Conjugated vaccine carrier proteins
Inventors
FAIRMAN, Jeffery C. • Heinrichs, Jon H. • Chan, Wei
Assignees
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Publication Number
US-11951165-B2
Publication Date
2024-04-09
Expiration Date
Abstract
Methods for the production of immunogenic compositions containing a non-natural amino acid are disclosed. The non-natural amino acid can be a site for attachment of antigens, such as bacterial capsular polysaccharides, to make immunogenic conjugates. Bio-orthogonal attachment chemistry incorporated into the non-natural amino acids allows for more efficient and potent antigen presentation to the immune system, simplified purification, and more well-defined structure of these semi-synthetic immunogens.
Core Innovation
The invention relates to a carrier protein for use in a crosslinked protein-antigen conjugate vaccine, where the carrier protein comprises at least 98% sequence identity to a defined CRM197-based sequence or to SEQ ID NO:9 or SEQ ID NO:14. The carrier includes the non-natural amino acid 2-amino-3-(4-(azidomethyl)phenyl)propanoic acid (pAMF) as a functional handle for conjugation, present at residues 34, 213, 245, 265, 386, and 527 numbered according to the referenced SEQ ID.
The invention further defines enhanced carrier protein concepts by modifying CRM197 using nnAAs positioned at defined residue locations. The modification concepts include avoiding T-cell activating epitopes by avoiding T-cell epitope regions, and optionally removing an Arg-Arg dipeptide. The enhanced carrier protein sequences are provided as SEQ ID NOs including a native CRM197 reference and modified enhanced variants.
The invention also relates to crosslinked protein-antigen conjugate vaccine constructs that use click-reaction approaches for conjugation chemistry based on azido/alkyne or azido/tetrazine handles. It describes broad polysaccharide antigen options, including pneumococcal capsular polysaccharides and other bacterial capsular saccharides, and antigen conjugation handle introduction using chemical handles such as DBCO-derivatives.
Claims Coverage
The combined independent claims cover carrier proteins for use in crosslinked protein-antigen conjugate vaccines. Across the claims, there are three main inventive feature groupings: sequence identity to SEQ ID NO:9 or SEQ ID NO:14, and site-specific incorporation of pAMF at residues 34, 213, 245, 265, 386, and 527.
Carrier protein at high sequence identity to a defined SEQ ID
A carrier protein for use in a crosslinked protein-antigen conjugate vaccine comprising at least 98% sequence identity to SEQ ID NO:9 or SEQ ID NO:14.
pAMF nnAA at defined numbered residues in the carrier protein
2-amino-3-(4-(azidomethyl)phenyl)propanoic acid (pAMF) non-natural amino acid (nnAA) is present at residues 34, 213, 245, 265, 386, and 527 numbered according to the applicable SEQ ID (SEQ ID NO:9 or SEQ ID NO:14).
CRM197-based enhanced carrier protein variants
Enhanced carrier protein sequences include a native CRM197 reference and modified enhanced variants, with nnAAs positioned at defined residue locations and concepts of avoiding T-cell activating epitopes and optionally removing an Arg-Arg dipeptide.
Overall, the claim coverage is grounded in carrier proteins for crosslinked protein-antigen conjugate vaccines, defined by a minimum sequence identity to SEQ ID NO:9 or SEQ ID NO:14 and by pAMF nnAA positioned at residues 34, 213, 245, 265, 386, and 527. The claimed context is use in crosslinked protein-antigen conjugate vaccines.
Stated Advantages
Elicited comparable or superior IgG/OPA responses versus benchmarks for multiple serotype conjugates.
No evidence of carrier epitope suppression.
High consistency and high valency of resulting polysaccharide-protein conjugates.
Elicits protective antibody responses against bacterial antigens, including capsular polysaccharides from Streptococcus pneumoniae serotypes and other listed bacterial antigens.
Documented Applications
Use in a crosslinked protein-antigen conjugate vaccine, including multivalent pneumococcal vaccine compositions using pneumococcal capsular polysaccharides as antigens.
Immunogenicity evaluation in mice and rabbits measuring total IgG responses and opsonophagocytic activity (OPA) for multiple pneumococcal serotype conjugates.
Conjugation embodiments for Streptococcus pneumoniae serotypes, Neisseria meningitidis, and Porphyromonas gingivalis.
Immunogenic conjugate vaccine compositions for parenteral administration to elicit protective antibody responses against bacterial antigens, including Streptococcus pneumoniae serotypes and antigens from Neisseria meningitidis, Haemophilus influenzae, Streptococcus pyogenes, Streptococcus agalactiae, and Porphyromonas gingivalis.
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