Alphaherpesvirus glycoprotein d-encoding nucleic acid constructs and methods

Inventors

Keller, Lorraine • Padidam, Malla

Assignees

MBF Therapeutics Inc

Abstract

This invention provides new compositions comprising nucleotide sequence(s) encoding alphaherpesvirus glycoprotein D protein(s) (gDP(s)) and antigen(s) that induce immune responses. Such sequences typically encode gDP:antigen fusion proteins and typically also include feature(s) that significantly enhance immune responses such as (a) sequences encoding ITIC signal transducing adaptor proteins, e.g., SLAM-associated proteins (SAPs), Ewing's sarcoma-associated transcript 2 proteins, or both, or non-gDP checkpoint inhibitor(s); (b) sequences encoding antigen-associated targeting sequences, e.g., polyubiquitin sequences; (c) deimmunized/modified antigen-encoding sequences; (d) gDP(s) with modified sequence(s); (e) expression-enhancing introns; (f) transfection-facilitating agents; or (g) combinations thereof. Methods of using such constructs to induce immune responses and other methods and compositions also are provided, including methods of using such constructs in animals not known to express Herpesvirus entry mediator (HVEM) receptors (e.g., pigs), animals not under disease agent-associated checkpoint inhibition, and other contexts.

Core Innovation

The invention provides a composition comprising an effective amount of nucleic acid(s) that encode a fusion protein and Ewing's Sarcoma-associated Transcript-2 (EAT-2) amino acid sequences. The fusion protein comprises one or more alphaherpesvirus glycoprotein D (gD) amino acid sequences comprising one or more gD receptor binding domains and one or more antigens associated with a disease-causing agent. The one or more gD amino acid sequences detectably facilitate dendritic cell uptake of the fusion protein.

The nucleic acid(s) further comprise one or more promoters that increase expression of the fusion protein and the one or more EAT-2 amino acid sequences. The composition is provided as a single DNA plasmid, two or more DNA plasmids, a single mRNA molecule, or two or more mRNA molecules that collectively comprise the relevant encoding sequences.

The disclosed framework also includes embodiments in which the composition is described for inducing immune responses or treating or preventing lymphoma, and it refers to dendritic-cell-targeted alphaherpesvirus gD fusion proteins combined with EAT-2 peptide tumor/immune-modulating domains. Additional described context includes immune activation outcomes such as cytokine/chemokine responses, checkpoint-related components, and checkpoint inhibitors including PD-L1, PD-1, and CTLA-4.

Claims Coverage

The independent claim coverage centers on nucleic-acid-based compositions that encode a gD receptor binding domain-containing fusion protein that detectably facilitates dendritic cell uptake, together with EAT-2 amino acid sequences. Across the independent-claim alternatives, there are three inventive features: the gD fusion architecture, EAT-2 co-encoding under expression-increasing promoters, and flexibility in DNA plasmid or mRNA format.

The claim coverage is a nucleic-acid composition that encodes a gD receptor binding domain-containing fusion protein designed to facilitate dendritic cell uptake, together with EAT-2 sequences under promoters that increase expression. The independent claim scope includes both DNA plasmid and mRNA configurations, in single or collective multi-component formats.

Stated Advantages

Documented Applications