WO1995019167A1 - Traitement therapeutique visant a inhiber la restenose vasculaire - Google Patents

Traitement therapeutique visant a inhiber la restenose vasculaire Download PDF

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WO1995019167A1
WO1995019167A1 PCT/US1995/000605 US9500605W WO9519167A1 WO 1995019167 A1 WO1995019167 A1 WO 1995019167A1 US 9500605 W US9500605 W US 9500605W WO 9519167 A1 WO9519167 A1 WO 9519167A1
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warm
blooded animal
rantes
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PCT/US1995/000605
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Leon R. Lyle
Beth Thomas-Miller
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Mallinckrodt Medical, Inc.
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Priority to EP95908532A priority Critical patent/EP0802792A1/fr
Priority to JP7519178A priority patent/JPH09508358A/ja
Publication of WO1995019167A1 publication Critical patent/WO1995019167A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • This invention relates generally to novel compounds for therapeutic use, and more particularly, to specific molecularly interactive compounds, to methods of preparing and using such specific compounds, and to pharmaceutical compositions comprising these specific compounds for therapeutic use in areas of vascular injury, sites of inflammation, vascular atheromatous disease and/or restenosis.
  • Balloon angioplasty, atherectomy, rotary ablation and similar therapeutic techniques used to improve circulation .in vivo are finding ever-increasing application in therapeutic cardiology.
  • balloon angioplasty procedures involve the introduction of a balloon-type catheter into the narrowed portion of an artery.
  • the narrowing of the artery may be caused by different factors but most commonly is caused by a build-up of "atherosclerotic plague" .
  • the balloon portion of the catheter is inflated.
  • the inflation of the balloon within the narrowed area of the artery serves to increase the diameter of the blood vessel thus improving circulation.
  • the present invention discloses novel oligonucleotide, peptide, and polypeptide compounds, methods of preparing these compounds, pharmaceutical compositions comprising these compounds and the use of these compounds in balloon-type catheters for therapeutic treatment to inhibit vascular restenosis.
  • Restenosis is a recurrent stenosis, i.e., a narrowing or stricture of a duct or canal.
  • Restenosis and the development of atheromatous lesions (the reason for the procedure in the first place) share several common pathological elements such as the accumulation of monocytes and macrophages at the area of injury or inflammation and the proliferation of vascular smooth muscle.
  • monocytes and macrophages which infiltrate the injured area in response to inflammatory stimuli.
  • the monocytes and macrophages present in the tissue represent stages of differentiation of the same cell lineage.
  • the cells are referred to as monocytes when in the blood.
  • the cells Upon deposition in tissue, the cells are called macrophages.
  • Monocyte Chemotactic Protein-1 hereinafter referred to as "MCP-1” is a member of the “C-C” family of chemo attractant cytokines or “chemokines” . It is a potent stimulator of monocyte chemotaxis and has an extremely high degree of specificity for this cell type.
  • Other family members include Human Macrophage Inflammatory Protein-1
  • MCP-2 RANTES, RANTES precursor and 1-309. All of these chemokines incorporate a cysteine-cysteine (C-C) motif, but
  • MCP-1 and MIP-1 Alpha are the ones most highly specific for monocytes and macrophages. MCP-1 and MIP-1 Alpha as well as the rest of the C-C chemokine family are produced by injured vascular smooth muscle cells. The C-C chemokines, e.g., MCP-1 so produced attract the monocytes and macrophages which infiltrate the area releasing growth factors and resulting in proliferation of vascular smooth muscle and restenosis.
  • the compound In using a olecularly interactive therapeutic compound to inhibit vascular restenosis as discussed herein, the compound must be highly specific. High specificity, which is essential in such therapeutic compounds, means that the compound, after having been introduced into the body, is active to a greater degree against the target molecule or tissue, i.e. the area of possible restenosis, than on other non-target molecules or tissues.
  • the high specificity of the particular agent used provides for the strong accumulation or retention of the therapeutic compound to the target molecule or the specific tissue or tissues targeted.
  • the site of accumulation and retention is in areas of injured vascular smooth muscle cells as compared with the accumulation and retention concentration thereof in other non-target tissues.
