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EP-4735036-A1 - IMMUNOTHERAPEUTIC METHODS, COMPOUNDS, AND COMPOSITIONS FOR TREATING OR PREVENTING CELIAC DISEASE

EP4735036A1EP 4735036 A1EP4735036 A1EP 4735036A1EP-4735036-A1

Abstract

The present application relates to a method for increasing tolerance to gliadin in a subject, in particular in a subject suffering from celiac disease, comprising repeatedly administered a polypeptide construct comprising several epitopes from gliadin isoforms preferably by epicutaneous route. The present application also relates to the polypeptide construct per se and a skin patch containing the same.

Inventors

  • DIOSZEGHY, VINCENT
  • MATTHEWS, Katie
  • HERVE, Pierre-Louis
  • ROUCAIROL, Camille
  • KOPPELMAN, Stef
  • ANDERSON, ROBERT PAUL
  • KONING, FRITS
  • MAILLERE, BERNARD

Assignees

  • DBV Technologies

Dates

Publication Date
20260506
Application Date
20241220

Claims (20)

  1. 1. An immunogenic polypeptide construct, comprising (i) at least one epitope from alpha-gliadin, (ii) at least one epitope from gamma-gliadin, and (iii) at least one epitope from omega-gliadin, each epitope being independently in non-deamidated form or in at least partially deamidated form, wherein: the at least one epitope from alpha-gliadin comprises a peptide selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, and combinations thereof; the at least one epitope from gamma-gliadin comprises a peptide selected from the group consisting of: SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, and combinations thereof, and the at least one epitope from omega-gliadin comprises a peptide selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, and combinations thereof.
  2. 2. The immunogenic polypeptide construct according to claim 1, further comprising a polypeptide of SEQ ID NO: 14, wherein: the at least one epitope from alpha-gliadin comprises a peptide of SEQ ID NO:4, the at least one epitope from gamma-gliadin comprises a peptide of SEQ ID NO: 6, and the at least one epitope from omega-gliadin comprises a peptide of SEQ ID NO:28.
  3. 3. The immunogenic polypeptide construct according to any one of claims 1 to 2, which comprises at least one QPEQPFP moiety.
  4. 4. The immunogenic polypeptide construct of claim 1, comprising: (i) at least one building block comprising an epitope from alpha-gliadin which is selected from the group consisting of a polypeptide having at least 80% sequence identity with SEQ ID NO: 15; a polypeptide having at least 80% sequence identity with SEQ ID NO: 18; a polypeptide having at least 80% sequence identity with SEQ ID NO: 19, and combinations thereof, (ii) at least one building block comprising an epitope of from gamma-gliadin which is selected from the group consisting of: a polypeptide having at least 80% sequence identity with SEQ ID NO: 16, a polypeptide having at least 80% sequence identity with SEQ ID NO: 17, and combinations thereof, and (iii) at least one building block comprising an epitope from omega-gliadin which is selected from the group consisting of a polypeptide having at least 80% with SEQ ID NO:20; a polypeptide having at least 80% sequence identity with SEQ ID NO:21, and combinations thereof, the said building blocks being directly connected or being connected by means of one or more linkers, in any order.
  5. 5. An immunogenic polypeptide construct which comprises at least four building blocks BB1, BB2, BB3, and BB4 defined as follows: BB l is a polypeptide of SEQ ID NO: 15 or which differs from SEQ ID NO: 15 by one, two, three, four, five, six, seven, eight, or nine amino acid change(s) (substitutions, insertions, and/or deletions), BB2 has at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID NO: 16 (BB2a) or at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID NO: 17 (BB2b), BB3 has at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID NO:20 (BB3a) or at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID N0:21 (BB3b), and BB4 has at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID NO: 18 (BB4a) or at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity with SEQ ID NO: 19 (BB4b), and BB1, BB2, BB3, and BB4 are directly connected or are connected by means of one or more linkers, in any order.
  6. 6. The immunogenic polypeptide construct according to claim 5, which comprises BB1, BB2a, BB3a, and BB4a
