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WO1997010829A1 - Compositions pharmaceutiques contenant un oligonucleotide et un polysaccharide anionique - Google Patents

Compositions pharmaceutiques contenant un oligonucleotide et un polysaccharide anionique Download PDF

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Publication number
WO1997010829A1
WO1997010829A1 PCT/GB1996/002245 GB9602245W WO9710829A1 WO 1997010829 A1 WO1997010829 A1 WO 1997010829A1 GB 9602245 W GB9602245 W GB 9602245W WO 9710829 A1 WO9710829 A1 WO 9710829A1
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WO
WIPO (PCT)
Prior art keywords
composition according
oligonucleotide
raf
regions
modified
Prior art date
Application number
PCT/GB1996/002245
Other languages
English (en)
Inventor
Paul Leslie Nicklin
Alan Steward
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to AU69370/96A priority Critical patent/AU6937096A/en
Publication of WO1997010829A1 publication Critical patent/WO1997010829A1/fr

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Classifications

    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters

Definitions

  • compositions Containing an Oligonucleotide and an Anionic Polysaccharide
  • This invention relates to oligonucleotide compositions, their preparation and their use.
  • Oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. For example, there have been identified antisense, triplex and other oligonucleotide compositions which are capable of modulating expression of genes implicated in viral, fungal and metabolic diseases.
  • Alterations in cellular genes which directly or indirectly control cell growth and differentiation are considered to be the main cause of cancer.
  • oncogenes which are implicated in human tumor formation.
  • Members of one such family, the raf gene family are frequently found to be mutated in human tumors.
  • the raf family includes three highly conserved genes termed A-, B- and c-raf (also called raf -I), c- Raf, the best characterized member of the raf family, is the cellular homologue of v-raf, the transforming gene of the murine sarcoma virus 36H.
  • Raf genes encode protein kinases that are thought to play important regulatory roles in signal transduction processes that regulate cell proliferation.
  • raf genes causing a truncation or other modification that leads to the expression of raf kinase without a functional negative regulatory domain at the amino-terminal end results in conversion to a form which is implicated in transformation of mammalian cells in culture, and tumor formation.
  • a raf gene having an absent or inactive regulatory domain is said to be "activated.”
  • Activated (truncated) raf has been detected in a variety of human cancers including small-cell lung carcinoma, primary stomach cancer, renal cancer, breast cancer, laryngeal cancer, skin fibroblasts from members of a cancer- prone family (Li-Fraumeni syndrome), and in a human glioblastoma cell line.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (A) an oligonucleotide and (B) an anionic polysaccharide.
  • oligonucleotide refers to an oligomer or polymer of nucleotide or nucleoside monomers consisting of naturally occurring bases, sugars and intersugar (backbone) linkages.
  • oligonucleotide also includes oligomers comprising non-naturally occurring monomers, or portions thereof, which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of properties such as, for example, enhanced cellular uptake and increased stability in the presence of nucleases.
  • the oligonucleotide may comprise, for example, up to 50 nucleotides, preferably 8 to 50 nucleotides, especially 16 to 24 nucleotides.
  • At least one nucleotide is modified at the 2' position of the sugar moiety.
  • Certain preferred oligonucleotides (A) are chimeric oligonucleotides.
  • "Chimeric oligonucleotides” or “chimeras”, in the context of this invention, are oligonucleotides which contain two or more chemically distinct regions, each made up of at least one nucleotide.
  • oligonucleotides typically contain at least one region of modified nucleotides that confers one or more beneficial properties (such as, for example, increased nuclease resistance, increased uptake into cells, increased binding affinity for the RNA target) and a region that is a substrate for RNase H cleavage.
  • a chimeric oligonucleotide comprises at least one region modified to increase target binding affinity and, usually, a region that acts as a substrate for RNAse H.
  • Affinity of an oligonucleotide for its target is routinely determined by measuring the Tm of an oligonucleotide/target pair, which is the temperature at which the oligonucleotide and target dissociate; dissociation is detected spectrophotometrically.
  • Tm the temperature at which the oligonucleotide and target dissociate
  • dissociation is detected spectrophotometrically. The higher the Tm, the greater the affinity of the oligonucleotide for the target.
  • the region of the oligonucleotide which is modified to increase mRNA binding affinity comprises at least one nucleotide modified at the 2' position of the sugar, particulariy a 2' - alkoxy, 2'-alkoxyalkoxy or 2'-fluoro-modified nucleotide.
