WO2001093905A1 - Immunostimulatory oligodeoxynucleotides - Google Patents

Immunostimulatory oligodeoxynucleotides Download PDF

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Publication number
WO2001093905A1
WO2001093905A1 PCT/EP2001/006433 EP0106433W WO0193905A1 WO 2001093905 A1 WO2001093905 A1 WO 2001093905A1 EP 0106433 W EP0106433 W EP 0106433W WO 0193905 A1 WO0193905 A1 WO 0193905A1
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WIPO (PCT)
Prior art keywords
monothiophosphate
monophosphate
deoxyinosine
odn
deoxycytosine
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PCT/EP2001/006433
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English (en)
French (fr)
Inventor
Walter Schmidt
Karen Lingnau
Carola Schellack
Alena Egyed
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Intercell Biomedizinische Forschungs- Und Entwicklungs Ag
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Priority claimed from AT0100000A external-priority patent/AT410173B/de
Priority to SK1815-2002A priority Critical patent/SK287689B6/sk
Priority to DK01960277T priority patent/DK1296713T3/da
Priority to PL358982A priority patent/PL211036B1/pl
Priority to JP2002501476A priority patent/JP5271471B2/ja
Priority to IL15295901A priority patent/IL152959A0/xx
Priority to DE2001600814 priority patent/DE60100814T2/de
Priority to AU8181201A priority patent/AU8181201A/xx
Priority to MXPA02012010A priority patent/MXPA02012010A/es
Priority to AU2001281812A priority patent/AU2001281812B2/en
Application filed by Intercell Biomedizinische Forschungs- Und Entwicklungs Ag filed Critical Intercell Biomedizinische Forschungs- Und Entwicklungs Ag
Priority to US10/297,555 priority patent/US8568742B2/en
Priority to BRPI0111639A priority patent/BRPI0111639B8/pt
Priority to EP20010960277 priority patent/EP1296713B1/en
Priority to AT01960277T priority patent/ATE249839T1/de
Priority to CA2411575A priority patent/CA2411575C/en
Priority to SI200130047T priority patent/SI1296713T1/xx
Priority to HU0301229A priority patent/HU228264B1/hu
Publication of WO2001093905A1 publication Critical patent/WO2001093905A1/en
Priority to IS6627A priority patent/IS1993B/is
Priority to IL152959A priority patent/IL152959A/en
Priority to NO20025835A priority patent/NO329492B1/no
Priority to HK03109011A priority patent/HK1056678A1/xx
Priority to US13/786,815 priority patent/US8945591B2/en
Priority to US14/585,740 priority patent/US9492537B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/18—Type of nucleic acid acting by a non-sequence specific mechanism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to immunostimulatory oligodeoxynucleic molecules (ODNs) and pharmaceutical compositions containing such ODNs .
  • ODNs immunostimulatory oligodeoxynucleic molecules
  • Vaccines can save more lives (and resources) than any other medical intervention (Nossal, 1998) . Owing to world-wide vaccination programs the incidence of many fatal diseases has been decreased drastically. Although this notion is valid for a whole panel of diseases, e.g. tuberculosis, diphtheria, pertussis, measles and tetanus, there are no effective vaccines for numerous infectious disease including most viral infections, such as AIDS. There are also no effective vaccines for other diseases, infectious or non-infectious claiming millions the lives of millions of patients per year including malaria or cancer. In addition, the rapid emergence of antibiotic-resistant bacteria and microorganisms calls for alternative treatments with vaccines being a logical choice. Finally, the great need for vaccines is also illustrated by the fact that infectious diseases, rather than cardiovascular disorders or cancer or injuries remain the largest cause of death and disability in the world (Bloom and Widdus, 1998) .
  • T cells which recognize molecules expressed on pathogen infected cells.
  • vaccines are designed that induce both T cells distinguishing diseased and/or infected cells from normal cells and, simultaneously, antibodies secreted by B cells recognising pathogens in extracellular compartments .
  • vaccines consist of live attenuated organism where the risk of reversion to the virulent wild-type strain exists. In particular in immunocompromised hosts this can be a live threatening scenario.
  • vaccines are administered as a combination of pathogen-derived antigens together with compounds that induce or enhance immune responses against these antigens (these compounds are commonly termed adjuvant) , since these subunit vaccines on their own are generally not effective.
  • Antigen presenting cells belong to the innate immune system, which has evolved as a first line host defence that limits infection early after exposure to microorganisms (Hoffmann et al . , 1999).
  • Cells of the innate immune sytem recognize patterns or relatively non-specific structures expressed on their targets rather than more sophisticated, specific structures which are recognised by the adaptive immune system (Hoffmann et al . , 1999).
  • Examples of cells of the innate immune system are macrophages and dendritic cells but also granulocytes (e.g. neutrophiles) , natural killer cells and others.
