# US 11,078,238 B2 · AAVrh.10 variants with host antibody escape capabilities and altered tissue targeting properties

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- Number: US 11,078,238 B2
- Document ID: US11078238B2
- Status: Granted
- Kind: B2
- Application number: 16/338,397
- Filed: 2017-09-29
- Published: 2019-11-14
- Granted: 2021-08-03
- Earliest claimed: 2016-09-29
- Assignees: University of Florida Research Foundation, Inc.
- Applicants: University of Florida Research Foundation, Incorporated
- Inventors: Mavis Agbandje-McKenna; Mario Mietzsch
- Web page: https://patentgrep.com/patent/US11078238B2

## CPC

- C07K 14/005: from viruses
- C12N 15/86: Viral vectors
- C12N 2015/8518: {expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles}
- C12N 2750/14122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

This disclosure relates to variant AAVrh.10 particles engineered to escape host neutralizing antibodies but retain or improve transduction efficiency, and their use as gene delivery vehicles.

## Claims

### Claim 1

A recombinant adeno-associated virus rh.10 (rAAVrh.10) particle comprising a capsid protein comprising one or more mutations in positions selected from the group consisting of: Q589, N590, and A592 of SEQ ID NO: 2, wherein said mutations result in modulated reactivity to a neutralizing antibody and/or altered transduction efficiency relative to a wild-type AAVrh.10 particle having a capsid protein with an amino acid sequence of SEQ ID NO: 2.

### Claim 2 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the neutralizing antibody is against AAVrh.10.

### Claim 3 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the neutralizing antibody is against AAV of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13.

### Claim 4 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the neutralizing antibody is ADK8, ADK9, IVIG, HL2381 or HL2383.

### Claim 5 (depends on 4)

The rAAVrh.10 particle of claim 4, wherein the reactivity to neutralizing antibodies is decreased by 5-100% compared to wild type AAVrh.10 particles.

### Claim 6 (depends on 4)

The rAAVrh.10 particle of claim 4, wherein the transduction efficiency is increased by 5-200% compared to wild type AAVrh.10 particles.

### Claim 7 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the transduction efficiency is decreased by 5-100% compared to wild type AAVrh.10 particles.

### Claim 8 (depends on 1)

The rAAVrh.10 particle of claim 1, further comprising one or more mutations in amino acid positions selected from the group consisting of: K259, K333, S453, S501, S559, S671, T674, Y708 and T719 of SEQ ID NO: 2.

### Claim 9 (depends on 8)

The rAAVrh.10 particle of claim 8, wherein the one or more mutations are selected from the group consisting of K259L, K333V, ΔS453, S501A, S559A, S671A, T674V, Y708A and T719V.

### Claim 10 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the one or more mutations are N590S and A592Q.

### Claim 11 (depends on 1)

The rAAVrh.10 particle of claim 1, wherein the one or more mutations are Q589N, N590S and/or A592Q.

### Claim 12 (depends on 8)

The rAAVrh.10 particle of claim 8, wherein the one or more mutations are ΔS453, S559A, Q589N, N590S, A592Q and T719V.

### Claim 13 (depends on 8)

The rAAVrh.10 particle of claim 8, wherein the one or more mutations are K259L, ΔS453, S559A, Q589N, N590S, A592Q and T719V.

### Claim 14 (depends on 1)

The rAAVrh.10 particle of claim 1, further comprising a transgene comprising a gene of interest.

### Claim 15 (depends on 14)

The rAAVrh.10 particle of claim 14, wherein the gene of interest encodes a therapeutic protein.

### Claim 16 (depends on 15)

The rAAVrh.10 particle of claim 15, wherein the therapeutic protein is an antibody, a peptibody, a growth factor, a clotting factor, a hormone, a membrane protein, a cytokine, a chemokine, an activating or inhibitory peptide acting on cell surface receptors or ion channels, a cell-permeant peptide targeting intracellular processes, a thrombolytic, an enzyme, a bone morphogenetic protein, a nuclease or other protein used for gene editing, an Fc-fusion protein, or an anticoagulant.

### Claim 17 (depends on 1)

A composition comprising a rAAVrh.10 particle of claim 1 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 15)

A method of delivering a protein of interest to a subject, the method comprising administering to the subject a composition comprising the rAAVrh.10 particle of claim 15.

### Claim 19

A capsid protein of serotype AAVrh.10 comprising one or more mutations in positions selected from the group consisting of: Q589, N590, and A592 of SEQ ID NO: 2.