JP-7857230-B2 - Cell vaccine platform and method of use

Inventors

• チョードリー， モダシール
• ヘンリー， トーマス

Assignees

• インティマ バイオサイエンス， インコーポレイテッド

Dates

Publication Date

20260512

Application Date

20210421

Priority Date

20200421

Claims (20)

1. Genetically modified human cells, a. Genomic disruption in at least one human leukocyte antigen (HLA) class I gene, or at least one transcription regulator of an HLA class I gene , wherein the genomic disruption inhibits the expression of the HLA protein encoded by the at least one HLA class I gene , b. An exogenous nucleic acid encoding a cell surface protein that binds to a protein expressed on the surface of phagocytic or cytolytic immune cells, or a functional fragment or functional variant of the cell surface protein, wherein the binding results in activation of the phagocytic or cytolytic activity of the immune cell, c. Nucleic acids encoding microbial proteins or their antigenic fragments, The genetically modified human cells, including the aforementioned cells.
2. The genetically modified human cell according to claim 1, wherein the HLA class I gene is an HLA-A gene, an HLA-B gene, an HLA-C gene, or a β-microglobulin gene.
3. The genetically modified human cell according to claim 2 , wherein the HLA class I gene is a β-microglobulin gene.
4. A genetically modified human cell according to any one of claims 1 to 3 , further comprising genomic disruption in an HLA class II gene or at least one transcription regulator of an HLA class II gene.
5. The genetically modified human cell according to claim 4 , wherein the HLA class II gene is the HLA-DP gene, HLA-DM gene, HLA-DOA gene, HLA-DOB gene, HLA-DQ gene, or HLA-DR gene.
6. The genetically engineered human cell according to claim 4 , wherein the at least one transcription regulator of the HLA class II gene is the CIITA gene, the RFX5 gene, the RFXAP gene, or the RFXANK gene.
7. The genetically engineered human cell according to claim 6 , wherein the at least one transcription regulator of the HLA class II gene is the CIITA gene.
8. The genetically modified human cell according to claim 1, wherein the immune cells are innate immune cells.
9. The genetically modified human cell according to claim 8 , wherein the innate immune cell is an NK cell, macrophage, dendritic cell, neutrophil, or eosinophil.
10. The genetically modified human cell according to claim 9 , wherein the innate immune cell is an NK cell.
11. The genetically modified human cell according to claim 10 , wherein the binding results in activation of the cytolytic activity of the NK cell.
12. The genetically modified human cell according to claim 9 or 10 , wherein the cell surface protein is a ligand that specifically binds to a natural killer (NK) cell activating receptor expressed on the surface of NK cells.
13. The genetically modified human cell according to claim 9 or 10, wherein the cell surface protein is selected from the group consisting of MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, CD155, CD112 (nectin- 2 ), B7-H6, Necl- 2 , and immunoglobulin Fc.
14. The genetically modified human cell according to claim 9 or 10 , wherein the cell surface protein is a natural killer (NK) cell activation ligand.
15. The genetically modified human cell according to claim 14, wherein the natural killer cell activating ligand is selected from the group consisting of MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, CD155, CD112 (nectin-2), B7-H6, and Necl- 2 .
16. The genetically engineered human cell according to claim 1, wherein the cell comprises a secretory protein that binds to a receptor expressed on the surface of a phagocytic or cytolytic immune cell, or an exogenous nucleic acid encoding a functional fragment or functional variant of the secretory protein, the secretory protein attracts the immune cell toward the genetically engineered human cell.
17. The genetically modified human cell according to claim 1, wherein the microbial protein comprises a nucleocapsidrin protein having at least 85% sequence identity with SEQ ID NO: 54.
18. The genetically modified human cell according to claim 1, wherein the microbial protein is secreted by the genetically modified human cell, expressed on the surface of the genetically modified human cell, or expressed in the cytoplasm of the genetically modified human cell.
19. The genetically modified human cell according to claim 1, wherein the microbial protein is a protein of a virus, bacterium, parasite, or protozoan.
20. The genetically modified human cells according to claim 1, wherein the genetically modified human cells are irradiated with radiation.

