JP-2026076189-A - Protein-antiviral compound conjugate

Abstract

[Problem] To provide a novel antibody and antibody-drug conjugate that can neutralize multiple subtypes of influenza A virus and can be used as a drug for the prevention or treatment of influenza A infection. [Solution] Compounds for the treatment of influenza-related diseases and disorders are provided, comprising antiviral compounds such as VX-787 and its derivatives, baloxavir and its derivatives, and baloxavir marboxil and its derivatives, as well as protein (e.g., antibody) drug conjugates thereof. [Selection Diagram] None

Inventors

• アリーナ バウム
• トーマス ニットリ

Assignees

• レゲネロン ファーマシューティカルス，インコーポレーテッド

Dates

Publication Date

20260511

Application Date

20251226

Priority Date

20200124

Claims (20)

1. Antibody-drug conjugates comprising an anti-influenza antibody or its antigen-binding fragment conjugated to an antiviral compound.
2. The antibody-drug conjugate according to claim 1, wherein the anti-influenza antibody or its antigen-binding fragment is conjugated to the antiviral compound via a linker.
3. The antibody-drug conjugate according to claim 1 having the following structure (Here, Ab is an anti-influenza antibody or its antigen-binding fragment; L is the linker; P is an antiviral compound; and k is an integer between 1 and 30.
4. The antibody-drug conjugate according to claim 3, wherein P is an influenza inhibitor.
5. The antibody-drug conjugate according to claim 3, wherein P is a polymerase inhibitor.
6. The antibody-drug conjugate according to claim 3, wherein P is VX-787, a derivative thereof, or a residue thereof.
7. The antibody-drug conjugate according to claim 3, wherein P is baloxavir, a derivative thereof, or a residue thereof.
8. The antibody-drug conjugate according to claim 3, wherein Ab is an anti-hemagglutinin antibody or an antigen-binding fragment thereof.
9. The antibody-drug conjugate according to claim 8, wherein P is an influenza inhibitor.
10. The antibody-drug conjugate according to claim 8, wherein P is a polymerase inhibitor.
11. The antibody-drug conjugate according to claim 8, wherein P is VX-787, a derivative thereof, or a residue thereof.
12. The antibody-drug conjugate according to claim 8, wherein P is baloxavir, a derivative thereof, or a residue thereof.
13. Compounds having the following structure (Here, L is the linker; BA is a binder; and k is an integer between 1 and 30.
14. Selected from the group consisting of, Here, BA is an antibody or its antigen-binding fragment; and k is an integer between 1 and 30. The compound according to claim 13.
15. The compound according to claim 13, wherein BA is an antibody or an antigen-binding fragment thereof.
16. The antibody-drug conjugate or compound according to any one of claims 1 to 15, wherein Ab or BA is a transglutaminase-modified antibody or antigen-binding fragment thereof containing at least one glutamine residue used for conjugation.
17. The antibody-drug conjugate or compound according to any one of claims 1 to 16, wherein Ab or BA is a transglutaminase-modified antibody or antigen-binding fragment thereof containing at least two glutamine residues used for conjugation.
18. The antibody-drug conjugate or compound according to any one of claims 1 to 17, wherein Ab or BA is a transglutaminase-modified antibody or antigen-binding fragment thereof containing at least three glutamine residues used for conjugation.
19. The antibody-drug conjugate or compound according to any one of claims 1 to 18, wherein Ab or BA is a transglutaminase-modified antibody or its antigen-binding fragment containing at least four glutamine residues available for conjugation.
20. The antibody-drug conjugate or compound according to claim 19, wherein Ab or BA is a transglutaminase-modified antibody or its antigen-binding fragment, wherein the conjugation is at two Q295 residues in the EU numbering system; and k is 2.