  • cells of the adaptive immune system recognize specific, antigenic structures, including peptides, in the case of T cells and peptides as well as three- dimensional structures in the case of B cells.
  • the adaptive immune system is much more specific and sophisticated than the innate immune system and improves upon repeat exposure to a given pathogen/antigen.
  • the innate immune system is much older and can be found already in very primitive organisms. Nevertheless, the innate immune system is critical during the initial phase of antigenic exposure since, in addition to containing pathogens, cells of the innate immune system, i.e. APCs, prime cells of the adaptive immune system and thus trigger specific immune responses leading to clearance of the intruders.
  • cells of the innate immune sytem and in particular APCs play a critical role during the induction phase of immune responses by a) containing infections by means of a primitive pattern recognition system and b) priming cells of the adaptive immune system leading to specific immune responses and memory resulting in clearance of intruding pathogens or of other targets (Roitt et al . , 1998). These mechanisms may also be important to clear or contain tumor cells . ,
  • cells of the innate immune system recognise patterns expressed on their respective targets .
  • examples are lipopolysaccharides ( PS) in the case of Gram-negative bacteria, mycobacterial glycolipids, lipoteichoic acids of Gram-positive bacteria, mannans of yeast and double stranded RNAs of viruses (Hoffmann et al . , 1999).
  • PS lipopolysaccharides
  • mycobacterial glycolipids lipoteichoic acids of Gram-positive bacteria
  • mannans of yeast double stranded RNAs of viruses
  • the immune system recognises lower organisms including bacteria probably due to structural and sequence usage differencies between pathogen and host DNA.
  • short stretches of DNA derived from non-vertebrates or in form of short synthetic ODNs containing nonmethylated cytosine-guanine dinucleotides (CpG) in a certain base context, are targeted (Krieg et al . , 1995) .
  • CpG motifs are found at the expected frequency in bacterial DNA but are much less frequent in vertebrate DNA (LipLord et al., 1998; Pisetsky, 1999).
  • non-vertebrate (i.e. bacterial) CpG motifs are not methylated whereas vertebrate CpG sequences are.
  • Natural CpG-containing DNA, ODNs, as well as thiophosphate-sub- stituted (exchange of thiophosphate residues for phosphate) ODNs containing CpG motifs are not only potent activators of immune cell proliferation and humoral immune responses (Krieg et al . , 1995), but also stimulate strong cellular immune responses (reviewed in Lipford et al . , 1998) .
  • DNA/ODNs containing non-methylated CpG motifs can directly activate monocytic cells (dendritic cells, macrophages) and B cells.
  • NK cells are not directly activated but respond to ono- cyte-derived IL-12 (interleukin 12) with a marked increase in their IFN- ⁇ production (Chace et al., 1997).
  • ono- cyte-derived IL-12 interleukin 12
  • CpG DNA promotes the induction of Thl-type responses and the development of cytotoxic T cells .
  • Ribonucleic acid based on inosine and cytosine like polyi- nosinic-polycytidylic acid (poly I:C), is known to promote Thl- specific immune responses. It is known to stimulate macrophages to produce cytokines such as IL-l ⁇ and IL-12 (Manetti et al . , 1995) , it is also known as a potent interferon type 1 inducer (Manetti et al . , 1995) and a potent NK cell stimulator (Cavanaugh et al. , 1996) .
  • ODNs containing non-methylated CpG motifs although being efficient in stimulating immune system, have essential disadvantages, especially with respect to specificity (high background) and induction of side effects, such as high systemic TNF- ⁇ generation.
  • High systemic TNF- ⁇ release is known to cause toxic shock syndrome, which can cause death of afflicted patients.
  • any X is 0 or S
  • NMP is a 2 ' deoxynucleoside monophosphate or monothiophosphate, selected from the group consisting of deoxyadenosine-, deoxyguanosine-, deoxyinosine-, deoxycytosine-, deoxyuridine-, deoxythymidine-, 2-methyl-deoxyinosine-, 5-methyl-deoxycytosine-, deoxypseudouridine-, deoxyribosepurine-, 2-amino-deoxyribosepu- rine-, 6-S-deoxyguanine-, 2-dimethyl-deoxyguanosine- or N-isopen- • tenyl-deoxyadenosine-monophosphate or -monothiophosphat
  • NUC is a 2' deoxynucleoside, selected from the group consisting of deoxyadenosine-, deoxyguanosine-, deoxyinosine-, deoxycytosine-, deoxyuridine-, deoxythy
  • ODNs containing deoxyinosine residues show an immunostimulatory effect comparable or in many instances even better than ODNs containing CpG motifs.
  • ODNs according to the present invention produce more specific immune responses to a given antigen or antigen fragment than CpG ODNs.
  • ODNs according to the present invention reduced the induction of adverse side reactions, especially the induction of systemic TNF- ⁇ or IL-6.
