Peptides that bind arid5a and uses thereof

Abstract

The subject matter described herein relates to peptides that bind to the human AT-rich interactive domain 5A protein (Arid5a). The subject matter described herein also relates to methods of inhibiting Interleukin 6 (IL-6) production in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides disclosed herein.

Description

Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025PEPTIDES THAT BIND ARI D5A AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATION

[0001] The application claims the benefit of and priority to U.S. Provisional Application No. 63 / 682,193, entitled “PEPTIDES THAT BIND ARID5A AND USES THEREOF”, filed on August 12, 2024, the content of which is hereby incorporated by reference its entirety.INCORPORATION BY REFERENCE

[0002] All patents, patent applications, patent publications, journal publications and other documents cited herein are hereby incorporated by reference in their entirety and for all purposes. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes.STATEMENT ON COPYRIGHT PROTECTION

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.BACKGROUND OF THE INVENTION

[0004] Interleukin-6 (IL-6) is the principal member of the cytokine IL-6 superfamily. IL-6 is released by leukocytes upon pattern recognition receptor activation and can activate both innate and adaptative immune responses. IL-6 recruits immune cells and triggers B and T cell response as part of the innate immune response. Dysregulation of IL-6 signaling is associated with chronic inflammation and autoimmune disorders, such as atherosclerosis. The human AT-rich interactive domain 5A protein (Arid5a) regulates IL-6 mRNA stability and IL-6 expression levels.SUMMARY OF THE INVENTION

[0005] In certain aspects, the subject matter described herein provides a peptide that binds to the human AT-rich interactive domain 5A protein (Arid5a), wherein the peptide binds to one or more amino acid residues lining a groove on Arid5a, wherein the groove comprises Arid5a amino acid residues 78 to 85 and 121 to 137, wherein the peptide does not bind Ariad5a aminoACTIVEUS 205211948 1Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 acid residues Glu58, Phe61, Leu62, Val63, Leu89, Tyr93, Leul38, Vall39, Tyrl42, Vall43, Hisl45, or Leul46.

[0006] In some embodiments, the peptide binds to a positively charged pocket within the groove, wherein the pocket comprises Arid5a amino acid residues R78, R133, and R137. In some embodiments, the peptide contains more than 3 amino acid residues. In some embodiments, one or more of the 3 amino acid residues from the N-terminus of the peptide bind to the positively charged pocket. In some embodiments, at least one of the one or more amino acid residues at the N-terminus of the peptide that bind to the positively charged pocket is negatively charged. In some embodiments, one or more of the 3 amino acid residues from the C- terminus of the peptide bind to the positively charged pocket. In some embodiments, at least one of the one or more amino acid residues at the C-terminus of the peptide that bind to the positively charged pocket is negatively charged.

[0007] In some embodiments, the pocket comprises a hydrophobic region. In some embodiments, one or more hydrophobic amino acid residues of the peptide bind to one or more amino acid residues in the hydrophobic region of the pocket. In some embodiments, at least one of the one or more hydrophobic amino acid residues of the peptide that bind to one or more amino acid residues in the hydrophobic region of the pocket is an aromatic residue. In some embodiments, one or more amino acid residues of the peptide form one or more salt bridges with Arid5a amino acid residue R78 and R133. In some embodiments, the peptide consists of 6, 7, 8, 9, or 10 amino acids. In some embodiments, the peptide consists of 8 amino acids.

[0008] In certain aspects, the subject matter described herein provides a peptide that comprises any one of SEQ ID NOs: 1-50.

[0009] In certain aspects, the subject matter described herein provides a peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to any one of SEQ ID NOs: 1-50.

[0010] In certain aspects, the subject matter described herein provides a peptide that comprises SEQ ID NO: 9, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO:ACTIVEUS 205211948 2Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202528, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 40.

[0011] In certain aspects, the subject matter described herein provides a peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to any one of SEQ ID NO: 9, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 40.

[0012] In certain aspects, the subject matter described herein provides a peptide that comprises SEQ ID NO: 9.

[0013] In certain aspects, the subject matter described herein provides a peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to SEQ ID NO: 9.

[0014] In certain aspects, the subject matter described herein provides a method of inhibiting Interleukin 6 (IL-6) production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0015] In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with an IL-6 therapy. An IL-6 therapy includes any intervention that impacts the IL-6 signaling pathway, for example by preventing binding of an IL-6 ligand to an IL-6 receptor. In some embodiments, the IL-6 therapy comprises an agent that binds to an IL- 6 receptor to disrupt IL-6 signaling. In some embodiments, the IL-6 therapy comprises an agent that binds to an IL-6 ligand to disrupt IL-6 signaling. In some embodiments, the IL-6 therapy comprises a tocilizumab therapy. In some embodiments, the IL-6 therapy comprises a siltuximab therapy. In some embodiments, the IL-6 therapy comprises a satralizumab therapy. In some embodiments, the IL-6 therapy comprises a sarilumab therapy. In some embodiments, the IL-6ACTIVEUS 205211948 3Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 therapy comprises an olokizumab therapy. In some embodiments, the IL-6 therapy comprises a clazakizumab therapy.

[0016] In certain aspects, the subject matter described herein provides a method of treating sepsis and / or septic shock in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0017] In some embodiments, the sepsis and / or septic shock is caused by lipopolysaccharide (LPS). In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments, the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors.

[0018] In certain aspects, the subject matter described herein provides a method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0019] In some embodiments, the acute respiratory syndrome is caused by one or more respiratory virus infection. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more corticosteroids.

[0020] In certain aspects, the subject matter described herein provides a method of treating inflammation or a disease related to inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides of any one of the peptides described herein.ACTIVEUS 205211948 4Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0021] In some embodiments, the disease related to inflammation is an autoimmune disorder. In some embodiments, the disease related to inflammation is rheumatoid arthritis. In some embodiments, the disease related to inflammation is Castleman’s syndrome. In some embodiments, the disease related to inflammation is idiopathic juvenile arthritis. In some embodiments, the disease related to inflammation is neuromyelitis optica spectrum disorder. In some embodiments, the disease related to inflammation is autoimmune epilepsy. In some embodiments, the disease related to inflammation is a gastrointestinal disorder. In some embodiments, the disease related to inflammation is inflammatory bowel disease. In some embodiments, the disease related to inflammation is Crohn’s disease. In some embodiments, the disease related to inflammation is ulcerative colitis. In some embodiments, the disease related to inflammation is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease related to inflammation is asthma.

[0022] In some embodiments, the inflammation relates to Interleukin-6 (IL-6) production. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments, the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors. In some embodiments, the pharmaceutical composition is administered in combination with one or more corticosteroids. In some embodiments, the one or more corticosteroids is dexamethasone. In some embodiments, the pharmaceutical composition is administered in combination with an IL-6 therapy. In some embodiments, the IL-6 therapy comprises a tocilizumab therapy.BRIEF DESCRIPTION OF FIGURES

[0023] The patent or application file contains at least one drawing originally in color.

[0024] FIG. 1 shows the best 50 peptides out of 864,000 peptides screened for ability to bindArid5a.ACTIVEUS 205211948 5Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0025] FIG. 2 shows screening of KMZ peptides having inhibitory effects on LPS-induced human IL-6 production by THP1 cells in vitro. KMZ5, KMZ6, KMZ9, KMZ10, KMZ36, and KMZ40 peptides exhibit higher than 70% inhibitory effect.

[0026] FIGS. 3A-3B show inhibitory effects of peptides of the present disclosure on human IL-6. FIG. 3A shows inhibitory effect of KMZ9, KMZ5, and KMZ 10 peptides on human IL-6 produced by LPS-stimulated THP-1 cells. FIG. 3B shows inhibitory effect of KMZ9, KMZ1, and KMZ2 peptides, but not KMZ50 peptide on murine IL-6 produced by LPS-stimulated RAW264 cells.

[0027] FIGS. 4A-4B show effects of KMZ9. FIG. 4A shows that KMZ9 peptide pretreatment decreases in vivo serum IL-6 production of B6 mice upon LPS challenge. FIG. 4B shows a Kaplan-Meier curve illustrating that KMZ9 peptide pre-treatment improves the survival of B6 mice upon LPS challenge.

[0028] FIGS. 5A-5D show modeled structures of Arid5a. FIG. 5A shows modeled structure of the Arid5a nucleotide binding domain with the peptide binding pocket annotated (residues 78 to 85 and 121 to 137 from human Arid5a sequence with accession number KAI2524333.1).Arid5a was modeled using homolog protein Mrf2-DNA complex (PDB ID: 2OEH). FIG. 5B shows the surface mode of the binding pocket. FIG. 5C shows the binding modes of KMZ1, KMZ2, KMZ5, KMZ6, KMZ9, and KMZ10 predicted by docking. The electrostatic surface of the Arid5a is shown. All peptides bind to the potential DNA binding site of Arid5a (highlighted in dashed circle) inferred from its homology protein Mrf2-DNA complex. FIG. 5D shows a detailed binding mode of KMZ9.

