AU2002230758A1 - Treatment and prevention of EBV infection and EBV-associated disorders - Google Patents
Treatment and prevention of EBV infection and EBV-associated disordersInfo
- Publication number
- AU2002230758A1 AU2002230758A1 AU2002230758A AU3075802A AU2002230758A1 AU 2002230758 A1 AU2002230758 A1 AU 2002230758A1 AU 2002230758 A AU2002230758 A AU 2002230758A AU 3075802 A AU3075802 A AU 3075802A AU 2002230758 A1 AU2002230758 A1 AU 2002230758A1
- Authority
- AU
- Australia
- Prior art keywords
- ebv
- env
- herv
- individual
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 40
- 206010015108 Epstein-Barr virus infection Diseases 0.000 title claims description 25
- 238000011282 treatment Methods 0.000 title claims description 12
- 230000002265 prevention Effects 0.000 title description 7
- 231100000617 superantigen Toxicity 0.000 claims description 56
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 claims description 47
- 101001064122 Homo sapiens Endogenous retrovirus group K member 18 Env polyprotein Proteins 0.000 claims description 43
- 101000956193 Homo sapiens Endogenous retrovirus group K member 18 Pro protein Proteins 0.000 claims description 43
- 101001066690 Homo sapiens Ribonuclease H Proteins 0.000 claims description 43
- 102100034344 Ribonuclease H Human genes 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 42
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 36
- 208000035475 disorder Diseases 0.000 claims description 28
- 239000012634 fragment Substances 0.000 claims description 28
- 229960005486 vaccine Drugs 0.000 claims description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 19
- 208000015181 infectious disease Diseases 0.000 claims description 17
- 201000006747 infectious mononucleosis Diseases 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 150000007523 nucleic acids Chemical class 0.000 claims description 13
- 230000004936 stimulating effect Effects 0.000 claims description 12
- 108020004707 nucleic acids Proteins 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 11
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 9
- 206010025323 Lymphomas Diseases 0.000 claims description 9
- 230000002163 immunogen Effects 0.000 claims description 9
- 239000005022 packaging material Substances 0.000 claims description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 208000017604 Hodgkin disease Diseases 0.000 claims description 7
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 7
- 208000030289 Lymphoproliferative disease Diseases 0.000 claims description 7
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 7
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 7
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 7
- 239000008177 pharmaceutical agent Substances 0.000 claims description 6
- 206010061598 Immunodeficiency Diseases 0.000 claims description 5
- 230000003292 diminished effect Effects 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 4
- 230000006548 oncogenic transformation Effects 0.000 claims description 4
- 238000002650 immunosuppressive therapy Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 231100000590 oncogenic Toxicity 0.000 claims description 3
- 230000002246 oncogenic effect Effects 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims description 2
- 208000017805 post-transplant lymphoproliferative disease Diseases 0.000 claims description 2
- 102100034353 Integrase Human genes 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 108010078428 env Gene Products Proteins 0.000 claims 1
- 230000036039 immunity Effects 0.000 claims 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 95
- 210000004027 cell Anatomy 0.000 description 33
- 230000000694 effects Effects 0.000 description 30
- 230000004044 response Effects 0.000 description 22
- 241000282414 Homo sapiens Species 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 20
- 210000000612 antigen-presenting cell Anatomy 0.000 description 19
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 19
- 210000003719 b-lymphocyte Anatomy 0.000 description 17
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 16
- 108700028369 Alleles Proteins 0.000 description 14
- 239000000427 antigen Substances 0.000 description 14
- 108091007433 antigens Proteins 0.000 description 14
- 102000036639 antigens Human genes 0.000 description 14
- 230000004073 interleukin-2 production Effects 0.000 description 14
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 10
- 206010062016 Immunosuppression Diseases 0.000 description 9
- 230000001506 immunosuppresive effect Effects 0.000 description 9
- 150000001413 amino acids Chemical group 0.000 description 8
- 229960004857 mitomycin Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 108700004025 env Genes Proteins 0.000 description 7
- 101150030339 env gene Proteins 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000006052 T cell proliferation Effects 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 241001529936 Murinae Species 0.000 description 5
- 230000006044 T cell activation Effects 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 210000004408 hybridoma Anatomy 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000005867 T cell response Effects 0.000 description 4
- 206010068348 X-linked lymphoproliferative syndrome Diseases 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 3
- 208000003950 B-cell lymphoma Diseases 0.000 description 3
- 102100036008 CD48 antigen Human genes 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 3
- 108020004635 Complementary DNA Proteins 0.000 description 3
- 208000005794 Hairy Leukoplakia Diseases 0.000 description 3
- 206010025280 Lymphocytosis Diseases 0.000 description 3
- 102000043131 MHC class II family Human genes 0.000 description 3
- 108091054438 MHC class II family Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 241000219061 Rheum Species 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000009739 binding Methods 0.000 description 3
- 238000010804 cDNA synthesis Methods 0.000 description 3
- 230000036952 cancer formation Effects 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 230000002101 lytic effect Effects 0.000 description 3
- 241001515942 marmosets Species 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003226 mitogen Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 206010030979 oral hairy leukoplakia Diseases 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 108020004463 18S ribosomal RNA Proteins 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000658388 Homo sapiens T cell receptor beta variable 13 Proteins 0.000 description 2
- 101000606220 Homo sapiens T cell receptor beta variable 6-5 Proteins 0.000 description 2
- 241000192019 Human endogenous retrovirus K Species 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 101001034843 Mus musculus Interferon-induced transmembrane protein 1 Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- 108010083644 Ribonucleases Proteins 0.000 description 2
- 102000006382 Ribonucleases Human genes 0.000 description 2
- 102100034886 T cell receptor beta variable 13 Human genes 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000000326 densiometry Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 e.g. Substances 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000008629 immune suppression Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 244000000010 microbial pathogen Species 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 230000008957 viral persistence Effects 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 101150106774 9 gene Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 101000658395 Homo sapiens Probable non-functional T cell receptor beta variable 17 Proteins 0.000 description 1
- 241000713887 Human endogenous retrovirus Species 0.000 description 1
- 241000235789 Hyperoartia Species 0.000 description 1
- 235000003332 Ilex aquifolium Nutrition 0.000 description 1
- 235000002296 Ilex sandwicensis Nutrition 0.000 description 1
- 235000002294 Ilex volkensiana Nutrition 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 102100026964 M1-specific T cell receptor beta chain Human genes 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 101500027988 Mus musculus ADGRV1 subunit beta Proteins 0.000 description 1
- 101000924587 Mus musculus Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101100096028 Mus musculus Smok1 gene Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 102100034883 Probable non-functional T cell receptor beta variable 17 Human genes 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 101100289792 Squirrel monkey polyomavirus large T gene Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- 102000006467 TATA-Box Binding Protein Human genes 0.000 description 1
- 108010044281 TATA-Box Binding Protein Proteins 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Chemical class 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 108010087408 alpha-beta T-Cell Antigen Receptors Proteins 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012677 causal agent Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 229960003983 diphtheria toxoid Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000009841 epithelial lesion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 244000039328 opportunistic pathogen Species 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000003322 phosphorimaging Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 210000004986 primary T-cell Anatomy 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000009589 serological test Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 230000007419 viral reactivation Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
- C12N2710/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Tropical Medicine & Parasitology (AREA)
- Immunology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Description
TREATMENT AND PREVENTION OF EBV INFECTION AND EBV-ASSOCIATED
DISORDERS
CROSS-REFERENCE TO RELATED APPLICATION
[001] This Application is based on Provisional Application 60/254,673, filed 11 December 2000, the content of which is relied upon and incorporated herein by reference in its entirety, and benefit priority under 35 U.S.C. §119(e) is hereby claimed.
GOVERNMENT FUNDING
[002] This invention was made with government support under AI 14910 awarded by
[003] the National Institutes of Health. The government has certain rights in the invention.
FIELD OF THE INVENTION
[004] The present invention relates to a method of treatment and prevention of Epstein- Barr Virus (EBV) infection and EBV-associated disorders.
BACKGROUND
[005] EBN is a ubiquitous human herpesvirus which infects the majority of the population and is associated with disease and neoplasia. A double-stranded DΝA virus of 172 kb, EBV can infect lymphocytes and epithelial cells. Infection of B lymphocytes with EBV results in their activation and proliferation. More than 90% of adults are latently infected with EBV. In most individuals, primary EBV infection occurs during childhood and does not result in clinical manifestations. If primary infection is delayed until adolescence, infectious mononucleosis (IM), a self-limiting proliferation of EBV-infected B cells, can result.
