WO2003020301A1 - Chromogranine a et fragments de celle-ci pour le traitement de maladies impliquant une permeabilite vasculaire accrue - Google Patents

Chromogranine a et fragments de celle-ci pour le traitement de maladies impliquant une permeabilite vasculaire accrue Download PDF

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Publication number
WO2003020301A1
WO2003020301A1 PCT/EP2002/008749 EP0208749W WO03020301A1 WO 2003020301 A1 WO2003020301 A1 WO 2003020301A1 EP 0208749 W EP0208749 W EP 0208749W WO 03020301 A1 WO03020301 A1 WO 03020301A1
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Prior art keywords
cga
fragments
tnf
induced
vascular leakage
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PCT/EP2002/008749
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English (en)
Inventor
Angelo Corti
Elisabetta Ferrero
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Fondazione Centro San Raffaele Del Monte Tabor
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention concerns the use of chromogranin A or fragments thereof for the treatment of diseases related to vascular leakage.
  • Chromogranin A is a 439-aminoacids, low isoelectric point acidic protein, characterised by various post-translational modifications, 5 such as glycosylation, sulphatation, phosphorylation, stored in secretory granules of several endocrine and neuroendocrine tissues (Winkler, H. et al., Neuroscience 49, 497-528 (1992) e Rosa, P. et al., J. Endocr. Invest 17, 207-225 (1994). Elevated levels of circulating CgA have been detected in the blood of patients with endocrine and neuroendocrine tumours, kidney 0 failure and heart failure.
  • CgA has been suggested to be involved in the storage of hormones within secretory granules and to be a precursor of biologically active peptides with endocrine, paracrine, and autocrine functions. It has been observed that N-terminal fragments 5 corresponding to aminoacids 1-76 and 1-1 13, respectively named vasostatin I and II, can suppress vasoconstriction in isolated blood vessels. Moreover, the fragment corresponding to residues 1-78 can induce adhesion of fibroblasts and smooth muscle cells on solid-phases, suggesting a role for CgA in modulating cell adhesion.
  • CgA protein and peptides derived therefrom can significantly reduce vascular leakage induced by agents that alter endothelial barrier function and are involved in various diseases related to increased vascular leakage and edema. It is well known that TNF- ⁇ , 5 thrombin, oxidants, bradykinin, histamine and similar substances induce cytoskeletal rearrangements and modifications of adhesion mechanisms in endothelial cells. It has now been found that CgA and fragments thereof can reduce endothelial vascular leakage induced by said active agents, in particular TNF- ⁇ , VEGF and thrombin.
  • region 7-57 contains the active site.
  • the disulfide bridge (Cys-Cys) present in this region is apparently not necessary for the interaction with endothelial cells, since the synthetic peptide CgA 7 . 57 . SEtM , wherein the two Cys residues are reduced and alkylated, show the same activity of the unmodified product.
  • Previous works demonstrate that the region 47-57 contains the active site for the adhesion of fibroblasts to solid surfaces (Ratti et al J. Biol. Chem. 275 (2000), 29257-29263). The importance of the region 47-57 for the biological activity of CgA is also reflected by the high degree of homology among different animal species, compared with other regions.
  • CgA or fragments thereof consists in their interaction with a component of the endothelial cellular membrane and in the subsequent inhibition of cytoskeletal rearrangement.
  • Previous observations show that agents that can inhibit actin depolimerisation can also inhibit leakage induced by other agonists (Lum, H. et al., Am. J. Physiol. 267 (1994), 223-241). While the invention should not be bound to any particular mechanism of action, it is likely that CgA and fragments thereof protect vessels by preventing shape modifications and contraction of endothelial cells, irrespectively of the particular stimulus that increases vascular leakage.
  • object of the present invention is the use of CgA or a fragment thereof for the preparation of a medicament useful for the treatment of diseases involving increased vascular leakage.
  • active fragment means a portion of CgA endowed with protection activity against increased leakage, preferably the portion containing the amino acid sequence 47-57 (sequence numbers according to Koneki et al. J.Biol. Chem. 262, 17026-17030, 1993), more preferably the sequence 7-57.
  • Preferred fragments are contained in the region comprised between residues 1-115, preferably between residues 1-78.
