WO2019160383A1 - Vaccin comprenant un épitope de protéine de choc thermique et utilisation associée - Google Patents

Vaccin comprenant un épitope de protéine de choc thermique et utilisation associée Download PDF

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Publication number
WO2019160383A1
WO2019160383A1 PCT/KR2019/001898 KR2019001898W WO2019160383A1 WO 2019160383 A1 WO2019160383 A1 WO 2019160383A1 KR 2019001898 W KR2019001898 W KR 2019001898W WO 2019160383 A1 WO2019160383 A1 WO 2019160383A1
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cancer
polypeptide
cell
vaccine composition
gene
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PCT/KR2019/001898
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English (en)
Korean (ko)
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박경화
강진호
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고려대학교 산학협력단
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Priority claimed from KR1020190018119A external-priority patent/KR102184377B1/ko
Application filed by 고려대학교 산학협력단 filed Critical 고려대학교 산학협력단
Priority to CN201980025974.6A priority Critical patent/CN113383006B/zh
Priority to JP2020543870A priority patent/JP7301391B2/ja
Priority to CA3091736A priority patent/CA3091736A1/fr
Priority to EP19754897.7A priority patent/EP3763727A4/fr
Publication of WO2019160383A1 publication Critical patent/WO2019160383A1/fr
Priority to US16/997,307 priority patent/US11446368B2/en
Priority to US17/885,255 priority patent/US20230084183A1/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
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to a vaccine comprising an epitope of a heat shock protein and a combination therapy thereof, and more particularly to a polypeptide which is an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2, a vaccine composition comprising the same, and the composition It relates to a method for treating or preventing cancer using.
  • Immunotherapy is a method of treating cancer using an immune response in a patient's body. This immunotherapy method can even prevent cancer.
  • Cancer immunotherapy is a method of treating cancer by activating immune cells specific to cancer by administering an antigen that causes cancer, as in the principle of vaccine, and then causing activated immune cells to specifically attack cancer in the body.
  • cancer-specific antigen is administered to the body in the absence of cancer, immune cells that are not activated are activated as cancer-specific memory immune cells, and specifically attack cancer cells when the cancer is caught.
  • Heat shock protein 90 is an ATPase-dependent molecular chaperone required for protein folding, maturation and conformational stabilization of many "client” proteins (Young et al., 2000; Kamal et al. al., 2003). Hsp90 interacts with several proteins implicated in CRPC, including growth factor receptors, cell cycle regulators and Akt-like signaling kinases, androgen receptors (AR) or Raf-1 (Whitesell et al., 2005; Takayama et al. , 2003).
  • Tumor cells express higher Hsp90 levels compared to positive cells (Kamal et al., 2003; Chiosis et al., 2003), and Hsp90 inhibition occurs as an targeting target for excitation in CRPC and other cancers.
  • Many Hsp90 inhibitors have developed while targeting their ATP-binding pockets, including natural compounds such as geldanamycin and analogs thereof, or synthetic compounds. These agents have been shown to inhibit Hsp90 function, leading to apoptosis in preclinical studies of colon, breast, PCa and other cancers (Kamal et al., 2003; Solit et al., 2003; Solit et al., 2002 ).
  • HSPPC-96 Oncophage®, Antigenics, Inc., New York, NY, USA
  • gp96 HSP peptide complex derived from autologous tumor cells has excellent therapeutic effect when combined with IL-2 in patients with stage 4 metastatic kidney cancer.
  • patients with stage 4 melanoma have no prolonged survival, but safety, effective induction of immune responses, and long-term immune memory have been reported.
  • it is derived from autologous tumor cells it is not applicable in patients with difficulty in acquiring tumor cells, it is difficult to commercialize due to the high cost of vaccine preparation and difficult standardization of manufacturing process and effects, and the epitope of tumor-specific proteins is not known. There is a difficult problem that monitoring is not possible.
  • the present inventors have made efforts to find a vaccine composition that can be used universally in a large number of patients and has excellent antitumor effect, and thus, includes a polypeptide that is an epitope of the heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2.
  • the present invention can be universally used in the majority of patients, is easy to industrialize, and has an excellent anti-tumor effect.
  • Another object of the present invention to provide a vaccine composition for the treatment or prevention of cancer comprising the polypeptide as an active ingredient.
  • Still another object of the present invention is to provide an anticancer composition comprising the polypeptide as an active ingredient.
  • Another object of the present invention to provide a method for treating or preventing cancer, comprising administering the vaccine composition to a cancer patient.
  • Another object of the present invention is to provide an antibody that specifically recognizes the polypeptide.
  • the present invention provides a polypeptide that is an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2.
  • the present invention also provides a gene encoding the polypeptide, a recombinant vector comprising the gene, and a recombinant microorganism into which the gene or the recombinant vector is introduced.
  • the present invention also comprises the steps of (a) culturing the recombinant microorganism to produce the polypeptide; And (b) provides a method for producing the polypeptide comprising the step of obtaining the generated polypeptide.
  • the present invention also provides a vaccine composition for the treatment or prevention of cancer comprising the polypeptide as an active ingredient, and a method for treating or preventing cancer comprising administering the vaccine composition to a cancer patient.
  • the present invention also provides an antibody that specifically recognizes an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2.
  • the vaccine composition comprising the epitope of the thermal shock protein 90 of the present invention can be used for the prevention and treatment of cancer economically since it is universally applicable to most patients, is easy to industrialize, and has an excellent antitumor effect. .
  • Figure 2 shows the results confirming the immunogenicity of the Hsp 90 multiple peptide vaccine of the present invention.
  • Figure 3 is a result confirming the antitumor effect of the Hsp 90 multiple peptide vaccine in the mouse model of the present invention.
  • Figure 4 shows the results of the combined treatment anti-tumor effect of HSP90 multi-peptide vaccine, STING agonist and CTLA-4 inhibitor in a mouse model.
