Alpha-synuclein single domain antibodies
Inventors
Assignees
Publication Number
US-12162929-B2
Publication Date
2024-12-10
Expiration Date
2039-02-19
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Abstract
The present disclosure is directed to single domain antibodies that bind to α-synuclein and the use of these antibodies for the treatment and diagnosis of α-synucleinopathies The present disclosure is also directed to polynucleotides encoding the α-synuclein single domain antibodies, therapeutic vectors comprising these polynucleotides and methods of administering these therapeutic vectors for the treatment of α-synucleinopathies.
Core Innovation
The present invention is directed to single domain antibodies that specifically bind to α-synuclein, including their use in the treatment, diagnosis, and monitoring of α-synucleinopathies. These antibodies or their binding fragments comprise a heavy chain variable region with defined complementarity-determining regions (CDRs) such as H-CDR1: ASGSIFSIN, H-CDR2: AGISRGGRTK, and H-CDR3: NVRSFVRTY, NARSFVRTY, or AATRWSWGTKSY. The patent also discloses polynucleotides encoding these antibodies, vectors containing such polynucleotides, and pharmaceutical compositions including the antibodies or fragments thereof.
The antibodies described can be isolated, humanized, chimeric, or engineered as fusion proteins or antibody mimetics, enabling their production in host cells and expression vectors. The invention overcomes previous deficiencies in the art by providing selective and specific reagents for α-synuclein, which is a key pathological protein in diseases such as Parkinson's disease, Lewy Body Dementia, Alzheimer’s disease, and Multiple System Atrophy.
The problem being addressed is the lack of specific α-synuclein imaging probes and effective therapeutics that target pathological α-synuclein. Such deficiencies make it difficult to diagnose, predict, or treat individuals with α-synucleinopathies, as α-synuclein deposits are not only found in multiple neurodegenerative diseases but also precede characteristic neurodegeneration. Detection and therapeutic targeting of α-synuclein would facilitate identification of presymptomatic individuals and personalized intervention.
Claims Coverage
There are multiple inventive features claimed, predominantly relating to anti-α-synuclein single-domain antibodies or binding fragments, their polynucleotide sequences, and associated compositions and methods.
Anti-α-synuclein single-domain antibody with specific CDRs
An anti-α-synuclein single-domain antibody or binding fragment comprising a heavy chain variable region that includes: - H-CDR1: ASGSIFSIN (SEQ ID NO: 18, 21, or 36) - H-CDR2: AGISRGGRTK (SEQ ID NO: 54, 57, or 72) - H-CDR3: any one of NVRSFVRTY (SEQ ID NO: 90), NARSFVRTY (SEQ ID NO: 93), and AATRWSWGTKSY (SEQ ID NO: 108)
Fusion polypeptide with two or more defined heavy chain variable regions
A fusion polypeptide comprising two or more heavy chain variable regions of the anti-α-synuclein single-domain antibody defined above, allowing tandem or multivalent antigen recognition.
Diagnostic kit including the antibody or binding fragment with detectable label
A diagnostic kit comprising the antibody or binding fragment as defined and a detectable label, enabling detection of α-synuclein protein or peptide.
Polynucleotide and vector encoding the defined antibody or binding fragment
An isolated polynucleotide encoding the antibody or binding fragment as defined, and a vector (including adeno-associated viral vectors) comprising the polynucleotide sequence.
Host cell expressing the polynucleotide encoding the antibody
A host cell comprising the vector described, suitable for expressing the defined anti-α-synuclein antibody or binding fragment.
Pharmaceutical composition containing the antibody or binding fragment
A pharmaceutical composition comprising the antibody or binding fragment and a pharmaceutical carrier, formulated for administration to a subject.
Method of inhibiting onset of α-synucleinopathy by administering the composition
A method of inhibiting onset of one or more symptoms of an α-synucleinopathy in a subject by administering an effective amount of the pharmaceutical composition described.
Method of treating α-synucleinopathy by administering the composition
A method of treating an α-synucleinopathy in a subject by administering the described pharmaceutical composition in an amount effective to treat the disease.
Method of diagnosing α-synucleinopathy using the antibody
A method of diagnosing an α-synucleinopathy in a subject by detecting accumulated α-synuclein protein or peptide with the antibody or binding fragment, and making a diagnosis based on that detection.
Method of monitoring progression of α-synucleinopathy
A method of monitoring progression of an α-synucleinopathy in a subject by periodically detecting α-synuclein protein or peptide using the defined antibody or binding fragment and monitoring changes over time.
The claims broadly cover anti-α-synuclein single-domain antibodies or fragments with defined CDRs, their encoding polynucleotides and vectors, diagnostic and therapeutic compositions, methods for diagnosis, treatment, monitoring, and kits for use in α-synucleinopathies.
Stated Advantages
The single domain antibodies described can recognize unique epitopes of α-synuclein that cannot be bound by traditional full-sized antibodies and/or bind epitopes more efficiently than conventional α-synuclein antibodies.
Single domain antibodies are about 10-times smaller than conventional IgG molecules, allowing for high stability, resistance to extreme pH and temperature, and high yield in expression systems.
The antibodies and their fragments enable detection and/or targeting of α-synuclein in diseases where current diagnostic and therapeutic tools are inadequate.
Humanized or chimeric forms of the antibodies can be engineered for desirable effector functions and improved clinical suitability.
Documented Applications
Diagnosis of α-synucleinopathies by detecting accumulated α-synuclein protein or peptide in a subject.
Treatment of α-synucleinopathies by administering pharmaceutical compositions comprising the antibodies or binding fragments.
Inhibition of onset of one or more symptoms of α-synucleinopathies in at-risk subjects.
Monitoring the progression of α-synucleinopathies by repeated detection of α-synuclein protein or peptide.
Use in diagnostic kits containing the antibody or binding fragment with a detectable label.
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