EP3541412A1 - Cyaa-polypeptide als immunomodulatorenverstärker - Google Patents
Cyaa-polypeptide als immunomodulatorenverstärkerInfo
- Publication number
- EP3541412A1 EP3541412A1 EP17809185.6A EP17809185A EP3541412A1 EP 3541412 A1 EP3541412 A1 EP 3541412A1 EP 17809185 A EP17809185 A EP 17809185A EP 3541412 A1 EP3541412 A1 EP 3541412A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- seq
- cyaa
- immunogenic composition
- sequence
- protein
- 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.)
- Withdrawn
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 35
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 33
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 29
- 239000003623 enhancer Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 39
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 38
- 230000002163 immunogen Effects 0.000 claims abstract description 36
- 108060000200 adenylate cyclase Proteins 0.000 claims abstract description 29
- 102000030621 adenylate cyclase Human genes 0.000 claims abstract description 29
- 239000013543 active substance Substances 0.000 claims abstract description 21
- 239000012634 fragment Substances 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 24
- 208000015181 infectious disease Diseases 0.000 claims description 20
- 150000001413 amino acids Chemical class 0.000 claims description 18
- 244000052769 pathogen Species 0.000 claims description 17
- 230000001717 pathogenic effect Effects 0.000 claims description 17
- 241000588779 Bordetella bronchiseptica Species 0.000 claims description 14
- 241000222697 Leishmania infantum Species 0.000 claims description 13
- 238000012217 deletion Methods 0.000 claims description 12
- 230000037430 deletion Effects 0.000 claims description 12
- 108010083528 Adenylate Cyclase Toxin Proteins 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 241000589902 Leptospira Species 0.000 claims description 9
- 241000222722 Leishmania <genus> Species 0.000 claims description 8
- 241000588807 Bordetella Species 0.000 claims description 7
- 230000001580 bacterial effect Effects 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 239000003053 toxin Substances 0.000 claims description 6
- 231100000765 toxin Toxicity 0.000 claims description 6
- 108700012359 toxins Proteins 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- 230000002238 attenuated effect Effects 0.000 claims description 4
- 239000012678 infectious agent Substances 0.000 claims description 4
- 108091033319 polynucleotide Proteins 0.000 claims description 4
- 102000040430 polynucleotide Human genes 0.000 claims description 4
- 239000002157 polynucleotide Substances 0.000 claims description 4
- 230000003612 virological effect Effects 0.000 claims description 4
- 108020004414 DNA Proteins 0.000 claims description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 3
- 230000003071 parasitic effect Effects 0.000 claims description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 2
- 241000589929 Leptospira interrogans Species 0.000 claims description 2
- 241001518154 Leptospira kirschneri serovar Grippotyphosa Species 0.000 claims description 2
- 102000018697 Membrane Proteins Human genes 0.000 claims description 2
- 108010052285 Membrane Proteins Proteins 0.000 claims description 2
- 241000204045 Mycoplasma hyopneumoniae Species 0.000 claims description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims description 2
- 241000589970 Spirochaetales Species 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 241000194021 Streptococcus suis Species 0.000 claims description 2
- 230000002538 fungal effect Effects 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229960005486 vaccine Drugs 0.000 abstract description 45
- 239000003228 hemolysin Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 108091007433 antigens Proteins 0.000 description 51
- 102000036639 antigens Human genes 0.000 description 51
- 239000000427 antigen Substances 0.000 description 50
- 241000282472 Canis lupus familiaris Species 0.000 description 42
- 235000018102 proteins Nutrition 0.000 description 34
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 26
- 239000002671 adjuvant Substances 0.000 description 25
- 230000028993 immune response Effects 0.000 description 22
- 235000001014 amino acid Nutrition 0.000 description 19
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 239000004202 carbamide Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 238000002255 vaccination Methods 0.000 description 13
- 239000000463 material Substances 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 210000001744 T-lymphocyte Anatomy 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 102000002689 Toll-like receptor Human genes 0.000 description 8
- 108020000411 Toll-like receptor Proteins 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 244000045947 parasite Species 0.000 description 8
