WO2022120423A1 - Peptides et leurs utilisations - Google Patents
Peptides et leurs utilisations Download PDFInfo
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- WO2022120423A1 WO2022120423A1 PCT/AU2021/051465 AU2021051465W WO2022120423A1 WO 2022120423 A1 WO2022120423 A1 WO 2022120423A1 AU 2021051465 W AU2021051465 W AU 2021051465W WO 2022120423 A1 WO2022120423 A1 WO 2022120423A1
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- amino acid
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- inflammatory
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/62—Leeches; Worms, e.g. cestodes, tapeworms, nematodes, roundworms, earth worms, ascarids, filarias, hookworms, trichinella or taenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
- C07K14/43536—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from worms
- C07K14/4354—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from worms from nematodes
Definitions
- the present invention relates to peptides for treating an inflammatory or autoimmune condition, pharmaceutical compositions comprising same, and methods of use comprising same.
- Related application [0002] This application claims priority from Australian provisional patent application AU 2020904544, the entire contents of which are hereby incorporated by reference.
- Background of the invention [0003] Inflammation is a non-specific reaction by the body's immune system in response to a perceived injury or theat. Inflammation may also occur in response to an autoimmune condition, where body's immune system mistakenly attacks the body's own cells. Examples of such conditions include inflammatory bowel diseases and asthma.
- IBDs Inflammatory bowel diseases
- UC ulcerative colitis
- CD Crohn's disease
- UC ulcerative colitis
- CD Crohn's disease
- Asthma primarily affects the respiratory tract and its incidence is rising in industrialized and developing countries, generating a burden on their health services.
- IBDs and asthma There is significant interest in developing therapeutics for inflammatory and/or autoimmune conditions such as IBDs and asthma. While some therapeutics have been developed, current treatments for both IBDs and asthma have significant limitations, for example adverse side effects or being ineffective for some patients.
- the present invention provides a peptide of formula (I): R 1 –X 1 –X 2 –X 3 –X 4 –X 5 –X 6 –X 7 –X 8 –X 9 –X 10 –X 11 –X 12 –X 13 –X 14 –X 15 –X 16 –X 17 –X 18 –X 19 –X 20 –R 2 (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is NH 2 or X 21 -NH 2 where X 21 is a hydrophobic amino acid or X 21 –X 22 –X 23 –X 24 – X 25 –X 26 –X 27 –X 28 –X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 –NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each independently a hydrophobic amino acid and X 26 ,
- R 1 is NH 2 or X 21 -NH 2 where X 21 is leucine or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 – X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 –NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each leucine and X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 and X 35 are each independently absent or leucine, especially NH 2 or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 – X 27 –X 28 –X 29 –X 30 –NH 2 where X 21 , X 22 , X
- R 1 is NH 2 or X 21 -NH 2 where X 21 is leucine or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 – X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 –NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each leucine and X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 and X 35 are each independently absent or leucine, especially NH 2 or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 – X 27 –X 28 –X 29 –X 30 –NH 2 where X 21 , X 22 , X
- the peptide is selected from SEQ ID NOs:1-4 8, especially SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially SEQ ID NO:3 or SEQ ID NO:4.
- a peptide of the invention may have a portion of the peptide which is substantially alpha-helical in structure.
- the peptide has a hydrogen bond present between at least the backbone peptide atoms of X 4 and X 8 .
- at least X 4 –X 8 of the peptide has a substantially alpha-helical structure.
- the present invention also provides a peptide comprising an amino acid sequence having at least about 70% sequence identity to any one of SEQ ID NOs:1-4, especially to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially SEQ ID NO:3 or SEQ ID NO:4, or a biologically active fragment or variant thereof, provided that 4E and 8L of SEQ ID NOs:1-4 are retained, or a pharmaceutically acceptable salt thereof.
- the peptide may have at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% sequence identity, or other % identity described herein, to any one of SEQ ID NOs:1-4, especially to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially to SEQ ID NO:3 or SEQ ID NO:4.
- the present invention also provides a peptide comprising an amino acid sequence having at least 1 amino acid substitution compared to any one of SEQ ID NOs:1-4, especially compared to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially compared to SEQ ID NO:3 or SEQ ID NO:4, provided that 4E and 8L of SEQ ID NOs:1-4 are retained, or a pharmaceutically acceptable salt thereof.
- the present invention may have at least 2, at least 3, at least 4, at least 5 or at least 6 amino acid substitutions, or other number described herein, compared to any one of SEQ ID NOs:1-4, especially compared to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially compared to SEQ ID NO:3 or SEQ ID NO:4.
- Any peptide described herein may exhibit a serum stability of at least 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% peptide remaining at 4, 5, 6, 7 or 8 hours.
- the serum stability is in vitro serum stability and is measured by any method known in the art or described herein in the Examples (e.g., Example 7). In one embodiment, the peptide is still detectable in after 24 hours.
- a peptide of the invention may be isolated, purified, substantially purified, enriched, synthetic or recombinant.
- the present invention also provides a pharmaceutical composition comprising, consisting essentially of or consisting of the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the present invention also provides a method for treating or preventing an inflammatory or autoimmune condition comprising administering to a subject in need thereof the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby treating or preventing an inflammatory or autoimmune condition in the subject.
- the peptide of the invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein may be administered, or formulated for administration by, any route described herein, preferably orally.
- the present invention also provides a method for the treatment of an inflammatory or autoimmune condition in a subject comprising the steps of: - identifying a subject having an inflammatory or autoimmune condition; and - administering to the subject in need thereof a therapeutically effective amount of the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby treating an inflammatory or autoimmune condition in the subject.
- the present invention also provides a method for inhibiting progression of an inflammatory or autoimmune condition comprising administering to a subject in need thereof the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby inhibiting progression of an inflammatory or autoimmune condition.
- the peptide of the invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein may be administered, or formulated for administration by, any route described herein, preferably orally.
- the present invention also provides a method for minimising, alleviating or ameliorating a symptom of an inflammatory or autoimmune condition comprising administering to a subject in need thereof the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby minimising, alleviating or ameliorating a symptom of an inflammatory or autoimmune condition.
- the peptide of the invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein may be administered, or formulated for administration by, any route described herein, preferably orally.
- the present invention also provides the use of the peptide of the invention described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory or autoimmune condition.
- the peptide of the invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein may be formulated for administration by any route described herein, preferably orally.
- the present invention also provides the peptide of the invention as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing an inflammatory or autoimmune condition.
- the peptide of the invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition described herein may be formulated for administration by any route described herein, preferably orally.
- the inflammatory or autoimmune condition may be selected from an inflammatory bowel disease, asthma, rheumatoid arthritis and coeliac disease, especially an inflammatory bowel disease.
- the inflammatory or autoimmune condition is inflammatory bowel disease
- the inflammatory bowel disease may be ulcerative colitis or Crohn's disease.
- the present invention also provides a nucleic acid comprising a nucleotide sequence encoding the peptide of the invention, or any other peptide described herein.
- the present invention also provides a vector or expression construct comprising a nucleic acid of the invention as described herein.
- FIG. 1 Graphs of the secondary shift analysis of SEQ ID NOs: 1-3 and 5.
- Figure 1A shows secondary shift analysis of SEQ ID NO:1 (left bars) and SEQ ID NO:5 (right bars) and
- Figure 1B shows secondary shift analysis of SEQ ID NO:2 (left bars) and SEQ ID NO:3 (right bars).