  • CgA can be prepared by purification from a tissutal or cellular extract, or can be produced by recombinant DNA techniques in eucariotic or procariotic cells (see Gasparri et al J. Biol. Chem. 272, 20835-20843, 1997, and Corti et al. Eur J. Biochem. 248, 692-699, 1997, herein fully incorporated by reference; as far as recombinant DNA techniques are concerned, see also Sambrook et al., Molecular cloning. A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, New York (1982)).
  • the fragments can be prepared by synthesis (see for instance Stewart and Young, Solid Phase Peptide Synthesis, 2 nd ed., Pierce Chemical Co.
  • aminoacidic residues of the native protein or of the fragments can be modified so as to improve the pharmacokinetic properties of the molecules for therapeutical use, without varying the specific biological activity.
  • single residues can be replaced by other L- or D-aminoacids or can be chemically modified by glycosylation, coupling to groups with different polarity or lipophilicity, amidation or esterification of carboxy groups, conjugation with other molecules or peptides.
  • CgA or fragments thereof Diseases that may benefit from the treatment with CgA or fragments thereof are those whose symptomatology or etiopathogenesis involve endothelial barrier alteration, and increased vascular leakage and/or leucocyte extravasation.
  • the pathologies involving increased vascular leakage include shock, acute and chronic inflammatory diseases, edema, particularly pulmonary edema, rheumatoid arthritis, congestive hearth failure, left ventricular dysfunction, and related tissutal damage.
  • chromogranin or fragments thereof are used for reducing TNF ⁇ -induced vascular leakage increase, which is associated to different pathologic conditions such as acute respiratory distress syndrome (SDRA) in adults, systemic inflammatory response syndrome, chronic or congestive hearth failure, rheumatoid arthritis and multiple sclerosis.
  • SDRA acute respiratory distress syndrome
  • CgA and fragments thereof can be used in angiogenic therapy, particularly as coadjuvants of gene therapy to reduce vascular leakage induced by VEGF or FGF.
  • CgA and fragments thereof can be formulated with pharmaceutically acceptable carriers and excipients, such as buffers, stabilizers, dissolution agents, preservatives, dispersants, surfactants, disintegrants, lubrificants, thickening agents, fillers, dyes and the like.
  • Pharmaceutical compositions can be administered through oral, intravenous, subcutaneous, intramuscular, transdermal, nasal, sublingual and topical route. Principles and methods for the preparation of pharmaceutical compositions are known to the expert in the art and are described for instance in Remington: The Science and Practice of Pharmacy, Lippincott, Williams and Wilkins Eds, Dec. 2000.
  • the dosage of CgA or fragments thereof varies according to the kind and severity of the disease and the general conditions of the patient. In general an amount of active principle comprised between 0.03 and 3 mg/kg, preferably 0.1-0.3 mg/kg, can be administered once or twice a day.
  • HUVECs were isolated from human umbilical veins by collagenase treatment as described (Ferrero, E. et al. FEBS Lett. 374, (1995), 323-326) and cultured in 1% gelatin coated flasks (Falcon, Becton-Dickinson,
  • Natural human CgA was purified from pheochromocytoma tissue extracts (heat stable fraction) by immunoaffinity chromatography, essentially as previously described (Corti, A. et al. Eur. J. Biochem. 235, (1996), 275-280), using a column bearing the anti-CgA mAb 5A8. SDS- PAGE of the final product revealed two bands of 70 and 60 kDa. To investigate the structure-activity relationships of CgA various recombinant and synthetic fragments were prepared. Each fragment is herein indicated with its sequence numbers (Konecki, D.S. et al. J. Biol. Chem. 262, (1987), 17026-17030).
  • Recombinant were obtained by expression in E.coli (Corti, A. et al. Eur. J. Biochem. 248, (1997), 692-699) and purified by reverse-phase HPLC using a SOURCE 15 RPC column (Pharmacia-Upjohn, Uppsala, Sweden) followed by gelfiltration chromatography on a Sephacryl S-200 HR column, as previously described (Ratti, S. et al. J. Biol. Chem. 275, (2000), 29257-29263) SDS-PAGE of and showed that both products were homogeneous under reducing and non-reducing conditions.
  • SEtM was 6038 Da (expected 6039 Da).