- 241000282465 Canis Species 0.000 description 7
- 210000001185 bone marrow Anatomy 0.000 description 7
- 206010024238 Leptospirosis Diseases 0.000 description 6
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 241000125945 Protoparvovirus Species 0.000 description 5
- 210000000612 antigen-presenting cell Anatomy 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000588832 Bordetella pertussis Species 0.000 description 4
- KXLUWEYBZBGJRZ-POEOZHCLSA-N Canin Chemical compound O([C@H]12)[C@]1([C@](CC[C@H]1C(=C)C(=O)O[C@@H]11)(C)O)[C@@H]1[C@@]1(C)[C@@H]2O1 KXLUWEYBZBGJRZ-POEOZHCLSA-N 0.000 description 4
- 241000712083 Canine morbillivirus Species 0.000 description 4
- GPFVKTQSZOQXLY-UHFFFAOYSA-N Chrysartemin A Natural products CC1(O)C2OC2C34OC3(C)CC5C(CC14)OC(=O)C5=C GPFVKTQSZOQXLY-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 108010006464 Hemolysin Proteins Proteins 0.000 description 4
- 208000004467 Infectious Canine Hepatitis Diseases 0.000 description 4
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 4
- 239000012648 POLY-ICLC Substances 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 230000024932 T cell mediated immunity Effects 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 238000003975 animal breeding Methods 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 230000028996 humoral immune response Effects 0.000 description 4
- 229960002751 imiquimod Drugs 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 230000035764 nutrition Effects 0.000 description 4
- 108700002563 poly ICLC Proteins 0.000 description 4
- 229940115270 poly iclc Drugs 0.000 description 4
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 4
- 239000008399 tap water Substances 0.000 description 4
- 235000020679 tap water Nutrition 0.000 description 4
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101150106931 IFNG gene Proteins 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 201000005702 Pertussis Diseases 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229940031626 subunit vaccine Drugs 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000005945 translocation Effects 0.000 description 3
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 101100454808 Caenorhabditis elegans lgg-2 gene Proteins 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000000655 Distemper Diseases 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 2
- -1 Poly IC Substances 0.000 description 2
- 208000005342 Porcine Reproductive and Respiratory Syndrome Diseases 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- VQQVWGVXDIPORV-UHFFFAOYSA-N Tryptanthrine Chemical compound C1=CC=C2C(=O)N3C4=CC=CC=C4C(=O)C3=NC2=C1 VQQVWGVXDIPORV-UHFFFAOYSA-N 0.000 description 2
- 108010069584 Type III Secretion Systems Proteins 0.000 description 2
- 206010047505 Visceral leishmaniasis Diseases 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 210000000172 cytosol Anatomy 0.000 description 2
- 229960003983 diphtheria toxoid Drugs 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000000415 inactivating effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000021633 leukocyte mediated immunity Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001446 muramyl group Chemical group N[C@@H](C=O)[C@@H](O[C@@H](C(=O)*)C)[C@H](O)[C@H](O)CO 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002773 nucleotide Chemical group 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000001173 tumoral effect Effects 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- 230000009278 visceral effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 101100148254 Actinobacillus pleuropneumoniae apxIA gene Proteins 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000039506 BAGE family Human genes 0.000 description 1
- 108091067183 BAGE family Proteins 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 239000001987 Bordet-Gengou agar Substances 0.000 description 1
- 241001477981 Bordetella hinzii Species 0.000 description 1
- 241000588780 Bordetella parapertussis Species 0.000 description 1
- 241001135529 Bordetella sp. Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 101100289995 Caenorhabditis elegans mac-1 gene Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000701114 Canine adenovirus 2 Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229920002271 DEAE-Sepharose Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 102000040452 GAGE family Human genes 0.000 description 1
- 108091072337 GAGE family Proteins 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 1
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 1
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- PXMQJPDWGONKAV-MYAGRZGASA-N OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O PXMQJPDWGONKAV-MYAGRZGASA-N 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000794282 Staphylococcus pseudintermedius Species 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- QQEHDZXXCDSAFE-JBSAMAPISA-N [(3s,8r,9s,10r,13s,14s,17r)-17-acetyl-6-chloro-3-hydroxy-10,13-dimethyl-1,2,3,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(Cl)C2=C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QQEHDZXXCDSAFE-JBSAMAPISA-N 0.000 description 1
