Complex comprising a cell penetrating peptide, a cargo and a TLR peptide agonist
Inventors
Derouazi, Madiha • BELNOUE, Elodie
Assignees
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Publication Number
US-12178788-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention provides a novel complex comprising a) a cell penetrating peptide, b) at least one antigen or antigenic epitope, and c) at least one TLR peptide agonist, wherein the components a)-c) are covalently linked. Moreover, the present invention also provides a nucleic acid encoding such a complex, wherein the complex is a peptide or a protein. Such a nucleic acid may be comprised by a vector, and such a vector may be comprised by a host cell. In particular, compositions, such as a pharmaceutical compositions and vaccines are provided, which may be useful for example in the prevention and/or treatment of a diseases and/or a disorder including cancer, hematological disorders, infectious diseases, autoimmunity disorders and transplant rejections.
Core Innovation
A covalently linked complex comprises a cell penetrating peptide, at least one antigen or antigenic epitope, and at least one toll-like receptor (TLR) peptide agonist, wherein the TLR peptide agonist is a TLR2 or TLR4 peptide agonist. The components are covalently linked in a defined complex format, and the complex is described as a recombinant polypeptide or recombinant protein in some embodiments.
Preferred embodiments define tumor and infectious disease antigen epitopes and corresponding SEQ ID sequences, including IL13Ralpha2 epitope sequence and epitopes for Human cytomegalovirus, EGFRvIII, EphA2, gp100, hTert, TRP-2, YKL-40, Brevican, Neuroligin 4, and PTPRz1. The disclosure also includes broad antigen and antigenic epitope content, multi-epitope and multi-antigen compositions, sequence-variant identity and functional-maintenance thresholds, and epitope fragment-length requirements.
A cell penetrating peptide embodiment is based on ZEBRA-derived minimal-domain fragments, including a ZEBRA minimal domain spanning residues 170 to 220 and allowed sequence variants preserving cell penetrating ability. The document further describes TLR2 agonist and TLR4 agonist peptides, component orderings, spacer/linker concepts, and nucleic-acid/vector/host-cell encoding, with use as a vaccine or medicament in an immune response context including dendritic cells and MHC class I/II context.
Claims Coverage
The independent claims are directed to covalently linked complexes with a cell penetrating peptide, at least one antigen or antigenic epitope, and a TLR2 or TLR4 peptide agonist, with one independent claim further limited to a recombinant polypeptide or recombinant protein. Across the claims, the main inventive features center on the covalent linkage of the three components and the specific selection of the TLR peptide agonist class and antigen/epitope incorporation.
Covalently linked CPP-antigen/epitope-TLR2 or TLR4 peptide agonist complex
A complex comprising a cell penetrating peptide, at least one antigen or antigenic epitope, and at least one toll-like receptor peptide agonist, wherein the TLR peptide agonist is a TLR2 or TLR4 peptide agonist, and wherein the components are covalently linked.
Recombinant covalently linked CPP-antigen/epitope-TLR2 or TLR4 peptide agonist complex
A complex comprising a cell penetrating peptide, at least one antigen or antigenic epitope, and at least one toll-like receptor peptide agonist, wherein the TLR peptide agonist is a TLR2 or TLR4 peptide agonist, wherein the components are covalently linked, and wherein the complex is a recombinant polypeptide or a recombinant protein.
ZEBRA minimal-domain-derived cell penetrating peptide fragment
The complex specifies that a cell penetrating peptide contains an amino-acid fragment of ZEBRA spanning residues 170 to 220 or a variant that preserves cell penetrating ability.
Named CPP sequence variants with functional preservation
The complex specifies cell penetrating peptide sequence variants with sequence identity thresholds while retaining cell-penetrating ability.
TLR peptide agonist constrained by sequence identity and activity
The complex specifies a TLR peptide agonist peptide with sequence identity thresholds while retaining TLR agonist activity.
Antigen and epitope classes with multi-epitope and multi-antigen multiplicity
The complex specifies that the antigen or antigenic epitope can be selected from peptide, polypeptide, protein, polysaccharide, lipid, lipoprotein, glycolipid, nucleic acid, or a small molecule drug or toxin, and includes compositions having multiple antigens or antigenic epitopes.
Vaccine component order options
The vaccine defines that the components are arranged in either N-terminal to C-terminal order as a-b-c or c-a-b.
The claims cover a covalently linked CPP-antigen/epitope-TLR2/TLR4 peptide agonist complex, including a recombinant polypeptide or recombinant protein form, with further refinements that constrain the CPP and TLR peptide agonist by sequence features, broaden antigen and epitope types, allow multi-epitope and multi-antigen compositions, and specify permitted component orders for vaccine formats.
Stated Advantages
Simultaneously promotes multi-epitopic cytotoxic T cell responses, Th cell induction, and immunological memory.
Induces dendritic cell maturation.
Promotes cross-presentation.
Induces CD4 and CD8 T-cell responses.
Provides tumor control in multiple mouse tumor models, including glioblastoma.
Exhibits synergistic activity requiring both CPP and TLR agonist.
Documented Applications
Cancer vaccination using the covalently linked immunogenic complex to promote immune responses for disease prevention and treatment.
Vaccine and pharmaceutical composition use employing the disclosed covalently linked CPP-antigen/epitope-TLR peptide agonist complex.
Loaded antigen-presenting cells, especially dendritic cells.
Diagnostic and imaging uses described in the document.
Tumor treatment / evaluation in multiple mouse tumor models, including glioblastoma.
Medicament use as described for the covalently linked complex.
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