[0029] FIG. 6 shows comparison of the IL-6 inhibitory effects of KMZ9 versus Arid5a peptide inhibitors listed in PCT / IB2020 / 056569. Pl, P2, and P3 are “Novel Arid5a Peptide Inhibitors” listed in PCT / IB2020 / 056569. Percent inhibition was calculated by the amount of human IL-6 secreted by LPS-stimulated THP-1 cells (human macrophage cell line) in the presence of the peptide divided by the amount of IL-6 secreted by LPS-stimulated THP-1 cells without peptide. Pl : ACTVGGYE (SEQ ID NO: 51; PIA), P2: EEACTVGG (SEQ ID NO: 52; HAN-13), P3: ACTVGGYEDGD (SEQ ID NO: 53).ACTIVEUS 205211948 6Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0030] FIG. 7 shows a schematic representation of two binding pockets on Arid5a. The Arid5a binding pocket for the peptides described herein is annotated. The binding pocket for the peptides described in PCT / IB2020 / 056569 is annotated.DETAILED DESCRIPTION

[0031] Peptides are short chains of amino acids, usually 2 to 50 amino acids in length. The amino acids in the peptide chain are covalently linked by peptide bonds. An amino acid chain comprises a terminus at each end: an amino-terminus (N-terminus or NEE-terminus) that initiates the amino acid chain, and a carboxyl-terminus (COOH-terminus or C-terminus) that marks the end of the amino acid chain. The amino acid residue at the N-terminus of the amino acid chain is known as, among other names, the N-terminal amino acid, whereas the amino acid residue at the C-terminus of the amino acid chain is known as, among other names, the C-terminal amino acid. The location of one or more amino acid residues within an amino acid chain (e.g., a peptide) can be identified by its proximity to either the N-terminus and / or the C-terminus of the amino acid chain, for example “three amino acid residues from the N-terminus of the peptide” or “three amino acid residues from the C-terminus of the peptide”. An amino acid chain of more than 51 amino acids in length is typically referred to as a polypeptide. Proteins can comprise one or more polypeptides. Peptides can interact with other peptides, proteins and other macromolecules. They play a major role in numerous important functions in cell signaling. Peptides can also act as immune modulators.

[0032] In some embodiments, a groove on a protein (e.g., Arid5a) is a concave and / or fold structure on the protein’s surface formed by one or more amino acid residues adjacent and / or in close physical proximity to one another. In some embodiments, a groove on a protein comprises one or more adjacent and / or close-proximity amino acid residues that together form a concave structure on the surface of the protein. In some embodiments, the protein is folded so that amino acid residues are in close physical proximity to one another despite not being directly connected by a peptide bond within an amino acid chain. In some embodiments, the groove comprises a charge. The charge of a groove on a protein is based on the net charge of individual amino acid residues within a region on the groove. For example, a groove comprised of positively charged amino acid residues will be a positively charged groove. The typical charge of amino acidACTIVEUS 205211948 7Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 residues in a physiological environment is known in the art. In some embodiments, the groove comprises a positively-charged region. In some embodiments, the groove comprises a negatively-charged region. In some embodiments, the groove does not have a charge (i.e. is hydrophobic). In some embodiments, the groove comprises a hydrophobic region. In some embodiments, the groove comprises multiple regions of distinct charge status. For example, the groove may comprise a positively-charged region and a hydrophobic (uncharged) region. In some embodiments, binding of the protein to a molecule (e.g., DNA or another protein) is facilitated by interaction between the groove of the protein and the molecule.

[0033] In certain aspects, the subject matter described herein provides a peptide that binds to the human AT-rich interactive domain 5a protein (Arid5a), wherein the peptide binds to one or more amino acid residues lining a groove on Arid5a, wherein the groove comprises Arid5a amino acid residues 78 to 85 and 121 to 137, wherein the peptide does not bind Ariad5a amino acid residues Glu58, Phe61, Leu62, Val63, Leu89, Tyr93, Leul38, Vall39, Tyrl42, Vall43, Hisl45, or Leul46. In some embodiments, the groove overlaps with an Arid5a nucleotide binding groove.

[0034] In some embodiments, a pocket on a protein (e.g., Arid5a) is any concave structure (e.g., a divot, valley, and / or hole) on the protein’s surface formed by one or more amino acid residues adjacent and / or in close physical proximity to one another. In some embodiments, the protein is folded so that amino acid residues are in close physical proximity to one another despite not being directly connected by a peptide bond within an amino acid chain. In some embodiments, the pocket comprises a charge. The charge of a pocket on a protein is based on the net charge of individual amino acid residues within a region on the pocket. For example, a pocket comprised of positively charged amino acid residues will be a positively charged pocket. In some embodiments, the pocket comprises a positively-charged region. In some embodiments, the positively-charged amino acid residue is arginine, histidine, or lysine. In some embodiments, the pocket comprises a negatively-charged region. In some embodiments, a negatively-charged amino acid residue is aspartate or glutamate. In some embodiments, the pocket does not have a charge (i.e. is hydrophobic). In some embodiments, the pocket comprises a hydrophobic region. In some embodiments, the pocket comprises multiple regions of distinct charge status. ForACTIVEUS 205211948 8Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 example, the pocket may comprise a positively-charged region and a hydrophobic (uncharged) region.

[0035] In some embodiments, binding the protein to a molecule (e.g., DNA or another protein) is facilitated by interaction between the pocket of the protein and the molecule including polar and hydrophobic interactions. In some embodiments, the interaction between the pocket and the molecule is facilitated by the charge status of the pocket and the molecule. For example, the molecule is a peptide, and the peptide comprises one or more negatively-charged amino acid residues that bind to a positively-charged region in the pocket.

[0036] In some embodiments, the peptide binds to a positively charged pocket within the groove, wherein the pocket comprises Arid5a amino acid residues R78, R133, and R137. In some embodiments, the peptide contains more than 3 amino acid residues. In some embodiments, one or more of the 3 amino acid residues from the N-terminus of the peptide bind to the positively charged pocket. In some embodiments, at least one of the one or more amino acid residues at the N-terminus of the peptide that bind to the positively charged pocket is negatively charged. In some embodiments, one or more of the 3 amino acid residues from the C- terminus of the peptide bind to the positively charged pocket. In some embodiments, at least one of the one or more amino acid residues at the C-terminus of the peptide that bind to the positively charged pocket is negatively charged.

[0037] In some embodiments, the pocket comprises a hydrophobic region. In some embodiments, the hydrophobic region of the pocket comprises one or more uncharged (i.e. hydrophobic) amino acid residues in close physical proximity to one another within the pocket. In some embodiments, the hydrophobic region comprises at least three hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises at least about three to at least about seven hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises three to seven hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises at least seven hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises seven or more hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises 3, 4, 5, 6, or 7 hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises 3 hydrophobicACTIVEUS 205211948 9Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 amino acid residues. In some embodiments, the hydrophobic region comprises 4 hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises 5 hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises 6 hydrophobic amino acid residues. In some embodiments, the hydrophobic region comprises 7 hydrophobic amino acid residues. In some embodiments, the hydrophobic amino acid residue is an alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, or tryptophan residue. In some embodiments, one or more hydrophobic amino acid residues of the peptide bind to one or more amino acid residues in the hydrophobic region of the pocket. In some embodiments, at least one of the one or more hydrophobic amino acid residues of the peptide that bind to one or more amino acid residues in the hydrophobic region of the pocket is an aromatic residue. An aromatic amino acid residue is an amino acid residue that comprises an aromatic ring. In some embodiments, the aromatic residue is a histidine, phenylalanine, tryptophan, or tyrosine residue. In some embodiments, one or more amino acid residues of the peptide form one or more salt bridges with Arid5a amino acid residue R78 and R133. A salt bridge is a combination of hydrogen bonding and ionic bonding that can occur between two amino acid residues in close physical proximity and can facilitate stability of binding between these two molecules. In some embodiments, the peptide consists of 6, 7, 8, 9, or 10 amino acids. In some embodiments, the peptide consists of 8 amino acids.

[0038] In certain aspects, the subject matter described herein provides a peptide that comprises any one of SEQ ID NOs: 1-50. In some embodiments, the peptide comprises SEQ ID NO: 1. In some embodiments, the peptide comprises SEQ ID NO: 2. In some embodiments, the peptide comprises SEQ ID NO: 3. In some embodiments, the peptide comprises SEQ ID NO: 4. In some embodiments, the peptide comprises SEQ ID NO: 5. In some embodiments, the peptide comprises SEQ ID NO: 6. In some embodiments, the peptide comprises SEQ ID NO: 7. In some embodiments, the peptide comprises SEQ ID NO: 8. In some embodiments, the peptide comprises SEQ ID NO: 9. In some embodiments, the peptide comprises SEQ ID NO: 10. In some embodiments, the peptide comprises SEQ ID NO: 11. In some embodiments, the peptide comprises SEQ ID NO: 12. In some embodiments, the peptide comprises SEQ ID NO: 13. In some embodiments, the peptide comprises SEQ ID NO: 14. In some embodiments, the peptide comprises SEQ ID NO: 15. In some embodiments, the peptide comprises SEQ ID NO: 16. InACTIVEUS 205211948 10Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 some embodiments, the peptide comprises SEQ ID NO: 17. In some embodiments, the peptide comprises SEQ ID NO: 18. In some embodiments, the peptide comprises SEQ ID NO: 19. In some embodiments, the peptide comprises SEQ ID NO: 20. In some embodiments, the peptide comprises SEQ ID NO: 21. In some embodiments, the peptide comprises SEQ ID NO: 22. In some embodiments, the peptide comprises SEQ ID NO: 23. In some embodiments, the peptide comprises SEQ ID NO: 24. In some embodiments, the peptide comprises SEQ ID NO: 25. In some embodiments, the peptide comprises SEQ ID NO: 26. In some embodiments, the peptide comprises SEQ ID NO: 27. In some embodiments, the peptide comprises SEQ ID NO: 28. In some embodiments, the peptide comprises SEQ ID NO: 29. In some embodiments, the peptide comprises SEQ ID NO: 30. In some embodiments, the peptide comprises SEQ ID NO: 31. In some embodiments, the peptide comprises SEQ ID NO: 32. In some embodiments, the peptide comprises SEQ ID NO: 33. In some embodiments, the peptide comprises SEQ ID NO: 34. In some embodiments, the peptide comprises SEQ ID NO: 35. In some embodiments, the peptide comprises SEQ ID NO: 36. In some embodiments, the peptide comprises SEQ ID NO: 37. In some embodiments, the peptide comprises SEQ ID NO: 38. In some embodiments, the peptide comprises SEQ ID NO: 39. In some embodiments, the peptide comprises SEQ ID NO: 40. In some embodiments, the peptide comprises SEQ ID NO: 41. In some embodiments, the peptide comprises SEQ ID NO: 42. In some embodiments, the peptide comprises SEQ ID NO: 43. In some embodiments, the peptide comprises SEQ ID NO: 44. In some embodiments, the peptide comprises SEQ ID NO: 45. In some embodiments, the peptide comprises SEQ ID NO: 46. In some embodiments, the peptide comprises SEQ ID NO: 47. In some embodiments, the peptide comprises SEQ ID NO: 48. In some embodiments, the peptide comprises SEQ ID NO: 49. In some embodiments, the peptide comprises SEQ ID NO: 50.

