WO1999052547A1 - Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof - Google Patents
Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof Download PDFInfo
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- WO1999052547A1 WO1999052547A1 PCT/US1999/008112 US9908112W WO9952547A1 WO 1999052547 A1 WO1999052547 A1 WO 1999052547A1 US 9908112 W US9908112 W US 9908112W WO 9952547 A1 WO9952547 A1 WO 9952547A1
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- adjuvant
- antigen
- cdl
- composition
- response
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- A—HUMAN NECESSITIES
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- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Vaccination induces specific immunity in a host against foreign viruses, bacteria or parasites. Many types of infectious agents and their products have been used as vaccines. However, not all vaccine compositions are capable of eliciting an immune response sufficient to protect the host against the challenge of infection. Similarly, many diseases, disorders or conditions exist in which the immune system is compromised or suppressed. Many treatments for such diseases or disorders are incapable or ineffective to boost or stimulate the immune system. Examples of such diseases or conditions are the AIDS disease, or a cancer patient that has undergone chemotherapy.
- a need exists to develop a composition or drug that stimulates or enhances the immune response.
- a need exists to enhance the immune response for vaccines that do not illicit a sufficient protective immune response in a host.
- a need exists for a composition that stimulates the immune system of an individual whose immune system is compromised.
- the present invention relates to methods of vaccinating or enhancing an immune response in a mammal to at least one CDl antigen that comprise administering (e.g., co- administering) to the mammal (e.g., individual) an effective amount of at least one CDl antigen (e.g., an non-peptide or lipid antigen) and at least one T-cell stimulating compound (e.g., an adjuvant), wherein the CDl antigen elicits a CDl -restricted response.
- CDl antigen e.g., an non-peptide or lipid antigen
- T-cell stimulating compound e.g., an adjuvant
- adjuvants examples include mineral salt adjuvants, Incomplete or Complete Freund's Adjuvants, Basille Calmette- Guerin adjuvants, block polymer adjuvants, cholera toxins, cytokines, CPG motif containing adjuvants, oil/water emulsion adjuvants, MF-59 adjuvants, LeIF adjuvants, liposome adjuvants, ISCOM adjuvants, Monophosphoryl A adjuvants, biodegradable microsphere adjuvants, muramyl dipeptide adjuvants, polyphosphozine adjuvants or saponin adjuvants (e.g., QS-7, QS-17, QS-18 and QS-21).
- adjuvants are mineral salt adjuvants, Incomplete or Complete Freund's Adjuvants, Basille Calmette- Guerin adjuvants, block polymer adjuvants, cholera toxins, cytokines, CPG motif containing adjuvants, oil/water emul
- the present methods elicit at least one immunological parameter, such as an antibody response to the antigen, cytotoxic T-Lymphocyte response, T-cell proliferation response, helper T-cell response or a T-cell modulated cytokine response.
- the methods can be used to enhance or boost the immune response of an individual who has an immuno-compromised disease, disorder or condition (e.g., AIDS or chemotherapy recipient).
- the present invention is used to elicit or boost an immune response for at least one bacterial infection (e.g., species of the Mycobacteria genus, Haemophilus genus, Streptococcus genus, Staphylococcus genus or Chlamydia genus) and /or at least one parasitic infection (e.g., species of the Plasmodium genus or Trypanosoma genus).
- the CDl antigen of the present invention can also be.
- a tumor associated or derived antigen that is involved in diseases such as cancer (e.g., melanoma, breast cancer, prostate cancer and colo-rectal cancer) or a self antigen that is involved in autoimmune diseases (e.g., diabetes, Lupus, rheumatoid arthritis).
- An embodiment of the methods can further include administering a peptide-based antigen from the same organism or cancer type, so that an individual can obtain a protective or enhancing immunological effect against a non-peptide antigen as well as a peptide antigen.
- the invention also pertains to immunogenic or vaccine compositions that comprise at least one T-cell stimulating compound (e.g., adjuvant), and at least one type of CDl antigen (e.g., non-peptide or lipid antigen), wherein the CDl antigen elicits a CDl -restricted response.
- T-cell stimulating compound e.g., adjuvant
- CDl antigen e.g., non-peptide or lipid antigen
- the CDl molecules are a family of molecules including CDla, CDlb, CDlc, CDld and CDle. Examples of adjuvants are described herein.
- the antigen of the composition is from at least one bacteria (e.g., species of the Mycobacteria genus, Haemophilus genus, Streptococcus genus, Staphylococcus genus or Chlamydia genus) and/or at least one parasite infection (e.g., species of the Plasmodium genus or Trypanosoma genus).
- bacteria e.g., species of the Mycobacteria genus, Haemophilus genus, Streptococcus genus, Staphylococcus genus or Chlamydia genus
- parasite infection e.g., species of the Plasmodium genus or Trypanosoma genus
- non-peptide antigen examples include a variety of lipids including a glycolipid, a phospholipid, a triglyceride, glycosylphosphatidylinositol (GPI), mycolic acid, glucose monomycolate (GMM), lipoarabinomannan (LAM), lipo-oligosaccharide or phosphatidylinositolmannoside (PIM).
- the composition can optionally comprise a carrier.
- kits that comprise at least one T-cell stimulating compound (e.g., adjuvant), and at least one type of CDl antigen (e.g., lipid antigen), wherein the CDl antigen elicits a CDl -restricted response.
- the kit comprises a CDl, e.g., lipid antigen from at least one bacteria and/or at least one parasite, and can optionally also comprise a peptide antigen (e.g., a peptide vaccine composition). Examples of adjuvants and types of lipid antigens are further described herein.
- the present invention provides more effective preventive and treatment options for individuals to obtain protection from serious bacterial and/or parasitic infections, or for cancer or autoimmune diseases, or immunotherapy for cancer or autoimmune diseases, by administering an adjuvant/CD 1 antigen composition.
- Figure 1 is a schematic illustrating mycobacterial lipid antigen preparation from Mycobacterium tuberculosis.
- Figure 2A is a bar graph showing the response of lymphocytes in Counts Per Minute (CPM), obtained from blood, to CDl -presented antigens: Ovalbumin (OVA), Mycobacterium phlei glucose monomycolate (GMM), Organic Extract (O/E), Acetone Fraction (Acetone Fx), Chloroform Fraction (CHC13 Fx), mycolic acid fractions (M. Acid).
- Ovalbumin Ovalbumin
- GMM Mycobacterium phlei glucose monomycolate
- O/E Organic Extract
- Acetone Fraction Acetone Fx
- Chloroform Fraction CHC13 Fx
- mycolic acid fractions M. Acid
- Figure 2B is a bar graph showing the response of lymphocytes in CPM, obtained from the spleen, to CDl -presented antigens: Ovalbumin (OVA), Mycobacterium phlei glucose monomycolate (GMM), Organic Extract (O/E), Acetone Fraction (Acetone Fx), Chloroform Fraction (CHC13 Fx), mycolic acid fractions (M. Acid).