  • a balloon-type catheter such as a balloon infusion catheter is coated or filled with a total, partial or synthetic antisense oligonucleotide or peptide to monocyte chemoattractant protein (MCP) material, such as monocyte chemoattractant protein-1 (MCP-1) , MIP-1 Alpha or other members of the C-C family of chemotactic cytokines or chemokines hereinafter referred to as "antisense MCP-1" or like member of the C-C family of chemokines as mentioned above and described in more detail below.
  • MCP-1 monocyte chemoattractant protein-1
  • MIP-1 Alpha monocyte chemoattractant protein-1
  • antisense MCP-1 or like member of the C-C family of chemokines as mentioned above and described in more detail below.
  • MCP-1 will be used as an example throughout although any other chemokine family member such as MIP-1 Alpha would also be a suitable target.
  • An antisense oligonucleotide such as an antisense oligonucleotide to MCP-1 inhibits the translation or transcription of MCP-1 mRNA within the vascular smooth muscle cells or surrounding interstitial space. Accordingly, MCP-1 production is severely inhibited.
  • monocytes are not attracted to the area of vascular injury in their usual numbers. As a result of the monocytes not infiltrating the area, growth factors (GFs) are not released. The relative lack of GFs does not support the proliferation of vascular smooth muscle cells which cause restenosis in cases of vascular injury.
  • Therapeutic treatment of vascular restenosis can also be achieved and augmented through the use of another embodiment of the present invention whereby the antisense oligonucleotide, to members of the C-C chemokine family, e.g., MCP-1 is labelled with a radionuclide for therapeutic use.
  • Radiolabelled antisense MCP-1 compounds for therapeutic use may be constructed using high energy Alpha or Beta emitting isotopes rather than the pure gamma emitters customarily used for diagnostic purposes which is also possible and will be discussed in more detail below.
  • Mature members of the C-C chemokine family are produced by post-translational modification of larger peptides.
  • the sense sequence of the mature MCP-1 polypeptide is as follows:
  • a in each of the examples represents Alanine
  • B represents Asparagine or Aspartic Acid
  • C represents
  • F Phenylalanine
  • G Glycine
  • H Histidine
  • I Isoleucine
  • K K
  • M Methionine
  • N Asparagine
  • P Proline
  • Q Q
  • S Serine
  • T represents.
  • V represents Valine
  • X represents an unspecified or variable amino acid
  • Y represents Tyrosine
  • Z represents Glutamine Acid.
  • the oligonucleotides in the messenger ribonucleic acid (mRNA) , antisense deoxyribonucleic acid (DNA) and antisense RNA corresponding to mRNA sequences for MCP-1 are as follows .
  • Antisense RNA
  • the sense MCP-1 polypeptide structural motif is as follows when flanked with five residues on either side as referenced in Yashimura, T., et al., FEBS Letters, vol. 244; pp. 487-493 (1989) :
  • Antisense RNA
  • the sense MIP-1 Alpha polypeptide structural motif sequence is as follows when flanked with five residues on either side as referenced in Blum, S., et al., DNA and Cell Biology, Vol. 9; pp. 589-602 (1990):
  • MIP -1 Alpha Antisense DNA 5' -CTG TGC GGC TGG CGG ACG ACG AAG TCG ATG TGG AGG - 3'.
  • the sense MIP-1 Beta polypeptide structural motif sequence is as follows when flanked with five residues on either side:
  • Antisense RNA
  • the sense RANTES and RANTES precursor polypeptide structural"motif sequence is as follows when flanked with five residues on either side as referenced in Schall, T.S., et al., Journal of Immunology, Vol. 141; pp. 1018-1025,
  • the sense 1-309 polypeptide structural motif sequence is as follows when flanked with five residues on either side as referenced in Miller, M.D., et al., Journal of Immunology, Vol. 145; pp. 2737-2744 (1990):
  • Antisense RNA
  • the antisense MCP-1 oligonucleotide to a molecule of the C-C chemokine family having similar specificity may be administered in vivo using a balloon infusion catheter with holes in it for delivery to the particular target site to prevent life- threatening restenosis.
