Compositions comprising immunoreactive reagents and saponins, and methods of use thereof

Abstract

The present invention relates to pharmaceutical compositions that are useful for the prevention and treatment of infectious diseases, primary and metastatic neoplastic diseases (i.e., cancer), neurodegenerative or amyloid diseases, or any other disease wherein the treatment of such disease would be improved by an enhanced immune response, and methods of formulating the compositions. The compositions comprise an immunoreactive reagent (i.e., an antigen binding protein comprising an antigen binding region and a region or regions of an antibody that mediate antibody dependent immunological processes) and a saponin. The present invention also relates to methods of using the compositions of the invention for the prevention and/or treatment of infectious diseases, primary and metastatic neoplastic diseases (i.e., cancer), neurodegenerative or amyloid diseases, or any other disease wherein the treatment of such disease would be improved by an enhanced immune response.

1 . A pharmaceutical composition comprising a saponin and an immunoreactive reagent, wherein said immunoreactive reagent specifically binds an antigen selected from the group consisting of a tumor-associated antigen, an antigen of an agent of infectious disease, an antigen associated with a neurodegenerative disease, and an antigen associated with an amyloid disease.  
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein the immunoreactive reagent is an antibody.  
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein the amount of saponin is at least 1 microgram.  
   
   
       4 . The pharmaceutical composition of  claim 3 , wherein the amount of saponin is 10 to 20 micrograms.  
   
   
       5 . The pharmaceutical composition of  claim 3 , wherein the amount of saponin is 20 to 100 micrograms.  
   
   
       6 . The pharmaceutical composition of  claim 3 , wherein the amount of saponin is 100 to 500 micrograms.  
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein the saponin is QS-7, QS-17, QS-18, QS-21, QS-21-V1, or QS-21-V2.  
   
   
       8 . The pharmaceutical composition of  claim 7 , wherein the saponin is QS-21.  
   
   
       9 . The pharmaceutical composition of  claim 1 , wherein the immunoreactive reagent specifically binds a tumor-associated antigen.  
   
   
       10 . The pharmaceutical composition of  claim 9 , wherein the tumor is a non-Hodgkin's lymphoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenström's macroglobulinemia, or heavy chain disease (B-cell lymphoma).  
   
   
       11 . The pharmaceutical composition of  claim 9 , wherein the tumor-associated antigen is Melan A, MART-1, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, tyrosinase, gp100, gp75, HER-2/neu, c-erb-B2, CEA, PSA, MUC-1, CA-125, Stn, TAG-72, KSA (17-1A), PSMA, p53, RAS, EGF-R, VEGF, GD2, GM2, GD3, Anti-Id, CD20, CD19, CD22, CD36, Aberrant class II, B1, CD25, or BPV.  
   
   
       12 . The pharmaceutical composition of  claim 1 , wherein the immunoreactive reagent binds specifically to an antigen of an agent of infectious disease.  
   
   
       13 . The pharmaceutical composition of  claim 12 , wherein the infectious disease is a viral disease.  
   
   
       14 . The pharmaceutical composition of  claim 13 , wherein the viral disease is viral meningitis, encephalitis, dengue or smallpox, or is a viral disease caused by hepatitis type A, hepatitis type B, hepatitis type C, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes simplex type U (HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, papilloma virus, papova virus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, small pox, human immunodeficiency virus type I (HIV-I), human immunodeficiency virus type II (HIV-II), and Epstein Barr virus.  
   
   
       15 . The pharmaceutical composition of  claim 1 , wherein the infectious disease is a bacterial disease.  
   
   
       16 . The pharmaceutical composition of  claim 15 , wherein the bacterial disease is caused by infection by mycobacteria  rickettsia , mycoplasma,  neisseria, streptococcus, staphylococcus , mycobacterium, tetanus, pertissus, anthrax, cholera, plague, diptheria, or chlamydia.  
   
   
       17 . The pharmaceutical composition of  claim 1 , wherein the infectious disease is a protozoal disease.  
   
   
       18 . The pharmaceutical composition of  claim 17 , wherein the protozoa is  leishmania , kokzidioa,  trypanosoma , or malaria.  
   
   
       19 . The pharmaceutical composition of  claim 1 , wherein the immunoreactive reagent binds specifically to an antigen associated with a neurodegenerative or amyloid disease.  
   
   
       20 . The pharmaceutical composition of  claim 19 , wherein the neurodegenerative or amyloid disease is Alzheimer's Disease, age-related loss of cognitive function, senile dementia, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's Disease, cerebral palsy, progressive supranuclear palsy, Guam disease, Lewy body dementia, prion diseases, spongiform encephalopathies, Creutzfeldt-Jakob disease, polyglutamine diseases, Huntington's disease, myotonic dystrophy, Freidrich's ataxia, ataxia, Gilles de la Tourette's syndrome, seizure disorders, epilepsy, chronic seizure disorder, stroke, brain trauma, spinal cord trauma, AIDS dementia, alcoholism, autism, retinal ischemia, glaucoma, autonomic function disorder, hypertension, neuropsychiatric disorder, schizophrenia, or schizoaffective disorder, type II diabetes, amyloidoses associated with chronic inflammatory disease, amyloidoses associated with infectious disease, or myeloma.  
   
   
       21 . The pharmaceutical composition of  claim 20 , wherein the antigen is β-amyloid, an oligomeric Aβ complex, an ApoE4-Aβ complex, tau protein, a mutant amyloid precursor, a mutant of presenillin, α-synuclein, a prion protein, or an antigenic fragment of any of the foregoing proteins.  
   
