WO2003066680A2 - Antigenes pour l'immunocontraception - Google Patents

Antigenes pour l'immunocontraception Download PDF

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Publication number
WO2003066680A2
WO2003066680A2 PCT/CA2003/000177 CA0300177W WO03066680A2 WO 2003066680 A2 WO2003066680 A2 WO 2003066680A2 CA 0300177 W CA0300177 W CA 0300177W WO 03066680 A2 WO03066680 A2 WO 03066680A2
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WIPO (PCT)
Prior art keywords
mammal
seq
zona pellucida
polypeptide
czp
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PCT/CA2003/000177
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English (en)
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WO2003066680A3 (fr
Inventor
Robert George Brown
Marc Mansour
Bill Pohajdak
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Immunovaccine Technologies Inc.
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Priority to AU2003244428A priority Critical patent/AU2003244428A1/en
Priority to EP03737229A priority patent/EP1474447A2/fr
Priority to US10/636,620 priority patent/US7056515B2/en
Publication of WO2003066680A2 publication Critical patent/WO2003066680A2/fr
Publication of WO2003066680A3 publication Critical patent/WO2003066680A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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

Definitions

  • the present invention relates to the field of immunology, in particular, to immunocontraceptive vaccines.
  • IC immunocontraception
  • IC can be a humane means of reducing fertility in domestic, feral and wild mammals (Oogjes, 1997), and several potential IC targets exist.
  • GnRH gonadotrophin-releasing hormone
  • a vaccine that used gonadotrophin-releasing hormone (GnRH) as antigen depressed ovarian activity in horses for one breeding season (Bradley et al . , 1999).
  • GnRH gonadotrophin-releasing hormone
  • the difficulty with GnRH directed vaccines is that there is a potential for endocrine dysfunction (Muller et al . , 1997) .
  • ZP Zona pellucida
  • This structure is an ideal candidate for a contraceptive target, since altering its structure can prevent pregnancy.
  • ZP immunisation has been effective in lowering fertilisation rates of many mammals (Willis et al . , 1994; Kirkpatrick et al . , 1996; 1996; Brown et al . , 1997a, b; Harris et al . , 2000) .
  • pig zona pellucida is an effective immunocontraceptive (although requires multiple boosters) in domestic cats (Ivanova et al . , 1995; Bradley et al . , 1999) .
  • Porcine zona pellucida has also been used in liposome-based immunocontraceptive vaccines for reducing fertility of certain mammals by 90-100% with a multi-year efficacy (Brown et al . , 2001).
  • use of pZP in such a liposome-based vaccine as a single administration vaccine for cats is ineffective in cats.
  • an immunocontraceptive vaccine for cats and/or dogs comprising a zona pellucida polypeptide, and/or a variant thereof, from a carnivorous mammal and a physiologically acceptable auxiliary.
  • a method for reducing fertility in cats and/or dogs comprising administering to a cat or a dog an immunocontraceptive vaccine comprising a zona pellucida polypeptide, and/or a variant thereof, from a carnivorous mammal and a physiologically acceptable auxiliary.
  • a zona pellucida polypeptide and/or a variant thereof, from a carnivorous mammal for reducing fertility in cats and/or dogs or for preparing a medicament for reducing fertility in cats and/or dogs.
  • composition comprising the polypeptide described above and a carrier or diluent suitable for use in a vaccine.
  • kits for inducing L5 infertility in a mammal comprising the polypeptide described above and instructions for its use in eliciting an immune response against native zona pellucida in a mammal.
  • a method for inducing anti-ZPB antibodies in a mammal comprising 20 administering to the mammal at least one polypeptide described above, wherein said administering induces production of an antibody that binds mammalian zona pellucida.
  • Figure 1 is a graph showing the production of anti-SIZP antibodies by rabbits immunised with porcine zona pellucida (pZP) or cat zona pellucida (cZP) encapsulated in liposomes with either FCA or alum adjuvant as a single administration delivery system.
  • pZP porcine zona pellucida
  • cZP cat zona pellucida
  • Figure 2 is a Western blot of a gel electrophoresis of dZP (lanes A and B) , feZP (lanes C and D) , cZP (lane E) and pZP (lanes F and G) probed with rabbit anti-cZP antibodies showing the cross-reactivity of rabbit anti-cZP antibodies to cZP, dZP, pZP, and feZP.