- Figure 3 A is a graph illustrating the in vitro lymphocyte response in CPM to a purified lipid antigen, an acetone Fx ( ⁇ g/mL), in immunized animals (guinea pigs) combined with adjuvants Monophosphoryl Lipid A (MPL) and QS-21.
- Figure 3B is a graph illustrating the in vitro lymphocyte response in CPM to Mycobacterium phlei glucose monomycolate (GMM) ( ⁇ g/mL) in immunized animal (guinea pigs) combined with adjuvants Monophosphoryl Lipid A (MPL) and QS-21.
- GMM Mycobacterium phlei glucose monomycolate
- Figure 3C is a graph illustrating the in vitro lymphocyte response in CPM to Ovalbumin (OVA) ( ⁇ g/mL), in immunized animal (guinea pigs) combined with adjuvants Monophosphoryl Lipid A (MPL) and QS-21.
- OVA Ovalbumin
- MPL Monophosphoryl Lipid A
- Figure 4A is a graph showing the maximal proliferate response of CD4 depleted cells (CPM) from an animal immunized with the following CDl presented antigens combined with adjuvants MPL and QS-21.: GMM, Acetone Fx, CHC13 Fx, M.acid, and OVA.
- Figure 4B is a bar graph showing the maximal proliferate response in CPM from an animal immunized with the following CDl presented antigens combined with adjuvants MPL and QS-21.: GMM, Acetone Fx, CHC13 Fx, M.acid, and OVA.
- Figure 5A is a graph showing the primary ex vivo cytotoxic T-lymphocyte responses (specific lysis (%)) against an ET ratio from animals immunized with
- Figure 5B is a graph showing the primary ex vivo cytotoxic T-lymphocyte responses (specific lysis (%)) against an ET ratio from animals immunized with Acetone fractions of either 50 mg/ml (Acetone 50) or 25 mg/ml (Acetone 25) combined with adjuvants MPL and QS-21 for a CDlc2 antigen presenting pathway.
- Figure 5C is a graph showing the primary ex vivo cytotoxic T-lymphocyte responses (specific lysis (%)) against an ET ratio from animals immunized with Acetone fractions of either 50 mg/ml (Acetone 50) or 25 mg/ml (Acetone 25) combined with adjuvants MPL and QS-21 in a Mock or control system.
- Figure 6 is a bar graph showing the proliferative response in CPM of CDl restricted Mycobacterium turbuculosis lipid antigens specific T-cell lines (S2-CD8.1) raised from animals immunized with these lipid antigens.
- Figure 7 is a bar graph illustrating the cytotoxic T-lymphocyte responses (specific lysis (%)) of specific T-cell line (S2-CD8.1) of Mycobaterum turbuculosis lipid antigen Organic Extract in 1, 10 and 20 ⁇ g/ml concentrations.
- This cell line lysed M.turbuculosis lipid antigen pulsed 104C1-CD1M, CDlb2 and CDlc3 transfectants.
- the present invention relates to a vaccine composition or an immunogenic composition comprising at least one type of non-peptide antigen (e.g., a lipid antigen) and at least one T-cell stimulating compound (e.g., an adjuvant).
- the present invention utilizes the discovery that an Antigen Presenting Cell (APC) presents non-peptide antigens to T-cells in association with CDl molecules.
- a CDl antigen such as a lipid or non-peptide antigen (e.g., from bacteria or parasites) is ingested by an APC (e.g., macrophage, B-cell or dentritic cell) and then represented in conjunction with a CDl molecule, to thereby induce T-cell proliferation.
- APC e.g., macrophage, B-cell or dentritic cell
- the present invention utilizes the concept that a CDl antigen when combined with a T-cell stimulating compound, such as an adjuvant, elicits or boosts an immune response to the non-peptide antigen.
- a CDl antigen when combined with a T-cell stimulating compound, such as an adjuvant, elicits or boosts an immune response to the non-peptide antigen.
- the composition that comprises a CD 1 antigen and T-cell stimulating compound produces a significantly more effective immunogenic response than the antigen alone.
- the invention relates to an immunogenic composition or vaccine composition comprising a CDl antigen and a T-cell stimulating compound, as well as methods of use thereof.
- the invention pertains to an immunogenic composition comprising at least one
- T-cell stimulating compound and at least one CDl antigen (e.g., the CDl antigen adjuvant or non-peptide/adjuvant composition), wherein the CDl antigen elicits a CDl -restricted response.
- An immunogenic composition refers to a composition that contains these components and can produce or boost an immune response through the CDl- antigen presenting pathway, as described herein.
- a CDl -restricted response is a response in which the CDl -antigen presenting pathway is utilized, and can be independent of the MHC antigen presenting pathway.
- the immune response refers to enhancing the immune response of an individual or mammal, as compared to the immune response prior to administration of the composition of the present invention.
- To "elicit” an immune response is to create an immune response to an antigen, sufficient to confer a protective or immune enhancing effect against the CDl antigen.
- T-cell proliferation occurs and/or antibodies are made in response to the antigen.
- Various immunological parameters can be measured to assess the enhancement or elicitation of an immune response, such as an antibody response to the antigen (e.g., level or titer), cytotoxic T-lymphocyte response, helper T-cell response, T-cell proliferative response, or a T-cell modulated cytokine response (e.g., a cytokine that is modulated by the T-cell response). See Example 1.
- an antibody response to the antigen e.g., level or titer
- cytotoxic T-lymphocyte response e.g., helper T-cell response
- T-cell proliferative response e.g., T-cell proliferative response
- T-cell modulated cytokine response e.g., a cytokine that is modulated by the T-cell response.
- the present invention includes methods and vaccine compositions to elicit a protective effect against the CDl antigen, as well as methods and immunogenic compositions for boosting or enhancing the immune response to the CDl antigen.
- the present invention further includes eliciting an immune enhancing effect to peptide antigens.
- non-peptide antigens can be used to combat one or more diseases, and can be combined with peptide based vaccines to produce a more effective and complete vaccine composition.
- the non-peptide antigen and adjuvant can be combined with one or more peptide antigens from the same organism or tumor cell to provide a composition which confers a protective or immune enhancing effect against a multitude of antigens, including peptide and non-peptide antigens.
- a tuberculosis vaccine can include a M. tuberculosis encoded peptide, a non-peptide antigen from the M. tuberculosis cell wall and an adjuvant. Such a vaccine can protect an individual from tuberculosis or disease caused by M.
- the present invention includes vaccine or immunogenic compositions that comprise not only the non-peptide or lipid antigen and adjuvant, but also a peptide based antigen.