  • In vitro permeability assay The assay was carried out by measuring the flux of radiolabeled albumin through HUVEC monolayers, cultured on gelatin-coated membranes of Transwell cell culture chambers (0.4 ⁇ m filters, Costar). HUVECs (5xl0 4 cells/well, in CM) were cultured for 5 days in the upper compartment of the Transwell device.
  • the culture medium was then replaced with human TNF (4 ng/ml) or thrombin (2 U/ml) solutions, either in the absence or in the presence of CgA or N-terminal fragments, in medium 199 containing 2 mM glutamine, 100 IU/ml penicillin, and 100 ⁇ g/ml streptomycin (200 ⁇ l/well).
  • the lower compartment was then filled with medium 199 containing 2 mM glutamine, 100 IU/ml penicillin, and 100 ⁇ g/ml streptomycin (600 ⁇ l/well) and incubated for 1 hour with gentle agitation. At various times, samples (30 ⁇ l) were taken from the lower compartment and their radioactivity was measured using a ⁇ -counter (Packard, Sterling, VA). Each experiment was carried out in triplicate and the results were expressed as mean + SD. In vivo permeability assay. The effect of murine TNF on the leakage of trypan blue-albumin complex from liver vessels was evaluated in anaesthetized male BALB/c mice (Charles River Italia, Calco, Italy) as described (Ferrero, E. et al.
  • Murine TNF (2 ng) in 0.2 ml 0.9% sodium chloride was injected intraperitoneally.
  • Other animals were treated with a mixture of TNF (2 ng) and CgA (1 ⁇ g), with or without mAb 5A8 (20 ⁇ g).
  • the liver of each animal was perfused for 5 min with 4 ml of a solution containing 0.4% bovine serum albumin, 0.5% trypan blue, 0.85% sodium chloride through the inferior vena cava.
  • the perfusate was drained from the portal vein, as described (Branster, M.V. & Morton, R.K. Nature (London) 180, (1957), 1283-1284).
  • HUVECs (1 x 10 5 cells in CM) were grown on glass coverslips for five days and incubated for 2 h with 4 ng/ml TNF alone, or in combination with
  • CgA,_ 78 or CgA in CM.
  • the cells were then washed, fixed with 2% paraformaldehyde for 15 min and stained with fluorescein isothiocyanate- conjugated goat anti-mouse immunoglobulins (Zymed Laboratories, Inc.,
  • the cells were then permeabilized with 0.01% Triton X-100 in PBS and incubated with fluorescein tetraisothiocyanate phalloidin (Sigma) to stain F-actin. Coverslips were mounted using 50% glycerol in PBS. Microscopic analysis was performed using a Bio-Rad MRC
  • cytotoxic activity of TNF in the presence or absence of CgA was estimated by standard cytolytic assays using L-M mouse fibroblasts (ATCC CCL1.2) as described (Corti, A. et al. J. Immunol. Meth. 177, (1994), 191- 198).
  • CgA and its N-terminal fragments (CgAj. 78 and CgA ⁇ _ ns ) protect vessels against TNF-induced plasma leakage in mice
  • CgA and its N-terminal fragments inhibit TNF-induced permeability of cultured HUVEC monolayers The mechanism of action was then investigated.
  • To assess whether the effect of CgA on TNF-induced vascular leakage was related to regulation of endothelial function was related to regulation of endothelial function we measured the activity of natural CgA and human TNF on the flux of radiolabeled albumin through confluent HUVECs monolayers, using the double chamber permeability assay. Natural CgA (3 ⁇ g/ml) did not affect the transendothelial flux of 125 I-albumin when added alone (Fig. 2a). In contrast, TNF (4 ng/ml) significantly increased the permeability of HUVECs (Fig. 2b).
  • CgA contains a site that affects endothelial cell function in vitro and in vivo. These effects were observed with HUVECs prepared from several different donors.
  • CgA does not block the TNF-TNF receptor interactions and inhibits the permeability of HUVEC monolayers induced with thrombin
  • TNF-receptor is necessary and sufficient for triggering an increase in vascular leakage in vivo and HUVEC monolayer permeability in vitro
  • CgA nor CgA,. ⁇ inhibited the cytolytic activity of human TNF (a selective murine p55-TNF agonist) or murine TNF (a p55- and p75-TNF-receptor agonist) against mouse L-M cells in a standard cytotoxicity assay. Since the cytolytic activity of murine TNF on these cells is dependent on both the p55 and p75 receptors (Pelagi, M. et al. Eur. Cytokine Net. 11, (2000), 580-588), these results imply that CgA does not inhibit the binding of TNF to both membrane receptors.