  • the vaccine composition comprising an epitope polypeptide of heat shock protein 90 (Hsp90) represented by the amino acid sequence of SEQ ID NO: 1 or 2 induces a Th1 immune response, and confirmed that the antitumor effect is excellent. It was.
  • Hsp90 heat shock protein 90
  • the present invention relates to a polypeptide which, in one aspect, is an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2.
  • epitope refers to a set of amino acid residues at the antigen-binding site recognized by a particular antibody, or to T cell receptor proteins and / or major histocompatibility complex (MHC) receptors in T cells. Residues. Epitopes are molecules that form a site recognized by an antibody, T cell receptor, or HLA molecule and refer to primary, secondary, and tertiary peptide structures, or charges.
  • MHC major histocompatibility complex
  • the Hsp 90 full sequence was used to generate 12 15-mer peptide sequences that are expected to have good binding affinity to the most common MHC class II alleles using five algorithm programs. After selection, two kinds of epitopes having good binding affinity to MHC class II alleles and excellent antitumor effect were obtained.
  • the present invention relates to a gene encoding the polypeptide.
  • the gene may be represented by the nucleotide sequence of SEQ ID NO: 3 or SEQ ID NO: 4.
  • the present invention relates to a recombinant vector comprising the gene and a recombinant microorganism into which the gene or the recombinant vector is introduced.
  • the present invention provides a method for producing a polypeptide comprising: (a) culturing the recombinant microorganism to produce the polypeptide; And (b) relates to a method for producing the polypeptide comprising the step of obtaining the polypeptide.
  • the vector refers to a DNA preparation containing a nucleotide sequence of the polynucleotide encoding the target protein operably linked to a suitable control sequence to express the target protein in a suitable host cell.
  • the regulatory sequence may comprise a promoter capable of initiating transcription, any operator sequence for regulating such transcription, a sequence encoding a suitable mRNA ribosomal binding site, and a sequence regulating the termination of transcription and translation, as desired It can be manufactured in various ways.
  • the promoter of the vector may be constitutive or inducible. After being transformed into a suitable host, the vector can replicate or function independently of the host genome and integrate into the genome itself.
  • the vector used in the present invention is not particularly limited as long as it can be replicated in a host cell, and any vector known in the art may be used.
  • Examples of commonly used vectors include natural or recombinant plasmids, phagemids, cosmids, viruses and bacteriophages.
  • pWE15, M13, ⁇ MBL3, ⁇ MBL4, ⁇ IXII, ⁇ ASHII, ⁇ APII, ⁇ t10, ⁇ t11, Charon4A, and Charon21A can be used as a phage vector or cosmid vector
  • pBR, pUC, pBluescriptII, pGEM system, pTZ system, pCL system and pET system can be used.
  • the vector usable in the present invention is not particularly limited and known expression vectors can be used.
  • expression control sequence refers to a DNA sequence essential for the expression of a coding sequence operably linked in a particular host organism.
  • regulatory sequences include promoters for performing transcription, any operator sequence for regulating such transcription, sequences encoding suitable mRNA ribosomal binding sites, and sequences that control termination of transcription and translation.
  • suitable control sequences for prokaryotes include promoters, optionally operator sequences, and ribosomal binding sites.
  • Eukaryotic cells include promoters, polyadenylation signals, and enhancers. The factor that most influences the amount of gene expression in the plasmid is the promoter.
  • an SR ⁇ promoter, a cytomegalovirus-derived promoter, or the like is preferably used.
  • any of a wide variety of expression control sequences can be used in the vector.
  • useful expression control sequences include, for example, early and late promoters of SV40 or adenovirus, lac system, trp system, TAC or TRC system, T3 and T7 promoters, major operator and promoter region of phage lambda, fd Regulatory regions of the code protein, promoters for 3-phosphoglycerate kinase or other glycolysis enzymes, promoters of the phosphatase such as Pho5, promoters of the yeast alpha-crossing system and prokaryotic or eukaryotic cells or viruses thereof And other sequences of constitution and induction known to modulate the expression of the genes, and various combinations thereof.
  • the T7 RNA polymerase promoter ⁇ 10 may be usefully used to express protein NSP in E. coli.
  • Nucleic acids are “operably linked” when placed in a functional relationship with other nucleic acid sequences. This may be genes and regulatory sequence (s) linked in such a way as to allow gene expression when appropriate molecules (eg, transcriptional activating proteins) bind to regulatory sequence (s).
  • DNA for a pre-sequence or secretion leader is operably linked to DNA for a polypeptide when expressed as a shear protein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence when it affects the transcription of the sequence;
  • the ribosomal binding site is operably linked to a coding sequence when it affects the transcription of the sequence;
  • the ribosomal binding site is operably linked to a coding sequence when positioned to facilitate translation.
  • “operably linked” means that the linked DNA sequences are in contact, and in the case of a secretory leader, are in contact and present within the reading frame. However, enhancers do not need to touch. Linking of these sequences is performed by ligation (linking) at convenient restriction enzyme sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers according to conventional methods are used.
  • expression vector generally refers to a fragment of DNA that is generally double stranded as a recombinant carrier into which fragments of heterologous DNA have been inserted.
  • heterologous DNA refers to heterologous DNA, which is DNA not naturally found in host cells.
  • the gene must be operably linked to transcriptional and translational expression control sequences that function in the selected expression host.
  • the expression control sequence and the gene of interest are included in one expression vector including the bacterial selection marker and the replication origin. If the expression host is a eukaryotic cell, the expression vector must further comprise an expression marker useful in the eukaryotic expression host.
  • expression host / vector combinations can be used to express the genes encoding the polypeptides of the invention.
  • Suitable expression vectors for eukaryotic hosts include, for example, expression control sequences derived from SV40, bovine papilloma virus, adenovirus, adeno-associated virus, cytomegalovirus and retrovirus.
