WO2003089593A2 - Adjuvant enhanced immunotherapy - Google Patents
Adjuvant enhanced immunotherapy Download PDFInfo
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- WO2003089593A2 WO2003089593A2 PCT/US2003/011663 US0311663W WO03089593A2 WO 2003089593 A2 WO2003089593 A2 WO 2003089593A2 US 0311663 W US0311663 W US 0311663W WO 03089593 A2 WO03089593 A2 WO 03089593A2
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- DTAKIVKNYKEEKI-VAEFPZBPSA-N C[C@@H](C1)C1NNC(Nc1cc(C(O)=O)c(C(c(ccc(O)c2)c2O2)=C(C=C3)C2=CC3O)cc1)=S Chemical compound C[C@@H](C1)C1NNC(Nc1cc(C(O)=O)c(C(c(ccc(O)c2)c2O2)=C(C=C3)C2=CC3O)cc1)=S DTAKIVKNYKEEKI-VAEFPZBPSA-N 0.000 description 1
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- A61K38/19—Cytokines; Lymphokines; Interferons
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Definitions
- the invention relates to an improved method for treating disease states characterized by the existence of pathogenic cell populations. More particularly, cell- targeted ligand-immunogen or ligand-hapten conjugates are administered to a diseased host to direct the host immune response to the pathogenic cells.
- the improvement to the method comprises using an adjuvant that biases the immune response towards a T H I response to enhance the immune response to the immunogen.
- the mammalian immune system provides a means for the recognition and elimination of tumor cells, other pathogenic cells, and invading foreign pathogens. While the immune system normally provides a strong line of defense, there are still many instances where cancer cells, other pathogenic cells, or infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity. Chemotherapeutic agents and radiation therapies have been developed to eliminate replicating neoplasms. However, most, if not all, of the currently available chemotherapeutic agents and radiation therapy regimens have adverse side effects because they work not only to destroy cancer cells, but they also affect normal host cells, such as cells of the hematopoietic system. Furthermore, chemotherapeutic agents have limited efficacy in instances where host drug resistance is developed.
- Foreign pathogens can also proliferate in a host by evading a competent immune response or where the host immune system has been compromised by drug therapies or by other health problems. Although many therapeutic compounds have been developed, many pathogens are or have become resistant to such therapeutics. The capacity of cancer cells and infectious organisms to develop resistance to therapeutic agents, and the adverse side effects of the currently available anticancer drugs, highlight the need for the development of new therapies specific for pathogenic cell populations and with reduced host toxicity.
- Another approach for selectively targeting populations of cancer cells or foreign pathogens in a host is to enhance the host immune response against the pathogenic cells, thereby avoiding the need for administration of compounds that may also exhibit independent host toxicity.
- One reported strategy for immunotherapy is to bind antibodies, for example, genetically engineered multimeric antibodies, to the tumor cell surface to display the constant region of the antibodies on the cell surface and thereby induce tumor cell killing by various immune-system mediated processes. (De Vita, V.T., Biologic Therapy of Cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, J.P., U.S. Patent 5,672,486).
- Another approach for killing unwanted cell populations utilizes IL-2 or Fab fragments of anti-thymocyte globulin linked to antigens to eliminate unwanted T cells; however, based on reported experimental data, the method appears to eliminate only 50% of the targeted cell population, and results in nonspecific cell killing in vivo (i.e., 50% of peripheral blood lymphocytes that are not T cells are also killed (Pouletty, P., PCT Publication Number WO 97/37690, published October 16, 1997)).
- therapies directed to treatment of disease states characterized by the existence of pathogenic cell populations in an affected host.
- the immune system may exhibit both specific and nonspecific immunity with specific immunity being mediated by B and T lymphocytes which display receptors on their surfaces for specific antigens.
- the specific immune response may involve humoral immunity (i.e., B cell activation with the production of antibodies), and cell-mediated immunity (i.e., activation of T cells, such as cytotoxic T lymphocytes, helper T lymphocytes, including T H I and T H 2 cells, and antigen- presenting cells).
- T H I responses elicit complement fixing antibodies, activation of cytotoxic T lymphocytes, and strong delayed-type hypersensitivity reactions and are associated with the production of IL-2, IL-12, TNF, lympho toxin, and ⁇ -interferon.
- T H 2 responses are associated with the production of IgE, and IL-4, IL-5, IL-6, and IL- 10.
- a specific immune response involves not only specificity, but also memory so that immune cells previously exposed to an antigen can rapidly respond to that same antigen upon future exposure to the antigen.
- Adjuvants are compounds or materials that stimulate immune responses, for example, by augmenting the immunogenicity of an antigen, either when administered with the antigen or when administered prior to the antigen.
- Adjuvants can act either nonspecifically, stimulating the immune response to a wide variety of antigens, or specifically (i.e., stimulating the immune response in an antigen-specific manner).
- Adjuvants that enhance specific immunity can act by stimulating the cell- mediated immune response or the humoral response or both.
- Adjuvants that stimulate the cell-mediated immune response can bias the immune response towards a T H 1 or a T H 2 response.
- Adjuvants that stimulate the humoral immune response can induce the production of an antibody isotype profile that differs depending on the adjuvant used.
- different adjuvants can stimulate the production of 1.) different antibody isotypes, 2.) different levels of antibodies of each isotype, and 3.) can stimulate the production of antibodies with differing affinities, resulting in divergent antibody populations depending on the adjuvant used.
- Saponins are glycosidic compounds that are widely distributed among higher plants and in some marine invertebrates of the phylum Echinodermata (ApSimon et al., Stud. Org. Chem. 17:273-286 (1984)). Saponins consist of an aglycone attached to one or more linear or branched sugar chains, and have molecular weights ranging from 600 to 2000 daltons or greater. Saponins are known to exhibit adjuvant activity.
- the quiUajasaponins are a family of closely related O-acylated triterpene glycoside structures, and are isolated from the bark of the Quillaja saponaria Molina tree.
- QuiUajasaponins are functionally well-characterized and are known to exhibit adjuvant activity.
- the quiUajasaponins stimulate both the cell- mediated and humoral immune responses.
- An aldehyde group on the triterpenoid group of quiUajasaponins is responsible for inducing cell-mediated immunity, and carbohydrate moieties on the quiUajasaponins appear to enhance humoral immunity.
- the quiUajasaponins generally induce a strong T H I response.
- An improvement is provided to a method of eliminating pathogenic cell populations in a host.
- the method is based on increasing host immune system recognition of and response to pathogenic cell populations by increasing the antigenicity of the pathogenic cells to enhance an endogenous immune response- mediated elimination of the population of pathogenic cells.
- ligand-immunogen or ligand-hapten conjugates are administered to the host for binding to the surface of the tumor cells or pathogenic organisms and the conjugates "label" the cells of the targeted cell population with the immunogen or hapten, thereby triggering an immune-mediated response directed at the labeled cell population.
- Antibodies existing or produced in the host bind to the immunogen or hapten and trigger endogenous immune responses.
- the immunogen or hapten can be recognized directly by immune cells in the host.
- the improvement to the method comprises using a T H I -biasing adjuvant to enhance the immune response to the immunogen/hapten.
- the method comprises administration of a ligand-immunogen conjugate or a ligand-hapten conjugate wherein the ligand is capable of specific binding to a population of pathogenic cells in vivo, and the ligand conjugated immunogen/hapten is capable of being recognized by antibodies or directly by immune cells in the host.