- Figure 2 Representations of the three dimensional structure of SEQ ID NO:1. The 20 lowest energy structures were determined based on NMR spectroscopy data.
- Figure 2A shows superposition of structures over the backbone atoms of residues 2-11 (RMSD 0.126 ⁇ ).
- Figure 2B shows superposition of structures of the backbone atoms of residues 11-18 (RMSD 1.003 ⁇ ).
- Figure 3. Graphs showing the protective effects of SEQ ID NOs:1-3 against weight loss and clinical symptoms induced by TNBS colitis.
- Figure 3A is a graph showing body weight percentage (na ⁇ ve mice: black circles; TNBS control mice: dark grey squares; SFTI-1: diamonds; NTQ-48: dark grey upward triangles; ES2-10/SEQ ID NO:3: light grey upward triangles; AIP-2-20/SEQ ID NO:1: light grey squares: AIP1- 13/SEQ ID NO:2: downward triangles),
- Figure 3B is a graph showing colon length
- Figure 3C is a graph showing macroscopic score.
- Statistical analyses were performed using GraphPad Prism 8 (2-way ANOVA and unpaired nonparametric Mann-Whitney t- test). *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001.
- FIG. 5A is a representative micrograph of periodic acid schiff-stained colonic tissue sections.
- Figure 5B is a graph showing histology scoring and
- Figure 5C is a graph showing goblet cell scoring. *P ⁇ 0.05; ** P ⁇ 0.01; *** P ⁇ 0.001.
- Figure 6. Graphs showing activity of SEQ ID NO:3 in human cells. SEQ ID NO:3 (100 ⁇ g/ml) was added to 1x10 6 PBMCs stimulated with 50 ng/ml of PMA and 1 ⁇ g/ml of ionomycin (Figure 7A) or 10 ng/ml of LPS ( Figure 7B).
- Figure 7C shows the SEQ ID NO:3 dose response from 0.1-100 ⁇ g/ml performed on 1 ⁇ 10 6 PBMCs stimulated with 10 ng/ml of LPS.
- Figure 7D shows the effects of SEQ ID NO:3 across genetically unrelated donors. All results were performed in triplicate. *P ⁇ 0.05; ** P ⁇ 0.01; *** P ⁇ 0.001. [0038] Figure 7.
- Graphs showing the protective effects of SEQ ID NO:3 against weight loss (left; na ⁇ ve mice: black circles and solid lines; TNBS control mice: dark grey squares and solid lines; ES10/SEQ ID NO:3: dark grey upward triangles and solid lines; sulfa: light grey downward triangles and solid lines; ntq48: light grey circles and solid lines; D6A/SEQ ID NO: 5: light grey upward triangles and dashed lines; K9A/SEQ ID NO:6: grey diamonds and dashed lines) and clinical symptoms (right) induced by TNBS colitis.
- FIG. 8 Graph showing stability of SEQ ID NOs:1-3 and 5 in human serum (AIP-2-20/SEQ ID NO:1: circles: AIP2-20D6P/SEQ ID NO:5: downward triangles; AIP1- 13/SEQ ID NO:2: squares; ES10/SEQ ID NO:3: upward triangles). The percentage of peptide remaining in the serum stability assay was assessed by RP-HPLC. All data are represented as mean ⁇ SD and were recorded in triplicate. [0040] Figure 9.
- Figure 9A is a graph showing body weight percentage
- Figure 9B is a graph showing daily clinical score.
- Statistical analyses were performed using GraphPad Prism 9 (2-way ANOVA). *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001. All results reported represent means ⁇ standard errors of the means (SEM). [0041] Figure 10.
- FIG. 10A is a graph showing body weight percentage
- Figure 10B is a graph showing daily clinical score.
- Statistical analyses were performed using GraphPad Prism 9 (2-way ANOVA). *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001; ****P ⁇ 0.0001. All results reported represent means ⁇ standard errors of the means (SEM).
- Hookworms are known to manipulate the immune system to prevent inappropriate immune responses, which promotes their long-term survival and results in chronic infection, primarily due to the secretion of a variety of hookworm excretory/secretory (ES) proteins. Hookworm proteins have been shown to have anti-inflammatory activity. The inventors have surprisingly found that relatively short peptide truncates of the hookworm proteins are also capable of exhibiting anti-inflammatory activity. Without wishing to be bound by theory, the present inventors have identified that a portion of the peptides of the invention may be capable of forming a substantially alpha-helical structure, and this portion may, at least in part, contribute to the anti-inflammatory activity of the peptides.
- the peptides of the invention have been shown to have utility in a number of well characterised models that are associated with activation of the inflammatory response, including colitis. These models are well characterised in the art to comprise episodes of acute and/or chronic inflammation. The inventors therefore recognise the application of the peptides of the invention for a wide range of conditions, disorders or diseases, including autoimmune conditions, which are accompanied by inflammation, of which those disclosed herein are just some examples. The inventors have also unexpectedly found that the peptides of the invention are capable of demonstrating anti-inflammatory activity when administered orally. [0049] As also shown in the Examples, the peptides of the invention are capable of reducing the secretion of pro-inflammatory cytokines from human immune cells.
- Non- limiting examples include IFN- ⁇ , TNF- ⁇ , IL-2 and IL-8.
- the peptides of the invention are also surprisingly shown to be non-toxic at high concentrations. Further, the peptides of the invention are shown to exhibit stability in serum. Definitions [0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below. [0051] The articles “a” and “an” are used herein to refer to one or to more than one (i.e.
- an element means one element or more than one element.
- the term “and/or”, e.g., “X and/or Y” will be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.
- the term “about” refers to a quantity, value, dimension, size, or amount that varies by as much as 30%, 25%, 20%, 15% or 10% to a reference quantity, value, dimension, size, or amount.
- amino acid refers to a compound having an amino group and a carboxylic acid group.
- the amino acid may be a L- or D- isomer or mixtures thereof.
- the amino acid may have a naturally occurring side chain (see Table 1) or a non-proteinogenic side chain.
- non-proteinogenic amino acid refers to an amino acid having a side chain that does not occur in the naturally occurring L- ⁇ -amino acids recited in Table 1.
- non-proteinogenic amino acids and derivatives include, but are not limited to, norleucine, 4-aminobutyric acid, 4-amino-3-hydroxy-5- phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, citrulline, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of natural amino acids [0058]
- ⁇ -amino acid refers to an amino acid that has a single carbon atom (the ⁇ -carbon atom) separating a carboxyl terminus (C-terminus) and an amino terminus (N-terminus).
- an ⁇ -amino acid includes naturally occurring and non-naturally occurring L-amino acids and their D-isomers and derivatives thereof such as salts or derivatives where functional groups are protected by suitable protecting groups.
- amino acid refers to an ⁇ - amino acid.
- hydrophobic amino acid refers to an amino acid having a side chain which is non-polar.
- Examples include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tryptophan, aminoisobutyric acid, cyclohexylalanine, cyclopentylalanine, norleucine, norvaline, tert- butylglycine and ethylglycine, especially alanine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tryptophan and aminoisobutyric acid.
- hydrophilic amino acid refers to an amino acid having a side chain which is polar or charged.
