WO1996034887A2 - Peptides anti-sens - Google Patents

Peptides anti-sens Download PDF

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Publication number
WO1996034887A2
WO1996034887A2 PCT/GB1996/001082 GB9601082W WO9634887A2 WO 1996034887 A2 WO1996034887 A2 WO 1996034887A2 GB 9601082 W GB9601082 W GB 9601082W WO 9634887 A2 WO9634887 A2 WO 9634887A2
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Prior art keywords
polypeptide
peptide
antisense
sequence
target
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PCT/GB1996/001082
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English (en)
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WO1996034887A3 (fr
WO1996034887B1 (fr
Inventor
Andrew David Miller
John Graham Raynes
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Imperial College Of Science, Technology & Medicine
London School Of Hygiene And Tropical Medicine
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Priority claimed from GBGB9509263.1A external-priority patent/GB9509263D0/en
Priority claimed from GBGB9607505.6A external-priority patent/GB9607505D0/en
Application filed by Imperial College Of Science, Technology & Medicine, London School Of Hygiene And Tropical Medicine filed Critical Imperial College Of Science, Technology & Medicine
Priority to AU56540/96A priority Critical patent/AU5654096A/en
Publication of WO1996034887A2 publication Critical patent/WO1996034887A2/fr
Publication of WO1996034887A3 publication Critical patent/WO1996034887A3/fr
Publication of WO1996034887B1 publication Critical patent/WO1996034887B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/545—IL-1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5421—IL-8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to antisense peptides or polypeptides capable of binding to a target ligand.
  • it relates to antisense peptides which will bind to biologically active molecules such as IL-l ⁇ and/or IL-l / ⁇ , TNF and Eotaxin, thereby altering their biological activity, and their use in medicine.
  • MRT Molecular Recognition Theory
  • hydrophobic amino acids are complemented by hydrophilic amino acids and vice versa, while, on average, "uncharged” residues are generally complemented by similar residues.
  • This pattern was shown to represent the origin of the protein-receptor binding pair interactions for the related protein, interleukin-2 (Kuo & Robb J. Immunol . , 137:1538-1543 (1986)), and it has been further postulated to result in the relationships that typify the immune system.
  • the early work to test the validity of this pattern in natural assay systems was based on high-affinity binding of complements to the naturally occurring peptides ACTH (adrenocorticotrophic hormone) and ⁇ -endorphin (Bost et al, (1985) supra) .
  • ACTH adrenocorticotrophic hormone
  • ⁇ -endorphin Bost et al, (1985) supra
  • anti-sense peptides can be designed which exert an antagonistic effect on target ligands by virtue of their ability to bind to complementary "sense" peptide sequences contained therein.
  • interleukin-1 encompasses the two structurally similar and potent cytokines, interleukin-l ⁇ and -13, which both have a MW of 17kDa, and almost identical tertiary structures despite being the product of two separate genes (Clore et al , Biochemistry, 29:5671-5676 (1991) ; Clore et al , Biochemistry, 30:2315 (1991) ; Driscoll e ⁇ al , Biochemistry, 29:3542-3556 (1990) ; Finzel et al, J.Mol.Biol.
  • AD Alzheimer's disease
  • APP Amyloid Precursor Proteins
  • Vasilakos et al FEBS Lett . , 354:289 (1994)) , a ubiquitous family of transmembrane glycoproteins expressed throughout the body tissues.
  • Tight control of IL-1 activity within biological systems is normally maintained by mechanisms which include a third member of the IL-1 family, namely the naturally occurring ⁇ -glycosylated interleukin 1 receptor antagonist (IL-lra) (Eisenberg et al , Nature, 343:341 (1990) ; Carter et al , Nature, 344:633-638 (1990); Hannum et al , Nature, 343:336-340 (1990) ; Seckinger et al , J. Immunol . , 139:1541 (1987) ; Vigers et al , J. Biol . Chem . ,
  • IL-lra the naturally occurring ⁇ -glycosylated interleukin 1 receptor antagonist
  • IL-lra was found to be more effective than traditional treatments for reduction of joint inflammation and discomfort. However, due to its short half-life, and high dosage requirements, it is of little therapeutic value.