  • the I-ODNs according to the present invention are - in contrast to ODNs based on the specific CpG motif - not dependent on a specific motif or a palindromic sequence as described for the CpG oligonucleotides (see e.g. EP 0 468 520 A2, WO96/02555, WO98/18810, W098/37919, WO98/40100, W098/52581, W099/51259 and W099/56755, all incoraliad herein by reference) .
  • one group of I-ODNs according to the present invention may preferably contain a CI motif (and therefore ODNs described in these incorporated references, wherein one or more guanosine residues are replaced with deoxyinosine residues are preferred embodiments of the present ODNs) . It is not necessary for its principle immunostimulatory property, since I-ODNs with an Inosine not placed in a CI or IC context exhibit immunostimulatory properties as well.
  • the I-ODN according to the present invention is therefore a DNA molecule containing a deoxyinosine residue which is preferably provided in single stranded form.
  • the I-ODN according to the present invention may be isolated through recombinant methods or chemically synthesized.
  • the I-ODN according to the present invention may also contain modified oligonucleotides which may be synthesized using standard chemical transformations, such as methylphosphon- ates or other phosphorous based modified oligonucleotides, such as phosphotriesters, phosphoamidates and phosphorodithiorates .
  • Other non-phosphorous based modified oligonucleotides can also be used (Stirchak et al . , MAR 17 (1989), 6129-6141), however, mono- phosphates or monothiophosphates being the preferred 2 'deoxynucleoside monophosphate to be used in the present invention.
  • the NMPs of the I-ODNs according to the present invention are preferably selected from the group consisting of deoxyadenosine-, deoxyguanosine-, deoxyinosine-, deoxycytosine-, deoxyuridine-, deoxythymidine-, 2-methyl-deoxyinosine-, 5-methyl-deoxycytosine- monophosphate or -monothiophosphate (as usual, the phosphate or thiophosphate group is 5' of the deoxyribose) .
  • this motif is unmethylated, this is surprisingly not the case for the ODNs according to the present invention, wherein e.g.
  • 2-methyl-deoxyinosine or 5-methyl-deoxycytosine residues have no general negative effect on immunostimulatory properties of the ODNs according to the present invention.
  • groups may be present at the 2-site of the ribose group, such as e.g. -F, -NH 2 , -CH , especially -CH .
  • -OH and SH groups are excluded for the I-ODNs according to the present invention to be present on the 2 '-site of the ribose, especially the ribose residue for the inosine NMP.
  • the length of the ODNs according to the present invention is in the range of the standard ODNs used according to the prior art. Therefore molecules with a total length under 4 and above 150 show gradually decreasing immunostimulatory potential.
  • Preferred ODNs contain between 10 and 60, especially between 15 and 40 bases (nucleosides) , implying that a + b in formula I is between 10 and 60, preferably between 15 and 40 in these preferred embodiments .
  • ribonucleic acid molecules containing inosine and cytidine described to be immunostimulatory in the prior art have been large and relatively undefined polynucleic acids with molecular weights far above 200,000 (a commercially available poly- inosinic-polycytidylic acid from Sigma Chemicals has a molecular weight ranging from 220,000 to 460,000 (at least 500-1000 C+I residues) .
  • the molecules according to the present invention are DNA molecules of much shorter length with a well defined length and composition, being highly reproducible in products.
  • the deoxyinosine containing NMP of the I-ODNs according to formula I is a monothiophosphate with one to four sulfur atoms and that also further NMPs, especially all further NMPs, are present as nucleoside monothiophosphates , because such ODNs display higher nuclease resistance (it is clear for the present invention that the "mono" in the "monothiophosphates" relates to the phosphate, i.e. that one phosphate group (one phosphor atom) is present in each NMP) .
  • at least one of X 1 and X2 is S and at least one of X3 and X4 is 0 in the
  • NMPs according to the present invention.
  • X and X are 0.
  • X may be (due to synthesis of the NMP) derived e.g. from the phosphate group or from the 3 '-group of the NMP-ribose) .
  • the ODNs according to the present invention contain the sequence hhh wdi dhh h nhh hhh wdi hhh hhh hhh wn, nhh wdi din hhh hdi ndi nh, nhh hhh wdi dhh hhh hhh wn or nhh wdi did hhh hdi ddi dh, wherein any n is a 2 '-deoxynucleoside monophosphate or monothiophosphate, selected from the group consisting of deoxyadenosine-, deoxyguanosine-, deoxycytosine- or deoxythymidine-monophosphate or -monothiophosphate, any h is a 2 ' -deoxynucleoside monophosphate or monothiophosphate, selected from the group consisting of deoxyadenosine-, deoxycytosine- or deoxythymidine-mono
  • a specific motif (such as CpG or a palindrome) is not necessary for the I-ODNs according to the present invention.
