Immunostimulatory compositions and methods
AssigneeUniversity of Lousville Research Foundation, Inc.
InventorsHaval Shirwan, Kutlu Elpek, Esma Yolcu
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Abstract
The invention provides conjugates comprising an immune co-stimulatory polypeptide and an antigen or infectious agent. The conjugates are useful for generating or enhancing an immune response against the antigen or infectious agent. The invention also provides immune cells modified with a conjuagte that are useful for generating or enhancing an immune response to an antigen or infectious agent. The invention also provides immunostimulatory moieties comprising an immune co-stimulatory polypeptide that are useful for stimulating an immune response. The invention also provides immunotherapy methods and methods of treating or preventing infections.
Claims121
A combination comprising:
- (a) a first conjugate comprising (i) a conjugate member comprising a first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair;
- and
- (b) a second conjugate comprising (i) a conjugate member comprising a first antigen and (ii) a conjugate member comprising a second member of said binding pair.
The combination of embodiment 1, wherein said first member of said binding pair comprises avidin or streptavidin and said second member of said binding pair comprises biotin.
The combination of embodiment 2, wherein said first member of said binding pair comprises core streptavidin.
The combination of embodiment 1, wherein said first conjugate comprises a fusion polypeptide comprising said first immune co-stimulatory polypeptide and said first member of said binding pair.
The combination of embodiment 1, wherein said first immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The combination of embodiment 5, wherein said first immune co-stimulatory polypeptide is 4-1BBL.
The combination of embodiment 6, wherein said first conjugate comprises a fusion polypeptide comprising the amino acid sequence of SEQ ID NO:8.
The combination of embodiment 1, wherein said first antigen is associated with an infectious agent.
The combination of embodiment 8, wherein said infectious agent is selected from the group consisting of human or avian influenza and human immunodeficiency virus.
The combination of embodiment 1, wherein said first antigen is a tumor associated antigen.
The combination of embodiment 10, wherein said tumor associated antigen is selected from the group consisting of human telomerase reverse transcriptase, survivin, MAGE-1, MAGE-3, human chorionic gonadotropin, carcinoembryonic antigen, alpha fetoprotein, pancreatic oncofetal antigen, MUC-1, CA 125, CA 15-3, CA 19-9, CA 549, CA 195, prostate-specific antigens;
- prostate-specific membrane antigen, Her2/neu, gp-100, mutant K-ras proteins, mutant p53, truncated epidermal growth factor receptor, chimeric protein p210BCR-ABL;
- HPV E6, HPV E7;
- Epstein-Barr virus EBNA3 protein, and mixtures or fragments thereof.
The combination of embodiment 1, wherein said first and second conjugates are provided as separate compositions.
The combination of embodiment 1, wherein said first and second conjugates are provided as a single composition.
The combination of embodiment 13, wherein said composition comprises a pharmaceutically acceptable carrier, excipient or diluent.
The combination of embodiment 13, wherein, as provided in said composition, said first conjugate is bound to said second conjugate via binding between said first and second binding pair members.
The combination of embodiment 1, wherein said first immune co-stimulatory polypeptide does not comprise the transmembrane domain of an immune co-stimulatory molecule.
The combination of embodiment 1, wherein said first immune co-stimulatory polypeptide comprises the extracellular domain of an immune co-stimulatory molecule, or a receptor binding portion thereof.
The combination of embodiment 1, further comprising a third conjugate comprising (i) a conjugate member comprising a second immune co-stimulatory polypeptide and a first member of a binding pair and (ii) a conjugate member comprising a second antigen and a second member of a binding pair, wherein:
- said second immune co-stimulatory polypeptide is the same as or different from said first immune co-stimulatory polypeptide;
- said second antigen is the same as or different from said first antigen;
- said first and second binding pair members of said third conjugate are the same as or different from said first and second binding pair members of said first and second conjugates, and
- said first conjugate member is bound to said second conjugate member via binding between said first and second binding pair members.
A combination comprising:
- (a) a first conjugate comprising (i) a conjugate member comprising a first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair;
- and
- (b) a second conjugate comprising (i) a conjugate member comprising an infectious agent and (ii) a conjugate member comprising a second member of said binding pair.
A method of generating or enhancing an immune response against a tumor which expresses a first tumor-associated antigen, comprising administering to a patient with said tumor:
- (a) a first conjugate comprising (i) a conjugate member comprising a first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair, and a second conjugate comprising (i) a conjugate member comprising said first tumor-associated antigen and (ii) a conjugate member comprising a second member of said binding pair;
- or
- (b) immune cells which have been treated in vitro with said first and second conjugates.
