AAV-mediated delivery of therapeutic antibodies to the inner ear

Inventors

Simons, Emmanuel John • Ng, Robert • McKenna, Michael

Assignees

Akouos Inc

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

The patent describes an adeno-associated virus (AAV) vector expression system configured for inner ear delivery and treatment of hearing loss. The AAV vector comprises a nucleotide sequence encoding a polypeptide comprising one or more soluble vascular endothelial growth factor (VEGF) receptors or a portion thereof, wherein the coding sequence comprises SEQ ID NO: 61 and the polypeptide is operably linked to a signal peptide.

The disclosed inner-ear approach includes promoter and Kozak sequence elements, polyadenylation signal sequences, and AAV inverted terminal repeats flanking the coding sequence and promoter. The disclosure further describes optional transcript arrangements to generate multiple polypeptides from one transcript, including optional IRES usage and sequences such as viral IRES and FMDV 2A cleavage sequence examples, together with reporter genes including LacZ, GFP/mCherry, and luciferase.

The document also describes soluble VEGF receptor forms, including VEGFR-1 extracellular region and VEGFR variants, and exemplars including bevacizumab, ranibizumab, aflibercept, and antigen-binding antibody fragments. In documented work, antibody chain products and detected expressed antibody and intact antibody support AAV-mediated inner-ear expression and secretion for anti-VEGF activity directed to VEGF proteins, including references to acoustic neuroma, vestibular schwannoma, and NF2.

Claims Coverage

The independent claims cover an inner-ear AAV-based system, the corresponding AAV-containing cell, a treatment method for an inner ear disorder, and an associated pharmaceutical composition. Across the independent claims, the coverage centers on four inventive feature themes: an inner-ear delivery formulation, a defined AAV vector encoding SEQ ID NO: 61 soluble VEGF receptor with signal peptide linkage, specific VEGF binding by the encoded polypeptide, and therapeutic administration to treat an inner ear disorder.

Across the independent claims, the patent’s core claimed subject matter is an inner-ear delivery AAV system encoding a soluble VEGF receptor polypeptide based on SEQ ID NO: 61, linked to a signal peptide and designed so the expressed polypeptide specifically binds mammalian VEGF proteins. The same vector/protein specificity is applied to an inner-ear composition, a cell containing the AAV vector, a method of treating an inner ear disorder by administering the AAV vector, and an inner-ear formulated pharmaceutical composition.

Stated Advantages

Documented Applications