KR-20260068140-A - Composition and method for expressing a therapeutic agent

Abstract

Compositions for modulating the expression of one or more therapeutic agents are described herein. In some aspects, the engineered polynucleotides comprise one or more expression cassettes encoding a first angiogenesis inhibitor and a second angiogenesis inhibitor. Additionally, methods of using the compositions described herein to modulate transgene expression and to treat a disease or condition, particularly therapeutic agents for treating an ocular disease or inhibiting neovascularization, are described herein.

Inventors

• 리우, 셩지앙
• 첸, 지안우

Assignees

• 에이버맥스 바이오파마 인크.

Dates

Publication Date

20260513

Application Date

20240806

Priority Date

20230807

Claims (20)

1. A engineered polynucleotide comprising one or more expression cassettes encoding a first angiogenesis inhibitor and a second angiogenesis inhibitor.
2. A engineered polynucleotide in which the first angiogenesis inhibitor and the second angiogenesis inhibitor are covalently linked by a linker, as described in claim 1.
3. A engineered polynucleotide according to claim 1 or 2, wherein the first angiogenesis inhibitor comprises a complement inhibitor.
4. In paragraph 3, the engineered polynucleotide in which the complement inhibitor comprises a complement 3 inhibitor or a C3 degradation fragment.
5. In paragraph 4, a engineered polynucleotide in which the complement 3 inhibitor comprises at least 80% identical amino acid sequences to any one of sequence identification numbers: 1-15.
6. A engineered polynucleotide according to any one of claims 1 to 5, wherein the first angiogenesis inhibitor or the second angiogenesis inhibitor comprises an inhibitor of the membrane attack complex (MAC).
7. In paragraph 6, a fabricated polynucleotide in which the MAC inhibitor includes CD59.
8. A engineered polynucleotide according to claim 7, wherein CD59 comprises at least 80% identical amino acid sequences to any one of sequence identification numbers: 41-45, 312-319, or 325-329.
9. A engineered polynucleotide according to any one of claims 1 to 8, wherein the second angiogenesis inhibitor comprises a natriuretic peptide.
10. In paragraph 9, the engineered polynucleotide wherein the natriuretic peptide comprises a C-type natriuretic peptide (CNP).
11. In paragraph 9 or 10, a engineered polynucleotide in which a natriuretic peptide is covalently linked to an antibody or a fragment thereof.
12. In paragraph 11, a engineered polynucleotide in which the antibody or its fragment comprises a crystallizable fragment (Fc) region.
13. A engineered polynucleotide according to any one of claims 9 to 12, wherein the natriuretic peptide comprises at least 80% identical amino acid sequences to any one of sequence identification numbers: 61-72.
14. A engineered polynucleotide according to any one of claims 1 to 8, wherein the second angiogenesis inhibitor comprises endostatin or a fragment thereof.
15. A engineered polynucleotide further encoding a third angiogenesis inhibitor in any one of claims 1 to 14.
16. A engineered polynucleotide comprising a viral vector, in any one of claims 1 to 15.
17. In paragraph 16, a engineered polynucleotide in which the viral vector contains an AAV vector.
18. In paragraph 17, the engineered polynucleotide in which the AAV vector is an AAV2 vector.
19. In paragraph 17, a engineered polynucleotide in which the AAV vector codes for an engineered AAV capsid.
20. In claim 19, the engineered polynucleotide wherein the engineered AAV capsid comprises an amino acid sequence of either sequence identification number: 161-182 and sequence identification number: 191-210.

