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-12220387-B2
Publication Date
2025-02-11
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 relates to eliciting or improving an immune response against one or more antigens selected from survivin, carcino-embryonic antigen (CEA) and achaete-scute homolog 2 (ASCL2) in a subject. The immune response comprises presentation of multiple epitopes of the antigen(s) by MHC class I and/or MHC class II molecules. The method is based on administering a complex that is covalently linked so that multiple components function together in vivo to drive the epitope presentation.
The complex comprises a cell penetrating peptide, at least three antigenic peptides, and at least one TLR peptide agonist. The antigenic peptides include peptides having amino acid sequences according to SEQ ID NO:95, SEQ ID NO:96 and SEQ ID NO:97. The TLR peptide agonist supports immune activation, with preferred TLR peptide agonists corresponding to TLR2 and TLR4.
The components a)-c) are covalently linked, optionally using cleavable linkers/spacers, to support multi-component covalent fusion protein designs. The document also describes antigen-presenting cells loaded with the complexes, and compositions, kits, vaccines, and pharmaceutical formulations comprising the complexes.
Claims Coverage
The independent claim coverage centers on a covalently linked complex that combines a cell penetrating peptide, at least three antigenic peptides, and at least one TLR peptide agonist to elicit or improve an immune response via MHC class I and/or MHC class II presentation of multiple epitopes. The provided claim excerpts identify 2 inventive features in the independent claim, with additional dependent-claim refinements in the excerpts.
Antigen-epitope immune response using MHC class I/II presentation
A method for eliciting or improving an immune response against one or more antigens selected from survivin, carcino-embryonic antigen (CEA) and achaete-scute homolog 2 (ASCL2) in a subject, wherein the immune response comprises presentation of multiple epitopes of the antigen(s) by MHC class I and/or MHC class II molecules.
Covalently linked multi-component vaccine complex
Administering a complex comprising a cell penetrating peptide, at least three antigenic peptides comprising peptides having amino acid sequences according to SEQ ID NO:95, SEQ ID NO:96, and SEQ ID NO:97, and at least one TLR peptide agonist, wherein the components are covalently linked.
The claim coverage is directed to a covalently linked CPP–multi-epitope–TLR peptide agonist complex for presentation of multiple epitopes by MHC class I and/or MHC class II. The excerpts also refer to dependent-claim restrictions involving peptide identity, sequence arrangement, linker use, and colorectal cancer co-agent contexts.
Stated Advantages
Increased multimer-positive antigen-specific T cells versus controls.
Provides antigen-specific immune responses characterized by presentation of multiple epitopes by MHC class I and/or MHC class II molecules.
Improved immune potency and construct efficacy in downstream immunotherapy comparisons.
Tumor growth/survival outcomes are reported in EG.7-OVA and MC38 models.
Repeated vaccination durability is reported.
Homing to tumor sites is reported.
Cytokine secretion and functional T-cell responses are reported.
Maturation of human dendritic cells is reported.
Antigen processing/presentation by human DCs with HLA I/II peptides identified by mass spectrometry is reported.
Synergy with PD-1 blockade (anti-PD1) together with ATP128/antigenic cargo construct vaccination is reported.
DC Activation Index measurements and human-construct activation data for multiple ATP series variants are reported.
Documented Applications
In vivo vaccination regimens in C57BL/6 mice evaluating CPP variants (Z14 or Z18) with MAD5 and the TLR4 agonist EDA (EDAZ14Mad5 and EDAZ18Mad5), showing increased multimer-positive antigen-specific T cells.
Downstream immunotherapy examples comparing construct efficacy and immune potency across additional antigenic cargos (including Z13Mad8Anaxa, Z13Mad11Anaxa, Z13Mad9Anaxa, and Z13Mad12Anaxa).
Tumor growth/survival studies in EG.7-OVA and MC38 models, including effects on tumor control and/or survival outcomes.
Repeated vaccination durability and homing to tumor sites as measured outcomes.
Human dendritic cell maturation and antigen processing/presentation by human DCs, with HLA I/II peptides identified by mass spectrometry.
Combination immunotherapy showing synergy with PD-1 blockade (anti-PD1) together with ATP128/antigenic cargo construct vaccination (e.g., Z13Mad12Anaxa + anti-PD1 synergy).
Human-construct activation measurements for multiple ATP series variants (ATP110/ATP112/ATP115/ATP117/ATP118/ATP119/ATP120/ATP122/ATP123/ATP125/ATP128) including DC Activation Index measurements.
Colorectal cancer context, including administration prior to, at the same time as, or sequentially with a co-agent for treating or stabilizing colorectal cancer.
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