- the immune system-mediated elimination of the pathogenic cells is directed by the binding of the immunogen/hapten conjugated ligand to a receptor, a transporter, or other surface-presented protein uniquely expressed, overexpressed, or preferentially expressed by the pathogenic cell.
- a surface-presented protein uniquely expressed, overexpressed, or preferentially expressed by the pathogenic cell is a receptor not present or present at lower amounts on non-pathogenic cells providing a means for selective elimination of the pathogenic cells.
- the targeted pathogenic cell population can be a cancer cell population, virus-infected endogenous cells, or a population of exogenous organisms such as bacteria, mycoplasma yeast or fungi.
- Antibody binding to the cell-bound ligand-immunogen or ligand-hapten conjugate results in complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody opsonization and phagocytosis, antibody-induced receptor clustering signaling cell death or quiescence or any other humoral or cellular immune response stimulated by antibody binding to cell-bound ligand-immunogen or ligand-hapten conjugates.
- the immune response can also involve direct recognition of the immunogen/hapten by host immune cells.
- At least one additional therapeutic factor for example, an immune system stimulant, a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, a cytotoxic immune cell, or an antimicrobial agent can be administered to the host animal to enhance therapeutic efficiency.
- the cytotoxic immune cell is a cytotoxic immune cell population that is isolated, expanded ex vivo, and is then injected into a host animal.
- an immune stimulant is used and the immune stimulant can be an interleukin such as IL-2, IL-12, or IL-15 or an IFN such as IFN- ⁇ , EFN-/3, or IFN- ⁇ , or GM-CSF.
- the immune stimulant can be a cytokine composition comprising combinations of cytokines, such as IL-2, IL-12 or IL-15 in combination with JJFN- ⁇ , IFN-
- cytokines such as IL-2, IL-12 or IL-15 in combination with JJFN- ⁇ , IFN-
- a method of enhancing an endogenous immune response-mediated specific elimination of a population of pathogenic cells in a preimmunized host animal harboring the population wherein the members of the cell population have an accessible binding site for a ligand.
- the method comprises the step of administering to the host a composition comprising an immunogen or a hapten conjugated to the ligand wherein the immunogen or the hapten is recognized by an endogenous antibody in the host or is recognized directly by an immune cell in the host, the improvement comprising the step of preimmunizing the host with the immunogen or an immunogenic hapten-carrier conjugate and a T H 1 -biasing adjuvant to elicit a preexisting immunity.
- a method is provided of enhancing an immune response in a host animal harboring a population of pathogenic cells to eliminate said pathogenic cell population wherein the pathogenic cells have an accessible binding site for a ligand.
- the method comprises the steps of administering to the host a T H 1- biasing adjuvant, and administering to the host a composition comprising an immunogen conjugated to the ligand.
- a composition is provided comprising therapeutically effective amounts of a T H 1 -biasing adjuvant and a hapten-carrier conjugate wherein the hapten is selected from the group consisting of fluorescein and dinitrophenyl.
- composition comprising therapeutically effective amounts of a T H I -biasing adjuvant and a ligand-immunogen conjugate.
- kits comprising a T H I -biasing adjuvant and a hapten-carrier conjugate wherein the hapten is selected from the group consisting of fluorescein and dinitrophenyl.
- a kit is provided comprising a T H 1 -biasing adjuvant, a hapten-carrier conjugate, and a ligand-hapten conjugate.
- the kit can comprise a T H 1 -biasing adjuvant and a ligand-immunogen conjugate, or can further comprise an immunogen.
- Fig. 1 shows the anti-FITC total IgG and anti-FITC IgG2a responses in mice immunized with KLH-FITC formulated with a saponin adjuvant (i.e., GPI- 0100).
- Fig. 2 shows the percentage survival of mice, having established intraperitoneal L1210A leukemia, immunized with KLH-FITC/saponin adjuvant and subsequently injected with PBS (control), IL2 + IFN- ⁇ , or folate-FITC + IL2 + IFN- ⁇ .
- Fig. 3 shows the percentage survival of mice, bearing established intraperitoneal M109 tumors, immunized with KLH-FITC/saponin adjuvant and subsequently inj ected with PBS, IL2 + IFN- ⁇ ; or folate-FITC + IL2 + IFN- ⁇
- Fig. 4 shows the percentage survival of mice, bearing early-stage intraperitoneal M109 tumors, immunized with KLH-FITC/saponin adjuvant and subsequently injected with PBS or folate-FITC.
- Fig. 5 shows the percentage survival of mice, bearing established intraperitoneal Ml 09 tumors, immunized with KLH-FITC/saponin adjuvant and subsequently injected with PBS or folate-FITC.
- Fig. 6 shows the tumor volume of subcutaneous Ml 09 tumors in mice immunized with KLH-FITC/saponin adjuvant and subsequently injected with PBS, IL2 + IFN- ⁇ , or folate-FITC + IL2 + IFN- ⁇
- Fig. 7 shows the structure of folate-FITC (EC 17).
- Fig. 8 shows the structure of KLH-FITC (EC90).
- An improvement is provided to a method of eliminating pathogenic cell populations in a host.
- the method is based on increasing host immune system recognition of and response to pathogenic cell populations by increasing the antigenicity of the pathogenic cells to enhance an endogenous immune response- mediated elimination of the population of pathogenic cells.
- ligand-immunogen or ligand-hapten conjugates are administered to the host for binding to the surface of the tumor cells or pathogenic organisms and the conjugates "label" the cells of the targeted cell population with the immunogen or hapten, thereby triggering an immune-mediated response directed at the labeled cell population.
- Antibodies existing or produced in the host or immune cells in the host bind to the immunogen/hapten and trigger endogenous immune responses.
- the improvement to the method in accordance with the present invention comprises using a T ⁇ l-biasing adjuvant to enhance the immune response to the immunogen/hapten.
- the improved method is utilized to enhance an endogenous immune response-mediated elimination of a population of pathogenic cells in a host animal harboring the population of pathogenic cells.
- the invention is applicable to populations of pathogenic cells that cause a variety of pathologies such as cancer and infectious diseases.
- the population of pathogenic cells can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or it can be non-tumorigenic.
- the cancer cell population can arise spontaneously or by such processes as mutations present in the germline of the host animal or somatic mutations, or it may be chemically-, virally-, or radiation-induced.
- the invention can be utilized to treat such cancers as carcinomas, sarcomas, lymphomas, Hodgkin's disease, melanomas, mesotheliomas, Burkitt's lymphoma, nasopharyngeal carcinomas, leukemias, and myelomas.
- the cancer cell population can include, but is not limited to, oral, thyroid, endocrine, skin, gastric, esophageal, laryngeal, pancreatic, colon, bladder, bone, ovarian, cervical, uterine, breast, testicular, prostate, rectal, kidney, liver, and lung cancers.
- the population of pathogenic cells can also be an exogenous pathogen or a cell population harboring an exogenous pathogen, e.g., a virus.
- the present invention is applicable to such exogenous pathogens as bacteria, fungi, viruses, mycoplasma, and parasites.
