Antibody molecules and peptide delivery systems for use in alzheimer's disease and related disorders
Inventors
Volker Côrte-Real, Sofia • SANTOS NEVES, Vera Luísa • CORREIA CANHÃO, Pedro Manuel • FLEMING OUTEIRO, Tiago • RICO BOTAS CASTANHO, Miguel Augusto • Castanheira Aires da Silva, Frederico Nuno • Santiago de Oliveira, Soraia Rafaela
Assignees
Technophage Investigacao e Desenvolvimento em Biotecnologia SA
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10654917-B2
Publication Date
2020-05-19
Expiration Date
Abstract
The present invention relates to antibody molecules and peptide delivery systems for use in the treatment and management of Alzheimer's disease and related disorders. In particular, the antibody molecules preferentially bind oligomeric forms of beta-amyloid peptide, in single domain format, and the peptide delivery systems facilitate specific transport of such antibody molecules, as well as other cargo molecules, across the blood-brain barrier. The invention also relates to constructs of the antibody molecules and the delivery peptides, as well as pharmaceutical compositions comprising effective amounts of the antibody molecules, delivery peptides, and/or their constructs, including humanized versions of the antibody molecules and constructs. The invention further relates to methods of making these products and pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions in treating or preventing Alzheimer's and related disorders, such as those involving accumulation of beta-amyloid peptide or other peptides that aggregate in the brain; as well as to methods and kits for diagnosing these disorders.
Core Innovation
The invention relates to an antibody molecule and delivery fusion protein associated with delivery across the blood brain barrier. In particular, the antibody molecule comprises immunospecificity to oligomeric form of beta-amyloid peptide 42 (BAP42) and/or to monomeric BAP42 while lacking immunospecificity to fibrillar BAP42. The antibody further comprises a single domain antibody that is a rabbit light chain variable domain (VL) having at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1-21, or a humanized form thereof.
The invention further provides delivery fusion proteins that facilitate specific delivery of a cargo molecule across the blood brain barrier. A hydrophobic fragment of the amino acid sequence SEQ ID NO: 22 or 24 is used in association with the cargo molecule, wherein the cargo molecule is at least one selected from the group consisting of an antibody molecule and a heterologous polypeptide. The delivery fusion protein thereby allows specific delivery across the blood brain barrier of a subject.
The invention also encompasses methods and compositions for Alzheimer’s treatment/diagnosis using the above antibodies and BBB-delivery constructs. It includes antibody-peptide constructs that comprise specific BBB crossing and improved brain washout, as well as pharmaceutical compositions, polynucleotides/vectors/host cells, and diagnostic/imaging methods and kits. Test samples can include cerebrospinal fluid and serum, and diagnostic workflows can include immunoassays and imaging using labeled components.
Claims Coverage
The provided portion includes three independent claims. Across these claims, the main inventive features are BBB-specific delivery using a hydrophobic fragment (SEQ ID NO: 22 or 24) associated with a cargo molecule, and an antibody with immunospecificity to oligomeric/monomeric BAP42 while not binding fibrillar BAP42, implemented as a rabbit VL single domain with defined sequence options.
Hydrophobic-fragment delivery fusion enabling BBB crossing
A delivery fusion protein comprising a hydrophobic fragment of the amino acid sequence SEQ ID NO: 22 or 24, and a cargo molecule in association with said hydrophobic fragment, wherein said cargo molecule is at least one selected from the group consisting of an antibody molecule and a heterologous polypeptide, and wherein said delivery fusion protein facilitates specific delivery of said cargo molecule across the blood brain barrier of said subject.
Method for specifically delivering a cargo across the blood brain barrier
A method for specifically delivering a cargo molecule across the blood brain barrier of a subject, said method comprising administering to said subject a hydrophobic fragment of the amino acid sequence SEQ ID NO: 22 or 24, wherein said fragment is in association with said cargo molecule, thereby allowing specific delivery of said cargo molecule across the blood brain barrier of said subject.
Rabbit single-domain antibody immunospecific to non-fibrillar BAP42
An antibody molecule, said molecule having immunospecificity to at least one oligomeric form of beta-amyloid peptide 42 (BAP42) and/or to monomeric BAP42, wherein said molecule does not have immunospecificity to fibrillar BAP42; and wherein said molecule comprises a single domain antibody that is a rabbit light chain variable domain (VL) having at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1-21, or a humanized form thereof.
Overall, the independent claims cover BBB-specific delivery fusion proteins using hydrophobic fragments defined by SEQ ID NO: 22 or 24 associated with an antibody or heterologous polypeptide cargo, a corresponding method of administering such fragments to enable BBB delivery, and an antibody molecule with immunospecificity to oligomeric/monomeric BAP42 but not to fibrillar BAP42, implemented as a rabbit VL single domain with defined SEQ ID NO: 1-21 or humanized forms.
Stated Advantages
Facilitates specific delivery of the cargo molecule across the blood brain barrier.
Lacks immunospecificity to fibrillar BAP42 while maintaining immunospecificity to oligomeric and/or monomeric BAP42.
Improved brain washout.
Documented Applications
Alzheimer’s treatment/diagnosis using antibodies and BBB-delivery constructs.
Diagnostic/imaging methods using test samples including cerebrospinal fluid and serum.
CSF human diagnosis using an immunoassay with BIAcore.
In vivo imaging using radiolabeled sdAb-pep constructs (SPECT).
Pre-clinical application in 5×FAD transgenic mice with reduced plaque burden using antibody-peptide constructs.
In vitro BBB model use with a bEnd3 transwell system to support BBB translocation/internalization.
Diagnostic/biomarker detection workflow described as detecting aggregation-prone BAP42 peptide in a subject by contacting an antibody with cerebrospinal fluid or serum and detecting binding.
Interested in licensing this patent?