  • the antisense MCP-1 oligonucleotide may also be radiolabeled prior to administration, using more than one method. The objective in radiolabeling is to increase therapeutic effect by bringing this cytostatic properly to bear upon smooth muscle and to force the cells into apoptosis.
  • Still another embodiment of the present invention is the introduction of an antisense oligonucleotide or the gene for the synthesis of antisense MCP-1 oligonucleotide into individual vascular smooth muscle cells in area(s) of vascular injury.
  • a tissue specific promoter such as the smooth muscle Alpha actin promoter to prevent life-threatening vascular restenosis.
  • Viral promoters may also be used such as the cytomegalovirus (CMV) promoter.
  • Such introduction is affected by infusion with a high concentration of oligonucleotide into the smooth muscle tissues with a balloon infusion catheter.
  • This typically requires high pressure(s) (greater than 2 atmospheres) and high concentrations of oligonucleotides (greater than 12.5 micrograms per milliliter) and is aided by agents which help to increase the solubility of membranes such as lipid rich liposomes.
  • the sequence to be introduced is derived from the antisense or DNA or RNA sequences previously given on pages 5 through 8.
  • cysteine cysteine (C-C) motif is a common feature characteristic of this family of chemokines and maintenance of this motif is a critical factor in preservation of biological activity. Therefore nucleotide sequences which would inhibit cysteine cysteine
  • (C-C) translation with preservation of specificity are particularly effective.
  • an antisense oligonucleotide was designed to inhibit translations of both the MCP-1 and MIP-1 Alpha Chemokine messages.
  • the designed antisense oligonucleotide sequence is as follows:
  • This antisense oligonucleotide was designed by first examining the amino acid sequences of MCP-1 and MIP-1 Alpha for regions of homology. By using the computer program MacVector, a high degree of homology was observed between residues 53 through 62 of MCP-1 and 55 through 64 in MIP-1 Alpha. A stretch of 10 residues was chosen so that the corresponding RNA would consist of 30 bases.
  • therapeutic effects of antisense oligonucleotides upon potentially proliferating smooth muscle cells are achieved by radiolabelling the antisense MCP-1 oligonucleotide with a suitable isotope such phosphorous 32 or phosphorous 33.
  • An antisense peptide is specified by the DNA strand complementary to that which specifies the ordinary sense peptide. These antisense peptides function by "hydropathic complementarity" to give binding activity with its corresponding sense peptides and can function as receptor like molecules in affinity chromatography as explained by Souza, S.J.U. and Bretani, R. J., Biol. Chem. 267: 13763-13773 (1992) . When an antisense peptide is used, one obtains complementary binding to and inactivation of the mature MCP-1 polypeptide.
  • the antisense MCP-1 of the present invention is represented by the following sequence:
  • the reaction in radiolabelling antisense peptides generally takes place between the amino groups in the peptide and the carbonyl group in the active ester of a specific ligand to form an amide bond.
  • the peptides can be radiolabelled using either a conventional method referred to as "post-formed chelate approach” or by a recent method referred to as “pre-formed chelate approach” developed by Fritzberg et al., U.S. Patent Numbers 4,965,392 and 5,037,630 incorporated herein by reference.
  • pre-formed approach "the desired ligand is complexed with the radionuclide and then conjugated to antisense MCP-1 polypeptide or a molecule having antisense MCP-1 activity.
  • the desired ligand is first conjugated to the antisense peptide and the resulting conjugate is incubated with the radionuclide along with a reducing agent.
  • the latter approach has the additional advantage of allowing preparation of the complex in kit form. Users merely add the radionuclide to the ligand antisense MCP-1 conjugate or a derivative thereof for labelling to occur. It is important to note an unique mechanism of the present invention whereby the conjugation reaction will only occur when the Alpha amino group is in the "free base” form, i.e., deprotonated to the NH 2 form. If the amino group is protonated, i.e., in the NH 3 * form, the reaction will not occur.
  • binding preferably occurs on the Alpha amino group in order to avoid potential interference with the ability of the antisense MCP-1 peptide to form a complementary complex with sense.