  • Expression vectors that can be used in bacterial hosts include a broader host range, such as bacterial plasmids, RP4, which can be exemplified in E. coli such as pBluescript, pGEX2T, pUC vectors, colE1, pCR1, pBR322, pMB9 and derivatives thereof.
  • Phage plasmids phage DNA that can be exemplified by a wide variety of phage lambda derivatives such as ⁇ gt10 and ⁇ gt11, NM989, and other DNA phages such as M13 and filamentary single-stranded DNA phages.
  • Useful expression vectors for yeast cells are 2 ⁇ plasmids and derivatives thereof.
  • a useful vector for insect cells is pVL 941.
  • Host cells transformed or transfected with the expression vectors described above constitute another aspect of the present invention.
  • transformation means that DNA is introduced into a host such that the DNA is replicable as an extrachromosomal factor or by chromosomal integration.
  • transfection means that the expression vector is accepted by the host cell whether or not any coding sequence is actually expressed.
  • the host cell of the present invention is a recombinant microorganism into which a vector having a polynucleotide encoding at least one target protein has been introduced, or a polynucleotide encoding at least one target protein is introduced into the microorganism so that the polynucleotide is integrated into a chromosome to express the target protein.
  • a recombinant microorganism infected with a trait It may be a prokaryotic or eukaryotic cell.
  • a host having a high DNA introduction efficiency and a high expression efficiency of the introduced DNA is usually used.
  • Known eukaryotic and prokaryotic hosts such as Escherichia coli, Pseudomonas, Bacillus, Streptomyces, fungi, yeast, insect cells such as Spodoptera pruperferda (SF9), animal cells such as CHO and mouse cells, COS 1, COS African green monkey cells such as 7, BSC 1, BSC 40 and BMT 10, and tissue cultured human cells are examples of host cells that can be used.
  • COS cells since SV40 large T antigen is expressed in COS cells, the plasmid having the origin of replication of SV40 is present as a large number of copies of the episome in the cells. And expression can be expected.
  • the introduced DNA sequence may be obtained from the same species as the host cell, may be of a different species than the host cell, or it may be a hybrid DNA sequence comprising any heterologous or homologous DNA.
  • the relative strength of the sequence, the controllability, and the compatibility with the DNA sequences of the present invention should be considered, particularly with regard to possible secondary structures.
  • Single cell hosts may be selected from a host for the selected vector, the toxicity of the product encoded by the DNA sequence of the invention, the secretory properties, the ability to accurately fold the protein, the culture and fermentation requirements, the product encoded by the DNA sequence of the invention from the host. It should be selected in consideration of factors such as the ease of purification. Within the scope of these variables, one skilled in the art can select a variety of vector / expression control sequence / host combinations capable of expressing the DNA sequences of the invention in fermentation or large scale animal culture.
  • binding method binding method
  • panning method panning method
  • film emulsion method film emulsion method
  • a conventionally known genetic manipulation method may be used, and the non-viral delivery method may be cell perforation, lipofection, microinjection, ballistic method, virosome, liposome.
  • Immunoliposomes, polyvalent cations or lipid nucleic acid conjugates, naked DNA, artificial virons, and chemical promoted DNA influx.
  • Sonoporation for example methods using the Sonitron 2000 system (Rich-Mar), can also be used for the delivery of nucleic acids.
  • Other representative nucleic acid delivery systems are Amaxa Biosystems (Cologne, Germany), Maxcyte, Inc. (Rockville, Maryland).
  • Suitable cations or neutral lipids for effective receptor-recognition lipofection of polynucleotides include lipids from Felgner (WO91 / 17424 and WO91 / 16024) and can be delivered to cells via in vitro introduction and to target tissues via in vivo introduction. have.
  • nucleic acid complexes including target liposomes, such as immunolipid complexes
  • Methods of preparing lipid: nucleic acid complexes, including target liposomes, such as immunolipid complexes, are well known in the art (Crystal, Science., 270: 404-410, 1995; Blaese et al., Cancer Gene Ther., 2: 291).
  • Lentiviral vectors are retroviral vectors that generate high viral titers by transducing or infecting non-dividing cells.
  • the target tissue determines the retroviral gene persistence system.
  • Retroviral vectors contain cis acting long terminal repeats that can pack 6-10 kb outer sequences. Minimal cis acting LTRs sufficient for replication and packaging of the vector can be used to integrate the therapeutic gene into target cells for permanent transgene expression.
  • Widely used retroviral vectors include murine leukemia virus (MuLV), gibbon leukemia virus (GaLV), monkey immunodeficiency virus (SIV), human immunodeficiency virus (HIV), and combination viruses thereof (Buchscher et al. , J. Virol., 66: 2731-2739, 1992; Johann et al., J. Virol., 66: 1635-1640 1992; Sommerfelt et al., Virol., 176: 58-59, 1990; Wilson et al. , J. Virol., 63: 2374-2378, 1989; Miller et al., J. Virol., 65: 2220-2224, 1991; PCT / US94 / 05700.
  • MiLV murine leukemia virus
  • GaLV gibbon leukemia virus
  • SIV monkey immunodeficiency virus
  • HAV human immunodeficiency virus
  • sucrose phosphorylase proteins are more common with adenovirus-based systems, and adenovirus-based vectors cause high efficiency transduction in many cells but do not require cell division.
  • the vector allows for high titers and high levels of expression and can be produced in large quantities in a simple system.
  • Adeno accessory virus (AAV) vectors are also used to transduce into cells with target nucleic acids, for example for the production of nucleic acids and peptides in vitro and for gene therapy in vivo and in vitro (West et al., Virology., 160: 38-47, 1987; US Pat. No.
  • pLASN and MFG-S are examples of retroviruses used in clinical trials (Dunbar et al., Blood., 85: 3048-305, 1995; Kohn et al., Nat.