  • ODNs containing a CI motif are preferred so that in a preferred embodiment the ODN according to formula I contains at least one 2 'deoxycytosine-monophosphate or -monothiophosphate 3 '-adjacent to a 2 '-deoxyinosine-monophosphate or -monothiophosphate to form such a 5'-CI 3 '-motif.
  • Preferred ODNs according to the present invention contain one or more of the sequence
  • gacitt, iacitt, gaictt, iaictt wherein a is deoxyadenosine-monophosphate or -monothiophosphate, g is deoxyguanosine-monophosphate or -monothiophosphate, i is deoxyinosine-monophosphate or -monothiophosphate, c is deoxycytosine-monophosphate or -monothiophosphate and t is deoxythymidine-monophosphate or -monothiophosphate.
  • the I-ODNs according to the present invention are especially suitable for application in the pharmaceutical field, e.g. to be applied as a medicine to an animal or to humans . They are specifically adapted to act as an immunostimulatory agent, especially in or together with vaccine compositions.
  • the present invention also relates to a pharmaceutical composition comprising an ODN according to the present invention.
  • a preferred pharmaceutical composition according to the present invention is a vaccine
  • this composition should contain an antigen besides the ODN according to the present invention.
  • the potential of this antigen to raise a. protection/immune response of the vaccinated individual is strongly increased by combining it with the ODNs according to the present invention, especially due to their immunostimulatory activity.
  • a vaccine can contain a whole variety of different antigens. Examples of antigens are whole-killed organisms such as inactivated viruses or bacteria, fungi, protozoa or even cancer cells. Antigens may also consist of subfractions of these organisms/tissues, of proteins, or, in their most simple form, of peptides.
  • Antigens can also be recognised by the immune system in form of glycosy- lated proteins or peptides and may also be or contain polysaccha- rides or lipids.
  • Short peptides can be used since for example cytotoxic T cells (CTL) recognize antigens in form of short usually 8-11 amino acids long peptides in conjunction with major histocompatibility complex (MHC) (Rammensee et al . , Immunogenet- ics 41, (1995), 178-228).
  • CTL cytotoxic T cells
  • MHC major histocompatibility complex
  • B cells recognize longer peptides starting at around 15 amino acids (Harrow et al, Cold Spring Harbor: Cold Spring Harbor Laboratory, (1988)).
  • T cell epitopes the three dimensional structure of B cell antigens may also be important for recognition by antibodies .
  • adjuvants are helpful to trigger immune cascades that involve all cells of the immune system necessary.
  • adjuvants are acting, but are not restricted in their mode of action, on so-called antigen presenting cells (APCs) . These cells usually first encounter the antigen (s) followed by presentation of processed or unmodified antigen to immune effector. Intermediate cell types may also be involved. Only effector cells with the appropriate specificity are activated in a productive immune response.
  • the adjuvant may also locally retain antigens and co-injected other factors.
  • the adjuvant may act as a chemoattractant for other immune cells or may act locally and/or systemically as a stimulating agent for the immune system.
  • T cell epitopes are used as antigens .
  • a combination of T cell epitopes and B cell epitopes may also be preferred.
  • antigens to be used in the present compositions are not critical. Also mixtures of different antigens are of course possible to be used according to the present invention. Preferably, proteins or peptides derived from a viral or a bacterial pathogen or from fungi or parasites are used as such antigens (including derivatized antigens or glycosylated ' or lipidated antigens or polysaccharides or lipids) . Another preferred source of antigens are tumor antigens .
  • Preferred pathogens are selected from human immunodeficiency virus (HIV) , hepatitis A and B viruses, hepatitis C virus (HCV) , rous sarcoma virus (RSV) , Epstein Barr virus (EBV) Influenza virus, Rotavirus, Staphylococcus aureus, Chlamydia pneumonias, Chlamydia trachomatis, Mycobacterium tuberculosis, Streptococcus pneumonias, Bacillus anthracis, Vibrio cholerae, Plasmodium sp. (Pi. falciparum, Pi. vivax, etc.), As- pergillus sp . or Candida albicans .
  • HCV human immunodeficiency virus
  • HCV hepatitis A and B viruses
  • HCV hepatitis C virus
  • RSV rous sarcoma virus
  • EBV Epstein Barr virus
  • Influenza virus Influenza virus
  • Antigens may also be molecules expressed by cancer cells (tumor antigens) .
  • the derivation process may include the purification of a specific protein from the pathogen/cancer cells, the inactivation of the pathogen as well as the proteolytic or chemical derivatization or stabilisation of such a protein.
  • tumor antigens cancer vaccines
  • autoimmune antigens may be used in the pharmaceutical composition according to the present invention. With such compositions a tumor vaccination or a treatment for autoimmume diseases may be performed.
