Binding agents and uses thereof for central nervous system delivery
View Patent ↗Disclosed herein are binding agents, conjugates, and extracellular vesicles that enhance penetration of the blood brain barrier. Uses thereof for delivery of agents, e.g., therapeutic agents, to the central nervous system are also provided.
1 . An extracellular vesicle (EV) comprising a first exogenous binding agent that specifically binds to Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3).
2 . The EV of claim 1 , wherein:
the first exogenous binding agent enhances transport of the EV across the blood brain barrier; and/or
the EV comprises one or more further exogenous binding agents.
3 . The EV of claim 1 , wherein the EV comprises a second the exogenous binding agent specifically binds to an endothelial cell protein selected from the group consisting of ARHGEF18, ASB12, BAD, DCAF12L1, ECHS1, GORASP2, GPHA2, GRID2IP, HOXD4, KCNT2, LIPJ, MESDC2, MTHFS, OCM, OR4X2, SCLT1, SERACI, SHOC2, SPRYD3, STAG1, TMED10, TRIM67, TTLL7, VLDLR, SFT2D2, CD74, HLA-DOA, ZP2, IFNLR1, HTR6, GPR37L1, MCHR2, CD164, B3GAT1-modified protein, and ST8SIA3-modified protein.
4 . The EV of claim 1 , wherein the exogenous binding agent is an antibody, or an antigen binding portion thereof, optionally wherein the antibody, or antigen-binding portion thereof, is:
an antibody fragment selected from the group consisting of a Fab, a F(ab′)2, an scFv, a tandem scFv, a diabody, a minibody, and a single domain antibody;
a humanized antibody, or an antigen binding portion thereof; and/or
a fully human antibody, or an antigen binding portion thereof.
5 . The EV of claim 1 , wherein the exogenous binding agent is a polypeptide ligand or an aptamer.
6 . The EV of claim 1 , wherein the EV:
is about 20 nm to about 250 nm in size;
is an exosome;
is a microvesicle;
is derived from a primary cell, a transformed cell, a stem/progenitor cell, a neural cell, a muscle cell, an immune cell, an adipose cell, or a tumor cell, optionally wherein:
the neural cell is an astrocyte, an oligodendrocyte, a neuron, or a glial cell;
the immune cell is a microglial cell or a dendritic cell; or
the stem/progenitor cell is an embryonic stem cell or an induced pluripotent stem cell, a neural progenitor cell, a neural stem cell, or a mesenchymal stem cell;
is derived from a cultured cell line, optionally wherein the cultured cell line is a CHO cell line, a HEK293 cell line, or a Vero cell line; and/or
is derived from cells that recombinantly express the exogenous binding agent.
7 . The EV of claim 1 , wherein the EV further comprises a small molecule, an exogenous nucleic acid, and/or an exogenous polypeptide, optionally wherein the exogenous nucleic acid is a siRNA, a shRNA, an antisense RNA, a miRNA, or a combination thereof.
8 . A pharmaceutical composition comprising a therapeutically effective amount of the EV of claim 1 , and a pharmaceutically acceptable carrier.
9 . A method of delivering an EV across the blood brain barrier of a subject, comprising administering to the subject a composition comprising the EV of claim 1 , or a pharmaceutical composition comprising a therapeutically effective amount of the EV of claim 1 .
10 . The method of claim 9 , wherein:
the composition is administered intravenously, intraarterially, intranasally, orally, intramuscularly, intrathecally, intraocularly, intradermally, intracranially, subcutaneously, or by inhalation; and/or
the EV is delivered to the brain or the central nervous system of the subject.