- polar uncharged amino acid refers to an amino acid having a side chain that has a dipole moment. Examples include, but are not limited to, serine, threonine, cysteine, tyrosine, asparagine and glutamine.
- positively charged amino acid refers to an amino acid having a side chain capable of bearing a positive charge.
- the term “negatively charged amino acid” refers to an amino acid having a side chain capable of bearing a negative charge. Examples include, but are not limited to, aspartic acid and glutamic acid.
- a peptide represents a series of two or more amino acids linked through a covalent bond formed between the carboxyl group of one amino acid and the amino group of another amino acid (i.e. the so-called peptide bond).
- alkyl refers to straight chain or branched hydrocarbon groups.
- the alkyl group may have a specified number of carbon atoms, for example, C 1-3 alkyl which includes alkyl groups having 1, 2 or 3 carbon atoms in a linear or branched arrangement.
- suitable alkyl groups include methyl, ethyl, n-propyl and i-propyl.
- alpha helical refers to a three dimensional structural conformation which is analogous to those found in proteins and peptides.
- the present invention provides peptides of formula (I): R 1 –X 1 –X 2 –X 3 –X 4 –X 5 –X 6 –X 7 –X 8 –X 9 –X 10 –X 11 –X 12 –X 13 –X 14 –X 15 –X 16 –X 17 –X 18 –X 19 –X 20 –R 2 (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is NH 2 or X 21 -NH 2 where X 21 is a hydrophobic amino acid or X 21 –X 22 –X 23 –X 24 – X 25 –X 26 –X 27 –X 28 –X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 –NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each independently a hydrophobic amino acid and X 26 , and X 25 are
- the peptides of formula (I) include a glutamic acid at X 4 (4E) and a leucine at X 8 (8L), also referred to herein as the EXXXL motif. As shown in the Examples, a hydrogen bond may be present between the backbone peptide bond atoms of X 4 and X 8 of the peptides. Further, a portion of the peptides may have a substantially alpha-helical structure in solution and/or when bound to a target molecule.
- the secondary structure of a peptide may be determined by methods known in the art, for example by nuclear magnetic resonance (NMR) chemical shift analysis (Mielke, S. P.; Krishnan, V. V. Characterization of protein secondary structure from NMR chemical shifts. Prog. Nucl. Magn. Reson. Spectrosc.
- the present inventors hypothesise that a portion of the peptides of the invention can form an alpha-helical structure as a result of intramolecular donor-acceptor hydrogen bonding interactions between backbone peptide bonds of the peptides, for example the hydrogen bond present between the backbone peptide bond atoms of X 4 and X 8 .
- the present inventors further hypothesise that the alpha-helical portion of the peptides of the invention may, at least in part, contribute to the anti-inflammatory activity of the peptides.
- the peptide of formula (I) may optionally comprise a functional moiety capable of imparting a function to the peptide.
- the functional moiety when present, may be conjugated to the N-terminus, C-terminus or a side chain of any one of the amino acids present in the peptide for fomula (I). Any suitable functional moiety may be used depending on the function to be imparted to the peptide.
- the functional moiety may be an imaging agent which can allow for visualisation of the peptide of fomula (I) by an appropriate imaging technique.
- the functional moiety may be a binding moiety which can allow the peptide of formula (I) to bind to a particular target.
- the functional moiety is biotin, which is preferably conjugated to the N-terminus of the peptide of formula (I), for example via an amide bond.
- R 1 is NH 2 or X 21 -NH 2 where X 21 is leucine or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 – X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 –NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each leucine and X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 and X 35 are each independently absent or leucine; R 2 is COOH or CONH 2 ; X 1 is a X 21 -NH 2 where X 21 is leucine or X 21 –X 22
- R 1 is NH 2 or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 –X 29 –X 30 –NH 2 where X 21 , X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 and X 30 are each leucine, especially NH 2 ; R 2 is COOH; X 1 is serine or threonine or proline; X 2 is glutamine or serine or proline.
- the peptide of formula (I) is selected from: SEQ ID NO:1 H 2 N-TPEEHDLLMDLMGDPKKAEE-OH SEQ ID NO:2 H 2 N-PSKEKADLGKYKA-OH SEQ ID NO:3 H 2 N-SQKEKDLLKE-OH SEQ ID NO:4 H 2 N-LLLLLLLLLLSQKEKDLLKE-OH [0074]
- R 1 is NH 2 or X 21 -NH 2 where X 21 is leucine or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 – X 29 –X 30 –X 31 –X 32 –X 33 –X 34 –X 35 —NH 2 where X 21 , X 22 , X 23 , X 24 and X 25 are each leucine and X 26 , X 27 ,
- R 1 is NH 2 or X 21 –X 22 –X 23 –X 24 –X 25 –X 26 –X 27 –X 28 –X 29 –X 30 –NH 2 where X 21 , X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 and X 30 are each leucine, especially NH 2 ;
- R 2 is COOH;
- X 1 is serine or threonine;
- X 2 is glutamine or proline;
- X 3 is lysine;
- X 5 is lysine;
- X 6 is aspartic acid;
- X 7 is leucine;
- X 9 is lysine or methionine;
- X 10 is glutamic acid;
- X 11 is absent or leucine;
- X 12 is absent or methionine;
- X 13 is absent;
- X 14 is
- X 1 is serine; X 2 is glutamine; X 9 is lysine; X 11 is absent; X 12 is absent.
- the peptide of formula (I) is SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; especially SEQ ID NO:3 or SEQ ID NO:4, more especially SEQ ID NO:3.
- the present invention also provides a peptide comprising an amino acid sequence having at least 70% sequence identity to any one of SEQ ID NOs:1-4, or a biologically active fragment or variant thereof, provided that 4E and 8L of SEQ ID NOs:1-4 are retained (i.e., the EXXXL motif of SEQ ID NOs:1-4 is retained), or a pharmaceutically acceptable salt thereof.
- the amino acid sequence has at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one of SEQ ID NOs:1-4.
- the amino acid sequence may have at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, at least 90% sequence identity to any one of SEQ ID NOs:1-4.
- the amino acid sequence of the peptide is any one of SEQ ID NOs:1-4, that is, the amino acid sequence has 100% sequence identity to any one of SEQ ID NOs:1-4.
- the amino acid sequence has at least 70% sequence identity to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4, especially to SEQ ID NO:3 or SEQ ID NO:4, or a biologically active fragment or variant thereof, provided that 4E and 8L of SEQ ID NOs:1, 3 and 4 are retained, or a pharmaceutically acceptable salt thereof.
- the amino acid sequence has at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4, especially SEQ ID NO:3 or SEQ ID NO:4.
- the amino acid sequence may have at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, at least 90% sequence identity to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; especially SEQ ID NO:3 or SEQ ID NO:4.
- the amino acid sequence of the peptide is SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; especially SEQ ID NO:3 or SEQ ID NO:4, that is, the amino acid sequence has 100% sequence identity to SEQ ID NO:1, SEQ ID NO:3 or SEQ ID NO:4.
- the present invention also provides a peptide comprising an amino acid sequence having at least 1 amino acid substitution compared to any one of SEQ ID NOs:1-4, especially compared to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; more especially compared to SEQ ID NO:3 or SEQ ID NO:4, provided that 4E and 8L of SEQ ID NOs:1-4 are retained (i.e., the EXXXL motif of SEQ ID NOs:1-4 is retained), or a pharmaceutically acceptable salt thereof.