  • any suitable ligand can be used to incorporate the preferred radionuclide metal ion such as for example but not limited to technetium, rhenium, indium, gallium, samarium, holmium, yttrium, copper, or cobalt, and more particularly, yttrium-90, rhenium-188, rhenium-186, indium-Ill, technetium-99m, and derivatives thereof.
  • the choice of the ligand entirely depends on the type of metal ion desired for therapeutic or even diagnostic purposes.
  • the radionuclide is a transition element such as technetium or rhenium
  • ligands containing amine, amide, and thiols are preferred to form a stable complex
  • the radionuclide is a lanthanide element
  • polyaminocarboxylates or phenolate type ligands are preferable.
  • the above-described unique characteristics of the present invention make the radiolabelled antisense MCP-1 polypeptide and its derivatives very attractive for therapeutic purposes or even diagnostic uses to identify sites of restenosis and/or vascular injury.
  • the compounds of the present invention may be labelled with any radionuclide favorable for these purposes.
  • suitable radionuclides for radiotherapy include but are not limited to rhenium-186, copper-67, rhenium-188 and cobalt-60.
  • the most suitable radionuclides include but are not limited to the transition metals as exemplified by technetium-99m and copper-62.
  • a preferred embodiment of the present invention is the antisense peptide, polypeptide or protein to MCP-1 or derivatives thereof used alone to prevent vascular restenosis.
  • additional embodiments of the present invention include antisense MCP- 1 or derivatives thereof radiolabelled using a pre-formed or post-formed methodology.
  • an antisense C-C cytokine e.g., MCP-1 or a molecule having sense MCP-1 interactive capability is first bonded to the N 3 S aminothiol ligand which is illustrated in
  • Figure 1 wherein is a whole number less than eleven and preferably 3; p is either 0 or 1; PGi is a suitable sulfur protecting group selected from the group consisting of C ⁇ -.
  • S-acyl such as alkanoyl, benzoyl and substituted benzoyl -whereby alkanoyl is preferable, S-acyl groups such as benzyl, t-butyl, trityl, 4-methoxybenzyl and 2,4-dimethoxybenzyl - whereby 2,4-dimethoxybenzyl is preferable, C ⁇ o alkoxyalkyl such as methoxymethyl, ethoxyethyl and tetrahydropyranyl -whereby tetrahydropyranyl is preferable, carbamoyl, and C j .
  • alkoxycarbonyl such as t-butoxycarbonyl and methoxycarbonyl -whereby t-butoxycarbonyl is preferable; and X is a coupling moiety selected from the group consisting of carboxyl, amino, isocyanate, isothiocyanate, imidate, maleimide, chlorocarbonyl, chlorosulfonyl, succinimidyloxycarbonyl, haloacetyl and C J .
  • JQ N- alkoxycarbamoyl -whereby N-methoxylcabamoyl is preferable.
  • antisense MCP-1 or a molecule having sense MCP-1 interactive capability is bonded to the N 2 S aminothiol ligand which is illustrated in Figure 2;
  • PG 2 and PG 3 may be the same or different sulfur protecting groups selected from the group consisting of S-acyl such as alkanoyl, benzoyl and substituted-benzoyl - whereby alkanoyl is preferable, C ⁇ o alkyl groups such as benzyl, t-butyl, 4-methoxybenzyl, trityl and 2,4- dimethoxybenzyl -whereby 2,4-dimethoxybenzyl is preferable, C 1 ⁇ 10 alkoxyalkyl such as for example methoxymethyl, ethoxyethyl, and tetrahydropyranyl -whereby tetrahydropyranyl is preferable, carbamoyl and C ⁇ o alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl -whereby t-butoxycarbonyl is preferable; and
  • an antisense C-C cytokine e.g., to MCP-1 or a molecule having interactive capability with sense MCP-1 is conjugated with the ligand illustrated in Figure 3,
  • n varies from 1 to 10
  • Y is a coupling moiety selected from the group consisting of carboxyl, amino, isocyanate, isothioganate, imidate, maleimide, chlorocarbonyl, chlorosulfonyl, succinimidyloxycarbonyl, 18 haloacetyl, and C ⁇ o N-alkoxycarbamoyl such as N- methoxycarbamoyl and t-butoxycarbamonyl -whereby t- butoxycarbamonyl is preferable; and R is selected from the group consisting of hydrogen and C ⁇ o alkyl such as methyl and t-butyl -whereby t-butyl is preferable.