  • Figure 3 is a Western blot of a gel electrophoresis of mZP (lanes A, B, and C) probed with rabbit anti-pZP antibodies (lane A) and rabbit anti-cZP antibodies (lanes B and C) showing the cross-reactivity of rabbit anti-cZP and anti-pZP antibodies to mZP.
  • Figure 4 shows an alignment of a number of mammalian zona pellucida sequences.
  • Figure 5 shows alignments of specific zona pellucida sequences between various species.
  • Figure 6 is a schematic depiction of the alignment of the zona pellucida sequences.
  • ZP Zona pellucida
  • IC immunocontraception
  • ZP antigens from carnivorous mammals are particularly useful in preparing immunocontraceptive vaccine that are capable of producing immune responses in cats and/or dogs.
  • ZPB is particularly useful as the antigen.
  • the carnivorous mammals may be selected from the group consisting of cat (e.g. Fells catus) , dog (e.g. Canis familiaris) , ferret (e.g. Mustela putorius furo) , and mink (e.g. Mustela viso ⁇ ) .
  • cat ZP (cZP) , dog ZP (dZP) , ferret ZP (feZP) , mink ZP (mZP) and/or variants thereof are particularly useful as antigens in the immunocontraceptive vaccine.
  • cat ZPB cZPB
  • dog ZPB dZPB
  • ferret ZPB feZPB
  • mink ZPB mZPB
  • variants are preferred.
  • ⁇ ariants' means recombinant or denatured proteins or peptides, or fragments thereof, or fragments of native ZP, which are capable of producing the desired immune response in cats and/or dogs. Substitutions, additions and/or deletions of native or recombinant ZP are encompassed by variants. Variants are generally at least 50% homologous to native ZP.
  • Variants having homology of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% to the native ZP are also particularly contemplated within the scope of the invention.
  • Fragments of native, recombinant or denatured ZP proteins or peptides are generally at least 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 44, 46, 48 or 50 amino acids in length.
  • such fragments include amino acids
  • VSTTQSPGTSRPPTPASRVTPQ amino acid numbers 29 to 50 of cat zona pellucida
  • PRNPPDQALVSSLSPS amino acid numbers 79 to 94 of cat zona pellucida
  • VRTTQSPQMLRTPAPPSGVTPQ (from SEQ ID NO 6)
  • PTLLSSLSYSPDQNR (from SEQ ID NO 8) .
  • polypeptides of the invention include any combination of the above fragments and their consensus sequences.
  • isolated polynucleotide is defined as a polynucleotide removed from the environment in which it naturally occurs.
  • a naturally-occurring DNA molecule present in the genome of a living bacteria or as part of a gene bank is not isolated, but the same molecule separated from the remaining part of the bacterial genome, as a result of, e . g. , a cloning event (amplification), is isolated.
  • an isolated DNA molecule is free from DNA regions ( e . g. , coding regions) with which it is immediately contiguous at the 5' or 3 ' end, in the naturally occurring genome.
  • Such isolated polynucleotides may be part of a vector or a composition and still be defined as isolated in that such a vector or composition is not part of the natural environment of such polynucleotide.
  • the present invention includes amino acid sequences which are homologous to SEQ ID NOS : 2 , 4 , 6 and 8 , and the fragments above.
  • homologous amino acid sequence is any polypeptide which is encoded, in whole or in part, by a nucleic acid sequence which hybridizes at 25-35°C below critical melting temperature (Tm) , to any portion of the nucleic acid sequence of SEQ ID NOS: 1, 3, 5 or 7.
  • Tm critical melting temperature
  • a homologous amino acid sequence may be one that differs from an amino acid sequence shown in SEQ ID NOS: 2, 4, 6 or 8 by one or more conservative amino acid substitutions .
  • homologous amino acid sequences include sequences that are identical or substantially identical to SEQ ID NOS: 2, 4, 6 or 8.
  • amino acid sequence substantially identical is meant a sequence that is at least 90%, preferably 95%, more preferably 97%, and most preferably 99% identical to an amino acid sequence of reference and that preferably differs from the sequence of reference by a majority of conservative amino acid substitutions.
  • amino acids having uncharged polar side chains such as asparagine, glutamine, serine, threonine, and tyrosine
  • amino acids having basic side chains such as lysine, arginine, and histidine
  • amino acids having acidic side chains such as aspartic acid and gluta ic acid
  • amino acids having nonpolar side chains such as glycine, alanine, valine, leucine, ' isoleucine, proline, phenylalanine, methionine, tryptophan, and cysteine .
