US2021363191A1PendingUtilityA1

Antibody-evading virus vectors

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Assignee: STRIDEBIO INCPriority: Apr 3, 2018Filed: Apr 3, 2019Published: Nov 25, 2021
Est. expiryApr 3, 2038(~11.7 yrs left)· nominal 20-yr term from priority
Inventors:Daniel MccoyGarrett E. Berry
C07K 14/005C12N 2310/20C12N 2750/14143C12N 15/86A61P 1/16A61K 38/465C12N 2750/14122A61K 31/7088C12N 7/00A61K 48/005A61K 48/00C12N 2750/14171
50
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Claims

Abstract

The present disclosure provides recombinant AAV capsid proteins comprising a modification in the amino acid sequence and virus vectors comprising the recombinant AAV capsid proteins. The disclosure also provides methods of administering the virus vectors and virus capsids of the disclosure to a cell or to a subject in vivo.

Claims

exact text as granted — not AI-modified
1 . A recombinant adeno-associated virus (AAV) capsid protein, wherein the capsid protein comprises a substitution in an antigenic site of the AAV capsid protein, wherein the substitution has a sequence of any one of SEQ ID NO: 9, 10, 11, 12, 13, 14, 15, 16, 17, 297, 298, 299, or 411-421. 
     
     
         2 . The recombinant AAV capsid protein of  claim 1 , wherein the substitution comprises a sequence of any one of SEQ ID NO: 9, 10, 14, or 17. 
     
     
         3 . The recombinant AAV capsid protein of  claim 1  or  2 , wherein the AAV capsid protein comprises a first amino acid substitution and a second amino acid substitution, wherein the first amino acid substitution and the second amino acid substitution each modify a different antigenic site on the AAV capsid protein, wherein the first amino acid substitution and the second amino acid substitution each comprise any one of SEQ ID NO: 9, 10, 11, 12, 13, 14, 15, 16, 17, 297, 298, 299, or 411-421. 
     
     
         4 . The recombinant AAV capsid protein of  claim 1  or  2 , wherein the AAV capsid protein comprises a first acid substitution, a second amino acid substitution, and a third amino acid substitution, wherein the first amino acid substitution, the second amino acid substitution, and the third amino acid substitution each modify a different antigenic site on the AAV capsid protein, wherein the first amino acid substitution, the second amino acid substitution and the third amino acid substitution each comprise any one of SEQ ID NO: 9, 10, 11, 12, 13, 14, 15, 16, 17, 297, 298, 299, or 411-421. 
     
     
         5 . The recombinant AAV capsid of  claim 4 , wherein the first amino acid substitution comprises SEQ ID NO. 9; the second amino acid substitution comprises any one of SEQ ID NO. 10, 11, 12, 13, 14, 15, 16, 297, 298, 299, or 411-421; and the third amino acid substitution comprises SEQ ID NO. 17. 
     
     
         6 . The recombinant AAV capsid of  claim 5 , wherein the first amino acid substitution comprises SEQ ID NO. 9; the second amino acid substitution comprises SEQ ID NO. 10; and the third amino acid substitution comprises SEQ ID NO. 17. 
     
     
         7 . The recombinant AAV capsid of  claim 5 , wherein the first amino acid substitution comprises SEQ ID NO. 9; the second amino acid substitution comprises SEQ ID NO. 14; and the third amino acid substitution comprises SEQ ID NO. 17. 
     
     
         8 . The recombinant AAV capsid protein of any one of  claims 1 - 7 , wherein the AAV capsid protein further comprises a substitution that modifies the HI loop of the capsid. 
     
     
         9 . The recombinant AAV capsid protein of  claim 8 , wherein the AAV capsid comprises one or more of the following substitutions in the HI loop:
 P661R, T662S, Q666G, S667D, wherein the numbering corresponds to the wildtype AAV8 capsid (SEQ ID NO: 6); or   P659R, T660S, A661T, K664G, wherein the numbering corresponds to the wildtype AAV9 capsid (SEQ ID NO: 7).   
     