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
- 229960005054 acepromazine Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940060265 aldara Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 229940030156 cell vaccine Drugs 0.000 description 1
- 230000002016 colloidosmotic effect Effects 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 102000006834 complement receptors Human genes 0.000 description 1
- 108010047295 complement receptors Proteins 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- AEMOLEFTQBMNLQ-YBSDWZGDSA-N d-mannuronic acid Chemical compound O[C@@H]1O[C@@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-YBSDWZGDSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 244000000058 gram-negative pathogen Species 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940045808 haemophilus influenzae type b Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical group CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 231100000568 intoxicate Toxicity 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- VQWNELVFHZRFIB-UHFFFAOYSA-N odn 1826 Chemical compound O=C1NC(=O)C(C)=CN1C(O1)CC(O)C1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC1CC(N2C3=C(C(NC(N)=N3)=O)N=C2)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C3=NC=NC(N)=C3N=C2)OC1COP(O)(=O)OC1CC(N2C3=C(C(NC(N)=N3)=O)N=C2)OC1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C(N=C(N)C=C2)=O)OC1COP(O)(=O)OC1CC(N2C(NC(=O)C(C)=C2)=O)OC1COP(O)(=O)OC(C(O1)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(O)=O)CC1N1C=C(C)C(=O)NC1=O VQWNELVFHZRFIB-UHFFFAOYSA-N 0.000 description 1
- DHYWDEXXBWTTEH-UHFFFAOYSA-N odn 2007 Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(O)=O)C(O)C1 DHYWDEXXBWTTEH-UHFFFAOYSA-N 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical group CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 231100000654 protein toxin Toxicity 0.000 description 1
- 244000000040 protozoan parasite Species 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229960003127 rabies vaccine Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007888 toxin activity Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/002—Protozoa antigens
- A61K39/008—Leishmania antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/099—Bordetella
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Definitions
- the present invention relates to vaccination and, in particular, to formulating vaccines so as to achieve an enhanced immunogenic response to an antigen.
- the central principle involves the injection or ingestion of a material that will elicit antibodies against said material, such that, when challenged later with a pathogenic organism containing homologous material, the individual to whom the material has been administered is protected against the pathogenic disease.
- the materials injected or ingested that have this property of eliciting antibodies are called antigens.
- the first step in making a vaccine is to separate the disease-making, from the immune-inducing activity. In practice this means isolating or creating an organism, or part of one, that is unable to cause full-blown disease, but that still retains the antigens responsible for inducing the host's immune response.
- whole organism vaccines are produced by killing/inactivating or attenuating/weakening organisms and
- Sub-unit vaccines include vaccines based on for example protein antigens and carbohydrate antigens. Some vaccines elicit a weak response meaning that materials apparently have little or no immunogenicity made to make high titers of antibody in in vivo systems.
- FCA Freund's complete adjuvant
- the adjuvants presently in use in mammals fall into two distinct types.
- the first type involves the so-called "depot” effect and the second type depends on general immunological stimulation of the system under study.
- the adjuvants which rely on the depot effect are believed to bring the immune cells to the antigen site, where the depot effect relies on the injected antigen being trapped or insolubilized in a medium, giving sustained circulating levels.
- the second type of adjuvant involving general stimulation of the immune system, appears to rely on an inflammatory reaction resulting in a series of cells being stimulated, such that any antigen has an improved chance of eliciting antibodies.
- Immune Response Enhancers are mainly polysaccharide such as for example conjugate of the capsular polysaccharide of Haemophilus influenzae type b to diphtheria toxoid as described in US4,496,538 and US4,619,828, or a beta-l,4-linked D-mannuronic acid as described in WO06034395.