  • sequence analysis software such as Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, WI 53705. Amino acid sequences are aligned to maximize identity. Gaps may be artificially introduced into the sequence to attain proper alignment. Once the optimal alignment has been set up, the degree of homology is established by recording all of the positions in which the amino acids of both sequences are identical, relative to the total number of positions.
  • homologous polynucleotide sequences are defined in a similar way.
  • a homologous sequence is one that is at least 45%, more preferably 50%, 55%, 60%, 65%, 70%, 75%, 80%, and even more preferably 85%, 87%, 90%, 93%, 96% and most preferably 99% identical to SEQ ID NOS: 1, 3, 5 or 7.
  • a fusion polypeptide is one that contains a polypeptide or a polypeptide derivative of the invention fused at the N- or C-terminal end to any other polypeptide.
  • a simple way to obtain such a fusion polypeptide is by translation of an in-frame fusion of the polynucleotide sequences, i.e., a hybrid gene.
  • the hybrid gene encoding the fusion polypeptide is inserted into an expression vector which is used to transform or transfect a host cell.
  • the polynucleotide sequence encoding the polypeptide or polypeptide derivative is inserted into an expression vector in which the polynucleotide encoding the peptide tail is •• already present.
  • a second aspect of the invention encompasses (i) an expression cassette containing a DNA molecule of the invention placed under the control of the elements required for expression, in particular under the control of an appropriate promoter; (ii) an expression vector containing an expression cassette of the invention; (iii) a procaryotic or eucaryotic cell transformed or transfected with an expression cassette and/or vector of the invention, as well as (iv) a.process for producing a .
  • polypeptide or polypeptide derivative encoded by a polynucleotide of the invention which involves culturing a procaryotic or eucaryotic cell transformed or transfected with an expression cassette and/or vector of the invention, under conditions that allow expression of the DNA molecule of the invention and, recovering the encoded polypeptide or polypeptide derivative from the cell culture.
  • a recombinant expression system is selected from procaryotic and eucaryotic hosts.
  • Eucaryotic hosts include yeast cells (e . g. , Sac cha omyces cerevisiae or Pichia pastoris) , mammalian cells ( e . g. , COS1, NIH3T3, or JEG3 cells), arthropods cells (e.g., Spodoptera frugiperda (SF9) cells), and plant cells.
  • a preferred expression system is a procaryotic host such as E. coli .
  • Bacterial and eucaryotic cells are available from a number of different sources including commercial sources to those skilled in the art, e. g. , the American Type Culture Collection (ATCC; Rockville, Maryland) . Commercial sources of cells used for recombinant protein expression also provide -instructions for usage of the cells.
  • Antigens of the present invention may be formulated into vaccines in a number of ways. Methods of 5 formulating vaccines in general are well known to those skilled in the art (for example, see Harlow et al . , 1988 the disclosure of which is herein incorporated by reference) . Ivanova et al . , 1995; Bradley et al . , 1999; and Brown et al . , 2001, the disclosures of which are herein incorporated
  • Immunocontraceptive vaccines comprising the ZP antigens of the present invention may be formulated as either single or multiple administration vaccines. Single administration vaccines using a system
  • L5 such as that described in Brown et al . , 2001 are preferred.
  • the amount of ZP antigen used in a dose of the immunocontraceptive vaccine can vary depending on the source of the antigen and the size of the cat or dog. One skilled in the art will be able to determine, without undue
  • the effective amount of antigen to use in a particular application falls in the range from about 15 ⁇ g to about 2 mg per dose.
  • the range is from about 20 ⁇ g to about 2 mg per dose, more preferably from about 20 ⁇ g to about 200 ⁇ g, and
  • the amount ⁇ for a small animal is about 50 ⁇ g per dose while for a large animal it is about 100 ⁇ g per dose.
  • auxiliaries for immunocontraceptive vaccines are generally known in the art.
  • SO Auxiliaries include carriers, diluents, adjuvants and any other typical vaccine ingredients.
  • Carriers and/or diluents are generally well known in the art.
  • aqueous solutions, aqueous emulsions of an oil such as mineral oil, and non-aqueous media such as pure mineral oil may be used as carriers and/or diluents.
