WO1992013874A2 - Peptides angiogeniques - Google Patents

Peptides angiogeniques Download PDF

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Publication number
WO1992013874A2
WO1992013874A2 PCT/US1992/000099 US9200099W WO9213874A2 WO 1992013874 A2 WO1992013874 A2 WO 1992013874A2 US 9200099 W US9200099 W US 9200099W WO 9213874 A2 WO9213874 A2 WO 9213874A2
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WIPO (PCT)
Prior art keywords
peptide
derivative
amino acid
sequence
thr
Prior art date
Application number
PCT/US1992/000099
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English (en)
Inventor
Beatrice Mintz
Original Assignee
Fox Chase Cancer Center
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Publication date
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Publication of WO1992013874A2 publication Critical patent/WO1992013874A2/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
    • C07K14/82—Translation products from oncogenes
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
    • 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
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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 peptides and peptide derivatives related to platelet factor 4 which
  • neovascularization angiogenesis the formation of new blood vessels, is necessary for normal development and is also an important aspect of wound repair, and pathological conditions like inflammation, and solid tumor growth (Leibovich et al. , 5
  • the angiogenic cascade involves endothelial cell migration, protease production and endothelial cell proliferation
  • ANGIOGENIC PEPTIDES Several protein growth factors have been identified which induce angiogenesis.
  • basic fibroblast growth factor a heparin-binding polypeptide mitogen.
  • Basic fibroblast growth factor (bFGF) proteins have a molecular weight of about 18 kDa, consistent with the predicted cDNA translation product of 155 amino acids, although higher K molecular weight forms have also been identified (Sommer et al., 1989, Bioche . Biophys. Res. Commun. 160:1267-1274; Abraham et al., 1986, EMBO J. 5:2523-2528)
  • PLATELET FACTOR 4 Platelet factor 4 (PF4) , a 70 amino acid heparin-binding protein, is released from the alpha granules of activated platelets. The exact biological function of PF4
  • PF4 is not known, although PF4 is a member of a multigene family involved in chemotaxis, coagulation, inflammation, and cell growth (Eis an et al., 1990, Blood 76:336-344) .
  • Leukocyte Biol. 3_9_:423-4344 stimulation of migration of pericytes but not of smooth muscle cells nor endothelial cells (Bernstein et al., 1982, J. Cell. Sci. (56); 71-82); and a potential anti-thro botic effect (Weerasinghe et al., 1984, Thromb. Res. 313 . : 625-632) .
  • Increased levels of PF4 have been identified in diabetic patients (Guastamacchia et al., 1985, Boll. Soc. Ital. Biol. Sper. 61:499-502;
  • the present invention relates to peptides and peptide derivatives related to platelet factor 4 which exhibit angiogenic activity, to pharmaceutical compositions comprising said peptides, and to methods for promoting angiogenesis utilizing said peptides. It is based, in part, on the discovery that an octapeptide derived from platelet factor 4 and seven structurally related peptides (depicted in FIGURE 1) were capable of inducing an angiogenic response in vivo as measured by neovascularization in rabbit corneal implant assay and by measurement of capillary endothelial cell chemoattraction. These eight peptides represent specific nonlimiting embodiments of the present invention.
  • the angiogenic peptides of the invention may be particularly useful in promoting wound healing, including incisional healing, bone repair, burn healing, and post- infarction repair in myocardial or central nervous system injury; and the assimilation of grafted tissues, particularly in persons suffering from vascular insufficiency, such as diabetic patients.
  • FIGURE 1 Amino acid sequences of angiogenic peptides
  • FIGURE 2 Amino acid sequence of PF4.
  • FIGURE 3 Bar graph showing angiogenic activities of Wohl 1-8 peptides (corresponding to P1-P8) compared to negative and positive (platelet derived angiogenic factor) controls.
  • FIGURE 4 Diagram for scoring capillary growth toward
  • Platelet factor 4 may be purified using any method known in the art.