  • peptide antigens In the case of peptide antigens the use of peptide mimitopes/ago- nists/superagonists/antagonists or peptides changed in certain positions without affecting the immunologic properties or non- peptide mimitopes/agonists/superagonists/antagonists (reviewed in Sparbier and Walden, 1999) is included in the current invention.
  • Peptide antigens may also contain elongations either at the carboxy or at the amino terminus of the peptide antigen facilitating interaction with the polycationic compound(s) or the immunostimulatory compound(s) .
  • peptide antagonists may be applied for the treatment of autoimmune diseases.
  • Antigens may also be derivatized to include molecules enhancing antigen presentation and targeting of antigens to antigen presenting cells.
  • the pharmaceutical composition serves to confer tolerance to proteins or protein fragments and peptides which are involved in autoimmune diseases .
  • Antigens used in this embodiments serve to tolerize the immune system or down- regulate immune responses against epitopes involved in autoimmune processes .
  • the pharmaceutical composition according to the present invention especially in the form of a vaccine, further comprises a polycationic polymer, preferably a polycationic peptide, especially polyarginine, polylysine or an antimicrobial peptide.
  • the polycationic compound (s) to be used according to the present invention may be any polycationic compound which shows the characteristic effect according to the WO 97/30721.
  • Preferred polycationic compounds are selected from basic polypeptides, organic polycations, basic polyaminoacids or mixtures thereof. These polyaminoacids should have a. chain length of at least 4 amino acid residues (see: Tuftsin as described in Goldman et al (1983)).
  • substances containing peptidic bounds like polylysine, polyarginine and polypeptides containing more than 20%, especially more than 50% of basic amino acids in a range of more than 8, especially more than 20, amino acid residues or mixtures thereof.
  • polypeptides e.g. polyethyleneimine
  • WO 99/38528 e.g. polyethyleneimine
  • these polypeptides contain between 20 and 500 amino acid residues, especially between 30 and 200 residues.
  • polycationic compounds may be produced chemically or recom- binantly or may be derived from natural sources .
  • Cationic (poly) eptides may also be polycationic anti-bacterial microbial peptides with properties as reviewed in (Ganz and Le- hrer, 1999; Hancock, 1999). These (poly)peptides may be of pro- karyotic or animal or plant origin or may be produced chemically or recombinantly (Andreu and Rivas, 1998; Ganz and Lehrer, 1999; Simmaco et al . , 1998). Peptides may also belong to the class of defensins (Ganz, 1999; Ganz and Lehrer, 1999) . Sequences of such peptides can be, for example, be found in the Antimicrobial Sequences Database under the following internet address : http: //www.bbcm.univ. trieste.it/-tossi/pa ⁇ l .html
  • Such host defense peptides or defensives are also a preferred form of the polycationic polymer according to the present invention.
  • a compound allowing as an end product activation (or down-regulation) of the adaptive immune system, preferably mediated by APCs (including dendritic cells) is used as polycationic polymer.
  • cathelicidin derived antimicrobial peptides or derivatives thereof are especially preferred for use as polycationic substance in the present invention.
  • antimicrobial peptides derived from mammal cathelicidin preferably from human, bovine or mouse, or neuroac- tive compounds, such as (human) growth hormone.
  • Polycationic compound's derived from natural sources include HIV- REV or HIV-TAT (derived cationic peptides, antennapedia peptides, chitosan or other derivatives of chitin) or other peptides derived from these peptides or proteins by biochemical or recombi- nant production.
  • Other preferred polycationic compounds are cathelin or related or derived substances from cathelin.
  • mouse cathelin is a peptide which has the amino acid sequence NH -RLAGLLRKGGEKIGEKLKKIGOKIKNFFQKLVPQPE-COOH.
  • Related or derived cathelin substances contain the whole or parts of the cathelin sequence with at least 15-20 amino acid residues.
  • Derivations may include the substitution or modification of the natural amino acids by amino acids which are not among the 20 standard amino acids. Moreover, further cationic residues may be introduced into such cathelin molecules . These cathelin molecules are preferred to be combined with the antigen and the immunogenic ODN according to the present invention. However, these cathelin molecules surprisingly have turned out to be also effective as an adjuvant for a antigen without the addition of further adjuvants. It is therefore possible to use such cathelin molecules as efficient adjuvants in vaccine formulations with or without further immunactivating substances.
  • Another preferred polycationic substance to be used according to the present invention is a synthetic peptide containing at least 2 KLK-motifs separated by a linker of 3 to 7 hydrophobic amino acids (A 1789/2000, incorporated herein by reference) .
  • B and E in formula I are common groups for 5' and/or 3' ends of nucleic acid molecules .
  • Examples for such groups are readily available for the skilled man in the art (see e.g. "Oligonucleotides and Analogues - A Practical Approach” (1991) , ed. Eckstein, Oxford University Press) .
