WO2022006588A1 - Il-38 et ses analogues pour le traitement de maladies neuro-inflammatoires et neurodégénératives - Google Patents

Il-38 et ses analogues pour le traitement de maladies neuro-inflammatoires et neurodégénératives Download PDF

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WO2022006588A1
WO2022006588A1 PCT/US2021/070791 US2021070791W WO2022006588A1 WO 2022006588 A1 WO2022006588 A1 WO 2022006588A1 US 2021070791 W US2021070791 W US 2021070791W WO 2022006588 A1 WO2022006588 A1 WO 2022006588A1
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seq
composition
amino acids
syndrome
cell
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WO2022006588A9 (fr
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Theoharis C. Theoharides
Vassilios KALABOKIS
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Trustees Of Tufts College
Bio-Techne Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • a Sequence Listing accompanies this application and is submitted as an ASCII text file of the sequence listing named “166118_01069_ST25.txt” which is 2 KB in size and was created on June 9, 2021.
  • the sequence listing is electronically submitted via EFS-Web with the application and is incorporated herein by reference in its entirety.
  • ASD Autism spectrum disorder
  • CSF cerebrospinal fluid
  • Neuroinflammation and associated neurodegeneration are also associated with many other diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), chronic inflammatory response syndrome (CIRS), long COVID syndrome, mast cell activation syndrome (MCAS), multisystem inflammatory syndrome (MIS), myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), pediatric acute neuropsychiatric syndrome (PAN), post-Lyme syndrome (PLS), sick building syndrome (SBS), traumatic brain injury (TBI) and toxic mold syndrome (TMS).
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's disease
  • CIRS chronic inflammatory response syndrome
  • MCAS mast cell activation syndrome
  • MIS multisystem inflammatory syndrome
  • ME/CFS multisystem inflammatory syndrome
  • PAN post-Lyme syndrome
  • SBS sick building syndrome
  • TBI traumatic brain injury
  • TMS toxic mold syndrome
  • a composition comprising a polypeptide having at least 90% amino acid identity to a portion of recombinant IL-38 (SEQ ID NO: 1) is provided.
  • the portion of IL-38 is selected from the group consisting of amino acids 2-152 of SEQ ID NO: 1, amino acids 3-152 of SEQ ID NO: 1 and amino acids 5-152 of SEQ ID NO: 1.
  • the composition may further comprise a pharmaceutically acceptable carrier or excipient.
  • the composition is formulated for intranasal administration.
  • a method of inhibiting IL-Ib or CXCL8 secretion from a cell comprises contacting the cell with a composition comprising a polypeptide having at least 90% amino acid identity to recombinant IL-38 (SEQ ID NO: 1) or a portion thereof.
  • the cells may be microglial cells, macrophages or mast cells, in some embodiments.
  • a method of treating a neuro-inflammatory or neuro degenerative disease in a subject comprises administering a composition comprising a polypeptide having at least 90% amino acid identity to recombinant IL-38 (SEQ ID NO: 1) or a portion thereof.
  • the disease being treated may include any of autism spectrum disorder (ASD), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), chronic inflammatory response syndrome (CIRS), long-COVID syndrome, mast cell activation syndrome (MCAS), multisystem inflammatory syndrome (MIS), myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), pediatric acute neuropsychiatric syndrome (PAN), post-Lyme syndrome (PLS), sick building syndrome (SBS), traumatic brain injury (TBI) and toxic mold syndrome (TMS).
  • ASSD autism spectrum disorder
  • ALS amyotrophic lateral sclerosis
  • CIRS chronic inflammatory response syndrome
  • MCAS mast cell activation syndrome
  • MIS multisystem inflammatory syndrome
  • ME/CFS multisystem inflammatory syndrome
  • PAN post-Lyme syndrome
  • SBS sick building syndrome
  • TBI traumatic brain injury
  • TMS toxic mold syndrome
  • a construct comprising a heterologous promoter operably linked to a polynucleotide encoding polypeptide having at least 90% amino acid identity to recombinant IL-38 (SEQ ID NO: 1) or a portion thereof is provided.
  • the portion of IL-38 encoded by the construct may consist of amino acids 2-152 of SEQ ID NO: 1, amino acids 3-152 of SEQ ID NO: 1 or amino acids 5-152 of SEQ ID NO: 1.
  • IL-38 inhibits secretion of IL-Ib (left) and CXCL8 (right) from adult human microglia stimulated by neurotensin.
  • FIG. 1 Dose-response of IL-38 on secretion of IL-Ib (left) and CXCL8 (right) from adult human microglia is stimulated by neurotensin.
  • FIG. 3 Effect of IL-38 on secretion of CXCL8 from neonatal human microglia stimulated by neurotensin.
  • Figure 4 Decreased gene expression levels of IL-38 and IL-36R in the amygdala of children with ASD. Gene expression levels of (A) IL-38 and (B) IL-36R in the amygdala of ASD and non- ASD subjects were measured by qRT-PCR. Gene expression was normalized to 18S rRNA control gene. Measurements were repeated 3 times each.
  • Figure 5 Increased IL-38 serum concentration in children with ASD as compared to controls without ASD. Symbols represent individual data points, the long horizontal lines represent the mean and the shorter ones show the SD (standard deviation) for each group.