  • PF4 may be purified from thrombm-activated platelet extracts by a modification of the method described by Medici et al. (1989, Thrombos. Res. E>4:277-287) .
  • the PF4 may be isolated by heparin sepharose affinity chromatography with elution of the factor at 1.7 M NaCl, followed by strong anion exchange chromatography on a polysulfoethyl- aspartamide column eluted with NaCl in the presence of about
  • the peptides of the invention include any peptide which comprises either (i) at least a four amino acid portion of PF4, the amino acid sequence of which is set
  • FIGURE 2 or a functionally equivalent sequence.
  • Ho ology is to be construed herein as referring to identity between lOa ino acid residues shared by different peptides; for example, a six amino acid residue peptide which is 66% homologous to a six amino acid fragment of PF4 shares 4 amino acid residues with the PF4 fragment which are not necessarily linked together.
  • the peptide or peptide derivative comprises the sequence Thr- Ser-Gln and/or Val-Arg-Pro, and more preferably Thr-Thr- Ser-Gln and/or Val-Arg-Pro-Arg.
  • the peptides of the invention may also comprise
  • these peptides may be derivatized by conjugation to other compounds, including, but not limited to, carbohydrate, lipid, phosphate, starch, antibody, Fab, Fab , enzyme, amino acid, peptide, or growth factor
  • PF4 amino acid sequence of PF4 as set forth in FIGURE 2, or a functionally equivalent sequence, should be construed to mean that the PF4 sequence may be (i) that sequence set forth in FIGURE 2 or (ii) the sequence as set
  • amino acid residues within the sequence can be substituted by another amino acid of a similar polarity which acts as a functional equivalent, resulting in a silent alteration.
  • Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs.
  • the nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, Sphenylalanine, tryptophan and methionine.
  • the polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine.
  • the positively charged (basic) amino acids include arginine, lysine and histidine.
  • the negatively charged (acidic) amino acids include aspartic 10acid and glutamic acid.
  • the peptides of the invention exhibit angiogenic activity as defined in section 5.3, infra.
  • the peptides of the invention may be prepared by ⁇ a y method known in the art.
  • the peptides may be synthesized (i) by cleavage from a larger peptide, such as, but not limited to, PF4; (ii) by recombinant DNA expression methods; and (iii) by chemical synthesis, including solid phase techniques as ⁇ described by Barany and Merrifield (1980, in "The Peptides” Vol. 2, Gross and Meienhofer, eds., Academic Press, N.Y.) .
  • tryptic digestion of PF4 may be performed to produce PF4 peptide fragments.
  • the protein may then be carboxymethylated
  • the resulting tryptic digest may then be injected into an appropriate reverse phase chromatography column, for example, a Vydac C18 column equilibrated with 2.7 percent acetonitrile/0.1 percent TFA/H 0 and may be chromatographed >at an appropriate flow rate, for example 0.5 ml/min with 1.0 minute fractions collected.
  • the elution program may be, for example, 2.7 percent buffer B(95 percent acetonitrile) in buffer A (0.1 percent TFA in water) for about ten minutes, and a gradient of about 27-95 percent buffer B in 123 lOminutes.
  • Elution of the peptides may be monitored spectrophoto etrically at a wavelength of 210 nm.
  • a Beckman System Gold HPLC System may be used for chromatography of both proteins and digests. Using the chromatography protocol set forth as an example supra,
  • Peptide fragments of PF4 may, according to the invention, be optionally chemically modified, and may be tested for angiogenic activity as set forth in the next section. 20
  • Peptides as described supra may be determined to have angiogenic activity using any m vitro or in vivo assay system known in the art to evaluate a factor for angiogenic
  • angiogenic activity should be construed herein to refer to an ability to (i) induce the formation of new blood vessels and/or (ii) attract endothelial cells.
  • peptides may be tested for angiogenic activity using an endothelial cell chemotaxis
  • endothelial cell movement in response to a particular peptide may be measured by detecting migration of endothelial cells into a porous membrane.