[0039] In certain aspects, the subject matter described herein provides a peptide that comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to any one of SEQ ID NOs: 1-50. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ IDACTIVEUS 205211948 11Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025NO: 2. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 3. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 4. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 5. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 6. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 8. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 9. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 10. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 11. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 12. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 13. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 14. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 15. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 16. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, atACTIVEUS 205211948 12Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 17. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 18. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 19. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 20. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 21. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 22. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 23. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 24. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 25. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 26. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 27. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 28. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 29. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 30. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 31. In some embodiments, the peptide comprises anACTIVEUS 205211948 13Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 32. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 33. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 34. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 35. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 36. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 37. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 38. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 39. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 40. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 41. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 42. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 43. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 44. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 45. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%ACTIVEUS 205211948 14Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 identity to SEQ ID NO: 46. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 47. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 48. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 49. In some embodiments, the peptide comprises an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 50.

[0040] Peptide SequencesACTIVEUS 205211948 15Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025ACTIVEUS 205211948 16Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0041] Peptide Use

[0042] In certain aspects, the subject matter described herein provides a peptide for use in inhibiting Interleukin 6 (IL-6) production in a subject in need thereof, wherein the subject is administered a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with an IL-6 therapy. In some embodiments, the IL- 6 therapy comprises a tocilizumab therapy. In some embodiments, the IL-6 therapy comprises a siltuximab therapy. In some embodiments, the IL-6 therapy comprises a satralizumab therapy. In some embodiments, the IL-6 therapy comprises a sarilumab therapy. In some embodiments, the IL-6 therapy comprises an olokizumab therapy. In some embodiments, the IL-6 therapy comprises a clazakizumab therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotics. In some embodiments, the pharmaceutical composition is administered in combination with a fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors.

[0043] In some embodiments, the peptide described herein is used in a therapy for sepsis treatment in a subject in need thereof. In some embodiments, the sepsis is caused by lipopolysaccharide (LPS). In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors.

[0044] In some embodiments, the peptide described herein is used in a therapy for septic shock treatment. In some embodiments, the septic shock is caused by lipopolysaccharide (LPS).ACTIVEUS 205211948 17Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments, the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments the pharmaceutical composition is administered in combination with one or more vasopressors.

[0045] In some embodiments, the peptide described herein is used in a therapy for acute respiratory syndrome in subject in need thereof. In some embodiments, the acute respiratory syndrome is caused by one or more respiratory virus infection. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more corticosteroids.

[0046] Peptide Production

[0047] The peptides disclosed herein can be produced by any method known in the art. The peptides disclosed herein can be produced by a step-wise, cyclic process of adding amino acids to a growing peptide chain where the carboxyl group of the incoming amino acid is coupled to the N-terminus of the growing peptide chain. Peptide synthesis must avoid side reactions that can reduce the length and cause branching of the peptide chain due to the multiple reactive groups on amino acids. Chemical groups can be used to bind to the amino acid reactive groups and block, or protect, the functional group from nonspecific reaction. Individual amino acids that have been purified are reacted with these protecting groups prior to being added to the synthesis reaction. Then specific protecting groups are removed from the newly added amino acid in a deprotection reaction. Deprotection occurs prior to adding the next amino acid to allow the next incoming amino acid to bind to the growing peptide chain in the proper orientation. Once the whole peptide chain is synthesized, all remaining protecting groups are removed.

[0048] Amino acid N-termini can be protected by “temporary” protecting groups. These groups are relatively easy to remove to allow peptide bond formation. For example, the “temporary” protecting group can be tert-butoxycarbonyl (Boc) or 9-fluorenylmethoxycarbonylACTIVEUS 205211948 18Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025(Fmoc). Boc chemistry requires acidic conditions for deprotection, while Fmoc is cleaved under mild, basic conditions.

[0049] The choice of a C-terminal protecting group depends on whether liquid-phase peptide synthesis or solid-phase peptides is being utilized. Liquid-phase requires protection of the C- terminus of the first amino acid, while solid-phase peptide synthesis does not, because the solid support itself acts as the protecting group for the only C-terminal amino acid that requires protection.

[0050] Many different protecting groups are required for the protection of amino acid side chains because they can have a broad range of functional groups and are a site of considerable reactivity. This variety of protecting groups is based on the benzyl (Bzl) or tert-butyl (tBu) groups. Side chain protecting groups are “permanent” protecting groups. They can withstand multiple cycles of chemical treatment necessary for the synthesis of the peptide chain. They are removed during treatment with strong acids after synthesis of the peptide is complete. Scavengers such as water, anisol or thiol derivatives can be added in excess during the deprotection step to react with any free reactive species that may have formed during removal of the protecting groups.

[0051] C-terminal carboxylic acid on the incoming amino acid must be activated using carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC). These coupling reagents form a highly reactive O-acylisourea intermediate on the carboxyl group that is quickly displaced through a nucleophilic attack reaction from the deprotected primary amino group on the N-terminus of the growing peptide chain. These reactions form the nascent peptide bond. Racemization might occur during the formation of nascent peptide bonds, in which amino acids lose their desired stereochemistry, especially when the intermediates generated by coupling reagents are highly reactive. Reagents that reduce the risk of racemization can be used to prevent racemization. Other coupling agents include, but are not limited to, benzotriazol- 1 -yl- oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).ACTIVEUS 205211948 19Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0052] Following successive cycles of amino acid deprotection and coupling, all remaining protecting groups are removed from the nascent peptide via cleavage by acidolysis. Strong acids such as hydrogen fluoride (HF), hydrogen bromide (HBr) or trifluoromethane sulfonic acid (TFMSA) can be used to cleave Boc and Bzl groups. A milder acid such as TFA can be used to cleave Fmoc and tBut groups. Cleavage results in the removal of the N-terminal protecting group of the last amino acid added, the C-terminal protecting group from the first amino acid on the chain as well as any remaining side-chain protecting groups. Scavengers can also be included during this step to react and neutralize any free protecting groups.

[0053] Incomplete deprotection of the peptide chain or reaction with free protecting groups can cause truncated or deletion sequences, isomers or other undesirable products. A longer peptide chain creates a greater probability that such undesirable products will be generated, decreasing the peptide yield. The peptides must be purified to remove the undesirable products. Purification strategies are based on a combination of separation methods and hydrophobicity. Separation methods exploit the physiochemical characteristics of peptides, including size and charge. Purification techniques include, but are not limited to, size-exclusion chromatography, ion exchange chromatography (IEC), partition chromatography, high-performance liquid chromatography (HPLC), or reverse-phase chromatography (RPC), which is the most widely used method of peptide purification. In HPLC, the stationary phase captures polar, hydrophilic molecules that are then differentially eluted with increasing concentration of polar solvents in the mobile phase. In RPC, hydrophobic molecules from aqueous solutions are captured by the stationary phase using hydrophobic C4, C8 or Cl 8 n-alkyl hydrocarbon ligands, and their retention time is a function of the hydrophobicity of the molecule and that of the mobile phase.

[0054] Peptide purity can be measured by any known method in the art. It can be measured as a percentage of the target peptide to impurities that absorb at the peptide bond absorption wavelength. In some embodiments, the peptides disclosed herein are synthesized with a purity of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, purity of the peptides is measured by any suitable method known in the art.ACTIVEUS 205211948 20Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0055] In some embodiments, the peptides disclosed herein are produced by culturing a cell transfected or transformed with a vector comprising nucleic acid sequences encoding a peptide described herein and isolating the peptide. In some embodiments, expression of a peptide comprises expression vector(s) containing a polynucleotide that encodes any of the peptides disclosed herein. Methods that are well known to those skilled in the art can be used to construct expression vectors comprising peptide coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Particular embodiments provide replicable vectors comprising a nucleotide sequence encoding a peptide disclosed herein operably linked to a promoter.