  7. 7. The polypeptide construct according to claim 5 which comprises or consists of a moiety of formula (I): [BBw]-[Ll]ni-[BBx]-[L2]n2-[BBy]-[L3]n3-[BBz] (I) wherein: BBw, BBx, BBy and BBz are building blocks selected from BB1, BB2, BB3, and BB4 as defined in claim 5, with the proviso that each building block is different, nl, n2, and n3 are independently 0 or 1, LI, L2, and L3 are linkers, each linker being of the following formula (II): -[CCl]a-[SPl]b-[CC2]c- (II) wherein: each a, b, and c is independently 0 or 1, each CC1 and CC2 are independently selected from peptides having from 2 to 20 amino acid residues in length, preferably from 1 to 10 amino acid residues in length, and comprising a cathepsin cleavage site, preferably KK, AYY, RR, or GPGPG, and SP1 is a spacer group comprising up to 200 carbon atoms and which optionally comprises a peptide moiety or a non-peptide moiety.
  8. 8. The immunogenic polypeptide construct according to claim 5 which comprises or consists of, a moiety of formula (la): [BBw]-[CCw]ai-[BBx]-[CCx]a2-[BBy]-[CCy]a3-[BBz] (la) wherein: BBw, BBx, BBy, and BBz are building blocks selected from BB1, BB2, BB3, and BB4 as defined in claim 5, with the proviso that each building block is different, ai, a2, and as are independently 0 or 1, preferably 1, and CCw, CCx, and CCy are independently selected from peptides having from 2 to 10 amino acid residues in length and comprising a cathepsin cleavage sites, preferably KK, AYY, RR, or GPGPG (SEQ ID NO:41).
  9. 9. The immunogenic polypeptide construct according to claim 8, wherein CCw, CCx, and CCy are each independently selected from the group consisting of KKKK (SEQ ID NO:32), KK, GPRRKK (SEQ ID NO:33), GPKK (SEQ ID NO:34), GARRKK (SEQ ID NO:35), KGKK (SEQ ID NO:45), AYY, RR, and GCRRKK (SEQ ID NO:36), preferably selected from the group consisting of GPRRKK, GPKK, GARRKK, and GCRRKK.
  10. 10. The immunogenic polypeptide construct according to claim 9 which is of formula (Ic): [BBl]-[CCw]-[BB2a]-[CCx]-[BB3a]-[CCy]-[BB4a] (Ic) wherein - CCw, CCx, and CCy are independently selected from the group consisting of KKKK (SEQ ID NO:32), KK, GPRRKK (SEQ ID NO:33), GPKK (SEQ ID NO:34), GARRKK (SEQ ID NO:35), AYY, RR, and GCRRKK (SEQ ID NO: 36), preferably selected from GPRRKK, GPKK, GARRKK, and GCRRKK, and - BB1 is of SEQ ID NO: 15, BB2a is of SEQ ID NO: 16, BB3a is of SEQ ID NO:20, and BB4a is of SEQ ID NO: 18.
  11. 11. The immunogenic polypeptide construct according to claim 1 which comprises, or consists of, a polypeptide having at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% sequence identity, preferably at least about 85%, at least about 90%, or at least about 95% sequence identity with a polypeptide selected from SEQ ID NO:22 or 23.
  12. 12. The immunogenic polypeptide construct according to claim 1 which comprises, or consists of, a polypeptide having at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% sequence identity, preferably at least about 85%, at least about 90%, or at least about 95% sequence identity with a polypeptide selected from SEQ ID NO:24 to 27, 42 to 44, and 46.
  13. 13. The immunogenic polypeptide construct according to any one of claims 1 to 12, wherein: - the C-terminal end of the polypeptide construct is amidated, and/or the N-terminal end of the polypeptide construct is acetylated, and/or the N-terminal amino acid residue in the polypeptide construct is lysine or arginine.
  14. 14. A polypeptide construct which comprises, or consists of, a polypeptide having at least 90%, or at least 95% sequence identity with a polypeptide selected from SEQ ID NO:22 or 23.
  15. 15. A polypeptide construct as defined in any one of claims 1-14, preferably as defined in any one of claims 2 to 14.
  16. 16. A skin patch, wherein the skin patch comprises: - a backing having a periphery adapted to create a hermetically closed chamber when applied on a subject’s skin, and - the polypeptide construct according to any one of claims 1 to 15, wherein the polypeptide construct is present in dry form, optionally in admixture with one or several pharmaceutically acceptable excipients, on the backing of the patch.
  17. 17. A skin patch for increasing immune tolerance to gliadin, which comprises a polypeptide construct as defined in any of claims 1-15.
  18. 18. The polypeptide construct according to any of claims 1 to 15, for use in the treatment of celiac disease.
  19. 19. The polypeptide construct according to claim 18, for use in the treatment of symptomatic celiac disease.
  20. 20. The polypeptide construct according to any of claims 1 to 15, for use in increasing immune tolerance to gliadin.