The method of embodiment 20, wherein said first and second conjugates are administered to said patient.
The method of embodiment 21, wherein said first and second conjugates are administered separately.
The method of embodiment 21, wherein said first and second conjugates are administered simultaneously.
The method of embodiment 20, wherein said first and second conjugates are provided in a single composition.
The method of embodiment 24, wherein, as provided in said composition, said first conjugate is bound to said second conjugate via binding between said first and second binding pair members.
The method of embodiment 21, wherein at least one of said first and second conjugates is administered by intratumoral injection.
The method of embodiment 20, wherein said first tumor-associated antigen is selected from the group consisting of human telomerase reverse transcriptase, survivin, MAGE-1, MAGE-3, human chorionic gonadotropin, carcinoembryonic antigen, alpha fetoprotein, pancreatic oncofetal antigen, MUC-1, CA 125, CA 15-3, CA 19-9, CA 549, CA 195, prostate-specific antigens;
- prostate-specific membrane antigen, Her2/neu, gp-100, mutant K-ras proteins, mutant p53, truncated epidermal growth factor receptor, chimeric protein p210BCR-ABL;
- HPV E6, HPV E7;
- Epstein-Barr virus EBNA3 protein, and mixtures or fragments thereof.
The method of embodiment 20, further comprising administering a third conjugate comprising (i) a conjugate member comprising a second immune co-stimulatory polypeptide and a first member of a binding pair and (ii) a conjugate member comprising a second tumor-associated antigen and a second member of a binding pair, wherein:
- said second immune co-stimulatory polypeptide is the same as or different from said first immune co-stimulatory polypeptide;
- said second antigen is the same as or different from said first antigen;
- said first and second binding pair members of said third conjugate are the same as or different from said first and second binding pair members of said first and second conjugates, and
- said first conjugate member is bound to said second conjugate member via binding between said first and second binding pair members.
The method of embodiment 28, wherein said second tumor-associated antigen is selected from the group consisting of human telomerase reverse transcriptase, survivin, MAGE-1, MAGE-3, human chorionic gonadotropin, carcinoembryonic antigen, alpha fetoprotein, pancreatic oncofetal antigen, MUC-1, CA 125, CA 15-3, CA 19-9, CA 549, CA 195, prostate-specific antigens;
- prostate-specific membrane antigen, Her2/neu, gp-100, mutant K-ras proteins, mutant p53, truncated epidermal growth factor receptor, chimeric protein p210BCR-ABL;
- HPV E6, HPV E7;
- Epstein-Barr virus EBNA3 protein, and mixtures or fragments thereof.
The method of embodiment 20, wherein said first member of said binding pair comprises avidin or streptavidin and said second member of said binding pair comprises biotin.
The method of embodiment 30, wherein said first member of said binding pair comprises core streptavidin.
The method of embodiment 20, wherein said first conjugate comprises a fusion polypeptide comprising said first immune co-stimulatory polypeptide and said first member of said binding pair.
The method of embodiment 20, wherein said first immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The method of embodiment 33, wherein said first immune co-stimulatory polypeptide is 4-1BBL.
The method of embodiment 34, wherein said first conjugate comprises a fusion polypeptide comprising the amino acid sequence of SEQ ID NO:8.
The method of embodiment 20, wherein said immune co-stimulatory polypeptide does not comprise a transmembrane domain of an immune co-stimulatory molecule.
The method of embodiment 20, wherein said immune co-stimulatory polypeptide comprises the extracellular domain of an immune co-stimulatory molecule, or a receptor binding portion thereof.
The method of embodiment 20, wherein said patient is administered immune cells which have been treated in vitro with said first and second conjugates.
The method of embodiment 38, wherein said immune cells comprise a receptor for said immune co-stimulatory polypeptide, and wherein said first conjugate is conjugated to said immune cells via binding between said immune co-stimulatory polypeptide and said receptors, and said second conjugate is conjugated to said immune cells via binding between said first and second binding pair members.
The method of embodiment 38, wherein said immune cells are treated with said first and second conjugates simultaneously.
The method of embodiment 38, wherein said immune cells are treated with said first and second conjugates separately.