  • Potential therapeutic strategies aimed at modulating IL-1 pathological activity have therefore been based on the development and introduction of more stable IL-lra analogues; site-directed mutagenesis studies have highlighted several mutations in the IL-1 sequence which give rise to partial antagonism (Ferreira et al , Nature, 334:698-700 (1988)) .
  • TNF ⁇ is widely appreciated as a principal mediator of systemic responses to sepsis and injury (Beutler, B., and Cerami, A., Ann. Rev. Biochem. , 57 :505-518 (1988)) .
  • TNF ⁇ induces a cascade of mediators that direct host immunological functions (Fong, et al , J. Exp . Med. , 170:1627-1633
  • TNF ⁇ may thus serve as an essential messenger in host defense
  • the excessive tissue production of TNF ⁇ can mediate detrimental sytem effects by acutely precipitating a syndrome similiar to that of septic shock (Tracey, et al, Science 234:470-474 (1986))
  • lesser degrees of chronic TNF ⁇ production appear to induce anorexia and cachexia (Moldawer, et al , Am. J. Physiol . , 254 :G450-G456 (1988) ; Tracey, et al , J. Exp . Med 167:1211-12278 (1988))
  • pathologic conditions may result from the excessive production and activity of TNF ⁇ .
  • TNF ⁇ The active form of TNF ⁇ is believed to be a homotrimer with 17-kDa subunit polypeptides (Smith., and Baglioni, C, J. Biol . Chem. , 262:6951-6954 (1987)) .
  • TNF ⁇ and TNF2, a related lymphokine, activities are mediated through two distinct receptors, TNFR-p55 and TNFR-p75 (Loetscher, et al , Cell , 61:361-370 (1990) ) . Both receptors bind TNF ⁇ and TNF(S with simililar affinities, but they are independently regulated.
  • Eotaxin was recently identified as an important eosinophil chemoattractant detected in bronchoalveolar lavage fluid (BAL) after allergen challenge of sensitised guinea-pigs (Jose et al , J. Exp. Med, 179:881-887 (1994)) .
  • the potency of this chemokine has been demonstrated by low dose induction of eosinphil accumulation in guinea- pig airways and skin in vivo , and by comparable eosinophil trafficking in guinea-pig and human cells in vi tro (Jose et al (1994) supra ; Bousquet.J. and Charez.P., N. , Eng.
  • Eotaxin appears to be unique, so far, among the chemokines in its ability to selectively activate eosinophils which accumulate in both guinea-pig skin and airways and is thus a selective subject for inhibition studies.
  • Interleukin-8 is a CXC class chemokine structurally related to platelet factor 4 (Baggiolini .M. , and Clark-Lewis. I. , FEBS, 307:97-101 (192)) . It is produced by phagocytes and mesenchymal cells exposed to inflammatory stimuli and activates neutrophils inducing chemotaxis, exocytosis and the respiratory burst (Seitz et al , J. Clin . Inv. , 87:463 (1991)) . As a product of different type ' s of cells it can arise in any tissue when the levels of IL-1 and TNF are enhanced.
  • the present invention provides a peptide or polypeptide comprising an amino acid sequence which is antisense to a target peptide or polypeptide sequence, wherein said antisense peptide or polypeptide binds to the target peptide or polypeptide, thereby altering the biological activity of the target peptide or polypeptide or the biological activity of a target molecule which comprises the target peptide or polypeptide.
  • anti-sense has heretofore generally been applied to nucleic acid sequences which are capable of binding to complementary nucleic sequences.
  • anti-sense DNA sequences can be generated which in turn can generate mRNA sequences which will bind to mRNA produced from coding/sense strands of DNA, thereby preventing translation.