- the administration of the CDl antigen and the T-cell stimulating compound can occur simultaneously or sequentially in time.
- the T-cell stimulating compound can be administered before, after or at the same time as the CDl antigen.
- co- administration is used herein to mean that the CDl antigen and the T-cell stimulating compound will be administered at times to achieve the protective or immune enhancing effect against the CDl antigen.
- the methods of the present invention are not limited to the sequence in which the CDl antigen and adjuvant are administered, so long as the adjuvant is administered close enough in time to produce the desired effect, e.g., boosting or eliciting a CDl restricted response to the CDl antigen.
- the administration of the non-peptide antigen/adjuvant composition occurs simultaneously.
- the methods also include co-administration with other drugs that aid in eliciting or boosting an immunogenic response (e.g., cytokines such as IL-2, GM-CSF, and IL-12 and/or antibodies).
- a CDl antigen refers to an antigen that can undergo the CDl antigen presenting pathway after its administration (e.g., an antigen that is presented to the immune system in association with a CDl molecule).
- a CDl antigen is also referred to herein as "a CDl -presented antigen," an antigen that can elicit or produce a CDl -restricted response.
- a non-peptide antigen refers to an antigen in which the whole or a portion thereof is not a peptide, e.g., does not contain two or more amino acids in which a carboxyl group of one is united with an amino group of the other, with elimination of a water molecule.
- a CDl antigen has a hydrophobic moiety which binds nonspecifically to a CD1- molecule, which in turn positions hydrophilic components of the antigen for highly specific interactions with T-cell antigen receptors.
- a form of a CDl antigen is a lipid antigen.
- a lipid antigen can be obtained from a variety of biological sources, or can be synthesized. Such antigens can be isolated or synthesized by standard methods known to those skilled in the art, so that characteristics which allow the non-peptide antigen to be presented in the context of the CDl -antigen presenting pathway remain.
- non-peptide or lipid antigens can be isolated from a variety of biological sources including bacteria (e.g., gram negative or gram positive), parasites, plants, fungus, or other mammalian origins.
- the non-peptide antigen of the invention can be present in the form of the whole, but inactivated bacteria or parasite; and/or bacterial or parasitic portions thereof which retain their antigenicity.
- These lipid antigens are found in the cell wall of bacteria, parasites and/or fungi.
- lipid antigen components of Mycobacteria can be isolated by standard methods described in Goren, M.B. and
- Lipid fractions can be prepared from cultures of bacteria (e.g., Mycobacterium tuberculosis), as shown in Figure 1. Lipid fractions can be obtained using an alcohol mixture such as acetone or methanol, or chloroform. Extraction with chloroform or methanol separates the organic extract (O/E) from insoluble, dilapidated cell wall fractions. The O/E is placed on a silicone column and eluded with chloroform, acetone, and then methanol, which yields three purified fractions. The chloroform fraction contains triglycerides and free fatty acids.
- O/E organic extract
- the chloroform fraction contains triglycerides and free fatty acids.
- the acetone fraction contains glycolipid
- the methanol fraction contains various phospholipids such as phosphatidyl inositol, phosphatidyl ethanolamine and phosphatidyl glycerol.
- a lipid fraction such as a chloroform, acetone, or methanol fraction can be used to isolate a lipid antigen for the present invention.
- An "isolated" lipid antigenic fraction refers to a fraction containing a substantially purified amount of lipid molecules or antigens (e.g., greater than 80%, 85%, 90%, or 95%).
- CDl antigens include lipid antigens such as a lipoglycan, a glycolipid, a phospholipid, a triglyceride, glycosylphosphatidylinositol (GPI), mycolic acid, glucose monomycolate (GMM), lipoarabinomannan (LAM), lipo-oligosaccharide or phosphatidylinositolmannoside (PIM).
- the lipid antigen can comprise lipid based molecules, other than those described herein.
- the present invention includes immunogenic compositions or vaccine compositions that contain a portion of a organism (e.g., contains a CDl or lipid antigen), or the entire organism which has been altered to provide a protective or immune enhancing response without producing infection of the naturally occurring, live organism, e.g., without causing disease.
- a portion of a organism e.g., contains a CDl or lipid antigen
- these vaccines are live organism attenuative vaccines, killed organism vaccines, subunit vaccines, or toxoid vaccines.
- bacteria or parasites which contain non-peptide or lipid antigens that are used in the present invention are bacteria or parasites such as species of the Plasmodium genus (malaria), Mycobacteria genus (tuberculosis and leprosy), Streptococcus genus (streptococcosis), Staphylococcus genus (staphylococosis and pneumonia), Haemophilus genus (influenza), Chlamydia genus (chlamydiosis), or the Trypanosoma genus (trypanosomiosis).
- bacteria or parasites such as species of the Plasmodium genus (malaria), Mycobacteria genus (tuberculosis and leprosy), Streptococcus genus (streptococcosis), Staphylococcus genus (staphylococosis and pneumonia), Haemophilus genus (in
- mycobacteria are a genus of aerobic intracellular bacterial organisms which upon invasion of their host, survive within endosomal compartments of monocytes and macrophages.
- Human Mycobacterial diseases include tuberculosis (caused by M. tuberculosis), leprosy (caused by M. leprae), Bairnsdale ulcers (caused by M. ulcerans) and various infections caused by M. Marimum, M. kansasii, M. scrofulaceum, M. szulgai, M. xenopi, M fortuitum, M. chelonei, M. haemoph ⁇ um and M. intracellulare. Wolinsky, E.
- Tuberculosis OTA-H-574.
- U.S. Government Printing Office Washington, D.C., 1993.
- Mycobacterial strains which were previously considered to be nonpathogenic strains (e.g., M. avium) have now become major killers of lmmunosuppressed AIDS patients.
- current Mycobacterial vaccines are either inadequate, in the case of the BCG vaccine to M. th., or, with regard to M. leprae, unavailable. Kaugmann S., Microbiol. Sci. 4:324-328 (1987); U.S. Congress, Office of Technology Assessment. The Continuing Challenge of Tuberculosis, pp62-61.
- OTAH-574 U.S.
- the present invention encompasses vaccine compositions comprising non-peptide synthetically derived antigens that are effective against one or more gram negative, gram positive bacteria (including Streptococcus sp. and/or Staphylococcus sp.), one or more parasites (including mala ⁇ a) and one or more tumor antigens.
- LPS lipopolysaccharides
- Most gram positive bacteria contain structurally-related glycolipids such as lipoteichoic acids.
- the chemical composition of many disease-causing protozoa includes glycolipids such as the lipophosphoglycans of Leishmania. Orlandi, P.A. and S.J. Turco, J. Biol. Chem. 2(52:10384-10391.