  • modifications are routinely inco ⁇ orated into oligonucleotides and these oligonucleotides have been shown to have a higher Tm (i.e., higher target binding affinity) than 2'-deoxyoligonucleotides against a given target.
  • RNAse H is a cellular endonuclease that cleaves the RNA strand of RNA.DNA duplexes; activation of this enzyme therefore results in cleavage of the RNA target, and thus can greatly enhance the efficiency of antisense inhibition. Cleavage of the RNA target can be routinely demonstrated by gel electrophoresis.
  • the chimeric oligonucleotide is also modified to enhance nuclease resistance. Cells contain a variety of exo- and endo-nucleases which can degrade nucleic acids.
  • nucleotide and nucleoside modifications have been shown to make the oligonucleotide into which they are inco ⁇ orated more resistant to nuclease digestion than the native oligodeoxynucleot.de.
  • Nuclease resistance is routinely measured by incubating oligonucleotides with cellular extracts or isolated nuclease solutions and measuring the extent or isolated nuclease solutions and measuring the extent of intact oligonucleotide remaining over time, usually by gel electrophoresis. Oligonucleotides which have been modified to enhance their nuclease resistance survive intact for a longer time than unmodified oligonucleotides.
  • oligonucleotide modifications have been demonstrated to enhance or confer nuclease resistance. Oligonucleotides which contain at least one phosphorothioate modification are presently more preferred. In some cases, oligonucleotide modifications which enhance target binding affinity are also, independently, able to enhance nuclease resistance.
  • oligonucleotides may contain phosphorothioate, phosphotriester, methyl phosphonate, short chain alkyl or cycloalkyl intersugar linkages, short chain heteroatomic or heterocyclic intersugar ("backbone”) linkages or combinations thereof or combinations of one or more thereof with one or more phosphodiester backbone linkages.
  • phosphorothioates and those with CH -NH-O-CH 2 , CH 2 - N(CH 3 )-O-CH 2 , CH 2 -O-N(CH 3 )-CH 2 , CH 2 -N(CH 3 )-N(CH 3 )-CH 2 and O-N(CH 3 )-CH 2 -CH 2 backbones or combinations thereof or combinations of one or more thereof with one or more phosphodiestr backbone linkages (where phosphodiester is O-P-O-CH 2 ).
  • oligonucleotides having morpholino backbone structures for example as described in U.S. Patent No. 5, 034, 506.
  • the phosphodiester backbone of the oligonucleotide may be replaced with a polyamide backbone, the bases being bound directly or indirectly to the aza nitrogen atoms of the polyamide backbone, as described by P.E. Nielsen, M. Egholm, R.H. Berg, O. Buchardt, Science 1991, 254, 1497.
  • Other preferred oligonucleotides may contain substituted, e.g.
  • alkyl and halogen-substituted, sugar moieties comprising one of the following at the 2' position: OH, SH, SCH 3 , F, OCN, OCH 2 OCH 3 , OCHzCHzOCHa.
  • Oligonucleotides may also have sugar mimetics such as cyclobutyls in place of the pentofuranosyl group.
  • Other preferred embodiments may include at least one modified base form or "universal base" such as inosine.
  • all nucleotides of the oligonucleotide (A) are 2'-deoxynucleotides and all backbone linkages are phosphorothioate linkages.
  • the oligonucleotide (A) is a chimeric oligonucleotide having one or more regions with 2'-deoxynucleotides and one or more regions with 2'-alkoxyalkoxynucleotides, particularly 2'-methoxyethoxynucleotides, the one or more, 2'-deoxynucleotide regions preferably having phosphorothioate backbone linkages and the one or more 2'-alkoxyalkoxynucleotide regions preferably having phosphodiester backbone linkages.
  • These chimeric oligonucleotides preferably comprise a region of 2'- deoxynucleotides between two regions of 2'-alkoxyalkoxy ⁇ ucleotides.
  • an oligonucleotide and its complementary nucleic acid target to which it hybridises is commonly referred to as "antisense".
  • Targetting an oligonucleotide to a chosen nucleic acid target may involve a multistep process. The process usually begins with identifying a nucleic acid sequence whose function is to be modulated. This may be, as examples, a cellular gene (or mRNA made from the gene) whose expression is associated with a particular disease state, or a foreign nucleic acid from an infectious agent.
  • the target is a nucleic acid encoding raf; in other words, the raf gene or mRNA expressed from the raf gene.
  • the targeting process also includes determination of a site or sites within the nucleic acid sequence for the oligonucleotide interaction to occur such that the desired effect - inhibition of abnormal raf gene expression- will result. Once the target site or sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired inhibition.
  • Hybridization in the context of this invention, means hydrogen bonding, also known as Watson-Crick base pairing, between complementary bases, usually on opposite nucleic acid strands or two regions of a nucleic acid strand. Guanine and cytosine are examples of complementary bases which are known to form three hydrogen bonds between them. Adenine and thymine are examples of complementary bases which form two hydrogen bonds between them.