[006] Subsequent to primary infection, EBV-infected cells persist within the host for life. Low levels of infectious virus are shed into the saliva in most asymptomatic seropositive individuals. EBV-infected B cells are kept from proliferating out of control in vivo by a properly functioning immune system. In individuals who are immunosuppressed, however, EBV-infected cells can give rise to lymphoproliferative disorders leading to disease or oncogenesis.
[007] EBV infection is known to be associated with a number of pathological conditions, including X-linked lymphoproliferative syndrome (XLP), malignancies such as nasopharyngeal carcinoma (NPC), endemic Burkitt's Lymphoma (BL) and Hodgkin's Disease (HD) (reviewed in Rickinson et al., Virology, Fields et al., eds., 3d ed. 1996, pp. 2397-2446, Lippincott-Raven, Philadelphia, Pa.). Additionally, 50% of breast cancer have recently been shown to be EBV positive (Gonnet M, Guinebrettiere J-M., Kremmer E., Grunewald V., Benhamou E,. Contesso G., Joab I. Detection of Epstein-Ban- Virus in invasive Breast Cancers. J. Nat. Cancer Inst. 91 : 1376-81, 1999) and autoimmune diseases such as lupus (Harley J.B., James J.A. Epstein-Ban- virus infection may be an environmental risk factor for systemic lupus erythematosus in children and teenagers. Arthritis Rheum. 1999 Aug; 42(8): 1782-3), rheumatoid arthritis (Takeda T., Mizugaki Y., Matsubara L., Imai S., Koike T., Takada K. Lytic Epstein-Ban- virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 2000 Jun;43(6):1218- 25) and Sjogren's syndrome (Saito I.B., Servenius T., Compton T., Fox R.I. Detection of Epstein-Ban- virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjogren's syndrome. J. Exp. Med. 169: 2191-98, 1989), have been also linked to EBV. Further, immunosuppressed individuals, such as organ transplant recipients being treated with immunosuppressive drugs, can develop EBV-positive B cell lymphomas. Individuals infected with human immunodeficiency virus (HIV) can also develop EBV-positive B cell lymphomas, which are called AIDS-related lymphomas (ARLs). Oral hairy leukoplakia (OHL), which manifests itself as EBV-infected epithelial lesions on the tongue, has also been observed in AIDS patients.
[008] High EBV titers, as well as high levels of T cells (e.g., Vβl3 T cells) have been reported in individuals suffering from EBV-associated autoimmune diseases, such as rheumatoid arthritis or Sjogren's syndrome (Saito et al., J. Exp. Med. 169: 2191-2198 (1989); Saito et al., J. Exp. Med. 169: 2191-2198 (1989); Sumida et al., J. Clin. Invest. 89: 681-685 (1992); Yonaha et al., Arthritis Rheum. 35: 1362-1367 (1992); and Sumida et al, Br. J. Rheumatol. 33: 420-424 (1994)).
[009] Pathogenic microbes are known to produce certain proteins, called Superantigens (SAgs), which elicit potent, antigen-independent T cell response that is believed to enhance the microbes' pathogenicity. There are two groups of microorganisms, bacterial and viral, that are known to have SAgs. While a large number of bacterial SAgs have been well characterized structurally and functionally, only three families of viruses have been associated with SAg
activity to date: retroviruses, rhabdovirus and herpesviruses. Huber, B.T., Hsu, P.N. & Sutkowski, N. Virus-encoded superantigens. Microbiol Rev 60, 473-482 (1996).
[0010] We have reported previously that EBV-infected-B cells express a SAg and proposed that SAg-mediated T cell activation contributes to the lymphocytosis seen during infectious mononucleosis (IM), a disease associated with acute EBV infection. (Sutkowski, N. et al. An Epstein-Barr vims-associated superantigen. J Exp Med 184, 971-980 (1996); Reinherz, E.L., O'Brien, C, Rosenthal, P. & Schlossman, S.F. The cellular basis for viral-induced immunodeficiency: analysis by monoclonal antibodies. J Immunol 125, 1269-1274 (1980); Henle, G., Henle, W. & Diehl, V. Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci US A 59, 94-101 (1968)). As mentioned earlier, SAg driven T cell activation facilitates progression of EBV infection towards lifelong viral persistence in the resting memory B cell compartment and/or plays a role in viral reactivation. Miyashita, E.M., Yang, B., Lam, K.M., Crawford, D.H. & Thorley-Lawson, D.A. A novel foπn of Epstein-Ban- virus latency in normal B cells in vivo. Cell 80, 593-601 (1995); Hasuike, S. et al. Isolation and localization of an IDDMKl,2-22-related human endogenous retro viral gene, and identification of a CA repeat marker at its locus. J Hum Genet 44. 343-347 (1999).
[0011] SAgs are microbial pathogen-derived proteins that evoke a strong T cell response from the host. They do this by associating with MHC class II molecules and binding to T cells that express particular T cell receptor (β-chain variable (TCRBV) genes. This distinguishes them from specific antigens that bind to the groove formed by the α and β chains of the TCR and, thus, activate a small population of T cells only.
[0012] It is believed that the T cell stimulation elicited by SAgs does not limit the pathogen, as would a normal T cell response. Paradoxically, the response seems to be beneficial, helping the pathogen to complete its life cycle. We found previously a T cell receptor β chain variable (TCRBVJ3) gene specific SAg activity associated with the ubiquitous herpesvirus Epstein-Barr virus (EBV). Sutkowski, N. et al. An Epstein-Barr vims-associated superantigen. J Exp Med 184, 971-980 (1996). We now discovered that this SAg is encoded by the env gene of an endogenous retrovirus, HERV-K18, winch is transactivated by EBV. This is the first report of an infectious agent borrowing a host encoded SAg. It appears that EBV uses this T cell stimulatory activity to facilitate the establishment of persistent infection in B cells. Deregulation of SAg mediated T cell activation is crucial in the pathogenesis of infectious mononucleosis, the EBV-
associated malignancies and EBV-associated autoimmune disorders, many of which are characterized by large T cell infiltrates.
[0013] Different approaches have been used to attempt to reduce pathology associated with EBV infection. For example, pyrophosphate analogs, thymidine kinase analogs, ribonucleoside reductase inhibitors, and nucleoside analogs, such as acyclovir, have been used to control diseases associated with EBV infection. None of these agents are effective against latent EBV, nor ideal for inhibiting EBV replication and associated pathology. In addition, use of these agents can result in inhibition of normal cellular processes, which in turn results in undesirable side effects. Antisense oligodeoxynucleotides have also been designed that are specific for various EBV genes, which are associated with the EBV lytic and latent cycles. U.S. Pat. No. 5,242,906 and No. 5,837,854; Roth et al., Blood 84: 582-587 (1994); WO 93/11267.
[0014] Therefore, there remains a great need for effective prevention and treatment of EBV infection and EBV-associated disorders.
SUMMARY OF THE INVENTION
[0015] We have discovered that EBV infection leads to induction of an endogenous retrovirus that expresses T cell superantigen (SAg) activity which, in turn, rapidly progresses into polyclonal T cell activation with widespread implications for EBV pathogenesis. For example, massive T cell infiltrates are characteristic of the EBV-associated tumors such as Hodgkin's lymphoma and naso-pharyngeal carcinoma; and activated T helper cells play a role in the development of transplant associated lymphomas. Furthermore, massive lymphocytosis is a characteristic of acute IM. Therefore, without wishing to be bound by theory, we believe that EBV induced SAg activity plays a role in a long list of diseases associated with these processes and that prevention or inhibition of such activity would be useful in treating and/or preventing EBV infection and EBV-associated disorders.
[0016] One embodiment of the invention provides a method of vaccination for prevention and treatment of EBV infection and EBV-associated disorders. Such method includes a vaccine for treating and/or preventing EBV infection and EBV-associated disorders comprised of HERV- K18 env (SEQ ID:1) or an immunogenic fragment thereof, or a nucleic acid encoding the HERV-K18 env, or a fragment thereof and a pharmaceutically acceptable earner.