- the cell walls and other cellular components of the fungi also contain lipoglycans. Therefore, the present invention includes vaccine composition comprising a non-peptide/lipid synthetic antigen/adjuvant complex which can be used to prevent or treat fungal infections of mammals.
- These antigens can include partial derivatives of LAM, GMM, PIM molecules or derivatives of similar glycolipids from microbial organisms, whether prokaryotic or eukaryotic in nature.
- the present invention uses various parasites or portions thereof as non-peptide antigens.
- diseases caused by protozoa include, but are not limited to, malaria, trichinosis, filariasis, trypanosomiasis, schistosomiasis, toxoplasmosis and leishmaniasis. Accordingly, the present invention provides methods and composition to treat parasite or protozoan infections.
- a synthetic antigen in accordance with this invention, is an antigen which is not naturally occurring in an organism.
- a synthetic antigen may be one that chemically synthesized, or parts thereof synthesized by combining elements, molecules or compounds. Further, a synthetic antigen can be constructed by combining two or more components, one or more of which is isolated or derived from an organism, thus producing a hybrid or chimeric antigen.
- a synthetic antigen comprising a lipid moiety and a hydrophilic moiety which is chemically synthesized, can be presented to a T cell by an APC in association with CDl molecules through the CDl antigen presenting pathway.
- T-cell stimulating compound is a compound that can increase T-cell proliferation or T-cell helper effects when introduced to the immune system with an antigen.
- T-cell stimulating compounds include adjuvants.
- An adjuvant is a substance which enhances the immunogenic response to an antigen.
- adjuvants are generally considered to be in one of two categories: 1) "vehicles” that help to transport and retain antigens in lymphoid tissues, or 2) "immuno-modulates” that stimulate locally secreted cytokines.
- Adjuvants can composed of bacteria or bacterial products which contribute to the immunogenicity of the antigen.
- adjuvants are mineral salt adjuvants (alum or calcium based adjuvant), Incomplete or Complete Freund's Adjuvant, Basille Calmette-Guerin (BCG) adjuvant, block polymer adjuvant (Titermax), cholera toxin (Cholera toxin-B-subunits, enterotoxin (LT) mutants), cytokines, CPG motif containing adjuvant, oil/water emulsion adjuvant (oil and water; water and oil; water, oil and water adjuvants), MF-59 adjuvants, LeIF adjuvants (e.g., protein based), liposome adjuvant, ISCOM adjuvant, Monophosphoryl A adjuvant (MPL), biodegradable microsphere adjuvant, muramyl dipeptide adjuvant, polyphosphozine adjuvant, and saponin adjuvant (QS-7, QS-17, QS-18, or QS-21).
- the compositions comprise two or more adjuvant
- lipid based vaccines are encompassed by the present invention.
- Individuals having diseases, such as cancer and autoimmune diseases can be vaccinated using a lipid/adjuvant composition.
- Cancers include melanoma, breast cancer, prostate cancer and colo-rectal cancer.
- Lipid based antigens from tumors can be used as the non- peptide antigen for the present invention.
- autoimmune diseases such as diabetes, Lupus, and rheumatoid arthritis can be treated with non-peptide/lipid antigens.
- a family of CDl molecules exists that participates in the CDl -antigen presenting pathway. In humans, the CD family is encoded by five non-polymorphic and closely linked genes located on a single chromosome.
- CDl proteins Five human CDl proteins exist, and are CDla, CDlb, CDlc, CDld and CDle. These CDl molecules are involved in the CDl antigen presenting pathway. Porcelli, S. et al., Immun. Rev., 120:137-183 (1991).
- the present invention can be used in mammals including humans, cats, dogs, horses, rodents, guinea pigs, etc.
- the present compositions and methods are intended for human as well as veterinarian use.
- the composition of the present invention can be administered with or without a carrier.
- pharmaceutically acceptable carrier or a “carrier” refer to any generally acceptable excipient or drug delivery composition that is relatively inert and non-toxic.
- Exemplary carriers include sterile water, salt solutions (such as Ringer's solution), alcohols, gelatin, talc, viscous paraffin, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidone, calcium carbonate, carbohydrates such as lactose, sucrose, dextrose, mannose, albumin, starch, cellulose, silica gel, polyethylene glycol (PEG), dried skim milk, rice flour, magnesium stearate, and the like.
- Suitable formulations and additional carriers are described in Remington's Pharmaceutical Sciences, (17 th Ed., Mack Pub. Co., Easton, PA), the teachings of which are incorporated herein by reference in their entirety.
- Such preparations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which do not deleteriously react with the active compounds. They can also be combined where desired with other active substances, e.g., enzyme inhibitors, to reduce metabolic degradation.
- a carrier e.g., a pharmaceutically acceptable carrier is preferred, but not necessary to administer the compound.
- compositions comprise a therapeutically (or prophylactically) effective amount of an immunogenic or vaccine compositions, including a CDl antigen, adjuvant, peptide antigen and/or a carrier.
- the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, or preservatives. Typical preservatives can include, potassium sorbate, sodium metabisulfite, methyl paraben, propyl paraben, thimerosal, etc.
- the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
- the method of administration can dictate how the composition will be formulated.
- the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
- the carrier can be added to the composition at any convenient time.
- the carrier can, for example, be added immediately prior to administration.
- the final product can be manufactured with the carrier.
- the immunogenic vaccine compositions of the invention can be administered intravenously, parenterally, intramuscular, subcutaneously, orally, nasally, topically, by inhalation, by implant, by injection, or by suppository.
- the composition can be administered in a single dose or in more than one dose (e.g., boosted) over a period of time to confer the desired effect.
- enteral or mucosal application particularly suitable are tablets, liquids, drops, suppositories or capsules.
- a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
- Topical application can also be used for example, in intraocular administration.
- Alternative methods of administration can include an immune-stimulating complex (ISCOM) as described in U.S. patent No. 4,900,549 (or European Patent Publication No. 0 604 727 Al (Publ. July 6, 1994).
- ISCOM immune-stimulating complex
- viral vectors, microspheres, and microcapsules are available and can be used.
- pulmonary administration such as an inhaler may be preferred for prophylactic purposes or for immediate and specific localized treatment.
- Pulmonary administration can be accomplished, for example, using any of various delivery devices know in the art. See. e.g., S.P. Newman (1984) in Aerosols and the Lung, Clarke and Davia (eds.), Butterworths, London, England, pp. 197-224; PCT Publication No. WO 92/16192; PCT Publication No. WO 91/08760; NTIS Patent.
- injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
- carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-polyoxypropylene block polymers, and the like. Ampules are convenient unit dosages.
- an effective amount of the drug is an amount of the drug which elicits or boosts an immune response to the non-peptide antigen. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol).