  • endothelial cell migration may be assayed by a method such as that described in Banda et al. (1982, Proc. Natl. Acad. Sci. 7 :7773-7777, incorporated by reference in its entirety herein) .
  • solutions of peptides to be tested may be diluted 5about 1:10 in Dulbecco's modified Eagle's medium supplemented with 10 percent rabbit platelet-poor plasma serum and placed in the bottom of Boyden blind-well chambers.
  • gelatin-coated 10- ⁇ m-pore-diameter polycarbonate filters (such as those available from 1 ⁇ Nucleopore) may be placed over the test solution and endothelial cells suspended in Dulbecco's modified Eagle's medium plus 10 percent platelet-poor serum may be added to the top compartment, and the chambers may be incubated for about 7 hours at 37°C. At the end of the incubation, the 15 tops of the filters may be wiped clean, and the filters may be fixed, stained, and evaluated by counting the number of cells that migrated to the bottom side of the filter.
  • peptides may be tested for angiogenic activity using an in vivo assay which tests for *°angiogenesis in vivo in response to a peptide of the invention comprised in an implant.
  • rabbit corneal implant assay (RCIA) method may be used (Gimbrone et al., 1974, J. Natl. Cancer Instit. _52:413 which is incorporated by reference in its entirety ⁇ herein) .
  • the peptide to be tested is mixed with an inert vehicle such as hydron, a methacrylate polymer,and then dried. The resulting pellet is then implanted in the cornea of a rabbit 2-3 mm from the superior limbus.
  • the present invention provides for peptides and peptide derivatives related to PF4 which may be used to promote angiogenesis, and for methods of treating patients that would benefit from increased angiogenesis.
  • the 5 invention provides for methods of inducing angiogenesis in a tissue comprising exposing the tissue to an effective amount of a peptide or peptide derivative related to PF4 which exhibits angiogenic activity. Methods of treatment comprise the administration of an effective amount of a peptide of
  • Administration of the peptide may be systemic or localized. Methods of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intranasal, oral, or any other appropriate mode.
  • Methods of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intranasal, oral, or any other appropriate mode.
  • •5 invention may be administered in any suitable pharmacologic carrier.
  • Patients who may benefit from increased angiogenesis include patients who suffer from vascular insufficiency, including arterial as well as venous insufficiency, syste ically or in a localized area. Examples include patients who are suffering from diabetes or
  • angiogenic peptides of the invention may be particularly useful as a atherosclerosis or disorders of the microcirculation. Distinct areas which might benefit from treatment with angiogenic peptides include, but are not limited to, the extremities, the heart, and the cerebrovascular system.
  • the angiogenic peptides of the invention may be particularly useful as a atherosclerosis or disorders of the microcirculation. Distinct areas which might benefit from treatment with angiogenic peptides include, but are not limited to, the extremities, the heart, and the cerebrovascular system.
  • the angiogenic peptides of the invention may be particularly useful as a atherosclerosis or disorders of the microcirculation.
  • Distinct areas which might benefit from treatment with angiogenic peptides include, but are not limited to, the extremities, the heart, and the cerebrovascular system.
  • the angiogenic peptides of the invention may be particularly useful as a atherosclerosis or disorders of the microcirculation.
  • the angiogenic peptides of the invention may also be used to promote wound healing in patients who may or may not suffer from vascular compromise.
  • wound healing may be generally promoted in surgical patients, 35 trauma patients, burn patients, or in patients who have suffered damage to the cardiovascular system, including myocardial infarction, or to the nervous system, including central nervous system injury such as trauma or infarction or peripheral nervous system injury.
  • the peptides of the 5 invention may, for example, be used in the treatment of spinal cord injuries.
  • the peptides may also be useful in improving the cosmetic appearance resulting from wound healing, for example, in scar revision.
  • the peptides of the invention may be useful in the treatment of acute as well as 0 chronic wounds.