Description

IMMUNOTHERAPEUTIC METHODS, COMPOUNDS, AND COMPOSITIONS FOR TREATING OR PREVENTING CELIAC DISEASE FIELD The present application relates to an immunotherapeutic method for treating or preventing celiac disease. BACKGROUND Celiac disease (CeD) is an immune-mediated disease caused by an abnormal intestinal T cell response to cereal gluten proteins. CeD is triggered by the intake of gluten proteins derived from wheat, barley, and rye (1). Gluten is a complex mix of proteins that can be divided into two fractions: gliadins and glutenins. Gliadins are the main trigger factors of CeD and can be subdivided into three main isoforms: a-gliadins (also referred to as alphagliadins), y-gliadins (also referred to as gamma-gliadins), and co-gliadins (also referred to as omega-gliadins). CeD has a strong genetic component; human leukocyte antigen (HLA) is the most important genetic determinant. More specifically, a strong association between CeD development and expression of certain human leukocyte antigen (HLA)-DQ allotype variants (HLA-DQ2 and HLA-DQ8) has been reported. The prevalence of CeD in the general population is estimated to be 1%, with a seroprevalence of 1.4% and a biopsy -proven prevalence of 0.7% (2). CeD prevalence is increasing in Western countries. Between the years 1975 and 2000, CeD prevalence increased 5-fold in the US, for reasons that are currently unknown. The prevalence of CeD is higher in first-degree CeD relatives (10-15%) and in other at-risk groups, particularly patients with Down syndrome, type 1 diabetes, or IgA deficiency. Symptoms of CeD can appear at any age from infancy well into senior adulthood. Symptoms usually occur in children after ingestion of gluten-containing grains between 4 and 24 months of age. There may be a delay or latent period between gluten intake and the onset of symptoms. Gastrointestinal system and extra-intestinal manifestations are common in CeD (3). The main symptoms of CeD are chronic diarrhea, recurrent abdominal pain, nausea, vomiting, and abdominal distension. Common extra-intestinal manifestations are failure to thrive, short stature, chronic anemia, osteopenia, osteoporosis, delayed puberty, dental enamel defect, irritability, chronic fatigue, neuropathy, arthritis, arthralgia, amenorrhea, and increased liver enzymes. CeD affects the proximal small intestine, leading to villus atrophy and crypt hyperplasia, together with an increased number of intraepithelial lymphocytes (lELs) and lamina propria lymphocytes in the mucosa. The histological changes are caused by an immune response to dietary gluten in the small intestine mucosa (4). Since gluten is highly resistant to proteolysis by gastrointestinal enzymes, long gluten peptides remain in the lumen of the intestine. After crossing the epithelial layer, some of these peptides are partially and/or fully deamidated by the enzymatic activity of tissue transglutaminase (tTG) which convert some glutamine residues (Q) to glutamates/glutamic acid (E) in the motifs Q-X-proline (P) where X is not a glycine (G) or a P, and in the motif Q-X-X where X is, for instance, a phenylalanine (F), a tyrosine (Y), a tryptophan (W), an isoleucine (I) or a leucine (L). Deamidation generates negatively charged immunogenic peptides with increased affinity for the major histocompatibility complex (MHC)-II molecules HLA-DQ2 and HLA-DQ8. This leads to the presentation of immunogenic peptides by dendritic cells (DCs). Based on studies conducted in mouse models, it is believed that DCs, having captured gliadin fragments, migrate from the lamina propria to the draining mesenteric lymph nodes where they encounter naive CD4+ T cells and induce their differentiation into gluten-specific Thl CD4+ T cells, which migrate back to the lamina propria. The contact of CD4+ T cells in the lamina propria with gluten fragments induces their activation and proliferation, resulting in the production of proinflammatory cytokines (especially IFN-y), metalloproteases, and keratinocyte growth factor by stromal cells. This in turn induces cryptal hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by lELs (5). Thl cells can also locally stimulate CD8+ T cells and natural killer (NK) cells, which causes apoptosis of the enterocytes. In addition to the CD4+ T cell response, an increased number of glutenspecific CD8+ cytotoxic T lymphocytes (CTLs) has been reported in the lamina propria of CeD patients. These CTLs express IFN-y, CD95, and granzyme B when stimulated with gliadin (6). Several HLA-DQ-restricted gluten T cell epitopes recognized by CD4+ T cells of CeD patients have been described to date (7-9). More specifically, various T cell epitopes from wheat gluten proteins (mainly from the alpha-, gamma-, and omega-isoforms of gliadins) have been reported. T cell epitopes from hordein (barley) and secalin (rye) have also been described and showed a high homology with those found in wheat. At present, the only available treat