- the amino acid sequence has at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 amino acid substitutions compared to any one of SEQ ID NOs:1-4.
- the amino acid sequence may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to any one of SEQ ID NOs:1-4.
- the amino acid sequence has at least 1 amino acid substitution compared to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; especially SEQ ID NO:3 or SEQ ID NO:4.
- the amino acid sequence has at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 amino acid substitutions compared to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:4; especially SEQ ID NO:3 or SEQ ID NO:4.
- the amino acid sequence may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to SEQ ID NO:1, SEQ ID NO:3 or SEQ ID NO:4.
- biologically active fragment refers to a portion of the peptide of the invention that retains substantially similar functional activity and/or substantially the same biological function or activity as the polypeptide, for example as shown in assays disclosed herein.
- biologically active variant is intended to encompass peptides having an amino acid sequence sufficiently similar to a peptide of the invention.
- the term “sufficiently similar” means a first amino acid sequence that contains a sufficient or minimum number of identical or equivalent amino acid residues relative to a second amino acid sequence such that the first and second amino acid sequences have a common structural domain and/or common functional activity.
- variants will be sufficiently similar to the amino acid sequence of the preferred peptides of the invention.
- Variants include polypeptides that differ in amino acid sequence due to mutagenesis.
- the terms “substantially similar functional activity” and “substantially the same biological function or activity” each mean that the degree of biological activity is within about 50% to 100% or more, within 80% to 100% or more, or within about 90% to 100% or more, of that biological activity demonstrated by the peptide to which it is being compared when the biological activity of each peptide is determined by the same procedure or assay.
- the “similarity” between two peptides is determined by comparing the amino acid sequence of a first peptide to the sequence of a second peptide. An amino acid of one peptide is similar to the corresponding amino acid of a second peptide if it is identical or a conservative amino acid substitution.
- amino acids belonging to one of the following groups represent conservative changes or substitutions: - Ala, Pro, Gly, Gln, Asn, Ser, Thr: - Cys, Ser, Tyr, Thr; - VaI, Ile, Leu, Met, Ala, Phe; - Lys, Arg, His; - Phe, Tyr, Trp, His; and - Asp, Glu.
- peptide of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.
- pharmaceutically-acceptable salts refers to those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicylic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
- pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric
- Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
- Basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
- a peptide of the invention may be isolated, purified, substantially purified, enriched, synthetic or recombinant.
- isolated in the context of the peptide of the invention means the peptide has been identified, separated and/or recovered from a component of its natural environment.
- substantially purified in the context of the peptide of the invention means the peptide is substantially free of contaminating agents, for example at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 65%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% free of contaminating agents.
- recombinant will be understood to mean the product of artificial genetic recombination.
- the term “recombinant peptide” in the context of the peptide of the invention is intended to encompass a peptide expressed by artificial recombinant means when it is in an expression system or cell, for example in which it is expressed.
- the peptides of the present invention may be prepared by known chemical methods, including solid-phase and solution-phase peptide synthesis using Fmoc or Boc protected amino acid residues. As shown in Example 1, the peptides of the invention may advantageously be synthesised by solid-phase peptide synthesis using suitable solid supports, protecting groups and coupling reagents, which allows for facile and rapid synthesis of the peptides.
- the peptides of the present invention may also be prepared by known recombinant DNA technologies, including cell-based and cell-free technologies.
- the peptide may be prepared from a nucleic acid sequence encoding the peptide.
- the present invention also provides a nucleic acid comprising a nucleotide sequence encoding the peptide of the invention as described herein.
- the peptides of the invention as described herein exhibit in vitro stability in serum.
- a peptide of the invention exhibit a serum stability, especially in vitro serum stability, of at least 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% peptide remaining at 4, 5, 6, 7 or 8 hours.
- the peptide is still detectable (i.e., present in an amount of at least 1%, at least 2%, at least 3%, at least 4%, or at least 5%) in serum after 24 hours.
- Serum stability may be measured by any method known in the art, for example the methods shown in the Examples. [0103] As shown in the Examples, the peptides of the invention as described herein are capable of exhibiting anti-inflammatory activity.
- compositions comprising, consisting essentially of, or consisting of the peptide of the invention as described herein, and at least one pharmaceutically acceptable carrier.
- the term “consisting essentially of” or “consisting of” in the context of the pharmaceutical composition will be understood to imply that the composition does not comprise any additional active agents other than those specified in the composition.
- the term “pharmaceutically acceptable carrier” as used herein refers to a solid or liquid filler, diluent, excipient, solvent or encapsulating substance that may be safely used in topical or systemic administration.
- the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
- the pharmaceutical composition may be suitably formulated for administration by a particular route. Suitable routes of administration include oral, transmucosal, transdermal, and parenteral administration.
- the composition is formulated for oral administration, topical administration such as buccal or sublingual administration or administration by transdermal patch, nasal administration, transdermal administration, or parenteral administration such as subcutaneous, intradermal, intramuscular, intraperitoneal or intravenous administration.
- the composition is formulated for oral administration, transdermal administration including administration by transdermal patch, or parenteral administration including subcutaneous, intradermal and intravenous administration.
- the composition is formulated for oral administration or parenteral administration, especially oral administration or intraperitoneal administration.
- compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) or parenteral (including intramuscular, subcutaneous, intradermal and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
- the peptides of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
- compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the peptides of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a peptide of the invention or a pharmaceutically acceptable salt or derivative of the peptide of the invention.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
- a low melting wax such as admixture of fatty acid glycerides or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
- parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
- the peptides according to the present invention may thus be formulated for parenteral administration (e.g.
- compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
- viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions.
- the peptides according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
- Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
- the peptides according to the invention may be encapsulated with cyclodextrins, or formulated with their agents expected to enhance delivery and retention in the nasal mucosa.
- Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may conveniently also contain a surfactant such as lecithin.
- the dose of drug may be controlled by provision of a metered valve.
- the active ingredient may be provided in the form of a dry powder, for example a powder mix of the active compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the powder carrier will form a gel in the nasal cavity.
- the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
- the active compound will generally have a small particle size for example of the order of 1 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
- formulations adapted to give sustained release of the active ingredient may be employed.
- the pharmaceutical preparations can be in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- Methods of use [0128]
- the peptides of the invention as described herein may be useful in the treatment of an inflammatory or autoimmune condition, such as an inflammatory bowel disease or asthma.
- the present invention provides a method for treating or preventing an inflammatory or autoimmune condition comprising administering to a subject in need thereof the peptide of the invention as described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby treating or preventing an inflammatory or autoimmune condition in the subject.
- the present invention also provides a method for the treatment of an inflammatory or autoimmune condition in a subject comprising the steps of: - identifying a subject having an inflammatory or autoimmune condition; and - administering to the subject in need thereof a therapeutically effective amount of the peptide of the invention described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, thereby treating an inflammatory or autoimmune condition in the subject.
- the present invention also provides the use of the peptide of the invention as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory or autoimmune condition.
- the present invention also provides the peptide of the invention as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing an inflammatory or autoimmune condition.
- inflammatory condition refers to a condition, disorder or disease characterised by inflammation. Symptoms of inflammation may include redness, swelling, heat, pain and loss of function. Examples of inflammatory conditions include inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease, and asthma.
