Compositions and methods for inhibition of FOXP3
Inventors
LaBelle, James • Eclov, Rachel • Bird, Gregory • Walensky, Loren D.
Assignees
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Publication Number
US-12344643-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Provided herein are peptide-based therapeutics that target FOXP3 and methods of use thereof to decrease the immuno-suppressive effects of Tregs and inhibit immune dysregulation, while sparring inhibition of activated cytotoxic T cells, for example, in the context of anti-tumor immune responses, autoimmunity, inflammatory conditions, etc.
Core Innovation
The invention relates to peptide-based therapeutics targeting forkhead box P3 (FOXP3) in order to reduce Treg immunosuppression and immune dysregulation while sparing activated cytotoxic T cells. The approach focuses on stapled alpha helical (SAH) peptides that mimic the FOXP3 leucine zipper coiled-coil (LZ) dimerization domain and the FOXP3/NFAT interface domain. The SAH peptides are capable of inhibiting FOXP3-associated protein interactions relevant to FOXP3 function.
The invention further provides peptide amphiphiles (PAs) that display FOXP3-mimicking peptides, and which may include cathepsin-cleavable linkers for intracellular release. The described designs include hydrocarbon stapling or stitching configurations and coverage of peptide sequence identity and sequence variants, including optional non-natural or modified amino acids. The peptides are used to modulate FOXP3/NFAT-related behavior and FOXP3-linked downstream effects.
The disclosure also describes delivery and formulation concepts for the peptides and PAs, including components such as PEGylation and lipid-tail related nanostructures or micelles, and targeting accessories such as anti-CD4. Multiple outcomes are reported that relate to binding specificity and effects on FOXP3 DNA binding, selectivity versus NFAT DNA binding, reduced Treg suppression in vitro, altered FOXP3 target gene expression, intracellular uptake, and assays of cell toxicity, apoptosis, and membrane disruption.
Claims Coverage
Based on the provided independent claim, the patent claims a stapled alpha helical peptide that inhibits FOXP3 oligomerization, with additional dependent coverage narrowing the peptide composition and/or the FOXP3 interaction being inhibited, and further extending to non-toxicity and pharmaceutical composition and use concepts. The independent claim contains 4 core inventive elements: identity to a defined sequence, a maximum peptide length, a single hydrocarbon staple, and inhibition of FOXP3 oligomerization.
Stapled alpha helical peptide with defined sequence identity and length
A stapled alpha helical (SAH) peptide comprising at least 70% sequence identity to SEQ ID NO: 44 and being 31 or fewer amino acids in length.
Single hydrocarbon staple SAH conformation
The SAH peptide having a single hydrocarbon staple.
Inhibition of FOXP3 oligomerization
The SAH peptide is capable of inhibiting forkhead box P3 (FOXP3) oligomerization.
Inhibition of FOXP3–NFAT heterodimerization
The SAH peptide is capable of inhibiting FOXP3 heterodimerization with nuclear factor of activated T cells (NFAT).
Blocking FOXP3 binding to cognate DNA
A SAH peptide is specified that can block FOXP3 binding to cognate DNA.
Non-toxicity to T cells and Tregs
The SAH peptide is non-toxic to T cells and Tregs.
Overall, the claimed subject matter centers on a short SAH peptide with a single hydrocarbon staple that is sequence-identity related to SEQ ID NO: 44 and inhibits FOXP3 oligomerization, with dependent narrowing to FOXP3–NFAT heterodimerization and blocking FOXP3 binding to cognate DNA, and with a non-toxicity constraint for T cells and Tregs.
Stated Advantages
Reduces Treg immunosuppression.
Reduces immune dysregulation.
Spares activated cytotoxic T cells.
Exhibits selectivity versus NFAT DNA binding.
Reduces Treg suppression in vitro.
Alters FOXP3 target gene expression.
Has an intracellular mechanism consistent with intracellular release for peptide amphiphiles.
Shows intracellular uptake.
Is non-toxic to T cells and Tregs.
Documented Applications
Therapeutic use in cancer immunotherapy contexts (as described in the document summary).
Therapeutic use in autoimmune/inflammatory diseases (as described in the document summary).
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