  • FIG. 6 Diagrammatic representation of the proposed interactions and sites of action of IL-38.
  • Neurotensin from an unidentified source (brain or gut) stimulates microglia in the amygdala to secrete inflammatory molecules (IL-Ib and CXCL8), which contribute to focal inflammation and disrupt neuronal connectivity. This process could be inhibited by IL-38 (green line showing the blocked end), the gene expression of which is reduced in amygdala of children with ASD, thus permitting inflammation.
  • Figure 7 Cartoon representation of the proposed IL-38 interactions in the brain.
  • IL-38 inhibits release of pro-inflammatory molecules from human brain microglia cells. Gene expression of IL-38 is decreased in the amygdala of autistic children suggesting that inflammation associated with low IL-38 in the amygdala may play a role in autism. Administration of IL-38 could be a treatment to reduce inflammation and symptoms of ASD or other neurodegenerative or neuroinflammatory diseases.
  • NT neurotensin
  • IL-38 like IL-37, also belongs to the IL-1 family and has been reported to have immune modulatory activity.
  • IL-38 exists intracellularly as a precursor full-length form called IL- 38 (aal-152, SEQ ID NO: 1) and must be cleaved at the N-terminus before it is secreted extracellularly as an active form (27). The cleavage required for secretion is presently not known.
  • the main receptor for IL-38 is IL-36R, which in combination with the cofactor IL1-R9 and IL-1 receptor accessory protein-like 1 (IL-lRAPLl) is also involved in the inhibitory action of IL-38.
  • IL-lRAPLl IL-1 receptor accessory protein-like 1
  • SEQ ID NO: 1 The amino acid sequence of full-length IL-38, also known as IL-ltheta or IL-1 family member 10, is provided herein as SEQ ID NO: 1.
  • the inventors compared the effect of the recombinant proposed active forms of IL-38 (aa2-152, aa5-152 and aa3-152) to that of IL-37 using both cultured adult and embryonic human microglia stimulated by NT.
  • the truncated forms of IL-38 were at least as good as IL-37 at inhibiting production of IL-Ib.
  • the inventors also investigated gene expression of IL-38 and its main receptor IL-36R in amygdala, which regulates behavior (14), (15), and microglia, which express receptors for NT (30) and report decreased expression of both in ASD subjects as compared to non-ASD controls.
  • Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication.
  • the pathogenesis of ASD is not known, but it involves activation of microglia.
  • the inventors have previously shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the pro- inflammatory molecules IL-Ib and CXCL8. This process is inhibited by the cytokine IL-37.
  • Another cytokine, IL-38 has been reported to have anti-inflammatory actions.
  • IL-38 (aa3- 152, 1-100 ng/ml) inhibits (p ⁇ 0.0001) NT-stimulated (10 nM) secretion of IL-Ib (at 1 ng/ml) and CXCL8 (at 100 ng/ml).
  • IL-38 (aa3-152, 1 ng/ml) is more potent than IL-37 (100 ng/ml).
  • IL-38 may also be useful in treating other neurodegenerative or neuroinflammatory diseases.
  • cytokine IL-38 inhibits secretion of proinflammatory mediators from human microglial cells.
  • expression of IL-38 is low in the amygdala, which regulates behavior, of autistic children as compared to non-ASD children. This finding, presented in the Examples, suggests that administering IL-38 could be a novel treatment for brain inflammation and may correct an underlying cause of autistic behavior.
  • IL-38 inhibits secretion of IL-Ib from adult human microglia stimulated by neurotensin (NT).
  • Human microglia were pre-treated with human recombinant IL- 37beta (100 ng/mL) and three human recombinant IL-38 analogues (aa2-152, aa5-152, aa3-152, 100 ng/mL) for 24 h and then were stimulated with NT (10 nM) for 24 hr to determine the secretion of IL-Ib and CXCL8.
  • the IL-38 analogues aa2-152 and a5-152 were equally potent to IL-37beta inhibiting IL-Ib and CXCL8 secretion from microglia by about 30% (Fig. 1).
  • IL-38 aa3-152 inhibited (pO.OOOl) IL-Ib secretion by 100% (Fig. 1).
  • IL-38 a member of the IL-36 subclass of the IL-1 family of cytokines, exists intracellularly as a precursor full-length form (aal-152), which must be cleaved at the N- terminus before it is secreted extracellularly as an active form, (29) like other members of the IL- 1 family.
  • the processing sites have not been identified.
  • the inventors synthesized the most plausible active analogues used in the present disclosure: (a) IL-38 aa3-152, (b) aa2-152 and (c) aa5-152 and the inventors report that the aa5-152 fragment shows the greatest inhibitory activity.
  • compositions including IL-38 or anti-inflammatory portions thereof are provided herein.
  • the portion of IL-38 may include or consist of amino acids 2-152 of SEQ ID NO: 1, amino acids 3-152 of SEQ ID NO: 1 and amino acids 5-152 of SEQ ID NO: 1. Included herein are compositions comprising polypeptides having at least 90%, 95%, 97%, 98%, 99%, or 100% sequence identity to recombinant IL-38 (SEQ ID NO: 1) or a portion thereof.