  • B and/or E are preferably selected independently from -H, -CH , -COCH , -OH, -CHO, a phosphate, thiophosphate, sulfate or a thiosulfate group, or a phosphoalkylgroup, especially with an alkyl length of C 1-C6 and/or with a terminal amino group (the amino group may e.g. be used for further labelling of the I-ODNs according to the present invention, e.g. -P0 (CH ) -NH or -PO - (CH 2) n-NH-Label) .
  • B Especially preferred as B are nucleosides, espe- cially the 2 'deoxynucleotides mentioned above (i.e. without the phosphate or thiophosphate group) .
  • these groups may also contain linker groups to other molecules, especially carrier molecules or labels .
  • these surfaces, particles, labels, etc. are then also part of the B and/or E groups .
  • the pharmaceutical composition according to the present invention may further comprise further active ingredients (pharmaceutically active substances), especially substances which are usable in a vaccine connection.
  • further active ingredients are cytokines, antiinflammatory substances, antimicrobial substances or combinations thereof.
  • composition according to the present invention may further contain auxiliary substances, especially a pharmaceutically acceptable carrier, buffer substances, stabilizers or combinations thereof.
  • the pharmaceutical composition according to the present invention preferably contains one or more ODNs according to the present invention, preferably 1 pg to 10 g, preferably 1 ng to 1 g, more preferred 100 ng to 10 mg, especially 10 mg to 1 mg.
  • the antigen as well as the polycationic polymer may be applied in similar dosages, a range of 1 to 10,000 mg antigen and 0.1 to 1,000 mg polycation per vaccination is preferred.
  • the present compositions may be applied to a patient, e.g. a vaccination candidate, in efficient amounts e.g. by weekly, biweekly or monthly intervals . Patients to be treated with the present compositions may also be vaccinated repeatedly or only once.
  • a preferred use of the present invention is the active immunisation, especially of humans or animals without protection against the specific antigen.
  • the route of application for the present composition is not critical, e.g. subcutaneous, intramuscular, intradermal or trans- dermal injection is suitable as well as oral uptake.
  • the present invention is therefore also directed to a kit comprising a composition containing the antigen and the polycationic polymer as one component and a composition containing dhe immunostimulating or chemotactic substance as a second component.
  • the components may be applied at the same site or time, however, an application at different sites or at a different time or for a different time period is also possible. It is also possible to vary the systemic or local applications of the composition or the components, respectively.
  • Fig. 1 shows the immune response against the ovalbumin-derived ginine (pR 60) and deoxyinosine I-containing oligodeoxynucleo- tides (I-ODN) or CpG 1668. Mice were injected into the hind footpads with mixtures as indicated. Four days later draining lymph node cells were ex vivo stimulated with OVAforce 25 c discipline7—2 n 6 r 4. The number of IFN-g-producing cells was determined 24 hours later using an ELISPOT assay. Results are expressed as the number of spots/lxlO 6 lymph node cells .
  • Fig. 2 shows the induction of systemic TNF-a production after the injection of OVA 257 _ 264 / poly-L-arginine (pR 60) and I-containing oligodeoxynucleotides (I-ODN) or CpG 1668. Mice were injected into the hind footpads with mixtures as indicated. One hour after injection blood was taken from the tail vein and serum was prepared. The concentration of TNF-a in the sera was determined using an ELISA.
  • Fig. 3 shows the immune response against the Ovalbumin-derived p ⁇ ep ⁇ tide OVA257-_264 after the inj-"ection of OVA justify25_ employ7- discipline26.
  • Mice were injected into the hind footpads with mixtures as indicated. Four days later, draining lymph node cells were ex vivo stimulated with OVA justify 25_ grasp7— haul264.
  • Fig. 4 shows the induction of systemic TNF-a production after the injection of OVA , poly-L-arginine (pR 60) and I-containing oligodeoxynucleotides (I-ODN), GpC or CpG 1668. Mice were injected into the hind footpads with mixtures as indicated. One hour after injection blood was taken from the tail vein and serum was prepared. The concentration of TNF-a and IL-6 in the sera was determined using cytokin-specific ELISAs.
  • Fig. 5 shows the immune response against the Ovalbumin-derived peptide OVA257—264 after the injection of TRP-2 , poly-L-arginine,
  • mice were injected into the hind footpads with mixtures as indicated. Four days later, draining lymph node cells were ex vivo stimu- . lated with TRP-2, an irrelevant peptide OVA 257— alone264 ' or pR 60. The number of IFN-g producing cells was determined 24 hours later using an ELISPOT assay. Results are expressed as the number of spots/lxlO 6 lymph node cells with standard deviation of triplicates .
  • Fig. 6 shows the combined injection of I-ODN and poly-L-arginine (pR 60) together with a Melanoma-derived peptide.
  • Fig. 7 shows that the combined injection of I-ODN and pR 60 together with a Melanoma-derived peptide reduces the induction of systemic TNF- ⁇ and IL-6.
