Chimeric protein comprising an anti-influenza virus antibody moiety and a mucoadhesive peptide fragment for preventing or treating influenza infections
Inventors
Liu, Cheng • CUI, Ziyou • Zhang, Hongbing • Yang, Zhiyuan • Xiong, Guangyan • Jin, Lu • Chen, Jinyun • LIU, Motao • Greene, Warner
Assignees
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Publication Number
US-12459988-B2
Publication Date
2025-11-04
Expiration Date
Abstract
The present application provides chimeric proteins comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a positively charged mucoadhesive peptide fragment. Compositions comprising the chimeric proteins described herein are useful for preventing or treating an infection caused by an influenza virus or a variant thereof in an individual.
Core Innovation
The invention describes a chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or an influenza virus variant, and a mucoadhesive peptide fragment comprising at least 5 positively charged amino acid residues. The mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
The mucoadhesive peptide fragment is characterized by positively charged amino acid residues, including lysine, arginine, histidine, and ornithine, and by sequence-defined options with limited substitutions. The disclosure also characterizes the fragment by molecular size of no more than 15 kD and by size, charge, and pI relationships relative to mucosal pH.
The antibody moiety is described in full-length and fragment formats, including VH/VL regions, CDR-defined sequences, Fc-related options, and influenza targets such as HA and NA. The disclosure further states pharmaceutical compositions with pharmaceutically acceptable carriers and embodiments in nucleic acid, vector, and host cell formats.
Claims Coverage
The document provides one independent claim directed to a chimeric protein, with dependent refinements that define the mucoadhesive peptide, the fusion arrangement, the influenza target component and antibody sequence constraints, and a functional use claim. The inventive features below reflect the main inventive elements emphasized in the claims.
Influenza-binding antibody moiety with mucoadhesive peptide-mediated mucosal attachment
A chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or an influenza virus variant, and a mucoadhesive peptide fragment comprising at least 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
Mucoadhesive peptide sequence and charge constraints
The mucoadhesive peptide fragment is defined by specific amino acid sequence ranges, including SEQ ID NO-defined peptide sequence sets and variants with limited substitutions, and by positively charged residue composition, pI/net-charge, and residue fraction ranges.
Mucoadhesive peptide molecular size limitation
The mucoadhesive peptide fragment has a molecular size of no more than 15 kD.
Full-length antibody with C-terminal fusion to the mucoadhesive peptide
The antibody moiety is a full-length antibody, with the mucoadhesive peptide fragment fused to the C-terminus of either the heavy chain or the light chain, optionally via a peptide linker.
Influenza HA targeting with defined chain sets
A chimeric protein defined for an influenza virus or variant HA, comprising specified groups of four polypeptide chains whose amino acid sequences match particular SEQ ID NOs or at least 90% sequence-identity variants, with alternative chain-set options.
Complement pathway activation by administration
A method for activating the complement pathway in an individual by administering an effective amount of the pharmaceutical composition of claim 23.
Claim coverage centers on a chimeric protein combining an influenza virus-binding antibody moiety with a mucoadhesive peptide fragment containing at least 5 positively charged amino acid residues, further constrained by sequence, charge, size, and antibody fusion architecture. The claim set also includes a functional use for activating the complement pathway by administration of a pharmaceutical composition.
Stated Advantages
Facilitates attachment of the chimeric protein to a mucosa.
Allows binding to a component of an influenza virus or an influenza virus variant.
Reduced influenza infection compared to unmodified antibodies.
Mucoadhesive chimeric proteins trigger complement pathway activation leading to pseudovirus killing/virolysis.
Mucoadhesive chimeric proteins maintain binding affinity, remain monomeric, and retain sialic-acid glycan blocking ability in a nasal spray buffer.
Functional persistence in cell infection assays is described for the mucoadhesive chimerics.
In vivo protection against multiple influenza strains is described.
Extension to canine influenza (CIV) using D7-based mucoadhesive chimerics is described.
Mucin-binding results are described for ACE2-targeting mucoadhesive chimeric proteins.
Virus neutralization/killing on mucosa.
Activates the complement pathway, including activation involving C1, C4, and membrane attack complex (MAC).
Longer mucosal residence and protection via the positively charged mucoadhesive tail concept.
Improved viral neutralization/entry blocking associated with the antibody-mucoadhesive chimeric formats.
Documented Applications
Nasal delivery context in which HA/NA mucoadhesive chimeric proteins are evaluated in a nasal spray buffer and assessed for retained binding and sialic-acid glycan blocking ability.
Prevention or treatment of influenza infection in animal models using HA1/HA2/HA15 or NA1/NA2 hIgG mucoadhesive chimerics, showing reduced infection and in vivo protection against multiple influenza strains.
Application to canine influenza (CIV) using D7-based mucoadhesive chimerics for evaluation.
Activating the complement pathway in an individual by administering a pharmaceutical composition of the document.
Prophylaxis and therapy via topical mucosal administration, including intranasal administration.
Preventing or treating an influenza infection.
Use directed to influenza virus targets, including HA (hemagglutinin) and NA (neuraminidase) proteins or variants.
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