US20210363191A1 - Antibody-evading virus vectors - Google Patents
Antibody-evading virus vectors Download PDFInfo
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- US20210363191A1 US20210363191A1 US17/045,091 US201917045091A US2021363191A1 US 20210363191 A1 US20210363191 A1 US 20210363191A1 US 201917045091 A US201917045091 A US 201917045091A US 2021363191 A1 US2021363191 A1 US 2021363191A1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14171—Demonstrated in vivo effect
Definitions
- the present disclosure provides methods and compositions comprising an adeno-associated virus (AAV) capsid protein, comprising one or more amino acid substitutions, wherein the substitutions introduce into an AAV vector comprising these modified capsid proteins the ability to evade host antibodies.
- AAV adeno-associated virus
- a method of treating a patient in need thereof comprising administering to the patient a therapeutically effective amount of an AAV viral vector of the disclosure.
- VP1 capsid subunit numbering The designation of all amino acid positions in the AAV capsid proteins in the disclosure and the appended claims is with respect to VP1 capsid subunit numbering. It will be understood by those skilled in the art that the modifications described herein if inserted into the AAV cap gene may result in modifications in the VP1, VP2 and/or VP3 capsid subunits. Alternatively, the capsid subunits can be expressed independently to achieve modification in only one or two of the capsid subunits (VP1, VP2, VP3, VP1+VP2, VP1+VP3, or VP2+VP3).
- parvovirus encompasses the family Parvoviridae, including autonomously replicating parvoviruses and dependoviruses.
- the autonomous parvoviruses include members of the genera Protoparvovirus, Erythroparvovirus, Bocaparvovirus, and Densovirus subfamily.
- Exemplary autonomous parvoviruses include, but are not limited to, minute virus of mouse, bovine parvovirus, canine parvovirus, chicken parvovirus, feline panleukopenia virus, feline parvovirus, goose parvovirus, H1 parvovirus, muscovy duck parvovirus, B19 virus, and any other autonomous parvovirus now known or later discovered.
- Other autonomous parvoviruses are known to those skilled in the art.
- the virus vectors of the disclosure can further be “targeted” virus vectors (e.g., having a directed tropism) and/or a “hybrid” parvovirus (i.e., in which the viral TRs and viral capsid are from different parvoviruses) as described in international patent publication WO00/28004 and Chao et al, (2000) Molecular Therapy 2:619.
- targeted virus vectors e.g., having a directed tropism
- a “hybrid” parvovirus i.e., in which the viral TRs and viral capsid are from different parvoviruses
- the present disclosure provides an adeno-associated virus (AAV) capsid protein, comprising one or more amino acid substitutions, wherein the one or more substitutions modify one or more antigenic sites on the AAV capsid protein.
- AAV adeno-associated virus
- the modification of the one or more antigenic sites results in inhibition of binding by an antibody to the one or more antigenic sites and/or inhibition of neutralization of infectivity of a virus particle comprising said AAV capsid protein.
- the one or more amino acid substitutions can be in one or more antigenic footprints identified by peptide epitope mapping and/or cryo-electron microscopy studies of AAV-antibody complexes containing AAV capsid proteins.
- the amino acid substitution may replace the following amino acids (VP1 numbering) in any of the above-listed AAV serotypes: 400-405, 406-411, 412-417, 418-423, 424-429, 430-435, 436-441, 442-447, 448-453, 454-459, 460-465, 466-471, 472-477, 478-483, 484-489, 490-495, 484-489, 490-495, 496-501, 502-507, 508-513, 514-519, 520-525, 526-531, 532-537, 538-543, 544-549, 550-555, 556-561, 562-567, 568-573, 574-579, 580-585, 586-591, 592-597, 598-603, 604-609, 610-615, 616-621, 622-627, 628-633, 634-639, 640-645, 646-651, 652-657, 658-663, 664-6
- any of the AAV capsids described herein may further comprise a modification (e.g., a substitution or a deletion) in the HI loop.
- the HI loop is a prominent domain on the AAV capsid surface, between ⁇ strands ⁇ H and ⁇ , that extends from each viral protein (VP) subunit overlapping the neighboring fivefold VP.
- an AAV capsid comprises one, two, three, four, five, six, seven, or eight amino acid substitutions in the HI loop.
- the virus capsids can be administered to block certain cellular sites prior to and/or concurrently with (e.g., within minutes or hours of each other) administration of a virus vector delivering a nucleic acid encoding a polypeptide or functional RNA of interest.
- a virus vector delivering a nucleic acid encoding a polypeptide or functional RNA of interest.
- the inventive capsids can be delivered to block cellular receptors on liver cells and a delivery vector can be administered subsequently or concurrently, which may reduce transduction of liver cells, and enhance transduction of other targets (e.g., skeletal, cardiac and/or diaphragm muscle).