  • Suitable adjuvants include alum, other compounds of aluminum, Bacillus of Calmette and Guerin (BCG) , TiterMaxTM, RibiTM, Freund' s Complete Adjuvant (FCA) and a new adjuvant disclosed by the United States Department of Agriculture's (USDA) National Wildlife Research Center on their web site at http: //www. aphis .usda .gov/ws/nwrc/pzp .htm based on Johne's antigen. Alum, .other compounds of aluminum, TiterMaxTM and the new USDA adjuvant are preferred.
  • Alum is particularly preferred as the adjuvant.
  • Alum is generally considered to be any salt of aluminum, in particular, the salts of inorganic acids. Hydroxide and phosphate salts are particularly useful as adjuvants.
  • a suitable alum adjuvant is sold under the trade name, ImjectAlumTM (Pierce Chemical Company) that consists of an aqueous solution of aluminum hydroxide (45 mg/ml) and magnesium hydroxide (40 mg/ml) plus inactive stabilizers.
  • ImjectAlumTM Pierce Chemical Company
  • Alum is a particularly advantageous adjuvant since it already has regulatory approval and it is widely accepted in the art .
  • the amount of adjuvant used depends on the amount of antigen and on the type of adjuvant. One skilled in the art can readily determine the amount of adjuvant needed in a particular application.
  • a suitable quantity of ImjectAlumTM may range from 0.1 ml/dose of vaccine to 0.5 ml/dose.
  • Liposomes are another typical vaccine ingredient.-
  • Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single bilayer membrane) or multilamellar vesicles (onion-like structures characterized by multimembrane bilayers, each separated from the next by an aqueous layer. Although any liposomes may be used, including liposomes made from archaebacterial lipids, particularly useful liposomes use phospholipids and unesterified cholesterol in the liposome formulation. The cholesterol is used.
  • Phospholipids that are preferably used in the preparation of liposomes are those with at least one head group selected from the group consisting of phosphoglycerol, phosphoethanolamine, phosphoserine, phosphocholine and phosphoinositol .
  • the amount of lipid used to form liposomes depends on the antigen being used but is typically in a range from about 0.05 gram to about 0.5 gram per dose of vaccine. Preferably, the amount is about 0.1 gram per dose. When unesterified cholesterol is also used in liposome formulation, the cholesterol is used in an amount equivalent to about 10% of the amount of lipid. The preferred amount of cholesterol is about 0.01 gram per dose of vaccine. If a compound other than cholesterol is used to stabilize the liposomes, one skilled in the art can readily determine the amount needed in the formulation.
  • the vaccine composition may be formulated by: encapsulating the antigen or an antigen/adjuvant complex in liposomes to form liposome- encapsulated antigen and mixing the liposdme-encapsulated ' antigen with a carrier. If an antigen/adjuvant complex is not used in the first step, a suitable adjuvant may be added to the liposome-encapsulated antigen, to the mixture of liposome-encapsulated antigen and carrier, or to the carrier before the carrier is mixed with the liposome-encapsulated antigen. The order of the process may depend on the type of adjuvant used.
  • the adjuvant and the antigen are mixed first to form an antigen/adjuvant complex followed by encapsulation of the antigen/adjuvant complex with liposomes.
  • the resulting liposome-encapsulated antigen is then mixed with the carrier.
  • liposome- encapsulated . antigen may refer to encapsulation of the antigen alone or to the encapsulation of the antigen/adjuvant complex depending on the context.
  • the antigen may be first encapsulated in liposomes and the resulting liposome-encapsulated antigen is then mixed into the adjuvant in a carrier.
  • Liposome-encapsulated antigen may be freeze-dried before being mixed with the carrier.
  • an antigen/adjuvant complex may be encapsulated by liposomes followed by freeze-drying.
  • the antigen may be encapsulated by liposomes followed by the addition of adjuvant then freeze-drying to form a freeze-dried liposome- encapsulated antigen with external adjuvant.
  • the antigen may be encapsulated by liposomes followed by freeze-drying before the addition of adjuvant.
  • Formulation of the liposome-encapsulated antigen into a hydrophobic substance may also involve the use of an emulsifier to promote more even distribution of the liposomes in the carrier.
  • Typical emulsifiers are well known in the art and include mannide oleate (ArlacelTM A) , lecithin, TweenTM 80, SpansTM 20, 80, 83 and 85. Mannide oleate is a preferred emulsifier.
  • the emulsifier is used in an amount effective to promote even distribution of the liposomes.
  • the volume ratio (v/v) of carrier to emulsifier is in the range of about 5:1 to about 15:1 with a ratio of about 10:1 being preferred.