  • anti-sense peptide or polypeptide refers to a peptide or polypeptide coded for by a nucleic acid sequence complementary to the nucleic acid sequence coding for the target sequence.
  • An anti-sense peptide or polypeptide within the context of the present invention also includes a peptide or polypeptide, at least part of whose sequence is anti-sense to a target sequence.
  • the concept of targeting a peptide or polypeptide sequence with an antisense peptide or polypeptide can be applied to relatively small biologically active peptides in order to affect their biological activity.
  • the target sequence will form part of a larger molecule, with the target sequence being involved in the biological activity of the molecule.
  • the anti-sense peptide or polypeptide can act as an antagonist to or inhibitor of the biological activity of the target sequence or molecule.
  • a preferred group of target molecules are cytokines, for example IL-l ⁇ and/or IL-1/3, IL-8 or TNF ⁇ .
  • the anti-sense peptide is preferably anti ⁇ sense to a target sequence located within the region of residues 47-55 of IL-l ⁇ . Examples of such antisense peptides include: -
  • the antisense peptide is preferably antisense to a target sequence located within the region of residues 83-91 or 29-34 of T ⁇ F ⁇ .
  • suitable peptides include: -
  • N-DLGLVRDGD N-DLGLVRDGD ; N-LGLVRDG ; and N- IGPAVQ .
  • an example of a suitable antisense peptide is : -
  • the antisense peptide is antisense to a target sequence located within the region 43-49 or 45-50 of Eotaxin.
  • suitable antisense peptides include: -
  • N-DILGQFG N-DILGQFG ; and N-HFVRFD .
  • these antisense peptides could form part of a larger peptide or polypeptide.
  • the key property which any such larger sequence must possess is of course the ability to bind to the target sequence.
  • anti-sense peptides or polypeptides can be applied generally to alter the biological properties of a range or “targets”. Techniques are readily available, as discussed in the examples below, for identification of target sequences, which may form part of larger, biologically active, molecules. Once such target sequences have been identified "antisense" peptides or polypeptides can be generated (again using standard techniques) and tested against the target molecule.
  • the invention provides an anti- sense peptide or polypeptide for use in altering the biological activity of a target sequence or molecule.
  • anti-sense peptides or polypeptides would be useful as therapeutic agents by virtue of their ability to alter biological activity of a target sequence or molecule.
  • the invention provides an anti-sense peptide or polypeptide for use in medicine, particularly in the treatment or prevention of an inflammatory condition and/or cancer.
  • the anti-sense peptides or polypeptides of the invention will find application in medicine in the form of a pharmaceutical formulation.
  • the invention provides the use of an antisense peptide or polypetide as defined herein in the manufacture of a medicament for use in the prophylaxis or treatment of a condition mediated by a cytokine.
  • the invention provides a pharmaceutical formulation comprising at least one anti-sense peptide or polypeptide as defined herein, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the target molecule is IL-l ⁇ and/or IL-1/3, TNF ⁇ , Eotaxin or IL-8 and the anti-sense peptides or polypeptides of the invention can be used to inhibit the biological action of these target molecules and thus find use in treating inflammatory conditions, e.g. septic shock, rheumatic diseases and degenerative arthropathies, including rheumatoid arthritis as well as, in the case of TNF ⁇ , cancer.
  • inflammatory conditions e.g. septic shock, rheumatic diseases and degenerative arthropathies, including rheumatoid arthritis as well as, in the case of TNF ⁇ , cancer.
  • the present invention provides a method of treating a condition mediated by a cytokine which comprises administering to a patient an effective amount of an antisense peptide or polypeptide as defined herein
  • the invention provides a method for the prophylaxis or treatment of an inflammatory condition which comprises administering to a patient an effective amount of an antisense peptide or polypeptide as defined herein, preferably in the form of a pharmaceutical formulation.