  • oligonucleotide and “complementary” are terms which are used to indicate a sufficient degree of complementarity such that stable and specific binding occurs between the DNA or RNA target and the oligonucleotide. it is understood that an oligonucleotide need not be 100% complementary to its target nucleic acid sequence to be specifically hybridizable.
  • An oligonucleotide is specifically hybridizable when binding of the oligonucleotide to the target interferes with the normal function of the target molecule to cause a loss of utility, and there is a sufficient degree of complementarity to avoid non-specific binding of the oligonucleotide to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, or, in the case of in vitro assays, under conditions in which the assays are conducted.
  • the oligonucleotide (A) is 8 to 50 nucleotides in length, especially 18 to 24 nucleotides in length, and is targeted to mRNA encoding human raf, particulariy c-raf or A-raf.
  • mRNA includes not only the coding region which carries the information to encode a protein using the three letter genetic code, but also associated ribonucleotides which form a region known to such persons as the 5'- untranslated region, the 3'-untranslated region, the 5' cap region, intron regions and intron/exon or splice junction ribonucleotides.
  • oligonucleotides may be formulated in accordance with this invention which are targeted wholly or in part to these associated ribonucleotides as well as to the coding ribonucleotides.
  • the oligonucleotide is targeted to a translation initiation site (AUG codon) or sequences in the 5' - or 3' -untranslated region of the human c- raf mRNA.
  • the functions of messenger RNA to be interfered with include all vital functions such as translocation of the RNA to the site for protein translation, actual translation of protein from the RNA, splicing or maturation of the RNA and possibly even independent catalytic activity which may be engaged in by the RNA.
  • the overall effect of such interference with the RNA function is to cause interference with raf protein expression.
  • Oligonucleotides targeted to mRNA encoding human A-raf and, especially, human c-raf are presently preferred; however, compositions for modulating expression of other forms of raf are also believed to have utility and are comprehended by this invention.
  • oligonucleotides used as component (A) of the composition of the invention may be conveniently and routinely made using well-known techniques such as solid phase synthesis. Equipment for such synthesis is available commercially from various sources including Applied Biosystems. The use of such techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives is well known.
  • CPG controlled-pore glass
  • oligonucleotide Nos. ON1 to ON43 include the following: No. Sequence (5' ⁇ 3"> Site SEQ ID NO:
  • ON1 to ON10 are oligodeoxynucleotides with phosphorothioate backbones desgined using the Genbank c-raf sequence HUMRAFR (Genbank listing x 03484), synthesised and tested for inhibition of c-raf mRNA expression in T24 bladder carcinoma cells using a Northern blot assay.
  • oligonucleotides include:
  • ON11 , ON12 and ON13 are oligonucleotides synthesised with phosphorothioate backbones and uniformly substituted at the 2' position of the sugar moiety by a methoxy group.
  • ON14 is synthesized with a phosphodiester backbone and is uniformly substituted by a propoxy group at the 2' position of the sugar moiety.
  • ON15 is synthesized with a phosphorothioate backbone and is uniformly substituted by fluoro at the 2' position of the sugar moiety.
  • chimeric oligonucleotides include:
  • ON16 to ON25 are chimeric oligonucleotides with uniform phosphorothiate backbones, the nucleotides shown underlined being substituted by methoxy at the 2' position of the sugar moiety.
  • chimeric oligonucleotides include:
  • ON26, ON27 and ON28 are chimeric oligonucleotides with uniform phosphorothioate backbones, the nucleotides shown underlined being substituted at the 2' position of the sugar moiety, in ON26 by propoxy and in ON27 and ON28 by fluoro.
  • chimeric oligonucleotides with 2' modifications and chimeric phosphorothiote/phosphodiester backbones include: No. Seguence Target Site SEQ ID NO:
  • ON29 and ON30 have regions, shown underlined, which have both 2'-propoxy substituents and phosphodiester backbones.
  • ON31 has regions, shown underlined, which have both 2'- methoxyethoxy substituents and phosphodiester backbones.
  • oligonucleotides targeted to portions of the A-raf mRNA and which inhibit A-raf expression will be useful for interfering with cell hyperproliferation.
  • the oligonucleotide (A) is 5 to 50 nucleotides in length and is specifically hybridizable with DNA or RNA derived from the gene encoding protein kinase C, particulariy such an oligonucleotide as described in WO 95/02069.
  • Preferred such oligonucleotides are those described in Examples 1 to 18 of WO 95/02069.