[0056] Various expression systems for producing peptides are known in the art, and include, prokaryotic (e.g., bacteria), plant, insect, yeast, and mammalian expression systems. Suitable cell lines can be transformed, transduced, or transfected with nucleic acids containing coding sequences for peptides or portions of peptides disclosed herein in order to produce the peptide of interest. Expression vectors containing such nucleic acid sequences, which can be linked to at least one regulatory sequence in a manner that allows expression of the nucleotide sequence in a host cell, can be introduced via methods known in the art. Practitioners in the art understand that designing an expression vector can depend on factors, such as the choice of host cell to be transfected and / or the type and / or amount of desired protein to be expressed. Enhancer regions, which are those sequences found upstream or downstream of the promoter region in non-coding DNA regions, are also known in the art to be important in optimizing expression. If needed, origins of replication from viral sources can be employed, such as if a prokaryotic host is utilized for introduction of plasmid DNA. However, in eukaryotic organisms, chromosome integration is a common mechanism for DNA replication. For stable transfection of mammalian cells, a small fraction of cells can integrate introduced DNA into their genomes. The expression vector and transfection method utilized can be factors that contribute to a successful integration event. For stable amplification and expression of a desired peptide, a vector containing DNA encoding a peptide of interest is stably integrated into the genome of eukaryotic cells (for example mammalian cells), resulting in the stable expression of transfected genes. A gene that encodes a selectable marker (for example, resistance to antibiotics or drugs) can be introduced into hostACTIVEUS 205211948 21Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 cells along with the gene of interest in order to identify and select clones that stably express a gene encoding a peptide of interest. Cells containing the gene of interest can be identified by drug selection wherein cells that have incorporated the selectable marker gene will survive in the presence of the drug. Cells that have not incorporated the gene for the selectable marker die. Surviving cells can then be screened for the production of the desired peptide.

[0057] In some embodiments, the peptides disclosed herein are encoded in a vector for expression in a cell line. In some embodiments, a vector comprises a polynucleotide sequence that encodes any peptide disclosed herein and the vector is transfected into one or more cell lines for expression. A host cell strain, which modulates the expression of the inserted sequences, or modifies and processes the nucleic acid in a specific fashion desired also may be chosen. Such modifications (for example, glycosylation and other post-translational modifications) and processing (for example, cleavage) of peptide products may be important for the function of the peptide. Different host cell strains have characteristic and specific mechanisms for the post- translational processing and modification of proteins and gene products. As such, appropriate host systems or cell lines can be chosen to ensure the correct modification and processing of the peptide expressed. Thus, eukaryotic host cells possessing the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.

[0058] In some embodiments, the peptide is administered to a subject for expression by a target cell in vivo. In some embodiments, the peptide is encoded by a vector and packaged in a virion. In some embodiments, the peptide is delivered using a viral vector. Viral vectors suitable for in vivo expression of a peptide include, but are not limited to, adenoviruses, adeno- associated viruses, lentiviruses, and retroviruses. Lundstrom, Kenneth. 2018. "Viral Vectors in Gene Therapy" Diseases 6, no. 2: 42. https: / / doi.org / 10.3390 / diseases6020042. In some embodiments, the peptide is administered to the subject for in vivo expression using a non-viral vector. In some embodiments, the non-viral vector is a lipid nanoparticle or a polymeric carrier. In some embodiments, the peptide is encoded by an RNA and delivered using a lipid nanoparticle. Lipid nanoparticles (LNPs) and methods of producing are disclosed, for example, in Kulkarni, Jayesh A., Pieter R. Cullis, and Roy Van Der Meel. "Lipid nanoparticles enablingACTIVEUS 205211948 22Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 gene therapies: from concepts to clinical utility." Nucleic acid therapeutics 28, no. 3 (2018): 146- 157. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the peptide encoded by the vector is administered to the subject in vivo to treat a disease or disorder.

[0059] Various culturing parameters can be used with respect to the host cell being cultured. Appropriate culture conditions for mammalian cells are well known in the art or can be determined by the skilled artisan (see, for example, Animal Cell Culture: A Practical Approach 2ndEd., Rickwood, D. and Hames, B. D., eds. (Oxford University Press: New York, 1992)). Cell culturing conditions can vary according to the type of host cell selected. Commercially available media can be utilized.

[0060] Peptides disclosed herein can be purified from any human or non-human cell that expresses the peptides, including those that have been transfected with expression constructs that express the peptide. For peptide recovery, isolation and / or purification, the cell culture medium or cell lysate is centrifuged to remove particulate cells and cell debris. The desired peptide is isolated or purified away from contaminating soluble proteins and polypeptides by suitable purification techniques. Non-limiting purification methods for proteins / antibodies include: size exclusion chromatography, affinity chromatography, ion exchange chromatography, ethanol precipitation; reverse phase HPLC; chromatography on a resin, such as silica, or cation exchange resin, e.g., DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, e.g., Sephadex G-75, Sepharose; protein A sepharose chromatography for removal of immunoglobulin contaminants; and the like. Other additives, such as protease inhibitors (e.g., PMSF or proteinase K) can be used to inhibit proteolytic degradation during purification.Purification procedures that can select for carbohydrates can also be used, e.g, ion-exchange soft gel chromatography, or HPLC using cation- or anion-exchange resins, in which the more acidic fraction(s) is / are collected.

[0061] Arid5a

[0062] The AT-rich interaction domain (Arid) is a DNA-binding domain with a helix-turn- helix motif. The ARID consensus sequence spans about 100 amino acids. This domain isACTIVEUS 205211948 23Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 characteristic for a family of 15 proteins in humans, however, not all of the family members bind DNA. This family of proteins plays a role in development, tissue-specific gene expression, cell proliferation, and inflammation.

[0063] Arid5a is a nucleic acid binding protein with DNA-binding domain carrying the helix-turn-helix motif typical for the family. Arid5a performs dual functions, transcriptional and post-transcription regulation of protein expression, mRNAs depending on its subcellular (nuclear or cytoplasmic) localization. Arid5a regulates the immune response through its dual-function regulation of several transcription factors and inflammatory mRNA transcripts, including IL-6. At rest, Arid5a is localized to the cell nucleus and regulates the function of transcription factors. Under inflammatory conditions, Arid5a relocates to the cytoplasm, where it is involved in mRNA stabilization. Lipopolysaccharide (LPS) can induce Arid5a expression in the early phase of stimulation through a NFKB signaling mechanism. Overexpression of NFKB in LPS-induced cells increases the activity of the Arid5a promoter. During the late phase of LPS stimulation another arm of the TLR4 pathway involving TRIF signaling promotes Arid5a-mediated IL6 expression. Nuclear 116 mRNA is increased in the early phase of LPS stimulation, whereas cytoplasmic 116 mRNA is increased at later time points. Both nuclear and cytoplasmic Arid5a have the ability to bind to inflammatory mRNAs, such as 116, even after LPS stimulation. Thus, Arid5a is a potential target for regulation of inflammation. Inhibiting Arid5a-associated transcriptional regulation in the nucleus and post-transcriptional regulation of inflammatory genes in the cytoplasm can improve symptoms of inflammation. Masuda, K., PNAS 2013, 110 (23) 9409-9414; Nyati, K.K, et al. Front. Immunol., 2022.

[0064] In some embodiments, the subject matter described herein relates to a method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide binds Arid5a. In some embodiments, the subject matter described herein relates to a method of treating sepsis and / or septic shock in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide binds Arid5a. In some embodiments, the subject matter describedACTIVEUS 205211948 24Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 herein relates to a method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide binds Arid5a. In some embodiments, the subject matter described herein relates to a method of inhibiting IL-6 production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide binds Arid5a.

[0065] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces Arid5a activity in a sample from the subject by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline Arid5a activity in a reference sample from the subject. In some embodiments, the reference sample is blood. In some embodiments, the reference sample is a biopsy sample. In some embodiments, the reference sample is from a healthy individual. In some embodiments, the reference sample is from a subject not treated with the peptide(s) disclosed herein or a composition thereof.

[0066] Interleukin-6 (IL-6)

[0067] IL-6 is a cytokine with a dual effect in inflammation. It can act as a defense mechanism against invading microorganisms. However, it can also have pre- inflammatory effects in chronic inflammation. IL-6 is produced at the site of inflammation and plays a major role in the acute phase of the inflammation response. The acute phase is characterized by the production of acute phase proteins. IL-6 binds its soluble receptor sIL-6Ra to regulate the transition from acute to chronic inflammation by changing the nature of leucocyte infiltrate. In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus promoting chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling can lead to effective prevention and treatment of chronic inflammatory diseases and sepsis. (Gabay, C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 8 (Suppl 2), S3 (2006)).

[0068] Lipopolysaccharides (LPS) are large amphipathic glycoconjugates located on the outer membrane of gram-negative bacteria. LPS generally consist of a lipid domainACTIVEUS 205211948 25Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025(hydrophobic) attached to a core oligosaccharide and a distal polysaccharide. LPS administration in vivo increases IL-6 mRNA and protein levels. The increase of IL-6 is part of the body’s immune response to bacterial exposure.

[0069] In some embodiments, the subject matter described herein relates to a method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide reduces or inhibits IL-6 production. In some embodiments, the subject matter described herein relates to a method of treating sepsis and / or septic shock in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide reduces or inhibits IL-6 production. In some embodiments, the subject matter described herein relates to a method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein, wherein the peptide reduces or inhibits IL-6 production. In some embodiments, the subject matter described herein relates to a method of inhibiting IL-6 production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0070] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces or inhibits IL-6 production in a sample from the subject by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline IL-6 production in a reference sample from the subject. In some embodiments, the reference sample is blood. In some embodiments, the reference sample is a biopsy sample. In some embodiments, the reference sample is from a healthy individual. In some embodiments, the reference sample is from a subject not treated with the peptide(s) disclosed herein or a composition thereof.