  • PA317 / pLASN was the first therapeutic vector used in gene therapy (Blaese et al., Science., 270: 475-480, 1995) Transduction efficiency of MFG-S packaging vector was 50% or more (Ellem et al., Immunol Immunother., 44 (1): 10-20, 1997; Dranoff et al., Hum. Gene Ther. , 1: 111-2, 1997).
  • rAAV Recombinant adeno-associated virus vectors
  • All vectors are derived from plasmids with AAV 145 bp inverted terminal repeats flanking the transgene expression cassette. Efficient gene delivery and stable transgene delivery due to integration into the genome of transduced cells is a great advantage of the vector system (Wagner et al., Lancet., 351: 9117-17023, 1998; Kearns et al., Gene Ther., 9: 748-55, 1996).
  • the present invention relates to a vaccine composition for the treatment or prevention of cancer comprising the polypeptide as an active ingredient.
  • the vaccine composition induces a Th1 immune response.
  • Th1 cells refers to a subset of helper T cell lymphocytes that are specified in terms of gene expression, protein secretion and functional activity.
  • Th1 cells exhibit cytokine expression patterns that synthesize IL-2 and IFN- ⁇ but not IL-4, IL-5, IL-10 and IL-13.
  • Th1 cells are involved in cell-mediated immune responses, organ-specific autoimmune diseases and delayed hypersensitivity to various intracellular pathogens.
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • CD152 Cluster of Differentiation 152
  • STING Simulator of InterferoN Gene
  • STING means a substance that exhibits anti-cancer effects by activating the signaling pathway related to STING to induce the production of inflammatory cytokines including interferon.
  • the cancer is for example squamous cell cancer (e.g. squamous cell cancer of the epithelium), small cell lung cancer, non-small cell lung cancer, lung cancer, peritoneal cancer, colon cancer, biliary tumor, nasopharyngeal cancer , Laryngeal cancer, Bronchial cancer, Oral cancer, Osteosarcoma, Gallbladder cancer, Kidney cancer, Leukemia, Bladder cancer, Melanoma, Brain cancer, Glioma, Brain tumor, Skin cancer, Pancreatic cancer, Breast cancer, Liver cancer, Bone marrow cancer, Esophageal cancer, Colon cancer, Stomach cancer, Cervical cancer, Prostate Cancer, ovarian cancer, head and neck cancer and rectal cancer may be characterized in that at least one selected from the group consisting of, but is not limited thereto.
  • squamous cell cancer of the epithelium small cell lung cancer, non-small cell lung cancer, lung cancer, peritoneal cancer, colon
  • the vaccine composition of the present invention is applicable to early cancer.
  • anticancer adjuvant may be used to increase the anticancer effect of the anticancer agent, to suppress or improve the side effects of the anticancer agent, and may be administered to the patient in combination with the anticancer agent.
  • prevention refers to any action of inhibiting or delaying the cancer by administration of a transformant expressing the Hsp 90 epitope protein of the present invention or a composition comprising the transformant as an active ingredient.
  • treatment refers to administration of a transformant expressing the Hsp 90 epitope protein of the present invention or a composition comprising the transformant as an active ingredient, and thus the cancer or tumor is not immortalized, All actions that benefit.
  • the composition may include all of the epitopes of the heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 and / or 2.
  • multiple peptide vaccine is a term defined to denote a vaccine containing two or more polypeptide epitopes described above.
  • the composition may be characterized in that it further comprises an immune anticancer agent.
  • the immune anticancer agent CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • PD-1 Programmed cell death protein 1
  • LAG-3 Lymphocyte Activation Gene-3
  • TIM-3 T is an immune gateway inhibitor to any one selected from the group consisting of -cell Immunoglobulin and Mucin-domain containing-3), T-cell Immunoreptor with IG and ITIM domain (TIGIT) and V-domain Ig Suppressor of T cell Activation (VISTA) , More preferably CTLA-4 inhibitor.
  • the composition may further include an anticancer adjuvant, and more preferably, the anticancer adjuvant may be, but is not limited to, a STING (STimulator of InterferoN Gene) agonist.
  • an anticancer adjuvant may be, but is not limited to, a STING (STimulator of InterferoN Gene) agonist.
  • immune anticancer agent is a therapeutic agent that induces immune cells to selectively attack only cancer cells by stimulating the immune system by injecting artificial immune proteins into the body, unlike conventional anticancer drugs that attack cancer itself. It is an anticancer agent that restores or enhances the tumor recognition ability or destruction ability of the immune system in order to overcome the acquired immunosuppression or immune evasion mechanism.
  • immune anticancer agents include, but are not limited to, immune gateway inhibitors, immune cell therapeutics and immunoviral therapeutics.
  • the term "immunity check inhibitor” refers to the immune checkpoint protein (Immune Checkpoint Protein) involved in T cell inhibition when some cancer cells evade immunity while utilizing the immune checkpoint of T cells which are immune cells in the body.
  • a kind of immune anticancer agent that acts to block the activation of T cells to attack cancer cells including CTLA-4 inhibitors, PD-1 inhibitors, PD-1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, Including but not limited to VISTA inhibitors.
  • the active ingredient is suitably used in the form of a pharmaceutically acceptable carrier, rather than being used alone.
  • pharmaceutically acceptable carriers include carriers, excipients and diluents commonly used in the pharmaceutical art.
  • Pharmaceutically acceptable carriers for use in the vaccine compositions of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Vaccine compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, oral formulations, such as emulsions, syrups, aerosols, external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • oral formulations such as emulsions, syrups, aerosols, external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • it may be prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations contain at least one excipient in the active ingredient, for example starch, calcium carbonate, sucrose, lactose, gelatin It can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, water-insoluble solvents, suspensions, emulsions, lyophilized formulations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • a liquid formulation it is preferable to mix and sterilize a bactericide by filtration through a bacterial capture filter or the like.
  • the so sterilized composition may be solidified, for example, by lyophilization, which, in use, is dissolved in sterile water or sterile diluent.