  • the anionic polysaccharide (B) may be, for example, an anionic dextran, polyinosinic acid, polyguanylic acid, polyxanthinylic acid or fucoidin.
  • the anionic polysaccharide (B) is preferably an anionic dextran or fucoidin, more preferably a dextran sulphate having a molecular weight of 5 to 500 kD, e.g. 5 to 50 kD, especially 5 to 10 kD.
  • the weight ratio of anionic polysaccharide to oligonucleotide may be generally from 1 :1 to 1000:1, for example from 1:1 to 100:1, preferably from 3:1 to 300:1, for example from 3:1 to 30:1, especially from 5:1 to 150:1, for example from 5:1 to 15:1 or from 10:1 to 100:1.
  • a composition of the invention may be prepared simply by mixing the oligonucleotide and anionic polysaccharide together, for example before dissolution in a medium such as water, phosphate buffered saline or other pharmaceutically acceptable aqueous medium for parenteral administration or by simultaneous or separate dissolution in such a medium.
  • a medium such as water, phosphate buffered saline or other pharmaceutically acceptable aqueous medium for parenteral administration or by simultaneous or separate dissolution in such a medium.
  • the invention includes a method of inhibiting the expression of human raf which comprises contacting tissues or cells which express human raf with a composition of the invention as hereinbefore described in which (A) is targeted to m RNA encoding human raf.
  • the invention also includes a method of treating mammalian cancer which comprises administering a composition of the invention as hereinbefore described to a mammal, particularly a human, in need of such treatment.
  • composition of the invention may be administered by pulmonary delivery or, preferably, parenterally, for example intravenously, subcutaneously, intraperitoneally or intramuscularly.
  • the dosage depends principally on the method of administration and on the severity and responsiveness of the condition to be treated. Individual doses and the administration regime can best be determined by individual judgement of a particular case of illness.
  • Diseases which may be treated with the composition include mammalian cancer, particularly human cancer such as lung cancer, stomach cancer, renal cancer, breast cancer, laryngeal cancer, pancreatic cancer, colorectal cancer and malignant melanoma.
  • the invention is illustrated by the following Examples.
  • Oligonucleotide ON3 as hereinbefore defined (15 ⁇ g) is mixed with dextran sulphate having a molecular weight of 8kD (150 ⁇ g). The resulting mixture is dissolved in phosphate buffered saline (0.2ml) to give a solution which can be administered by intravenous injection.
  • Example 1 is repeated, using 15 ⁇ g of the dextran sulphate instead of the amount used in Example 1 , to give a solution which can be administered by intravenous injection.
  • Example 1 is repeated, using 1500 ⁇ g of the dextran sulphate instead of the amount used in Example 1 , to give a solution which can be administered by intravenous injection.
  • Example 1 is repeated, using oligonucleotide ON31 in place of ON3, to give a solution which can be administered by intravenous injection.
  • Example 3 is repeated using oligonucleotide Isis # 3521 as described in WO 95/02069 in place of ON3, to give a solution which can be administered by intravenous injection.
  • Example 6 is repeated using oligonucleotide Isis # 3521 as described in WO 95/02069 in place of ON3, to give a solution which can be administered by intravenous injection.
  • Oligonucleotide ON3 as hereinbefore defined in tritiated form (15 ⁇ g) is mixed with dextran sulphate having a molecular weight of 8 kD (1500 ⁇ g).
  • a solution of the resulting mixture in water (0.2ml) is administered by intravenous injection to nude mice having tumours formed by innocuiation 10 days previously with human lung adenocarcinoma A549 cells implanted subcutaneously under the dorsal outer skin.
  • the oligonucleotide dosage is 0.6 mg kg. Two hours after the injection, the mice are sacrificed and the content of the radioactively labelled oligonucleotide in the tumours is determined.
  • the above test procedure is repeated using a solution of oligonucleotide ON3 alone, at the same dosage, instead of the mixture with dextran sulphate, in water.
  • the content of the oligonucleotide in the tumour is 0.351 ⁇ g/g following injection with the oligonucleotide-dextran sulphate mixture, but only 0.249 ⁇ g/g following injection with the oligonucleotide alone (average of 6 replicates in each case).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique comprenant A) un oligonucléotide et B) un polysaccharide anionique tel que le sulfate de dextrane et utilisable pour le traitement du cancer chez les mammifères.
PCT/GB1996/002245 1995-09-19 1996-09-12 Compositions pharmaceutiques contenant un oligonucleotide et un polysaccharide anionique WO1997010829A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69370/96A AU6937096A (en) 1995-09-19 1996-09-12 Pharmaceutical compositions containing an oligonucleotide and an anionic polysaccharide

