharmaceut.3c00775
Abstrakt: Monoclonal antibodies (mAbs) possess favorable pharmacokinetic properties, high binding specificity and affinity, and minimal off-target effects, making them promising therapeutic agents for central nervous system (CNS) disorders. However, their development as effective therapeutic and diagnostic agents for brain disorders is hindered by their limited ability to efficiently penetrate the blood-brain barrier (BBB). Therefore, it is crucial to develop efficient delivery methods that enhance the penetration of antibodies into the brain. Previous studies have demonstrated the potential of cadherin-derived peptides (i.e., ADTC5, HAVN1 peptides) as BBB modulators (BBBMs) to increase paracellular porosities for penetration of molecules across the BBB. Here, we test the effectiveness of the leading BBBM peptide, HAVN1 (Cyclo(1,6)SHAVSS), in enhancing the permeation of various monoclonal antibodies through the BBB using both in vitro and in vivo systems. In vitro, HAVN1 has been shown to increase the permeability of fluorescently labeled macromolecules, such as a 70 kDa dextran, 50 kDa Fab1, and 150 kDa mAb1, by 4- to 9-fold in a three-dimensional blood-brain barrier (3D-BBB) microfluidics model using a human BBB endothelial cell line (i.e., hCMEC/D3). HAVN1 was selective in modulating the BBB endothelial cell, compared to the pulmonary vascular endothelial (PVE) cell barrier. Co-administration of HAVN1 significantly improved brain depositions of mAb1, mAb2, and Fab1 in C57BL/6 mice after 15 min in the systemic circulation. Furthermore, HAVN1 still significantly enhanced brain deposition of mAb2 when it was administered 24 h after the administration of the mAb. Lastly, we observed that multiple doses of HAVN1 may have a cumulative effect on the brain deposition of mAb2 within a 24-h period. These findings offer promising insights into optimizing HAVN1 and mAb dosing regimens to control or modulate mAb brain deposition for achieving desired mAb dose in the brain to provide its therapeutic effects.
Databáze: MEDLINE