  • an antisense C-C chemokine e.g., MCP-1 or a molecule having interactive capability with sense MCP-1 can be conjugated with the metal complex illustrated in Figure 4
  • Figure 4 wherein is a whole number less than eleven and more preferably 3; p is either 0 or 1; X' is a coupling moiety selected from the group consisting of carboxyl, amino, isocyanate, isothiocyanate, imidate, maleimide, chlorocarbonyl, chlorosulfonyl, sucininimidyloxycarbonyl, haloacetyl and C ⁇ o N-alkoxycarbamoyl such as N- methoxycarbamoyl and t-butoxycarbamoyl -whereby t-butoxycarbamoyl is preferable and M is a radionuclide suitable for diagnostic imaging or therapeutic use such as technetium, rhenium, copper, cobalt, indium, gallium, samarium, yttrium and holmium.
  • M is a radionuclide suitable for diagnostic imaging or therapeutic use such as technetium, rhenium, copper, cobalt, in
  • an antisense C-C chemokine e.g., MCP-1 or a molecule having interactive capability with sense MCP-1 can be conjugated with a metal complex as illustrated in Figure 5 wherein Y' and n are defined the same respectively as Y and n in Figure 3 and M is defined the same as M in Figure 4.
  • an antisense C-C chemokine e.g., MCP-1 or a molecule having interactive capability with sense MCP-1 can be conjugated with a metal complex as shown in Figure 6.
  • an antisense C-C chemokine e.g., MCP-1 or a molecule having interactive capability with sense MCP-1 can be conjugated with a metal complex as shown in Figure 7.
  • esters which have been found useful in this labelling technique are o- and p- nitrophenyl, 2- chloro-4-nitrophenyl, cyanomethyl, 2-mercaptopyridyl, hydroxybenztriazole, N-hydroxysuccinimide, trichlorophenyl, tetrafluorophenyl, thiophenyl, tetrafluorothiophenyl, o-nitro-p-sulfophenyl, N-hydroxyphthalimide and the like.
  • the esters will be formed from the reaction of the carboxylate with an activated phenol, particularly, nitro-activated phenols, or a cyclic compound based on hydroxylamine.
  • the advantages of using sulfur protecting groups include the fact that a separate step for removal of the sulfur-protective group is not necessary.
  • the protecting groups are displaced from the compound during the labelling in what is believed to be a metal-assisted acid cleavage: i.e., the protective groups are displaced in the presence of a radionuclide at an acid pH and the radionuclide is bound by the chelating compound.
  • the radiolabeling procedure thus is simplified, which is a significant advantage • when the chelating compounds are to be radiolabelled in a hospital laboratory shortly before use.
  • another advantage of the present invention is that the basic pH conditions and harsh conditions associated with certain known radiolabeling procedures or procedures for removal of other sulfur protected groups are avoided.
  • Suitable sulfur-protecting groups when taken together with the sulfur atom to be protected, include hemithioacetal groups such as ethoxyethyl, tetrahydrofuranyl, methoxymethyl, and tetrahydropyranyl.
  • Other suitable sulfur protecting groups are C x . 20 acyl groups, preferably alkanoyl or benzoyl.
  • Other possible formulas for the chelating compounds are described in U.S. Patent Number 4,965,392 incorporated herein by reference.
  • the radiolabelled antisense C-C chemokine e.g., MCP-1, or derivatives thereof
  • MCP-1 may be injected into a patient for therapeutic use or even diagnostic imaging depending on the radionuclide used.
  • the radiolabelled antisense MCP-1 compound of the present invention is capable of radiotherapeutic use or reliably visualizing areas of potential restenosis within minutes post-injection.
  • the antisense MCP-1 peptide when radiolabelled with the Re-186 or Re-188 triamide thiolate bifunctional chelate is particularly efficacious as an in vivo radiotherapeutic agent for areas of restenosis.