     
         10 . The recombinant AAV capsid protein of any one of  claims 1  to  9 , wherein the AAV capsid protein is of an AAV serotype selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.8, AAVrh.10, AAVrh32.33, AAVrh74, bovine AAV and avian AAV. 
     
     
         11 . The recombinant AAV capsid protein of any one of  claims 1  to  9 , wherein the AAV capsid protein is chimeric. 
     
     
         12 . The recombinant AAV capsid protein of  claim 11 , wherein the AAV capsid protein comprises sequences derived from two or more AAV serotypes. 
     
     
         13 . The recombinant AAV capsid protein of  claim 12 , wherein the AAV capsid protein comprises sequences derived from three or more AAV serotypes. 
     
     
         14 . The recombinant AAV capsid protein of any one of  claims 1 - 10 , wherein the AAV capsid protein comprises an amino acid sequence that has at least 90% sequence identity with any one of SEQ ID NOs: 18-80, 300-410, 422-612, or 783-785. 
     
     
         15 . The recombinant AAV capsid protein of  claim 14 , wherein the AAV capsid protein comprises an amino acid sequence of any one of SEQ ID NOs: 18-80, 300-410, 422-612, or 783-785. 
     
     
         16 . The recombinant AAV capsid protein of  claim 15 , wherein the AAV capsid protein comprises an amino acid sequence of SEQ ID NO: 380 or SEQ ID NO: 384. 
     
     
         17 . The recombinant AAV capsid protein of any one of  claims 1  to  16 , wherein the modification of the one or more antigenic sites results in inhibition of binding by an antibody to the one or more antigenic sites. 
     
     
         18 . The recombinant AAV capsid protein of any one of  claims 1  to  17 , wherein the modification of the one or more antigenic sites results in inhibition of neutralization of infectivity of a virus particle comprising said AAV capsid protein. 
     
     
         19 . A recombinant AAV capsid protein comprising the amino acid sequence of SEQ ID NO: 49. 
     
     
         20 . The recombinant AAV capsid protein of  claim 19 , wherein the AAV capsid protein is modified by replacing the region spanning amino acids 454-460 of SEQ ID NO: 49 with SEQ ID NO: 9. 
     
     
         21 . The recombinant AAV capsid protein of any one of  claim 19  or  20 , wherein the AAV capsid protein is modified by replacing the region spanning amino acids 493-500 of SEQ ID NO: 49 with any one of SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 297, 298, 299, or 411-421. 
     
     
         22 . The recombinant AAV capsid protein of any one of  claims 19  to  21 , wherein the AAV capsid protein is modified by replacing the region spanning amino acids 585-590 of SEQ ID NO: 49 with SEQ ID NO: 17. 
     
     
         23 . The recombinant AAV capsid protein of any one of  claims 19  to  22 , wherein the AAV capsid protein is modified by replacing the region spanning amino acids 454-460 of SEQ ID NO: 49 with SEQ ID NO: 9, the region spanning amino acids 493-500 of SEQ ID NO: 49 with any one of SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 297, 298, 299, or 411-421, and the region spanning amino acids 585-590 of SEQ ID NO: 49 with SEQ ID NO: 17. 
     
     
         24 . The recombinant AAV capsid protein of any one of  claims 19  to  23 , wherein the modification results in inhibition of binding by an antibody to the AAV capsid protein. 
     
     
         25 . The recombinant AAV capsid protein of any one of  claims 19  to  24 , wherein the modification results in inhibition of neutralization of infectivity of a virus particle comprising the AAV capsid protein. 
     
     
         26 . A recombinant AAV capsid protein comprising the amino acid sequence of any one of SEQ ID NO: 18-80, 300-410, 422-612, or 783-785. 
     
     
         27 . A recombinant AAV capsid protein comprising the amino acid sequence of SEQ ID NO: 380 or SEQ ID NO: 384. 
     
     
         28 . A nucleotide sequence encoding a recombinant AAV capsid protein of any one of  claims 1  to  27 . 
     
     
         29 . The nucleotide sequence of  claim 28 , wherein the nucleotide sequence is a DNA sequence. 
     