Description

(Government licensing rights) This invention was developed with government support under Contract HHSO100201700020C, granted by the U.S. Department of Health and Human Services. The Government reserves certain rights in this invention. (Cross-reference of related applications) This application is based on U.S. Provisional Application No. 62/965,7, filed on January 24, 2020, under Section 119 of the U.S. Patent Act. This asserts the benefits of Patent No. 35 and U.S. Provisional Application No. 63/094,285, filed on October 20, 2020, the contents of which are incorporated in their entirety herein by reference. (Field) Provided herein are antiviral compounds and their protein conjugates, as well as methods for treating various diseases, disorders, and conditions, the methods comprising administering the antiviral compounds and their protein conjugates. (background) Influenza is a highly contagious disease with a long history characterized by waves of global pandemics, epidemics, resurgences, and major outbreaks. Despite annual vaccination efforts, influenza infections result in significant morbidity and mortality rates. Influenza viruses consist of three main types: A, B, and C. Influenza A viruses require hemagglutinin, which is necessary for the virus to attach to and enter host cells. They can be classified into subtypes based on allele mutations in the antigenic regions of two genes encoding surface glycoproteins: (HA) and neuraminidase (NA). Hemagglutinin is a trimeric glycoprotein containing two structural domains: a globular head domain consisting of a receptor-binding site (which is subject to frequent antigenic drift) and a stem region (which is more conserved among various strains of influenza virus). The HA protein is synthesized as a precursor (HA0), which undergoes proteolytic processing to produce two subunits (HA1 and HA2), which associate with each other to form a stem/globular head structure. The HA1 peptide is involved in the attachment of the virus to the cell surface. The HA2 peptide mediates the fusion of the virus with the cell membrane within endosomes and forms a stem-like structure that enables the release of the ribonucleoprotein complex into the cytoplasm. Currently, there are 18 subtypes (H1-H18) defined by the hemagglutinin protein. These 18 HAs can be classified into two groups. Group 1 includes H1, H2, H5, It consists of H6, H8, H9, H11, H12, H13, H16, H17, and H18 subtypes, and Group 2 consists of H3, H4, H Includes subtypes 7, H10, H14, and H15. Despite decades of research, no commercially available antibodies or antibody-drug conjugates (ADCs) exist that broadly neutralize or inhibit influenza A virus infection, or mitigate illness caused by influenza A virus. Therefore, there is a need to identify novel antibodies and ADCs that can neutralize multiple subtypes of influenza A virus and can be used as agents for the prevention or treatment of influenza A infection. (overview) Provided herein are compounds useful, for example, in antiviral therapy. In one embodiment, such compounds include VX-787 and its derivatives, baloxavir and its derivatives, and/or baloxavir marboxil and its derivatives. In one embodiment, provided are an antibody-drug conjugate comprising a payload (e.g., an antiviral compound), a linker-payload (e.g., a linker-antiviral compound), and/or an anti-influenza antibody or its antigen-binding fragment conjugated to a compound. In one embodiment, the provided compound has the following structure. (Here, L is the linker; BA is the binder; and k is an integer between 1 and 30). In one embodiment, the following structure is provided. (Here, L is the linker; and RG is the reactive part.) Alternatively, it is a linker-payload (e.g., a linker-antiviral compound) having a pharmaceutically acceptable salt thereof. In another embodiment, methods for preparing the payloads or compounds, linker-payloads, or antibody-drug conjugates and compositions described herein are described herein. In another embodiment, provided herein are methods for treating, preventing, mitigating or inhibiting an infection-associated disease, disorder, or condition described herein in a subject, the methods comprising administering to the subject an effective amount of a payload (e.g., an antiviral compound), a linker-payload (e.g., a linker-antiviral compound), an antibody-drug conjugate, or a pharmaceutical composition described herein. (Brief explanation of the drawing) Figure 1A shows the intensity-weighted average linker-payload (e.g., linker-antiviral compound) loading measured by LC-MS for 11729-Q295-11. Figure 1B shows the intensity-weighted average linker-payload (e.g., linker-antiviral compound) loading measured by LC-MS for isotype control-Q295-11. Figure 2A shows the intensity-weighted average linker-payload (e.g., linker-antiviral compound) loading measured by LC-MS for 11729-HC-Cterm-11. Figure 2B shows the intensity-weighted average linker-payload (e.g., linker-antiviral compoun