- Infectious agents that can be treated with the present invention are any art-recognized infectious organisms that cause pathogenesis in an animal, including such organisms as bacteria that are gram-negative or gram-positive cocci or bacilli, DNA and RNA viruses, including, but not limited to, DNA viruses such as papilloma viruses, parvoviruses, adenoviruses, herpesviruses and vaccinia viruses, and RNA viruses, such as arenaviruses, coronaviruses, rhinoviruses, respiratory syncytial viruses, influenza viruses, picornaviruses, paramyxoviruses, reoviruses, retroviruses, and rhabdoviruses.
- DNA viruses such as papilloma viruses, parvoviruses, adenoviruses, herpesviruses and vaccinia viruses
- RNA viruses such as arenaviruses, coronaviruses, rhinoviruses, respiratory syncytial viruses,
- bacteria that are resistant to antibiotics such as antibiotic-resistant Streptococcus species and Staphlococcus species, or bacteria that are susceptible to antibiotics, but cause recurrent infections treated with antibiotics so that resistant organisms eventually develop.
- antibiotics such as antibiotic-resistant Streptococcus species and Staphlococcus species
- Such organisms can be treated with the ligand-immunogen or ligand-hapten conjugates of the present invention in combination with lower doses of antibiotics than would normally be administered to a patient to avoid the development of these antibiotic-resistant bacterial strains.
- the present invention is also applicable to any fungi, mycoplasma species, parasites, or other infectious organisms that cause disease in animals.
- fungi examples include fungi that grow as molds or are yeastlike, including, for example, fungi that cause diseases such as ringworm, histoplasmosis, blastomycosis, aspergillosis, cryptococcosis, sporotrichosis, coccidioidomycosis, paracoccidio- idomycosis, and candidiasis.
- the present invention can be utilized to treat parasitic infections including, but not limited to, infections caused by somatic tapeworms, blood flukes, tissue roundworms, ameba, and Plasmodium, Trypanosoma, Leishmania, and Toxoplasma species.
- Parasites of particular interest are those that express folate receptors and bind folate; however, the literature is replete with reference to ligands exhibiting high affinity for infectious organisms.
- penicillins and cephalosporins known for their antibiotic activity and specific binding to bacterial cell wall precursors can similarly be used as ligands for preparing ligand- immunogen or ligand-hapten conjugates for use in accordance with this invention.
- the ligand-immunogen or ligand-hapten conjugates of the invention can also be directed to a cell population harboring endogenous pathogens wherein pathogen- specific antigens are preferentially expressed on the surface of cells harboring the pathogens, and act as receptors for the ligand with the ligand specifically binding to the antigen.
- the method of the present invention can be used for both human clinical medicine and veterinary applications.
- the host animals harboring the population of pathogenic organisms and treated with ligand-immunogen or ligand- hapten conjugates can be humans or, in the case of veterinary applications, may be a laboratory, agricultural, domestic, or wild animal.
- the present invention can be applied to host animals including, but not limited to, humans, laboratory animals such rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
- rodents e.g., mice, rats, hamsters, etc.
- rabbits, monkeys, chimpanzees domestic animals
- domestic animals such as dogs, cats
- rabbits agricultural animals
- cows, horses, pigs, sheep, goats and wild animals in captivity
- the host is preimmunized with an immunogen or a hapten-carrier (e.g., KLH or BSA) conjugate and a THI- biasing adjuvant to elicit a preexisting immunity to the immunogen or hapten.
- the ligand-immunogen or ligand-hapten conjugate is then administered to the host resulting in an humoral or cell-mediated immune response, or both, directed against the ligand-immunogen or ligand-hapten conjugate bound to the targeted pathogenic cells.
- the preexisting immunity can be an innate immunity against the immunogen (e.g., an immunogen such as a superantigen or muramyl dipeptide).
- the T H I -biasing adjuvant and the ligand- immunogen conjugate can be co-administered to enhance the immune response derived, at least in part, from the innate immunity.
- the preexisting immunity can be an immunity developed via normally scheduled vaccinations or prior natural exposure to an antigen (e.g., poliovirus, tetanus, influenza, and the like).
- the immunogen comprises an antigen that elicited the preexisting immunity and the T H I- biasing adjuvant and the ligand-immunogen conjugate are co-administered to enhance the immune response resulting from the preexisting immunity.
- the ligand-immunogen conjugate and the T H 1 -biasing adjuvant can be co-administered to elicit an immune response where there is no preexisting immunity.
- the T H I -biasing adjuvant enhances the immune response to the immunogen upon co-administration of the adjuvant and the ligand-immunogen conjugate.
- the ligand-immunogen conjugate, the T H I -biasing adjuvant, and passively administered antibodies can be co-administered.
- the passively administered antibodies help to augment the immune response to the immunogen.
- co-administration is defined as administration at a time prior to, at the same time as, or at a time following administration of the ligand-immunogen, ligand-hapten, or hapten-carrier conjugate or -l ithe immunogen.
- co-administration can also mean administration in the same or different solutions.
- Adjuvants suitable for use in accordance with the invention are adjuvants that bias the immune response towards a T H I response.
- An adjuvant- induced T H I -biased immunity can be measured in mice through immunoglobulin isotype distribution analysis.
- Adjuvants that bias the immune response towards a T H 1 response are adjuvants that preferentially increase IgG2a antibody levels in mice relative to IgGl antibody levels.
- An antigen-specific IgG2a/IgGl ratio of > 1 can be indicative of a T H I -like antibody subclass pattern.
- any adjuvant that increases the production of antigen-specific antibodies and, at the same time, increases the relative IgG2a/IgGl ratio to about > 0.3 drives the immune response towards a T H 1 -biased immune response.
- Such adjuvants can include saponin adjuvants (e.g., the quiUajasaponins, including lipid-modified quillajasaponin adjuvants), CpG, 3-deacylated monophosphoryl lipid A (MPL), Bovine Calmette-Guerin (BCG), double stem- loop immunomodulating oligodeoxyribonucleotides (d-SLEVI), heat-killed Brucella abortus (HKBA), heat- killed Mycobacterium vaccae (SRL172), inactivated vaccinia virus, cyclophosphamide, prolactin, thalidomide, actimid, revimid, and the like.
- saponin adjuvants e.g., the quiUajasaponins, including lipid-modified quillajasaponin adjuvants
- CpG 3-deacylated monophosphoryl lipid A
- MPL 3-deacylated monophosphoryl lipid A
- the ligand-immunogen or ligand-hapten conjugates can be selected from a wide variety of ligands, immunogens, and haptens.
- the ligands should be capable of preferentially targeting a population of pathogenic cells in the host animal due to preferential or overexpression of a receptor for the ligand, accessible for ligand binding, on the pathogenic cells.
- Acceptable ligands include folic acid, analogs of folic acid and other folate receptor-binding molecules, other vitamins, peptide ligands identified from library screens, tumor-specific peptides, tumor-specific aptamers, tumor-specific carbohydrates, tumor-specific monoclonal or polyclonal antibodies, Fab or scFv (i.e., a single chain variable region) fragments of antibodies such as, for example, an Fab fragment of an antibody directed to EphA2 or other proteins specifically expressed or uniquely accessible on metastatic cancer cells, small organic molecules derived from combinatorial libraries, growth factors, such as EGF, FGF, insulin, and insulin-like growth factors, and homologous polypeptides, somatostatin and its analogs, transferrin, lipoprotein complexes, bile salts, selectins, steroid hormones, Arg-Gly-Asp containing peptides, retinoids, various Galectins, ⁇ - opioid receptor ligands, chole
- ligands that bind to infectious organisms are any molecules, such as antibiotics or other drugs, that are known in the art to preferentially bind to the microorganism.