  • FIGURE la shows an alignment of the gene-derived amino acid sequences of IL-l ⁇ , IL-lS and IL-lra;
  • FIGURE lb shows the DNA sequence coding for the j ⁇ -bulge of IL-l / ⁇ (Boraschi loop) in alignment with the complementary/antisense DNA sequence;
  • FIGURE lc shows a comparison of the Kyte- Doolittle hydropathic profiles of the Boraschi loop sequence, QGEESND ( ⁇ , antisense peptide, VITFFSL (D) and control peptide (•) ;
  • FIGURE 2a shows the dose dependent inhibition by antisense peptide VITFFSL of IL-13 stimulated synthesis of serum amyloid A (SAA) (black bars) and haptoglobin (hatched bars) in HuH7 hepatoma cell supernatants after 48h of stimulation;
  • SAA serum amyloid A
  • haptoglobin hatching bars
  • FIGURE 2b shows the inhibition of IL-13 interaction with soluble human IL-1 receptor type II (sIL-1 RII) by antisense peptides, VITFFSL ( ⁇ ) and VITFFS (D) ;
  • FIGURE 3a shows surface plasmon resonance (SPR) affinity profiles obtained from the interaction of antisense peptide, VITFFSL, with immobilised IL-lJ.
  • Peptide concentrations were 20 ⁇ M (—) , 40 ⁇ M (- -) , 70 ⁇ M ( ⁇ •• ) , 90 ⁇ M (- -) , lOO ⁇ M (- • -) and 200 ⁇ M (-) ;
  • FIGURE 3b shows the maximum affinity profile response changes (after background correction) plotted as afunction of VITFFSL concentration. Results were obtained with immobilised IL-13
  • FIGURE 4 shows a comparison of the hydropathic profiles of TNF ⁇ residues 83-91 and the corresponding antisense peptide
  • FIGURE 5 shows a comparison of the hydropathic profiles of the antisense peptide for region 83-91 of TNF ⁇ and the region 91-99 of TNFR 55;
  • FIGURE 6 shows a comparison of the hydropathic *
  • FIGURE 7 shows the results of TNF inhibition assays using two antisense peptides
  • FIGURE 8 shows a comparison of the average hydropathy of huMCP-1 and gp EOTXAIN
  • FIGURE 9 shows a comparison of the average hydropathy of hEOTAXIN and hMCP-1
  • FIGURE 10 shows a comparison of the hydropathic profiles of gp EOTAXIN (45-50) , a corresponding antisense peptide (HFVRFD) and CCCKR3 receptor fragment 146-152;
  • FIGURE 11 shows a comparison of the hydropathic profiles of a portion of the sequence of IL-8 (AKELR) , a corresponding antisense peptide (SKLFS) and IL-8R sequence (AKFLT) .
  • Freeze dried peptides were desalted on P2 Biogel gel filtration column (2 cm x 30 cm) eluted with 0.1% TFA then loaded onto a Pharmacia biotech.
  • the first stage in the design antisense peptide inhibitors was to identify a suitable target region, from amongst the overlapping functional regions of IL-l ⁇ and IL-1/3, against which antisense peptides could be designed to act. Therefore, the X-ray crystal structure of IL-1/3 (Finzel et al , (1989) supra ; Priestle et al , (1988) , supra) , IL-l ⁇ (Graves et al , (1990) , supra) and IL-lra (Vigers et al , (1994) , supra) were reviewed in conjunction with the results of recent mutational studies performed on all three proteins (Evans et al , J. Biol . Chem.
  • both IL-1/3 and IL-l ⁇ possess a /3-bulge structure, proximal to the known receptor binding amino acid residues, which is absent in the antagonist IL-lra. This appeared to represent the only significant difference between the three-dimensional structures of IL-lra and the other two IL-1 isoforms. This absence of secondary structure was also mirrored at the primary amino acid sequence level, where IL-lra was found to have no equivalent stretch of amino acids to the 3-bulge regions of IL-1/3 (residues 48-54 [mature protein sequence] ) or IL-l ⁇ (residues 60-66 [mature protein sequence] ) (fig la) .
