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AssigneeNykode Therapeutics ASA
InventorsAudun Trygge Haugen Bersaas, Pierre Dillard, Bruno Douradinha, Lars-Egil Fallang, Stine Granum, Joel Benjamin Heim, Gunnstein Norheim, Monika Sekelja, Flourina Kumar Thakor, Inga Winge, Louise Bjerkan
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The present disclosure relates to vectors, such as DNA plasmids, comprising multiple nucleic acid sequences of interest engineered to be co-expressed as separate molecules, pharmaceutical compositions comprising such vectors and the use of such vectors and such pharmaceutical compositions in the treatment or prevention of diseases or in the prophylactic or therapeutic treatment of autoimmune diseases, allergic diseases and graft rejection.
A vector comprising:
The vector according to any one of the previous claims, wherein the one or more epitopes and/or the one or more further epitopes are derived from one or more pathogen, optionally wherein the one or more pathogens are selected from the group consisting of viruses, bacteria, fungi and parasites.
The vector according to any one of the preceding claims, wherein the further antigenic unit of at least one of the one or more further polypeptides comprises one or more full length proteins, wherein said one or more full length proteins comprises the one or more further epitopes.
The vector according to any one of the previous claims, wherein the further antigenic unit of at least one of the one or more further polypeptides comprises an antigen or a part thereof, wherein said antigen or a part thereof comprises the one or more further epitopes.
The vector according to any one of the previous claims, wherein the antigenic unit of the first polypeptide and/or the further antigenic unit of at least one of the one or more further polypeptides comprise at least one universal CD4+ T cell epitope, such as at least two universal CD4+ T cell epitopes.
The vector according to any one of the previous claims, wherein the further antigenic unit of at least one of the one or more further polypeptides comprises an antigen and/or a furin linker amino acid sequence.
The vector according to any one of the previous claims, wherein the antigenic unit comprises one or more T cell epitopes from an antigen, such as an antigen from a pathogen, and at least one of the one or more further antigenic unit comprises a further antigen, such as an antigen from a pathogen, such as a full length antigen from a pathogen.
The vector according to any one of the previous claims, wherein the antigenic unit comprises an antigen, such as an antigen from a pathogen, and at least one of the one or more further antigenic unit comprises a further antigen which is identical to the first antigen.
The vector according to any one of the previous claims, wherein the antigen and at least one of the one or more further antigens can form a multimer, such as a dimer or a trimer.
The vector according to any one of the previous claims, wherein the antigenic unit comprises one or more T cell epitopes from an antigen, such as an antigen from a pathogen, and at least one of the one or more further antigenic unit comprises a further antigen which is a membrane bound antigen, such as a membrane bound antigen from a pathogen.
The vector according to any one of the previous claims, wherein at least one of the one or more further polypeptides comprises an interaction unit, preferably wherein the interaction unit is selected from the group consisting of a dimerization unit, a trimerization unit, and a tetramerization unit.
The vector according to any one of the previous claims, wherein the first polypeptide comprises a sequence which interacts with the interaction unit, such as a first leucine zipper motif, if the interaction unit is a second leucine zipper motif or a first coiled coil dimer-forming peptide, if the interaction unit is a second coil dimer-forming peptide.
The vector according to any one of the previous claims, wherein the antigenic unit comprises one or more T cell epitopes from an antigen, such as an antigen from a pathogen, and at least one of the one or more further polypeptides comprises an interaction unit which is an oligomerization unit, such a homotrimerization unit, such as a T4-phage fibritin trimerization domain or ferritin, and a further antigenic unit that comprises a further antigen, such as one or more further antigens from a pathogen.
The vector according to any one of the previous claims, wherein the multimerization unit of the first polypeptide and the interaction unit of at least one of the one or more further polypeptides are capable of forming a first polypeptide/further polypeptide multimer, such as a dimer, such as a heterodimer, optionally wherein the multimerization unit and the interaction unit are different.
The vector according to any one of the previous claims, wherein more than one further polypeptide comprises an interaction unit and said interaction units are capable of forming a multimer, such as a homo- or heteromultimer of said further polypeptides.
The vector according to any one of the previous claims, wherein the interaction unit of at least one of the one or more further polypeptides comprises a sequence that facilitates the trimerization of the antigens comprised in the antigenic unit of the first polypeptide and the antigens comprised in the further antigenic unit of the at least one further polypeptide, such as a hetero-trimerization sequence, e.g., a coiled coil peptide.
The vector according to any one of the previous claims, wherein the vector encodes at least 3 further polypeptides comprising an interaction unit that comprises a sequence that facilitates the trimerization of the antigens comprised in the further antigenic units of said further polypeptides, such as a heterotrimerization sequence, e.g., a coiled coil peptide or a homotrimerization unit, such as a T4-phage fibritin trimerization domain.
The vector according to any one of the previous claims, wherein at least one of the one or more further polypeptide comprises an interaction unit which is a self-assembly unit, such as ferritin.
The vector according to any one of the previous claims, wherein at least one of the one or more further polypeptide comprises an interaction unit which is an oligomerization unit, such as sortase A.