  • compositions can be used to treat inflammatory diseases, in particular neuroinflammatory or neurodegenerative diseases, such as autism spectrum disorder (ASD), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), chronic inflammatory response syndrome (CIRS), long- COVID syndrome, mast cell activation syndrome (MCAS), multisystem inflammatory syndrome (MIS), myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), pediatric acute neuropsychiatric syndrome (PAN), post-Lyme syndrome (PLS), sick building syndrome (SBS), traumatic brain injury (TBI) and toxic mold syndrome (TMS).
  • ASD autism spectrum disorder
  • ALS amyotrophic lateral sclerosis
  • CIRS chronic inflammatory response syndrome
  • MCAS mast cell activation syndrome
  • MIS multisystem inflammatory syndrome
  • ME/CFS multisystem inflammatory syndrome
  • PAN post-Lyme syndrome
  • SBS sick building syndrome
  • TBI traumatic brain injury
  • TMS toxic mold syndrome
  • IL-38 amino acids 3-152 was able to inhibit both IL-Ib and CXCL8 secretion in mature human microglia cells in response to NT treatment, whereas all three portions tested were able to inhibit IL-Ib from these adult microglia cells. All three IL-38 polypeptides tested were able to inhibit CXCL8 secretion from embryonic microglial cells.
  • % sequence identity refers to the percentage of amino acid residue matches between at least two amino acid sequences aligned using a standardized algorithm. Methods of amino acid sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail below, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. Percent identity for amino acid sequences may be determined as understood in the art. (See, e.g. , U.S. Patent No. 7,396,664, which is incorporated herein by reference in its entirety).
  • NCBI National Center for Biotechnology Information
  • BLAST Basic Local Alignment Search Tool
  • the BLAST software suite includes various sequence analysis programs including “blastp,” that is used to align a known amino acid sequence with other amino acids sequences from a variety of databases.
  • protein refers to a polymer of amino acid residues linked together by peptide (amide) bonds.
  • the terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long.
  • a protein, peptide, or polypeptide may refer to an individual protein or a collection of proteins.
  • One or more of the amino acids in a protein, peptide, or polypeptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc.
  • a protein, peptide, or polypeptide may also be a single molecule or may be a multi-molecular complex.
  • a protein, peptide, or polypeptide may be just a fragment of a naturally occurring protein or peptide.
  • a protein, peptide, or polypeptide may be naturally occurring, recombinant, or synthetic, or any combination thereof.
  • a protein may comprise different domains, for example, a nucleic acid binding domain and a nucleic acid cleavage domain.
  • a protein comprises a proteinaceous part, e.g., an amino acid sequence constituting a nucleic acid binding domain.
  • Nucleic acids, proteins, and/or other compositions described herein may be purified.
  • purified means separate from the majority of other compounds or entities, and encompasses partially purified or substantially purified. Purity may be denoted by a weight by weight measure and may be determined using a variety of analytical techniques such as but not limited to mass spectrometry, HPLC, etc.
  • Polypeptide sequence identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues.
  • Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
  • nucleic acid and “nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides.
  • Nucleic acids generally refer to polymers comprising nucleotides or nucleotide analogs joined together through backbone linkages such as but not limited to phosphodiester bonds.
  • Nucleic acids include deoxyribonucleic acids (DNA) and ribonucleic acids (RNA) such as messenger RNA (mRNA), transfer RNA (tRNA), etc.
  • DNA deoxyribonucleic acids
  • RNA ribonucleic acids
  • mRNA messenger RNA
  • tRNA transfer RNA
  • nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage.
  • nucleic acid refers to individual nucleic acid residues (e.g., nucleotides and/or nucleosides).
  • nucleic acid refers to an oligonucleotide chain comprising three or more individual nucleotide residues.
  • nucleic acid encompasses RNA as well as single and/or double-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule.
  • a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA/RNA hybrid, or include non- naturally occurring nucleotides or nucleosides.
  • the terms “nucleic acid,” “DNA,” “RNA,” and/or similar terms include nucleic acid analogs, i.e., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc.
  • nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications.
  • a nucleic acid sequence is presented in the 5' to 3' direction unless otherwise indicated.
  • a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2- thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2- aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5- propynyl-cytidine, C5-methylcytidine, 2-aminoadeno sine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-
  • compositions including these polypeptides and a pharmaceutically acceptable carrier are provided.
  • the compositions provided may be used in combination.
  • a composition comprising both amino acids 3-152 of SEQ ID NO: 1 and amino acids 5-152 of SEQ ID NO: 1 may be used in combination, i.e., co-administered or may be administered in sequence, i.e., one polypeptide given at one time point and a second given at a second time point.
  • the composition is formulated to reach a final concentration in the tissue of interest of a subject in need thereof of between 1 ng/ml and 1 mg/ml or any amount there between.
  • the composition may be provided as a suspension or solvate with a final concentration of at least 1 ng/ml, 10 ng/ml, 100 ng/ml, 1 pg/ml, 10 pg/ml, 100 pg/ml or 1 mg/ml. Suitable dosages may be determined by those skilled in the art.
