[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2019133647A1 - Combinaison d'un vaccin à protéine de fusion avec un anticorps anti-ox40 destinée à être utilisée pour déclencher des réponses immunitaires spécifiques de l'antigène - Google Patents

Combinaison d'un vaccin à protéine de fusion avec un anticorps anti-ox40 destinée à être utilisée pour déclencher des réponses immunitaires spécifiques de l'antigène Download PDF

Info

Publication number
WO2019133647A1
WO2019133647A1 PCT/US2018/067576 US2018067576W WO2019133647A1 WO 2019133647 A1 WO2019133647 A1 WO 2019133647A1 US 2018067576 W US2018067576 W US 2018067576W WO 2019133647 A1 WO2019133647 A1 WO 2019133647A1
Authority
WO
WIPO (PCT)
Prior art keywords
antigen
composition
amino acid
seq
binding domain
Prior art date
Application number
PCT/US2018/067576
Other languages
English (en)
Inventor
Chia-Mao Wu
Yin-Ching LIN
Original Assignee
Thevax Genetics Vaccine Co., Ltd.
Healthbanks Biotech Usa Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thevax Genetics Vaccine Co., Ltd., Healthbanks Biotech Usa Inc. filed Critical Thevax Genetics Vaccine Co., Ltd.
Publication of WO2019133647A1 publication Critical patent/WO2019133647A1/fr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/104Pseudomonadales, e.g. Pseudomonas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55516Proteins; Peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55561CpG containing adjuvants; Oligonucleotide containing adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55572Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55577Saponins; Quil A; QS21; ISCOMS
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/57Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/57Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/70Multivalent vaccine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/40Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/20011Papillomaviridae
    • C12N2710/20022New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011Details
    • C12N2710/20011Papillomaviridae
    • C12N2710/20034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00Reverse transcribing DNA viruses
    • C12N2730/00011Details
    • C12N2730/10011Hepadnaviridae
    • C12N2730/10111Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011Details
    • C12N2750/10011Circoviridae
    • C12N2750/10034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/10011Arteriviridae
    • C12N2770/10034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011Details
    • C12N2770/24011Flaviviridae
    • C12N2770/24211Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24234Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against 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 generally to a pharmaceutical formulation, and more specifically to a fusion protein vaccine in combination with anti-OX40 antibody for use in treatment of infections or tumors.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a mixture of:
  • A a vaccine composition, comprising a therapeutically effective amount of a fusion protein and a saponin-base adjuvant or a Toll-like receptor (TLR) agonist adjuvant, wherein the saponin-base adjuvant is selected from the group consisting of GPI-0100 and QS-21, and the Toll-like receptor (TLR) agonist adjuvant is selected from the group consisting of monophosphoryl lipid A (MPL) and CpG oligonucleotide; and
  • TLR Toll-like receptor
  • fusion protein comprises:
  • APC antigen-presenting cell
  • a protein transduction domain located at the C-terminus of the APC-binding domain or the CD91 receptor-binding domain, the protein transduction domain being selected from the group consisting of:
  • a T cell sensitizing signal-transducing peptide consisting of 28-53 amino acid residues in length, comprising the amino acid sequence of SEQ ID NO: 31 , in which Xaa 8 is I or L; Xaa 10 is V, F or A, Xaa 11 is M or L, Xaa 17 is L or I, being located at the N-terminus of the fusion polypeptide;
  • translocation peptide consisting of 34-1 12 amino acid residues in length, comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 3, 4, 20 or 41 ; and (3) a linker, comprising SEQ ID NO: 15 linking the T cell sensitizing signal- transducing peptide and the translocation peptide;
  • T cell-sensitizing signal-transducing peptide consisting of 28-53 amino acid residues in length, comprising the amino acid sequence of SEQ ID NO: 31, in which Xaa 8 is I or L; Xaa 10 is V, F or A, Xaa 11 is M or L, Xaa 17 is L or I; and