- the invention also applies to ligands which are molecules, such as antimicrobial drugs, designed to fit into the binding pocket of a particular receptor, based on the crystal structure of the receptor, or other cell surface protein, and wherein such receptors are preferentially expressed on the surface of tumors, bacteria, viruses, mycoplasma, fungi, parasites, or other pathogens. It is also contemplated, in one embodiment, that ligands binding to any tumor antigens or other molecules preferentially expressed on the surface of tumor cells can be utilized.
- the ligand is a vitamin or an analog or derivative thereof.
- Acceptable vitamins include niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B ⁇ , and the lipid soluble vitamins A, D, E and K. These vitamins, and their receptor-binding analogs and derivatives, constitute the targeting entity that forms the ligand-immunogen or ligand-hapten conjugates for use in accordance with the invention.
- Preferred vitamin moieties include folic acid, biotin, riboflavin, thiamine, vitamin B ⁇ 2 , and receptor-binding analogs and derivatives of these vitamin molecules, and other related vitamin receptor-binding molecules (see U.S. Patent Nos.
- vitamin analog is a folate analog containing a glutamic acid residue in the D configuration (folic acid normally contains one glutamic acid in the L configuration linked to pteroic acid).
- the binding site for the ligand can include receptors for any molecule capable of specifically binding to a receptor wherein the receptor or other protein is preferentially expressed on the population of pathogenic cells, including, for example, receptors for growth factors, vitamins, peptides, including opioid peptides, hormones, antibodies, carbohydrates, and small organic molecules.
- the binding site can also be a binding site for any molecule, such as an antibiotic or other drug, where the site is known in the art to preferentially exist on microorganisms.
- the subject binding sites may be binding sites in the bacterial cell wall for a ⁇ -lactam antibiotic such as penicillin, or binding sites for an antiviral agent uniquely present on the surface of a virus.
- the invention also applies to binding sites for ligands, such as antimicrobial drugs, designed to fit into the binding site of the receptor, based on the crystal structure of the receptor, and wherein the receptor is preferentially expressed on the surface of the pathogenic cells or organisms.
- tumor-specific antigens can function as binding sites for ligands.
- An example of a tumor-specific antigen that could function as a binding site for ligand-immunogen or ligand-hapten conjugates is an extracellular epitope of a member of the Ephrin family of proteins, such as EphA2. EphA2 expression is restricted to cell-cell junctions in normal cells, but EphA2 is distributed over the entire cell surface in metastatic tumor cells.
- EphA2 on metastatic cells would be accessible for binding to, for example, an Fab fragment of an antibody conjugated to an immunogen or a hapten, whereas the protein would not be accessible for binding to the Fab fragment on normal cells, resulting in a ligand-immunogen or ligand-hapten conjugate specific for metastatic cancer cells.
- the invention further contemplates the use of combinations of ligand-immunogen or ligand-hapten conjugates to maximize targeting of the pathogenic cells for elimination by the immune response.
- Suitable immunogens include antigens or antigenic peptides against which a preexisting immunity has developed via normally scheduled vaccinations or prior natural exposure to such agents as poliovirus, tetanus, typhus, rubella, measles, mumps, pertussis, tuberculosis, and influenza antigens, and ⁇ -galactosyl groups.
- the ligand-immunogen conjugates are used to redirect a previously acquired humoral or cellular immunity to a population of pathogenic cells in the host animal for elimination of the foreign cells or pathogenic organisms, and the T H I- biasing adjuvant augments the immune response to enhance the elimination of the pathogenic cells.
- Antigens or antigenic peptides to which the host animal has developed an innate immunity are also suitable immunogens for use in accordance with the invention.
- the T H I- biasing adjuvant and the ligand-immunogen conjugates are co-administered and the adjuvant enhances the immune response to the immunogen resulting from innate immunity.
- a preexisting immunity can be developed by preimmumzation with an immunogen or a hapten.
- a novel preexisting immunity can be developed through immunization with the immunogen or hapten (e.g., fluorescein, dinitrophenyl, trinitrophenyl, ⁇ -gal epitopes, synthetic peptides or glycopeptides derived from common viruses, bacteria, carbohydrates, oligosaccharides, gangliosides, and low molecular weight drugs).
- the hapten is typically conjugated to a carrier to form a hapten-carrier conjugate.
- the host is preimmunized with the hapten-carrier conjugate and the T H 1 -biasing adjuvant.
- the T H I -biasing adjuvant enhances the immune response to the hapten upon subsequent administration of the ligand-hapten conjugate.
- a preexisting immunity can be developed by preimmumzation with the immunogen and the T H 1- biasing adjuvant.
- any immunogen that induces an immune response upon co-administration of the T H I- biasing adjuvant and the ligand-immunogen conjugate can be used.
- Carriers that can be used in accordance with the invention include keyhole limpet hemocyanin (KLH), haliotis tuberculata hemocyanin (HtH), inactivated diptheria toxin, inactivated tetanus toxoid, purified protein derivative (PPD) of Mycobacterium tuberculosis, bovine serum albumin (BSA), ovalbumin (OVA), g-globulins, thyroglobulin, peptide antigens, and synthetic carriers, such as poly-L-lysine, dendrimer, and liposomes.
- KLH keyhole limpet hemocyanin
- HtH haliotis tuberculata hemocyanin
- PPD purified protein derivative
- BSA bovine serum albumin
- OVA ovalbumin
- the ligand or the carrier can be conjugated to the immunogen or the hapten by using any art-recognized method of forming a complex.
- This can include covalent, ionic, or hydrogen bonding of the carrier or ligand to the immunogen or hapten, either directly or indirectly via a linking group such as a divalent linker.
- the hapten-carrier, ligand-immunogen, and ligand-hapten conjugates are typically formed by covalent bonding through the formation of amide, ester or imino bonds between acid, aldehyde, hydroxy, amino, or hydrazo groups on the respective components of the conjugates.
- the linker typically comprises about 1 to about 30 carbon atoms, more typically about 2 to about 20 carbon atoms. Lower molecular weight linkers (i.e., those having an approximate molecular weight of about 20 to about 500) are typically employed.
- the linker can comprise an indirect means for associating the ligand or the carrier with the immunogen or the hapten, such as by connection through intermediary linkers, spacer arms, or bridging molecules. Both direct and indirect means for association should not prevent the binding of the ligand to the receptor on the cell membrane for operation of the method of the present invention.
- the ligand is folic acid, an analog of folic acid, or any other folate-receptor binding molecule
- the folate ligand is conjugated to the immunogen or hapten by a procedure that utilizes trifluoroacetic anhydride to prepare ⁇ -esters of folic acid via a pteroyl azide intermediate.
- This procedure results in the synthesis of a folate ligand, conjugated to the immunogen or hapten only through the ⁇ -carboxy group of the glutamic acid groups of folate (see Fig. 7) wherein the ⁇ - conjugate binds to the folate receptor with high affinity, avoiding the formation of mixtures of an ⁇ -conjugate and the ⁇ -conjugate.
- pure ⁇ -conjugates can be prepared from intermediates wherein the ⁇ -carboxy group is selectively blocked, the ⁇ -conjugate is formed and the ⁇ -carboxy group is subsequently deblocked using art-recognized organic synthesis protocols and procedures.
- the endogenous immune response-mediated elimination of the pathogenic cell population is enhanced by immunization with the T H 1- biasing adjuvant.