Applications Claiming Priority (2)

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GBGB9519109.4A GB9519109D0 (en) 1995-09-19 1995-09-19 Compositions
GB9519109.4 1995-09-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057716A3 (fr) * 2002-01-08 2004-03-04 New River Pharmaceuticals Inc Encapsulation dendritique d'agents actifs
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002069A1 (fr) * 1993-07-09 1995-01-19 Isis Pharmaceuticals, Inc. Modulation oligonucleotidique de la proteine kinase c
WO1995032987A1 (fr) * 1994-05-31 1995-12-07 Isis Pharmaceuticals, Inc. MODULATION OLIGONUCLEOTIDIQUE ANTISENS DE L'EXPRESSION DU GENE raf

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002069A1 (fr) * 1993-07-09 1995-01-19 Isis Pharmaceuticals, Inc. Modulation oligonucleotidique de la proteine kinase c
WO1995032987A1 (fr) * 1994-05-31 1995-12-07 Isis Pharmaceuticals, Inc. MODULATION OLIGONUCLEOTIDIQUE ANTISENS DE L'EXPRESSION DU GENE raf

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIMURA Y ET AL: "Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN", JOURNAL OF BIOCHEMISTRY (TOKYO), 116 (5). 1994. 991-994., XP000616565 *
YAO GQ ET AL: "Demonstration of oligonucleotide binding proteins on plasma membranes of human cells (Meeting abstract).", PROC ANNU MEET AM ASSOC CANCER RES;35:A1839 1994, XP000617230 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057716A3 (fr) * 2002-01-08 2004-03-04 New River Pharmaceuticals Inc Encapsulation dendritique d'agents actifs
US7438900B2 (en) 2002-01-08 2008-10-21 Shire Llc Dendritic encapsulation of active agents
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances

Also Published As

Publication number Publication date
AU6937096A (en) 1997-04-09
GB9519109D0 (en) 1995-11-22

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