  • the fusion protein comprises the endoplasmic reticulum retention signal.
  • the antigen is selected from the group consisting of human
  • HPV papillomavirus
  • HBV Hepatitis B virus
  • HCV Hepatitis C virus
  • Flu virus M2 antigen Flu virus M2 antigen
  • a tumor associated antigen a tumor associated antigen.
  • the APC-binding domain or the CD91 receptor-binding domain is a Pseudomonas exotoxin A (PE) binding domain I and the protein transduction domain is the
  • PE Pseudomonas exotoxin A
  • the GPI-0100 is the sole adjuvant.
  • the APC-binding domain or the CD91 receptor-binding domain is a polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence selected from the group consisting of SEQ ID NOs: 5, 9, 6, 7 and 8.
  • the protein transduction domain is the fusion polypeptide comprising:
  • the CpG oligonucleotide is the sole adjuvant.
  • the protein transduction domain comprises the amino acid sequence of SEQ ID NO: 30.
  • the pathogen is at least one selected f om the group consisting of Human
  • the tumor associated antigen is selected from the group consisting of SSX2, MAGE- A3, NY-ESO-1, iLRP, WT12-281, RNF43, and CEA-NE3.
  • the protein transduction domain is the Pseudomonas exotoxin A (PE) translocation peptide
  • the fusion protein further comprises a nuclear export signal comprising the amino acid sequence of SEQ ID NO: 44, located between the antigen and the endoplasmic reticulum retention signal, or between the translocation peptide and the antigen.
  • the antigen comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 21 or 22, and
  • the APC-binding domain or the CD91 receptor-binding domain is a polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 9, and the protein transduction domain is the Pseudomonas exotoxin A (PE) translocation peptide; or (ii) the APC-binding domain or the CD91 receptor-binding domain is a polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 5; and the protein transduction domain comprises the sequence of SEQ ID NO: 30.
  • the invention relates to use of a pharmaceutical composition according to the invention in the manufacture of a medicament for inducing an enhanced cell-mediated immune response or an enhanced pathogen antigen or tumor antigen specific T cell response in a subject in need thereof.
  • the invention relates to use of a pharmaceutical composition according to the invention in the manufacture of a medicament for inhibiting growth of cancer resulting from human papillomavirus (HPV) and increasing cancer patient survival in a subject in need thereof, wherein the antigen is human papillomavirus (HPV) E7 protein in a subject in need thereof.
  • HPV human papillomavirus
  • the invention relates to a method for preparation of a pharmaceutical composition according to the invention, comprising the steps of:
  • the mixture is formed by admixing the vaccine composition and the anti-
  • the fusion protein comprises the amino acid sequence of SEQ ID NO: 54 or 55.
  • the T cell sensitizing signal-transducing peptide comprises the amino acid sequence of SEQ ID NO: 1 or 2.
  • FIG. 1A shows an immunization schedule for mice vaccinated with various compositions as indicated in FIG. 1B to test the immunogenicity elicited by a mixture of PEK+GPI-0100 (TVGV-1 ) and OX40 agonistic antibody.
  • FIG. IB shows the results of ELISA analyses of humoral immunogenicity in mice of FIG. 1A.
  • TVGV-1 stands for PEK+GPI-0100.
  • aOX40 stands for agonistic antibodies to OX40.
  • FIG. 1C shows CD4 + immune cell populations in the splenocytes from mice of FIGs. 1A-B.
  • the splenocytes were analyzed by flow cytometry.
  • FIG. ID shows CD8 + immune cell populations in the splenocytes from mice of FIGs. 1A-B.
  • FIG. 2 A shows an immunization schedule for TC- 1 tumor-bearing mice vaccinated with various compositions as indicated in FIG. 2B to examine the effects of the combination of PEK+GPI-0100 (TVGV-1) and OX40 agonistic antibody on tumor growth and survival rate in tumor-bearing mice.
  • FIG. 2B shows the survival rate in each group of the TC-1 tumor mice of FIG. 2A after vaccinations. Mice were considered and counted as dead if they had a tumor size larger than 2000 mm 3 or had a tumor with an average diameter greater than 20 mm.
  • FIG. 2C shows the size of the tumors in each group of the TC-1 tumor mice of FIG. 2B.
  • P value 0.039 (calculated between the group of TVGV-1 mixed with OX-40 agonist antibody and the group of TVGV-1 mixed with IgG). A difference is statistically significant if a p value is less than 0.05.
