Isolation of blood-brain barrier-crossing antibodies from a phage display library by competitive elution and their ability to penetrate the central nervous system
| Autor: | Natalia Rodrigo, Carl I. Webster, Ian Gurrell, Jon P. Hatcher, Arron Hearn, Judy Paterson, George Thom, Arthur Beljean |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Phage display Immunoconjugates Blood-Brain Barrier (BBB) medicine.drug_class Immunology Central nervous system Blood–brain barrier 03 medical and health sciences Mice 0302 clinical medicine Report medicine Immunology and Allergy Animals Humans Pharmacokinetic (PK) biology bEND.3 Endothelial Cells Biological Transport Human brain mechanical hyperalgesic pain model Receptor antagonist Molecular biology IL1 receptor antagonist (IL-1RA) Cell biology Rats Endothelial stem cell Mice Inbred C57BL FMAT Interleukin 1 Receptor Antagonist Protein 030104 developmental biology medicine.anatomical_structure Transcytosis Blood-Brain Barrier biology.protein Neuralgia Female Antibody Cell Surface Display Techniques 030217 neurology & neurosurgery Single-Chain Antibodies |
| Zdroj: | mAbs |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | The blood-brain barrier (BBB) is a formidable obstacle for delivery of biologic therapeutics to central nervous system (CNS) targets. Whilst the BBB prevents passage of the vast majority of molecules, it also selectively transports a wide variety of molecules required to maintain brain homeostasis. Receptor-mediated transcytosis is one example of a macromolecule transport system that is employed by cells of the BBB to supply essential proteins to the brain and which can be utilized to deliver biologic payloads, such as antibodies, across the BBB. In this study, we performed phage display selections on the mouse brain endothelial cell line, bEND.3, to enrich for antibody single-chain variable fragments (scFvs) that could compete for binding with a known BBB-crossing antibody fragment, FC5. A number of these scFvs were converted to IgGs and characterized for their ability to bind to mouse, rat and human brain endothelial cells, and subsequent ability to transport across the BBB. We demonstrated that these newly identified BBB-targeting IgGs had increased brain exposure when delivered peripherally in mice and were also able to transport a biologically active molecule, interleukin-1 receptor antagonist (IL-1RA), into the CNS. The antagonism of the interleukin-1 system within the CNS can result in the relief of neuropathic pain. We demonstrated that the BBB-targeting IgGs were able to elicit an analgesic response in a mouse model of nerve ligation-induced hypersensitivity when fused to IL-1RA. |
| Databáze: | OpenAIRE |
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