- IBDs inflammatory bowel diseases
- the term “autoimmune condition” refers to a condition, disorder or disease in which the body'ss immune system mistakenly attacks the body'ss own cells resulting in an abnormal immune response.
- Autoimmune conditions may be genetic and/or caused by environmental factors such as infection and chemicals including drugs.
- autoimmune conditions include rheumatoid arthritis and coeliac disease. It will be appreciated that an autoimmune condition may also be an inflammatory condition [0135]
- the terms “treating” or “treatment” of a subject include the administration of a peptide of the invention or a composition described herein to a subject with the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the inflammation associated with the disease or condition, or the symptom of the disease or condition.
- treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury.
- the terms “preventing” or “prevention” are intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a condition, disorder or disease (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
- a subject in need of treatment of an inflammatory condition may present a number of symptoms depending on the type of condition, disorder or disease that the inflammation is associated with.
- a subject in need of treatment may exhibit symptoms including pain, redness, swelling, fatigue, fever, rashes, chest pain, and abdominal pain.
- the existence of, improvement in, or treatment or prevention of inflammation may be determined by any clinically or biochemically relevant method as described herein or known in the art.
- a relevant method may be measurement of symptoms including symptoms including pain, redness, swelling, fatigue, fever, rashes, chest pain, or abdominal pain.
- the improvement, treatment or prevention may be determined directly from the subject, or a sample or biopsy therefrom.
- the sample or biopsy may be of the inflamed or diseased tissue.
- levels of pro-inflammatory cytokines and/or anti-inflammatory cytokines may be measured before and after treatment as an indicator of treatment success. Presence of inflammatory leukocytes may be yet another indicator. In some embodiments, it will be understood that decreased levels of one or more of IFN- ⁇ , TNF- ⁇ , IL-1 ⁇ , IL-2, IL-6 and IL-8 compared to untreated tissue would be an indicator of decreased inflammation or an anti-inflammatory response.
- a subject in need of treatment of an autoimmune condition may present a number of symptoms depending on the type of condition, disorder or disease that the inflammation is associated with. Symptoms vary for affected location, disease causing agents and individuals. Symptoms of early autoimmune disease include fatigue, fever, malaise, joint pain and rash.
- Autoimmune diseases are typically diagnosed using a combination of clinical history, blood tests (to assess autoantibodies, inflammation, organ function) and other investigations such as x-rays and biopsy of affected tissues.
- a relevant method may be measurement of symptoms including inflammation, fatigue, fever, rashes and pain.
- the improvement, treatment or prevention may be determined directly from the subject, or a sample or biopsy therefrom.
- the sample or biopsy may be of the affected tissue.
- levels of immune cells and molecule e.g. antigens
- a method of the invention comprises administering a therapeutically or prophylactically effective amount of the peptide of the invention as described herein or the pharmaceutical composition as described herein.
- the term “therapeutically effective amount” is generally intended to refer to an amount of an active agent, such as a peptide of the invention, that (i) treats the particular condition, disorder or disease, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular condition, disorder or disease, or (iii) delays the onset of one or more symptoms of the particular condition, disorder or disease as described herein.
- an active agent such as a peptide of the invention
- prophylactically effective amount is intended to refer to a sufficient quantity of a peptide to prevent or inhibit or delay the onset of one or more detectable symptoms of a clinical condition. Those skilled in the art will be aware that such an amount will vary depending on, for example, the particular subject and/or the type or severity or level of condition and/or predisposition (genetic or otherwise) to the condition.
- Suitable dosages of a peptide of the invention will vary depending on the specific the condition to be treated and/or the subject being treated. It is within the ability of a skilled physician to determine a suitable dosage, for example by commencing with a sub-optimal dosage and incrementally modifying the dosage to determine an optimal or useful dosage.
- a suitable dose is within a range of circulating concentrations that include the ED 50 of the active compound with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
- a therapeutically/prophylactically effective dose can be estimated initially from cell culture assays.
- a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration or amount of the compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
- a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more of the peptide of the invention, and all combinations and sub-combinations of ranges therein.
- the pharmaceutical composition as described herein can be formulated to contain a peptide of the invention or a pharmaceutically acceptable salt or solvent thereof a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
- compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1%, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%.
- the compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
- the active agent can, for example, be present in a concentration of about 5%.
- the peptide of the invention as described herein or the pharmaceutical composition as described herein may be administered, or formulated for administration by, any route described herein.
- the term “administered” means administration of a therapeutically effective dose of the peptide of the invention to the subject.
- the term “formulated for administration” means a therapeutically effective dose of the peptide of the invention is formulated in such a way that is suitable for the route of administration.
- the peptide of the invention (or pharmaceutical composition) is administered orally or parenterally, especially orally.
- the peptide of the invention is formulated for oral or parenteral administration, especially oral administration.
- the therapeutically effective amount of a compound corresponds to preferably between about 1 to about 50 mg/kg, or between about 1 to 25 mg/kg, or between about 1 to about 10 mg/kg, between about 5 to about 25 mg/kg, or between about 10 to about 20 mg/kg.
- the frequency of administration of a peptide of the invention or pharmaceutical composition as described herein may be once daily, twice daily or three times daily.
- the treatment period may be for the duration of the detectable disease.
- the inflammatory or autoimmune condition is selected from an inflammatory bowel disease, asthma, rheumatoid arthritis and coeliac disease, especially an inflammatory bowel disease or asthma, more especially an inflammatory bowel disease.
- the inflammatory or autoimmune condition is inflammatory bowel disease
- the inflammatory bowel disease may be ulcerative colitis or Crohn’s disease.
- IBD Inflammatory bowel disease is a group of chronic inflammatory disorders of the digestive tract.
- Crohn's disease is a condition characterised by chronic inflammation in the lining of the digestive system. There may be a small patch of inflammation, or it may spread quite a way along the gut, or there may be several patches in different places.
- Typical symptoms include recurring diarrhoea, often with a feeling of urgency to get to the toilet, and often with a feeling of wanting to go to the toilet but with nothing to pass, abdominal pain and cramping, which is usually worse after eating, extreme tiredness (fatigue) and/or weight loss.
- Colonoscopy is used for diagnosis via sampling of small tissue samples (biopsies) for examination under the microscope.
- Ulcerative colitis is a chronic inflammatory condition that usually occurs in the rectum (the part of the large bowel that lies just inside the anus) and lower part of the colon, but it may affect the entire large intestine (colon). The colon becomes inflamed and, if this inflammation becomes severe, the lining of the colon is breached and ulcers may form.
- Diagnosis of ulcerative colitis may be performed via blood test, to check for inflammation, anaemia and protein levels, stool sample, which is checked for infection, X-rays, to help assess the extent of the condition, sigmoidoscopy, to examine the extent of inflammation in the rectum and lower part of the colon and/or colonoscopy, to examine the inside of the entire colon.
- Asthma is a condition in which the airway becomes inflamed, narrow and swell and produce extra mucus. This may make breathing difficult and cause chest pain, coughing and wheezing.
- Diagnosis may be performed by monitoring the pattern of symptoms and response to therapy over time, and spirometry to determine the volume of air that can forcibly be blown out in first 1 second, after full inspiration (FEV1).
- Rheumatoid arthritis is a chronic autoimmune and inflammatory condition that primarily affects joints, typically causing pain and swelling of the joints.
- the immune system targets the lining of the joints, causing inflammation and joint damage.
