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Isolation of blood-brain barrier-crossing antibodies from a phage display library
by competitive elution and their ability to penetrate the central nervous system
#MMPMID29182455
Thom G
; Hatcher J
; Hearn A
; Paterson J
; Rodrigo N
; Beljean A
; Gurrell I
; Webster C
MAbs
2018[Feb]; 10
(2
): 304-314
PMID29182455
show ga
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.
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