  • compositions provided herein may be used to make pharmaceutical compositions.
  • Pharmaceutical compositions comprising the compositions provided herein and a pharmaceutically acceptable carrier are provided.
  • a pharmaceutically acceptable carrier is any carrier suitable for in vivo administration. Examples of pharmaceutically acceptable carriers suitable for use in the composition include, but are not limited to, water, buffered solutions, glucose solutions, oil-based or bacterial culture fluids. Additional components of the compositions may suitably include, for example, excipients such as stabilizers, preservatives, diluents, emulsifiers and lubricants.
  • Examples of pharmaceutically acceptable carriers or diluents include stabilizers such as carbohydrates (e.g., sorbitol, mannitol, starch, sucrose, glucose, dextran), proteins such as albumin or casein, protein-containing agents such as bovine serum or skimmed milk and buffers (e.g., phosphate buffer). Especially when such stabilizers are added to the compositions, the composition is suitable for freeze-drying or spray-drying. The composition may also be emulsified.
  • carbohydrates e.g., sorbitol, mannitol, starch, sucrose, glucose, dextran
  • proteins such as albumin or casein
  • protein-containing agents such as bovine serum or skimmed milk
  • buffers e.g., phosphate buffer
  • compositions provided herein may be administered in any order, at the same time or as part of a unitary composition.
  • Two of the analogues of IL-38 or one analog in combination with another composition to reduce neuroinflammation or neurodegeneration may be administered such that one is administered before the other with a difference in administration time of 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 4 weeks or more.
  • the compounds described herein may be administered by any means known to those skilled in the art, including, but not limited to, oral, topical, intranasal, intraperitoneal, parenteral, intravenous, intramuscular, subcutaneous, intrathecal, transcutaneous, nasopharyngeal, or transmucosal absorption.
  • the compounds may be formulated as an ingestable, injectable, topical or suppository formulation.
  • the compounds may also be delivered with in a liposomal or time-release vehicle.
  • Administration of the compounds to a subject in accordance with the invention appears to exhibit beneficial effects in a dose-dependent manner. Thus, within broad limits, administration of larger quantities of the compounds is expected to achieve increased beneficial biological effects than administration of a smaller amount. Moreover, efficacy is also contemplated at dosages below the level at which toxicity is seen.
  • constructs including polynucleotides encoding the polypeptides provided herein are also provided.
  • the constructs may include a heterologous promoter operably linked to the polynucleotides encoding the polypeptides of SEQ ID NO: 1 or a portion thereof or polypeptides having at least 90%, 92%, 95%, 97%, 98%, 99% or 100% sequence identity to the polypeptide of SEQ ID NO: 1 or a portion thereof.
  • the portions of IL-38 may include polynucleotides encoding the polypeptides consisting of amino acids 2-152 of SEQ ID NO: 1, amino acids 3-152 of SEQ ID NO: 1 and amino acids 5-152 of SEQ ID NO: 1.
  • the term “construct” refers to recombinant polynucleotides including, without limitation, DNA and RNA, which may be single-stranded or double-stranded and may represent the sense or the antisense strand.
  • Recombinant polynucleotides are polynucleotides formed by laboratory methods that include polynucleotide sequences derived from at least two different natural sources or they may be synthetic. Constructs thus may include new modifications to endogenous genes introduced by, for example, genome editing technologies. Constructs may also include recombinant polynucleotides created using, for example, recombinant DNA methodologies. Constructs may be plasmids, viral vectors, expression cassettes or vectors, artificial chromosomes or any other construct known or available to those of skill in the art.
  • constructs provided herein may be prepared by methods available to those of skill in the art. Notably each of the constructs claimed are recombinant molecules and as such do not occur in nature.
  • nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, and recombinant DNA techniques that are well known and commonly employed in the art. Standard techniques available to those skilled in the art may be used for cloning, DNA and RNA isolation, amplification and purification. Such techniques are thoroughly explained in the literature.
  • heterologous promoter operably linked to any one of the polynucleotides described herein.
  • heterologous promoter refer generally to transcriptional regulatory regions of a gene, which may be found at the 5’ or 3’ side of the polynucleotides described herein, or within the coding region of the polynucleotides, or within introns in the polynucleotides.
  • a promoter is a DNA regulatory region capable of binding RNA polymerase in a cell and initiating transcription of a downstream (3’ direction) coding sequence.
  • the typical 5’ promoter sequence is bounded at its 3’ terminus by the transcription initiation site and extends upstream (5’ direction) to include the minimum number of bases or elements necessary to initiate transcription at levels detectable above background.
  • a transcription initiation site (conveniently defined by mapping with nuclease SI), as well as protein binding domains (consensus sequences) responsible for the binding of RNA polymerase.
  • the polynucleotides are operably connected to the heterologous promoter.
  • a polynucleotide is “operably connected” or “operably linked” when it is placed into a functional relationship with a second polynucleotide sequence.
  • a promoter is operably linked to a polynucleotide if the promoter is connected to the polynucleotide such that it may affect transcription of the polynucleotides.
  • Heterologous promoters useful in the practice of the present invention include, but are not limited to, constitutive, inducible, temporally regulated, developmentally regulated, chemically regulated, tissue-preferred and tissue-specific promoters.