- Diagnosis may be performed by monitoring symptoms and from various test including blood tests for detecting inflammation and antibodies such as anti-cyclic citrullinated peptide (anti-CCP) and x-rays.
- Coeliac disease is a chronic autoimmune condition that primarily affects the small intestine and is caused by a reaction to gluten. Coeliac disease usually occurs in people who are genetically predisposed. Symptoms typically include gastrointestinal problems including chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally. Diagnosis may be performed by a combination of tests including blood test for detecting antibodies, intestinal biopsies and genetic testing. [0156] Although the peptide of the invention finds application in humans, it will be understood that the invention is also useful for veterinary purposes. Thus in all aspects the invention is useful for domestic animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals.
- the general term “subject” or “subject to be / being treated” will be understood to include all animals (such as humans, apes, dogs, cats, horses, and cows) that may have an inflammatory or autoimmune condition.
- TIMPs matrix- metalloproteinases
- Ac-TIMP-1 and Ac-TIMP-2 have subsequently been referred to as Ac- AIP-1 and Ac-AIP-2, and have been tested in mouse models of colitis and asthma, respectively (Ferreira, I. B.; Pickering, D. A.; Troy, S.; Croese, J.; Loukas, A.; Navarro, S. Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis. Clin. Transl. Immunology 2017, 6, e157; Navarro, S.; Pickering, D. A.; Ferreira, I. B.; Jones, L.; Ryan, S.; Troy, S.; Leech, A.; Hotez, P.
- SEQ ID NOs:1-3 are truncates of Ac-AIP-2 from Ancylostoma caninum, NECAME 07191 from Necator americanus (herein Na-AIP-1) and AceES-2 from Ancylostoma ceylanicum, respectively.
- SEQ ID NO:1 (herein AIP2-20) is composed of residues 115-134 of Ac-AIP-2
- SEQ ID NO:2 (herein AIP1-13) is composed of residues 125-137 of Na-AIP-1
- SEQ ID NO:3 (herein ES2-10 or ES-10 or ES10C) is composed of residues 93-102 of AceES-2.
- AIP2-20, AIP1-13 and ES2-10 were synthesised using Fmoc solid-phase peptide synthesis (SPPS) chemistry on a 0.1 mmol scale, purified using RP-HPLC and the mass analysed using MALDI mass spectrometry.
- SPPS Fmoc solid-phase peptide synthesis
- a mutant form of SEQ ID NO:1 in which Asp6 was replaced with a proline residue, H 2 N-TPEEHPLLMDLMGDPKKAEE- OH SEQ ID NO:5, herein AIP2-20D6P
- peptides were synthesised using solid phase peptide synthesis (SPPS) on a Protein Technologies PS3 synthesiser using fluorenylmethyloxycarbonyl (Fmoc) chemistry on a 0.1 mmol scale.
- SPPS solid phase peptide synthesis
- Fmoc fluorenylmethyloxycarbonyl
- the peptides were synthesised on 2-chlorotrityl chloride resin.
- Amino acids (2 equivalents) were activated in 0.5 M 2-(1H-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate with 10 equivalents of dichloromethane. The first amino acid was coupled manually to the resin.
- a comparison of the secondary shifts is given in Figure 1.
- Chemical shift analysis often provides an indication of the type of secondary structure present in peptides, with consecutive shifts more negative than -0.1 indicating the presence of helical structure (Mielke, S. P.; Krishnan, V. V. Characterization of protein secondary structure from NMR chemical shifts. Prog. Nucl. Magn. Reson.
- AIP2-20 displayed consecutive negative chemical shifts in the N- terminal region of the peptide, and AIP1-13 and ES2-10 have consecutive negative secondary shifts for a large proportion of the molecules, albeit with some of the shifts being relatively close to random coil values.
- the negative shifts present in AIP2-20 are disrupted in AIP2-20D6P at residues 5 and 6.
- this analysis indicates a modest propensity for helical structure in the isolated peptides with the exception of AIP2- 20D6P where the disruption of negative shifts indicates that the helical region would also be disrupted.
- AIP2-20 was found to contain a well-defined helix over residues 2-11, consistent with the modelled structure of Ac-AIP-2 and the structures of the related proteins. Furthermore, the presence of slowly exchanging amide protons is consistent with hydrogen bonds stabilizing the structure.
- the three- dimensional structures of AIP2-20 were calculated using CYANA, initially based on the NOESY data and dihedral angle restraints predicted using TALOS+. Based on the preliminary structures and slowly exchanging amide protons (Leu8, Gly9, Tyr11, Lys12, Ala13), hydrogen bond restraints were included. The final ensemble of AIP2-20 structures is shown in Figure 2.
- the N-terminal region displays a well-defined ⁇ -helical region (Figure 2A), in contrast to the C-terminal region, which does overlay to some extent but does not appear to possess regular secondary structure (Figure 2B).
- Figure 2A A hydrogen bond is present in the crystal structure of AceES-2 and in the modelled structures of Ac-AIP-2, Na-AIP-1 between the conserved E and L residues in the EXXXL motif. This hydrogen bond is also present in the structures of AIP2-20, suggesting that this interaction may be an important feature for stabilising the structure. This may provide an indication that the EXXXL motif may play a role in the structure- function relationships of the peptides.
- Proline residues generally have a low propensity for helix formation and can result in disruption of helical secondary structure.
- a proline residue was introduced into the helical region of AIP2-20 to determine if this change disrupted the structure and influenced the activity.
- the NOESY spectra of AIP2-20D6P showed limited medium or long range NOEs and the TALOS+ analysis did not provide any definitive prediction for the dihedral angles, but slowly exchanging amide protons were evident in the D 2 O exchange experiments. The presence of slowly exchanging amide protons is generally indicative of hydrogen bonds suggesting that the peptide is structured in solution.
- the structure calculations for AIP2-20D6P resulted in flexible structures with no defined secondary structure.
- AIP1-13 and ES2- 10 would also display well-defined helical structures in solution, but this is not appear to be the case as the structures were not able to be defined in this study. It is noted the apparent discrepancy between NOEs, and chemical shifts, and slowly exchanging amide protons has been previously observed in an unrelated protein (D'Amelio, N.; Bonvin, A.; Czisch, M.; Barker, P.; Kaptein, R. The C terminus of apocytochrome b(562) undergoes fast motions and slow exchange among ordered conformations resembling the folded state. Biochemistry 2002, 41, 5505-5514).
- cytochrome b 562 showed chemical shifts and slowly exchanging amide protons consistent with the presence of helical structure, but was not supported by the NOE data. Relaxation analysis indicated the presence of conformational exchange as the likely reason for the discrepancy. It is possible that similar conformational exchange could be happening with ES2-10 and AIP1-13.
- the results of this study may provide an indication that a small helical region may be present in the peptides of the invention.
- Example 3. TNBS colitis assay [0175] SEQ ID NOs:1-4 were tested for activity in an animal model of TNBS induced colitis.
- mice were either left untreated (na ⁇ ve) or were treated with peptide at a dose of 1mg/kg 5 hours prior to administration of TNBS.
- the effective induction of TNBS- induced colitis was confirmed by weight loss during the course of the experiment, which happens due to the inflammation and colonic mucosa damage.
- the mice were euthanased using gas asphyxiation and examined for assessment of protection against colitis [0176] Specifically, experiments were conducted in accordance with the James Cook University Animal Ethics Committee approved guidelines under the project #A2012. All experiments were performed with C57BL/6 strain mice in groups of five males (5 weeks old).