- IREs are small molecule immune potentiators such as tryptanthrin as described in US 8,193,185 or palmitoyl-Cys(2[R],3-dilauroyloxy-propyl)-Abu-D-Glu-NH2 as described in WO2012129483 or imidizoquinolines as described by Hemmi H et al. ("small antiviral compounds activate immune cells via TLR7 MyD88 dependent signaling pathway", Nature Immunol. , 2002, 3: 196-200). It is important to note that the first generation of imidizoquinoline is licensed as an antiviral as well as anticancer topical therapy (Aldara) and not a vaccine potentiator.
- Aldara anticancer topical therapy
- the invention relates to an immunogenic composition
- an immunogenic composition comprising i) a polypeptide comprising a sequence derived from an adenylate cyclase toxin (CyaA) protein or a fragment thereof, or a polynucleotide encoding for such a polypeptide and ii) at least one active agent.
- the invention also relates to a method for vaccinating or treating a human and/or a non- human animal comprising administering an immunogenic composition as defined above.
- the invention also relates to an immunogenic composition as defined above for the use of treating or vaccinating a human and/or a non-human animal against various diseases.
- the invention may be used in human(s) and/or non-human animal(s) to treat or vaccinate against various diseases.
- the present invention provides an immunogenic composition
- a polypeptide comprising a sequence derived from an adenylate cyclase toxin (CyaA) protein or a fragment thereof, or a polynucleotide encoding for such a polypeptide and ii) at least one active agent.
- CyaA adenylate cyclase toxin
- the sequence derived from an adenylate cyclase toxin (CyaA) protein comprises a deletion in the N amino-terminal adenylate cyclase (AC) domain.
- Bordetella pertussis the etiological agent of the highly contagious respiratory disease known as pertussis or whooping cough, secretes an adenylate cyclase toxin (CyaA also called ACT or AC-Hly), which belongs to the broad and important RTX (Repeats in ToXin) family of toxins secreted by Gram-negative pathogens.
- CyaA primarily targets host myeloid cells expressing complement receptor 3 (CR3), also known as the ⁇ 2 integrin, CDllb/CD18, or Mac-1. Besides CR3-expressing cells, the toxin can also bind and intoxicate with cAMP, at reduced but detectable levels, a broad variety of other cells, including mammalian erythrocytes on which CyaA can exert its hemolytic activity.
- CR3 complement receptor 3
- the CyaA of Bordetella species in particular of Bordetella pertussis is a 1706 residue-long (177-kDa, Accession number CPI05197, SEQ ID NO:l) and has been described as an amino acid sequence and a nucleotide sequence by Glaser P.
- CyaA protein or wild-type CyaA protein refers to the adenylate cyclase toxin protein from a Bordetella sp., such as CyaA protein from Bordetella pertussis (Accession number CPI 05197, SEQ ID NO:l), from Bordetella bronchiseptica (Accession number KDS81064, SEQ ID NO:2), from Bordetella hinzii (Accession number AAY57201, SEQ ID NO:l), or Bordetella parapertussis (Accession number CAB76450, SEQ ID NO:3).
- CyaA is a bifunctional protein that consists of an amino-terminal adenylate cyclase (AC) domain of about 400 residues (N-terminal residues 1 to 373) and of a RTX hemolysin domain (Hly). Intriguingly, insertion of large passenger peptides removes the enzymatic activity but not the cell-invasive capacity of the AC domain. This has repeatedly been exploited for delivery of heterologous antigens into the cytosolic pathway of CDllb-expressing dendritic cells by CyaA/AC(-) toxoids, thus enabling their processing and presentation on major histocompatibility complex (MHC) class I molecules to cytotoxic CD8(+) T lymphocytes (CTLs).
- MHC major histocompatibility complex
- AC domain refers to the amino-terminal adenylate cyclase domain of CyaA protein. The skilled person can simply identify such AC domain in the CyaA protein sequence. As an example, such AC domain corresponds to the amino acid 1 to 373 from SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3. .