  • Fig. 8 shows the combined injection of a random 10-mer I-ODN and pR 60 together with a Melanoma-derived peptide.
  • Fig. 9 shows that the combined application of ovalbumin (OVA) with oligo-dIC 2 6-mer and pR enhances production of OVA-specific IgG antibodies.
  • OVA ovalbumin
  • Mice were injected subcutaneously into the footpad with mixtures as indicated.
  • sera were collected and screened by ELISA for OVA-specific IgG2a (A) and IgGl (B) antibodies. The results are shown as the antibody titer.
  • thiophosphate-substituted ODNs (with thiophosphate residues substituting for phosphate, hereafter called "thiophosphate substituted oligodeoxynucleotides") were used since such ODNs display higher nuclease resistance (Ballas et al., 1996; Krieg et al . , 1995; Parronchi et al . , 1999).
  • Poly-L-arginine60 (pR60) Poly-L-arginine with an average degree of polymerization of 60 arginine residues; SIGMA chemicals
  • mice On day 0 mice were injected into each hind footpad with a total volume of 100 ml (50 ml per footpad) containing the above mentioned compounds. Animals, were sacrificed 4 days after injection and popliteal lymph nodes were harvested. Lymph nodes were passed through a 70 mm cell strainer and washed twice with DMEM medium (GIBCO BRL) containing 5% fetal calf serum (FCS, SIGMA chemicals) . Cells were adjusted to 3xl0 6 cells/ml in DMEM/5%/FCS. An IFN-g ELISPOT assay was carried out in triplicates as described (Miyahira et al . , 1995). This method is.
  • Lymphocytes were stimulated ex vivo with medium background-control, OVA flood 25_ exert7— fashion264-peptide or Concanavalin A (Con A). Spots representing single IFN-g producing T cells were counted and the number of background spots was substracted from all samples. The high number of spots detected after the stimulation with Con A (data not shown) indicate a good condition of the used lymphocytes . For each experimental group of mice the number of spots/lxlO 6 cells are illustrated in Figure 1.
  • Peptide OVA 257 2 relieve64-Peptide (SIINFEKL) , a MHC class I
  • Poly-L-arginine 60 (pR60) Poly-L-arginine with an average degree of polymerization of 60 arginine residues; SIGMA chemicals Dose: lOO ⁇ g/mouse
  • CpG motif tec at ⁇ ac ⁇ ttc ctg atg ct, were synthesized by NAPS GmbH, G ⁇ ttingen.
  • mice On day 0 mice were injected into each hind footpad with a total volume of lOO ⁇ l (50 ⁇ l per footpad) containing the above mentioned compounds. Animals were sacrificed 4 days after injection and popliteal lymph nodes were harvested. Lymph nodes were passed through a 70um cell strainer and washed twice with DMEM medium (GIBCO BRL) containing 5% fetal calf serum (FCS, SIGMA chemicals) . Cells were adjusted to 3xl0 6 cells/ml in DMEM/5%FCS. An IFN-g ELISPOT assay was carried out in triplicates as described (Miyahira et al., 1995). This method is a widely used procedure allowing the quantification of antigen-specific T cells .
  • Lymphocytes were stimulated ex vivo in triplicates with medium (background) , OVA 257264 -peptide, an irrelevant peptide TRP- 2 181—188 (murine tyrosinase related protein-2 , VYDFFVWL) , pR 60 and
  • Concanavalin A (Con A) . Spots representing single IFN-g producing T cells were counted and the number of background spots was substracted from all samples. The high number of spots detected after the stimulation with Con A (data not shown) indicate a good condition of the used lymphocytes . For each experimental group of mice the number of spots/lxlO 6 cells are illustrated in Figure 3, the standard deviation of ex vivo-stimulated triplicates are given. One hour after injection blood was taken from the tail vein and serum was prepared to determine the induction of systemic TNF-a and IL-6 using cytokine-specific ELISAs ( Figure 4) .
  • Example 3 Example 3 :
  • Poly-L-arginine 60 (pR60) Poly-L-arginine with an average degree of polymerization of 60 arginine residues; SIGMA chemicals Dose: lOO ⁇ g/mouse
  • CpG motif tec at ⁇ ac ⁇ ttc ctg atg ct, were synthesized by NAPS GmbH, G ⁇ ttingen.
  • TRP-2 + wdi + pR 60 10.TRP-2 + wdidin + pR 60 ll.TRP-2 + wdid + pR 60 12.TRP-2 + wdidid + pR 60
  • mice On day 0 mice were injected into each hind footpad with a total volume of lOO ⁇ l (50 ⁇ l per footpad) containing the above mentioned compounds. Animals were sacrificed 4 days after injection and popliteal lymph nodes were harvested. Lymph nodes were passed through a 70 ⁇ m cell strainer and washed twice with DMEM medium (GIBCO BRL) containing 5% fetal calf serum (FCS, SIGMA chemicals) . Cells were adjusted to 3xl0 6 cells/ml in DMEM/5%FCS. An IFN-g ELISPOT assay was carried out in triplicates as described (Miyahira et al . , 1995).