- mice were purchased from the Animal Resources Centre (Perth, Australia) and housed in the animal care facility unit at James Cook University under specific pathogen free conditions. After arriving at the facility, mice were placed inside plastic cages with unlimited access to food and water. [0177] Mice were divided randomly into different groups: Na ⁇ ve, 2,4,6- trinitrobenzenesulfonic acid (TNBS), AIP peptides and SFTI-1 (control peptide). Mice received intraperitoneal (i.p) injections of peptides and protein. Ketamine/xylazine solution was used to anaesthetise the mice prior to administration of TNBS.
- TNBS 2,4,6- trinitrobenzenesulfonic acid
- AIP peptides AIP peptides
- SFTI-1 control peptide
- mice received 100 ⁇ L of 5% (w/v) TNBS solution in 60% ethanol by intra-colonic instillation using a 20 gauge soft catheter (Terumo), which was inserted into the colon. Mice were monitored daily for piloerection, survival, stool consistency, body weight, rectal bleeding and decreased motor activity. After cull, a score of macroscopic pathology was calculated for each colon. This macroscopic pathology was made by harvesting each colon and opening it longitudinally, then washing the colon with sterile phosphate buffer saline. Following this, the colon was visualised using a microscope (Olympus SZ61, 0.67-4.5x).
- Tissues were assessed and scored for pathological changes as follows: adhesion (0 to 3), bowel wall thickening (0 to 3), mucosal oedema (0 to 3), ulceration (0 to 3), and colon length as described previously (Ferreira, I.; Smyth, D.; Gaze, S.; Aziz, A.; Giacomin, P.; Ruyssers, N.; Artis, D.; Laha, T.; Navarro, S.; Loukas, A.; McSorley, H. J. Hookworm excretory/secretory products induce interleukin-4 (IL-4)(+) IL-10(+) CD4(+) T cell responses and suppress pathology in a mouse model of colitis. Infect. Immun.
- IL-4 interleukin-4
- AIP2-20, AIP1-13 and ES2-10 displayed significant protective effects in the TNBS assay as shown in Figure 3.
- AIP2-20 had the greatest effect in reducing weight loss in the TNBS assay, but both AIP1-13 and ES2-10 also had significant effects in reducing weight loss.
- each colon was removed and scored macroscopically using these parameters: adhesion, bowel wall thickening, mucosal oedema, ulceration, necrosis, and colon length.
- AIP2-20D6P did not show protection in the TNBS mouse model as shown in Figure 4. This may provide an indication that Asp6 of AIP2-20 is important for bioactivity. Alternatively, the structural changes observed as a consequence of this mutation could result in changes to the bioactivity.
- Example 4 Histological evaluation of colitis [0181] Histological analysis of tissue samples from the TNBS colitis assay of Example 3 was performed using the following procedure. Histology tissue was fixed in formalin and then transferred to a solution of 70% alcohol. The tissue was embedded in paraffin and sectioned longitudinally for histology at 4 ⁇ m thickness. Periodic acid-Schiff (PAS) stain was used to assess goblet cell destruction. Scoring of the images was determined in a blinded fashion following the scoring method of Hong et al (Hong, T.; Yang, Z.; Lv, C.
- the control peptide, SFTI-1 was not statistically different to the TNBS-only treated mice [0183]
- the results of this study may provide an indication that the peptides of the invention have anti-inflammatory activity and may be useful for the treatment of inflammatory conditions such as inflammatory bowel diseases.
- Example 5 The results of this study may provide an indication that the peptides of the invention have anti-inflammatory activity and may be useful for the treatment of inflammatory conditions such as inflammatory bowel diseases. Example 5.
- PBMCs peripheral blood mononuclear cells
- PMA phorbol 12- myristate 13-acetate
- LPS lipopolysaccharide
- PBMCs were isolated from whole blood by density gradient centrifugation using Ficoll-Paque media.
- PBMCs were activated with a cell stimulation cocktail of 50 ng/ml of PMA and 1 ⁇ g/ml of ionomycin (eBioscience).
- PMA + ionomycin-stimulated cells were treated with 0.1-100 ⁇ g/ml of hookworm AIP peptide or remained untreated.
- PBMCs were activated with 10 ng/ml LPS (Sigma-Aldrich). LPS- stimulated PBMCs were treated with 0.1-100 ⁇ g/ml of AIP peptide or remained untreated.
- the cell culture plates were incubated overnight at 37°C and 6.5% CO 2 . After incubation, the samples were centrifuged at 1,500 x g for 5 minutes and the culture supernatants were collected for cytokine analysis. Toxicity assays were performed with the LIVE/DEAD Cell Viability Assay (Thermo Fisher Scientific) and readout using flow cytometry. This dye binds to amines in cells with compromised cell membranes but cannot enter healthy cells.
- Interleukin (IL)-1 ⁇ , IL-2, IL-6, IL-8, IFN- ⁇ and tumour necrosis factor (TNF)- ⁇ from PBMC culture supernatant were quantified using BDTM Cytometric Bead Array (CBA) (BD Biosciences).
- CBA Cytometric Bead Array
- the CBA assays were performed according to the manufacturer’s instruction using a five laser Special Order LSRFortessaTM with HTS (BD Biosciences). Cytokine concentrations (pg/ml) were calculated based on the sample MFI compared to the cytokine standard curves.
- BDTM FCAP Array software version 3.0 was used for data analysis. Graphs and statistical analysis were produced using GraphPad Prism version 7.02 (GraphPad Software Inc).
- ES-10 is non-toxic to human lymphocytes at high concentrations and displays bioactivity on both T cell and myeloid lineages.
- AIP2-20, AIP1-13 and ES-10 all displayed activity in the TNBS mouse model, only ES-10 appeared to display bioactivity with human PBMCs.
- the peptides each include the EXXXL motif, but there is sequence diversity amongst them which may contribute to the differences observed with the human cells.
- Oral activity of peptide SEQ ID NO:3 [0189] The oral activity of ES-10 was investigated using a TNBS model following the procedure in Example 3 except that the peptides were administered orally.
- a mixture of 50% olive oil was mixed with each peptide dissolved in phosphate buffered saline (PBS).
- PBS phosphate buffered saline
- the peptides were administered at a dose of 5 mg/kg.
- the mixture was administered using an oral gavage.
- the oral activity of the peptide was compared with NTQ48, which is a protein corresponding to the C-terminally truncated version of Ac-AIP2, and two mutant peptides of ES-10 in which the Asp6 or Lys9 were mutated to an alanine, respectively H 2 N-SQKEKALLKE-OH (SEQ ID NO:6, herein D6A) and H 2 N-SQKEKDLLAE-OH (SEQ ID NO:7, herein K9A).
- mice treated with ES-10 showed significantly higher percent weight loss and lower clinical score compared to the negative control mice.
- ES-10 treated mice had higher percent weight loss and improved clinical score compared to those treated with NTQ48, Sulfa or mutants D6A and K9A.