  • the heterologous promoter may be a plant, animal, bacterial, fungal, viral, or synthetic promoter.
  • Methods of inhibiting IL-Ib or CXCL8 secretion from a cell by contacting the cell with any one of the compositions provided herein are also contemplated. These methods may result in decreased inflammation and/or inflammatory cytokine release by the cells as compared to similar cells not contacted with the compositions including IL-38 or its analogues described herein.
  • Cells may be contacted with the agent directly or indirectly in vivo , in vitro , or ex vivo.
  • Contacting encompasses administration to a cell, tissue, mammal, patient, or human. Further, contacting a cell includes adding an agent to a cell culture. Other suitable methods may include introducing or administering an agent to a cell, tissue, mammal, or patient using appropriate procedures and routes of administration as defined below.
  • the cells may be any cell expressing or capable of expressing IL-36R. In the Examples, microglial cells are used, but macrophages and mast cells are also responsive to IL-38 and thus could be used in the methods provided herein.
  • the method may result in the contacted cell being inhibited from secreting IL-Ib and/or CXCL8 by at least 50% after contacting as compared to a control cell.
  • the cells may be contacted with a second composition in combination with the IL-38 to aid in reduction of inflammation.
  • the second composition may be a second composition comprising a different portion of IL-38 or the second composition may be another composition with anti-inflammatory action.
  • the second composition may include IL-37 or an analogue of IL-38.
  • the composition may be added such that a final concentration in the target cell of between 1 ng/ml and 1 mg/ml is reached.
  • compositions provided herein can also be administered to a subject in need of treatment for a neuroinflammatory or neurodegenerative disease.
  • the compositions are provided in a therapeutically effective amount and are able to treat the disease by reducing the secretion of inflammatory mediators, such as IL-Ib and CXCL8.
  • compositions described are useful for treating a subject.
  • treating or “to treat” each mean to alleviate symptoms, eliminate the causation of resultant symptoms either on a temporary or permanent basis, and/or to slow the appearance or to reverse the progression or severity of resultant symptoms of the named disease or disorder.
  • Treating a subject as used herein refers to any type of treatment that imparts a benefit to a subject afflicted with a disease associated with neuroinflammation or neurodegeneration or at risk of developing neuroinflammation or neurodegeneration. Treatment includes improvement in the condition of the subject (e.g., in one or more symptoms), delay in the progression of the disease, delay in the onset of symptoms or slowing the progression of symptoms, etc.
  • a “subject” may be interchangeable with “patient” or “individual” and means an animal, which may be a human or non-human animal, in need of treatment.
  • a “subject in need of treatment” may include a subject having a disease, disorder, or condition that is responsive to therapy with IL-38 and its analogues as disclosed herein.
  • a “subject in need of treatment” may include a subject having a neurodegenerative or neuroinflammatory disease such as ASD, ALS, Alzheimer's disease or any of the other neuroinflammatory or neurodegenerative diseases known to those of skill in the art.
  • the term “effective amount” refers to the amount or dose of the composition, upon single or multiple dose administration to the subject, which provides the desired effect in the subject under diagnosis or treatment.
  • the disclosed methods may include administering an effective amount of the disclosed compositions (e.g ., as present in a pharmaceutical composition) for treating a neurodegenerative or neuroinflammatory disease.
  • An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a typical daily dose may contain from about 0.01 mg/kg to about 100 mg/kg (such as from about 0.05 mg/kg to about 50 mg/kg and/or from about 0.1 mg/kg to about 25 mg/kg) of the compound used in the present method of treatment.
  • neuroinflammation is defined as an inflammatory response within the brain or spinal cord. This inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers.
  • a neuroinflammatory component such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the anti-inflammatory action of IL-38 could extend to other cells types similar to microglia, such as macrophages and mast cells that are involved in other inflammatory diseases.
  • Alzheimer's disease refers to a progressive neurologic disorder that causes the brain to shrink (atrophy) and brain cells to die. Alzheimer's disease is the most common cause of dementia, which is defined as a continuous decline in thinking, behavioral and social skills that affects a person's ability to function independently.
  • amyotrophic lateral sclerosis is defined as is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS is also known as Lou Gehrig's disease. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease.
  • CIRS chronic inflammatory response syndrome
  • long-COVID syndrome refers to a range of neuropsychiatric symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection.
  • mast cell activation syndrome refers to a condition in which a patient experiences repeated episodes of the symptoms of anaphylaxis allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing and severe diarrhea. High levels of mast cell mediators are released during those episodes. The episodes respond to treatment with inhibitors or blockers of mast cell mediators. The episodes are not caused by allergic antibody or secondary to other known conditions that activate normal mast cells.
  • MIS multisystem inflammatory syndrome
  • MIS-C multisystem inflammatory syndrome in children
  • M/CFS myalgic encephalomyelitis/chronic fatigue syndrome
  • pediatric acute neuropsychiatric syndrome refers to a condition defined by sudden onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms. Examples of other symptoms include anxiety, depression, tics, personality changes, decline in school performance, and sensory sensitivities. Symptoms typically begin during childhood but may begin at any age. Symptoms may go away for a while and then come back (referred to as a relapsing and remitting course). However, symptoms may be worse and last longer with each episode. PANS is thought to have a variety of possible causes.