  • Such angiogenic peptides may also be useful in promoting the incorporation of a grafted piece of tissue by providing the tissue with improved blood perfusion.
  • the present invention therefore also provides for methods for • °facilitating the assimilation of grafted tissue comprising exposing the grafted tissue to an effective concentration of angiogenic peptide.
  • the angiogenic peptides of the invention may be used for the treatment of human as well as animal subjects.
  • the present invention also contemplates the development of peptides structurally related to the angiogenic peptides of the invention which inhibit angiogenesis.
  • Such anti-angiogenic peptides would be useful in the treatment of disorders of increased vascularization 5 or in which it is desirable to limit the blood supply or vascularization, such as malignant tumors, hemangiomas, and endothelial angiomatosis rheumatoid arthritis and psoriasis.
  • PF4 was purified from thrombin-activated platelet extracts by a modification of the method described by Medici et al. (1989, Thrombos. Res. 54:277-287). PF4 was isolated 5 — _ _
  • TRYPTIC DIGESTION OF PF4 Tryptic digestion was performed by dissolving iyophilized PF4 in 50 ⁇ l of 0.4M Na CO /8M urea pH 9.0, in a microcentrifuge tube. The protein was then reduced by addition of 5 ⁇ l of 45mM DTT in pH 9.0 buffer for 15 minutes at 50°C. The protein was carboxymethylated by addition of 5/_l of iodoacetic acid in 0.5N NaOH and incubated for 15 minutes in the dark, at room temperature. Finally, 140.1 deionized water and 5 ⁇ l of ImM HCl solution of sequencer grade trypsin (200 ⁇ g/ml) was added and the sample incubated for 24 hours at 37°C.
  • the tryptic digest was injected onto a Vydac C. R column equilibrated with 2.7% Acetonitrile/0.1% TFA/H 2 0 and was chromatographed at a flow rate of 0.5ml/min with 1.0 minute fractions collected.
  • the elution pattern was as follows: 2.7% buffer B (95% acetonitrile) in buffer A (0.1% TFA in water) for 10 minutes, 2.7%-95% B in 123 minutes (see FIGURE 1) .
  • the elution of the peptides was monitored at 210nm.
  • a Beckman System Gold HPLC System was used for chromatography of both proteins and digests.
  • Rabbit wound capillary endothelial cells were grown to 60-85 percent confluency on 3-4 Primaria (Falcon #3824) 75 cm flasks. Approximately 20-24 hours before the assay, the media was removed and the flasks were rinsed twice with Ca/Mg-free Hank's Balanced Salt Solution. Then 12-15 ml of 0.1% lactalbumin in MEDIA 199 (Media-Tech) was added to each flask and the cultures were maintained overnight. The next day, the lactalbumin/media was removed from the flasks and the cells were rinsed with 6-10 ml HBSS.
  • RWCE Rabbit wound capillary endothelial cells
  • FILTERS Nucleopore polypropylene filters ( ⁇ .O ⁇ m pores, PVPF, from Neuro Probe, Inc.) were used in the experiment. One side of the filter was coated with a fibronectin 0 S olution (l ⁇ g fibronectin per ml HBSS; 3-4 ml were used to coat each filter by putting the solution in a petri dish and then laying the filter over the fibronectin solution) .
  • the bottom chamber contained an angiogenic peptide
  • the cells from the top layer would have migrated into and through the filter.
  • non-migrated cells which 5 simply adhered to the filter needed to be removed. Therefore, the portion of the filter which had been in contact with the cell-containing chamber was wet in phosphate buffered saline (PBS) and the cells were cleared from this surface using a wiper blade.
  • PBS phosphate buffered saline
  • the filter which at 10that point substantially contained migrated cells, was then dried overnight, stained in Leukostat (Fisher) , and the absorbance of portions of the filter were read using a densitomer. Relative increases in the densitometry tracing were indicative of greater cell migration and therefore of activity of the test peptide contained in the corresponding lower chamber.