  • FIG. 3 A shows an immunization schedule for TC-1 tumor-bearing mice. The mice were sacrificed a week after the last vaccination and the tumors were removed to examine tumor- infiltrating lymphocytes (TILs).
  • TILs tumor- infiltrating lymphocytes
  • FIG. 3B-C show percentage of double positive in CD3+ T cells in splenocytes from mice of FIG. 3A.
  • the splenocyte IFN ⁇ -5 was color stained and analyzed by flow cytometry.
  • FIG. 3D-E show the number of double-positive in CD3+ T cells in tumor tissue cell supernatants from mice of FIG. 3A.
  • FIG. 3F-G show the number of double-positive in CD3+ T cells in tumor tissue total cells from mice of FIG. 3 A.
  • FIG. 4A shows an immunization schedule for TC- 1 tumor-bearing mice vaccinated with various compositions as indicated in FIG. 4B to examine the effects of the combination of RAP1- CD28convPEt-E7-K3+CpG1826 (TVGV-2) and OX40 agonistic antibody on tumor growth and survival rate in tumor-bearing mice.
  • FIG. 4B shows the survival rate in each group of the TC-1 tumor mice of FIG. 4A after vaccinations. Mice were considered and counted as dead if they had a tumor size larger than 2000 mm 3 or had a tumor with an average diameter greater than 20 mm.
  • FIG. 4C shows the size of the tumors in each group of the TC-1 tumor mice of FIGs. 4A-B.
  • P value 0.037 (calculated between the group of TVGV-2 mixed with OX-40 agonist antibody and the group of TVGV-2 mixed with IgG).
  • FIGs. 4D-E show percentage of double positive in CD3+ T cells in splenocytes from mice of FIG. 4A.
  • the splenocyte IFN ⁇ -5 was color stained and analyzed by flow cytometry.
  • FIG. 4F shows percentage of double positive in CD3+ T cells in tumor tissue from mice of FIG. 4A.
  • FIG. SA shows an immunization schedule for TC-1 tumor-bearing mice vaccinated with various compositions as indicated in FIG. 5B to examine the effects of the combination of RAP1- CD28convPEt-E7-K3+CpG1826 (TVGV-2) and aCD40 or aOX40 agonistic antibody on tumor growth and survival rate in tumor-bearing mice.
  • FIG. 5B shows the average area of the tumors in each treatment group of the TC-1 tumor mice of FIGs. 5 A.
  • P value 0.006 (calculated between the group of TVGV-2 mixed with OX-40 agonist antibody and the group of TVGV-2 mixed with IgG);
  • P value 0.002 (calculated between the group of TVGV-2 mixed with OX-40 agonist antibody and the group of TVGV-2 mixed with CD-40 agonist antibody).
  • Immunogenic proteins such as fusion proteins for use as immunogenic enhancers for inducing antigen-specific T cell responses are disclosed in the U.S. Patent No. 20140154285 Al and 20140154280 A 1 , each of which is incorporated herein by reference in its entirety.
  • the saponin derivative GPI- 100 is a semi-synthetic triterpenoid glycoside. It is derived from QS-7, one of the purified components of Quil A, a saponin adjuvant extracted from the bark of the Molina tree Quillaia saponaria.
  • 3D-MPL is sold under the name MPL by GlaxoSmithKline Biologicals N.A. and is referred throughout the document as MPL or 3 D-MPL.
  • QUIL-A® adjuvant contains the water-extractable fraction of saponins from the South-American tree, Quillaja saponaria Molina. QUIL-A®, and fractions thereof are described in U.S. Pat. No. 5,057,540 and "Saponins as vaccine adjuvants", Kensil, C. R., Crit Rev Ther Drug Carrier Syst, 1996, 12 (1-2): 1-55; and EP 0 362 279 Bl.
  • QS-21 is a natural saponin derived from the bark of Quillaja saponaria Molina. It is a HPLC purified non-toxic fraction of Qutl A and is disclosed in U.S. patent No. 5,057,540.
  • CD 134 (OX40) is a member of the tumor necrosis factor receptor superfamily. It acts as a costimulatory receptor on T cells.
  • an antigen-presenting cell or accessory cell refers to a cell that displays foreign antigens complexed with major histocompatibility complexes (MHC's) on their surfaces. T- cells may recognize these complexes using their T-cell receptors (TCRs). These cells process antigens and present them to T-cells.
  • T-cell receptors TCRs
  • DCs dendritic cells
  • macrophages macrophages
  • monocytes and certain B-cells.
  • an antigen-presenting cell (APC)-binding domain refers to a domain that can bind to an antigen-presenting cell (APC).
  • the APC-binding domain may be a polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7, 8, and 9.
  • An APC-binding domain is a ligand that recognizes and binds to a receptor on APC.
  • CD91 Cluster of differentiation 91