[0017] Another embodiment of the invention provides a method for preventing EBV infection and EBV-associated disorders in an individual at risk for such infection or disorder
comprising administering to such individual a vaccine comprising a peptide having the amino acid sequence of SEQ ID:1, SEQ ID:2 (cpkeipkgski-tevl), SEQ ID:3, and SEQ ID:4.
[0018] In a preferred embodiment, the HERV-K18 env or immunogenic fragment thereof has a diminished or eliminated SAg T cell stimulatory activity. As used herein the term "diminished" means that the SAg T cell stimulatory activity is reduced by at least 50% compare to the normal, more preferably by at least 75%, and even more preferably by 95%. Sag T cell stimulatory activity can be measured as described more fully in the Examples infra. SAg T cell stimulatory activity can be diminished, and preferably eliminated, using standard techniques including amino acid substitutions, additions and deletions. SAg T cell stimulatory activity can be tested against VB13+ T cells.
[0019] Yet another embodiment of the invention provides a method for treating an individual having an EBV-associated disorder, such as IM and EBV-induced lymphomas, and includes administering to such individual a treatment effective amount of an antibody or a fragment thereof against HERV-K18 env. The antibody fragments include, for example, Fab, Fab', F(ab')2 or Fv fragments. The antibody may be a single chain antibody, a humanized antibody or a chimeric antibody. In adolescents, for example, the recovery period for IM is protracted, often lasting for a period of months. However, early identification of the disease, followed by the administration of a pharmaceutical composition comprising the antibody which would block activation of HERV-K18 env SAg, would reduce the duration and severity of the disease. Early identification of IM is accomplished by administering, for example, a monospot or an EBV specific serological test to individual presenting common symptoms of the disease (e.g., swollen glands, sore throat, etc.).
[0020] Yet another embodiment of the invention provides a method of passive immunotherapy to infection by EBV in an individual susceptible to infection by EBV. This method involves administering to said individual a HERV-K18 env antibody composition.
[0021] In a further embodiment, we provide a method for treating and/or preventing oncogenic transfomiation in immunocompromised (immunosuppressed) individual. The method includes identifying immunocompromised individuals exhibiting clinical symptoms associated with early stage oncogenic transformation, and administering to such individuals, a therapeutically effective amount of a vaccine comprising a peptide having the amino acid sequence of SEQ ID:1, SEQ ID:2, SEQ ID:3, and SEQ ID:4 or an antibody or a fragment thereof against HERV-K18 env. The antibody or a fragment thereof may be administered before the
commencement of immunosuppressive therapy. Preferably, the antibody administration continues throughout the immunosuppressive therapy. The oncogenic transfomiation can result in lymphomas including Hodgkin's lymphoma, Post-transplant-lymphoproliferative disorders, Lympho-proliferative Disorders, EBV-positive breast cancer, Burkitt's lymphoma, and Naso- Pharyngeal-Carcinoma.
[0022] ImmunocompiOmised (immunosuppressed) individuals are characterized by a general depletion of T cell function. Reactivation of EBV in such individuals has been linked to oncogenesis. Therefore, by preventing or interfering with HERV-K18 env SAg activity EBV- induced oncogenesis can be eliminated, or substantially reduced.
[0023] Immunosuppression can arise in a variety of ways. For example, many pathogens suppress immune responses in general. E1Y infection represents an extreme case of pathogen- induced immune suppression. The ultimate cause of death in AIDS is usually infection with an opportunistic pathogen (a pathogen which is present in the environment but does not usually cause disease because it is controlled by the nomial immune response). Therefore, in the case of an individual suffering from pathogen-induced immune suppression, the administration of an antibody or a fragment thereof against HERV-K18 env, would be indicated for the duration of the pathogen-induced immunosuppression.
[0024] Medically-induced immunosuppression (iatrogenic immunosuppression) is required, for example, in connection with organ and bone manow transplant. Cyclosporin A is widely used in clinical transplantation because it is both effective and relatively non-toxic. An unrelated compound with similar activity is FK506. These compounds prevent the synthesis of IL-2 by blocking a late stage of the signaling pathway initiated by the T cell receptor.
[0025] Individuals receiving organ transplants are acutely immunosuppressed (i.e., immunoincompetent) for some period of time (e.g., one to several months) following solid organ transplant. Following this period of acute immunosuppression, a degree of immunocompetence is allowed to establish, although a basal level of immunosuppression is generally maintained for the lifetime of the individual. To prevent oncogenic transformation in such individuals, the administration of a pharmaceutical composition comprising an antibody or a fragment thereof against HERV-K18 env is provided in the present invention. Preferably, the period of administration is the period of acute immunosuppression.
[0026] Bone marrow transplant recipients also require a period of immunosuppression following transplant. The period of inuriunosuppression is required to permit repopulation of the
transplanted cells. During this period of immunosuppression, the administration of a pharmaceutical composition comprising an antibody or a fragment thereof against HERV-K18 env, would prevent EBV induced lymphomas.
[0027] In yet another embodiment, a method of treating an EBV-associated autoimmune disorder is also provided. The method involves identifying an EBV-positive individual acutely afflicted with an autoimmune disorder and administering to such individual, an effective amount of an antibody or a fragment thereof against HERV-K18 env.
[0028] Finally, there is provided an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein said packaging material comprises a label which indicates said pharmaceutical may be administered, for a sufficient tem at an effective dose, for treating EBV infection and EBV-associated disorders, wherein said pharmaceutical agent comprises an antibody or a fragment thereof against HERV- K18 env together with a pharmaceutically acceptable carrier.
DEFINITIONS
[0029] The tenn "EBV-associated disorder(s)", as used herein, refers to any disease or disorder caused directly or indirectly by EBV, including, but not limited to, X-linked lymphoproliferative syndrome XLP), nasopharyngeal carcinoma, Burkitt's Lymphoma, Hodgkin's Disease, breast cancer, AIDS-related lymphomas, oral hairy leukoplakia, lupus, rheumatoid arthritis and Sjorgen's syndrome among others.
[0030] The temi "nucleic acid", as used herein, refers to either DNA or RNA, including complementary DNA (cDNA), genomic DNA and messenger RNA (mRNA). As used herein, "genomic" means both coding and non-coding regions of the isolated nucleic acid molecule. "Nucleic acid sequence" refers to a single- or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases read from the 5' to the 3' end. It includes both self-replicating plasmids, infectious polymers of DNA or RNA, including viral nucleic acids, and nonfunctional DNA or RNA.
[0031] The term "polypeptide", as used herein, refers to either the full length gene product encoded by the nucleic acid, or portions thereof. Thus, "polypeptide" includes not only the full- length protein, but also partial-length fragments, including peptides less than fifty amino acid residues in length.
[0032] The phrase "nucleic acid molecule encoding" refers to a nucleic acid molecule which directs the expression of a specific polypeptide. The nucleic acid sequences include both the DNA strand sequence that is transcribed into RNA, the complementary DNA strand, and the RNA sequence that is translated into protein. The nucleic acid molecule includes both the full length nucleic acid sequence as well as non-full length sequences. It being further understood that the sequence includes the degenerate codons of the native sequence or sequences which may be introduced to provide codon preference in a specific host cell.
[0033] The term "pharmaceutical composition" refers to preparations which are in such form as to permit the biological activity of the active ingredients to be unequivocally effective, and which contain no additional components which are toxic to the subjects to which the composition would be administered. Such pharmaceutical compositions may be prepared and formulated in dosage fonns by methods known in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition 1975.
[0034] "Pham aceutically acceptable" excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed. Typical vehicles include saline, dextrose solution, Ringer's solution, etc. but non-aqueous vehicles may also be used.
[0035] In a phamiacological sense, in the context of the present invention, an "effective amount" of the antibody, such as an anti-HERV-K18 env antibody refers to an amount effective in control of EBV-associated condition. In this context, the temi "control" is used to include both prophylaxis and treatment of such disorders. Accordingly, the antibody may be administered prophylactically (i.e prior to the appearance of the infection or disorder), or therapeutically (i.e. after appearance of the infection or disorder).
[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. In addition, the materials, methods and examples are illustrative only and not intended to be limiting. In case of conflict, the present specification, including definitions, controls.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the mvention and, together with the description, serve to explain the objects, advantages, and principles of the invention.