  • the vaccine composition according to the present invention can be administered to mammals such as cattle, rats, mice, livestock, dogs, humans and the like by various routes. All modes of administration can be expected, for example by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
  • the dosage of the vaccine composition according to the present invention is selected in consideration of the age, weight, sex, physical condition and the like of the animal.
  • the amount required to induce an immunoprotective response in an animal without any adverse side effects may vary depending on the presence of epitopes and excipients used as immunogens.
  • each dose contains 0.1 to 1000 ⁇ g of protein, preferably 0.1 to 100 ⁇ g, per ml of sterile solution of the immunogenic amount of the polypetide of the present invention.
  • initial doses may optionally be followed by optionally repeated antigenic stimulation.
  • the present invention relates to a method of treating or preventing cancer comprising administering the vaccine composition to a cancer patient.
  • the vaccine composition may be characterized in that it is administered in combination with an immune anticancer agent, it may be characterized in that it is administered in combination with an antibody therapeutic agent.
  • An immunocancer or antibody therapeutic agent used in combination with the vaccine composition of the present invention may be administered simultaneously or sequentially with each other, and may be selected according to an appropriate time and cycle.
  • the vaccine composition can be administered in combination with an anticancer agent.
  • the immune anticancer agents are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death protein 1 (PD-1), Lymphocyte Activation Gene-3 (LAG-3), and T-cell Immunoglobulin and Mucin.
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • PD-1 Programmed cell death protein 1
  • LAG-3 Lymphocyte Activation Gene-3
  • T-cell Immunoglobulin and Mucin T-cell Immunoglobulin and Mucin.
  • immuno-gateway inhibitor for any one selected from the group consisting of -domain containing-3), T-cell Immunoreptor with IG and ITIM domain (TIGIT), and V-domain Ig Suppressor of T cell Activation (VISTA), more preferably CTLA-4 inhibitors, but are not limited to these.
  • the vaccine composition may further be administered in combination with an anticancer adjuvant, and the anticancer adjuvant may be, but is not limited to, a STING (STimulator of InterferoN Gene) agonist.
  • an anticancer adjuvant may be, but is not limited to, a STING (STimulator of InterferoN Gene) agonist.
  • the cancer is for example squamous cell cancer (e.g. squamous cell cancer of the epithelium), small cell lung cancer, non-small cell lung cancer, lung cancer, peritoneal cancer, colon cancer, biliary tumor, nasopharyngeal cancer , Laryngeal cancer, Bronchial cancer, Oral cancer, Osteosarcoma, Gallbladder cancer, Kidney cancer, Leukemia, Bladder cancer, Melanoma, Brain cancer, Glioma, Brain tumor, Skin cancer, Pancreatic cancer, Breast cancer, Liver cancer, Bone marrow cancer, Esophageal cancer, Colon cancer, Stomach cancer, Cervical cancer, Prostate Cancer, ovarian cancer, head and neck cancer and rectal cancer may be characterized in that at least one selected from the group consisting of, but is not limited thereto.
  • squamous cell cancer of the epithelium small cell lung cancer, non-small cell lung cancer, lung cancer, peritoneal cancer, colon
  • the present invention also provides an anticancer composition
  • an anticancer composition comprising an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 and / or 2.
  • composition may further include other components for stabilization of the active ingredient in addition to the epitope.
  • the term "injection” or “administration” may vary depending on the age, sex, weight, etc. of the subject to be administered, and the dosage of the vaccine may also vary depending on the route of administration, degree of disease, sex, weight, age, and the like. have.
  • concanavalin A (positive control) activates T cells but does not activate B cells (inactivating B cells also activates).
  • B cells inactivating B cells also activates.
  • concanavalin A since several cancer cells show higher cohesiveness to Con A than normal cells, it is used as a means of studying the specificity of cancer cell membrane structure.
  • the present invention relates to an antibody that specifically recognizes an epitope of heat shock protein 90 represented by the amino acid sequence of SEQ ID NO: 1 or 2.
  • the antibody may be characterized in that the monoclonal or polyclonal antibody.
  • the term "antibody” is a substance produced by the stimulation of the antigen in the immune system, also known as immunoglobulin, and specifically binds to a specific antigen to float the lymph and blood, causing an antigen-antibody reaction. While antibodies exhibit specificity for specific antigens, immunoglobulins include both antibodies and antibody-like substances lacking antigen specificity. The latter polypeptide is produced at low levels, for example in the lymphatic system, and at elevated levels by myeloma.
  • the antibody may be an antibody against an antigen of a gene sequence including a portion of an Hsp 90 epitope protein, preferably an amino acid sequence of SEQ ID NO: 1, an amino acid sequence of SEQ ID NO: 2 or an amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 2 It may be an antibody against the fused form of the antigen.
  • therapeutically effective amount as used in combination with an active ingredient in the present invention means an amount effective for preventing or treating a target disease
  • the therapeutically effective amount of the composition of the present invention may be various factors, for example, a method of administration. It may vary depending on the purpose, location of the patient and the condition of the patient. Therefore, when used in humans, the dosage should be determined in an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from an effective amount determined through animal testing.
  • MHC class II alleles in humans are DRB1 * 0101, DRB1 * 1501, DRB1 * 0301, DRB1 * 0401, DRB1 * 0404, DRB1 * 0405, DRB1 * 0701, DRB1 * 0802, DRB1 * 0901, DRB1 * 1101, DRB1 * 1201, DRB1 * 1302, DRB3 * 0101, DRB4 * 0101 and DRB5 * 0101.
  • Table 1 below shows the selected Hsp 90 15-mer peptide sequences.