- Serum stability of peptides [0191] The serum stability of AIP2-20, SIP1-13, ES-10 and SIP2-20D6P was tested over a 24 hour period using human male AB plasma (Sigma-Aldrich) following methods previously described (Yang, J. Y.; Yan, R. X.; Roy, A.; Xu, D.; Poisson, J.; Zhang, Y. The I-TASSER Suite: protein structure and function prediction. Nat. Methods 2015, 12, 7-8). The peptides were tested at a concentration of 200 ⁇ M, incubated in serum or PBS at 37°C and 40 ⁇ L aliquots were taken at 0 h, 3 h and 8 h.
- the aliquots of serum were quenched with 40 ⁇ L of 20% TFA and incubated for 10 minutes at 4°C to precipitate serum proteins.
- PBS received the same treatment as serum.
- the samples were then centrifuged at 17000 g for 10 min and 90 ⁇ L of supernatant analysed by RP- HPLC at a flow rate of 0.3 mL/min using a Phenomenex Jupiter Proteo C 12 analytical column (150 x 2.00 mm, 4 ⁇ m, 90 ⁇ ) using a linear 1% min -1 acetonitrile gradient (0- 50% solvent B).
- the eluent was observed using a dual wavelength UV detector set to 214 and 280 nm.
- SEQ ID NO:4 (herein ES10C-10L) was synthesised using Fmoc SPPS on a 0.2 mmole scale.2-Chlorotrityl chloride resin as used as the solid support.
- Fmoc protected amino acids (4.2 equivalents) were activated by O-(1H-6-chlorobenzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU; 4.2 equivalents) and N, N-diisopropylethylamine (DIPEA; 6.2 equivalents) in N,N-dimethylformamide (DMF), and the Fmoc group was deprotected by 20% piperidine. After the final amino acid was attached, the resin washed by DMF and methanol, and dried in a desiccator.
- HCTU O-(1H-6-chlorobenzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- DIPEA N, N-diisopropylethylamine
- DMF N,N-dimethylformamide
- Crude peptide was cleaved from the resin using a trifluoroacetic acid (TFA) cocktail (TFA/water/triisopropylsilane (95% : 2.5% : 2.5%) and precipitated with diethyl ether. Crude peptide was then purified using RP-HPLC. The purity and molecular weight of the peptide was characterized by analytical HPLC and MALDI-TOF mass spectrometry.
- TFA trifluoroacetic acid
- SEQ ID NO:8 (herein ES10C-biotin) was synthesised using the Fmoc SPPS synthesis outlined above for ES10C-10L except that after the final amino acid of the peptide sequence was coupled and Fmoc group deprotected, 1 equivalent of N- succinimidyl D-biotinate in DMF solution (0.1 M) was conjugated to the peptide N- terminal after activation with 1 equivalent of HCTU and 1 equivalent of DIPEA. The ES10C-biotin was then cleaved and purified using the same protocol as ES10C-10L. The mass of the peptide was 1443.2 Da based on LCMS.
- Example 9 The mass of the peptide was 1443.2 Da based on LCMS.
- TNBS colitis assay [0195] The oral activities of ES10C, ES10C-10L and ES10C-biotin were investigated using a TNBS model. Mice were orally administrated with ESC10 (PBS/oil emulsion; 5 mg/kg), ES10C-biotin (PBS/oil emulsion; 5 mg/kg) or ES10C-Leu (PBS; 10 mg/kg) on day -1, 0, 1, 2 separately. TNBS control mice were administered PBS/oil emulsion or PBS without peptide. On day 0, 5 hours prior to administration of peptides, 100 ⁇ L of 5% (w/v) TNBS was intrarectally delivered to mice to induce colitis.
- mice were weighted on day 0, 1, 2, 3 and scored (piloerection, mobility, faeces, rectal thickening) on day 0, 1, 2.
- mice were euthanised by gas asphyxiation after being weighed.
- Mice colons were harvested, colon length was recorded, and the colon adhesion, ulceration on colon, mucosal oedema of colon and bowel wall thickening were examined under a stereomicroscope (Olympus SZ61, 0.67-4.5x).
- GraphPad Prism version 9 (GraphPad Software Inc) was used to perform the statistical analyses and generate graphs.
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Abstract
La présente invention concerne un peptide pour le traitement d'une affection inflammatoire ou auto-immune, des compositions pharmaceutiques les comprenant, et des procédés d'utilisation les comprenant.
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WO2006135799A2 (fr) * | 2005-06-10 | 2006-12-21 | Yale University | Detection de coproantigenes d'ankylostome |
US20070044171A1 (en) * | 2000-12-14 | 2007-02-22 | Kovalic David K | Nucleic acid molecules and other molecules associated with plants and uses thereof for plant improvement |
US20130330335A1 (en) * | 2010-03-23 | 2013-12-12 | Iogenetics, Llc | Bioinformatic processes for determination of peptide binding |
WO2015048334A2 (fr) * | 2013-09-25 | 2015-04-02 | Pronutria, Inc. | Polypeptides nutritifs d'espèces comestibles et leurs procédés de production et d'utilisation |
WO2016164637A1 (fr) * | 2015-04-07 | 2016-10-13 | Alector Llc | Anticorps anti-sortiline et leurs méthodes d'utilisation |
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WO2018068135A1 (fr) * | 2016-10-12 | 2018-04-19 | Feldan Bio Inc. | Agents navette peptidiques synthétiques conçus de manière rationnelle pour administrer des cargos polypeptidiques d'un espace extracellulaire au cytosol et/ou au noyau d'une cellule eucaryote cible, leurs utilisations, méthodes et kits associés |
WO2020018935A2 (fr) * | 2018-07-19 | 2020-01-23 | University Of Washington | Conception de novo de commutateurs protéiques |
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WO2002014361A2 (fr) * | 2000-08-17 | 2002-02-21 | Agensys, Inc. | Acides nucleiques et proteines correspondantes appeles 83p2h3 et catrf2e11 utiles dans le traitement et la detection du cancer |
US20070044171A1 (en) * | 2000-12-14 | 2007-02-22 | Kovalic David K | Nucleic acid molecules and other molecules associated with plants and uses thereof for plant improvement |
US20060123505A1 (en) * | 2002-05-30 | 2006-06-08 | National Institute Of Agrobiological Sciences | Full-length plant cDNA and uses thereof |
WO2006135799A2 (fr) * | 2005-06-10 | 2006-12-21 | Yale University | Detection de coproantigenes d'ankylostome |
US20130330335A1 (en) * | 2010-03-23 | 2013-12-12 | Iogenetics, Llc | Bioinformatic processes for determination of peptide binding |
WO2015048334A2 (fr) * | 2013-09-25 | 2015-04-02 | Pronutria, Inc. | Polypeptides nutritifs d'espèces comestibles et leurs procédés de production et d'utilisation |
WO2016164637A1 (fr) * | 2015-04-07 | 2016-10-13 | Alector Llc | Anticorps anti-sortiline et leurs méthodes d'utilisation |
WO2016172722A1 (fr) * | 2015-04-23 | 2016-10-27 | Nantomics, Llc | Néo-épitopes de cancer |
WO2018068135A1 (fr) * | 2016-10-12 | 2018-04-19 | Feldan Bio Inc. | Agents navette peptidiques synthétiques conçus de manière rationnelle pour administrer des cargos polypeptidiques d'un espace extracellulaire au cytosol et/ou au noyau d'une cellule eucaryote cible, leurs utilisations, méthodes et kits associés |
WO2020018935A2 (fr) * | 2018-07-19 | 2020-01-23 | University Of Washington | Conception de novo de commutateurs protéiques |
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