Fusion comprising a cell penetrating peptide, a multi epitope and a TLR peptide agonist for treatment of cancer
Inventors
Derouazi, Madiha • BELNOUE, Elodie
Assignees
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Publication Number
US-11338027-B2
Publication Date
2022-05-24
Expiration Date
Abstract
The present invention provides a complex for use in the prevention and/or treatment of cancer, the 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. In particular, compositions for use in the prevention and/or treatment of cancer, such as a pharmaceutical compositions and vaccines are provided.
Core Innovation
The invention provides a complex for colorectal cancer vaccination/immunotherapy that comprises a cell penetrating peptide, at least three antigenic peptides, and at least one TLR peptide agonist, wherein the components are covalently linked. The antigenic peptides are defined by specific amino acid sequences provided as SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97. The arrangement is described as supporting immune responses including CTL (CD8), Th (CD4), and immunological memory with improved anti-tumor activity.
The cell penetrating peptide is described with detailed options and variant definitions, including ZEBRA (Zta/Z/EB1/BZLF1) derived CPP sequences and fragments, and sequence identity and length constraints. The description includes retro-inverso peptides and peptidomimetics and sequence acceptance thresholds, and the antigenic peptide content is defined in the context of tumor-associated, tumor-specific, and neoantigens with MHC class I/II epitopes for CD8+ and CD4+ responses.
The patent text enumerates colorectal cancer antigens and epitopes such as EpCAM, MUC-1, survivin, CEA, KRas, MAGE-A3, and ASCL2, and provides multiple epitope SEQ ID NOs for these targets. The TLR peptide agonist is described with preferences including TLR2 and/or TLR4 agonists and variants, including specific sequence identifiers for a TLR2 agonist and a TLR4 agonist motif. The disclosure also describes composition formats including nucleic acid, vector, host-cell, and loaded cell formats.
Claims Coverage
The provided claim content centers on one principal independent claim directed to a covalently linked complex combining a cell penetrating peptide, at least three antigenic peptides, and at least one TLR peptide agonist. The claim features focus on the combination of these components, with the antigenic peptides defined by SEQ ID NO: 95, 96, and 97, and dependent refinements adding sequence identity constraints, TLR member specificity, and additional composition formats.
Covalently linked cell penetrating peptide, antigenic peptides, and TLR peptide agonist complex
A complex comprising a cell penetrating peptide, at least three antigenic peptides, and at least one TLR peptide agonist, wherein the components are covalently linked and the at least three antigenic peptides comprise peptides having amino acid sequences according to SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97.
Cell penetrating peptide length and ZEBRA minimal domain fragment variation limits
The cell penetrating peptide is defined as 5 to 50 amino acids long and/or contains a fragment of the ZEBRA minimal domain spanning residues 170 to 220 (SEQ ID NO: 3) with 0 to 5 amino acid substitutions, deletions, and/or additions that do not abolish its cell-penetrating ability.
TLR peptide agonist specified as TLR2, TLR4, and/or TLR5 peptide agonist
The complex includes at least one TLR peptide agonist that is a TLR2, TLR4 and/or TLR5 peptide agonist.
Sequence identity constraints for cell penetrating peptide and TLR agonist variants
The cell-penetrating peptide and its TLR agonist are each specified by particular SEQ ID sequences or functional variants with at least 90% sequence identity.
Antigen-epitope-containing polypeptide form defined by SEQ ID and sequence identity
The complex includes a polypeptide having at least 80% sequence identity to SEQ ID NO: 89 and comprising SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97.
Composition formats including nucleic acid, vector, host cell, and loaded cell
A composition is claimed that includes at least one of the complex, a nucleic acid encoding the complex, a vector containing the nucleic acid, a host cell containing the vector, or a cell loaded with the complex.
Overall claim coverage is centered on a covalently linked complex combining a cell penetrating peptide, at least three antigenic peptides defined by SEQ ID NO: 95, 96, and 97, and at least one TLR peptide agonist, with refinements specifying peptide variant constraints, particular TLR members, and additional composition formats such as nucleic acid, vector, host cell, and loaded cell.
Stated Advantages
The antigen can be presented on MHC I and MHC II.
The resulting immune response depends on CD4+ and/or CD8+ T cells with MHC class I/II restriction.
MHC cross-presentation and antigen-specific T-cell responses are induced.
Improved anti-tumor activity.
Supports simultaneous multi-epitopic CTL (CD8) induction and Th (CD4) induction.
Supports immunological memory.
Can mature human dendritic cells, with activation markers including CD86, CD80, CD83, and HLA-DR.
Can elicit antigen-specific T-cell responses in vivo and in vitro.
Shows tumor control effects in multiple mouse tumor models.
Shows limited or route-dependent cytokine release for certain constructs.
Shows synergistic tumor control when combined with a PD-1 inhibitor.
Preliminary toxicity and cytokine-release observations are reported for a representative complex.
Tumor control, survival, and metastasis inhibition are evaluated.
Documented Applications
Immunotherapy context for colorectal cancer.
Colorectal cancer vaccination/immunotherapy complexes for prevention and/or treatment of colorectal cancer.
Combination contexts with chemotherapy, targeted and immunotherapeutics.
Immune checkpoint modulators including PD-1 pathway modulation.
Generation of cells loaded with the covalently linked complex, notably antigen-presenting cells such as dendritic cells.
Tumor control in multiple mouse tumor models.
Combination with a PD-1 inhibitor to show synergistic tumor control.
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