  • Hsp 90 multi-peptide vaccine In order to confirm the immunogenicity of the Hsp 90 multi-peptide vaccine in mouse models, FVB mice (6-8 weeks old) were placed in each group of physiological saline (PBS) and immune adjuvant (CFA / IFA) or Hsp 90 groups. Divided into peptide and immunoadjuvant groups, administered three times every 10 days by subcutaneous injection, etc., 10 days after the last administration, spleen cells of mice were isolated to separate splenocytes, and interferon gamma (IFN ⁇ ) -fixed enzyme antibody method (EezymeLinked Immuno). -SPOT assay, ELISPOT) was used to observe Hsp 90 multiple peptide specific T cell responses.
  • PBS physiological saline
  • CFA / IFA immune adjuvant
  • Hsp 90 groups Divided into peptide and immunoadjuvant groups, administered three times every 10 days by subcutaneous injection, etc., 10 days after the last administration, spleen cells of
  • mice spleen cell preparation and freezing the mechanisms and materials are shown in Table 2.
  • Mouse T Cell Media is 500 mL RPMI-1640 (L-Glut + Hepes) [Mediatech Cellgro], 5 mL penicillin-streptomycin solution [Mediatech Cellgro, # 30-002-CI] , 50 mL heat-inactivated fetal bovine serum [SAFC Biosciences, if available, others available], 0.5 mL 1000X 2-mercaptoethanol [GIBCO, # 21985 ] Was filtered with plasticware.
  • Freezing Media contains 45ml heat-inactivated FBS and 5ml DMSO and stored at 4 ° C after filtering.
  • ACK Lysis Buffer (RBC solution) contained 1 L ddH 2 O, 8.29 g NH 4 Cl (final 150 mM) and 1 g KHCO 3 (final concentration 10 mM), pH 7.2-7.4, filtered.
  • the mouse T cell medium was poured into a 50 ml tube, heated in a 37 ° C. water bath, and left in a p100 dish with only 3 ml of medium and fresh spleen. . Afterwards, the spleen is chopped using a blade. Cell strainer (cell strainer) was put in a 50ml tube and chopped spleen and medium were added. The spleen was transferred to a cell strainer using a 1.5 ml tube, and the cells were filtered by dispensing the cell strainer with 10 ml warm T cell media. In addition, cells of a p100 dish were also obtained.
  • the resultant was centrifuged at 1,200 rpm for 8 minutes using a centrifuge.
  • the supernatant is carefully removed, and then the pellet is resuspended by adding 10 ml warm Mouse T cell media.
  • the supernatant was carefully removed.
  • 10 ml of Mouse T cell media was added, and centrifuged at 1,200 rpm for 8 minutes using a centrifuge, and the supernatant was carefully removed as completely as possible.
  • 10 ml of warm mouse matis media was added, and 15 ul was transferred to a new tube for cell counting.
  • the centrifuge was centrifuged at 1,200 rpm for 8 minutes and the supernatant was carefully removed.
  • the cells When using splenocytes on the same day, the cells were put in suspension after adjusting the desired concentration. When freezing splenocytes, 2ml of freeze media was added and resuspended, and then aliquots were added to the two tubes. It was then stored overnight in a -80 degree freezer and transferred to LN2 the next day.
  • the antibody was removed by using a multichannel pipette. Dispense 200 ul of 1 ⁇ PBS and wash three times. In the last wash, PBS was completely removed without damaging the plate. 200ul of mouse T cell media is dispensed to each well and blocked. Incubated for 2 hours in a 37 °C incubator (incubator). Labeled on the plate lid and inside.
  • Well B7-B12 (Vaccine Peptide) 100 uL cells + 100 uL 2X Peptide
  • Biotinylated anti-mouse IFN ⁇ antibody (1 mg / ml, stored at 4 ° C., yellow cap) was diluted to 5 ug / ml using 1 ⁇ PBS + 0.05% tween-20 (5ul). / ml). 50 ul was dispensed into each well. An amount of 5 ml per 96-well plate is required. The plate was capped and wrapped in a wrap and incubated for 16-24 hours at 4 ° C. (must be covered) (Day 4 end).
  • the medium of the plate was carefully removed with a multichannel pipette. Wash 4 times by dispensing 200ul each of 1x PBS. At the last wash, PBS was completely removed without damaging the plate. The bottom of the plate was separated to dry the PBS with a tissue.
  • a mouse breast cancer cell line (mouse mary cancer cell-FVB / N-Tg (MMTVneu) -202Mul mouse-derived HER-2 overexpressing breast cancer cell line) was used.
  • MMTVneu transgenic mouse females were divided into 6 groups of 10 males each in physiological saline, immunosuppressive group, HSP90 peptide and immunosuppressive group, subcutaneous injection three times every 10 days and mouse breast cancer cell line 10 days after the last administration. Subcutaneous injection was applied to the flank and tumor growth was observed at 3-4 day intervals and tumor size was measured to determine the antitumor effect of the HSP90 multiple peptide vaccine.
  • the experimental method is the same as in Example 2.
  • the tumor size of the Hsp90 multiple peptide vaccine group was significantly smaller than that of the control group in the mouse model (FIG. 3A).
  • the HSP90 multi-peptide vaccine group showed higher specific reactivity due to the secretion of interferon gamma (IFN- ⁇ ) in the HSP90 peptide response than in the control group (FIG. 3B).
  • IFN- ⁇ interferon gamma
  • the Hsp90 multiple peptide vaccine composition of the present invention exhibits immunogenicity and is excellent in antitumor effect.
  • Example 4 Confirmation of antitumor effect of HSP90 multiple peptide vaccine / STING agonist / immunomodulatory inhibitor (CTLA-4) combination in mouse model
  • HSP90 vaccine and STING agonist were administered three times subcutaneously and intraperitoneally, and anti-mouse CTLA-4 (CD152, Bioxcell) was tested twice a week. Intraperitoneal injection was performed until the end. During the experiment, tumor growth was measured at 3-4 day intervals. After 10 days of the last administration, the spleens of the mice were extracted to separate splenocytes, and HSP90 multi-peptide-specific T cell responses were confirmed by using an interferon-gamma (IFN ⁇ ) -fixed enzyme antibody (EISymeLinked Immuno-SPOT assay). Mouse spleen cell preparation and freezing, ELISPOT test method was carried out in the same manner as in Example 2.