[0071] Inflammation and SepsisACTIVEUS 205211948 26Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0072] Inflammation is a complex defense mechanism of the body against offending antigens or antigens the body perceives as foreign. The process involves migration of leukocytes from the vasculature into damaged tissues to destroy the agents that can cause tissue injury. Acute inflammation had a limited beneficial response during an infectious challenge the body needs to overcome. However, chronic inflammation is a persistent phenomenon that can lead to progressive tissue damage over time. Chronic inflammation is associated with the presence of mononuclear cells, such as macrophages and lymphocytes.

[0073] Inflammation often occurs in response to microbials such as pathogen-associated molecular patterns (PAMPs) which activate germline-encoded pattern-recognition receptors (PRRs) expressed in both immune and nonimmune cells. Toll-like receptors (TLRs) are a family of PRRs that play a role in the activation of the inflammatory response. Signaling through TLRs activates an intracellular signaling cascade resulting in nuclear translocation of transcription factors, such as activator protein-1 (AP-1) and NF-KB. Pro-inflammatory stimuli and cytokines such as interleukin- ip (IL- 1 (3), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR). Receptor activation activates signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-KB), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. Chen., L., et al., Oncotarget. 2018, 9(6): 7204-7218.

[0074] One form of inflammation is cytokine release syndrome (CRS), a systemic inflammatory response triggered by variety of factors such as infection, cell therapy, and certain drugs. In patients, CRS can present with fevers, myalgias, hypotension, and hypoxia. Severe CRS can cause high-grade fevers and hemodynamic compromise, requiring vasopressor support, capillary leak, and severe hypoxia requiring ventilator support. IL-6 is a major cytokine implicated in the parthenogenesis of CRS and may be responsible for some of the more serious symptoms of CRS such as capillary leakage, hypotension, and myocardial dysfunction. Murthy, Hemant, Madiha Iqbal, Julio C. Chavez, and Mohamed A. Kharfan-Dabaja. "Cytokine release syndrome: current perspectives." ImmunoTargets and therapy (2019): 43-52.ACTIVEUS 205211948 27Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0075] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces one or more symptoms associated with inflammation by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline of the one or more symptoms of inflammation prior to administration. In some embodiments, symptoms of inflammation include, but are not limited to, skin redness, skin heat, swelling, pain, activation of mast cells, activation of basophils, activation of eosinophils, cytokine release, and histamine release.

[0076] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces one or more symptoms associated with cytokine release syndrome (CRS) by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline of the one or more symptoms of CRS prior to administration. In some embodiments, symptoms of CRS include, but are not limited to, fever, myalgia, hypotension, hypoxia, capillary leakage, activation of complement pathway and coagulation pathways, and myocardial dysfunction.

[0077] Sepsis is a life-threatening response of the body to an infection. During this exaggerated response the infection-fighting mechanisms attack the body itself leading to organ failure. Sepsis is fundamentally an inflammatory disease mediated by the host immune response. Symptoms of sepsis include, but are not limited to, fast and shallow breathing, shivering, and lightheadedness. Sepsis can progress to septic shock with a dramatic drop in blood pressure. Symptoms of septic shock include, but are not limited to, not being able to stand up, strong sleepiness or difficulty staying awake, and major change in mental status, such as extreme confusion.

[0078] In some embodiments, the subject matter described herein relates to a method of treating inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein. In some embodiments, the subject matter described herein relates to a method of treating sepsis and / or septic shock in a subject in need thereof, the methodACTIVEUS 205211948 28Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein. In some embodiments, the subject matter described herein relates to a method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein. In some embodiments, the subject matter described herein relates to a method of inhibiting IL-6 production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0079] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces one or more symptoms associated with sepsis by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline of the one or more symptoms of sepsis prior to administration. In some embodiments, symptoms of sepsis include, but are not limited to, body chills, confusion or delirium, nausea, vomiting, fever or low body temperature (hypothermia), lightheadedness due to low blood pressure, rapid heartbeat, skin rash or mottled skin, skin redness, skin heat, swelling, pain, activation of mast cells, activation of basophils, activation of eosinophils, cytokine release, and histamine release.

[0080] In some embodiments, administration of the peptide(s) disclosed herein or pharmaceutical compositions thereof reduces one or more symptoms associated with septic shock by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% compared to a baseline of the one or more symptoms of septic shock prior to administration. In some embodiments, symptoms of septic shock include, but are not limited to, body chills, confusion or delirium, nausea, vomiting, fever or low body temperature (hypothermia), lightheadedness due to low blood pressure, rapid heartbeat, skin rash or mottled skin, skin redness, skin heat, swelling, pain, activation of mast cells, activation of basophils, activation of eosinophils, cytokine release, and histamine release.ACTIVEUS 205211948 29Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0081] Tocilizumab (Actemra, Tofidence, tocilizumab-bavi, Tyenne, tocilizumab-aazg) therapy

[0082] Tocilizumab is an immunosuppressive drug approved to treat adults with moderately to severely active rheumatoid (RA). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Tocilizumab blocks the inflammatory protein IL-6, which improves joint pain and swelling from arthritis and other symptoms caused by inflammation. Tocilizumab can be administered either as an injection under the skin or as an intravenous infusion. When it is injected under the skin, it can be used every week or every other week, usually given in the skin of the abdomen or the thighs. When it is given as an infusion, it is given once every 4 weeks. In some embodiments, the method described herein further comprises administering to the subject an effective amount of tocilizumab. In some embodiments, the effective amount of tocilizumab is about 50 mg, about 75 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. In some embodiments, the effective amount of tocilizumab is about 162 mg.

[0083] Siltuximab (Sylvant) therapy

[0084] Siltuximab is a human-mouse chimeric monoclonal antibody against IL-6. It prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. Siltuximab reduces inflammation and is used to treat multicentric Castleman’s disease (MCD), a rare immune dysregulation disorder. Siltuximab is given at 11 mg / kg via 1-hour infusion every 3 to 6 weeks. In some embodiments, the method described herein further comprises administering to the subject an effective amount of siltuximab. In some embodiments, the effective amount of siltuximab is about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg. In some embodiments, the effective amount of siltuximab is about 11 mg / kg.

[0085] Satralizumab (Enspryng) therapyACTIVEUS 205211948 30Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0086] Satralizumab is a humanized monoclonal antibody that blocks the IL-6 receptor. It is approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD). This is an autoimmune disorder, in which recurrent attacks by the body’s own immune system can cause severe, life-long disability. The disorder can affect other regions of the central nervous system. An initial loading dose of 120 mg is administered by subcutaneous injection every other week for 3 injections followed by 120 mg subcutaneously every 4 weeks. In some embodiments, the method described herein further comprises administering to the subject an effective amount of satralizumab. In some embodiments, the effective amount of satralizumab is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg. In some embodiments, the effective amount of satralizumab is about 120 mg.

[0087] Sarilumab (Kevzara) therapy

[0088] Sarilumab is an injectable human monoclonal antibody that functions as an IL-6 receptor blocker. It is used for treatment of moderately to severely active rheumatoid arthritis (RA). Sarilumab is administered in a 200 mg dosage injected under the patient’s skin once every 2 weeks. In some embodiments, the method described herein further comprises administering to the subject an effective amount of sarilumab. In some embodiments, the effective amount of sarilumab is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg. In some embodiments, the effective amount of sarilumab is about 200 mg.

[0089] Olokizumab therapy

[0090] Olokizumab is a humanized monoclonal antibody that binds directly to IL-6 to block its function. It is currently in clinical trial for treatment of rheumatoid arthritis (RA). Tanaka Y, Martin Mola EIL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab; Annals of the Rheumatic Diseases 2014;73: 1595-1597. Olokizumab has been tested for administration in a 60mg, 120mg, or 240mg dose every two or four weeks. In some embodiments, the method described herein further comprises administeringACTIVEUS 205211948 31Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 to the subject an effective amount of olokizumab. In some embodiments, the effective amount of olokizumab is about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, or about 240 mg. In some embodiments, the effective amount of olokizumab is about 60 mg. In some embodiments, the effective amount of olokizumab is about 120 mg. In some embodiments, the effective amount of olokizumab is about 240 mg.

[0091] Clazakizumab therapy

[0092] Clazakizumab is a monoclonal antibody targeting the IL-6 ligand. It is currently in clinical trial for treatment of cardiovascular risk in patients with cardiovascular disease and / or diabetes receiving maintenance dialysis with high sensitivity C-reactive protein (hs-CRP) > 2 mg I’1at baseline. Chertow, G.M., Chang, A.M., Felker, G.M. et al. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nat Med 30, 2328-2336 (2024). https: / / doi.org / 10.1038 / s41591-024-03043-l. Clazakizumab has been tested for administration in a 2.5mg, 5mg, or lOmg dose every four weeks. In some embodiments, the method described herein further comprises administering to the subject an effective amount of clazakizumab. In some embodiments, the effective amount of clazakizumab is about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about lOmg, about 10.5mg, about l lmg, about 11.5mg, or about 12mg. In some embodiments, the effective amount of clazakizumab is about 2.5mg. In some embodiments, the effective amount of clazakizumab is about 5mg. In some embodiments, the effective amount of clazakizumab is about lOmg.

[0093] Sepsis treatment

[0094] The primary treatment for sepsis, severe sepsis or septic shock is antibiotics. Broadspectrum antibiotics are effective against a variety of bacteria that are the cause of sepsis or septic shock. The antibiotic can be tailored to the specific bacteria strain causing sepsis if the strain is known. Vasopressors can be useful in the treatment of sepsis because they narrow theACTIVEUS 205211948 32Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 blood vessels in the body leading to an increase in blood pressure. Fluids such as saline can also be administered.