Description

Cross-referencing of related applications: This international PCT application claims priority and benefit to U.S. Provisional Patent Application No. 63/013,387, filed on 21 April 2020, and U.S. Provisional Patent Application No. 63/056,460, filed on 24 July 2020, the contents of which are incorporated in their entirety by reference. Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy, created on 19 April 2021, is named 199827-757601_SL.txt and has a size of 40,840 bytes. Current vaccine development strategies primarily rely on the delivery of attenuated or inactivated microbial pathogens combined with immunostimulatory adjuvants to induce a host immune response and generate persistent antigen-specific antibodies and memory lymphocytes. However, these strategies rely on non-physiological methods of antigen exposure and non-physiological adjuvants, and may not adequately generate the immune response required for a vaccine. Therefore, novel vaccine strategies that more closely mimic and modulate physiological immune responses are needed. Invocation by Reference: All publications, patents, and patent applications herein are invoked by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being invoked by reference. In the event of any conflict between the terms herein and the terms in an invoked reference, the terms herein shall prevail. Provided herein, in particular, are cell vaccines, allogeneic universal vaccine-producing cells, and methods for producing and using them. Some embodiments provide genetically engineered human cells comprising: (a) genomic disruption in at least one human leukocyte antigen (HLA) gene or at least one transcription factor of an HLA gene; and (b) an exogenous nucleic acid encoding a cell surface protein that binds to a protein expressed on the surface of phagocytic or cytolytic immune cells, or a functional fragment or functional variant of the cell surface protein, wherein the binding results in activation of the phagocytic or cytolytic activity of the immune cells. In some embodiments, the genome disruption inhibits the expression of the HLA protein encoded by at least one HLA gene on the surface of the genetically engineered human cell. In some embodiments, the genome disruption results in reduced HLA or MHC-mediated T cell activation and/or proliferation compared to equivalent cells lacking the genome disruption. In some embodiments, the genome disruption reduces HLA or MHC-mediated T cell activation and/or proliferation compared to equivalent cells lacking the genome disruption. In some embodiments, the equivalent cells include human cells lacking the genome disruption. In some embodiments, the equivalent cells include human cells expressing the HLA gene. In some embodiments, the equivalent cells include the genetically engineered human cells lacking the disruption. In some embodiments, the genome disruption completely inhibits the expression of the HLA protein encoded by at least one HLA gene on the surface of the genetically engineered human cell. In some embodiments, the genomic disruption in at least one human leukocyte antigen (HLA) gene or at least one transcription factor of the HLA gene results in reduced HLA or MHC-mediated T cell activation or proliferation upon administration of the genetically modified human cells to a subject, compared to administration of equivalent cells without the genomic disruption in at least one human leukocyte antigen (HLA) gene or at least one transcription factor of the HLA gene. In some embodiments, the genomic disruption in at least one human leukocyte antigen (HLA) gene or at least one transcription factor of the HLA gene results in reduced HLA or MHC-mediated T cell activation or proliferation compared to equivalent cells without the genomic disruption in at least one human leukocyte antigen (HLA) gene or at least one transcription factor of the HLA gene. In some embodiments, the genome disruption is located in an HLA class I gene. In some embodiments, the HLA class I gene is an HLA-A gene, an HLA-B gene, an HLA-C gene, or a β-microglobulin gene. In some embodiments, the HLA class I gene is a β-microglobulin gene. In some embodiments, the genome disruption is located in HLA class II genes. In some embodiments, the HLA class II genes are HLA-DP, HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, and HLA-DR genes. In some embodiments, at least one transcription factor of the HLA gene is the CIITA gene, the RFX5 gene, the RFXAP gene, or the RFXANK gene. In some embodiments, the HLA gene is the CIITA gene. In some embodiments, the genetically modified human cells include genomic disruption of at least one HLA class I gene or at least one transcription factor of the HLA class I gene, and genomic disruption of at least one HLA class II gene or at lea