- a deletion in the AC domain refers to a deletion inactivating the amino-terminal adenylate cyclase activity of the AC domain.
- said deletion in the AC domain refers to a deletion of at least 100 amino acids, preferably of at least 200 amino acids, and most preferably of at least 300 amino acids in said domain -.e.g. SEQ ID NO:4-. More preferably, the polypeptide of the invention does not comprise the sequence of the AC domain -e.g. the sequence SEQ ID NO:4.
- the sequence derived from an adenylate cyclase toxin (CyaA) protein consists of residues 235 to 1706 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3, more preferably residues 321 to 1706 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3, even more preferably residues 372 to 1706 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3 or 374 to 1706 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3.
- CyaA-AAC constructs that delivered passenger CTL epitopes into antigen- presenting cells (APCs) and induced strong antigen-specific CD8(+) CTL responses in vivo in mice and ex vivo in human peripheral blood mononuclear cell cultures (Holubova J. et al., 2012, Infect. Immun., 80:1181-92 - Jelinek J. et al., 2012, Bone Marrow Transpl., 47:243-50).
- APCs antigen-presenting cells
- RTX hemolysin (Hly) domain which follows the AC domain, and consisting of residues 374 to 1706 of CyaA (SEQ ID NO.l, SEQ ID NO:2 or SEQ ID NO:3), harbors all structural information involved in translocation of the N-terminal AC domain across target cell membranes.
- the Hly domain can form small cation selective membrane pores that allow efflux of potassium ions from cells and can cause colloid-osmotic cell lysis, such as hemolysis of erythrocytes.
- the capacity of CyaA to penetrate cellular membranes, to form pores, and to deliver the AC domain into the cytosol of target cells depends on covalent posttranslational fatty acylation of pro-CyaA at the ⁇ -amino groups of the internal lysine residues 983 and 860 by a co-expressed protein toxin acyltransferase, CyaC.
- Toxin activities further require loading of calcium ions into the numerous binding sites formed by the glycine and aspartate rich nonapeptide repeats of the RTX domain.
- CyaA is indeed a less potent hemolysin, forming smaller pores than all the other RTX cytolysins that do not have homologous segments at the N-terminal ends of their pore-forming domains. Indeed, CyaA forms cation-selective membrane pores of an inner diameter of 0.6 to 0.8 nm while the best characterized RTX hemolysins, such as E. coli HlyA or Actinobacillus pleuropneumoniae ApxIA, form larger pores with estimated inner diameters of 1.5 to 2 nm and about an order of magnitude higher unit conductance than CyaA (Benz R. et al., 1994, J. Biol.
- Hly linking segment refers to the about 100 amino acid sequence following the AC domain in the CyaA protein, preferably refers to the residues 374 to 500 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3 and corresponding to the sequence SEQ. ID NO:5.
- a "mutated Hly linking segment” refers to a Hly linking segment comprising at least one amino acid modification in its sequence -i.e. as compared to its wild type sequence (e.g. SEQ ID NO:5)-, preferably between residues 37 to 107 of its sequence -i.e. as compared to SEQ ID NO:5 and corresponding to residues 410 to 480 of SEQ ID NO: 1 SEQ ID NO:2 or SEQ ID NO:3 -; and still preferably between residues 71 to 81 of its sequence -i.e. as compared to SEQ ID NO:5 and corresponding to residues 444 to 454 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3.
- amino acid modification refers to amino acid addition, amino acid deletion, and/or to amino acid substitution.
- the sequence derived from a CyaA protein consists in a sequence derived from the Hly domain of CyaA -i.e. excluding a part of the AC domain - and corresponding, for example, to the amino acids 372 to 1706 or 374 to 1706 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3.
- a mutated Hly linking segment refers to a Hly linking segment comprising one or more amino acid substitutions in its sequence.