  • Vaccine compositions may be administered parenterally (including intramuscularly, sub-cutaneously) or rectally. Parenteral administration is preferred.
  • unit dosage forms are ampoules .
  • Techniques that deliver the vaccine by injection and by remote delivery using darts, spring loaded syringes with jab sticks, air/carbon dioxide powered rifles, Wester gun and/or BallistivetTM biobullets and retain the biological activity are particularly preferred.
  • the SIZP was encapsulated in liposomes formed using soybean L- ⁇ -lecithin (Calbiochem-Novabiochem, San Diego, CA, USA) and cholesterol (Calbiochem-Novabiochem) in a ratio of 10:1.
  • Single administration vaccines were formulated with 1 of 2 adjuvants, i.e. with Freund' s complete adjuvant (FCA) or with alum.
  • FCA Freund' s complete adjuvant
  • a single dose of the vaccine with alum contained pZP (100 ⁇ g) and alum (Imject®alum, Pierce Chemical Co., Rockford, IL, USA) encapsulated in multilamellar liposomes (0.1 g lecithin and 0.01 g cholesterol) that were suspended in saline (0.15 mL) and emulsified in mineral oil/mannide oleate (8.5:1.5, v:v, 0.25mL) .
  • Rabbits were immunised with pZP in either vaccine with FCA or vaccine with alum or with cZP in vaccine with FCA.
  • Serum samples were taken monthly to measure the production of anti-SIZP antibodies. Production of anti-SIZP antibodies was measured as described by Brown et al . (1997b) , the disclosure of which is herein incorporated by reference, using protein A/alkaline phosphatase.
  • the blots were washed 5X with TBS-TweenTM and then incubated with peroxidase labelled secondary antibody (goat anti- ' rabbit Ig, Jackson, 1:8000 in TBS-TweenTM) for 30 minutes at room temperature. Blots were then washed 5X with TBS-TweenTM and signals were detected by chemiluminescence (Santa Cruz) using X-ray film.
  • peroxidase labelled secondary antibody goat anti- ' rabbit Ig, Jackson, 1:8000 in TBS-TweenTM
  • Another row in each plate received doubling dilutions of a reference rabbit anti-pZP serum. Titers were determined using the linear portion of the titration curve and all titers are expressed as a percentage of the reference serum to control for interassay variability .
  • Rabbits immunised with pZP or cZP produced similar anti-SIZP titers 2 months post-immunisation although the anti-cZP titer was lower than the anti-pZP titers obtained with either vaccine with FCA or vaccine with alum 1 month post-immunisation (Figure 1) . This may be due to less antigen being placed in the vaccine (1/2 the content of pZP) .
  • One skilled in the art can predict that production of anti-cZP antibodies will continue to increase and yield a titer similar to the anti-pZP titers. Such titers have been shown to be immunocontraceptive in a variety of mammals.
  • Cross-reactivity can also be measured by ELISA.
  • titers of two cat anti-pZP sera were measured using pZP, the titers were 41% and 15% of the reference serum.
  • titers of the same antisera were measured using cZP, the titers were 2% and 2% of the reference serum. This indicates that antibodies raised in cats against pZP have little affinity for cZP and consequently cat oocytes.
  • the titers of two rabbit anti-cZP sera were measured using pZP, the titers were 7% and 40% of the reference serum.
  • titers of the same antisera were measured using cZP, the titers were 32% and 200% of the reference serum.
  • SEQ ID NO. 1 is the partial ferret DNA sequence that codes for the equivalent- of cat ZPB amino acid region 309-428. (Cat ZPB, including the leader sequence, is a total of 570 amino acids in length. )
  • This ferret sequence was cloned by reverse transcription/degenerate PCR method. Primers were based on multiple alignments that included ZPB sequences from cat, cow, human, possum, mouse, rat and pig ZPB. A search of GenBankTM indicates that SEQ ID NO. 1 matches best with cZPB, suggesting that feZP will have many epitopes in common with ' cZP and therefore will be effective as an antigen in a cat immunocontraceptive vaccine.
  • ferret partial amino acid sequence corresponding to the nucleotide sequence above is given by SEQ ID No. 2:
  • SEQ ID NO. 3 is the partial nucleotide sequence of Canine ZPB . ( SEQ ID NO . 3 ) :
  • the dog partial amino acid sequence corresponding to the nucleotide sequence above is given by SEQ ID NO. 4. -.
  • SEQ ID NO. 5 is another partial ferret DNA sequence that codes for SEQ ID NO 6.
  • SEQ ID NO. 7 is another partial dog DNA sequence that codes for SEQ ID NO 8.
  • GSVTRDS IFRLRVSCSYSISSNAFPVNVHVFTFPPPHSETQPGPLTLELKIAKDKHYGSY YTAGDYP WKLLRDP I YVEVS I RHRTDPHLGLLLHYCWATP SR1TPQHQPQWLMLVKGC P

