Compositions for preventing or treating viral and other microbial infections
Inventors
Liu, Cheng • Zhang, Hongbing • Yang, Zhiyuan • Xiang, Jingyi • CUI, Ziyou • LIU, Jianying
Assignees
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Publication Number
US-11440952-B2
Publication Date
2022-09-13
Expiration Date
Abstract
The present application relates to compositions for preventing or treating viral and other microbial infections. In some embodiments, the present application provides chimeric proteins comprising a target-binding moiety that specifically binds to a pathogen that infects through a mucosa, and a positively charged mucoadhesive peptide fragment. Also provided are antibodies and constructs thereof that specifically binds to an S1 subunit of a spike protein of SARS-CoV-2. Compositions comprising the chimeric proteins, antibodies, or constructs described herein are useful for preventing or treating a microbial infection in an individual, such as a coronavirus infection.
Core Innovation
The invention relates to compositions for preventing or treating mucosa-infecting pathogens, including viral infections such as SARS-CoV-2. It provides chimeric protein constructs that combine an antibody moiety or antigen-binding fragment that specifically binds to a SARS-CoV-2 spike (S) protein with a mucoadhesive peptide fragment comprising about 5 to about 50 contiguous positively charged amino acid residues. The mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
The antibody component is described in connection with the spike S1 subunit, affinity maturation, anti-S1 scFvs, and chimeric IgG/scFv constructs. The document also describes antibody formats and antigen-binding structures including IgG, IgA, IgM, IgD, Fab, Fv, scFv, and VHH, together with binding to spike regions and variant forms.
The mucoadhesive peptide fragment comprises positively charged amino acid residues such as lysine, arginine, histidine, and ornithine, including polylysine and polyhistidine embodiments. The document further describes prophylaxis and therapy, mucosal delivery and nasal administration, and associated constructs such as vectors and host cells.
Claims Coverage
The claim content centers on a chimeric protein and identifies one principal inventive combination: a SARS-CoV-2 spike-binding antibody or antigen-binding fragment together with a mucoadhesive peptide fragment comprising about 5 to about 50 contiguous positively charged amino acid residues that facilitates attachment to mucosa. Dependent claims refine the mucoadhesive peptide and antibody features, and add pharmaceutical composition scope.
SARS-CoV-2 spike-binding antibody or antigen-binding fragment fused to a mucoadhesive peptide
A chimeric protein comprising an antibody or antigen binding fragment thereof that specifically binds to a SARS-CoV-2 spike (S) protein, and a mucoadhesive peptide fragment comprising about 5 to about 50 contiguous positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
Minimum threshold for contiguous positively charged residues in the mucoadhesive peptide
A chimeric protein in which the mucoadhesive peptide fragment contains at least about 6 contiguous positively charged amino acid residues.
Multiple mucoadhesive peptide fragments in the chimeric protein
A chimeric protein that includes two or more mucoadhesive peptide fragments.
Specified residue-count range for each positively charged mucoadhesive fragment
A chimeric protein in which each mucoadhesive peptide fragment contains about 11 to about 15 positively charged amino acid residues.
Defined HC-CDR and LC-CDR sequences for the antibody component
A chimeric protein whose antibody or antigen binding fragment includes specified heavy-chain and light-chain complementarity determining regions (HC-CDR1/2/3 and LC-CDR1/2/3) defined by SEQ ID NOs 37–42.
Pharmaceutical composition including the chimeric protein with a pharmaceutically acceptable carrier
A pharmaceutical composition that includes the chimeric protein together with a pharmaceutically acceptable carrier.
Claim coverage is centered on attaching a SARS-CoV-2 spike-binding antibody or antigen-binding fragment to a mucoadhesive peptide of about 5 to about 50 contiguous positively charged residues for mucosal attachment, with dependent claims refining antibody features, mucoadhesive peptide architectures, and formulation scope.
Stated Advantages
Improved mucin binding and retention via attachment to mucosa using positively charged mucoadhesive peptide fragments.
Neutralization and blocking of ACE2-S1 interaction.
In vitro and in vivo protection demonstrated using mouse models.
Reduced risk of antibody-dependent enhancement (ADE).
Cost reduction versus systemic antibody approaches.
Inhibition of pseudovirus infection and protection in a transgenic mouse model.
Documented Applications
Prophylaxis and therapy using chimeric proteins that attach to mucosa.
Nasal administration and related nasal mucosal delivery formulations for preventing or treating infections by mucosa-infecting pathogens, including SARS-CoV-2.
Use of constructs including vectors and host cells for producing the chimeric proteins.
Diagnostic immunoassays using anti-S1 antibodies.
Inhibition of pseudovirus infection and variant protection in a transgenic K18-ACE2 mouse model.
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