[0038] Figures 1 a-c illustrate that HERV- 18 env alleles preferentially activate hTCRBV13 and UTCRBV9 THys, as does the EBV-associated SAg. Figure la shows the IL-2 production in response to untransfected A20 cells, or five individual clones of A20 stably transfected with HERV-K18.2 env, pretreated with PMA, then resuspended with an equal number of hTCRBV13Sl or I1TCPBV8 THy. The IL-2 response was compared to PMA treated B95-8 transfom ed B LCL from the K18.2 env donor, and to the maximal IL-2 production obtained by anti-CD3 crosslinkage. Figures lb-h show the IL-2 production in response to A20 transfected with HERV-K18 env alleles 1 or 2, or vector only (A20/K18.1 env, A20/K18.2 env, A20/pCDLI, respectively); B95-8 transfoπned LCL, BL41 and BL41/B95-8 infected cells were pretreated with PMA/ itomycin C, and resuspended with the indicated hTCRBVTEy at APC:responder ratios of 5:1 (black bars) or 1 :1 (white bars). The results are expressed as percentage maximal IL-2 production based on the stimulation of each THy by anti-CD3 crosslinkage. Maximal IL-2 production (pg/ml) for this assay: TCRBV2 = 389.1+108.2; TCRBV3 = 255.7 ± 16.3; TCRBV8 = 497.2 ± 11.7; TCRBV9 = 34.1 ± 14.7; TCRBV13S1 = 141.2 ± 13.5; TCRBV13S2 = 19.8 ± 9.9; and TCRBV17S1 = 58.05 ± 36.9.
[0039] Figures li-m illustrate that anti-HERV Kl 8 env antiserum and MHC class II antibodies block activation of THy by K18 env transfectants and the EBV-associated SAgs. Figure li & lj shows the IL-2 production in response to PMA/mitomycin-C-pretreated A20/K18.1 env, A20/K18.2 env incubated with Env antiserum, diluted 1 :100 or 1 :200, or with preimmune serum (1 :100) for 30 min prior to addition of hTCRBV13Sl THy or hTCRBV13S2 at an APC/responder ratio of 2:1. IL-2 production was measured after 24 hr. The response was compared with A20/pCDLI (negative control). Figures Ik & II show the IL-2 production in response to PMA/mitomycin-C-pretreated B95-8 marmoset cells, B95-8 LCL, BL41, or BL41/B95-8 incubated with the hTCRBV13Sl THy or hTCRBV13S2 Thy. B95-8 LCL and BL41/B95-8 were also pretreated with Env antiserum, diluted 1: 100 or 1:200, or with preimmune serum (1 :100) for 30 min prior to addition of hTCRBV13Sl THy or hTCRBV13S2 at an APC/responder ratio of 2:1. IL-2 production was measured 24 hi- later. The responses were compared with those elicited by anti-CD3 crosslinkage. As toxicity control, the Env antiserum
was also added to anti-CD3 wells. Figure lm shows the IL-2 production in response to PMA- pretreated A20, A20/K18.1 env, or B95-8 LCL preincubated with antibodies specific for HLA.DR, H-2Dd, I-Ad, or I-E1^ and then added to hTCRBVBSl at an APC/responder ratio of 1:1. IL-2 production was measured after 24 hr.
[0040] Figures 2a-c illustrate that B95-8 EBV transcriptionally activates HERV-K18 env expression in B cells. Figure 2a shows total RNA from B95-8 transformed LCL, BL41, and BL41/B95-8 infected cells, treated for 0, 2, 8, of 16 h with PMA, incubated with riboprobes specific for HERV-K18 env alleles and hTBP (loading control), then digested with RNases and n on a 6% polyacrylamide gel. Protected fragments for HERV-K18 env were detected at 300 b and for hTBP as a doublet at 161 b. The 200 b doublet represents a partial digests of hTBP. As controls, RNA from A20 and A20 transfected with HERV K18.1 were included. The a20/K18.1 env construct has an additional 30 b of Bluescript vector sequence that is protected by the riboprobe, accounting for the difference in size between positive control and the 300 b K18 env band. Densitometry value ratios for the Kl 8 env: hTBP doublet are indicated below each lane. Figure 2b shows a relative quantitative RT-PCR that was perfomied using RNA derived from purified B cells from three different donors (1-3) and B95-8 transformed B LCL from the same three donors. Primers were designed to detect a 161 bp HERV K18 read-through transcript that traverses the env gene, 3' LTR, and adjacent chromosome 1 sequences located up to 122 bp downstream of the 3' LTR. 25 PCR cycles were detem ined to yield product within the linear range. Because the read-through transcripts were extremely rare, PCR was performed in the presence of [32P] α-dCTP. As endogenous standard, primers specific for an 18s rRNA 489 bp product were used in each reaction; and as negative controls, H2O only and no RT reactions were simultaneously perfomied. PCR products were separated on a 6% denaturing aciylamide gel and quantified by Phosphorimaging. The ratios of HERV Kl 8: 18s rRNA are printed below each lane, and the fold induction of HERV K18 transcripts after B95-8 transformation is depicted for each individual (B95-8:B). Figure 2c shows the IL-2 production in response to purified primary B cells from three individuals treated with LPS and compared with B95-8-transformed B LCL derived from the same blood donors. Both LPS B cells and B95-8 LCL were pretreated with PMA, washed, and incubated with the hTCRBV13Sl THy at various APC/responder ratios using 2x104 THy per quadruplicate well. IL-2 production was measured 48 hr later.
[0041 ] Figures 3a and 3b illustrate that the EBV-associated SAg activity is caused by Kl 8 env. Figure 3a shows that A20 transfected with Kl 8.1 env activated peripheral blood T cells with kinetics and magnitude similar to the EBV-associated SAg. PMA/mitomycin C treated
A20/K18.1 env or A20/pCDLI, and autologous B95-8 transfomied LCL were used as APC in 48 hr T cell proliferation assays, as measured by the incorporation of [Η]thymidine, APC:responder ratios of 1 : 1 (black bars), 1 :3 (grey bars), and 1:10 (white bars), show that T cell proliferation is dependent upon antigen dose. The response is compared to the mitogen PHA, and APC are only shown for comparison. Figure 3b shows that K18 env anti-peptide (a.a. 116- 130) antiserum blocked 48 h T cell proliferation to PMA/mitomycin C treated A20/K18.1, preincubated at 1 : 100 and 1 :200 dilutions, while preimmune serum did not. In addition, T cell proliferation to autologous B95-8 transformed LCL from an EBV seronegative donor was blocked by the env antiserum, but not the preimmune seram, while the env antiserum had no effect on T cell proliferation due to PHA. The B95-8 mamioset cell line, which produces high titer EBV, was not stimulatory to the EBV seronegative donor T cells.
[0042] Figure 4 shows HERV-K18 env amino acid sequence of SEQ ID: 1, SEQ ID:3, and SEQ ID:4.
DESCRIPTION OF THE INVENTION
[0043] We have identified a possible causal agent of EBV-associated disorders in humans as EBV-mediated transactivation of human endogenous retrovirus HERV-K18 env with superantigen (SAg) activity capable of stimulating large fractions of T cells. This transactivation of endogenous SAg may facilitate progression of EBV infection towards a lifelong viral persistence which, under conducive conditions, may result in numerous disorders such as infectious mononucleosis (IM), EBV-induced lymphomas, EBV-associated autoimmune diseases such as lupus, rheumatoid arthritis and Sjogren's syndrome.
VACCINES AND PROPHYLAXIS FOR EBV INFECTION AND EBV-ASSOCIATED
DISORDERS
[0044] The present invention provides substances suitable for use as vaccines for the prevention of EBV infection and EBV-associated disorders and methods for administering them. The vaccines are directed against HERV-K18 env (SEQ ID:1) and most preferably comprise antigens obtained from HERV-K18 env. Preferred antigens include SEQ ID:2 (cpkeipkgskntevl), SEQ ID:3 and SEQ ID:4 (see Fig. 4). Most preferably, the SAg T cell stimulatory activity of the HERV-K18 env is diminished or eliminated. In another embodiment, the vaccine contains a nucleic acid encoding HERV-K18 env or an immunogenic fragment thereof.
[0045] Tins invention provides a method of vaccinating a subject against EBV and EBV- associated disorders, comprising administering to the subject an effective amount of HERV-K18 env (SEQ ID:1 (see Fig. 4)) or an immunogenic fragment thereof, or a nucleic acid encoding the antigen, and a suitable acceptable carrier, thereby vaccinating the subject. One or more boosts may be administered.