- kits comprising at least one T-cell stimulating compound (e.g. adjuvant) and at least one non-peptide antigen (e.g., a lipid antigen) wherein the non-peptide antigen elicits a CDl restricted response.
- the antigen can be obtained or isolated from at least one bacteria and/or parasite, or any other organism containing a lipid-based antigen.
- the antigen can also be a tumor associated (e.g., cancer) or a self (e.g., autoimmune disease) antigen.
- the kit can comprise various adjuvants as described herein.
- the adjuvant is QS-7, QS-17, QS-18, or QS-21.
- the kit can comprise a peptide antigen or vaccine, as described herein.
- EXEMPLIFICATION Example 1 Measuring Immunological Parameters including Antibody Response, Cytokine Response and T-cell Response
- Methods for assessing the antibody or cytokine response to a non-peptide antigen include several suitable assays that are known in the art.
- a sample from an individual who has received the adjuvant/non-peptide antigen composition can be analyzed.
- the level of cytokines which are affected by T-cell proliferation can be measured, as well as the level of antibody specific to the non-peptide that is made.
- An increase in the level of cytokines and or antibodies specific to the non-peptide antigen occurs after administration of the adjuvant/non-peptide antigen composition of the present invention.
- the sample can be any biological component that contains the cytokine or antibodies to the antigen (e.g., blood sample, urine sample, sputum sample, etc.).
- Suitable assays encompass immunological methods, radioimmunoassay, Flow cytometric assays, enzyme-linked immunosorbent assays (ELISA) and chemiluminescence assays.
- an assay includes combining or contacting the sample to be tested with the non-peptide antigen being assessed (e.g., the bacteria and/or parasitic antigen or portion thereof) under conditions suitable for formation of a complex between antibody and the antigen. The level of the complex formation is then detected or measured (directly or indirectly).
- immunological assays can be used. Instead of contacting the sample with the non-peptide antigen, as is done for assessing the level of antibody in the sample, one can combine the sample containing the cytokine with an antibody specific to the cytokine under conditions that are suitable for the formation of a complex between the cytokine and an anti-cytokine antibody. The level of the cytokine/anti-cytokine complex can then be detected.
- the sample can be obtained directly or indirectly (e.g., provided by a healthcare provider), and can be prepared by a method suitable for the particular sample and the assay format selected. For example, suitable methods for whole blood collection are venipuncture or obtaining blood from an in-dwelling arterial line.
- the container into which a healthcare provider deposits the blood can contain an anti-coagulant such as ACD-A, heparin, or EDTA.
- Suitable labels can be detected directly, such as radioactive, fluorescent or chemiluminescent labels. They can also be indirectly detected using labels such as enzyme labels and other antigenic or specific binding partners like biotin.
- labels examples include fluorescent labels such as fluorescein, rhodamine, CY5, chemiluminescent labels such as luciferase, radioisotope labels such as 32 P, 125 1, 131 I, enzyme labels such as horseradish peroxidase, and alkaline phosphatase, ⁇ -galactosidase, biotin, avidin, spin labels and the like.
- fluorescent labels such as fluorescein, rhodamine, CY5
- chemiluminescent labels such as luciferase
- radioisotope labels such as 32 P, 125 1, 131 I
- enzyme labels such as horseradish peroxidase, and alkaline phosphatase, ⁇ -galactosidase, biotin, avidin, spin labels and the like.
- the detection of antibodies in a complex can also be done immunologically with a second antibody which is then detected (e.g., by means of a label).
- the titer is determined by titration of the antiserum by serial dilution, and the point at which binding falls to 50% of the maximum.
- the titer is expressed as the reciprocal of the serum dilution which defines the end point.
- T-cell responses can also be measured using methods known in the art.
- a sample from an individual can be obtained, such as blood, bone marrow, lymphoid organs, epithelia and tissue or cells from an inflammation site.
- T-cell functions can be measured in various ways (e.g., target cell killing (CTL assays), macrophage activation, T-cell proliferation, B-cell activation, or lymphokine production.
- CTL assays target cell killing
- macrophage activation e.g., macrophage activation, T-cell proliferation, B-cell activation, or lymphokine production.
- T cells are detected by their effects on target cells displaying antigen, or the secretion of specific cytokines that act on such target cells. Measuring these effector functions forms the basis for T-cell bioassays used to assess both T-cell specificity for antigen and T-cell effector functions.
- Activated T cells generally kill any cells that display the specific peptide or lipid. Therefore, CD8 T-cell function can be determined using the simplest and most rapid T-cell bioassay-the killing of a target cell by a cytotoxic T cell. This can be detected in a 51 Cr-release assay. Live cells will take up, but do not spontaneously release, radioactively labeled sodium chromate, Na 2 51 CrO 4 . When these labeled cells are killed, the radioactive chromate is released and its presence in the supernatant of mixtures of target cells and cytotoxic T cells can be measured.
- proliferating lymphocytes can be labeled with 3 H-thymidine, which is incorporated into the replicating DNA. The cells are then collected and the incorporated CPM determined.
- These assays provide a rapid, sensitive, and specific measure of the activity of T cells.
- CD4 T-cell functions involve the activation rather than the killing of cells bearing specific antigen.
- the activating effects of CD4 T cells on B cells or macrophages are mediated in large part by non-specific mediator proteins called cytokines, which are released by the T cell when it recognizes antigen.
- cytokines non-specific mediator proteins
- Cytokines can be detected by their activity in biological assays of cell growth, where they serve either as growth factors or growth inhibitors, or more specifically by a modification of ELISA, known as a capture or sandwich ELISA, as described herein.
- the cytokine is characterized by its ability to bridge between two monoclonal antibodies reacting with different epitopes on the cytokine molecule.
- Sandwich ELISA can also be carried out by placing the cells themselves on a surface coated with antibody to a cytokine.
- cytokine released by each cell is trapped on the antibody coat and the presence of cytokine- secreting cells can be revealed when the cells are washed off and a labeled second anti- cytokine antibody is added.
- the cytokine released by each cell makes a distinct spot in this assay, which is therefore known as an ELISPOT assay.
- ELISPOT can also be used to detect specific antibody secretion by B cells, in this case using antigen-coated surfaces to trap specific antibody, and labeled anti-immunoglobulin to detect the bound antibody.
- Sandwich ELISA avoids a major problem of cytokine bioassays, the ability of different cytokines to stimulate the same response in a bioassay.
- Bioassays must always be confirmed by inhibition of the response with monoclonal antibodies against the cytokine.
- An alternative method is to identify cytokine mRNA, either in a cell population by reverse transcriptase-polymerase chain reaction (RT-PCR) or by in situ hybridization of single cells.