  • a protein transduction domain refers to a polypeptide or a fusion polypeptide having a function to sensitize T-cells and thus enhance antigen-specific T cell responses, and/or to guide or direct an antigen toward (i.e., to target to) class I major histocompatibility complex (MHC-I) pathway (i.e., a cytotoxic T cell pathway) of antigen presentation.
  • MHC-I major histocompatibility complex
  • to sensitize T cells generally means that CD8+ and CD4+ T cells are sensitized and as a result, CD8+ (CTL) and CD4+ T cell responses to an antigen challenge are enhanced.
  • An antigen-specific cell mediated immune response is measured by quantifying the production of antigen-specific induced ⁇ -interferon in response to an antigen.
  • an antigen alone may induce weak or no cell mediated immune response at all, i.e., weak or no production of antigen-specific ⁇ -interferon from CD8+ and CD4+ T cells, while in the presence of a sensitization signal (the protein transduction domain), the antigen may induce an enhanced cell mediated immune response.
  • the function of a sensitization signal is to sensitize CD4+ and CD8+ T cells in a host so that when the host is later challenged by an antigen, the antigen can induce an enhanced antigen-specific T cell mediated immune response due to prior CD4+ and CD8+ T cell sensitization.
  • a protein transduction domain may be "a fusion polypeptide", in which the fusion polypeptide comprises a T cell sensitizing signal-transducing peptide, a tinker, and a translocation peptide.
  • the fusion polypeptide may be the polypeptide "CD28convPE ".
  • CD28conv refers to a CD28 conserved region, which is a "T cell sensitizing signal- transducing peptide”. It's an epitope for inducing CD28 agonist antibody.
  • PE or "PE t Core” refers to a PE translocation domain core with 34 amino acid residues in length.
  • a linker is present between the "CD28conv” and the "PE «”.
  • the orientation or arrangement of the fusion polypeptide "CD28convPE t " is important in that "CD28conv” (or the T cell sensitizing signal-transducing peptide) must be at the upstream to the PE t ( or the translocation peptide), i.e., PE t must be at the C-terminus of the "CD28conv” to obtain enhanced T-cell responses.
  • the "CD28convPE” can raise much higher IgG titer (called CD28-specific agonist antibody) specific to CD28conv than the reversed orientation fusion peptide PE t CD28conv.
  • the CD28-specific agonist antibody can sensitize both CD4+ and CD8+ T cells.
  • the correct orientation fusion polypeptide CD28convPE t contains a linker (R'X 2 R 3 X 4 K 5 R 6 ) between CD28conv and PE t domains.
  • the linker contains an antigen presenting cell (APC)-specific protease (cathepsin L) cutting site Lys-Arg (KR). Therefore, the fusion protein RAPl-CD28convPE t -Antigen-K3 can be digested into the two fragments: RAPl-CD28conv and PE t -Antigen-K3.
  • the RAPl-CD28conv fragment can be further digested in the lysosome and the epitope of CD28conv is then presented to the APC cell surface via MHC II pathway, which in turn elicits a humoral immune response producing CD28 agonist antibody.
  • CD28 agonist antibody is produced by B cells. This CD28 agonist antibody can bind to CD28 on the T cell surface and pre-activate the T cells (CD4+ and CD8+ T cells).
  • US Patent No. 9481714 disclose a fusion protein RAP l-CD28convPE t - Antigen (without the ER retention signal K3) can still elicit strong T-cell responses.
  • a "T cell-sensitizing signal-transducing peptide” has 28-53 amino acid residues in length and comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 31, in which X 8 is I or L; X'°is V, F or A, X" is M or L, X 17 is L or I.
  • the T cell-sensitizing signal-transducing peptide comprises the critical region ⁇ 1 ⁇ 2 ⁇ 3 ⁇ 4 ⁇ 5 ⁇ 6 ⁇ 7 ⁇ 8 ⁇ 9 ⁇ 10 (SEQ ID NO: 32) , wherein X 2 is I or L; X 4 is V, F or A, X 5 is M or L.
  • a T cell sensitizing signal-transducing peptide (TDIYFCKIEFMYPPPYLDNEKSNGTIIH; SEQ ID NO: 31, wherein X 8 is I, X 10 is F, X 11 is M, X 17 is L) specific for mice was illustrated in the U.S. Patent No. 9481714.
  • a PE translocation peptide may comprise an amino acid sequence that is at least 90% identical to SEQ ID NO: 3, 4, 20 or 41.
  • the amino acid sequence of a PE translocation peptide may be a.a. 280 - a.a. 313 (SEQ ID NO: 3), a.a. 268 - a.a. 313 (SEQ ID NO: 20), a.a. 253 - a.a. 313 (SEQ ID NO: 41), or a.a. 253 - a.a. 364 (SEQ ID NO: 4) of full length PE (SEQ ID NO: 10). That is, the amino acid sequence of a PE translocation peptide may contain any region of the PE domain II (a.a. 253 to a.a. 364; SEQ ID NO: 4) as long as it comprises a.a. 280-a.a. 313 (SEQ ID NO: 3) essential fragment.