     
         30 . The nucleotide sequence of  claim 28 , wherein the nucleotide sequence is an RNA sequence. 
     
     
         31 . An expression vector comprising the nucleotide sequence of any one of  claims 28 - 30 . 
     
     
         32 . A cell comprising the nucleotide sequence of any one of  claims 28 - 30 , or the expression vector of  claim 31 . 
     
     
         33 . An AAV viral vector comprising the recombinant capsid protein of any one of  claims 1  to  27 . 
     
     
         34 . The AAV viral vector of  claim 33 , further comprising a cargo nucleic acid encapsidated by the capsid protein. 
     
     
         35 . The AAV viral vector of  claim 34 , wherein the cargo nucleic acid encodes a therapeutic protein or RNA. 
     
     
         36 . The AAV viral vector of any one of  claims 34 - 35 , wherein the cargo nucleic acid encodes a gene-editing molecule. 
     
     
         37 . The AAV viral vector of  claim 36 , wherein the gene-editing molecule is a nuclease. 
     
     
         38 . The AAV viral vector of  claim 37 , wherein the gene-editing molecule is a Cas9 nuclease. 
     
     
         39 . The AAV viral vector of  claim 37 , wherein the gene-editing molecule is a Cpf1 nuclease. 
     
     
         40 . The AAV viral vector of  claim 36 , wherein the gene-editing molecule is a single guide RNA. 
     
     
         41 . A pharmaceutical composition comprising the AAV viral vector of any one of  claims 33  to  40 . 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         43 . A pharmaceutical composition comprising the cell of  claim 32  or the expression vector of  claim 31 . 
     
     
         44 . The pharmaceutical composition of  claim 43  wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         45 . A method of treating a patient in need thereof comprising administering to the patient a therapeutically effective amount of an AAV viral vector of any one of  claims 33 - 40  or the pharmaceutical composition of any one of  claims 41 - 44 . 
     
     
         46 . The method of  claim 45 , wherein the patient has a liver disease or disorder. 
     
     
         47 . The method of  claim 46 , wherein the liver disease or disorder is primary biliary cirrhosis, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), autoimmune hepatitis, hepatitis B, hepatitis C, alcoholic liver disease, fibrosis, jaundice, primary sclerosing cholangitis (PSC), Budd-Chiari syndrome, hemochromatosis, Wilson's disease, alcoholic fibrosis, non-alcoholic fibrosis, liver steatosis, Gilbert's syndrome, biliary atresia, alpha-1-antitrypsin deficiency, alagille syndrome, progressive familial intrahepatic cholestasis, Hemophilia B, Hereditary Angioedema (HAE), Homozygous Familial Hypercholesterolemia (HoFH), Heterozygous Familial Hypercholesterolemia (HeFH), Von Gierke's Disease (GSD I), Hemophilia A, Methylmalonic Acidemia, Propionic Acidemia, Homocystinuria, Phenylketonuria (PKU), Tyrosinemia Type I, Arginase I Deficiency, Argininosuccinate Lyase Deficiency, Carbamoyl-phosphate synthetase 1 deficiency, Citrullinemia Type 1, Citrin Deficiency, Crigler-Najjar Syndrome Type 1, Cystinosis, Fabry Disease, Glycogen Storage Disease Ib, LPL Deficiency, N-Acetylglutamate Synthetase Deficiency, Ornithine Transcarbamylase Deficiency, Ornithine Translocase Deficiency, Primary Hyperoxaluria Type I, or ADA SCID. 
     
     
         48 . The method of  claim 46 , wherein the liver disease or disorder is liver cancer or metastasis. 
     
     
         49 . The method of any one of  claims 45 - 48 , wherein the patient is a mammal. 
     
     
         50 . The method of  claim 49 , wherein the patient is a human. 
     
     
         51 . A method of introducing a nucleic acid molecule into a cell, comprising contacting the cell with the AAV viral vector of any one of  claims 33 - 40 . 
     
     
         52 . An AAV viral vector of any one of  claims 33 - 40  for use as a medicament. 
     
     
         53 . An AAV viral vector of any one of  claims 33 - 40  for use in a method of treatment.

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