  • IL-l/3 (residues 47-55 [mature protein] ) , possesses partial
  • /3-bulge of IL-1/3 is more pronounced than that of IL- l (fig la) and therefore it was anticipated that /3-bulge directed inhibitors might be more effective against IL-1/3 than IL-l ⁇ .
  • antisense peptides were designed to primarily target the /3-bulge region of IL-1/3, which was re-christened the Boraschi loop.
  • Antisense peptides to the Boraschi loop were designed with reference to the DNA sequence of IL-1/3 (March et al, Nature, 315:641 (1985)) . Having identified the DNA sequence coding for the loop, the complementary/antisense DNA sequence was deduced and the code translated in the 5' ⁇ 3' direction (fig lb) . Two antisense peptides were then synthesised (see above) on the basis of the antisense code. The first with the sequence VITFFS, complementary to Boraschi-loop segment GEESND (IL-1/3 residues 49-54) , and the second with the sequence VITFFSL, complementary to the Boraschi-loop segment QGEESND (IL-1/3 residues 48-54) .
  • the antisense peptides were tested for biological effect using an HuH7 hepatoma cell line assay system (Bevan & Raynes, J. Immunol , 147:2574 (1991)) .
  • serum amyloid A (SAA) and haptoglobin are induced directly in response to IL-1 (Raynes et al , Clin . Exp . Immunol . , 83:448 (1991)) .
  • Antisense peptide was predissolved in DMSO (lOmg/ml) and diluted, to various concentrations (see fig 2a) , in the wells of 24-well plates which contained confluent HuH7 cells under the stimulation of IL-1/3(lng/ml) . Specific protein concentrations were measured by ELISA.
  • Antisense peptides VITFFSL and VITFFS, were found to inhibit both IL-1/3 and IL-l ⁇ stimulated synthesis of SAA and haptoglobin in a dose dependent manner (fig2a; table 1) .
  • the levels of inhibition are approaching or even exceeding those observed when either IL-lra or soluble human IL-1 type II receptor (sIL-1 RII) were used as inhibitors in the same assy system (table 1) .
  • the data show (fig 2a: table 1) that SAA was inhibited more readily than haptoglobin consistent with previous observations with IL-lra (Bevan & Raynes (1991) , supra) .
  • Table 1 Table 1
  • N-VFITSFL' ⁇ 10 ⁇ 10 ⁇ 10 ⁇ 10 ⁇ 10
  • VFITSFL (a reordered peptide with altered hydropathic profile; fig Id) failed to measurably inhibit IL-1.
  • LSFFTIV the reverse peptide with an identical profile
  • LLSLLRV a peptide with similar profile but different sequence
  • VITFFSL was unable to interact with IL-lra (see above) which lacks the /3-bulge structure (fig 1) .
  • both VITFFSL and VITFFS were found to be weak inhibitors of the association between IL-1/3 and the low affinity antibody BhrD2 which is specific to IL-1/3 amino acid residues 45-87 (incorporating the Boraschi loop structure) .
  • MBHA resin purchased from Novabiochem, and (ii) Schimadzu RF SPPS automated synthesizer. Peptide purification
  • Freeze dried peptides were desalted on a P2 Biogel gel filtration column (2cm x 30cm) eluted with 0.1% TFA, 20% Acetonitrile (ACN) peptides were further purified by loading onto a Pharmacia biotech. Pep RPC HR 10/10 column and eluted at 1.0 ml/min on a linear gradient from 0.1%TFA, 20% ACN to 0.1%TFA, 100% ACN. Their identity is verified by +ve FABMS.