- virus vectors of the present disclosure can also be used for various non-therapeutic purposes, including but not limited to use in protocols to assess gene targeting, clearance, transcription, translation, etc., as would be apparent to one skilled in the art.
- the virus vectors can also be used for the purpose of evaluating safety (spread, toxicity, immunogenicity, etc.). Such data, for example, are considered by the United States Food and Drug Administration as part of the regulatory approval process prior to evaluation of clinical efficacy.
- cancer encompasses tumor-forming cancers.
- cancer tissue encompasses tumors.
- cancer cell antigen encompasses tumor antigens.
- cells may be removed from a subject with cancer and contacted with a virus vector expressing a cancer cell antigen according to the instant disclosure.
- the modified cell is then administered to the subject, whereby an immune response against the cancer cell antigen is elicited.
- This method can be advantageously employed with immunocompromised subjects that cannot mount a sufficient immune response in vivo (i.e., cannot produce enhancing antibodies in sufficient quantities).
- a further aspect of the disclosure is a method of administering the virus vector, virus particle and/or virus capsid of this disclosure to a subject.
- the present disclosure also provides a method of delivering a nucleic acid to a subject, comprising administering to the subject a virus particle, virus vector and/or composition of this disclosure.
- Administration of the virus vectors, virus particles and/or capsids according to the present disclosure to a human subject or an animal in need thereof can be by any means known in the art.
- the virus vector, virus particle and/or capsid is delivered in a therapeutically effective dose in a pharmaceutically acceptable carrier.
- a therapeutically effective amount of the virus vector, virus particle and/or capsid is delivered.
- the virus vectors and/or capsids of the disclosure can further be administered to elicit an immunogenic response (e.g., as a vaccine).
- immunogenic compositions of the present disclosure comprise an immunogenically effective amount of virus vector and/or capsid in combination with a pharmaceutically acceptable carrier.
- the dosage is sufficient to produce a protective immune response (as defined above).
- the degree of protection conferred need not be complete or permanent, as long as the benefits of administering the immunogenic polypeptide outweigh any disadvantages thereof.
- Subjects and immunogens are as described above.
- Administration can also be to a tumor (e.g., in or near a tumor or a lymph node).
- a tumor e.g., in or near a tumor or a lymph node.
- the most suitable route in any given case will depend on the nature and severity of the condition being treated and/or prevented and on the nature of the particular vector that is being used.
- Administration to skeletal muscle includes but is not limited to administration to skeletal muscle in the limbs (e.g., upper arm, lower arm, upper leg, and/or lower leg), back, neck, head (e.g., tongue), thorax, abdomen, pelvis/perineum, and/or digits.
- limbs e.g., upper arm, lower arm, upper leg, and/or lower leg
- head e.g., tongue
- thorax e.g., abdomen, pelvis/perineum, and/or digits.
- the disclosure is used to treat and/or prevent disorders of skeletal, cardiac and/or diaphragm muscle.
- a method of treating and/or preventing muscular dystrophy in a subject in need thereof comprising:
- virus vectors and virus capsids can be administered to tissues of the CNS (e.g., brain, eye) and may advantageously result in broader distribution of the virus vector or capsid than would be observed in the absence of the present disclosure.
- 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.
- liver disease or disorder is liver cancer or metastasis.
- An AAV viral vector of any one of embodiments 33-40 for use in a method of treatment is also possible.
- FIG. 2C The AAVs isolated during the second round of evolution ( FIG. 2C ) where then reintroduced into a third non-human primate. Liver was harvested at day 7 post-infection and sequenced to identify single recombinant AAV isolates ( FIG. 2D ).
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US11905523B2 (en) | 2019-10-17 | 2024-02-20 | Ginkgo Bioworks, Inc. | Adeno-associated viral vectors for treatment of Niemann-Pick Disease type-C |
CN112961220A (zh) * | 2021-04-19 | 2021-06-15 | 信念医药科技(上海)有限公司 | 新型腺相关病毒衣壳蛋白及包含其的新型腺相关病毒载体 |
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EP3774854A1 (en) | 2021-02-17 |
KR20210006357A (ko) | 2021-01-18 |
US20240051998A1 (en) | 2024-02-15 |
AU2019247748A1 (en) | 2020-10-08 |
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CA3094311A1 (en) | 2019-10-10 |
JP7406677B2 (ja) | 2023-12-28 |
BR112020020266A2 (pt) | 2021-01-19 |
IL277664A (en) | 2020-11-30 |
JP2024016041A (ja) | 2024-02-06 |
JP2021519099A (ja) | 2021-08-10 |
MX2020010464A (es) | 2021-01-29 |
WO2019195449A1 (en) | 2019-10-10 |
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