  • An antigen may be a pathogenic protein, polypeptide or peptide that is responsible for a disease caused by the pathogen, or is capable of inducing an immunological response in a host infected by the pathogen, or tumor-associated antigen (TAA) which is a polypeptide specifically expressed in tumor cells.
  • TAA tumor-associated antigen
  • the antigen may be selected from a pathogen or cancer cells including, but not limited to, Human Papillomavirus (HPV), Porcine reproductive and respiratory syndrome virus (PRRSV), Human immunodeficiency virus- 1 (HIV- 1), flu virus, Dengue virus, Hepatitis C virus (HCV), Hepatitis B virus (HBV), Porcine Circovirus 2 (PCV2), Classical Swine Fever Virus (CSFV), Foot- and-mouth disease virus (FMDV), Newcastle disease virus (NDV), Transmissible gastroenteritis virus (TGEV), Porcine epidemic diarrhea virus (PEDV), Influenza virus, Pseudorabies virus, Parvovirus, Pseudorabies virus, Swine vesicular disease virus (SVDV), Poxvirus, Rotavirus, Mycoplasma pneumonia, Herpes virus, infectious bronchitis, or infectious bursal disease virus, non- small cell lung cancer, breast carcinoma, melanoma, lymphomas, colon carcinoma, hepato
  • HPV E7 protein E7
  • HCV core protein HCV core
  • HBV X protein HBx
  • the antigen may be a fusion antigen from a fusion of two or more antigens selected from one or more pathogenic proteins.
  • a fusion antigen of PRRSV ORF6 and ORF5 fragments or a fusion of antigenic proteins from PRRSV and PCV2 pathogens.
  • an endoplasmic reticulum retention signal is to assist translocation of an antigen from an endocytotic compartment into ER and retains it in the lumen. It comprises the sequence Lys Asp Glu Leu (K.DEL) or RDEL.
  • An ER retention sequence may comprise, or consists essentially of, or consist of, the sequence of KKDLRDELKDEL (SEQ ID NO: 16), KKDELRDELKDEL (SEQ ID NO: 17), KKDELRVELKDEL (SEQ ID NO: 18), or KDELKDELKDEL (SEQ ID NO: 19).
  • Receptor-associated protein with a molecular weight of 39 kDa is an ER resident protein and molecular chaperone for LDL receptor-related protein. It has a high binding affinity to CD91 (Kd ⁇ 3 nM) and is composed by three functional-similar domains.
  • the PE 407 (or PE1-407; SEQ ID NO. 40) is described in prior patent (US 7,335,361 B2) as ⁇ ( ⁇ ).
  • a nuclear export signal refers to a short amino acid sequence of 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport.
  • the NES is recognized and bound by exportins.
  • the most common spacing of the hydrophobic residues to be L 1 X 2 X 3 K 4 L 5 X 6 X 7 L , X 9 L ,0 X 11 (SEQ ID NO. 44), where **L" is leucine, "K” is lysine and " ⁇ 2 3 ⁇ 6 ⁇ 7 ⁇ 9 11 " is any naturally occurring amino acid.
  • an artificial NES may comprise the sequence Leu Gin Lys Lys Leu Glu Glu Leu Glu Leu Ala (LQKKLEELELA; SEQ ID NO: 45).
  • NESK refers to a fusion peptide of a NES and an ER retention signal (i.e., a NES fused to an ER retention signal). It is an artificial peptide possessing the function of a nuclear export signal (NES) and an ER retention sequence. Thus, it can export an antigen from the cell nucleus to the cytoplasm through the nuclear pore complex and assist translocation of an antigen from the cytoplasm to ER and retain the antigen in the lumen of the ER.
  • the amino acid sequence of NESK may be LQKKLEELELAKDEL (SEQ ID NO: 43).
  • a fusion protein comprising NESK has been disclosed in US Patent No. 9339536.
  • subject refers to a human or a non-human animal.
  • treating refers to administration of an effective amount of the fusion protein to a subject in need thereof, who has cancer or infection, or a symptom or predisposition toward such a disease, with the purpose of cure, alleviate, relieve, remedy, ameliorate, or prevent the disease, the symptoms of it, or the predisposition towards it.
  • a subject can be identified by a health care professional based on results from any suitable diagnostic method.
  • an effective amount refers to the amount of an active compound that is required to confer a therapeutic effect on the treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on rout of administration, excipient usage, and the possibility of co- usage with other therapeutic treatment.
  • CD 28 Cluster of Differentiation 28;
  • TVGV-1 PE 407 -E7-K3 (PEK) + GPI-0100;