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Abstract

Cette invention concerne des vaccins immunocontraceptifs comprenant un polypeptide de zone pellucide (ZP) et/ou une variante de celui-ci appartenant à un mammifère carnivore tel qu'un chat, un chien, un furet ou un vison. Ces vaccins servent à réduire la fertilité des chats et/ou des chiens.
PCT/CA2003/000177 2002-02-08 2003-02-10 Antigenes pour l'immunocontraception WO2003066680A2 (fr)

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AU2003244428A AU2003244428A1 (en) 2002-02-08 2003-02-10 Antigens for immunocontraception
EP03737229A EP1474447A2 (fr) 2002-02-08 2003-02-10 Antigenes pour l'immunocontraception
US10/636,620 US7056515B2 (en) 2002-02-08 2003-08-08 Antigens for immunocontraception

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Cited By (6)

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US6793923B2 (en) * 2000-11-07 2004-09-21 Immunovaccine Technologies, Inc. Vaccines with enhanced immune response and methods for their preparation
WO2005014816A1 (fr) * 2003-08-08 2005-02-17 Immunovaccine Technologies Inc. Antigenes pour immunocontraception
US9925142B2 (en) 2005-10-07 2018-03-27 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase as a vehicle for cancer treatment
US10105435B2 (en) 2011-10-06 2018-10-23 Immunovaccine Technologies Inc. Liposome compositions comprising an adjuvant that activates or increases the activity of TLR2 and uses thereof
US10232052B2 (en) 2007-09-27 2019-03-19 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase for delivery of polynucleotides in vivo
US11717563B2 (en) 2008-06-05 2023-08-08 Immunovaccine Technologies Inc. Compositions comprising liposomes, an antigen, a polynucleotide and a carrier comprising a continuous phase of a hydrophobic substance

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1994011019A1 (fr) * 1992-11-09 1994-05-26 Zonagen, Inc. Materiaux et procedes utiles pour l'immunocontraception

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1994011019A1 (fr) * 1992-11-09 1994-05-26 Zonagen, Inc. Materiaux et procedes utiles pour l'immunocontraception

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6793923B2 (en) * 2000-11-07 2004-09-21 Immunovaccine Technologies, Inc. Vaccines with enhanced immune response and methods for their preparation
US7824686B2 (en) 2000-11-07 2010-11-02 Immunovaccine Technologies, Inc. Vaccines with enhanced immune response and methods for their preparation
US8628937B2 (en) 2000-11-07 2014-01-14 Immunovaccine Technologies, Inc. Vaccines with enhanced immune response and methods for their preparation
US9114174B2 (en) 2000-11-07 2015-08-25 Immunovaccine Technologies Inc. Vaccines with enhanced immune response and methods for their preparation
US7056515B2 (en) 2002-02-08 2006-06-06 Immunovaccine Technologies Inc. Antigens for immunocontraception
WO2005014816A1 (fr) * 2003-08-08 2005-02-17 Immunovaccine Technologies Inc. Antigenes pour immunocontraception
US9925142B2 (en) 2005-10-07 2018-03-27 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase as a vehicle for cancer treatment
US10272042B2 (en) 2005-10-07 2019-04-30 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase as a vehicle for cancer treatment
US10232052B2 (en) 2007-09-27 2019-03-19 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase for delivery of polynucleotides in vivo
US11235069B2 (en) 2007-09-27 2022-02-01 Immunovaccine Technologies Inc. Use of liposomes in a carrier comprising a continuous hydrophobic phase for delivery of polynucleotides in vivo
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