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Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo
- Source :
- FASEB J
- Publication Year :
- 2020
-
Abstract
- Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood-tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site-specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM-1 (CD31) and ICAM-1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post-injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding-detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one-to-one protein conjugates. Bivalent mAb-TM was superior to monovalent scFv-TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end-to-end anti-ICAM mAb-TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.
- Subjects :
- 0301 basic medicine
Biodistribution
Endothelium
medicine.drug_class
Pharmacology
Thrombomodulin
Monoclonal antibody
Ligands
Biochemistry
Article
03 medical and health sciences
0302 clinical medicine
Drug Delivery Systems
Pharmacokinetics
In vivo
Genetics
medicine
Animals
Humans
Tissue Distribution
Molecular Biology
Lung
ICAM-1
Chemistry
Antibodies, Monoclonal
Endothelial Cells
Intercellular Adhesion Molecule-1
Platelet Endothelial Cell Adhesion Molecule-1
030104 developmental biology
medicine.anatomical_structure
Targeted drug delivery
Endothelium, Vascular
030217 neurology & neurosurgery
Biotechnology
Single-Chain Antibodies
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- FASEB J
- Accession number :
- edsair.doi.dedup.....5b9896ce16430b1c4fb810ee359a96fa