  • the immunogenic proteins were expressed in E. coli expression system as described in U.S. Patent No. 9,775,898. They may be antigen itself only fused to the C-terminus of RAP1- CD28convPE t fusion protein to generate RAP 1 -CD28convPE t -( Antigen) fusion protein (without the ER retention signal K3).
  • US Patent No. 9481714 discloses a fusion protein RAPl-CD28convPE,- Antigen (without the ER retention signal K3) can still elicit strong T-cell responses.
  • the immunogenic protein may be an antigen and an ER retention signal (K3) fused to the C- terminus of Pseudomonas exotoxin A domains I and II (i.e., PE 407 ) to generate PEto7-(antigen)-K3 fusion protein, or an antigen and an ER retention signal fused to the C-terminus of RAP1- CD28convPE t fusion protein to generate RAPl-CD28convPE t -(Antigen)-K3 fusion protein.
  • K3 ER retention signal
  • the antigen HPV E7 antigen was used to construct two fusion protein PE 407 -E7-K3 (SEQ ID NO: 54) and RAPl-CD28convPE t -E7-K3 (SEQ ID NO: 55) for illustrations of the invention.
  • Spleen tissues were isolated from mice and processed into single cell suspensions using PP micro centrifuge sample pestle. Splenocytes were seeded on 6-well plates at 2x10 7 /2ml, stimulated with or without HPV16E7-peptide and cultured overnight in a C0 2 -containing incubator. The cells were then treated with the protein transport inhibitor monensin (Cat. no. 00-4505-51) and brefeldin (Cat. no. 00-4506-51) for 4 hours at 37°C. Afterward, cells were harvested, washed twice with PBS and stained for the surface marker CD3, CD4 and CD8 for 30 minutes at 4°C. After washing, the cells were fixed for 30 minutes at the room temperature using intracellular (IC) fixation buffer (Cat. no. 00-8222-49), then washed in permeabilization buffer (Cat. no. 00-8333-56) and stained with IFN ⁇ antibody.
  • IC intracellular
  • Tumor tissues were isolated from mice and processed into single cell suspensions using a mouse tumor dissociation kit (Cat. no. 130-096-730). Cells were seeded on 10 cm-petri dishes at 1x10 7 cells/10 ml, stimulated with or without HPV16E7 -peptide and cultured overnight in a CO 2 - containing incubator. The cells were then treated with the protein transport inhibitor monensin and brefeldin for 4 hours at 37°C, harvested, washed twice with PBS, and stained for the surface marker CD3, CD4, COS, or isotype control rat IgG for 30 minutes at 4°C. After washing, the cells were fixed for 30 min at the room temperature using IC fixation buffer, washed in permeabilization buffer and stained with IFN ⁇ antibody or TNFa antibody.
  • a mouse tumor dissociation kit Cat. no. 130-096-730.
  • tissue samples were analyzed for individual mice.
  • tissue samples were pooled within the groups in order to have a sufficient number of tumor tissue cells for analyses.
  • Events of 1.5 million cells were acquired on the BACKMAN COULTER® GALLIOSTM.
  • Flow data were analyzed using Kaluza software (vl.2). Populations were first gated on viable lymphocytes using forward and side scatter, subsequently gated on CD3+ T cells, and then sub-gated on desired double-positive T cells (e.g. CD4+/IFN ⁇ +, CD8+/ ⁇ +, CD4+/TNFa+ or CD8+/TNF ⁇ +).
  • desired double-positive T cells e.g. CD4+/IFN ⁇ +, CD8+/ ⁇ +, CD4+/TNFa+ or CD8+/TNF ⁇ +.
  • CD8-PE CD8 monoclonal antibody, R- phycoerythrin
  • CD3-AF647 ALEXA FLUOR® 647 anti-mouse CD3 antibody
  • CD4-AF700 ALEXA FLUOR® 700 anti-mouse CD4 antibody
  • AF488 ALEXA FLUOR® 488 Dye
  • the E7 immunogenic proteins comprises the antigen HPV E7.
  • the exemplified E7 fusion proteins are PE 407 -E7-K3, and RAPl-CD28convPE t -E7-K3.
  • Each fusion protein were combined with the adjuvant GPI-0100 (Hawaii Biotech) or CpG1826 (Cat. No. tlrl-1826, InvivoGen), and anti- OX40 antibody (Cat. No. 1 19408, Biolegend) and the immunogenicity of each mixture was tested in mice.
  • mice C57BL/6 at 5 weeks old of age were purchased from BioLASCO Taiwan Co., Ltd.
  • mice/cage with a 12-hour day/12-hour night light cycle Given free access to food and water, the mice were housed for one week and maintained under standard conditions prior to experimentation. Mice were vaccinated once per week for 3 weeks with vaccine formulations as indicated in Table 1 and FIG. 1A. All mice were sacrificed 7 days after the last immunization, and the spleens were harvested. Splenocytes were isolated and analyzed by flow cytometric analysis.
  • Table 1 shows PE 407 -E7-K3 (PEK) vaccination groups, adjuvant GPI-0100, OX40 antibody doses.