  • Test and control proteins were immobilised onto carboxymethyl dextran (CMD) coated cuvette surfaces at 37°C and pH 7.4, in PBS buffer using a standard NHS/EDC coupling protocol (described in the Iasys manual) . Coupling times of 30-40 mins were allowed to generate a surface concentration suitable for analyte assay runs.
  • CMD carboxymethyl dextran
  • Peptides were attached to a Pharmacia activated CH sepharose 4B employing standard NHS coupling methods and packed on a CRlO/10 column. Ligand binding is assessed by both zonal and continuous elution methods (Shai et al , Biochemistry, 26:669-675 (1987)) .
  • TNF ⁇ seg . 29 - 34 is known to be critical in binding to the p75 receptor only.
  • a complementary peptide to this region could specifically prevent p75 activation and thus allow the local cytotoxic TNF response mediated by the TNFRp55. This could provide the therapeutic basis for administering high doses of TNF ⁇ in anti-cancer therapy without the systemic toxicity dependent on p75 activation (Van Ostade et al , Nature, 361:266-269 (1993)) .
  • An antisense peptide designed to bind to this region is - shown below. TNF ⁇ seg . 29 - 34
  • the Molecular Recognition theory (MRT) theory purports an idea that antisense relationships form the basis of receptor-effector recognition. This supposition was tested theoretically for TNF ⁇ : if recognition between receptors and effectors is based on antisense, then an antisense peptide designed against a known activating region of TNF ⁇ might share some amino acid homology with conserved sections of the p55 and p75 receptors. An antisense homology search for TNF 83-91 revealed this to be the case: a 5 residue section of the nine residue effector sequence shared homology (including conservative substitutions) with a section of the p55 and p75 receptors. Moreover, the hydropathy plots for these receptor segments and for the antisense peptides aFNT were very similar and display a strong inverse correlation with the hydropathy trace for TNF 83-91 (figs 4,5,6) .
  • L929 cells are trypsinized, washed and resuspended at 8 x 10 5 cells/ml and 50 ⁇ l added to wells of a 96 well plate.
  • TNF ⁇ standards of 30, 10, 3, 1 0.3 and 0.1 U/ml were added and either 7.5 or 3.75 U/ml of TNF incubated with various concentrations of peptide for less than 30 in. before adding to the cells.
  • Actinomycin D was added to a final concentration of l ⁇ g/ml to increase sensitivity.
  • eotaxin The cDNA cloning and expression of eotaxin revealed interesting relationships between sequence homology and respective selectivities of other CC chemokines. It shared the greatest homology (53%) with human monocyte chemoattractant protein 1 (MCPl) , a monocyte chemotaxant but not an eosinophil attractant in guinea-pig or human assay (Jose et al , (1994) supra) . Less homolgy is observed for the human macrophage inflammatory protein
  • eosinophils have, among others, a shared receptor for eotaxin, CC CKR3 (Combadiere et al, J. Biol . Chem. , 270;27:16941-16949 (1995)) .
  • CC CKR3 a shared receptor for eotaxin
  • an eotaxin receptor would include a region antisense to the putative effector region on eotaxin.
  • IL-8 in humans is known to elicit its response through two distinct seven transmembrane spanning receptors, IL- 8R1 and IL-8R2.
  • IL-8R1 and IL-8R2 Two distinct seven transmembrane spanning receptors.
  • a search for homology between the ELR antisense complementary sequences and the receptor sequences revealed several segments satisfying the antisense combinations; of these one was integral to a 5 residue sequence whose hydropathy profile displays excellent negative correlation to the AKELR IL-8 N terminal region (fig. 11) .

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Abstract

On utilise des peptides anti-sens pour exercer une action antagoniste sur les effets biologiques de molécules cibles. La molécule cible est plus particulièrement une cytokine telle que IL-1α ou IL-1β, TNFα ou IL-8 et les peptides anti-sens sont par conséquent utilisables dans le traitement ou la prévention de pathologies propagées par ces cytokines, les pathologies inflammatoires ou le cancer par exemple.