- the endogenous immune response can include an humoral response, a cell- mediated immune response, and any other immune response endogenous to the host animal, including complement-mediated cell lysis, antibody-dependent cell-mediated cytoxicity (ADCC), antibody opsonization leading to phagocytosis, clustering of receptors upon antibody binding resulting in signaling of apoptosis, antiproliferation, or differentiation, and direct immune cell recognition of the delivered immunogen/hapten.
- ADCC antibody-dependent cell-mediated cytoxicity
- the endogenous immune response will employ the secretion of cytokines that regulate such processes as the multiplication and migration of immune cells.
- the endogenous immune response can include the participation of such immune cell types as B cells, T cells, including helper and cytotoxic T cells, macrophages, natural killer cells, neutrophils, LAK cells, and the like.
- the preexisting antibodies, induced antibodies, or passively administered antibodies will be redirected to the tumor cells or infectious organisms by preferential binding of the ligand-immunogen or ligand-hapten conjugates to these invading cells or organisms and that the pathogenic cells will be killed by the immune responses described above.
- the cytotoxic process can also involve secondary responses that arise when the attracted antigen-presenting cells phagocytose the unwanted cells and present natural tumor antigens or antigens of foreign pathogens to the cellular arm of the immune system for elimination of the cells or organisms bearing the antigens.
- the immune response can be induced by such processes as normally scheduled vaccination, or active immunization with a natural immunogen or an unnatural immunogen or hapten (e.g., fluorescein or dinitrophenyl), with the unnatural immunogen or hapten inducing a novel immunity.
- Active immunization can involve multiple injections of the natural immunogen or unnatural immunogen or hapten (e.g., as a hapten-carrier conjugate) scheduled outside of a normal vaccination regimen to induce immunity.
- the T H I -biasing adjuvant can be administered with the immunogen or hapten using any immunization schedule, such as at a time prior to, at the same time as, or at a time following administration of a natural or an unnatural immunogen or hapten.
- the T H I -biasing adjuvant can be administered in the same solution or in a different solution than the immunogen or hapten.
- the immune response can also result from an innate immunity where the host animal has a natural preexisting immunity, such as an immunity to ⁇ -galactosyl groups, and, in the case of an innate immunity, the T H I -biasing adjuvant augments the immune response resulting from the innate immunity.
- At least one additional composition comprising a therapeutic factor can be administered to the host in combination with the above-detailed methodology, to enhance the endogenous immune response-mediated elimination of the population of pathogenic cells, or more than one additional therapeutic factor can be administered.
- the therapeutic factor can be selected from a compound capable of stimulating an endogenous immune response, a chemotherapeutic agent, an antimicrobial agent, or other therapeutic factor capable of complementing the efficacy of the administered ligand-immunogen or ligand-hapten conjugate, such as a cytoxic immune cell.
- the cytotoxic immune cell is a cytotoxic immune cell population that is isolated, expanded ex vivo, and is then injected into a host animal.
- the method of the invention can also be performed by administering to the host, in addition to the above- described conjugates, compounds or compositions capable of stimulating an endogenous immune response including, but not limited to, cytokines or immune cell growth factors such as interleukins 1-18, IL-23, stem cell factor, basic FGF, EGF, G- CSF, GM-CSF, FLK-2 ligand, FLT-3 ligand, HILDA, MIP-lo, TGF- ⁇ , TGF- ⁇ , M- CSF, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , soluble CD23, LIF, and combinations thereof.
- cytokines or immune cell growth factors such as interleukins 1-18, IL-23, stem cell factor, basic FGF, EGF, G- CSF, GM-CSF, FLK-2 ligand, FLT-3 ligand, HILDA, MIP-lo, TGF- ⁇ , TGF- ⁇ , M- CSF, IFN- ⁇ , IFN- ⁇ , I
- therapeutically effective combinations of these cytokines can also be used.
- therapeutically effective amounts of IL-2 for example, in amounts ranging from about 0.1 MIU/m 2 /dose/day to about 60 MIU/m 2 /dose/day in a multiple dose daily regimen
- IJFN- ⁇ for example, in amounts ranging from about 0.1 MIU/m 2 /dose/day to about 10 MIU/m 2 /dose/day in a multiple dose daily regimen
- MIU million international units
- m 2 approximate body surface area of an average human.
- IL-12 and IFN- ⁇ are used in therapeutically effective amounts
- IL-15 and IFN- ⁇ are used in therapeutically effective amounts.
- IL-2, IFN- ⁇ or IFN- ⁇ , and GM-CSF are used in combination.
- the therapeutic factor(s) used such as IL-2, IL-12, JX-15, IFN- ⁇ , IFN- ⁇ , and GM- CSF, including combinations thereof, can activate natural killer cells and/or T cells.
- the therapeutic factor or combinations thereof, including an interleukin in combination with an interferon and GM-CSF can activate other immune effector cells such as macrophages, B cells, neutrophils, NK cells, NKT cells, T cells, LAK cells, or the like.
- the invention also contemplates the use of any other effective combination of cytokines including combinations of other interleukins and interferons and colony stimulating factors.
- Chemotherapeutic agents which are cytotoxic themselves and can work to enhance tumor permeability, suitable for use as therapeutic factors in accordance with the invention include adrenocorticoids, alkylating agents, antiandrogens, antiestrogens, androgens, estrogens, antimetabolites such as cytosine arabinoside, purine analogs, pyrimidine analogs, and methotrexate, busulfan, carboplatin, chlorambucil, cisplatin and other platinum compounds, tamoxiphen, taxol, cyclophosphamide, plant alkaloids, prednisone, hydroxyurea, teniposide, antibiotics such as mitomycin C and bleomycin, nitrogen mustards, nitrosureas, vincristine, vinblastine, inflammatory and proinflammatory agents, and any other art- recognized chemotherapeutic agent.
- therapeutic factors include penicillins, cephalosporins, vancomycin, erythromycin, clindamycin, rifampin, chloramphenicol, aminoglycosides, gentamicin, amphotericin B, acyclovir, trifluridine, ganciclovir, zidovudine, amantadine, ribavirin, and any other art-recognized antimicrobial compound.
- the therapeutic factor can also be an antibody directed against the immunogen or hapten, such as natural antibodies collected from serum or monoclonal antibodies that may or may not be genetically engineered antibodies, including humanized antibodies, and can be passively administered to the host animal to augment the elimination of the pathogenic cells.
- the passively administered antibodies can be co-administered with the ligand-immunogen or ligand-hapten conjugate.
- the elimination of the population of pathogenic cells will comprise a reduction or elimination of tumor mass or of pathogenic organisms resulting in a therapeutic response.
- "elimination" of pathogenic cells means a partial or complete elimination of the cells.
- the elimination can be an elimination of cells of the primary tumor or of cells that have metastasized or are in the process of dissociating from the primary tumor.
- a prophylactic treatment to prevent return of a tumor after its removal by any therapeutic approach including surgical removal of the tumor, radiation therapy, chemotherapy, or biological therapy is also contemplated in accordance with this invention and is considered to be an elimination of pathogenic cells.
- the prophylactic treatment can be an initial treatment with the T H I -biasing adjuvant and the hapten- carrier conjugate or the immunogen followed by treatment with the ligand- immunogen or ligand-hapten conjugate, such as treatment in a multiple dose daily regimen, and/or can be an additional treatment or series of treatments with the ligand- immunogen or ligand-hapten conjugate after an interval of days or months following the initial treatments(s) with or without administration of the T H l-biasing adjuvant.