[0046] The vaccine can be made using synthetic peptide or recombinantly-produced polypeptide described above as antigen. Typically, a vaccine will include from about 0.1 to 1 mg of antigen. Typically, the vaccine is formulated so that a dose includes about 0.5 milliliters. The vaccine may be administered by any route known in the art. Preferably, the route is parenteral. More preferably, it is subcutaneous or intramuscular.
[0047] There are a number of strategies for amplifying an antigen's effectiveness, particularly as related to the art of vaccines. For example, cyclization or circularization of a peptide can increase the peptide's antigenic and immunogenic potency. See U.S. Pat. No. 5,001,049. More conventionally, an antigen can be conjugated to a suitable canier, usually a protein molecule. This procedure has several facets. It can allow multiple copies of an antigen, such as a peptide, to be conjugated to a single larger carrier molecule. Additionally, the carrier may possess properties winch facilitate transport, binding, absorption or transfer of the antigen.
[0048] For parenteral administration, such as subcutaneous injection, examples of suitable earners are the tetanus toxoid, the diphtheria toxoid, serum albumin and lamprey, or keyhole limpet hemocyanin because they provide the resultant conjugate with minimum genetic restriction. Conjugates including these universal carriers can function as T cell clone activators in individuals having very different gene sets.
[0049] The conjugation between a peptide and a carrier can be accomplished using one of the methods known in the art. Specifically, the conjugation can use bifunctional cross-linkers as binding agents as detailed, for example, by Means and Feeney, "A recent review of protein modification techniques," Bioconjugate Chem. 1:2-12 (1990).
[0050] The vaccines may be administered by any conventional method for the administration of vaccines including oral and parenteral (e.g., subcutaneous or intramuscular) injection. Intramuscular administration is preferred. The treatment may consist of a single dose of vaccine or a plurality of doses over a period of time. It may be preferred that the dose be given to a human patient within the first 8 months of life.
[0051] Those of skill will readily recognize that it is only necessary to expose a mammal to appropriate epitopes in order to elicit effective immunoprotection. The epitopes are typically segments of amino acids winch are a small portion of the whole protein. Using recombinant genetics, it is routine to alter a natural protein's primary structure to create derivatives embracing epitopes that are identical to or substantially the same as (immunologically equivalent to) the naturally occurring epitopes. Such derivatives may include peptide fragments, amino acid substitutions, amino acid deletions and amino acid additions.
ADMINISTRATION
[0052] The subjects to be treated may be a mammal, or more specifically a human, horse, pig, rabbit, dog, monkey, or rodent. In the preferred embodiment the subject is a human.
[0053] The compositions are administered in a manner compatible with the dosage fom ulation, and in a therapeutically effective amount. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each subject.
[0054] Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration.
[0055] As used herein "administration" means a method of administering to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, administration topically, parenterally, orally, intravenously (i.v.), intramuscularly (i.m.), subcutaneously or by aerosol. Administration of the agent may be effected continuously or intennittently such that the therapeutic agent in the patient is effective to treat a subject with an EBV-associated disorder.
[0056] The pharmaceutical formulations or compositions of this invention may be in the dosage form of solid, semi-solid, or liquid such as, e.g., suspensions, aerosols or the like. Preferably the compositions are administered in unit dosage forms suitable for single administration of precise dosage amoimts. The compositions may also include, depending on the formulation desired, pharmaceutically-acceptable, nontoxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or
fonnulation may also include other carriers, adjuvants; or nontoxic, nontherapeutic, nonimmunogeiήc stabilizers and the like. Effective amounts of such diluent or carrier are those amounts which are effective to obtain a pharmaceutically acceptable composition in terms of solubility of components, or biological activity, etc.
IMMUNOLOGICAL THERAPY
[0057] There is provided an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein said packaging material comprises a label which indicates said phannaceutical may be administered, for a sufficient tem at an effective dose, for treating EBV infection and EBV-associated disorders, wherein said pharmaceutical agent comprises an antibody or a fragment thereof against HERV-K18 env together with a phannaceutically acceptable carrier.
[0058] The antibody may be administered to a patient either singly or in a cocktail containing two or more antibodies, other therapeutic agents, compositions, or the like, including, but not limited to, immunosuppressive agents, potentiators and side-effect relieving agents. All of these agents are administered in generally accepted efficacious dose ranges such as those disclosed in the Physician Desk Reference (2000), Publisher Edward R. Barnhart, New Jersey.
[0059] The antibody may be foπnulated into an injectable preparation. Parenteral formulations are known and are suitable for use in the invention, preferably for i.m. or i.v. administration. The fonnulations containing therapeutically effective amounts of antibodies are either sterile liquid solutions, liquid suspensions or lyophilized versions and optionally contain stabilizers or excipients. Lyophilized compositions are reconstituted with suitable diluents, e.g., water for injection, saline, 0.3% glycine and the like, at a level of about from 0.01 mg/kg of host body weight to 10 mg/kg where appropriate. Typically, the pharmaceutical compositions containing the antibodies will be administered in a therapeutically effective dose in a range of from about 0.01 mg/kg to about 5 mg/kg of the treated individual. A preferred therapeutically effective dose of the pharmaceutical composition containing antibody will be in a range of from about 0.01 mg/kg to about 0.5 mg/kg body weight of the treated individual administered over several days to two weeks by daily intravenous infusion, each given over a one hour period, in a sequential patient dose-escalation regimen.
[0060] Antibody may be administered systemically by injection i.m., subcutaneously or intraperitoneally. The dose will be dependent upon the properties of the antibody employed, e.g., its activity and biological half-life, the concentration of antibody in the formulation, the site
and rate of dosage, the clinical tolerance of the patient involved, the disease afflicting the patient and the like as is well within the skill of the physician.
[0061] The antibody of the present invention may be administered in solution. The pH of the solution should be in the range of pH 5 to 9.5, preferably pH 6.5 to 7.5. The antibody or derivatives thereof should be in a solution having a suitable pharmaceutically acceptable buffer such as phosphate, tris (hydroxymethyl) aminomethane-HCl or citrate and the like. Buffer concentrations should be in the range of 1 to 100 inM. The solution of antibody may also contain a salt, such as sodium chloride or potassium chloride in a concentration of 50 to 150 mM. An effective amount of a stabilizing agent such as an albumin, a globulin, a gelatin, a protamine or a salt of protamine may also be included and may be added to a solution containing antibody or immunotoxin or to the composition from which the solution is prepared.
[0062] Systemic administration of antibody is made daily, generally by intramuscular injection, although intravascular infusion is acceptable. Administration may also be intranasal or by other nonparenteral routes. Antibody may also be administered via microspheres, liposomes or other microparticulate delivery systems placed in certain tissues including blood.
[0063] The antibodies may be raised against either a peptide of or the whole molecule. Such a peptide may be presented together with a carrier protein, such as an KLH, to an animal system or, if it is long enough, say 25 amino acid residues, without a carrier.
[0064] Polyclonal antibodies generated by the above technique may be used direct, or suitable antibody producing cells may be isolated from the animal and used to fomi a hybridoma by known means (Kohler and Milstein, Nature 256:795. (1975)). Selection of an appropriate hybridoma will also be apparent to those skilled in the art.
[0065] It will be appreciated that antibodies for use in accordance with the present invention may be monoclonal or polyclonal as appropriate. Antibody equivalents of these may comprise: the Fab' fragments of the antibodies, such as Fab, Fab', F(ab')2 and Fv; idiotopes; or the results of allotope grafting (where the recognition region of an animal antibody is grafted into the appropriate region of a human antibody to avoid an immune response in the patient), for example. Single chain antibodies may also be used. Other suitable modifications and/or agents will be apparent to those skilled in the art.