- Reverse transcriptase is an enzyme that is used by RNA viruses, like the human immunodeficiency virus that causes Acquired Immune Deficiency Syndrome (AIDS), to convert an RNA genome into a DNA copy, or cDNA.
- RNA viruses like the human immunodeficiency virus that causes Acquired Immune Deficiency Syndrome (AIDS)
- AIDS Acquired Immune Deficiency Syndrome
- the amount of product is proportional to its representation in the RNA in the responding cell.
- In situ hybridization uses labeled anti-sense RNA probes to hybridize with sense RNA in single cells, either isolated from culture or directly in tissue sections. This allows the number of cells making RNA encoding a particular cytokine to be determined. Janeway, Charles A., and Travers, Paul, "T-cell effector functions can be measured in four ways-target-cell killing, macrophage activation, B-cell activation, or lymphokine production," In Immuno Biology, The Immune System in Health and Disease, (New York and London: Garland Publishing Inc.), pp 2:31-2:33, the teaching of which are incorporated by reference herein in their entirety.
- Example 2 Methods for preparing lipid fractions, immunizing mammals, and other procedures for assessing immunological parameters.
- the lipid fractions disclosed herein were prepared from cultures of Mycobacterium tuberculosis cells by standard extraction methods. These extractions are diagramed in Figure 1. Following extraction with chloroform and methanol, the organic extract (O/E) was separated from the insoluble, delipidated cell wall fraction. The O/E was placed on a silica column and eluted with chloroform, acetone, and then methanol, which yielded three purified fractions. The chloroform fraction contained triglycerides and free fatty acids and represented 34% of the total extract by weight. A variety of glycolipids eluted with the acetone fraction which contained 12% of the extract.
- the methanol fraction comprised 29%o of the extract and contained various phospholipids such as phosphatidyl inositol, phosphatidyl ethanolamine and phosphatidyl glycerol.
- the delipidated cell walls were saponified and precipitated to yield isolated mycolic acid which represented 24% of the total cellular extract.
- Glucose monomycolate was purified to homogeneity from rapidly- growing Mycobacterium phlei cultures. M. phlei cells were hydrolyzed to yield GMM by drying on glass and treating with 2M TFA at 121° C for 2 hrs (G.S. Besra, et al. (1994) Proc. Nat. Acad. Set, USA 97:12737). The yield of the resulting glycolipid was characterized by TLC in comparison with authentic GMM standards. ESI-MS analysis revealed ions of the expected m/z for GMM. For immunization of Hartley strain guinea pigs, whole heat-killed M.
- tuberculosis cells or a mixture of the acetone, chloroform and methanol eluted fractions were combined with various adjuvants and, in some samples, incorporated into liposomes.
- Ovalbumin (OVA) was also added to mixtures. Ovalbumin stimulates immune responses of CD4 + T cells through an MHC class II restricted response and was a positive control demonstrating T cell activity to protein antigen.
- Incomplete Freund's Adjuvant (IF A) is an oil- in-water emulsion.
- TitermaxTM is a block copolymer (CRL89-41 or CRL-8300) combined with squalene and a microparticulate stabilizer (Vaxcel, Inc., Norcross, Georgia, USA).
- QS-21 (Aquila Biopharmaceuticals, Inc., supra) and bone marrow derived dendritic cells (BMDCs) were also used as adjuvants.
- Monophosphoryl Lipid A (MPL) was purchased from RIBI ImmunoChem Research, Inc., Hamilton, MT 59840-3131. Liposomes were produced from phospholipids which are known to be nonstimulatory to the immune system of mammals. The ovalbumin and MPL comprised a minor component of the liposomes which were used to deliver the lipid mixture.
- Guinea pigs were inoculated with one of the above-described immunogenic complexes. The administration was parenteral and subcutaneous. A second administration was made 2-4 weeks apart. Cell samples were taken for ex vivo measurements of T cell responses three weeks following the last immunization. The results are shown in the Table infra.
- Example 3 Results showing a lipid antigen and adjuvant composition increases the immune response in a mammal.
- QS-21 has been shown to boost immune responses when combined with a wide variety of disease specific antigens. Compared to the use of liposomes alone, the improved immunogenicity using an adjuvant such as QS-21 is significant.
- Lymphocytes isolated from guinea pigs immunized with the isolated or purified antigens in liposomes containing QS-21 and MPL responded to the lipid antigens in vitro.
- Peripheral blood mononuclear cells responded to all antigens compared to exposure to the cell medium alone. Medium devoid of antigen was used as a negative control. See Figure 2A. The strongest responses were to OVA, GMM, and the organic extract combining all the hydrophobic fractions.
- the peripheral blood mononuclear cells were prepared by passing blood over a gradient to extract red blood cells and granular monocytes. The eluate consisted of T and B cells and monocytes. This procedure, however, results in an enriched T cell population with less than 10% of immune-responding cells comprising B cells.
- the response demonstrated in Figure 2A is primarily a T cell response.
- Splenic lymphocytes were purified by passing cells over a gradient and then through nylon wool by standard procedures known to those of skill in the art to enrich the T cell population. These procedures result in a T cells to B cells ratio of greater than 10:1. Irradiated spleen cells are added in a ratio of 1 :1 to include CD1 + antigen presenting cells. These splenic fractions showed proliferation in the presence of OVA, GMM, organic extract, acetone and mycolic acid fractions. See Figure 2B. When the cell suspension was treated with anti-CD4 antibodies to remove the
- CD4 + T cell fraction the response to OVA was diminished as shown in Figures 3A-3B and 4.
- the T cell fraction responding to the presence of antigens in these suspensions is comprised of CD4 CD8 ' T cells and CD8 + T cells.
- a comparison of these responses showing the significant responses to GMM, the acetone fraction, and mycolic acid is shown in Figure 4.
- the antigen-specific response was dose-dependent and the highest values are compared.
- Lipid mixture of Acetone (glycolipid), Chloroform (neutral lipid) and Methanol (phospholipid) eluted fractions.
- BMDC Bone marrow derived dendritic cells
- Figures 5 A-C show primary ex vivo cytotoxic responses of T lymphocytes isolated from Strain 2 guinea pigs immunized with purified mycobacterial lipid antigens reconstituted as an immunogenic composition by incorporation into liposomes with adjuvants.
- Strain 2 guinea pigs were immunized with a purified lipid antigen mixture that included M. tuberculsosis glycolipids (i.e., the lipid fraction eluted from a silica colum using acetone as the solvent; refer to Figure 1 for details) inserted into liposomes composed of inert phospholipids and cholesterol and mixed with the adjuvants QS-21 and MPL in the form of liposome twice.
- M. tuberculsosis glycolipids i.e., the lipid fraction eluted from a silica colum using acetone as the solvent; refer to Figure 1 for details
- the guinea pigs were sacrificed and the splenic T-cells were obtained.