A method of modifying immune cells to generate or enhance an immune response to a tumor expressing a tumor-associated antigen or to an infectious agent, comprising contacting immune cells expressing a receptor for a first immune co-stimulatory polypeptide with:
- (a) a first conjugate comprising (i) a conjugate member comprising said first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair;
- and
- (b) a second conjugate comprising (i) a conjugate member comprising an antigen associated with said tumor or infectious agent or said infectious agent and (ii) a conjugate member comprising a second member of said binding pair,
- wherein said first conjugate is conjugated to said immune cells via binding between said immune co-stimulatory polypeptide and said receptor, and said second conjugate is conjugated to said immune cell via binding between said first and second binding pair members.
The method of embodiment 42, wherein said first conjugate and second conjugates are contacted separately.
The method of embodiment 42, wherein said first and second conjugates are contacted simultaneously.
The method of embodiment 44, wherein said first and second conjugates are provided in a single composition.
The method of embodiment 45, wherein, as provided in said composition, said first conjugate is bound to said second conjugate via binding between said first and second binding pair members.
The method of embodiment 42, wherein said contacting is effected by administering said first and second conjugates to a patient containing said immune cells.
The method of embodiment 47, wherein said second conjugate comprises a tumor associated antigen, said patient further comprises said tumor, and at least one of said first and second conjugates is administered by intratumoral injection.
The method of embodiment 42, wherein said immune cell is a T cell or neutrophil.
The method of embodiment 49, wherein said T cell is selected from the group consisting of CD4+ cells, CD8+ cells, natural killer cells, monocytes and dendritic cells.
The method of embodiment 42, wherein said second conjugate comprises a tumor-associated antigen.
The method of embodiment 51, wherein said tumor-associated antigen is selected from the group consisting of human telomerase reverse transcriptase, survivin, MAGE-1, MAGE-3, human chorionic gonadotropin, carcinoembryonic antigen, alpha fetoprotein, pancreatic oncofetal antigen, MUC-1, CA 125, CA 15-3, CA 19-9, CA 549, CA 195, prostate-specific antigens;
- prostate-specific membrane antigen, Her2/neu, gp-100, mutant K-ras proteins, mutant p53, truncated epidermal growth factor receptor, chimeric protein p210BCR-ABL;
- HPV E6, HPV E7;
- Epstein-Barr virus EBNA3 protein, and mixtures or fragments thereof.
The method of embodiment 42, wherein said second conjugate comprises an antigen associated with an infectious agent or the infectious agent.
The method of embodiment 42, wherein said infectious agent is a bacteria.
The method of embodiment 54, wherein said bacteria is selected from the group consisting of Mycobacterium tuberculosis;
- Bacillus anthracis;
- Staphylococcus aureus.
The method of embodiment 42, wherein said infectious agent is a virus.
The method of embodiment 56, wherein said virus is selected from the group consisting of Adenoviridae;
- Arenaviridae Caliciviridae;
- Coronaviridae;
- Filoviridae;
- Flaviviridae;
- Hepadnaviridae;
- Herpesviridae;
- Orthomyxoviridae;
- Papillomaviridae;
- Picomaviridae;
- Poxviridae;
- Reoviridae;
- Retroviridae;
- Rhabdoviridae;
- and Togaviridae;
The method of embodiment 42, wherein said infectious agent is a parasite
The method of embodiment 58, wherein said parasite is selected from the group consisting of Plasmodium and Leishmania.
The method of embodiment 42, wherein said infectious agent is a fungus
The method of embodiment 60, wherein said fungus is selected from the group consisting of Aspergillis;
- Candida;
- Coccidia;
- Cryptococci;
- Geotricha;
- Histoplasma;
- Microsporidia;
- and Pneumocystis
The method of embodiment 47, wherein said patient is selected from the group consisting of equine, ovine, caprine, bovine, porcine, avian, canine, feline and primate species.
The method of embodiment 47, wherein said patient is human.
The method of embodiment 42, wherein said immune cells comprise a receptor for a second immune co-stimulatory polypeptide, the method further comprising contacting said immune cells with a third conjugate comprising (i) a conjugate member comprising said second immune co-stimulatory polypeptide and a first member of a binding pair and (ii) a conjugate member comprising a second antigen associated with said tumor or infectious agent or said infectious agent and a second member of said binding pair, wherein:
- said second immune co-stimulatory polypeptide is the same as or different from said first immune co-stimulatory polypeptide;
- said second antigen, if present, is the same as or different from said first antigen, if present;
- said first and second binding pair members of said third conjugate are the same as or different from said first and second binding pair members of said first and second conjugates, and
- said first conjugate member is bound to said second conjugate member via binding between said first and second binding pair members.
The method of embodiment 42, wherein said first member of said binding pair comprises avidin or streptavidin and said second member of said binding pair comprises biotin.