   
       22 . A method of treating or preventing cancer in an individual in whom such treatment or prevention is desired, comprising administering to the individual an amount of an immunoreactive reagent that specifically binds to an antigen of said type of cancer, and a saponin, which amount is effective to treat or prevent cancer in the individual.  
   
   
       23 . A method of treating or preventing an infectious disease in an individual in whom such treatment or prevention is desired, comprising administering to the individual an amount of an immunoreactive reagent that specifically binds to an antigen of said type of cancer, and a saponin, which amount is effective to treat or prevent the infectious disease in the individual.  
   
   
       24 . A method of treating or preventing a neurodegenerative or amyloid disease in an individual in whom such treatment or prevention is desired, comprising administering to the individual an immunoreactive reagent that specifically binds to an antigen of said neurodegenerative or amyloid disease, and a saponin, which amount is effective to treat or prevent the neurodegenerative or amyloid disease in the individual.  
   
   
       25 . The method of  claim 22 ,  23  or  24 , wherein the immunoreactive reagent is an antibody.  
   
   
       26 . The method of  claim 22 ,  23  or  24 , wherein the amount of saponin is at least 1 microgram.  
   
   
       27 . The method of  claim 26 , wherein the amount of saponin is 10 to 20 micrograms.  
   
   
       28 . The method of  claim 27 , wherein the amount of saponin is 20 to 100 micrograms.  
   
   
       29 . The method of  claim 27 , wherein the amount of saponin is 100 to 500 micrograms.  
   
   
       30 . The method of  claim 22 ,  23  or  24 , wherein the saponin is QS-7, QS-17, QS-18, QS-21, QS-21-V1, or QS-21-V2.  
   
   
       31 . The method of  claim 30 , wherein the saponin is QS-21.  
   
   
       32 . A method of enhancing antibody dependent cellular cytotoxicity or phagocytosis of a target in an individual in whom such enhancement is desired, comprising administering to the individual an amount of an immunoreactive reagent that specifically binds to an antigen of said target, and a saponin, which amount is effective to enhance antibody dependent cellular cytotoxicity or phagocytosis of the target in the individual.  
   
   
       33 . The method of  claim 32 , wherein the immunoreactive reagent is an antibody.  
   
   
       34 . The method of  claim 32 , wherein the amount of saponin is at least 1 microgram.  
   
   
       35 . The method of  claim 34 , wherein the amount of saponin is 10 to 20 micrograms.  
   
   
       36 . The method of  claim 34 , wherein the amount of saponin is 20 to 100 micrograms.  
   
   
       37 . The method of  claim 34 , wherein the amount of saponin is 100 to 500 micrograms.  
   
   
       38 . The method of  claim 32 , wherein the saponin is QS-7, QS-17, QS-18, QS-21, QS-21-V1, or QS-21-V2.  
   
   
       39 . The method of  claim 38 , wherein the saponin is QS-21.  
   
   
       40 . A method of enhancing passive immunotherapy in an individual in whom such enhancement is desired, wherein said immunotherapy comprises administration of an amount of an immunoreactive reagent that specifically binds to an antigen of a target, said method comprising further administering an amount of a saponin, which amount is effective to enhance the passive immunotherapy in the individual.  
   
   
       41 . The method of  claim 40 , wherein the immunoreactive reagent is an antibody.  
   
   
       42 . The method of  claim 40 , wherein the amount of saponin is at least 1 microgram.  
   
   
       43 . The method of  claim 42 , wherein the amount of saponin is 10 to 20 micrograms.  
   
   
       44 . The method of  claim 42 , wherein the amount of saponin is 20 to 100 micrograms.  
   
   
       45 . The method of  claim 42 , wherein the amount of saponin is 100 to 500 micrograms.  
   
   
       46 . The method of  claim 40 , wherein the saponin is QS-7, QS-17, QS-18, QS-21, QS-21-V1, or QS-21-V2.  
   
   
       47 . The method of  claim 46 , wherein the saponin is QS-21.  
   
   
       48 . A kit comprising, in one or more containers, a saponin and an immunoreactive reagent, wherein said immunoreactive reagent specifically binds an antigen selected from the group consisting of a tumor-associated antigen, an antigen of an agent of infectious disease, an antigen associated with a neurodegenerative disease, and an antigen associated with an amyloid disease.  
   
   
       49 . The kit of  claim 48 , wherein the saponin and immunoreactive reagent are in separate containers.  
   
   
       50 . The kit of  claim 49 , wherein the immunoreactive reagent is formulated for intravenous administration, and the saponin is formulated for administration other than intravenous administration.  
   
   
       51 . The kit of  claim 49 , wherein the immunoreactive reagent is an antibody.  
   
   
       52 . The kit of  claim 49 , wherein the saponin is QS-21.  
   
   
       53 . The kit of  claim 49 , wherein the immunoreactive reagent is an antibody and the saponin is QS-21.  
   
   
       54 . The method of  claim 22 ,  23 ,  24 ,  32 , or  40 , wherein the immunoreactive reagent and the saponin are administered at different times from one another.  
   
   
       55 . The method of  claim 54 , wherein the saponin is administered prior to the immunoreactive reagent.  
   
   
       56 . The method of  claim 55 , wherein the saponin is administered at least one day prior to the immunoreactive reagent.