  • CgA can also inhibit the activity of other inflammatory agents independent of the TNF/TNF receptor system.
  • the effect of natural CgA on the thrombin-induced permeability of HUVECs was measured. As shown in Fig. 4, 3 ⁇ g/ml CgA inhibited the increase of cell permeability caused by thrombin.
  • CgA and CgA,_ 78 inhibit endothelial cytoskeleton reorganization
  • TNF- ⁇ and thrombin are known to promote changes in the size and shape of endothelial cells by rearranging the F-actin cytoskeleton and converting peripheral actin bundles into stress fibers (Goldblum, S.E. et al. Am. J. Physiol. 264, (1993), C894-905). Since this phenomenon is believed to correlate with an increase in endothelial permeability to macromolecules, we investigated the effect of CgA ⁇ g and CgA on TNF-induced cytoskeleton rearrangement of HUVECs by confocal microscopy. As expected, human TNF induced marked actin reorganization (Fig. 5a and b).
  • CgA ⁇ . 78 increases the survival of C57BL6 mice at lethal doses of TNF and galactosamine. To verify the ability of CgA]. 78 to protect the animals from the lethal effect of TNF, some C57BL6 mice were treated with 150 ng of mTNF and 36 mg of galactosamine, with or without pre-treatment with CgA 1-78 (3 ⁇ g). In this model TNF can trigger a strong inflammatory response, leukocyte transmigration through the endothelial barrier and fulminating hepatitis within 24 h. The results, reported in Table 1 , show that CgA,. 78 increases mice survival.
  • CgA and its fragments inhibit VEGF-induced permeability of cultured HUVEC monolayers
  • the experiment was carried out using HUVEC monolayers as described in "Materials and Methods".
  • the cell monolayers were preincubated with peptide 7-57 (3 ⁇ g/ml, 15 min) and peptide 7-57 (3 ⁇ g/ml) plus VEGF (lOng/ml) for 2 h before 125 I-BSA. Control wells were incubated with medium alone. The results are reported in the following Table. Table 2. Effect of peptide CgA 7-57 on VEGF-induced endothelial cell permeability
  • mice TNF (2 ng); mAb 5A8 (20 ⁇ g); mAb 19E12 (20 ⁇ g); CgA,_ 78 (3 ⁇ g); CgA 1-U5 (3 ⁇ g); CgA (0.4 ⁇ g, upper panel; 1 ⁇ g, lower panel, a).
  • TNF 2 ng
  • mAb 5A8 (20 ⁇ g
  • mAb 19E12 (20 ⁇ g)
  • CgA,_ 78 3 ⁇ g
  • CgA 1-U5 3 ⁇ g
  • CgA 0.4 ⁇ g, upper panel; 1 ⁇ g, lower panel, a).
  • Each bar represents the mean + SD of three mice. ⁇ 0.05 (*); PO.005 (**), by unpaired t-test, two-tailed.
  • FIG. 1 Effect of CgA on human TNF-induced permeability of cultured HUVEC monolayers.
  • the assay was carried out with cells untreated (a) or treated (b and c) with 4 ng/ml human TNF.
  • the effect of CgA and TNF was measured also in the presence of the anti-CgA mAb 5A8 (30 ⁇ g/ml) (c).
  • the (Y) axis reports the 125 I-albumin present in the lower chamber of the Transwell systems after 1 h, expressed as % of control (cells treated with TNF alone). Dashed bars represent the basal permeability observed in the absence of TNF; black bars represent the TNF-induced permeability.
  • FIG. 3 Effect of CgA N-terminal fragments on human TNF-induced permeability of cultured HUVEC monolayers.
  • the assay was carried out with cells treated with culture medium alone (a) or medium containing 3 ⁇ g/ml of CgA (b), CgA M 15 (c), CgA 7 . 57 . SEtM (d) or (e, j) in the absence (o) or in the presence (•) of 4 ng/ml human TNF.
  • the radioactivity present in the lower chamber of the Transwell systems was measured at the indicated times.