[0066] Chimeric and humanized antibodies are also within the scope of the invention. It is expected that chimeric and humanized antibodies would be less immunogenic in a human subject than the corresponding non-chimeric antibody. A variety of approaches for making chimeric
antibodies, comprising for example a non-human variable region and a human constant region, have been described. See, for example, Morrison et al., Proc. Nati. Acad. Sci. U.S.A. 81,6851 (1985); Takeda et al., Nature 314,452(1985), Cabilly et al., U.S. Pat. No. 4,816,567; Boss et al., U.S. Pat. No. 4,816,397; Tanaguchi et al., European Patent Publication EP 171496; European Patent Publication 0173494, United Kingdom Patent GB 2177096B. Additionally, a chimeric antibody can be further "humanized" such that parts of the variable regions, especially the conserved framework regions of the antigen-binding domain, are of human origin and only the hypervariable regions are of non-human origin. Such altered immunoglobulin molecules may be made by any of several techniques known in the art, (e.g., Teng et al., Proc. Natl. Acad Sci. U.S.A., 80, 7308-7312 (1983); Kozbor et al., Immunology Today. 4, 7279 (1983); Olsson et al, Meth. Enzymol., 92, 3-16 (1982)), and are preferably made according to the teachings of PCT Publication WO92/06193 or EP 0239400. Humanized antibodies can be commercially produced by, for example, Scotgen Limited, 2 Holly Road, Twickenham, Middlesex, Great Britain. Antibodies for use in accordance with the present invention may also be prepared using the methods described in US Pat. No. 6,111,166, incorporated herein by reference in its entirety.
[0067] Another method of generating specific antibodies, or antibody fragments, reactive against EBV is to screen phage expression libraries encoding immunoglobulin genes, or portions thereof, with a protein of the invention, or peptide fragment thereof. For example, complete Fab fragments, V H regions and V-region derivatives can be expressed in bacteria using phage expression libraries. See for example Ward, et al., Nature 341,544-546: (1989); Huse, et al.. Science 246, 1275-1281 (1989); and McCafferty, et al., Nature 348, 552-554 (1990).
[0068] The invention will be further characterized by the following examples which are intended to be exemplary of the invention.
EXAMPLES
Experimental Techniques
[0069] We found that EBV transactivates the human endogenous retro vims HERV-K18 (8) (which was recently localized to chromosome Iq21.2-q22 in the first intron of CD48) that has SAg activity. An EBV inducible enhancer had been previously mapped to a region 1.58 kb upstream of the CD48 start site . It was also shown that the IDDMKlι222 retrovims is an allelic variant of HERV-K18 (designated allele 1 or K18.1), whose env gene encodes SAg activity. These findings led us to test whether any of the HERV-K18 env alleles possessed TCRBV13 SAg activity that could be induced by EBV. Tonjes, R.R., Czaudema, F. & Kurth, R. Genome-
wide screening, cloning, chromosomal assignment, and expression of full-length human endogenous retrovh-us type K. J Virol 73, 9187-9195 (1999); Thorley-Lawson, D.A., Schooley, R.T., Bhan, A.K. & Nadler, L.M. Epstein-Barr vims superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. Cell 30, 415-425 (1982); Klaman, L.D. & Thorley-Lawson, D.A. Characterization of the CD48 gene demonstrates a positive element that is specific to Epstein-Ban* vims immortalized B-cell lines and contains an essential NF-kappa B site. J Virol 69, 871-881 (1995); Conrad, B. et al. A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell 90, 303-313 (1997); Barbulescu, M. et al. Many human endogenous retrovirus K (HERV- K) proviruses are unique to humans. Curr Biol 9, 861-868 (1999).
[0070] The HERV-K18 env alleles 1 and 2, Kl 8.1 and Kl 8.2, differ at several positions; the K-18.1 Env has a stop codon at a.a. 153, while the K18.2 Env is a full length 553 amino acid protein. Since the K 18.1 allele had been previously characterized, we tested whether the full length env of K18.2 could stimulate T cells. We therefore cloned the entire HERV-K18.2 provirus, using as PCR primers the chromosome 1 insertion sequences previously reported. After sequencing, the env gene was subcloned into the bicistronic expression vector pCDLI with the marker EYFP (enhanced yellow fluorescent protein) in the second cistron. Murine A20 B lymphoma cells were chosen for transfection experiments, because the mouse genome does not have any HERV related proviruses. Fleischer, B., Necker, A., Leget, C, Malissen, B. & Romagne, F. Reactivity of mouse T-cell hybridomas expressing human Vbeta gene segments with staphylococcal and streptococcal superantigens. Infect Immun 64, 987-994 (1996). Stable clones expressing different levels of EYFP were selected by flow cytometry and tested for TCRBV 13 T cell activation.
[0071] We have previously described a system to assay for EBV-associated SAg activity based on the stimulation of murine T cell hybridomas (THys) with EBV-infected B cell lines acting as antigen presenting cells (APC). These THys bear clήmeric TCR composed of a human (h) TCRBV gene product with murine α chain and CD3 proteins (note 1). As can be seen in Fig la, all of the K18.2 env transfectants (A20/K18.2) stimulated the hTCRBV13 THy, but not the hTCRBVS THy, whereas both THys were equally activated by CD3 crosslinking. The magnitude of the response was similar to that elicited by a lymphoblastoid cell line (LCL) made from B cells from a K18.2 donor transfomied by the B95-8 strain of EBV, while untransfected A20 cells gave no response. Similar results were obtained by transfecting Kl 8.2 env into the
human EBV" B cell lymphoma BJAB (data not shown). These data indicate that the K18.2 env allele is recognized by TCRBV 13 similar to the EBV-associated SAg .
[0072] To test whether the Kl 8.2 env transfectants stimulated other T cell subsets, we used a panel of murine THys expressing different TCRBV genes. In addition, we examined the response to the truncated K18.1 env transfected into A20 cells. The results (note 2), depicted in Figs, lb-h, show the comparison between the response obtained with a B95-8 LCL and B95-8 infected Burkitt's lymphoma (BL) BL41 versus uninfected BL41 cells . The EBV+ BL and LCL and both K18 env alleles expressed in A20 stimulated the hTCRBV 13S1 and hTCRBV 13 S2 THys , but not the hTCRBV2, 3, 8, or 17 THys , while A20 transfected with pCDLI vector alone did not stimulate any of the hybridomas. At APC:responder ratios of 5:1, the K18 Env alleles and B95-8 infected BL41 and LCL also stimulated the hTCRBV9 THy , suggesting an additional specificity. In addition, uninfected BL41 at high APC ratios weakly stimulated the very sensitive hTCRBV 13S1 THy, most likely due to the low level of endogenous K18 env expression in these cells (see Figs. 2a-c). It should be mentioned that pretreatment of all APC lines with the phorbol ester PMA was necessary for stimulation of the THys, as was previously shown for the EBV-associated SAg activity . These data show that both Kl 8 env alleles have the same TCRBV specificity as the EBV-associated SAg.
[0073] To test whether the SAg activity was due to Kl 8 Env, we employed a rabbit antiserum raised against the K18 env peptide 116-130, selected by the hydrophilicity index of Kyte and Doolittle . This antiserum specifically blocked immune recognition of the K 18.1 and K18.2 env alleles by the TCRBV13S1 and TCRBV13S2 THys in a dose dependent manner (Figs, li&j), while the preimmune serum had no effect (note 3). We then used tins antiserum to prove that the TCRBV13 activation by EBV infected cells was mediated by K18 env. As shown in Figs, lk&l, the env antiserum blocked stimulation of these THys by EBV transformed LCL and EBV infected BL41.
[0074] On the other hand, the Env antiserum had no effect on the anti-CD3 response, and nonspecific blocking was not observed with the preimmune serum. Moreover, the maπnoset cell line B95-8, which expresses both EBV latent and lytic genes and produces high titers of vims, but does not contain the HERV-K18 provirus , did not stimulate the TCRBV13 THys. These data provide evidence that the TCRBV13 specific EBV SAg activity is due to the env gene product of the endogenous HERV-K18 provirus.
[0075] To test whether EBV could upregulate HERV-K18 env expression, as it does CD48 , we used a RNase protection assay (note 4), designed to detect all of the K18 env alleles, but not other HERV-K env transcripts . As can be seen in Figs. 2a-c, the env transcripts are readily detected in a B95-8 EBV transfomied LCL and are also highly upregulated when EBV" BL41 cells are converted to EBV+ by infection with B95-8 vims. Treatment of the APC with PMA had no effect on Kl 8 env transcription. Thus, the PMA enhancement of SAg activity does not work at the level of K18 env transcription. More likely, PMA is acting to increase the efficacy of SAg presentation, perhaps through upregulation of MHC class II or accessory molecules. These data show that EBV transcriptionally activates K18 env expression.