  • FIG. IB shows the results of the ELISA analysis of the humoral immune response.
  • TVGV-1 stands for PE 407 -E7-K3 (PEK) plus GPI-0100.
  • Rat IgG served as OX40 control antibody.
  • FIG. 2 A shows an immunization schedule for TC-1 tumor-bearing mice.
  • Table 2 shows the dose of PE*o7-E7-K3 (PEK), adjuvant GPI-0100 (also abbreviated as "GPI"), OX40 antibody (also abbreviated as "aOX40") in each group.
  • PKI PE*o7-E7-K3
  • GPI-0100 also abbreviated as "GPI”
  • OX40 antibody also abbreviated as "aOX40”
  • Rat IgG served as OX40 control antibody. Mice were considered and counted as dead if they had a tumor size larger than 2000 mm 3 or had a tumor with an average diameter greater than 20 mm.
  • TILs tumor-infiltrating lymphocytes
  • mice were injected s.c. with 1x10 3 TC-1 tumor cells in 200 ⁇ 1 PBS prior to vaccinations to examine tumor growth and cell-mediated immunities.
  • mice were sacrificed (FIG. 3A), tumors removed, and the relationship between TILs and tumor cells were studied via flow cytometric analyses as described above. Table 3 shows the vaccination groups and doses.
  • PEK plus GPI-0100 with anti-OX40 antibody elicited the greatest number of CD8+/IFN ⁇ + double-positive T cells, but not the CD4+ IFN ⁇ + T cells in the splenocytes (FIG. 3C) and the tumor cell supernatant (FIGs. 3D-E). This indicated that PEK plus GPI-0100 with anti-OX40 antibody induced more cytotoxic T-cells to infiltrate into the tumor tissues.
  • Mixing the antigen- specific fusion protein TVGV-1 (PEK+GPI-0100) and anti-OX40 antibody together before injection produced a better outcome in increasing cytotoxic CD8+ T cells than being injected separately (FIGs. 3C-E).
  • PEK plus GPI-0100 with anti-OX40 antibody also elicited the greatest number of CD8+/IFN ⁇ + double positive T cells, but not the CD4+/IFN ⁇ + T cells in the total tumor cells (FIGs. 3F-G).
  • FIG. 4A shows an immunization schedule for TC-1 tumor-bearing mice.
  • the amount per dose for antigenic fusion protein is 100 ⁇ g, the adjuvant CpG1826 20 ⁇ g, the OX 40 agonistic antibody 100 ⁇ g.
  • Rat IgG served as OX40 control antibody.
  • the fusion protein vaccine TVGV-2 and OX40 monoclonal antibody were mixed before the injection. After sacrifice, spleen and tumor tissues were separately collected and analyzed by flow cytometric analysis as described above.
  • RAPl-CD28convPE t -E7-K3+CpG1826 with anti-OX40 antibody showed the greatest increase in tumor mouse survival and the greatest decrease in tumor size (FIGs. 4B-C).
  • the combination of RAPl-CD28convPE t -E7-K3/CpG 1826 with anti-OX40 antibody in a mixture also showed the greatest increase in CD4+/IFN ⁇ + and CD8+/IFN ⁇ + double-positive T cells in splenocytes (FIG. 4D-E).
  • FIG. 5 A shows an immunization schedule for TC-1 tumor-bearing mice.
  • the amount per dose for the antigenic fusion protein RAPl-CD28convPE t -E7-K3 was 50 ⁇ g, the adjuvant CpG1826 20 ⁇ g, the anti-CD40 antibody 100 ⁇ g or the anti-OX 40 agonistic antibody 100 ⁇ g (200 ⁇ l).
  • the fusion protein vaccine TVGV-2 and monoclonal antibody were mixed before the injection.
  • Table 4 shows the SEQ ID NOs. of the components of various fusion proteins.
  • Table 5 shows the fusion proteins tested for the effects on T cell-mediated immune responses in animals and the sequences of antigens.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un mélange d'une composition vaccinale et d'un anticorps anti-OX40. Le vaccin comprend une protéine de fusion et un adjuvant à base de saponine ou un adjuvant de type agoniste des récepteurs de type Toll (TLR). La protéine de fusion comprend un domaine se liant aux cellules présentatrices d'antigène ou un domaine se liant aux récepteurs CD91, un domaine de transduction protéique, un antigène et éventuellement un signal de rétention du réticulum endoplasmique. Le domaine de transduction protéique est choisi parmi (i) un polypeptide de fusion, comprenant un peptide de transduction de signal de sensibilisation aux cellules T, un peptide de translocation et un lieur ; (ii) un peptide de transduction de signal de sensibilisation aux cellules T ; et (iii) un peptide long de 34 à 112 résidus acides aminés.
PCT/US2018/067576 2017-12-29 2018-12-26 Combinaison d'un vaccin à protéine de fusion avec un anticorps anti-ox40 destinée à être utilisée pour déclencher des réponses immunitaires spécifiques de l'antigène WO2019133647A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762611777P 2017-12-29 2017-12-29
US62/611,777 2017-12-29