  • IFN ⁇ interferon-gamma
  • HER2 ECD Human epidermal growth factor receptor type2 ExtraCellular Domain
  • Carbonate Buffer (Carbonate buffer): 0.8g Na 2 CO 3 and 1.47g NAHCO 3 in a 1-liter beaker, add 400ml of first distilled water, dissolve, adjust the pH 9.6 and fill the first distilled water up to 500ml. After filtration it was stored at 4 °C.
  • Diluent buffer (Diluent buffer; 1X PBS / 1% BSA): When 10g BSA was dissolved in 100ml in 10x PBS, the first distilled water was added to the volume of 1 liter. After filtering it was stored at 4 °C.
  • Blocking Buffer (1 ⁇ PBS / 5% BSA): 50 g BSA was added to 10 ml of 10 ⁇ PBS and dissolved in primary distilled water up to a volume of 1 liter. After filtering it was stored at 4 °C.
  • Wash Buffer (1 ⁇ PBS / 0.1% Tween-20): Prepared by mixing 100ml 10 ⁇ PBS, 1ml Tween-20 and 899ml primary distilled water.
  • Mouse IgG Standard Antibodies Mouse IgG standard antibodies were purchased from Sigma (cat # I-4506). After purchase, the antibody was stored at ⁇ 20 ° C. in a final concentration of 2 mg / ml using 150 mM NaCl as the dilution buffer.
  • TMB solution TMB solution purchased from Sigma (cat # T0440), and stored at 4 °C.
  • the ELISA experiment was carried out through the following steps. Steps 1 and 2 were carried out under ice conditions.
  • HSP90 recombinant protein was prepared at a concentration of 1 ug / ml using fresh carbonate buffer.
  • the HSP90 recombinant protein was dispensed by 50ul per well in Coat columns # 1 ⁇ # 10. In column # 11, only carbonate buffer was dispensed, and the plates were covered with microseal and the antigen-antibody reaction was performed overnight at 4 ° C (step 2). Wash three times with 200ul wash buffer and wash wash plate thoroughly with paper towels to remove wash buffer completely (step 3). The blocking solution was then dispensed by 100ul per well and reacted for 1 to 2 hours at room temperature (step 4). The same washing as in step 3 was performed (step 5).
  • Dilution Buffer Serum was mixed in a fresh 1.5 ml tube in a 1: 1 ratio and vortexed to 50 ul in each well (step 6). 50ul of dilution buffer was dispensed into plate columns # 11 and # 12 (step 7). The plate was covered with a microseal and then reacted overnight at 4 ° C. (step 8). The same washing as in step 3 was performed (step 9). HRP conjugated antibody was diluted 1: 10,000 using dilution buffer, 50ul per well was dispensed and reacted with stirring for 45 minutes at room temperature (step 10). The same washing as in step 3 was performed (step 11).
  • the TMB solution was taken out to room temperature, prepared, and then 100 ⁇ l of each TMB solution was dispensed and reacted for 20 minutes at room temperature without light (step 12). Each reaction stop solution was dispensed 50ul per well (step 13). Fluorescence intensity was measured at 450 nm using a microplate reader instrument (step 14).
  • the HER2 ECD blood concentration change was measured by an enzyme immunoassay (EezymeLinked Immunosorbent assay, ELISA).
  • ELISA EnzymeLinked Immunosorbent assay
  • the HSP90 peptide vaccine can be used as a vaccine since the effect of the HSP90 peptide vaccine is increased and decreased by combining and treating the HSP90 peptide vaccine of the present invention with a STING agonist / CTLA-4 exogenous agent.

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Abstract

La présente invention concerne un vaccin comprenant un épitope d'une protéine de choc thermique, et une polythérapie associée. L'invention concerne également une composition de vaccin comprenant un polypeptide, qui est un épitope de la protéine de choc thermique 90 représentée par la séquence d'acides aminés de SEQ ID NO : 1 ou 2 ; ladite composition peut être utilisée d'une manière générale chez la plupart des patients, peut être facilement mise à l'échelle industrielle, présente un excellent effet antitumoral et peut être ainsi utilisée dans la prévention et le traitement du cancer de manière avantageuse sur le plan économique.