[0095] Acute Respiratory Syndrome / Severe Acute Respiratory Syndrome

[0096] Acute Respiratory Syndrome (ARS) is a viral respiratory disease that can be caused by coronavirus. It is a serious lung condition that can lead to low blood oxygen. Fluid can build up inside the small air sacs of the lungs and the surfactant lining of the air sacks can break down. Supplying oxygen is the main treatment.

[0097] Methods of Treatment

[0098] In one embodiment, the subject matter disclosed herein relates to a preventive medical treatment started after following diagnosis of a disease (e.g., sepsis, septic shock, or acute respiratory syndrome) in order to prevent the disease from worsening or curing the disease. In one embodiment, the subject matter disclosed herein relates to prophylaxis of subjects who are believed to be at risk for moderate or severe disease associated with sepsis, septic shock, or acute respiratory syndrome or have previously been diagnosed with another disease. In one embodiment, the subjects are administered the pharmaceutical composition described herein. The invention contemplates using any of the peptides produced by the systems and methods described herein. In one embodiment, the compositions described herein are administered subcutaneously or intravenously via syringe or any other suitable method known in the art.

[0099] The peptide (s) disclosed herein, or pharmaceutical compositions comprising the peptide(s) may be administered to a cell, mammal, or human by any suitable means. In some embodiments, one or more peptides disclosed herein are prepared in a cocktail of DNA-encoding peptide(s) or mRNA-encoding peptide(s) and delivered to a subject for in vivo expression of the encoded peptide(s).

[0100] As will be readily apparent to one skilled in the art, the effective in vivo dose to be administered and the particular mode of administration will vary depending upon the age, weight and species treated, and the specific use for which the compound or combination of compounds disclosed herein are employed. The determination of effective dose levels, that is the dose levelsACTIVEUS 205211948 33Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Generally, human clinical applications of products are commenced at lower dose levels, with dose level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods. Effective animal doses from in vivo studies can be converted to appropriate human doses using conversion methods known in the art.

[0101] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing sepsis, septic shock, and acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject any of the peptides disclosed herein. In some embodiments, the method further comprises administering to the subject epinephrine. In some embodiments, the method further comprises administering to the subject omalizumab. In some embodiments, the method further comprises administering to the subject palforzia. In some embodiments, the method further comprises administering to the subject one or more antibiotics. In some embodiments, the method further comprises administering to the subject fluids. In some embodiments, the method further comprises administering to the subject one or more vasopressin.

[0102] In some embodiments, the peptide binds Arid5a. In some embodiments, the peptide inhibits Arid5a function. In some embodiments, the peptide inhibits IL-6 production. In some embodiments, the peptide inhibits IL-6 activity. In some embodiments, the peptide inhibits IL-6 production upon lipopolysaccharide (LPS) challenge.

[0103] In certain aspects, the subject matter described herein provides a method of inhibiting Interleukin 6 (IL-6) production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0104] In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with an IL-6 therapy. In some embodiments, the IL-6 therapyACTIVEUS 205211948 34Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 comprises a tocilizumab therapy. In some embodiments, the IL-6 therapy comprises a siltuximab therapy. In some embodiments, the IL-6 therapy comprises a satralizumab therapy. In some embodiments, the IL-6 therapy comprises a sarilumab therapy. In some embodiments, the IL-6 therapy comprises an olokizumab therapy. In some embodiments, the IL-6 therapy comprises a clazakizumab therapy.

[0105] In certain aspects, the subject matter described herein provides a method of treating sepsis and / or septic shock in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0106] In some embodiments, the sepsis and / or septic shock is caused by lipopolysaccharide (LPS). In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments, the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors.

[0107] In certain aspects, the subject matter described herein provides a method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides described herein.

[0108] In some embodiments, the acute respiratory syndrome is caused by one or more respiratory virus infection. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more corticosteroids.

[0109] In certain aspects, the subject matter described herein provides a method of treating inflammation or a disease related to inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising aACTIVEUS 205211948 35Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 therapeutically effective amount of any one of the peptides of any one of the peptides described herein.

[0110] In some embodiments, the disease related to inflammation is an autoimmune disorder. In some embodiments, the disease related to inflammation is rheumatoid arthritis. In some embodiments, the disease related to inflammation is Castleman’s syndrome. In some embodiments, the disease related to inflammation is idiopathic juvenile arthritis. In some embodiments, the disease related to inflammation is neuromyelitis optica spectrum disorder. In some embodiments, the disease related to inflammation is autoimmune epilepsy. In some embodiments, the disease related to inflammation is a gastrointestinal disorder. In some embodiments, the disease related to inflammation is inflammatory bowel disease. In some embodiments, the disease related to inflammation is Crohn’s disease. In some embodiments, the disease related to inflammation is ulcerative colitis. In some embodiments, the disease related to inflammation is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease related to inflammation is asthma.

[0111] In some embodiments, the inflammation relates to Interleukin-6 (IL-6) production. In some embodiments, the inflammation is related to cytokine release syndrome (CRS) or cytokine storm. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more antibiotic therapy. In some embodiments, the pharmaceutical composition is administered in combination with an intravenous fluids therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more vasopressors.

[0112] In some embodiments, the disease related to inflammation is cytokine release syndrome (CRS) or cytokine storm. In some embodiments, the pharmaceutical composition is administered in combination with another therapy. In some embodiments, the pharmaceutical composition is administered in combination with one or more corticosteroids. In some embodiments, the one or more corticosteroids is dexamethasone. In some embodiments, the pharmaceutical composition is administered in combination with an IL-6 therapy. In some embodiments, the IL-6 therapy comprises a tocilizumab therapy.ACTIVEUS 205211948 36Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0113] Pharmaceutical Compositions

[0114] In some embodiments, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the peptides disclosed herein, including without limitation peptides described in section entitled “Peptide Sequences.”

[0115] In some embodiments, the pharmaceutical composition disclosed herein further comprises one or more pharmaceutically-acceptable diluents, one or more pharmaceutically- acceptable carriers, or one or more pharmaceutically-acceptable excipients.

[0116] In some embodiments, the subject matter disclosed herein provides a polynucleotide encoding the any of the peptides disclosed herein, including without limitation peptides described in section entitled “Peptide Sequences.” In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising any of the peptides disclosed herein, including without limitation peptides described in section entitled “Peptide Sequences.” In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising a polynucleotide encoding the any of the peptides disclosed herein, including without limitation antibodies described in section entitled “Peptide Sequence.”

[0117] In certain aspects, also herein provided are pharmaceutical compositions comprising the above-described peptides (or one or more polynucleotides encoding one or more peptides). In some embodiments, the subject matter described herein relates to a pharmaceutical composition comprising an effective amount of the peptides (or one or more polynucleotides encoding one or more peptides) described herein and a pharmaceutically-acceptable diluent, carrier or excipient.

[0118] As used herein, “pharmaceutical composition” means a therapeutically effective formulation according to the invention. A “therapeutically effective amount,” or “effective amount,” or “therapeutically effective,” as used herein, refers to that amount which provides a therapeutic effect for a given condition and administration regimen. A therapeutically effective amount can be determined by a skilled person based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art.ACTIVEUS 205211948 37Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0119] In some embodiments, the pharmaceutical compositions described herein can be administered as solid compositions. In some embodiments, the solid compositions comprise excipients including but not limited to lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. In some embodiments, the pharmaceutical compositions described herein can be administered as aqueous suspensions and / or elixirs. In some embodiments, the pharmaceutical compositions described herein may be combined with various sweetening or flavouring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0120] In some embodiments, the pharmaceutical compositions described herein can be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intra- thecally, intraventricularly, intrasternally, intracranially, intra-muscularly or subcutaneously, or they may be administered by infusion techniques. In some embodiments, the pharmaceutical compositions described herein can be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0121] In some embodiments, pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions can be presented in unit-dose or multi-dose containers. The pharmaceutical compositions can be sealed ampoules or vials. The pharmaceutical compositions can be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, such as water for injections, immediately prior to use.

[0122] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desiredACTIVEUS 205211948 38Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 therapeutics or medical procedures (e.g., antibodies can be used in combination treatment with another treatment). The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another therapeutic or prophylactic).

[0123] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0124] Compositions can be formulated with appropriate carriers and adjuvants using techniques to yield compositions suitable for prophylaxis or treatment. The compositions can include an adjuvant, such as, for example but not limited to, alum, poly IC, MF-59, squalene- based adjuvants, or liposomal based adjuvants suitable for prophylaxis or treatment.

[0125] In some embodiments, an effective amount of the peptide(s) described herein is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g.

[0126] In some embodiments, an effective dosage of the peptide(s) described herein or the pharmaceutical composition thereof is about 0.01 mg / kg, about 0.05 mg / kg, about 0.10 mg / kg, about 0.15 mg / kg, about 0.20 mg / kg, about 0.25 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.45 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65, mg / kg about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg,ACTIVEUS 205211948 39Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, or about 7 mg / kg.