  • PANDAS a subtype of PANS
  • Other possible causes of PANS include psychological trauma and underlying autoimmune, neurological, endocrine, or metabolic disorders. There are likely non-infectious triggers that have not yet been identified.
  • Lyme disease refers to the disease caused by the bacterium Borrelia burgdorferi and rarely, Borrelia mayonii. It is transmitted to humans through the bite of infected blacklegged ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system. Lyme disease is diagnosed based on symptoms, physical findings (e.g., rash), and the possibility of exposure to infected ticks. Laboratory testing is helpful if used correctly and performed with validated methods. Most cases of Lyme disease can be treated successfully with a few weeks of antibiotics.
  • PLS post-Lyme syndrome
  • sick building syndrome refers to a syndrome affecting occupants of a building wherein the occupants experience acute health and comfort effects that appear to be linked to time spent in a building, but no specific illness or cause can be identified.
  • the complaints may be localized in a particular room or zone, or may be widespread throughout the building.
  • a 1984 World Health Organization Committee report suggested that up to 30 percent of new and remodeled buildings worldwide may be the subject of excessive complaints related to indoor air quality (IAQ). Often this condition is temporary, but some buildings have long-term problems. Frequently, problems result when a building is operated or maintained in a manner that is inconsistent with its original design or prescribed operating procedures. Sometimes indoor air problems are a result of poor building design or occupant activities.
  • TMS toxic mold syndrome
  • Symptoms of TMS include chronic fatigue, chronic cough, increased allergy or asthma, and skin conditions like eczema or psoriasis.
  • Neurologic symptoms such as light headedness, headaches, tremors or panic attacks are also known to occur in TMS.
  • Many mycotoxins and metabolites secreted by molds may disrupt or translocate through the blood-brain barrier and cause neuroinflammation (53).
  • traumatic brain injury refers to a syndrome resulting from direct (concussion) or indirect (explosion) damage to the brain.
  • IL-38 inhibits secretion of IL-Ib from adult human microglia stimulated by neurotensin.
  • Human microglia were pretreated with human recombinant IL-37 (100 ng/mL) and three human recombinant IL-38 analogues (aa2-152, aa5-152, aa3-152, 100 ng/mL) for 24 hr and then were stimulated with NT (10 nM) for 24 hr to determine the level of secretion of IL-Ib and CXCL8.
  • IL-38 analogues aa2-152 and aa5-152 were equally potent as compared to IL-37b, inhibiting IL-Ib and CXCL8 secretion from microglia by about 30% (Fig. 1, left panel). However, IL-38 aa3-152 inhibited (p ⁇ 0.0001) IL-Ib and CXCL8 secretion by 100% (Fig. 1, right panel).
  • IL-38 Dose-response of IL-38 on secretion of IL-Ib and CXCL8 from adult human microglia stimulated by neurotensin is provided in Fig. 2.
  • IL-38 aa3-152 inhibited (pO.OOOl) secretion of IL-Ib by almost 90% even at 1 ng/ml (Fig. 2)
  • IL-38 The effect of IL-38 on secretion of IL-Ib and CXCL8 on secretion from embryonic human microglia stimulated by neurotensin is shown in Fig. 3.
  • Embryonic microglia HMC3 were pretreated with human recombinant IL-37b (100 ng/mL) and the three human recombinant IL-38 analogues (aa2-152, aa5-152, aa3-152, 100 ng/mL) for 24 h and then were stimulated with NT (10 nM) for 24 hr to determine the secretion of IL-Ib and CXCL8.
  • HMC3 Embryonic microglia
  • IL-38 and IL-36R are decreased in the amygdala of children with ASD.
  • IL-38 can inhibit NT-stimulated secretion of pro-inflammatory molecules from cultured human adult (IL-Ib and CXCL8) and embryonic (CXCL8) microglia.
  • Embryonic microglia do not secrete IL- 1 b.(31)
  • the inventors chose to use human embryonic microglia (32) because in contrast to adult microglia, they may better reflect how microglia from children with ASD would respond to potential treatments. (33) IL-38 is known to inhibit immune processes (34), but its effect on human microglia or its gene expression in the brain had not been investigated until now.
  • IL-38 is a more potent inhibitor than IL-37, which the inventors had previously reported to be able to inhibit NT-stimulated gene expression and secretion of IL- 1b and CXCL8 from cultured human adult microglia.(12)
  • the inventors also demonstrated decreased gene expression of IL-38 and IL-36R in amygdala of children with ASD. Previously, the inventors had reported that gene expression of IL-37 is increased in the brain of children with ASD. (12) The reason for these seemingly opposite findings is not clear. The inventors speculate that the increase in IL-37 may serve to compensate for the decreased expression of IL-38.