PCT/KR2019/001898 2018-02-19 2019-02-18 Vaccin comprenant un épitope de protéine de choc thermique et utilisation associée WO2019160383A1 (fr)

Priority Applications (6)

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CN201980025974.6A CN113383006B (zh) 2018-02-19 2019-02-18 包含热休克蛋白表位的疫苗及其用途
JP2020543870A JP7301391B2 (ja) 2018-02-19 2019-02-18 熱ショックタンパク質のエピトープを含むワクチン及びこの用途
CA3091736A CA3091736A1 (fr) 2018-02-19 2019-02-18 Vaccin comprenant un epitope de proteine de choc thermique et utilisation associee
EP19754897.7A EP3763727A4 (fr) 2018-02-19 2019-02-18 Vaccin comprenant un épitope de protéine de choc thermique et utilisation associée
US16/997,307 US11446368B2 (en) 2018-02-19 2020-08-19 Vaccine comprising epitope of heat shock protein, and use thereof
US17/885,255 US20230084183A1 (en) 2018-02-19 2022-08-10 Vaccine comprising epitope of heat shock protein, and use thereof

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KR10-2019-0018119 2019-02-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110511277A (zh) * 2019-09-11 2019-11-29 江苏莱森生物科技研究院有限公司 一种抗hsp90单克隆抗体及其应用
CN113521303A (zh) * 2021-07-07 2021-10-22 中山大学附属第一医院 一种共同负载pd-l1抗体和sting激动剂的纳米囊泡及其制备方法与应用

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
WO1991016024A1 (fr) 1990-04-19 1991-10-31 Vical, Inc. Lipides cationiques servant a l'apport intracellulaire de molecules biologiquement actives
WO1991017424A1 (fr) 1990-05-03 1991-11-14 Vical, Inc. Acheminement intracellulaire de substances biologiquement actives effectue a l'aide de complexes de lipides s'auto-assemblant
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993024641A2 (fr) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Virus adeno-associe a sequences terminales inversees utilisees comme promoteur
JP2003533445A (ja) * 2000-04-17 2003-11-11 イー． ロスマン，ジェイムズ 熱ショックタンパク質に対するタンパク質抗原のジャベリン化
KR20070050918A (ko) * 2004-07-02 2007-05-16 뉴텍 파마 피엘씨 암의 치료
JP5042301B2 (ja) * 2002-05-29 2012-10-03 イマティクス バイオテクノロジーズ ゲーエムベーハー Ｍｈｃ分子に結合する腫瘍関連ペプチド
KR101594403B1 (ko) * 2014-03-11 2016-02-16 연세대학교 산학협력단 HSP 90a 를 포함하는 암 또는 바이러스 질환 치료용 조성물
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4261975A (en) 1979-09-19 1981-04-14 Merck & Co., Inc. Viral liposome particle
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4946787A (en) 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US5049386A (en) 1985-01-07 1991-09-17 Syntex (U.S.A.) Inc. N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US4774085A (en) 1985-07-09 1988-09-27 501 Board of Regents, Univ. of Texas Pharmaceutical administration systems containing a mixture of immunomodulators
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
WO1991016024A1 (fr) 1990-04-19 1991-10-31 Vical, Inc. Lipides cationiques servant a l'apport intracellulaire de molecules biologiquement actives
WO1991017424A1 (fr) 1990-05-03 1991-11-14 Vical, Inc. Acheminement intracellulaire de substances biologiquement actives effectue a l'aide de complexes de lipides s'auto-assemblant
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
WO1993024641A2 (fr) 1992-06-02 1993-12-09 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Virus adeno-associe a sequences terminales inversees utilisees comme promoteur
JP2003533445A (ja) * 2000-04-17 2003-11-11 イー． ロスマン，ジェイムズ 熱ショックタンパク質に対するタンパク質抗原のジャベリン化
JP5042301B2 (ja) * 2002-05-29 2012-10-03 イマティクス バイオテクノロジーズ ゲーエムベーハー Ｍｈｃ分子に結合する腫瘍関連ペプチド
KR20070050918A (ko) * 2004-07-02 2007-05-16 뉴텍 파마 피엘씨 암의 치료
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit
KR101594403B1 (ko) * 2014-03-11 2016-02-16 연세대학교 산학협력단 HSP 90a 를 포함하는 암 또는 바이러스 질환 치료용 조성물

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
AHMAD ET AL., CANCER RES., vol. 52, 1992, pages 4817 - 4820
BLAESE ET AL., CANCER GENE THER., vol. 2, 1995, pages 291 - 297
BLAESE ET AL., SCIENCE, vol. 270, 1995, pages 475 - 480
BUCHSCHER ET AL., J. VIROL., vol. 66, 1992, pages 1635 - 1640
DATABASE Nucleotide 12 February 2018 (2018-02-12), XP055632729, Database accession no. NM_001017963.2 *
DRANOFF ET AL., HUM. GENE THER., vol. 1, 1997, pages 111 - 2
DUNBAR ET AL., BLOOD., vol. 85, 1995, pages 3048 - 305
ELLEM ET AL., IMMUNOL IMMUNOTHER., vol. 44, no. 1, 1997, pages 10 - 20
GAO ET AL., GENE THERAPY., vol. 2, 1995, pages 710 - 722
HERMONATMUZYCZKA, PNAS., vol. 81, 1984, pages 6466 - 6470
KEARNS ET AL., GENE THER., vol. 9, 1996, pages 748 - 55
KOHN ET AL., NAT. MED., vol. 1, 1995, pages 1017 - 102
KOTIN, HUMANGENE THERAPY., vol. 5, 1994, pages 793 - 801
MALECH ET AL., PNAS., vol. 94, no. 22, 1997, pages 12133 - 12138
MILLER ET AL., J. VIROL., vol. 65, 1991, pages 2220 - 2224
MUZYCZKA, J. CLIN. INVEST., vol. 94, 1994, pages 1351
REMY ET AL., BIOCONJUGATE CHEM., vol. 5, 1994, pages 382389 - 654
SAMULSKI ET AL., J VIROL., vol. 63, 1989, pages 038223828
SOMMERFELT ET AL., VIROL., vol. 176, 1990, pages 58 - 59
TRATSCHIN ET AL., MOL. CELL. BIOL., vol. 4, 1984, pages 20722081
TRATSCHIN ET AL., MOL. CELL. BIOL., vol. 5, 1985, pages 3251 - 3260
WAGNER ET AL., LANCET, vol. 351, 1998, pages 9117 - 17023
WEST ET AL., VIROLOGY., vol. 160, 1987, pages 38 - 47
WILSON ET AL., J. VIROL., vol. 63, 1989, pages 2374 - 2378

Cited By (4)

* Cited by examiner, † Cited by third party
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CN110511277A (zh) * 2019-09-11 2019-11-29 江苏莱森生物科技研究院有限公司 一种抗hsp90单克隆抗体及其应用
CN110511277B (zh) * 2019-09-11 2022-07-26 江苏莱森生物科技研究院有限公司 一种抗hsp90单克隆抗体及其应用
CN113521303A (zh) * 2021-07-07 2021-10-22 中山大学附属第一医院 一种共同负载pd-l1抗体和sting激动剂的纳米囊泡及其制备方法与应用
CN113521303B (zh) * 2021-07-07 2024-01-02 中山大学附属第一医院 一种共同负载pd-l1抗体和sting激动剂的纳米囊泡及其制备方法与应用

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