[0127] In some embodiments, the peptide(s) described herein or the pharmaceutical composition thereof is administered by injection at a dosage of about 0.001 mg / ml, about 0.005 mg / ml, about 0.01 mg / ml, about 0.02 mg / ml, about 0.03 mg / ml, about 0.04 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml, about 0.1 mg / ml, about 0.2 mg / ml, about 0.3 mg / ml, about 0.4 mg / ml, about 0.5 mg / ml, about 0.6 mg / ml, about 0.7 mg / ml, about 0.8 mg / ml, about 0.9 mg / ml, about 1 mg / ml, about 1.1 mg / ml, about 1.2 mg / ml, about 1.3 mg / ml, about 1.4 mg / ml, about 1.5 mg / ml, about 1.6 mg / ml, about 1.7 mg / ml, about 1.8 mg / ml, about 1.9 mg / ml, about 2.0 mg / ml, about 2.1 mg / ml, about 2.2 mg / ml, about 2.3 mg / ml, about 2.4 mg / ml, about 2.5 mg / ml, about 2.6 mg / ml, about 2.7 mg / ml, about 2.8 mg / ml, about 2.9 mg / ml, about 3.0 mg / ml, about 3.1 mg / ml, about 3.2 mg / ml, about 3.3 mg / ml, about 3.4 mg / ml, about 3.5 mg / ml, about 3.6 mg / ml, about 3.7 mg / ml, about 3.8 mg / ml, about 3.9 mg / ml, about 4.0 mg / ml, about 4.1 mg / ml, about 4.2 mg / ml, about 4.3 mg / ml, about 4.4 mg / ml, about 4.5 mg / ml, about 4.6 mg / ml, about 4.7 mg / ml, about 4.8 mg / ml, about 4.9 mg / ml, about 5.0 mg / ml, about 5.1 mg / ml, about 5.2 mg / ml, about 5.3 mg / ml, about 5.4 mg / ml, about 5.5 mg / ml, about 5.6 mg / ml, about 5.7 mg / ml, about 5.8 mg / ml, about 5.9 mg / ml, about 6.0 mg / ml, about 6.1 mg / ml, about 6.2 mg / ml, about 6.3 mg / ml, about 6.4 mg / ml, about 6.5 mg / ml, about 6.6 mg / ml, about 6.7 mg / ml, about 6.8 mg / ml, about 6.9 mg / ml, about 7.0 mg / ml, about 7.1 mg / ml, about 7.2 mg / ml, about 7.3 mg / ml, about 7.4 mg / ml, about 7.5 mg / ml, about 7.6 mg / ml, about 7.7 mg / ml, about 7.8 mg / ml, about 7.9 mg / ml, about 8.0 mg / ml, about 8.1 mg / ml, about 8.2 mg / ml, about 8.3 mg / ml, about 8.4 mg / ml, about 8.5 mg / ml, about 8.6 mg / ml, about 8.7 mg / ml, about 8.8 mg / ml, about 8.9 mg / ml, about 9 mg / ml, about 9.1 mg / ml, about 9.2 mg / ml, about 9.3 mg / ml, about 9.4 mg / ml, about 9.5 mg / ml, about 9.6 mg / ml, about 9.7 mg / ml, about 9.8 mg / ml, about 9.9 mg / ml, about 10 mg / ml, about 10.5 mg / ml, about 11 mg / ml, aboutACTIVEUS 205211948 40Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202511.5 mg / ml, about 12 mg / ml, about 12.5 mg / ml, about 13 mg / ml, about 13.5 mg / ml, about 14 mg / ml, about 14.5 mg / ml, about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, about 29 mg / ml, about 30 mg / ml, about 31 mg / ml, about 32 mg / ml, about 33 mg / ml, about 34 mg / ml, about 35 mg / ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml, about 44 mg / ml, about 45 mg / ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml, or about 50 mg / ml.

[0128] In some embodiments, the peptide(s) described herein or the pharmaceutical composition thereof is administered by injection at a volume of about 0.01 ml, about 0.02 ml, about 0.03 ml, about 0.04 ml, about 0.05 ml, about 0.06 ml, about 0.07 ml, about 0.08 ml, about 0.09 ml, about 0.1 ml, about 0.15 ml, about 0.2 ml, about 0.25 ml, about 0.30 ml, about 0.35 ml, about 0.40 ml, about 0.45 ml, about 0.5 ml, about 0.55 ml, about 0.60 ml, about 0.65 ml, about 0.70 ml, about 0.75 ml, about 0.80 ml, about 0.85 ml, about 0.90 ml, about 0.95 ml, about 1.0 ml, about 1.1 ml, about 1.2 ml, about 1.3 ml, about 1.4 ml, about 1.5 ml, about 1.6 ml, about 1.7 ml, about 1.8 ml, about 1.9 ml, about 2.0 ml, about 2.5 ml, about 3.0 ml, about 3.5 ml, about 4.0 ml, about 4.5 ml, about 5.0 ml, about 5.5 ml, about 6.0 ml, about 6.5 ml, about 7.0 ml, about 7.5 ml, about 8.0 ml, about 8.5 ml, about 9.0 ml, about 9.5 ml, about 10.0 ml, about 15.0 ml, about 20.0 ml, about 25.0 ml, about 30.0 ml, about 35.0 ml, about 40.0 ml, about 45.0 ml, or about 50.0 ml.

[0129] In some embodiments, the peptide disclosed herein or the pharmaceutical composition thereof is administered in one a day, twice a day, there time a day, four time a day, or five time a day. In some embodiments, the peptide disclosed herein or the pharmaceutical composition thereof is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days.

[0130] Kits of the Invention

[0131] In one embodiment, the subject matter disclosed herein relates to a kit for generating the peptides disclosed herein and instructions for use. In one embodiment, the subject matterACTIVEUS 205211948 41Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 disclosed herein relates to a kit for generating the peptides disclosed herein comprising one or more vectors comprising a polynucleotide sequence of any of the peptides described above binding Arid5a. The kit can further include at least one additional reagent or one or more additional therapies for us with the peptides disclosed herein. The kit usually has a label indicating the intended use of the kit contents. The term label includes all documents and is attached to the kit or with the kit, or otherwise attached to the kit.

[0132] In some embodiments, the kits further provide written material that can include instructions for use, discussion of clinical studies and / or listing of side effects. The kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. In some embodiments, the kit further contains another active pharmaceutical ingredient. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit.

[0133] In some embodiments, the kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. The kits may also be marketed directly to the consumer. In some embodiments, the disclosure provides a kit of a pharmaceutical composition comprising the peptide(s) disclosed herein for use in the treatment of sepsis, septic shock, and acute respiratory syndrome. In some embodiments, the disclosure provides a kit of a pharmaceutical composition comprising the peptide(s) disclosed herein for use in reducing, alleviating, or ameliorating one or more symptoms associated with sepsis, septic shock, and acute respiratory syndrome.

[0134] In some embodiments, administration of the peptide(s) disclosed herein or a pharmaceutical composition comprising the peptides disclosed herein, is by any method that enables delivery of the peptides to the site of action. These methods include oral routes,ACTIVEUS 205211948 42Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 intraduodenal routes, parenteral injection (including intravenous, intra-arterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds can also be administered intraadiposally or intrathecally.

[0135] In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) described herein or a pharmaceutically acceptable salt thereof for use in reducing, alleviating, or ameliorating one or more symptoms associated with inflammation. In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) described herein for use in preventing the occurrence of one or more symptoms associated with inflammation. In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) disclosed for use in inhibiting IL-6 productions. In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) disclosed herein for use in inhibiting immune cell activation. In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) disclosed herein for use in inhibiting cytokine release from immune cells. In some embodiments, the subject matter described herein provides a kit comprising the peptide(s) disclosed herein for use in inhibiting histamine release from immune cells.EXAMPLES

[0136] Example 1

[0137] 864,000 peptides were screened for their potential to bind Arid5a using a computer algorithm. An Arid5a groove defined by residues 78 to 85 and 121 to 137 (human Arid5a sequence, accession number KAI2524333.1) was used to design peptide binders and the binders were used to test the peptides for potential binding to Arid5a. A library of 864,000 peptides 8 amino acids in length was generated with an in-house script. Then, a 3D model for each peptide was generated using Modeller software available at https: / / salilab.org / modeller / . Peptide binding to the groove was scored using AutoDock Vina available at https: / / vina.scripps.edu / . Fifty peptides (KMZ1-KMZ50), shown in FIG. 1, demonstrated binding to Arid5a in silico and were selected for further investigation.ACTIVEUS 205211948 43Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025

[0138] The 50 peptides were further tested for their ability to inhibit IL-6 production by the human macrophage cell line THP-1 in response to LPS. Several peptides demonstrated high inhibitory activity, as shown in FIG. 2. These include KMZ5, KMZ6, KMZ9, KMZ10, KMZ36, and KMZ40.

[0139] Example 2

[0140] FIG. 3A shows another IL-6 inhibition assay using THP-1 cells. FIG. 3B shows an IL-6 inhibition assay using a murine macrophage cell line, RAW264. Both figures illustrate the capacity of different concentrations of KMZ peptides to inhibit IL-6 production at lug / ml LPS. One peptide, identified as KMZ9, consistently inhibited IL-6 production in human and murine macrophages to the greatest degree as shown in FIGS. 3A-3B.

[0141] Example 3

[0142] When KMZ9 peptide was administered intravenously to C57BL / 6 mice 10 minutes before LPS was given intraperitoneally, the treatment with KMZ9 peptide was able to inhibit IL- 6 production in the sera upon LPS challenge as shown in FIG. 4A. KMZ9 peptide was also able to improve the survival of LPS-challenged mice as shown in FIG. 4B.