  • Lymphocytes were stimulated ex vivo in triplicates with medium (background) , TRP-2-peptide, an irrelevant 0VA 257 _ 264 _ Pep- tide, pR 60 and Concanavalin A (Con A) . Spots representing single IFN-g producing T cells were counted and the number of background spots was substracted from all samples. The high number of spots detected after the stimulation with Con A (data not shown) indicate a good condition of the used lymphocytes . For each experimental group of mice the number of spots/lxlO 6 cells are illustrated in Figure 5, the standard deviation of ex vivo-stimu- lated triplicates are given.
  • mice On day 0 mice were injected into each hind footpad with a total volume of 100 ⁇ l (50 ⁇ l per footpad) containing the above mentioned compounds. Animals were sacrificed 4 days after injection and popliteal lymph nodes were harvested. Lymph nodes were passed through a 70 ⁇ m cell strainer and washed twice with DMEM medium (GIBCO BRL) containing 5% fetal calf serum (FCS, SIGMA chemicals) . Cells were adjusted to 3x10 cells/ml in DMEM/5%/FCS. An IFN- ⁇ ELISPOT assay was carried out in triplicates as described (Miyahira et al . , 1995).
  • Lymphocytes were stimulated ex vivo in triplicates with medium background-control, TRP-2i8i-i88-peptide, an irrelevant OVA25 7 _254 ⁇ peptide and Concanavalin A (Con A) . Spots representing single IFN- ⁇ producing T cells were counted and the number of background spots was substracted from all samples . The high number of spots detected after the stimulation with Con A (data not shown) indicate a good condition of the used lymphocytes . For each experimental group of mice the number of spots/lxlO cells are illustrated in Figure 6, the standard deviation of ex vivo- stimulated triplicates are given.
  • mice On day 0 mice were injected into each hind footpad with a total volume of 100 ⁇ l (50 ⁇ l per footpad) containing the above mentioned compounds. Animals were sacrificed 4 days after injection and popliteal lymph nodes were harvested. Lymph nodes were passed through a 70 ⁇ m cell strainer and washed twice with DMEM medium (GIBCO BRL) containing 5% fetal calf serum (FCS, SIGMA chemicals). Cells were adjusted to 3xl0 6 cells/ml in DMEM/5%/FCS. An IFN- ⁇ ELISPOT assay was carried out in triplicates as described (Miyahira et al . , 1995) .
  • This method is a widely used procedure allowing the quantification of antigen-specific T cells .
  • Lymphocytes were stimulated ex vivo in triplicates with medium background-control, TRP-2 ⁇ 8 ⁇ -i88-peptide, an irrelevant OVA 2 5 7 _2g4-peptide and Concanavalin A (Con A) .
  • Spots representing single IFN- ⁇ producing T cells were counted and the number of background spots was substracted from all samples .
  • the high number of spots detected after the stimulation with Con A indicate a good condition of the used lymphocytes.
  • the number of spots/lxl0 D cells are illustrated in Figure 8, the standard deviation of ex vivo- stimulated triplicates are given.
  • Poly-L-arginine60 (pR60] Poly-L-arginine with an average degree of polymerization of 60 arginine residues; SIGMA chemicals
  • I-ODN 2 thiophosphate substituted ODNs containing deoxyinosine tec atg aci ttc ctg atg ct, were synthesized by NAPS GmbH, G ⁇ ttingen. Dose: 5nmol/mouse
  • oligo-deoxyIC 26 -mer and poly-L-arginine (pR) enhances the ovalbumin (OVA) -specific humoral response.
  • Ovalbumin Ovalbumin from chicken egg, grade V, SIGMA Chemicals, A-5503, Lot 54H7070 Dose: 50 ⁇ g/mouse
  • Poly-L-arginine (pR) Poly-L-arginine with an average degree of polymerization of 60 arginine residues; SIGMA Chemicals, P-4663, Lot 68H5903 Dose: 100 ⁇ g/mouse
  • mice were injected into each hind footpad with a total volume of lOO ⁇ l (50 ⁇ l per footpad) containing the above listed ⁇ compounds.
  • serum was collected and screened by ELISA for the presence of OVA-specific antibodies.
  • CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol 160, 870-876.
  • CpG DNA A potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci U S A 96, 9305-9310.
  • Polyinosinic acid polycytidylic acid promotes T helper type 1-specific immune responses by stimulating macrophage production of interferon-a and interleukin-12.
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US8568742B2 (en) 2013-10-29
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HUP0301229A2 (hu) 2003-08-28
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US9492537B2 (en) 2016-11-15
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