Compositions and methods for the treatment of viral infections
Inventors
Balkovec, James M. • BENSEN, Daniel C. • Borchardt, Allen • Brady, Thomas P. • CHEN, Zhi-Yong • Cole, Jason • Do, Quyen-Quyen Thuy • DOEHRMANN, Simon • Jiang, Wanlong • Lam, Thanh • Noncovich, Alain • Tari, Leslie W.
Assignees
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Publication Number
US-11833213-B2
Publication Date
2023-12-05
Expiration Date
Abstract
Compositions and methods for the treatment of viral infections include conjugates containing inhibitors of viral neuraminidase (e.g., zanamivir, peramivir, or analogs thereof) linked to an Fc monomer, an Fc domain, and Fc-binding peptide, an albumin protein, or albumin-binding peptide. In particular, conjugates can be used in the treatment of viral infections (e.g., influenza viral infections).
Core Innovation
The invention relates to a conjugate described by formula (D-I) in which each of A1 and A2 is zanamivir. The conjugate includes E comprising an Fc domain monomer with an amino acid sequence selected from SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, and SEQ ID NO: 68, and each Fc domain optionally lacks C-terminal Lys447. A covalent linker L is attached to each of A1, A2, and E, with L covalently attached to each of A1 and A2 independently at position C7 or position C9 of zanamivir.
The conjugate further defines n as 1 or 2 and T as the number of A1-L-A2 moieties conjugated to each E, with each T independently being an integer from 1 to 20. The disclosed framework therefore combines two zanamivir units with a defined Fc-domain monomer through covalent linker attachment and specifies the conjugation stoichiometry. Pharmaceutically acceptable salts of the conjugate are also encompassed.
Claims Coverage
The independent claim coverage centers on a zanamivir-Fc conjugate defined by formula (D-I), with four inventive features: restricted Fc domain monomer sequence selection, covalent linker attachment to zanamivir at C7 or C9 and to E, stoichiometry defined by n and T, and pharmaceutically acceptable salt coverage. Dependent refinements further specify Fc dimerization when n=2, linker attachment to the nitrogen atom of a surface exposed lysine of E, selection of SEQ ID NO: 68, and narrower constraints on T.
Zanamivir-Fc conjugate defined by formula (D-I)
A conjugate wherein each of A1 and A2 is zanamivir and E comprises an Fc domain monomer.
Restricted Fc domain monomer sequence options
E comprises an Fc domain monomer comprising an amino acid sequence selected from any one of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 67, and SEQ ID NO: 68, wherein each Fc domain optionally lacks C-terminal Lys447.
Covalent linker attachment at zanamivir C7 or C9
L is a linker covalently attached to each of A1, A2, and E, wherein L is covalently attached to each of A1 and A2 independently at position C7 or position C9 of zanamivir.
Stoichiometry controlled by n and T
n is 1 or 2; and T is the number of A1-L-A2 moieties conjugated to each E and each T is, independently, an integer from 1 to 20.
Pharmaceutically acceptable salt coverage
The conjugate is covered as a pharmaceutically acceptable salt thereof.
Fc dimerization with n=2
n equals 2 and the two Es dimerize to form an Fc domain.
Linker attachment via surface-exposed lysine nitrogen
Each L group is covalently attached to the nitrogen atom of a surface exposed lysine of E.
Specific Fc sequence selection for E
Each E element is defined by an amino acid sequence corresponding to SEQ ID NO: 68.
Narrowed T range
T is an integer between 1 and 10.
Population average T constraint
A population of conjugates has an average T value between 1 and 5.
Overall, the claims focus on a zanamivir-linked Fc domain monomer conjugate with selected Fc sequences, optional absence of C-terminal Lys447, defined linker attachment at zanamivir positions C7 or C9, and stoichiometric limits set by n and T. Dependent claims further refine Fc dimerization, linker attachment to surface-exposed lysine, specific sequence selection, and narrower T constraints.
Stated Advantages
C7-linked designs reduce C7→C9 migration.
C7-linked designs increase stability and homogeneity.
C7-linked designs are expected to increase efficacy.
Enhanced antiviral activity through Fc-mediated phagocytosis and ADCC.
Fc-gamma receptor signaling via ITAM/ITIM motifs leading to downstream activation including Src/Syk and PI3K/Ras pathways.
Documented Applications
Influenza CPE assays using multiple Influenza B isolates and a high-pathogenic Influenza A H7N9 isolate.
Lethal mouse efficacy for selected conjugates against Influenza B.
In vitro and in vivo activity reporting for specific conjugates against high-pathogenic Influenza strains.
Preparation and characterization of zanamivir-based linker conjugates and related Fc-aglycosylated conjugates, including protein A affinity and SEC purification and MALDI TOF-derived average mass and DAR values.
In vitro neuraminidase inhibition assays.
Cell-based assays including MDCK cells and A549 cells and CPE microneutralization.
In vivo mouse pharmacokinetics and mouse efficacy in a lethal mouse influenza model.
Therapeutic or prophylactic treatment of viral infections, including influenza virus and parainfluenza virus, in immunocompromised subjects.
Antiviral activity mediated by FcγR engagement and immune effector functions such as phagocytosis and ADCC against viruses targeted by neuraminidase inhibition.
In vivo evaluation and PK results for Conjugate 6, including lethal mouse influenza efficacy studies (H1N1) and toxicity, multi-route dosing outcomes, resistance to oseltamivir, and rat and non-human primate PK with lung distribution.
Regioisomer distribution characterization for influenza conjugate intermediates, including relative % of C7 versus C9 linkages and corresponding monomer/dimer compositions.
In vivo efficacy assessment for Conjugate 33 in lethal influenza mouse models, including survival and body-weight protection after single SC dosing, lung PFU burden and cytokine modulation at day 4, efficacy in SCID mice, and activity against a pandemic H1N1 strain.
Delayed IV treatment showing superior protection compared to oseltamivir.
Stability comparison between Int-80 and Int-4, including reported degradation.
Examples describing synthesis/functionalization of additional zanamivir-PEG/fc conjugate components and examples of new conjugates and intermediates, including Conjugate 42 and Conjugate 43, together with click-conjugation outcomes including reported DAR values.
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