  • Antisense RNA or DNA or a derivative thereof for purposes of inhibition of translation is prepared by oligonucleotide synthesis using the solid phase phosphotrizster method detailed by Woods, et al., Proc.
  • Example 5 To 100 uL of a solution containing 5 mg of sodium gluconate and 0.1 mg of stannous chloride in water, 500 ul of 99m-Tc04 (pertechnetate) is added. After incubation at room temperature for about 10 minutes, a solution of 500 uL of the antisense MCP-1 polypeptide, or derivatives thereof, conjugates (1 mg/mL in 0.1 M carbonate/bicarbonate buffer, pH 9.5) as described in Examples 1 or 2 is then added and the entire mixture is incubated at 37°C for about 1 hour.
  • 99m-Tc04 pertechnetate
  • the desired labelled peptide is separated from unreacted 99mTc-gluconate and other small molecular weight impurities by gel filtration chromatography (Sephadex G-50) using phosphine buffered physiological saline, (hereinafter PBS), 0.15M NaCl, pH 7.4 as eluent.
  • PBS phosphine buffered physiological saline
  • Antisense DNA or a derivative thereof for purposes of inhibition of MCP-1 synthesis by inhibition of transcription by self replication within smooth muscle cells is prepared by introduction of such DNA sequences into a plasmid (a circular piece of DNA) consisting of a smooth muscle actin or viral promoter coupled to antisense DNA to MCP-1 and appropriate start and stop signals.
  • a plasmid a circular piece of DNA
  • This plasmid is introduced into smooth muscle cells by using a balloon infusion catheter.
  • the plasmid DNA is suspended to a concentration of between 10 and 100 micrograms per milliliter in Tris chloride EDTA (10 mM, 1 mM ETDA) (TE) and is infused at a pressure of between 2 and 8 atmospheres. Infusion time varies between 5 and 30 minutes.
  • the compound is used with a pharmaceutically acceptable carrier in a method of performing therapy or radiotherapy or a method of performing a diagnostic imaging procedure using a gamma camera or like device.
  • a pharmaceutically acceptable carrier for example by means of a balloon injector catheter, to a warm-blooded animal an effective amount of the present invention and then in the case of diagnostic use, exposing the warm ⁇ blooded animal to an imaging procedure using a suitable detector, e.g. a gamma camera.
  • Images are obtained by recording emitted radiation of tissue or the pathological process in which the radioactive peptide or oligonucleotide has been incorporated, which in the present case are potential sites of restenosis, thereby imaging at least a portion of the body of the warm-blooded animal.
  • Pharmaceutically acceptable carriers for either diagnostic or therapeutic use include those that are suitable for injection . or administration such as aqueous buffer solutions, e.g.
  • the carriers may contain a chelating agent, e.g. a small amount of ethylenediaminetetraacetic acid (EDTA), calcium, disodium salt, or other pharmaceutically acceptable chelating agents.
  • EDTA ethylenediaminetetraacetic acid
  • concentration of the labelled or unlabelled peptide and the pharmaceutically acceptable carrier varies with the particular field of use. A sufficient amount is present in the pharmaceutically acceptable carrier in the present invention when satisfactory visualization of areas of vascular injury is achievable or satisfactory therapeutic results are achievable.
  • composition is administered to the warm- blooded animals so that the composition remains in the living animal for about six to seven hours, although shorter and longer residence periods are normally acceptable.
  • the antisense MCP-1 compounds of the present invention or antisense MCP-1 derivative thereof, prepared as described herein, provide means of in vivo therapeutic, radiotherapeutic or diagnostic imaging of areas of potential restenosis.

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Abstract

L'invention concerne une composition appropriée pour être administrée à un animal à sang chaud. Cette composition comprend un oligonucléotide antisens par rapport à la famille de C-C chémokine, typifiée par les protéines MCP-1 et MIP-1 alpha, qui peut ou non être marqué par un radionucléide au moyen d'un ligand chélateur. Cette composition peut être administrée à un animal pour produire des images visuelles fiables des zones de resténose potentielle ou pour produire des effets thérapeutiques sur ces dernières.