[0143] Example 4

[0144] A groove defined by residues 78 to 85 and 121 to 137 (human Arid5a sequence, accession number KAI2524333.1) was used to design peptide binders (FIGS. 5A and 5B). Surprisingly, the binding mode analysis of peptides KMZ1, KMZ2, KMZ5, KMZ6, KMZ9, and KMZ 10 showed that all six peptides bind to this same groove. FIG. 5 A depicts a modeled structure of the Arid5a nucleotide binding domain. The peptide binding pocket is annotated and includes residues 78 to 85 and 121 to 137 of the human Arid5a sequence (accession number KAI2524333.1). Arid5a is modeled based on the structure of homolog protein Mrf2-DNA complex (PDB ID: 2OEH). FIG. 5B shows the surface of the binding pocket of Arid5a where the peptides described herein bind. FIG. 5C depicts binding modes of peptides KMZ1, KMZ2, KMZ5, KMZ6, KMZ9, and KMZ 10 (dark pink, light green, green, yellow-gray, pink, orange, respectively), as predicted by docking modeling. The electrostatic surface of Arid5a is annotatedACTIVEUS 205211948 44Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 by a dotted oval and includes regions of positive, neutral, and negative electrostatic potential. All peptides bind to the potential DNA binding site of Arid5a (highlighted in dashed circle) inferred from its homolog protein Mrf2-DNA complex, suggesting, the peptide binding groove overlaps with the potential nucleotide binding site of Arid5a, as shown in the model of FIG. 5C. Without being bound by theory, the peptides described herein can compete with the nucleotide target of Arid5a for binding to Arid5a, suggesting that the discovered peptide binding could impact the binding of Ariad50 to DNA. An electrostatics analysis, performed using APBS (the Adaptive Poisson-Boltzmann Solver) in PyMOL software, showed that the binding site has a positively charged pocket defined by residues R78, R133, and R137 which are critical for nucleotide binding (FIGS. 5C and 7). The rest of the groove is more hydrophobic. The six peptides KMZ1, KMZ2, KMZ5, KMZ6, KMZ9, and KMZ10 bind to the negatively charged nucleotide binding pocket of Arid5a with either N- or C-terminal residues to engage the hydrophobic region of the binding site use hydrophobic and aromatic residues. Further analysis showed that KMZ9 uses Glul to form two salt bridges with R78 and R133 from Abrid5a (R78 and R133 are shown in FIG. 5D), which may explain the stronger inhibition of KMZ9. Thus, peptides with negatively charged residues at N- or C-terminus and hydrophobic and aromatic residues in the middle are preferred for binding this Abrid5a site.

[0145] Example 5

[0146] FIG. 6 shows comparison of the IL-6 inhibitory effects of KMZ9 versus Arid5a peptide inhibitors listed in PCT / IB2020 / 056569. Pl, P2, and P3 are “Novel Arid5a Peptide Inhibitors” listed in PCT / IB2020 / 056569. KMZ9 has a greater, dose-dependent inhibitory effect compared to Pl, P2, or P3.

[0147] Example 6

[0148] FIG. 7 is a different model depicting the Arid5a binding pocket for the peptides described herein (grey). The model is generated using PyMOL software (available at https: / / www.pymol.org / ) by superimposing the modeled Arid5a to the structure of homolog protein Mrf2-DNA complex (PDB ID: 2OEH). The two homolog domains show over 80% sequence identity. This pocket does not overlap with the binding pocket for the peptidesACTIVEUS 205211948 45Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025 described in PCT / IB2020 / 056569 (red). The orange backbone represents the nucleotide target of Arid5a while the green and teal helices are the helices of the Arid5a peptide.

[0149] References:1. Masuda K, Ripley B, Nishimura R, Mino T, Takeuchi O, Shioi G, Kiyonari H, Kishimoto T. 2013. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc. Natl. Acad. Sci. USA. 110: 9409-9414.2. Zaman MM, Masuda K, Nyati KK, Dubey KP, Ripley B, Wang K, Chalise JP, Higa M, Hanieh H and Kishimoto T. 2016. Arid5a exacerbates IFN-y-mediated septic shock by stabilizing T-bet mRNA. Proc. Natl. Acad. Sci. USA. 113:11543-48.3. Masuda K, Ripley B, Nyati KK, Dubey KP, Zaman MM, Hanieh H, Higa M, Yamashita K, Standley MD, Mashima T, Katahira M, Okamoto T, Matsuura Y, Takeuchi O, and Kishimoto T. 2016. Arid5a regulates naive CD4+ T cell-fate through selective stabilization of Stat3 mRNA. J. Exp. Med. 213: 605-619.4. Cai, S., Zhu, L., Zhang, Z., Chen, Y. 2007. Determination of the Three-dimensional Structure of the Mrf2-DNA Complex Using Paramagnetic Spin Labeling. Biochemistry 46: 4943-4950.ACTIVEUS 205211948 46

Claims

Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 2025CLAIMSWhat is claimed is:

1. A peptide that binds to the human AT-rich interactive domain 5 A protein (Arid5a), wherein the peptide binds to one or more amino acid residues lining a groove on Arid5a, wherein the groove comprises Arid5a amino acid residues 78 to 85 and 121 to 137, wherein the peptide does not bind Ariad5a amino acid residues Glu58, Phe61, Leu62, Val63, Leu89, Tyr93, Leul38, Vall39, Tyrl42, Vall43, Hisl45, or Leul46.

2. The peptide of claim 1, wherein the peptide binds to a positively charged pocket within the groove, wherein the pocket comprises Arid5a amino acid residues R78, R133, and R137.

3. The peptide of claim 2, wherein the peptide contains more than 3 amino acid residues.

4. The peptide of claim 3, wherein one or more of the 3 amino acid residues from the N- terminus of the peptide bind to the positively charged pocket.

5. The peptide of claim 4, wherein at least one of the one or more amino acid residues at the N-terminus of the peptide that bind to the positively charged pocket is negatively charged.

6. The peptide of claim 3, wherein one or more of the 3 amino acid residues from the C- terminus of the peptide bind to the positively charged pocket.

7. The peptide of claim 6, wherein at least one of the one or more amino acid residues at the C-terminus of the peptide that bind to the positively charged pocket is negatively charged.

8. The peptide of any one of claims 2-7, wherein the pocket comprises a hydrophobic region.

9. The method of claim 8, wherein the hydrophobic region comprises about 3 to about 7 hydrophobic amino acid residues.

10. The peptide of any one of claims 2-9, wherein one or more hydrophobic amino acid residues of the peptide bind to one or more amino acid residues in the hydrophobic region of the pocket.ACTIVEUS 205211948 47Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202511. The peptide of claim 10, wherein at least one of the one or more hydrophobic amino acid residues of the peptide that bind to one or more amino acid residues in the hydrophobic region of the pocket is an aromatic residue.

12. The peptide of any one of claims 1-11, wherein one or more amino acid residues of the peptide form one or more salt bridges with Arid5a amino acid residue R78 and R133.

13. The peptide of any one of claims 1-12, wherein the peptide consists of 6, 7, 8, 9, or 10 amino acids.

14. The peptide of claim 13, wherein the peptide consists of 8 amino acids.

15. A peptide that comprises any one of SEQ ID NOs: 1-50.

16. A peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to any one of SEQ ID NOs: 1-50.

17. A peptide that comprises SEQ ID NO: 9, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 40.

18. A peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to any one of SEQ ID NO: 9, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, or SEQ ID NO: 40.

19. A peptide that comprises SEQ ID NO: 9.

20. A peptide that comprises an amino acid sequence with at least 80%, 85%, 90%, 95%, or 99% identity to SEQ ID NO: 9.ACTIVEUS 205211948 48Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202521. A method of inhibiting Interleukin 6 (IL-6) production in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides of claims 1 -20.

22. The method of claim 21, wherein the pharmaceutical composition is administered in combination with another therapy.

23. The method of claim 21, wherein the another therapy comprises an IL-6 therapy.

24. The method of claim 23, wherein the IL-6 therapy comprises a tocilizumab therapy.

25. The method of claim 23, wherein the IL-6 therapy comprises a siltuximab therapy.

26. The method of claim 23, wherein the IL-6 therapy comprises a satralizumab therapy.

27. The method of claim 23, wherein the IL-6 therapy comprises a sarilumab therapy.

28. A method of treating sepsis and / or septic shock in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides of claims 1 -20.

29. The method of claim 28, wherein the sepsis and / or septic shock is caused by lipopolysaccharide (LPS).

30. The method of claim 28 or 29, wherein the pharmaceutical composition is administered in combination with another therapy.

31. The method of claim 30, wherein the another therapy comprises one or more antibiotic therapy.

32. The method of claim 30, wherein the another therapy comprises intravenous fluids therapy.

33. The method of claim 30, wherein the another therapy comprises administering one or more vasopressors.ACTIVEUS 205211948 49Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202534. A method of treating acute respiratory syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides of claims 1 -20.

35. The method of claim 34, wherein the acute respiratory syndrome is caused by one or more respiratory virus infection.

36. The method of claim 34 or 35, wherein the pharmaceutical composition is administered in combination with another therapy.

37. The method of claim 36, wherein the another therapy comprises administering one or more corticosteroids.

38. A method of treating inflammation or a disease related to inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any one of the peptides of claims 1-20.

39. The method of claim 38, wherein the inflammation relates to Interleukin-6 (IL-6) production.

40. The method of claim 38 or 39, wherein the pharmaceutical composition is administered in combination with another therapy.

41. The method of claim 40, wherein the another therapy comprises one or more antibiotic therapy.

42. The method of claim 40, wherein the another therapy comprises intravenous fluids therapy.

43. The method of claim 40, wherein the another therapy comprises administering one or more vasopressors.

44. The method of claim 23, wherein the IL-6 therapy comprises an olokizumab therapy.

45. The method of claim 23, wherein the IL-6 therapy comprises a clazakizumab therapy.ACTIVEUS 205211948 50Attorney Docket No.: 0019240.01333WO1 Date of Electronic Filing: August 11, 202546. The method of any one of claims 37-43, wherein the disease related to inflammation is cytokine release syndrome (CRS).ACTIVEUS 205211948 51

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