Description

Composition and method for expressing a therapeutic agent Cross-reference The present application claims priority to U.S. provisional application serial number 63/531,202 filed August 7, 2023 and U.S. provisional application serial number 63/665,105 filed June 27, 2024, the full text of each of which is incorporated herein by reference. Neovascularization, including angiogenesis, neovascularization, and arteriogenesis, is regulated by a wide variety of cellular signaling pathways. One such pathway is regulated by vascular endothelial growth factor (VEGF). VEGF acts as a potent mitogen for endothelial cells, inducing proliferation, migration, vascular duct formation, and permeability. Therefore, an increase in the VEGF signaling pathway increases neovascularization signals, whereas a decrease or inhibition of the VEGF signaling pathway reduces neovascularization signals. VEGF inhibition is one of the most popular therapeutic options for diseases or conditions associated with neovascularization. For example, the treatment of ocular diseases often involves the use of angiogenesis inhibitors, such as VEGF inhibitors. Current treatments using VEGF inhibitors can be cumbersome due to the short half-life of VEGF inhibitors, which leads to the need for repeated monthly injections to achieve and sustain inhibition of neovascularization. Therefore, there remains a need for therapeutic agents to treat ocular diseases. Additionally, there remains a need for therapeutic agents to inhibit neovascularization by targeting signaling pathways other than or combined with the VEGF signaling pathway. Accordingly, in some aspects, engineered polynucleotides comprising one or more expression cassettes encoding a first angiogenesis inhibitor and a second angiogenesis inhibitor are described herein. In some embodiments, the first angiogenesis inhibitor and the second angiogenesis inhibitor are covalently linked by a linker. In some embodiments, the first angiogenesis inhibitor comprises a complement inhibitor. In some embodiments, the complement inhibitor comprises a complement 3 inhibitor or a C3 degradation fragment. In some embodiments, the complement 3 inhibitor comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1-15. In some embodiments, the first angiogenesis inhibitor or the second angiogenesis inhibitor comprises an inhibitor of the membrane attack complex (MAC). In some embodiments, the MAC inhibitor comprises CD59. In some embodiments, CD59 comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 41-45, 312-319, or 325-329. In some embodiments, the second angiogenesis inhibitor comprises a natriuretic peptide. In some embodiments, the natriuretic peptide comprises a C-type natriuretic peptide (CNP). In some embodiments, the natriuretic peptide is covalently linked to an antibody or a fragment thereof. In some embodiments, the antibody or its fragment comprises a crystallizable fragment (Fc) region. In some embodiments, the natriuretic peptide comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 61-72. In some embodiments, the second angiogenesis inhibitor comprises an endostatin or a fragment thereof. In some embodiments, a third angiogenesis inhibitor is encoded. In some embodiments, the engineered polynucleotide comprises a viral vector. In some embodiments, the viral vector comprises an AAV vector. In some embodiments, the AAV vector is an AAV2 vector. In some embodiments, the AAV vector codes for an engineered AAV capsid. In some embodiments, the engineered AAV capsid comprises an amino acid sequence of either Sequence Identification No. 161-182 and Sequence Identification No. 191-210. In some embodiments, the first angiogenesis inhibitor comprises a complement 3 inhibitor, and the second angiogenesis inhibitor comprises CNP36. In some embodiments, the engineered polynucleotide further codes for a third angiogenesis inhibitor. In some embodiments, the third angiogenesis inhibitor comprises an inhibitor of the membrane attack complex (MAC), wherein the MAC inhibitor comprises CD59. In some embodiments, the first angiogenesis inhibitor comprises CD59, and the second angiogenesis inhibitor comprises a complement 3 inhibitor fused to Fc-CNP36. In some embodiments, the first angiogenesis inhibitor comprises a complement 3 inhibitor, and the second angiogenesis inhibitor comprises an endostatin. In some embodiments, the first angiogenesis inhibitor comprises a complement 3 inhibitor, and the second angiogenesis inhibitor comprises Fc-CNP36, wherein the engineered polynucleotide further codes for a third angiogenesis inhibitor comprising CD59. In some embodiments, the first angiogenesis inhibitor comprises CD59, and the second angiogenesis inhibitor comprises a complement 3 inhibitor, wherein the engineered polynucleotide further codes for a third angiogenesis inhibitor comprising Fc-CNP36. In some embodiments, the fi