- the invention is also directed to a composition comprising therapeutically effective amounts of a T H I -biasing adjuvant and a hapten-carrier conjugate.
- the hapten can be fluorescein or dinitrophenyl or any other hapten.
- a composition comprising therapeutically effective amounts of a T H l-biasing adjuvant and a ligand-immunogen conjugate.
- This composition can further comprise an amount of the therapeutic factor effective to enhance the elimination of the pathogenic cells.
- the therapeutic factor is selected from the group consisting of a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, an antimicrobial agent, a cytotoxic immune cell, and a compound capable of stimulating an endogenous immune response.
- the therapeutic factor can comprise a cytokine such as IL-2, IL-12, IL-15, or IL-23 or combinations of cytokines, including IL-2, IL-12, IL- 15, or IL-23 and interferons such as IFN- ⁇ , IFN- ⁇ , and EFN- ⁇ and combinations of interferons, interleukins, and colony stimulating factors, such as GM-CSF.
- Kits comprising the above-described components are also contemplated.
- a kit comprising a T ⁇ l-biasing adjuvant, a hapten-carrier conjugate, and a ligand-hapten conjugate is also contemplated.
- the kit can comprise an immunogen, a T H l-biasing adjuvant, and a ligand-immunogen conjugate.
- the kits can further comprise a therapeutic factor.
- the dosages of the adjuvant, the immunogen, the hapten-carrier conjugate, the ligand-immunogen conjugate, and the ligand-hapten conjugate can vary depending on the host condition, the disease state being treated, the molecular weight of the conjugate or immunogen, route of administration and tissue distribution, and the possibility of co-usage of other therapeutic treatments such as radiation therapy.
- the effective amounts to be administered to a patient are based on body surface area, patient weight, and physician assessment of patient condition. Effective doses of the adjuvant can range from about 0.01 ⁇ g to about 100 mg per patient, or from about 100 ⁇ g to about 50 mg per patient, or from about 500 ⁇ g to about 10 mg per patient.
- Effective doses of the hapten-carrier conjugate or the immunogen can range from about 1 ⁇ g to about 100 mg per patient, or from about 10 ⁇ g to about 50 mg per patient, or from about 50 ⁇ g to about 10 mg per patient.
- Effective doses of the ligand- immunogen or ligand-hapten conjugate can range from about 1 ng/kg to about 1 mg/kg, or from about 1 ⁇ g/kg to about 500 ⁇ g/kg, or from about 1 ⁇ g/kg to about 100 ⁇ g/kg.
- any effective regimen for administering the T ⁇ l-biasing adjuvant, the immunogen, the hapten-carrier conjugate, the ligand-immunogen conjugate, the ligand-hapten conjugate and the therapeutic factor to redirect the immune response to the tumor cells or infectious organisms can be used.
- the T H l-biasing adjuvant, the immunogen, the conjugates, and the therapeutic factor can be administered as single doses, or they can be divided and administered as a multiple- dose daily regimen.
- a staggered regimen for example, one to three days per week can be used as an alternative to daily treatment, and for the purpose of defining this invention such intermittent or staggered daily regimen is considered to be equivalent to every day treatment and within the scope of this invention.
- the host is treated with multiple injections of the ligand-hapten conjugate and the therapeutic factor, after three initial doses of the T H 1 -biasing adjuvant and the hapten-carrier conjugate, to eliminate the population of pathogenic cells.
- the host is injected multiple times (e.g., about 2 up to about 50 times) with the ligand-hapten conjugate, for example, at 12-72 hour intervals or a 48-72 hour intervals. Additional injections of the ligand-hapten conjugate can be administered to the patient at an interval of days or months after the initial injections(s) and the additional injections prevent recu ⁇ ence of disease.
- the initial injection(s) of the ligand-hapten conjugate may prevent recurrence of disease.
- the ligand-immunogen conjugate or ligand-hapten conjugate can be subsequently administered with a therapeutic factor.
- the therapeutic factor can be administered to the host animal prior to, after, or at the same time as the ligand-immunogen conjugate or the ligand-hapten conjugate and the therapeutic factor can be administered as part of the same composition containing the ligand- immunogen conjugate or the ligand-hapten conjugate or as part of a different composition than the conjugate. Any such therapeutic composition containing the therapeutic factor at a therapeutically effective dose can be used in the present invention. In another embodiment where no preexisting immunity has been developed, the therapeutic factor can be co-administered with the T H 1 -biasing adjuvant and the ligand-immunogen conjugate.
- hapten-carrier conjugate ligand-immunogen conjugate
- ligand-immunogen conjugate ligand-hapten conjugate
- the host animal can be preimmunized with both fluorescein-carrier and dinitrophenyl-carrier conjugates and subsequently treated with fluorescein and dinitrophenyl linked to the same or different ligands in a co-dosing protocol.
- the therapeutic factor can be administered at a suboptimal dose along with the ligand-immunogen conjugate or the ligand-hapten conjugate in a combination therapy to avoid development of resistance to the chemotherapeutic or antimicrobial agent by the host animal.
- the T H I -biasing adjuvant, the immunogen, the hapten-carrier conjugate, the ligand-immunogen conjugate, the ligand-hapten conjugate and the therapeutic factor are preferably injected parenterally and such injections can be intradermal injections, intraperitoneal injections, subcutaneous injections, intramuscular injections, intravenous injections, or intrathecal injections.
- the T H I -biasing adjuvant, the immunogen, and the conjugates can be administered to the host animal by other medically useful processes, such as oral administration, and any suitable therapeutic dosage form can be used.
- parenteral dosage forms include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carriers such as liquid alcohols, glycols, esters, and amides.
- the parenteral dosage form in accordance with this invention can also be in the form of a reconstitutable lyophilizate.
- any of a number of prolonged release dosage forms known in the art can be administered such as, for example, the biodegradable carbohydrate matrices described in U.S. Patent Nos. 4,713,249; 5,266,333; and
- the method of the present invention can be used in combination with additional therapies such as surgical removal of a tumor, radiation therapy, chemotherapy, or biological therapies such as other immunotherapies including, but not limited to, monoclonal antibody therapy, treatment with immunomodulatory agents, adoptive transfer of immune effector cells, treatment with hematopoietic growth factors, cytokines and vaccination.
- additional therapies such as surgical removal of a tumor, radiation therapy, chemotherapy, or biological therapies
- additional therapies such as surgical removal of a tumor, radiation therapy, chemotherapy, or biological therapies
- additional therapies such as surgical removal of a tumor, radiation therapy, chemotherapy, or biological therapies such as other immunotherapies including, but not limited to, monoclonal antibody therapy, treatment with immunomodulatory agents, adoptive transfer of immune effector cells, treatment with hematopoietic growth factors, cytokines and vaccination.
- GPI-0100 is a saponin adjuvant that is a lipid- modified derivative of partially purified quiUajasaponins. The preparation and use of GPI-0100 are described in U.S. Patent No. 6,080,725, incorporated herein by reference.
- each animal was injected intraperitoneally approximately 5 weeks after the first immunization with 2.5 x 10 4 L1210A cells, a syngeneic mouse leukemia cell line that expresses high levels of the high-affinity folate receptor. The cancer cells were then allowed to proliferate and grow in vivo for 7 days.