  • the amygdala is responsible for social behavior (14; 15) and dysfunctional neuronal connectivity in the amygdala has been associated with ASD. (35) Schumann and colleagues have shown that brains of patients with ASD have an increased number of neurons and greater dendritic density in the basal amygdala than age-matched non-ASD controls. (36) They also reported that enlargement of the amygdala in toddlers with ASD related to severity of behavior. (37) Their findings are consistent with decreased synaptic pruning by microglia when they are in their activated pro-inflammatory phase (M2). This data is also consistent with our hypothesis that focal inflammation in the amygdala could contribute to the pathogenesis of ASD. (38)
  • IL-38 exists intracellularly as a precursor full-length form (aal-152) (SEQ ID NO:l), which must be cleaved at the N-terminus before it is secreted extracellularly as an active form, (27) like other members of the IL-1 family (27).
  • the processing sites have not been identified.
  • the inventors synthesized the most plausible active analogues used in the present study: (a) IL- 38 aa3-152, (b) aa2-152 and (c) aa5-152 and the inventors show that the aa3-152 fragment shows the greatest inhibitory activity.
  • Human recombinant IL-37, Isoform b, N-terminus: Val46 and IL-38 analogues (aa2-152, aa5-152 and aa3-152) were synthesized by R&D Systems (Minneapolis, MN).
  • Human recombinant IL-37, Isoform b (Val46-Asp218) was from from R&D Systems, cat # 7585-IL.
  • DNA sequences encoding IL-38 analogues (aa2-152, aa5-152 and aa3-152) were expressed in E. coli at R&D Systems (Minneapolis, MN).
  • IL-38 proteins were purified by standard chromatographic methods to greater than 95% purity and the N-termini were confirmed by N-terminal sequencing analysis. Endotoxin level of all IL-38 variants was less than 0.10 EU per 1 pg of the protein by the limulus amebocyte lysate (LAL) method (R&D Systems (Minneapolis, MN). NT and LPS were purchased from Sigma-Aldrich. TaqMan gene expression primers were purchased from Applied Biosystems. ELISA kits for IL-38, IL-Ib and CXCL8 were purchased from R&D Systems.
  • LAL limulus amebocyte lysate
  • NT and LPS were purchased from Sigma-Aldrich.
  • TaqMan gene expression primers were purchased from Applied Biosystems.
  • ELISA kits for IL-38, IL-Ib and CXCL8 were purchased from R&D Systems.
  • Blood (1 mL) was obtained on empty stomach or at least two hours from a meal because NT is known to increase postprandially.(44) Blood was obtained between 9 and 11 am to avoid any diurnal variations, which has been reported to affect even allergic responses. (45; 46) Blood was collected in serum separator vacutainer tubes (BD Biosciences, Rockville, MD). One blood sample was collected in EDTA containing tubes in order to separate the plasma for later use. The second blood sample was allowed to clot at room temperature for about 15-30 min, and then was centrifuged at 1,000-2,000 x g for 10 min at 4°C. The upper clear fraction (serum) was carefully removed and aliquoted (0.5 mL/tube) into clean plastic capped tubes. All ASD and non-ASD control blood samples were labeled with a code number, age and sex, and were stored at -80°C. They were later shipped on dry ice to Tufts University for further analysis.
  • IL-38 (DY9110-05) levels in serum samples from children with ASD or controls were quantified by using commercially available ELISA kits (R&D Systems, Minneapolis, MN) as per manufacturer’s instructions. For all experiments the minimum detectable level by ELISA was 5 pg/mL.
  • Tissue samples were from amygdala. The only inclusion criteria used were males, 1-12 years of age, who had died in car accidents. Unfortunately, there is no available information of how diagnosis of ASD was reached, what the level of cognitive or functional level was before death, or the presence of any co-morbidities. Controls were selected without any known brain disease or trauma and were matched to the subjects with ASD to the extent possible.
  • Frozen brain tissues were sectioned (30 pm thickness) using a cryostat. Multiple areas of the brain were available from the same subjects, which allowed direct comparisons of outcome measures between regions of the brain within the same subjects. Samples were provided from males because ASD is four times more common in males than females, and to avoid any additional gender and hormonal variabilities. The deceased children whose brain samples were analyzed were unrelated to those whose serum was obtained.
  • Reverse transcription (RT) was performed with 500- 1000 ng of total RNA using the Superscript ® III First-Strand Synthesis System (Invitrogen, Life Technologies, Carlsbad, CA).
  • RNA purity was calculated and RNA integrity numbers (RIN) for all samples were reported by the brain bank.
  • Quantitative RT-PCR was performed using TaqMan gene expression assays (Applied Biosystems, Waltham, MA) to assess the gene expression of IL-38 (Hs00544661_ml) and IL- 36R (Hs00543916_ml). All qPCR studies were conducted using inventoried TaqMan gene expression probes from Invitrogen (Carlsbad, CA), which were validated by the vendor and publicly available. Samples were run for 45 cycles using the Applied Biosystems 7300 Real- Time PCR System (Waltham, MA). Normalization of gene expression to 18S rRNA (4310893E) and comparison of gene expression between groups was calculated according to the 2 -AACt method by Schmittgen (47).
  • tissue samples were included if RIN is above 5.0.
  • RIN postmortem interval
  • pH measures were used as indicators of tissue quality, as these factors have been reported to correlate with protein levels (49).
  • cause of death was used as an additional indicator of tissue integrity (50).