The method of embodiment 65, wherein said first member of said binding pair comprises core streptavidin.
The method of embodiment 42, wherein said first conjugate comprises a fusion polypeptide comprising said first immune co-stimulatory polypeptide and said first member of said binding pair.
The method of embodiment 42, wherein said first immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The method of embodiment 68, wherein said first immune co-stimulatory polypeptide is 4-1BBL.
The method of embodiment 69, wherein said first conjugate comprises a fusion polypeptide comprising the amino acid sequence of SEQ ID NO:8.
The method of embodiment 42, wherein said immune co-stimulatory polypeptide does not comprise a transmembrane domain of an immune co-stimulatory molecule.
The method of embodiment 42, wherein said immune co-stimulatory polypeptide comprises the extracellular domain of an immune co-stimulatory molecule, or a receptor binding portion thereof.
A population of immune cells made by the method of embodiment 42, wherein said immune cells generate or enhance an immune response to said tumor when contacted with other immune cells.
A modified immune cell expressing a receptor for a first immune co-stimulatory polypeptide, wherein said modified immune cell comprises:
- a) a first conjugate comprising (i) a conjugate member comprising said first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair;
- and
- (b) a second conjugate comprising (i) a conjugate member comprising a first antigen or infectious agent and (ii) a conjugate member comprising a second member of said binding pair,
- wherein said first conjugate is conjugated to said immune cell via binding between said immune co-stimulatory polypeptide and said receptor, and said second conjugate is conjugated to said immune cell via binding between said first and second binding pair members.
The immune cell of embodiment 74, wherein said immune cell is selected from the group consisting of T cells, neutrophils, natural killer cells, monocytes and dendritic cells.
The immune cell of embodiment 75, wherein said T cell is selected from the group consisting of CD4+ cells and CD+ cells.
The immune cell of embodiment 76, wherein said first member of said binding pair comprises avidin or streptavidin and said second member of said binding pair comprises biotin.
The immune cell of embodiment 76, wherein said first member of said binding pair comprises core streptavidin.
The immune cell of embodiment 74, wherein said first conjugate comprises a fusion polypeptide comprising said first immune co-stimulatory polypeptide and said first member of said binding pair.
The immune cell of embodiment 74, wherein said first immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The immune cell of embodiment 80, wherein said first immune co-stimulatory polypeptide is 4-1BBL.
A method of inducing or enhancing an immune response against an infectious agent, comprising administering to a patient suffering from or at risk of infection with said infectious agent:
- a) a first conjugate comprising (i) a conjugate member comprising a first immune co-stimulatory polypeptide and (ii) a conjugate member comprising a first member of a binding pair;
- and
- (b) a second conjugate comprising (i) a conjugate member comprising a first antigen associated with said infectious agent or comprising said infectious agent and (ii) a conjugate member comprising a second member of said binding pair.
The method of embodiment 82, wherein said first and second conjugates are administered separately.
The method of embodiment 82, wherein said first and second conjugates are administered simultaneously.
The method of embodiment 84, wherein said first and second conjugates are provided in a single composition.
The method of embodiment 85, wherein, as provided in said composition, said first conjugate is bound to said second conjugate via binding between said first and second binding pair members.
The method of embodiment 82, wherein at least one of said first and second conjugates is administered by a route selected from the group consisting of:
- oral;
- sublingual;
- transmucosal;
- transdermal;
- rectal;
- vaginal;
- subcutaneous;
- intramuscular;
- intravenous;
- intra-arterial;
- intrathecal;
- via catheter;
- via implant;
- and directly into a tumor.
The method of embodiment 82, wherein said infectious agent is a bacteria.
The method of embodiment 88, wherein said bacteria is selected from the group consisting of Mycobacterium tuberculosis;
- Bacillus anthracis;
- Staphylococcus aureus.
The method of embodiment 82, wherein said infectious agent is a virus.
The method of embodiment 90, wherein said virus is selected from the group consisting of Adenoviridae;
- Arenaviridae Caliciviridae;
- Coronaviridae;
- Filoviridae;
- Flaviviridae;
- Hepadnaviridae;
- Herpesviridae;
- Orthomyxoviridae;
- Papillomaviridae;
- Picomaviridae;
- Poxviridae;
- Reoviridae;
- Retroviridae;
- Rhabdoviridae;
- and Togaviridae;
The method of embodiment 82, wherein said infectious agent is a parasite
The method of embodiment 92, wherein said parasite is selected from the group consisting of Plasmodium and Leishmania.