The vector according to any one of the previous claims, wherein at least one of the one or more further polypeptide comprises an interaction unit which is a self-assembly unit derived from the self-forming structure component of a self-assembling molecule, such as lumazine synthase from Aquifex aeolicus (LS), E2 from Geobacillus stearothermophilus, or 13-01-modified 2-dehydro-3-deoxy-phosphogluconate aldolase (=2-Keto-3-deoxy-6-phosphogluconate (KDPG) aldolase) and/or wherein the oligomerization unit of at least one further polypeptide is selected from the group consisting of:
The vector according to any one of the previous claims, wherein the first polypeptide comprises a first leucine zipper motif and wherein the interaction unit of at least one of the one or more further polypeptides comprises a second leucine zipper motif, and wherein the first and second leucine zipper motifs are capable of forming a dimer.
The vector according to any one of the previous claims, wherein at least two of the one or more further polypeptides comprise an interaction unit which is a leucine zipper motif, wherein the leucine zipper motifs are capable of forming a dimer between the at least two further polypeptides.
The vector according to any one of the previous claims, wherein at least one of the one or more further polypeptides comprises a further targeting unit.
The vector according to any one of the previous claims, wherein the first nucleic acid sequence encodes a signal peptide and/or at least one of the one or more further nucleic acid sequences encodes a further signal peptide, optionally wherein the further signal peptide is different from the signal peptide.
The vector according to any one of the preceding claims, wherein the targeting unit and/or the further targeting unit comprises or consists of a moiety that interacts with a surface molecule selected from the group consisting of CD14, CD40, CLEC9A, chemokine receptors, such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and XCR1, and Toll-like receptors (TLRs), such as TLR-2, TLR-4 and TLR-5.
The vector according to any one of the preceding claims, wherein the targeting unit and/or the further targeting unit comprises or consists of an antibody-binding region, such as antibody variable domains (VL and VH) with specificity for MHC/HLA, CD14, CD40, CLEC9A or Toll-like receptors;
The vector according to any one of claims 29 to 34, wherein the targeting unit and/or the further targeting unit comprises or consists of human CCL3L1 and the signal peptide and/or the further signal peptide comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence 1-23 of SEQ ID NO:
The vector according to any one of the preceding claims, wherein the targeting unit and/or the further targeting comprises or consists of a moiety that binds to a receptor selected from the group consisting of TGFβ receptor, such as TGFβR1, TGFβR2, or TGFβR3, IL10R, such as IL-10RA and IL10-RB, IL2R, IL4R, IL6R, IL11R and IL13R, IL27R, IL35R, IL37R, GM-CSFR, FLT3, CCR7, CD11b, CD11c, CD103, CD14, CD36, CD205, CD109, VISTA, MARCO, MHCII, CD83, SIGLEC, MGL/Clec10A, ASGR (ASGR1/ASGR2), CD80, CD86, Clec9A, Clec12A, Clec12B, DCIR2, Langerin, MR, DC-Sign, Treml4, Dectin-1, PDL1, PDL2, HVEM, CD163, CD32b and CD141.
The vector according to any one of the preceding claims, wherein at least one of the one or more further polypeptides comprises one or more full length antigens.
The vector according to according to any one of the previous claims, wherein said vector comprises one or more co-expression elements causing the transcription of the first polypeptide and of the one or more further polypeptides on a single transcript, and the independent translation into a separate first polypeptide and separate one or more further polypeptides, preferably wherein at least one of the one or more co-expression elements are IRES elements, or nucleic acid sequences encoding 2A self-cleaving peptides.
The vector according to any one of the preceding claims, wherein the multimerization unit of the first polypeptide is selected from the group consisting of dimerization unit, trimerization unit, such as a collagen-derived trimerization unit, such as a human collagen-derived trimerization domain, such as human collagen derived XVIII trimerization domain or human collagen XV trimerization domain or the C-terminal domain of T4 fibritin and tetramerization unit, such as a domain derived from p53 and wherein said multimerization unit optionally comprises a hinge region, such as hinge exon h1 and hinge exon h4.
The vector according to any one of the previous claims, wherein the multimerization unit of the first polypeptide is a dimerization unit and said dimerization unit further comprises another domain that facilitates dimerization, preferably wherein the other domain is an immunoglobulin domain, more preferably an immunoglobulin constant domain, such as a carboxyterminal C domain derived from IgG, preferably from IgG3.
The vector according to any one of the previous claims, wherein the dimerization unit of the first polypeptide further comprises a dimerization unit linker, such as glycine-serine rich linker, such as GGGSSGGGSG (SEQ ID NO:
The vector according to any one of the previous claims, wherein the dimerization unit of the first polypeptide comprises hinge exon h1 and hinge exon h4, a dimerization unit linker and a CH3 domain of human IgG3.
The vector according to any one of the previous claims, wherein the first nucleic acid sequence encodes a first polypeptide which further comprises a unit liker that connects the antigenic unit to the multimerization unit, and wherein the unit linker is a non-immunogenic linker and/or flexible or rigid linker.
The vector according to any one of the preceding claims, comprising one or more additional nucleic acid sequences encoding one or more immunostimulatory compounds.
The vector according to any one of the preceding claims, comprising one or more additional nucleic acid sequences encoding one or more immunoinhibitory compounds.
A method of producing a vector as defined in any one of the previous claims, the method comprising the following steps:
Dependencies are inferred from the claim text.