- the tumor-bearing mice were treated intraperitoneally with phosphate buffered saline (PBS) or were co-injected with PBS, IL-2 (250,000 IU/dose), and IFN- ⁇ (75,000 IU/dose), or with a folate-FITC conjugate (EC17; see Fig. 7; 1800 nmol kg), IL-2 (250,000 IU/dose), and IFN- ⁇ (75,000 IU/dose) on days 7, 8, 9, 11, and 14 after tumor cell implantation. Animal gross morphology, behavior, and survival were monitored daily. As shown in Fig. 2, while cytokines alone extended the survival of tumor bearing mice to some degree, the mice treated with EC 17, IL-2, and IFN- ⁇ were cured (confirmed by histopatho logical analysis).
- PBS phosphate buffered saline
- mice Six to eight week-old (-20-22 grams) female Balb/c mice were immunized three times subcutaneously at 2-week intervals with 35 ⁇ g of KLH-FITC formulated with 100 ⁇ g of GPI-0100. After confirming that anti-FITC antibody titers were high in all mice as described in Example 1, each animal was injected intraperitoneally, approximately 5 weeks after the first immunization, with 7.5 x 10 5 Ml 09 cells, a syngeneic mouse lung cancer cell line that expresses high levels of the high-affinity folate receptor. The cancer cells were then allowed to proliferate in vivo for 7 days.
- mice were injected subcutaneously with PBS or were co-injected with PBS, IL-2 (5,000 IU/dose), and IFN- ⁇ (25,000 IU/dose), or with PBS, EC17 (1800 nmol/kg), IL-2 (5,000 IU/dose), and IFN- ⁇ (25,000 IU/dose) on days 7-11, 14-18, and 21-25 after tumor cell implantation.
- EC17 and IFN- ⁇ were dosed at 3 times per week.
- IL-2 was dosed at 5 times per week. Animal gross morphology, behavior, and survival were monitored daily. As shown in Fig. 3, while cytokines alone extended the survival of tumor bearing mice to some degree, the survival of mice treated with EC 17, IL-2, and IFN- ⁇ was prolonged substantially.
- mice Six to eight week-old (-20-22 grams) female Balb/c mice were immunized three times subcutaneously at 2-week intervals with 35 ⁇ g of KLH-FITC formulated with 100 ⁇ g of GPI-0100. After confirming that anti-FITC antibody titers were high in all mice as described in Example 1, each animal was injected intraperitoneally, approximately 5 weeks after the first immunization, with 7.5 x 10 Ml 09 cells. One day later, the tumor-bearing mice were injected subcutaneously with PBS or were co-injected with PBS and EC17 (1800 nmol/kg) on days 1, 2, 5, 7, 9, 12, 14, and 16 after tumor cell implantation. Animal gross morphology, behavior, and survival were monitored daily. As shown in Fig. 4, while the mice in the PBS control group all died at about 24-25 days after tumor implantation, the survival of mice treated with EC 17 was prolonged substantially.
- mice Six to eight week-old (-20-22 grams) female Balb/c mice were immunized three times subcutaneously at one-week intervals with 35 ⁇ g of KLH- FITC formulated with 100 ⁇ g of GPI-0100. After confirming that anti-FITC antibody titers were high in all mice as described in Example 1, each animal was injected intraperitoneally with 0.5 x 10 5 M109-cells. The cancer cells were then allowed to grow in vivo for 7 days. Thereafter, the tumor-bearing mice were injected intraperitoneally with PBS or with PBS and EC17 (1800 nmol/kg/day) on days 7-11, 14-18, and 21-25 after tumor cell implantation. EC 17 and INF- ⁇ were dosed at 3 times per week.
- IL-2 was dosed at 5 times per week. Animal gross morphology, behavior, and survival were monitored daily. As shown in Fig. 5, EC 17 alone exhibited a minor extension of lifespan of the tumor-bearing mice compared to the PBS control. Accordingly, the results shown in Fig. 4 and Fig. 5 taken together demonstrate that EC 17 alone has significant antitumor effect at the early stage of tumor development. More importantly, the results shown in Fig. 3 and Fig. 5 taken together demonstrate that EC 17 and cytokines, such as IL-2 and IFN- ⁇ , cause a synergistic increase in the lifespan of tumor-bearing mice compared to treatment with EC 17 or cytokines alone.
- cytokines such as IL-2 and IFN- ⁇
- mice Six to eight week-old (-20-22 grams) female Balb/c mice were immunized three times subcutaneously at one-week intervals with 35 ⁇ g of KLH- FITC formulated with 100 ⁇ g of GPI-0100. After confirming that anti-FITC antibody titers were high in all mice as described in Example 1, each animal was injected subcutaneously in the shoulder with 1 x 10 6 M109 cells. The cancer cells were then allowed to grow for a week to 30-50 mm 3 .
- the tumor-bearing mice were injected intraperitoneally with PBS or were co-injected with PBS, IL-2 (40,000 IU/dose), and IFN- ⁇ (25,000 IU/dose), or with PBS, EC17 (1800 nmol/kg), IL-2 (40,000 IU/dose), and IFN- ⁇ (25,000 IU/dose) on days 7-11, 14-18, and 21-25 after tumor cell implantation.
- EC 17 and IL-2 were dosed at 5 times per week.
- IFN- ⁇ was dosed at 3 times per week. Tumor volumes were measured every other day using a caliper. As shown in Fig.