  • RESULTS AND DISCUSSION Peptide 4 was sequenced in a Porton 2090e 20 sequencer after adsorption onto a Porton proprietary peptide support.
  • the sequence of the peptide was: Thr-27.5pm, Thr- 23.5pm, Ser-30.0pm, Gln-26.5pm, Val-22.6pm, Arg-10.5pm, Pro-9.2pm, Arg-4.7pm. Amino acid analysis using the Beckman
  • FIGURE 3 summarized results with the original octapeptide (peptide
  • IMPLANT Implant pellets were prepared by mixing a solution of 10 percent hydron, 1 percent polyethylene glycol, and 70 percent ethanol with an equal volume of test 5peptide (50 ⁇ l hydron solution: 50 ⁇ l peptide solution containing about 5-10 ⁇ g of peptide) . The resulting mixture was vigorously vortexed, and 20 ⁇ l aliquots were then placed on a sheet of plastic and desiccated to form dry pellets. Each pellet contained about 1 or 2 ⁇ g of test peptide. 0 7.1.2. SURGICAL PROCEDURE
  • the resulting implants were placed in the corneas of rabbits under general anesthesia approximately 2-3 n from the superior limbus capillary bed. The pellets did not lie closer than 1 mm from the capillary bed. 5
  • the eyes were checked on days 3, 5, and 7 for direct growth of capillaries towards the pellet, and were graded according to Figure 4 (Gimbrone et al. 1974, J. Natl. CCancer Inst. 5_2:413-427) . Photographs were taken of the eyes on day 5 and/or 7 to record capillary growth. On day
  • the 2.O ⁇ g/implant is shown in Table II.
  • the 1.O ⁇ g/implant was found to exhibit a higher angiogenic index than the 2.O ⁇ g/implant.

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Abstract

La présente invention se rapporte à des peptides et à des dérivés de peptides associés au facteur plaquettaire 4 et présentant une activité angiogénique, à des composition pharmaceutiques comprenant lesdits peptides, et à des procédés servant à promouvoir l'angiogénèse au moyen desdits peptides. L'invention se base, en partie, sur la découverte qu'un octapeptide dérivé du facteur plaquettaire 4 et sept peptides de structure apparentée sont capables de provoquer une réponse angiogénique in vivo telle que mesurée par néoformation de vaisseaux sanguins dans une analyse d'implant de cornée chez le lapin et par mesure de l'attraction chimique capillaire des cellules endothéliales. Ces huit peptides représentent des modes de réalisation spécifiques et non restrictifs de la présente invention. Les peptides angiogéniques de l'invention pouvent être particulièrement utiles pour favoriser la cicatrisation des plaies, y compris la cicatrisation des incisions, la réparation osseuse, la guérison des brûlures et la réparation post-infarctus dans des lésions myocardiques ou du système nerveux central, ainsi que l'assimilation de tissus greffés, en particulier chez des personnes souffrant d'une insuffisance vasculaire, telle que chez des patients diabétiques.
PCT/US1992/000099 1991-01-02 1992-01-02 Peptides angiogeniques WO1992013874A2 (fr)

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US63679891A 1991-01-02 1991-01-02
US636,798 1991-01-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0563329A1 (fr) * 1990-12-21 1993-10-06 Curative Technologies, Inc. Peptides angiogeniques
WO2009039987A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide thr-thr-ser-gln-val-arg-pro-arg en tant qu'agent thérapeutique
WO2009039986A3 (fr) * 2007-09-11 2009-05-14 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0563329A1 (fr) * 1990-12-21 1993-10-06 Curative Technologies, Inc. Peptides angiogeniques
EP0563329A4 (fr) * 1990-12-21 1994-12-21 Curative Tech Inc
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2009039987A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide thr-thr-ser-gln-val-arg-pro-arg en tant qu'agent thérapeutique
WO2009039986A3 (fr) * 2007-09-11 2009-05-14 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique

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