Immunogenic compositions comprising Mycobacterium tuberculosis polypeptides and fusions thereof
Inventors
Reed, Steven G. • Coler, Rhea N. • Ireton, Gregory C. • Bertholet, Sylvie
Assignees
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Publication Number
US-12344641-B2
Publication Date
2025-07-01
Expiration Date
Abstract
The present invention relates to compositions and fusion proteins containing at least two Mycobacterium sp. antigens, and polynucleotides encoding such compositions and fusion proteins. The invention also relates to methods for their use in the treatment, prevention and/or diagnosis of tuberculosis infections.
Core Innovation
The invention relates to recombinant Mycobacterium tuberculosis antigen fusion polypeptides comprising two or more M. tuberculosis antigens covalently linked in the form of a fusion polypeptide. The fusion polypeptides include defined antigen components such as Rv3478 and Rv3619, with embodiments also described using additional named M. tuberculosis antigens and variants having at least 90% sequence identity to recited sequences.
The document describes cloning and recombinant expression of multiple M. tuberculosis antigen fusion proteins, followed by inclusion-body processing and Ni-NTA purification. The recombinant proteins and fusion proteins are assessed in immunological assays using human PPD+ PBMC and splenocytes from M. tuberculosis-infected mice, with IFN-gamma and TNF readouts.
Immunological results indicate that many recombinant Mtb proteins and fusion proteins elicit Th1-type memory recall responses in the tested models. The document also includes serological diagnosis experiments identifying antigen panels or fusions with improved reactivity for tuberculosis serodiagnosis, and describes vaccination with selected recombinant proteins or antigen mixtures with adjuvants that reduces lung bacterial burden and can increase survival after aerosol challenge.
Claims Coverage
The claim coverage centers on administering a composition containing two or more Mycobacterium tuberculosis antigens covalently linked as a fusion polypeptide. Two inventive features are expressly emphasized in the independent claim family: inclusion of Rv3478 and Rv3619, and sequence-identity-defined variants of those antigens, with dependent refinements adding additional antigen inclusions, tighter identity thresholds, covalent linkage via an amino acid linker, and optional immunostimulant selection.
Covalently linked fusion polypeptide antigen set for immune stimulation
Administering to a subject an effective amount of a composition containing two or more Mycobacterium tuberculosis antigens, wherein the two or more antigens are covalently linked in the form of a fusion polypeptide.
Rv3478 and Rv3619 fusion polypeptide identity definition
The fusion polypeptide comprises Rv3478 and Rv3619, or antigens comprising amino acid sequences having at least 90% sequence identity to the recited sequences.
Additional named antigen inclusion
The fusion composition further includes Rv1886 or an antigen having at least 90% sequence identity to Rv1886.
Tighter sequence-identity requirement for an added antigen
The fusion includes an antigen with an amino acid sequence having at least 99% sequence identity to the amino acid sequence of Rv1886.
Specific fusion polypeptide ID91
The fusion polypeptide is ID91 or a sequence with at least 90% identity to the recited sequence.
Covalent linking via an amino acid linker
Two or more antigens are connected using an amino acid linker.
Optional immunostimulant selection
The method includes an immunostimulant selected from a specified group of listed immunostimulant agents, or a combination of them.
Overall, the claims define immune stimulation by administering an effective amount of a composition with two or more Mycobacterium tuberculosis antigens covalently linked as a fusion polypeptide, particularly including Rv3478 and Rv3619 or variants with at least 90% sequence identity, with dependent claims further specifying additional antigens, tighter sequence-identity thresholds, ID91, amino acid linker linkage, and an optional immunostimulant.
Stated Advantages
Reduces lung bacterial burden after aerosol challenge.
Can increase survival after aerosol challenge.
Many recombinant Mtb proteins and fusion proteins elicit Th1-type memory recall responses, with IFN-gamma and/or TNF.
Improved reactivity for tuberculosis serodiagnosis using antigen panels or fusions.
Documented Applications
Immunization with recombinant proteins or antigen mixtures with adjuvants for tuberculosis, assessed by lung bacterial burden and survival after aerosol challenge.
Immune response stimulation in subjects, assessed using human PPD+ PBMC and splenocytes from M. tuberculosis-infected mice with IFN-gamma and TNF readouts.
Serological diagnosis for tuberculosis using antigen panels or fusions with improved reactivity for TB-positive/NEC-negative serum panels.
Immunogenicity assessment of an adenovirus vector expressing an antigen (Ad5-ID83).
Immunotherapy combining recombinant antigens with antibiotic therapy to improve survival.
Diagnostic use to detect Mycobacterium tuberculosis infection in samples using antigen combinations or fusion polypeptides, antibodies, or monoclonal antibody binding, including kit formats.
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