[0076] To confirm the stimulatory activity of Kl 8 env on primary T cells, we measured proliferation of peripheral blood T cells induced by A20 cells that were transfected with K18.1 env. Proliferation was assessed 48 h after co-culture (note 5). As can be seen in Fig. 3a, PMA/mitomycin C pretreated A20/ K18.1 env vigorously and rapidly stimulated T cells, while pretreated A20/pCDLI confen-ed only minimal activity. The response was comparable to that elicited with autologous B95-8 transfomied LCL, as was previously shown for EBV-associated SAg activity , or the mitogen PHA. To demonstrate that EBV induction of K18 env was driving this polyclonal proliferation, we again perfomied antibody blocking experiments (note 6) using the rabbit antiserum raised against the Kl 8 env peptide (Fig 3b). The antiserum blocked peripheral blood T cells from responding to A20/K18.1 env in a dose dependent manner, while preimmune serum was not inhibitory. The env antiserum also completely blocked the T cell proliferative response of an EBV seronegative donor to autologous LCL derived from in vitro transfomiation of B cells with B95-8 EBV, while the response to the mitogen PHA was unaffected. In addition, these data exclude the possibility that the elicited T cell proliferation was due to a potent recall response. Moreover, no response by this EBV" donor was seen to the EBV+ marmoset cell line B95-8, similar to the results obtained with the THys (Figs. lk&l). It is interesting that marmosets, although easily infected with EBV, do not establish persistent infection. It is thus possible, that the SAg activity elicited by HERV-K18 env upon EBV infection is required for the long-term latency of EBV in the host.
[0077] We have shown that EBV infection of B cells leads to transactivation of HERV-K18 env alleles, wlήch express a TCRBV 13 specific SAg activity, previously identified as an EBV- associated SAg. Sutkowski, N. et al. An Epstein-Barr vims-associated superantigen. J Exp Med 184, 971-980 (1996). This represents the first demonstration of a microbial pathogen inducing an endogenous SAg for its own use. It will be interesting to study the interplay of biological
activity that has allowed the evolutionary retention of an endogenous retrovirus that potentially benefits a persistent heipesvims. Detection of this SAg activity required a highly defined system whereby murine transfectants presented the K18 env gene product to hTCRBV specific THys. The chimeric human/mouse TCR of the THys revealed the preference for TCRBV 13.1, 13.2 and 9 gene products. In primary cells the EBV-associated T cell response, while initially TCRBV13 restricted , rapidly became polyclonal. Indeed, we have shown here that K18 env induced a polyclonal response in peripheral blood T cells, whether presented by mouse APC or EBV infected B cells. Similar effects have been seen in toxin titration experiments with bacterial SAgs and might account for controversy over the initial finding of TCRBV7 specificity of K 18.1 Env .
[0078] Thus, in vivo, EBV infection leads to expression of an endogenous provirus with powerful T cell stimulatory activity has widespread implications for understanding EBV pathogenesis. Extensive T cell infiltrates are characteristic of the EBV-associated tumors Hodgkin's lymphoma and naso-pharyngeal carcinoma; and there is good evidence for a role of activated T helper cells in the development of transplant associated lymphomas. Furthermore, massive lymphocytosis is characteristic of acute infectious mononucleosis. EBV induced SAg activity could play a role in any of these processes.
[0079] The following notes and references are cited throughout the specification and are incorporated herein by reference.
Notes
[0080] (Note 1) All cell lines were grown in RPMI (Gibco) supplemented with 10%FCS, glutamine, HEPES, Na pymvate, β-mercaptoethanol. EBV cell lines and stable A20 transfectants expressing HERV-K18.2 env, were treated overnight with PMA (Calbiochem, 10 ng/ml) at 37° C, then with mitomycin C (Sigma, 0.1 mg/ml) for 1 h, and washed extensively with PBS. Cells were counted and resuspended with THy in quadruplicate wells of 96 well round bottom plates, using 2 x 104 of each cell type/well. After 48 h at 37° C, the plates were frozen at -80° C to lyse the cells, and thawed supernatants were tested for the presence of mIL-2 by ELISA (Phamiingen), and compared to a standard curve with rIL-2 (R&D Systems). As positive control, the THy were stimulated with platebound anti-CD3 (145 2C11, Phamiingen).
[0081] (Note 2) A20 transfected with Kl 8.1 or Kl 8.2 env, or pCDLI, and EBV cell lines were PMA/mitomycin C treated as above, and resuspended at APC:responder of 5: 1 or 1 : 1 with
THy, using 2 x 104 THy/well. IL-2 production for each THy was expressed as % maximal based on the response to platebound anti-CD3.
[0082] (Note 3) Antiserum blocking studies were performed by preincubating APC for 30 min at 37° C with rabbit anti-E/zv peptide 116-130 antiserum diluted 1:100 or 1 :200, or preimmune serum at 1 :100. APC:responder ratio was 2:1, with 2x104 THy per well. Plates were frozen at 24h, and thawed supematants were tested for mIL-2 as above.
[0083] (Note 4) 2 x 108 BL41, BL41/B95-8 (a from G. Lenoir) or B95-8 LCL (made by transfonning 106 peripheral blood B cells with 1 ml of 5 d B95-8 vims supernatant, diluted 1:1 in media, for 1.5 h at 37° C, then expanded for several weeks in 10% FCS/complete RPMI media), were treated for 0, 2, 8 or 16 h with PMA (10 ng/ml), then total RNA was prepared with Trizol (Gibco BRL). The RNase protection assay was perfomied as previously described , but with 100 μg total RNA/lane. As controls, 100 μg RNA from untransfected A20 cells, and 20 μg RNA from A20 transfected with HΕRV-K18.1 env (IDDM465) were loaded on the gel. (It should be noted that this transfectant vastly overexpressed the env gene compared to LCL). Densitometry values were obtained by scanning the autoradiograph with a Biorad Gel Doc 1000, using Molecular Analyst program. The ratio of K18 env. hTBP (human TATA binding protein) was determined.
[0084] (Note 5) Peripheral blood mononuclear cells were obtained from healthy adult volunteers, plated overnight at 37° C in 10% FCS/complete RPMI media to allow monocytes to adhere and then used as a source of T cells. A20 transfected with HERV-K18.1 env or pCDLI only or B95-8 LCL, transformed from autologous B cells, were treated overnight with PMA (10 ng/ml), then with mitomycin C (0.1 mg/ml) for 1 h, and washed extensively with PBS. APC and T cells were resuspended at various ratios, using 105 T cells per well in quadruplicate in 96 well round bottom plates. After 48 h at 37°C, cells were pulsed with (3H)thymidine (lμCi/well) for 12 h, then harvested and counted for ( H) incorporation.
[0085] (Note 6) Antiserum blocking studies were performed identically; however, prior to addition of T cells, APC were preincubated for 30 min with Env antise m diluted 1 : 100 or 1 :200, or preimmune serum at 1 : 100.
[0086] It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations
of this invention provided they come within the scope of the appended claims and their equivalents.
[0087] The references appearing throughout the application are incorporated herein by reference.
Claims (17)
1. A vaccine for treating and/or preventing EBV infection and EBV-associated disorders comprising HERV-K18 env SEQ ID:1 or an immunogeiήc fragment thereof, or a nucleic acid encoding the HERV-K18 env, or a fragment thereof and a pharmaceutically acceptable carrier.
2. The vaccine of claim 1, wherein the immunogenic fragment is selected from the group consisting of SEQ ID:2, SEQ ID:3 and SEQ ID:4.
3. The vaccine of claim 1, wherein the immunogenic fragment is SEQ ID:2.
4. An isolated peptide having the amino acid sequence of SEQ ID:2.
5. The vaccine of claim 1 , wherein the immunogenic fragment comprises the whole HERV- K18 env protein, or a peptide thereof, in winch the superantigen T cell stimulatory activity of HERV-K18 env is diminished.
6. A method for preventing EBV infection and EBV-associated disorders in an individual at risk for said infection comprising administering to said individual the vaccine of claims 1, 2 or 3.
7. A method for treating an individual having an EBV-associated disorder comprising administering to said individual a treatment effective amount of an antibody or a fragment thereof against HERV-K18 env.
8. The method of claim 7, wherein the EBV-associated disorder is infectious mononucleosis or an EBV induced lymphoma.
9. A method for providing passive immunity to infection by EBV in an individual susceptible to infection by EBV, said method comprising administering to said individual a HERV-K18 env antibody composition.