Publications (1)

Publication Number Publication Date
WO2019133647A1 true WO2019133647A1 (fr) 2019-07-04

Family

ID=67068103

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/067576 WO2019133647A1 (fr) 2017-12-29 2018-12-26 Combinaison d'un vaccin à protéine de fusion avec un anticorps anti-ox40 destinée à être utilisée pour déclencher des réponses immunitaires spécifiques de l'antigène

Country Status (1)

Country Link
WO (1) WO2019133647A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11246915B2 (en) 2010-09-15 2022-02-15 Applied Molecular Transport Inc. Cholix toxin-derived fusion molecules for oral delivery of biologically active cargo
US11324833B2 (en) 2018-11-07 2022-05-10 Applied Molecular Transport Inc. Cholix-derived carriers for oral delivery of heterologous payload
US11426466B2 (en) 2018-03-08 2022-08-30 Applied Molecular Transport Inc. Toxin-derived delivery constructs for pulmonary delivery

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160250324A1 (en) * 2015-02-26 2016-09-01 Thevax Genetics Vaccine Co., Ltd. Vaccine composition comprising an immunogenic protein and combination adjuvants for use in eliciting antigen-specific t-cell responses
US20170275371A1 (en) * 2015-08-06 2017-09-28 Glaxosmithkline Intellectual Property Development Limited Methods Of Treatment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160250324A1 (en) * 2015-02-26 2016-09-01 Thevax Genetics Vaccine Co., Ltd. Vaccine composition comprising an immunogenic protein and combination adjuvants for use in eliciting antigen-specific t-cell responses
US20170275371A1 (en) * 2015-08-06 2017-09-28 Glaxosmithkline Intellectual Property Development Limited Methods Of Treatment

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11246915B2 (en) 2010-09-15 2022-02-15 Applied Molecular Transport Inc. Cholix toxin-derived fusion molecules for oral delivery of biologically active cargo
US11426466B2 (en) 2018-03-08 2022-08-30 Applied Molecular Transport Inc. Toxin-derived delivery constructs for pulmonary delivery
US11324833B2 (en) 2018-11-07 2022-05-10 Applied Molecular Transport Inc. Cholix-derived carriers for oral delivery of heterologous payload
US11504433B2 (en) 2018-11-07 2022-11-22 Applied Molecular Transport Inc. Cholix-derived carriers for oral delivery of heterologous payload

Similar Documents

Publication Publication Date Title
US9775898B2 (en) Vaccine composition comprising an immunogenic protein and combination adjuvants for use in eliciting antigen-specific T-cell responses
US9676827B2 (en) Fusion proteins for use as immunogenic enhancers for inducing antigen-specific T cell responses
US20230295245A1 (en) Mutant fragments of ospa and methods and uses relating thereto
Kim et al. Effect of immunological adjuvant combinations on the antibody and T-cell response to vaccination with MUC1–KLH and GD3–KLH conjugates
WO2019133647A1 (fr) Combinaison d'un vaccin à protéine de fusion avec un anticorps anti-ox40 destinée à être utilisée pour déclencher des réponses immunitaires spécifiques de l'antigène
Kim et al. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women
Volckmar et al. Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver
JP4223813B2 (ja) 免疫増強特性を有するムチンペプチド
Klopfleisch et al. Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver
EA046886B1 (ru) МУТАНТНЫЕ ФРАГМЕНТЫ OspA И СВЯЗАННЫЕ С НИМИ СПОСОБЫ И ПРИМЕНЕНИЕ

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18895655

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18895655

Country of ref document: EP

Kind code of ref document: A1