Multivalent Kaposi sarcoma-associated herpesvirus-like particles and uses thereof
Inventors
Ogembo, Javier Gordon • MUTSVUNGUMA, Lorraine Zvichapera • MULAMA, David H. • MUNIRAJU, Murali • WUSSOW, Felix
Assignees
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Publication Number
US-12156911-B2
Publication Date
2024-12-03
Expiration Date
Abstract
Vaccine compositions comprising a single KSHV-LP comprising two or more KSHV glycoproteins and/or one or more T cell antigens and methods of preventing or treating KSHV infections using the vaccine compositions. An expression system or a single expression vector for co-expressing two or more KSHV glycoproteins simultaneously to generate a vaccine comprising a single virus-like particle. The expression system may include a single plasmid inserted with two or more nucleic acid sequences that encode two or more KSHV glycoproteins linked by one or more linking sequences such that the KSHV glycoproteins are co-expressed simultaneously.
Core Innovation
The described invention relates to a multivalent Kaposi sarcoma-associated herpesvirus-like particle (KSHV-LP) vaccine. The KSHV-LP comprises four KSHV glycoproteins or immunogenic fragments thereof, specifically including a gpK8.1 ectodomain fused to a Newcastle disease virus (NDV) structural protein sequence, a gB ectodomain fused to an NDV structural protein sequence, a gH ectodomain fused to an NDV structural protein sequence, and a full-length gL glycoprotein. The multivalent KSHV-LP thereby incorporates KSHV entry glycoproteins in a particle format.
The invention also provides an approach for expressing and assembling the KSHV envelope glycoproteins into one or more glycoprotein complexes. In particular, an expression system co-expresses four KSHV envelope glycoproteins simultaneously from a multivalent vector inserted with four nucleic acid sequences, where the sequences are linked by one or more linking sequences. The encoded glycoproteins can self-cleave and/or self-process to assemble into one or more glycoprotein complexes forming the multivalent KSHV-LP.
In addition to the multivalent KSHV-LP comprising the four KSHV glycoproteins, the described formulations can optionally include one or more T cell antigens, including LANA1 and immunogenic fragments thereof. The overall rationale presented is that adjuvanted KSHV-LPs elicit glycoprotein-specific IgG and in vitro neutralization of KSHV. The document further discusses production and characterization of the KSHV-LPs and presents immunogenicity and functional data across multiple human-permissive cell types.
Claims Coverage
The independent claim set covers three distinct aspects of the invention: a multivalent KSHV-like particle containing four KSHV glycoproteins with specific NDV fusion features, vaccine or pharmaceutical compositions that combine the multivalent KSHV-LP with one or more T cell antigens and a therapeutically effective amount, and an expression system that co-expresses the four KSHV envelope glycoproteins from a multivalent vector with linking sequences that enables co-expression, self-cleaving and self-processing to assemble glycoprotein complexes.
Multivalent KSHV-LP with NDV-fused gpK8.1, gB, gH and full-length gL
A multivalent Kaposi sarcoma-associated herpesvirus-like particle (KSHV-LP) comprising four KSHV glycoproteins or immunogenic fragments thereof, wherein the four KSHV glycoproteins incorporated by the multivalent KSHV-LP comprise a gpK8.1 ectodomain fused to an Newcastle disease virus (NDV) structural protein sequence, a gB ectodomain fused to an NDV structural protein sequence, a gH ectodomain fused to an NDV structural protein sequence, and a full-length gL glycoprotein.
Vaccine or pharmaceutical composition with therapeutically effective amount and one or more T cell antigens
A vaccine composition or a pharmaceutical composition comprising a therapeutically effective amount of a multivalent KSHV-LP comprising four KSHV glycoproteins and one or more T cell antigens, wherein the four KSHV glycoproteins incorporated by the multivalent KSHV-LP comprise a gpK8.1 ectodomain fused to an NDV structural protein sequence, a gB ectodomain fused to an NDV structural protein sequence, a gH ectodomain fused to an NDV structural protein sequence, and a full-length gL glycoprotein.
Expression system with linked nucleic acid sequences encoding four co-expressed KSHV envelope glycoproteins
An expression system for co-expressing four KSHV envelope glycoproteins including a multivalent vector inserted with four nucleic acid sequences that encode four KSHV envelope glycoproteins, linked by one or more linking sequences, such that the four KSHV envelope glycoproteins can be co-expressed simultaneously, self-cleaved and/or self-processed to assemble into one or more glycoprotein complexes, wherein the four KSHV envelope glycoproteins incorporated by the multivalent KSHV-LP comprise a gpK8.1 ectodomain fused to an NDV structural protein sequence, a gB ectodomain fused to an NDV structural protein sequence, a gH ectodomain fused to an NDV structural protein sequence, and a full-length gL glycoprotein.
Overall, the claim coverage centers on a multivalent KSHV-LP built from four KSHV glycoprotein components that include NDV structural protein fusion features for gpK8.1, gB, and gH, together with full-length gL, with compositions optionally further including one or more T cell antigens. The claims also extend to an expression system using a multivalent vector with linked nucleic acid sequences to enable simultaneous co-expression and self-cleaving/self-processing assembly into glycoprotein complexes.
Stated Advantages
Adjuvanted KSHV-LPs elicit glycoprotein-specific IgG.
Adjuvanted KSHV-LPs elicit in vitro neutralization of KSHV.
Neutralization is assessed across multiple human-permissive cell types including epithelial, fibroblast, endothelial, and B cells.
Documented Applications
Prevention of a disease associated with KSHV infection by administering the vaccine or pharmaceutical composition to a subject in need.
Treatment of KSHV infection or a KSHV-associated condition by administering the vaccine or pharmaceutical composition to a subject in need.
Neutralization in vitro by contacting a KSHV-permissive cell line with the KSHV-LP to produce a neutralizing antibody.
Immunization regimen involving one or more doses of the vaccine or pharmaceutical composition administered to a subject in need.
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