AAV-mediated delivery of antibodies to the inner ear
Inventors
Simons, Emmanuel John • Ng, Robert • McKenna, Michael
Assignees
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Publication Number
US-12077783-B2
Publication Date
2024-09-03
Expiration Date
Abstract
Provided herein are methods that include introducing into an inner ear of a mammal a therapeutically effective amount of an adeno-associated virus (AAV) vector that includes a nucleotide sequence encoding (a) a polypeptide including an antibody heavy chain variable domain operably linked to a signal peptide and a polypeptide including an antibody light chain variable domain operably linked to a signal peptide; (b) a polypeptide including an antigen-binding antibody fragment operably linked to a signal peptide; or (c) a soluble vascular endothelial growth factor receptor operably linked to a signal peptide.
Core Innovation
A method of delivering anti-VEGF antibody to an inner ear of a mammal is provided, comprising delivering via intra-cochlear administration an adeno-associated virus (AAV) vector into the inner ear. The mammal has an inner ear disorder, where the inner ear disorder is vestibular schwannoma or neurofibromatosis type II.
The AAV vector comprises a nucleotide sequence encoding a first polypeptide with an antibody heavy chain variable domain operably linked to a first signal peptide and a second polypeptide with an antibody light chain variable domain operably linked to a second signal peptide. The nucleotide sequence further comprises a sequence encoding a Thosea asigna virus 2A (T2A) peptide present between the first coding sequence and the second coding sequence.
The first and second polypeptides together specifically bind to one or more mammalian VEGF proteins. Delivery of the AAV vector results in a reduction in VEGF activity in the inner ear of the mammal.
Claims Coverage
The consolidated content includes one independent claim describing 3 main inventive elements: intra-cochlear AAV delivery, an encoded anti-VEGF antibody heavy/light variable expression architecture using signal peptides and T2A, and VEGF-activity reduction in specified inner ear disorders.
Intra-cochlear AAV vector delivery into the inner ear
Delivering via intra-cochlear administration an adeno-associated virus (AAV) vector into the inner ear of the mammal.
AAV-encoded anti-VEGF antibody heavy and light variable domains with signal peptides and T2A
The AAV vector comprises a nucleotide sequence encoding a first polypeptide with an antibody heavy chain variable domain operably linked to a first signal peptide and a second polypeptide with an antibody light chain variable domain operably linked to a second signal peptide, with a Thosea asigna virus 2A (T2A) peptide sequence present between the first coding sequence and the second coding sequence.
Specific VEGF binding and reduction of VEGF activity in inner ear disorders
The first and second polypeptides together specifically bind to one or more mammalian VEGF proteins, and delivery results in a reduction in VEGF activity in the inner ear of the mammal, where the inner ear disorder is vestibular schwannoma or neurofibromatosis type II.
The inventive coverage is directed to intra-cochlear AAV-mediated expression of an anti-VEGF antibody composed of heavy and light chain variable domains with signal peptides and T2A, with the expressed polypeptides specifically binding VEGF and reducing VEGF activity in the inner ear for vestibular schwannoma or neurofibromatosis type II.
Stated Advantages
Reduction in VEGF activity in the inner ear of the mammal.
Documented Applications
Treatment of inner ear disorders including vestibular schwannoma and neurofibromatosis type II by intra-cochlear administration of an AAV vector encoding an anti-VEGF antibody, resulting in reduced VEGF activity in the inner ear.
Use of intra-cochlear AAV delivery to treat inner ear disorders such as acoustic neuroma/vestibular schwannoma/NF2 via reduced VEGF activity.
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