- the splenic T cells were cultured with the M. tuberculosis glycolipid fraction for 6 days in the presence of irradiated splenic adherent cells (i.e., a source of CDl + antigen presenting cells) and 0.87 nM human recombinant interleukin-2. Live cells were isolated and used as effector cells in a standard chromium release assay for cytotoxic T cell activity.
- T cells lysed target cells that were engineered to express either of two different guinea pig CDl molecules (gpCDlbl or gpCDlc2) by transfection of cDNAs encoding these molecules into a guinea pig cell line (104C1) that normally lacks expression of CDl molecules.
- Target cell lysis was observed if the target cells were first incubated with M. tuberculosis glycolipid antigens at a concentration of 50 ug/ml (i.e., represented as "Acetone 50" in Fig. 5), and to a lesser extent if the target cells were incubated with the glycolipid antigens at a concentration of 25 ug/ml (represented as "Acetone 25 in Fig. 5).
- cytotoxic activity of the T cells against any target cell was observed if the targets were cultured in medium that did not contain mycobacterial lipid antigen (indicated as "medium” in Fig. 5). This demonstrated that the cytotoxic T cells present in the culture were lipid antigen specific, and that the antigen recognition was dose dependent. In addition, no target cell lysis was observed if the target cells did not express CDl molecules, which is the case for the 104C1 mock transfected targets ( Figure 5C). This demonstrated that the lipid antigen specific T cells present in the cultures were restricted by either CDlbl or CDlc2 molecules.
- FIG. 6 shows the proliferative response of a CDl -restricted M. tuberculosis lipid antigen specific T cells lines (S2-CD8.1) raised from the animal immunized with CDl-presented antigens.
- a strain 2 guinea pig was immunized twice by the subcutaneous route using an immunogenic lipid antigen/adjuvant formulation
- the proliferative responses (Counts Per Minute (CPM)of tritiated thymidine incorporation) of the T cell line were measured in the presence of the T cell line alone; the T cell line cultured together with bone marrow derived dendritic cells (BM-DCs; a source of CDl + antigen presenting cells); the T cell line plus BM-DCs plus a monoclonal antibody specific for all currently known forms of guinea pig CDl (anti-CD ImAb); the T cell line plus BM-DCs and the M.
- CPM Cost Per Minute
- tuberculosis lipid antigens a total lipid chloroform/methanol extract of M. tuberculosis, indicated as "M.Tbc O/E"; consult Figure 1 for details
- M.Tbc O/E M. tuberculosis lipid antigens
- the results show that the T cells proliferated strongly when exposed to lipid antigens in the presence of CDl + antigen presenting cells (BM-DCs), but not in the absence of CDl + antigen presenting cells. This proliferation was dependent on the presence of the lipid antigens, and was strongly inhibited by the anti- CD 1 mAb.
- FIG. 7 illustrates the CDl restriction elements of M. tuberculosis lipid antigen specific T cell line (S2-CD8.1).
- S2-CD8.1 T cell line lysed M. tuberculosis lipid antigen pulsed 104Cl/CDlbl.-b2 and c3 transfectants, but not a mock transfectant or transfectants expressing CDlb3, -b5 or -c2.
- T cell line S2-CD8.1 was derived from a strain 2 guinea pig immunized with an immunogenic lipid antigen/adjuvant composition consisting of the M.
- tuberculosis total lipid extract inserted into liposomes composed of inert phospho lipids and cholesterol and mixed with the adjuvants QS-21 and MPL. After immunization, the guinea pigs were sacrificed and T cells were isolated from the spleen. These T cells were stimulated four times in vitro by culture with a CD1+ antigen presenting cell (BM-DCs) plus M. tuberculosis lipid extract at 20 ug/ml.
- BM-DCs CD1+ antigen presenting cell
- the resulting T cell lines were expanded by the addition of human recombinant interleukin- 2, and the cells were harvested and used in a standard chromium release assay to assess the presence of lipid antigen specific cytotoxic T cells and their restriction by individual members of the CDl family.
- the results demonstrated significant lipid antigen dependent lysis of 104C1 target cells that had been transfected to express either CDlbl, -b2 or -c3 molecules. This recognition was dose dependent, showing generally greater responses when the target cells were incubated with lipid antigen at 20 ug/ml compared to 10 ug/ml. In contrast, no significant lysis was observed of mock transfected 104C1 cells that do not express CDl molecules in the presence or absence of lipid antigens.
- CDlb3, b5 and -c2 three other forms of guinea pig CDl (CDlb3, b5 and -c2) proved to be minimally active or inactive at endowing the 104C1 cells with the ability to present the lipid antigens to T cell line S2-CD8.1.
- CDlb3, b5 and -c2 three other forms of guinea pig CDl (CDlb3, b5 and -c2) proved to be minimally active or inactive at endowing the 104C1 cells with the ability to present the lipid antigens to T cell line S2-CD8.1.