The method of embodiment 82, wherein said infectious agent is a fungus
The method of embodiment 94, wherein said fungus is selected from the group consisting of Aspergillis;
- Candida;
- Coccidia;
- Cryptococci;
- Geotricha;
- Histoplasma;
- Microsporidia;
- and Pneumocystis
The method of embodiment 82, wherein said patient is selected from the group consisting of equine, ovine, caprine, bovine, porcine, avian, canine, feline and primate species.
The method of embodiment 96, wherein said patient is human.
The method of embodiment 82, wherein said infection is human or avian influenza and said first antigen is selected from the group consisting of H, N, M1, M2e, NS1, NS2 (NEP), NP, PA, PB1, and PB2.
The method of embodiment 82, wherein said infection is HIV and said first antigen is selected from the group of HIV antigens consisting of Gag proteins, Pol, Vif, Vpr, Rev, Vpu, envelope eptiopes, Tat, and Nef.
The method of embodiment 82, further comprising administering a third conjugate comprising (i) a conjugate member comprising a second immune co-stimulatory polypeptide and a first member of a binding pair and (ii) a conjugate member comprising a second antigen associated with said infection or said infectious agent and a second member of said binding pair, wherein:
- said second immune co-stimulatory polypeptide is the same as or different from said first immune co-stimulatory polypeptide;
- said second antigen, if present, is the same as or different from said first antigen, if present;
- said first and second binding pair members of said third conjugate are the same as or different from said first and second binding pair members of said first and second conjugates, and
- said first conjugate member is bound to said second conjugate member via binding between said first and second binding pair members.
The method of embodiment 100, wherein said infection is human or avian influenza and said second antigen is selected from the group consisting of H, N, M1, M2e, NS1, NS2 (NEP), NP, PA, PB1, and PB2.
The method of embodiment 101, wherein said infection is HIV and said second antigen is selected from the group of HIV antigens consisting of Gag proteins, Pol, Vif, Vpr, Rev, Vpu, envelope eptiopes, Tat, and Nef.
The method of embodiment 82, wherein said first member of said binding pair comprises avidin or streptavidin and said second member of said binding pair comprises biotin.
The method of embodiment 103, wherein said first member of said binding pair comprises core streptavidin.
The method of embodiment 82, wherein said first conjugate comprises a fusion polypeptide comprising said first immune co-stimulatory polypeptide and said first member of said binding pair.
The method of embodiment 82, wherein said first immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The method of embodiment 106, wherein said first immune co-stimulatory polypeptide is 4-1BBL.
The method of embodiment 107, wherein said first conjugate comprises a fusion polypeptide comprising the amino acid sequence of SEQ ID NO:8.
The method of embodiment 82, wherein said immune co-stimulatory polypeptide does not comprise a transmembrane domain of an immune co-stimulatory molecule.
The method of embodiment 82, wherein said immune co-stimulatory polypeptide comprises the extracellular domain of an immune co-stimulatory molecule, or a receptor binding portion thereof.
A conjugate consisting essentially of an immune co-stimulatory polypeptide and avidin or streptavidin, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The conjugate of embodiment 111, comprising core streptavidin.
The conjugate of embodiment 111, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, ICOSL, PD-L1, PD-L2, OX40L, CD27L, CD30L, LIGHT, BAFF, and APRIL.
A method of inducing an immunostimulatory response in an animal consisting essentially of administering to the animal a conjugate consisting essentially of an immune co-stimulatory polypeptide and avidin or streptavidin.
The method of embodiment 114, wherein said conjugate comprises core streptavidin.
The method of embodiment 114, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The method of embodiment 116, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, ICOSL, PD-L1, PD-L2, OX40L, CD27L, CD30L, LIGHT, BAFF, and APRIL.
A conjugate comprising an immune co-stimulatory polypeptide and avidin or streptavidin, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
A method of inducing an immunostimulatory response in an animal comprising administering to the animal a conjugate comprising an immune co-stimulatory polypeptide and avidin or streptavidin, wherein said immune co-stimulatory polypeptide is selected from the group consisting of 4-1BBL, CD86, ICOSL, PD-L1, PD-L2, B7-H3, B7-H4, OX40L, CD27L, CD30L, LIGHT, BAFF, APRIL, CD80 and CD40L.
The method of embodiment 119, further comprising administering an antigen to the animal.
The method of embodiment 120, wherein said antigen is administered as a conjugate comprising said antigen and a member of a binding pair.
Dependencies are inferred from the claim text.