  • the immortalized human microglia-SV40 cell line derived from primary human microglia was purchased from Applied Biological Materials Inc. (ABM Inc., Richmond, BC, Canada) and was cultured in Prigrow III medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin in type I collagen-coated T25-flasks (ABM Inc.).
  • Microglia-SV40 maintain their phenotype and proliferation rates for over 10 passages, during which all experiments were performed using multiple microglia thaws and sub-cultured cells. Experiments were carried out in type-I collagen coated plates (BD PureCoat ECM Mimetic Cultureware Collagen I peptide plates, Becton Dickinson, Bedford, MA) (51). Cell viability was determined by trypan blue (0.4 %) exclusion.
  • the HMC3 cell line was isolated from primary mixed cultures of human spinal cord and cortical cells derived from 8-tol2-week-old embryos.
  • the HMC3 cells were immortalized through transfection with SV40 large T antigen, were purchased from ATCC (Manassas, VA) and were cultured in EMEM (ATCC ® 30-2003TM) medium supplemented with 10% fetal bovine serum (FBS) (ATCC ® 30-2020TM) and 1% penicillin/streptomycin in Corning ® T-75 flasks (Corning, NY).
  • HMC3 microglia cells maintain their phenotype and proliferation rates for over 10 passages, during which all experiments were performed using multiple microglia thaws and sub-cultured cells. Experiments were carried out in clear polystyrene plates (Corning, NY). Cell viability was determined by trypan blue (0.4 %) exclusion.
  • the cultured microglia were not used after 10 passages in order to avoid the possibility they may change their phenotype while in culture.
  • IL-Ib and CXCL8 secretion from human adult and embryonic microglia
  • SV40 microglia (0.5 xlO 5 cells/well) were seeded in twelve-well, type I collagen or poly- L-lysine-coated plates (Becton Dickinson) and HMC3 microglia were seeded in twelve-well plates (Corning, NY) for 24 hrs.
  • Pre-treatment with human rIL-38 (100 ng/mL) was allowed for 24 hrs followed by stimulation with NT (10 nM) or LPS (10 ng/mL) (Sigma-Aldrich) for 24 hrs.
  • IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment.

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Abstract

L'IL-38 peut inhiber l'activation de la microglie et inhiber la sécrétion d'IL-Ιβ et de CXCL8 par ces cellules. L'invention concerne des analogues d'IL-38 et des méthodes d'utilisation de l'IL-38 et de ses analogues pour inhiber la production de médiateurs inflammatoires dans les cellules ou la sécrétion de médiateurs par les cellules. L'invention concerne également des méthodes d'administration de ces analogues d'IL-38 pour traiter des maladies neuroinflammatoires ou neurodégénératives.
PCT/US2021/070791 2020-06-29 2021-06-29 Il-38 et ses analogues pour le traitement de maladies neuro-inflammatoires et neurodégénératives WO2022006588A1 (fr)

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Citations (3)

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US20170218039A1 (en) * 2014-07-25 2017-08-03 Fraunhofer-Gesellschaft Zur Fördeung Angewandten Forschung E.V. N-terminally truncated interleukin-38
CN108003181A (zh) * 2017-12-25 2018-05-08 佛山汉方中医医院有限公司 一种小胶质细胞IL-1β分泌抑制剂、其制备方法及用途
US20200101142A1 (en) * 2017-06-12 2020-04-02 Obsidian Therapeutics, Inc. Pde5 compositions and methods for immunotherapy

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US20170218039A1 (en) * 2014-07-25 2017-08-03 Fraunhofer-Gesellschaft Zur Fördeung Angewandten Forschung E.V. N-terminally truncated interleukin-38
US20200101142A1 (en) * 2017-06-12 2020-04-02 Obsidian Therapeutics, Inc. Pde5 compositions and methods for immunotherapy
CN108003181A (zh) * 2017-12-25 2018-05-08 佛山汉方中医医院有限公司 一种小胶质细胞IL-1β分泌抑制剂、其制备方法及用途

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NARIAI YUKO, KAMINO HIROKI, OBAYASHI EIJI, KATO HIROAKI, SAKASHITA GYOSUKE, SUGIURA TOMOKO, MIGITA KIYOSHI, KOGA TOMOHIRO, KAWAKAM: "Generation and characterization of antagonistic anti-human interleukin (IL)-18 monoclonal antibodies with high affinity: Two types of monoclonal antibodies against full-length IL-18 and the neoepitope of inflammatory caspase-cleaved active IL-18", ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, vol. 663, 1 March 2019 (2019-03-01), US , pages 71 - 82, XP055896922, ISSN: 0003-9861, DOI: 10.1016/j.abb.2019.01.001 *
TSILIONI IRENE, PANTAZOPOULOS HARRY, CONTI PIO, LEEMAN SUSAN E., THEOHARIDES THEOHARIS C.: "IL-38 inhibits microglial inflammatory mediators and is decreased in amygdala of children with autism spectrum disorder", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 117, no. 28, 14 July 2020 (2020-07-14), pages 16475 - 16480, XP055896966, ISSN: 0027-8424, DOI: 10.1073/pnas.2004666117 *

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