  • Panel / effect of different doses of CgA 1 . 78 on cell permeability, as measured after 2 h (see Fig. 2 for bar explanation).
  • FIG. 4 Effect of CgA on thrombin-induced permeability of cultured HUVEC monolayers. Untreated cells ( ⁇ ); cells treated with 2 U/ml thrombin (o); cells treated with 2 U/ml thrombin and 3 ⁇ g/ml CgA (•).

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Abstract

L'invention concerne l'utilisation de chromogranine A ou de fragments de celle-ci pour le traitement de maladies ayant trait à des fuites vasculaires, telles que collapsus cardio-vasculaire, maladies inflammatoires aiguës et chroniques, oedèmes, en particulier oedème pulmonaire, arthrite rhumatoïde, insuffisance cardiaque congestive, dysfonctionnement ventriculaire gauche et endommagement des tissus y relatif.
PCT/EP2002/008749 2001-08-31 2002-08-06 Chromogranine a et fragments de celle-ci pour le traitement de maladies impliquant une permeabilite vasculaire accrue WO2003020301A1 (fr)

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IT2001MI001833A ITMI20011833A1 (it) 2001-08-31 2001-08-31 Agenti che regolano la permeabilita' vascolare

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008085035A1 (fr) * 2007-01-12 2008-07-17 Erasmus University Medical Center Rotterdam Marqueurs peptidiques pour le diagnostic d'une maladie neurodégénérative
WO2010096385A2 (fr) * 2009-02-17 2010-08-26 The Regents Of The University Of Colorado, A Body Corporate, A Colorado Non-Profit Procédés et compositions pour le traitement des maladies auto-immunes
ITMI20091125A1 (it) * 2009-06-25 2010-12-26 San Raffaele Centro Fond Uso di cromogranina a e dei suoi derivati peptidici nel trattamento delle infiammazioni del canale
US8497074B2 (en) 2008-10-10 2013-07-30 Universitetet I Oslo Granin proteins as markers of heart disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19514647A1 (de) * 1995-04-20 1996-10-24 Tilman Schulz Haarwuchsmittel
US5747454A (en) * 1993-06-09 1998-05-05 Albert Einstein College Of Medicine Of Yeshiva University Chromogranin peptides
FR2792638A1 (fr) * 1999-04-26 2000-10-27 Inst Nat Sante Rech Med Peptides derives de la vasostatine i et leur utilisation comme antifongiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747454A (en) * 1993-06-09 1998-05-05 Albert Einstein College Of Medicine Of Yeshiva University Chromogranin peptides
DE19514647A1 (de) * 1995-04-20 1996-10-24 Tilman Schulz Haarwuchsmittel
FR2792638A1 (fr) * 1999-04-26 2000-10-27 Inst Nat Sante Rech Med Peptides derives de la vasostatine i et leur utilisation comme antifongiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KONECKI D S ET AL: "THE PRIMARY STRUCTURE OF HUMAN CHROMOGRANIN A AND PANCREASTATIN", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 262, no. 35, 15 December 1987 (1987-12-15), pages 17026 - 17030, XP000616262, ISSN: 0021-9258 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008085035A1 (fr) * 2007-01-12 2008-07-17 Erasmus University Medical Center Rotterdam Marqueurs peptidiques pour le diagnostic d'une maladie neurodégénérative
US8497074B2 (en) 2008-10-10 2013-07-30 Universitetet I Oslo Granin proteins as markers of heart disease
WO2010096385A2 (fr) * 2009-02-17 2010-08-26 The Regents Of The University Of Colorado, A Body Corporate, A Colorado Non-Profit Procédés et compositions pour le traitement des maladies auto-immunes
WO2010096385A3 (fr) * 2009-02-17 2011-03-24 The Regents Of The University Of Colorado Procédés et compositions pour le traitement des maladies auto-immunes
ITMI20091125A1 (it) * 2009-06-25 2010-12-26 San Raffaele Centro Fond Uso di cromogranina a e dei suoi derivati peptidici nel trattamento delle infiammazioni del canale
WO2010150082A3 (fr) * 2009-06-25 2011-05-19 Universita' Degli Studi Di Milano Utilisation de la chromogranine a et de ses derives peptidiques dans le traitement de l'inflammation

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