Compositions and methods for the treatment of viral infections
Inventors
Borchardt, Allen • Brady, Thomas P. • CHEN, Zhi-Yong • Lam, Thanh • Tari, Leslie W.
Assignees
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Publication Number
US-11510992-B1
Publication Date
2022-11-29
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 Fc-based conjugates described by formula (D-II-6) and related structures, wherein each E comprises an Fc domain monomer or J comprises two Fc domain monomers, and a linker L is covalently attached as indicated by the squiggly line. The conjugates include n being 1 or 2, T being an integer from 1 to 20, R7 selected from C1-C20 alkyl, and pharmaceutically acceptable salts.
The disclosure further refines the conjugates by specifying covalent attachment to a nitrogen atom on a solvent-exposed lysine or to a sulfur atom on a solvent-exposed cysteine, and by narrowing T to an integer from 1 to 10 in some embodiments. Sequence-defined Fc domain monomers are also referenced through defined SEQ ID NO selections and mature human IgG1 Fc variants.
The document also describes additional Fc-based conjugate structural variants with linker remainder L' and linker segment parameters, together with broader linker architectures and PEG-like spacer embodiments. The partial content further refers to neuraminidase-inhibitor conjugates, zanamivir conjugates, regioisomer-controlled populations linked at C7 or C9 positions, and albumin or albumin-binding peptide components with conjugation-capable cysteine and lysine sites.
Claims Coverage
The consolidated claim coverage centers on Fc-based conjugates with a covalently attached linker L. Across the independent claims, the claim coverage focuses on the Fc domain architecture, the covalent linker attachment indicated by the squiggly line, the parameter T constrained to 1 to 20, and R7 selected from C1-C20 alkyl, with pharmaceutically acceptable salts included.
Fc domain monomer conjugate with covalently attached linker
A conjugate described by formula (D-II-6), wherein each E comprises an Fc domain monomer, n is 1 or 2, T is an integer from 1 to 20, L is a linker, R7 is selected from C1-C20 alkyl, and the squiggly line indicates that L is covalently attached to E, or a pharmaceutically acceptable salt thereof.
Fc domain comprising two Fc domain monomers with covalently attached linker
A conjugate described by the structure, wherein J is an Fc domain comprising two Fc domain monomers, T is an integer from 1 to 20, L is a linker, R7 is selected from C1-C20 alkyl, and the squiggly line indicates that L is covalently attached to J, or a pharmaceutically acceptable salt thereof.
Conjugate with narrowed T range
The conjugate of 27, wherein T is an integer from 1 to 10.
Covalent attachment at solvent-exposed lysine or cysteine
The linker L is covalently attached to a nitrogen atom on a solvent-exposed lysine or to a sulfur atom on a solvent-exposed cysteine.
Fc monomer sequence selection by SEQ ID NO
Fc domain monomer amino acid sequences are independently selected from defined SEQ ID NO sets.
Overall, the claims cover Fc-based conjugates with covalently attached linker L, either to an Fc domain monomer unit or to an Fc domain comprising two Fc domain monomers, with T constrained to 1 to 20 and, in one dependent formulation, 1 to 10, and with R7 constrained to C1-C20 alkyl. Dependent refinements also specify attachment to solvent-exposed lysine nitrogen or cysteine sulfur and selection of Fc sequences by defined SEQ ID NOs.
Stated Advantages
Improved survival in lethal influenza mouse models compared with vehicle and hIgG1 Fc.
Improved body-weight retention versus vehicle and hIgG1 Fc.
Reduced viral burden and improved clinical parameters in additional efficacy testing in a ferret non-lethal H1N1 model.
Antiviral potency measured in vitro against high-pathogenic H5N1 and H7N9 isolates and against seasonal, pandemic, and drug-resistant strains.
Combination with baloxavir yields >10-fold EC50 reductions and enhanced protection versus either agent alone without antagonism.
Improved crude purity reported for an alternative conjugation route achieving a defined average DAR.
Enhanced FcRn binding is related to increased half-life of Fc-containing conjugates.
Demonstrated stability comparison between Int-80 and Int-4 using HPLC degradation percentages at 37°C and 60°C.
FcγR-mediated immune activation that engages ITAM and ITIM signaling and results in phagocytosis and ADCC.
Inhibition of viral replication via delivery of neuraminidase inhibitors to viral neuraminidase.
Optimized lung tissue distribution characterized by epithelial lining fluid to plasma concentration ratios.
More homogeneous product and increased stability of the C7 linkage, with retained influenza efficacy and reduced migration from C7 to C9.
Provides pharmaceutical formulations for Fc-based antiviral conjugates in injectable and oral dosage forms.
Documented Applications
Influenza therapeutic use in preclinical characterization and efficacy testing, including lethal and non-lethal influenza mouse models and a ferret non-lethal H1N1 model.
Antiviral activity testing in vitro against high-pathogenic influenza H5N1 and H7N9 isolates as well as seasonal, pandemic, and drug-resistant influenza strains.
Combination therapy with baloxavir.
Pharmacokinetic and pharmacodynamic distribution characterization in mice, including plasma versus epithelial lining fluid measurements.
Treating or prophylaxis of viral infections, including influenza and parainfluenza viruses.
Reducing likelihood of secondary infections as stated in the partial content.
Fc-containing conjugates with increased half-life associated with enhanced FcRn binding.
Antiviral conjugates for delivering neuraminidase inhibitors to inhibit viral replication through viral neuraminidase inhibition.
Immune activation applications involving FcγR signaling leading to phagocytosis and ADCC.
Lung tissue distribution described using epithelial lining fluid exposure and comparison to plasma exposure.
Influenza efficacy of zanamivir conjugates, including regioisomer-controlled conjugate populations.
Use of the described pharmaceutical compositions for administration of Fc-based antiviral conjugates via multiple routes including parenteral injectable and oral formats.
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