PCT/GB1996/001082 1995-05-05 1996-05-07 Peptides anti-sens WO1996034887A2 (fr)

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Cited By (5)

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WO1997021728A1 (fr) * 1995-12-12 1997-06-19 Karolinska Innovations Ab PEPTIDE FIXANT LA SEQUENCE KLVFF DE L'AMYLOIDE $g(b)
WO1998020866A2 (fr) * 1996-11-13 1998-05-22 Gill Parkash S Procede de traitement du sarcome de kaposi par des agonistes des recepteurs de la vitamine-d¿3?
US7060670B1 (en) 1999-05-05 2006-06-13 Neurochem (International) Limited Stereoselective antifibrillogenic peptides and peptidomimetics thereof
US7109291B2 (en) * 2001-05-22 2006-09-19 Gradient Compounds capable of modulating the activity and stimulating the production of a catalytic antibody
WO2007131274A1 (fr) * 2006-05-11 2007-11-22 Wholesome Biopharma Pty Ltd Petits acides ribonucléiques d'interférence pour le traitement d'allergies

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EP0411503A1 (fr) * 1989-07-31 1991-02-06 TECNOGEN Società Consortile per azioni Procédé pour l'identification et la synthèse des sites de liaison de protéines interagissants
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WO1994009128A1 (fr) * 1992-10-22 1994-04-28 Mallinckrodt Medical, Inc. Traitement therapeutique permettant d'inhiber la restenose vasculaire

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EP0231728A2 (fr) * 1986-02-07 1987-08-12 SCLAVO S.p.A. Peptide synthétique à activité de l'interleucine 1 humaine
US5039790A (en) * 1989-01-11 1991-08-13 Monsanto Company Bioactive fragment of interleukin-1-B that has antagonistic activity
EP0411503A1 (fr) * 1989-07-31 1991-02-06 TECNOGEN Società Consortile per azioni Procédé pour l'identification et la synthèse des sites de liaison de protéines interagissants
WO1994009128A1 (fr) * 1992-10-22 1994-04-28 Mallinckrodt Medical, Inc. Traitement therapeutique permettant d'inhiber la restenose vasculaire

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Title
C.H.SCHNEIDER E.A.: "PEPTIDES 1992" 1992 , ESCOM , LEIDEN XP002014585 A.SISTO: Increase of the affinity between antisense peptides by optimization of hydropath. compl see page 747 - page 748 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021728A1 (fr) * 1995-12-12 1997-06-19 Karolinska Innovations Ab PEPTIDE FIXANT LA SEQUENCE KLVFF DE L'AMYLOIDE $g(b)
US6331440B1 (en) 1995-12-12 2001-12-18 Karolinska Innovations Ab Peptide binding the KLVFF-sequence of amyloid-β
US7288523B2 (en) 1995-12-12 2007-10-30 Neurochem (International) Limited Peptide binding the KLVFF-sequence of amyloid-β
WO1998020866A2 (fr) * 1996-11-13 1998-05-22 Gill Parkash S Procede de traitement du sarcome de kaposi par des agonistes des recepteurs de la vitamine-d¿3?
WO1998020866A3 (fr) * 1996-11-13 1998-07-23 Parkash S Gill Procede de traitement du sarcome de kaposi par des agonistes des recepteurs de la vitamine-d¿3?
US7060670B1 (en) 1999-05-05 2006-06-13 Neurochem (International) Limited Stereoselective antifibrillogenic peptides and peptidomimetics thereof
US7109291B2 (en) * 2001-05-22 2006-09-19 Gradient Compounds capable of modulating the activity and stimulating the production of a catalytic antibody
WO2007131274A1 (fr) * 2006-05-11 2007-11-22 Wholesome Biopharma Pty Ltd Petits acides ribonucléiques d'interférence pour le traitement d'allergies

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