10. A method for preventing EBV-associated disorders in immunosuppressed individuals comprising administering to said individuals the vaccine of claims 1, 2, and 3.
11. The method of claim 10, wherein the vaccine is administered before commencement of immunosuppressive therapy.
12. The method of claim 7, comprising administering to said individual a treatment effective amount of an antibody or a fragment thereof against HERV-K18 env.
13. The method of claim 7, comprising administering to said individual a treatment effective amount of an antibody or a fragment thereof against HERV-K18 env.
14. A method for treating an EBV-associated autoimmune disorder, the method comprising: a) identifying an EBV-positive immunocompromised individual; and b) administering to the innnunocompromised individual, an effective amount of an antibody or a fragment thereof against HERV-K18 env.
15. A method for treating oncogenic transformation in an innnunocompromised individual, the method comprising: a) identifying an immunocompromised individual exhibiting clinical symptoms associated with early stage oncogenic transformation; and b) administering to the innnunocompromised individual, an effective amount of an antibody or a fragment thereof against HERV-K18 env.
16. A method of claim 15, wherein the oncogenic transfonnation results in Hodgkin's lymphoma, Post-transplant-lymphoproliferative disorders, Lympho-proliferative Disorders, EBV-positive lymphomas, EBV-positive breast cancer, Burkitt's lymphoma, and Naso-Pharyngeal-Carcinoma.
17. An article of manufacture comprising packaging material and a pharmaceutical agent contained witlήn said packaging material, wherein said packaging material comprises a label which indicates said phannaceutical may be administered, for a sufficient temi at an effective dose, for treating EBV infection and EBV-associated disorders, wherein said pharmaceutical agent comprises an antibody or a fragment thereof against HERV-K18 env together with a phannaceutically acceptable carrier.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25467300P | 2000-12-11 | 2000-12-11 | |
US60254673 | 2000-12-11 | ||
PCT/US2001/047885 WO2002047720A2 (en) | 2000-12-11 | 2001-12-11 | Treatment and prevention of ebv infection and ebv-associated disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2002230758A1 true AU2002230758A1 (en) | 2002-06-24 |
Family
ID=22965136
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2002230758A Abandoned AU2002230758A1 (en) | 2000-12-11 | 2001-12-11 | Treatment and prevention of EBV infection and EBV-associated disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1385542A4 (en) |
JP (1) | JP2004517839A (en) |
AU (1) | AU2002230758A1 (en) |
CA (1) | CA2429755A1 (en) |
WO (1) | WO2002047720A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117656334A (en) * | 2024-02-01 | 2024-03-08 | 广州市亿安劳保用品有限公司 | Glove dipping processing device for glove production line |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1423416A2 (en) * | 2001-08-31 | 2004-06-02 | NovImmune S.A. | Allelic variants of herv-k18 provirus and their use in analysis |
EP1425299A2 (en) * | 2001-09-06 | 2004-06-09 | NovImmune S.A. | Peptides derived from the superantigen (sag) env protein of herv-k18 and their use in obtaining sag-inhibitory antibodies and in vaccination |
DE102004011564A1 (en) * | 2004-03-08 | 2005-09-29 | Rwth Aachen | Vaccine for the prevention and / or treatment of a herpes virus infection |
BRPI0509497B1 (en) * | 2004-03-30 | 2022-07-19 | Institut Gustave Roussy | POLYPEPTIDE SEQUENCE INVOLVED IN MODULATION OF THE IMMUNOSUPPRESSIVE EFFECT OF VIRAL PROTEINS |
GB0707208D0 (en) * | 2007-04-13 | 2007-05-23 | Istituto Superiore Di Sanito | Novel disease treatments |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5858723A (en) * | 1995-12-05 | 1999-01-12 | Behringwerke Aktiengesellschaft | Polypeptides and antibodies for diagnosing and treating seminoma |
EP1425299A2 (en) * | 2001-09-06 | 2004-06-09 | NovImmune S.A. | Peptides derived from the superantigen (sag) env protein of herv-k18 and their use in obtaining sag-inhibitory antibodies and in vaccination |
-
2001
- 2001-12-11 JP JP2002549290A patent/JP2004517839A/en active Pending
- 2001-12-11 AU AU2002230758A patent/AU2002230758A1/en not_active Abandoned
- 2001-12-11 EP EP01991002A patent/EP1385542A4/en not_active Withdrawn
- 2001-12-11 WO PCT/US2001/047885 patent/WO2002047720A2/en not_active Application Discontinuation
- 2001-12-11 CA CA002429755A patent/CA2429755A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117656334A (en) * | 2024-02-01 | 2024-03-08 | 广州市亿安劳保用品有限公司 | Glove dipping processing device for glove production line |
CN117656334B (en) * | 2024-02-01 | 2024-04-12 | 广州市亿安劳保用品有限公司 | Glove dipping processing device for glove production line |
Also Published As
Publication number | Publication date |
---|---|
WO2002047720A2 (en) | 2002-06-20 |
JP2004517839A (en) | 2004-06-17 |
EP1385542A4 (en) | 2005-11-16 |
EP1385542A2 (en) | 2004-02-04 |
CA2429755A1 (en) | 2002-06-20 |
WO2002047720A3 (en) | 2003-10-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Chen et al. | Intracellular antibodies as a new class of therapeutic molecules for gene therapy | |
Tilley et al. | A human monoclonal antibody against the CD4-binding site of HIV1 gp120 exhibits potent, broadly neutralizing activity | |
Thali et al. | Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding | |
Robertson et al. | Role and specificity of T-cell subsets in spontaneous recovery from Friend virus-induced leukemia in mice | |
US5994515A (en) | Antibodies directed against cellular coreceptors for human immunodeficiency virus and methods of using the same | |
US5854400A (en) | Monoclonal antibodies which neutralize HIV-1 infection | |
CA2094713A1 (en) | Neutralizing human monoclonal antibodies specific for the v3 loop and cd-4 binding site of hiv-1 gp120 | |
US9149519B2 (en) | Chimeric human immunodeficiency virus type 1 (HIV-1) with enhanced dendritic cell and macrophage tropism comprising the simian immunodeficiency virus (SIV) minimal Vpx packaging domain | |
Riddell et al. | T-cell therapy of cytomegalovirus and human immunodeficiency virus infection | |
EP1001815A1 (en) | Vectors derived from antibodies for transferring substances into cells | |
Fung et al. | Monoclonal Antibodies that Neutralize HIV–1 Virions and Inhibit Syncytium Formation by Infected Cells | |
Letvin et al. | Vaccine-elicited V3 loop-specific antibodies in rhesus monkeys and control of a simian-human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate envelope | |
Duan et al. | Intracellular immunization against HIV-1 infection of human T lymphocytes: utility of anti-rev single-chain variable fragments | |
EP0853662A1 (en) | Novel replication competent human immunodeficiency virus type 2 (hiv-2) proviral clone designated hiv-2kr | |
EP0910659B1 (en) | Antibodies against a complex of cd4 and a chemokine receptor domain, and their use against hiv infections | |
US20040096457A1 (en) | Treatment and prevention of ebv infection and ebv-associated disorders | |
KR19990063761A (en) | Glycoprotein B of RFHV / KSHV subfamily belonging to herpes virus | |
AU2002230758A1 (en) | Treatment and prevention of EBV infection and EBV-associated disorders | |
Ardavin et al. | Retrovirus-induced target cell activation in the early phases of infection: the mouse mammary tumor virus model | |
Hasenkrug et al. | Differing T-cell requirements for recombinant retrovirus vaccines | |
Dittmer et al. | Different immunological requirements for protection against acute versus persistent Friend retrovirus infections | |
Lucchiari et al. | Human immune response to HIV-1-Nef. I. CD45RO− T lymphocytes of non-infected donors contain cytotoxic T lymphocyte precursors at high frequency | |
CN110144325A (en) | A kind of targeting T lymphocyte and its preparation method and application | |
Hioe et al. | Enhanced HIV type 1 neutralization by human anti-glycoprotein 120 monoclonal antibodies in the presence of monoclonal antibodies to lymphocyte function-associated molecule 1 | |
WO1993019786A1 (en) | High affinity, strongly neutralizing monoclonal antibodies against the cd-4 binding site of gp120 of human immunodeficiency virus |