Brain delivery protein
Inventors
Lannfelt, Lars • Sehlin, Dag • HULTQVIST, Greta • SYVÄNEN, Stina
Assignees
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Publication Number
US-11498974-B2
Publication Date
2022-11-15
Expiration Date
Abstract
The present invention relates to a brain delivery protein, comprising a target binding antibody which binds to a target in a mammalian brain; two carrier moieties, each of which being capable of monovalent interaction with a protein expressed on a blood brain barrier (BBB) endothelial cell, wherein each of said carrier moieties is linked to a C-terminal end of the target binding antibody. The present invention moreover relates to use of such brain delivery proteins in therapy or diagnosis or for research of e.g. neurodegenerative disorders, and other brain diseases.
Core Innovation
The invention relates to a brain delivery protein comprising a target binding antibody that binds to a target in a mammalian brain. The brain delivery protein further comprises two carrier moieties, each capable of monovalent interaction with a protein expressed on a blood brain barrier (BBB) endothelial cell, through one single epitope.
Each of the carrier moieties is linked to a C-terminal end of a light chain of the target binding antibody by a linker. Each linker individually consists of a peptide having an amino acid sequence consisting of 5–15 amino acid residues, supporting monovalent interaction between the brain delivery protein and the BBB endothelial cell expressed protein.
Embodiments specify selected brain targets and BBB carrier moieties. The documented examples include Aβ, including Aβ peptide/protofibrils/oligomers, with mAb158/BAN2401 and alpha-synuclein with mAb48, where radiolabeled constructs show increased brain uptake and retention.
Claims Coverage
The independent claim defines a brain delivery protein with four inventive features: a target binding antibody for a mammalian brain target, two BBB carrier moieties, monovalent interaction through one single epitope with BBB endothelial cell proteins, and two short peptide linkers of 5–15 residues linking each carrier moiety to the C-terminal end of the antibody light chain.
Monovalent BBB carrier interaction via single epitope
Two carrier moieties are each capable of monovalent interaction with a protein expressed on a blood brain barrier (BBB) endothelial cell, wherein the interaction takes place through one single epitope.
C-terminal light chain linkage of BBB carriers
Each carrier moiety is linked to a C-terminal end of a light chain of the target binding antibody by a linker.
Short peptide linkers enabling monovalent interaction
Each linker individually consists of a peptide having an amino acid sequence consisting of 5–15 amino acid residues, thereby enabling monovalent interaction of the brain delivery protein with the BBB endothelial cell expressed protein.
Brain target binding antibody engagement
A target binding antibody binds to a target in a mammalian brain, where the brain delivery protein comprises said target binding antibody.
The core inventive concept is a brain delivery protein that combines a brain-target binding antibody with two BBB carrier moieties that engage BBB endothelial cell proteins monovalently via one single epitope, using short 5–15 residue linkers attached to the antibody light-chain C-terminus.
Stated Advantages
Enables monovalent interaction with BBB endothelial cell proteins through one single epitope, avoiding high-avidity bivalent binding to improve BBB transport.
Shows markedly increased brain uptake and retention for the documented examples.
Reduces Aβ pathology after treatment with RmAb158-scFv8D3.
Documented Applications
Diagnosis and/or detection of a neurodegenerative brain disorder in a mammal at risk or suspected of having it by administering a brain-delivery protein with a label and detecting the labeled target in the brain.
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