Conformational epitopes in respiratory syncytial virus G protein central conserved region
Inventors
Dubois, Rebecca • FEDECHKIN, Stas • Kauvar, Lawrence M.
Assignees
Trellis Bioscience Inc • University of California San Diego UCSD
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Publication Number
US-11773143-B2
Publication Date
2023-10-03
Expiration Date
Abstract
X-ray crystallography has defined conformational properties of a key functional region of the G protein of respiratory syncytial virus (RSV). Mimics of these epitopes have utility as immunogens, as tools for discovery of antibodies and other monoclonal binding agents, and as pharmacological agents to modulate activity of the host receptors for this viral protein.
Core Innovation
The invention relates to respiratory syncytial virus (RSV) G protein central conserved region (CCR) conformational epitopes defined by X-ray structures of peptides bound to high-affinity monoclonal antibodies 3D3, 2D10, and 3G12. It focuses on mutant peptides or peptidomimetics derived from defined RSV G protein residue ranges corresponding to SEQ ID NOs 1-6, with amino acid substitutions at selected positions.
The mutant peptides or peptidomimetics are designed to preserve native conformation when binding to mAb 3D3, and/or 2D10, and/or 3G12 while diminishing CX3CR1 activation compared to the respective unmodified peptides comprising SEQ ID NOs 1-6. The document addresses RSV G protein CCR activation of CX3CR1 and aims to provide CX3CR1-disabling, immunogen-optimized mutants that remain immunoreactive with the relevant monoclonal antibodies.
The document provides structural rationale for engineering these mutants by using crystallographic determination of mAb-peptide complexes to support chemically stabilized native-like conformations during antibody binding. It also describes methods to assess fidelity of candidate molecules by binding to affinity-diverse mAbs and to identify binding moieties, including non-immunoglobulin binding moieties, meeting affinity and strain-independence criteria.
Claims Coverage
The independent claim defines RSV G protein-derived mutant peptides or peptidomimetics with specified residue-range derivation from SEQ ID NOs 1-6, selected amino-acid substitutions, diminished CX3CR1 activation relative to unmodified peptides, immunoreactivity with mAb 3D3 and/or 2D10 and/or 3G12, and chemical stabilization to maintain native conformation during antibody binding. Four inventive features are identified.
RSV G-derived mutant peptide or peptidomimetic with specified residue ranges and substitutions
A mutant peptide or peptidomimetic comprising amino acid residues 161-197 (SEQ ID NO: 1), 162-172 (SEQ ID NO: 2), 169-198 (SEQ ID NO: 3), 157-197 (SEQ ID NO: 4), 148-197 (SEQ ID NO: 5), or 161-191 (SEQ ID NO: 6), with at least one amino acid substitution at amino acid residue 162, 164, 166, 177, 187, 192, or 193 as applicable to the selected residue range.
Diminished CX3CR1 activation compared to unmodified peptides
The mutant peptide or peptidomimetic comprises diminished activation of CX3CR1 as compared to the respective unmodified peptide comprising SEQ ID NOS: 1-6.
Immunoreactivity with mAb 3D3 and/or 2D10 and/or 3G12
The mutant peptide or peptidomimetic is immunoreactive with mAb 3D3 and/or 2D10 and/or 3G12.
Chemical stabilization to maintain native conformation during mAb binding
The mutant peptide or peptidomimetic is chemically stabilized to maintain its native conformation when binding to mAb 3D3 and/or 2D10 and/or 3G12.
Overall, claim coverage centers on RSV G protein CCR-derived mutant peptides or peptidomimetics that combine specified substitutions with diminished CX3CR1 activation, preserved immunoreactivity with mAbs 3D3/2D10/3G12, and chemical stabilization maintaining native conformation during binding. Dependent claims further refine these features and include pharmaceutical/veterinary composition and vaccine use.
Stated Advantages
Diminished activation of CX3CR1 compared to the respective unmodified peptides comprising SEQ ID NOS: 1-6.
Documented Applications
A pharmaceutical or veterinary composition or vaccine contains, as its active ingredient, the mutant or peptidomimetic described in claim 1.
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