- mice injected with EC 17, IL-2, and IFN- ⁇ exhibited a decrease in size over 35 days post implantation compared to significant growth of tumors in mice injected with PBS or with PBS, IL-2, and IFN- ⁇
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN038144425A CN1662251B (en) | 2002-04-19 | 2003-04-16 | Adjuvant enhanced immunotherapy |
JP2003586306A JP2005532296A (en) | 2002-04-19 | 2003-04-16 | Immunotherapy enhanced by adjuvants |
AU2003224989A AU2003224989B2 (en) | 2002-04-19 | 2003-04-16 | Adjuvant enhanced immunotherapy |
CA002482924A CA2482924A1 (en) | 2002-04-19 | 2003-04-16 | Adjuvant enhanced immunotherapy |
EP03721690A EP1496934A4 (en) | 2002-04-19 | 2003-04-16 | Adjuvant enhanced immunotherapy |
NZ536609A NZ536609A (en) | 2002-04-19 | 2003-04-16 | Use of an TH1-biasing adjuvant to enhance the immune response to the immunogen in immunotherapy |
IL16454604A IL164546A0 (en) | 2002-04-19 | 2004-10-13 | Adjuvant enhanced immunotherapy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37381802P | 2002-04-19 | 2002-04-19 | |
US60/373,818 | 2002-04-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003089593A2 true WO2003089593A2 (en) | 2003-10-30 |
WO2003089593A3 WO2003089593A3 (en) | 2003-12-24 |
Family
ID=29251090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/011663 WO2003089593A2 (en) | 2002-04-19 | 2003-04-16 | Adjuvant enhanced immunotherapy |
Country Status (12)
Country | Link |
---|---|
US (1) | US20030198643A1 (en) |
EP (1) | EP1496934A4 (en) |
JP (2) | JP2005532296A (en) |
CN (1) | CN1662251B (en) |
AR (1) | AR039429A1 (en) |
AU (1) | AU2003224989B2 (en) |
CA (1) | CA2482924A1 (en) |
IL (1) | IL164546A0 (en) |
NZ (1) | NZ536609A (en) |
TW (1) | TW200406220A (en) |
WO (1) | WO2003089593A2 (en) |
ZA (1) | ZA200408427B (en) |
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JP2008539249A (en) * | 2005-04-26 | 2008-11-13 | エーザイ株式会社 | Compositions and methods for cancer immunotherapy |
JP2013241424A (en) * | 2005-09-01 | 2013-12-05 | Celgene Corp | Immunological use of immunomodulatory compound for vaccine and anti-infectious disease therapy |
US10076491B2 (en) | 2013-02-05 | 2018-09-18 | Nitto Denko Corporation | Vaccine composition |
US10590180B2 (en) | 2015-06-19 | 2020-03-17 | National University Corporation Shizuoka University | Immune function development promoter and growth promoter |
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CZ304942B6 (en) * | 2000-03-31 | 2015-02-04 | Purdue Research Foundation | Medicament for increasing specific elimination of tumor cell population and pharmaceutical composition containing phosphate-FITC conjugate or phosphate-dinitrophenyl |
EP1390077B1 (en) | 2001-05-02 | 2014-07-16 | Purdue Research Foundation | Treatment and diagnosis of macrophage mediated disease |
CA2461877A1 (en) * | 2001-09-28 | 2003-04-10 | Purdue Research Foundation | Method of treatment using ligand-immunogen conjugates |
US8043602B2 (en) | 2002-02-07 | 2011-10-25 | Endocyte, Inc. | Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology |
US8043603B2 (en) * | 2002-02-07 | 2011-10-25 | Endocyte, Inc. | Folate targeted enhanced tumor and folate receptor positive tissue optical imaging technology |
RU2341289C2 (en) * | 2003-02-21 | 2008-12-20 | ХАСУМИ Эл-Эл-Си (Ди-Би-Эй ШУКОКАЙ ИНТЕРНЭШНЛ) | Method of enhancement of immune response to antigene in mammals |
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CN101128152A (en) * | 2004-12-23 | 2008-02-20 | 普渡研究基金会 | Positron emission tomography imaging method |
ATE460668T1 (en) | 2005-03-30 | 2010-03-15 | Purdue Research Foundation | METHOD FOR PREDICTING BREAST CANCER USING QUANTIFICATION OF CELLULAR FOLATE VITAMIN RECEPTORS |
JP5175723B2 (en) | 2005-07-05 | 2013-04-03 | パーデュー・リサーチ・ファウンデーション | Preparation of compositions for treating monocyte-mediated diseases |
WO2007038346A2 (en) | 2005-09-23 | 2007-04-05 | Purdue Research Foundation | Multiphoton in vivo flow cytometry method and device |
US20070134259A1 (en) * | 2005-11-21 | 2007-06-14 | David Bundle | Methods and compositions for pharmacologially controlled targeted immunotherapy |
WO2007092299A2 (en) * | 2006-02-03 | 2007-08-16 | Purdue Research Foundation | Targeted conjugates and radiation |
EP2066348A1 (en) * | 2006-09-26 | 2009-06-10 | Alexion Pharmaceuticals, Inc. | Compositions and methods for enhancing an adjuvant |
CA2668197A1 (en) | 2006-11-03 | 2008-05-15 | Philip S. Low | Ex vivo flow cytometry method and device |
WO2008098112A2 (en) | 2007-02-07 | 2008-08-14 | Purdue Research Foundation | Positron emission tomography imaging method |
EP2164525A2 (en) * | 2007-05-25 | 2010-03-24 | Purdue Research Foundation | Method of imaging localized infections |
US20090012009A1 (en) * | 2007-06-01 | 2009-01-08 | Low Philip S | Composition and Method for Treating Inflammatory Disease |
EP2222328A4 (en) * | 2007-11-15 | 2013-06-05 | Endocyte Inc | Method of administering conjugates |
WO2014151423A1 (en) * | 2013-03-15 | 2014-09-25 | Newlink Genetics Corporation | Carbohydrate-modified glycoproteins and uses thereof |
WO2018187259A1 (en) * | 2017-04-05 | 2018-10-11 | University Of Miami | Methods and compositions for stimulating the immune system |
CN109061172B (en) * | 2018-09-21 | 2021-07-06 | 中国烟草总公司郑州烟草研究院 | Enzyme linked immunosorbent assay kit for detecting butralin and application thereof |
WO2020200481A1 (en) * | 2019-04-05 | 2020-10-08 | Biontech Rna Pharmaceuticals Gmbh | Treatment involving interleukin-2 (il2) and interferon (ifn) |
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- 2003-04-16 EP EP03721690A patent/EP1496934A4/en not_active Ceased
- 2003-04-16 AR ARP030101333A patent/AR039429A1/en unknown
- 2003-04-16 WO PCT/US2003/011663 patent/WO2003089593A2/en active Application Filing
- 2003-04-16 NZ NZ536609A patent/NZ536609A/en not_active IP Right Cessation
- 2003-04-16 CA CA002482924A patent/CA2482924A1/en not_active Abandoned
- 2003-04-16 AU AU2003224989A patent/AU2003224989B2/en not_active Ceased
- 2003-04-16 CN CN038144425A patent/CN1662251B/en not_active Expired - Fee Related
- 2003-04-17 US US10/417,903 patent/US20030198643A1/en not_active Abandoned
- 2003-04-18 TW TW092109085A patent/TW200406220A/en unknown
-
2004
- 2004-10-13 IL IL16454604A patent/IL164546A0/en unknown
- 2004-10-18 ZA ZA200408427A patent/ZA200408427B/en unknown
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2010
- 2010-07-09 JP JP2010157088A patent/JP2011012065A/en active Pending
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008539249A (en) * | 2005-04-26 | 2008-11-13 | エーザイ株式会社 | Compositions and methods for cancer immunotherapy |
US8603482B2 (en) | 2005-04-26 | 2013-12-10 | Eisai R&D Management Co., Ltd. | Compositions and methods for cancer immunotherapy |
JP2013241424A (en) * | 2005-09-01 | 2013-12-05 | Celgene Corp | Immunological use of immunomodulatory compound for vaccine and anti-infectious disease therapy |
US10076491B2 (en) | 2013-02-05 | 2018-09-18 | Nitto Denko Corporation | Vaccine composition |
US10590180B2 (en) | 2015-06-19 | 2020-03-17 | National University Corporation Shizuoka University | Immune function development promoter and growth promoter |
Also Published As
Publication number | Publication date |
---|---|
CN1662251A (en) | 2005-08-31 |
WO2003089593A3 (en) | 2003-12-24 |
EP1496934A4 (en) | 2006-08-02 |
ZA200408427B (en) | 2007-03-28 |
CN1662251B (en) | 2012-10-10 |
JP2005532296A (en) | 2005-10-27 |
CA2482924A1 (en) | 2003-10-30 |
IL164546A0 (en) | 2005-12-18 |
NZ536609A (en) | 2007-11-30 |
AU2003224989B2 (en) | 2008-12-04 |
AR039429A1 (en) | 2005-02-16 |
TW200406220A (en) | 2004-05-01 |
AU2003224989A1 (en) | 2003-11-03 |
JP2011012065A (en) | 2011-01-20 |
US20030198643A1 (en) | 2003-10-23 |
EP1496934A2 (en) | 2005-01-19 |
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