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Priority Applications (4)
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EP99917473A EP1071452A1 (en) | 1998-04-13 | 1999-04-13 | Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof |
AU35588/99A AU3558899A (en) | 1998-04-13 | 1999-04-13 | Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof |
JP2000543157A JP2002511421A (en) | 1998-04-13 | 1999-04-13 | Vaccine composition comprising CD-1 antigen and T cell stimulating compound and method of using the same |
CA002323733A CA2323733A1 (en) | 1998-04-13 | 1999-04-13 | Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof |
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US8163898P | 1998-04-13 | 1998-04-13 | |
US60/081,638 | 1998-04-13 |
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WO1999052547A9 WO1999052547A9 (en) | 2000-03-02 |
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PCT/US1999/008112 WO1999052547A1 (en) | 1998-04-13 | 1999-04-13 | Vaccine compositions comprising cd-1 antigens and t-cell stimulating compound and methods of use thereof |
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EP (1) | EP1071452A1 (en) |
JP (1) | JP2002511421A (en) |
AU (1) | AU3558899A (en) |
CA (1) | CA2323733A1 (en) |
WO (1) | WO1999052547A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000024406A1 (en) * | 1998-10-27 | 2000-05-04 | The Walter And Eliza Hall Institute Of Medical Research | A method of activating t cells and agents useful for same |
WO2002074334A1 (en) * | 2001-03-20 | 2002-09-26 | Stanford Rook Limited | Mycrobacterial extract and its use in inflammatory bowel disease |
EP1335741A2 (en) * | 2000-08-25 | 2003-08-20 | Yeda Research And Development Co. Ltd. | METHODS OF TREATMENT OR PREVENTION OF AUTOIMMUNE DISEASES WITH CpG-CONTAINING POLYNUCLEOTIDE |
US7052909B1 (en) * | 1999-04-19 | 2006-05-30 | Institut National De La Sante Et De La Recherche Medicale | Method for activating NKT cells using PIMs |
US7253159B2 (en) | 2003-04-18 | 2007-08-07 | The Brigham And Women's Hospital, Inc. | Methods and compositions for immunomodulation using CD1 antigens |
WO2008025095A1 (en) | 2006-09-01 | 2008-03-06 | Csl Limited | Method of eliciting or inducing an immune response |
EP1938836A1 (en) * | 2006-12-28 | 2008-07-02 | Universite Rene Descartes (Paris V) | Compositions comprising a B subunit of shiga toxin and a means stimulating NKT cells |
EP2047860A1 (en) * | 2007-10-12 | 2009-04-15 | Centre National De La Recherche Scientifique (Cnrs) | Phamaceutical compositons comprosing actinomycete glycerol acyl derivatives antigens, their process of extractin, and their use against tuberculosis. |
US8999353B2 (en) | 2007-10-12 | 2015-04-07 | Csl Limited | Method of eliciting an immune response against pandemic influenza virus |
US9539209B2 (en) | 2009-06-04 | 2017-01-10 | National Institute Of Infectious Diseases | Vaccine for mycoplasma infection |
WO2019071009A3 (en) * | 2017-10-05 | 2019-06-13 | Nantcell, Inc. | Lipid-based antigens and t-cell receptors on nk cells |
EP3833743A4 (en) * | 2018-08-08 | 2022-05-04 | NantBio, Inc. | Recombinant cd1-restricted t cells and methods |
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WO1996012190A2 (en) * | 1994-10-13 | 1996-04-25 | Brigham & Women's Hospital | Presentation of hydrophobic antigens to t-cells by cd1 molecules |
WO1998039025A2 (en) * | 1997-03-03 | 1998-09-11 | Adcock Ingram Limited | A composition comprising a carrier and a purified mycobacterial lipid cell-wall component and its use in the prevention, treatment and diagnosis of disease |
WO1999012562A1 (en) * | 1997-09-12 | 1999-03-18 | Brigham & Women's Hospital | Synthetic antigens for cd1-restricted immune responses |
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1999
- 1999-04-13 AU AU35588/99A patent/AU3558899A/en not_active Abandoned
- 1999-04-13 WO PCT/US1999/008112 patent/WO1999052547A1/en not_active Application Discontinuation
- 1999-04-13 EP EP99917473A patent/EP1071452A1/en not_active Withdrawn
- 1999-04-13 CA CA002323733A patent/CA2323733A1/en not_active Abandoned
- 1999-04-13 JP JP2000543157A patent/JP2002511421A/en not_active Withdrawn
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WO1996012190A2 (en) * | 1994-10-13 | 1996-04-25 | Brigham & Women's Hospital | Presentation of hydrophobic antigens to t-cells by cd1 molecules |
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Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000024406A1 (en) * | 1998-10-27 | 2000-05-04 | The Walter And Eliza Hall Institute Of Medical Research | A method of activating t cells and agents useful for same |
US7052909B1 (en) * | 1999-04-19 | 2006-05-30 | Institut National De La Sante Et De La Recherche Medicale | Method for activating NKT cells using PIMs |
EP1335741A2 (en) * | 2000-08-25 | 2003-08-20 | Yeda Research And Development Co. Ltd. | METHODS OF TREATMENT OR PREVENTION OF AUTOIMMUNE DISEASES WITH CpG-CONTAINING POLYNUCLEOTIDE |
EP1335741A4 (en) * | 2000-08-25 | 2005-10-26 | Yeda Res & Dev | METHODS OF TREATMENT OR PREVENTION OF AUTOIMMUNE DISEASES WITH CpG-CONTAINING POLYNUCLEOTIDE |
WO2002074334A1 (en) * | 2001-03-20 | 2002-09-26 | Stanford Rook Limited | Mycrobacterial extract and its use in inflammatory bowel disease |
US7253159B2 (en) | 2003-04-18 | 2007-08-07 | The Brigham And Women's Hospital, Inc. | Methods and compositions for immunomodulation using CD1 antigens |
CN101522213A (en) * | 2006-09-01 | 2009-09-02 | Csl有限公司 | Method of eliciting or inducing an immune response |
WO2008025095A1 (en) | 2006-09-01 | 2008-03-06 | Csl Limited | Method of eliciting or inducing an immune response |
US9150619B2 (en) | 2006-09-01 | 2015-10-06 | Csl Limited | Method of elicting or inducing an immune response |
WO2008080926A1 (en) * | 2006-12-28 | 2008-07-10 | Universite Rene Descartes Paris 5 | Compositions comprising a b subunit of shiga toxin and a means stimulating nkt cells |
US8685408B2 (en) | 2006-12-28 | 2014-04-01 | Universite Rene Descartes Paris 5 | Compositions comprising a B subunit of Shiga toxin and a means stimulating NKT cells |
EP1938836A1 (en) * | 2006-12-28 | 2008-07-02 | Universite Rene Descartes (Paris V) | Compositions comprising a B subunit of shiga toxin and a means stimulating NKT cells |
WO2009047363A1 (en) * | 2007-10-12 | 2009-04-16 | Centre National De La Recherche Scientifique (C.N.R.S) | Pharmaceuticals compositions comprising actinomycete glycerol acyl derivatives antigens, their process of extraction, and their use against tuberculosis |
EP2047860A1 (en) * | 2007-10-12 | 2009-04-15 | Centre National De La Recherche Scientifique (Cnrs) | Phamaceutical compositons comprosing actinomycete glycerol acyl derivatives antigens, their process of extractin, and their use against tuberculosis. |
US8999353B2 (en) | 2007-10-12 | 2015-04-07 | Csl Limited | Method of eliciting an immune response against pandemic influenza virus |
US9539209B2 (en) | 2009-06-04 | 2017-01-10 | National Institute Of Infectious Diseases | Vaccine for mycoplasma infection |
US10232026B2 (en) | 2009-06-04 | 2019-03-19 | National Institute Of Infectious Diseases | Vaccine for mycoplasma infection |
WO2019071009A3 (en) * | 2017-10-05 | 2019-06-13 | Nantcell, Inc. | Lipid-based antigens and t-cell receptors on nk cells |
EP3833743A4 (en) * | 2018-08-08 | 2022-05-04 | NantBio, Inc. | Recombinant cd1-restricted t cells and methods |
Also Published As
Publication number | Publication date |
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WO1999052547A9 (en) | 2000-03-02 |
JP2002511421A (en) | 2002-04-16 |
AU3558899A (en) | 1999-11-01 |
EP1071452A1 (en) | 2001-01-31 |
CA2323733A1 (en) | 1999-10-21 |
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