PCT/US1995/000605 1994-01-14 1995-01-13 Traitement therapeutique visant a inhiber la restenose vasculaire WO1995019167A1 (fr)

Priority Applications (2)

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EP95908532A EP0802792A1 (fr) 1994-01-14 1995-01-13 Traitement therapeutique visant a inhiber la restenose vasculaire
JP7519178A JPH09508358A (ja) 1994-01-14 1995-01-13 血管再狭窄を抑止するための医療的処置

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US18291794A 1994-01-14 1994-01-14
US08/182,917 1994-01-14

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WO1997035974A1 (fr) * 1996-03-26 1997-10-02 Institut Pasteur Sequences en amont du gene sm22, vecteurs les contenant et leurs utilisations therapeutiques, notamment dans le traitement des maladies vasculaires
WO1997038730A2 (fr) * 1996-04-17 1997-10-23 Olivier Bertrand Systeme de radiotherapie locale
WO1998023299A2 (fr) * 1996-11-26 1998-06-04 Angiogene Inc. Oligonucleotide d'adn radiomarque, procede de preparation et utilisations therapeutiques associes
US6673915B1 (en) 1996-09-30 2004-01-06 General Hospital Corporation Nucleic acid encoding monocyte chemotactic protein 4
US6736769B2 (en) 1996-04-17 2004-05-18 Olivier Bertrand Radioactivity local delivery system
US7713521B2 (en) 2005-08-12 2010-05-11 Schering Corporation MCP1 fusions
CN101174331B (zh) * 2006-11-01 2011-07-27 深圳市蓝韵实业有限公司 一种医学影像最大密度投影生成方法
US8524217B2 (en) 2010-05-11 2013-09-03 Merck Sharp & Dohme Corp. MCP1-Ig fusion variants

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035974A1 (fr) * 1996-03-26 1997-10-02 Institut Pasteur Sequences en amont du gene sm22, vecteurs les contenant et leurs utilisations therapeutiques, notamment dans le traitement des maladies vasculaires
FR2746815A1 (fr) * 1996-03-26 1997-10-03 Pasteur Institut Sequences en amont du gene sm 22, vecteurs les contenant et leurs utilisations therapeutiques, notamment dans le traitement des maladies vasculaires
WO1997038730A2 (fr) * 1996-04-17 1997-10-23 Olivier Bertrand Systeme de radiotherapie locale
WO1997038730A3 (fr) * 1996-04-17 1997-12-11 Olivier Bertrand Systeme de radiotherapie locale
US6736769B2 (en) 1996-04-17 2004-05-18 Olivier Bertrand Radioactivity local delivery system
US6673915B1 (en) 1996-09-30 2004-01-06 General Hospital Corporation Nucleic acid encoding monocyte chemotactic protein 4
WO1998023299A3 (fr) * 1996-11-26 1998-12-17 Angiogene Canada Inc Oligonucleotide d'adn radiomarque, procede de preparation et utilisations therapeutiques associes
WO1998023299A2 (fr) * 1996-11-26 1998-06-04 Angiogene Inc. Oligonucleotide d'adn radiomarque, procede de preparation et utilisations therapeutiques associes
US7713521B2 (en) 2005-08-12 2010-05-11 Schering Corporation MCP1 fusions
US7972591B2 (en) 2005-08-12 2011-07-05 Schering Corporation Methods for treating rheumatoid arthritis and multiple sclerosis using MCP1 fusions
US8282914B2 (en) 2005-08-12 2012-10-09 Merck, Sharp & Dohme Corp. Method for treating atherosclerosis by administering human MCP1 fusions
CN101174331B (zh) * 2006-11-01 2011-07-27 深圳市蓝韵实业有限公司 一种医学影像最大密度投影生成方法
US8524217B2 (en) 2010-05-11 2013-09-03 Merck Sharp & Dohme Corp. MCP1-Ig fusion variants

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Publication number Publication date
EP0802792A1 (fr) 1997-10-29
JPH09508358A (ja) 1997-08-26
CA2181035A1 (fr) 1995-07-20

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