- said one or more amino acid substitutions refer to the substitution of negatively charged residues -i.e. Glutamate (E) or Aspartate (D)- by another residue such as neutral residues -i.e.
- the mutated Hly linking segment comprising at least one substitution at residue 445(D), 446(D) or 448(E) (numbering with respect to SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3).
- the mutated Hly linking segment comprises at least one substitution selected from the group consisting of the residue 445 by an Asparagine (D445N) and by a Serine (D445S), of the residue 446 by an Asparagine (D446N) and by a Serine (D446S) and of the residue 448 by a Glutamine (E448Q) and by a Serine (E448S).
- the mutated Hly linking segment comprises the substitution D445N, D446N and E448Q.
- the sequence derived from a CyaA protein consists in a SEQ ID NO:8.
- fragment refers to a sequence of at least 500 consecutive amino acids, preferably of at least 1000 consecutive amino acid residues.
- the term "derived from” or “derivative” refers to an amino acid sequence having a percentage of identity of at least 75% with the amino acid sequence of a CyaA protein (i.e. a wild-type CyaA such as SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3) or a fragment thereof, preferably of at least 79%, at least 80%, or at least 85%, still preferably of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of identity.
- a CyaA protein i.e. a wild-type CyaA such as SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3
- a fragment thereof preferably of at least 79%, at least 80%, or at least 85%, still preferably of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of identity.
- percentage of identity between two amino acids sequences, means the percentage of identical amino-acids, between the two sequences to be compared, obtained with the best alignment of said sequences, this percentage being purely statistical and the differences between these two sequences being randomly spread over the amino acids sequences.
- best alignment or “optimal alignment” means the alignment for which the determined percentage of identity (see below) is the highest. Sequences comparison between two amino acids sequences are usually realized by comparing these sequences that have been previously aligned according to the best alignment; this comparison is realized on segments of comparison in order to identify and compare the local regions of similarity.
- the sequence derived from an adenylate cyclase toxin (CyaA) protein may have a percentage of identity of at least 95%, or even 100% with the amino acid sequence of a CyaA protein (i.e. a wild-type CyaA such as SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3).
- CyaA adenylate cyclase toxin
- the polypeptide from the composition of the invention may also be post-translationally modified.
- said polypeptide can be modified by post-translational acylation of at least one of its residues, in particular at least one of the two, preferably the two, lysine residues corresponding to the residues located in positions 860 and 983 of SEQ ID NO:l CyaA protein.
- acylation it is meant herein palmitoylation, i.e., addition of palmitate and/or palmitoleate group(s) on such residue(s).
- polypeptide of the invention bears a palmitoyl group on some of these residues, preferably on one of the two, or the two, lysine residues corresponding to the residues 860 and 983 of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3.
- corresponding to it is meant that the residue(s) which is (are) post-translationally modified in the polypeptide of the invention has (have) the position(s) which matches the lysines 860 and 983 in the sequence of CyaA of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3.
- polypeptides of the invention can be carried out by the person skilled in the art, for example by mass spectrometry.
- the polypeptide as defined above comprising a sequence derived from a CyaA protein or a fragment thereof is fused to a heterologous sequence This fusion is a covalent fusion through a peptide bond.
- Such fusions are engineered on the level of the polypeptide-encoding DNA sequence by genetic fusion of two polypeptide-encoding DNA segments.
- heterologous sequence it is meant that this sequence is without any identical residues (100% identity) over more than 7 consecutive amino acid residues that originate from a CyaA protein (e.g. SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3). Therefore, said sequence is said heterologous, if it is not identical and/or has an identity which is less than 50%, less than 40%, less than 30%, less than 20% or even less than 10% of identity with a part of SEQ ID NO:l, SEQ ID NO:2 or SEQ ID NO:3 having the same size.
- the heterologous sequence has a size ranging from 9 to 500 amino acid residues, in particular 9 to 400 residues, 9 to 300 residues, 9 to 200 residues, 9 to 100 residues, 20 to 500 residues, 20 to 400 residues, 20 to 300 residues, 20 to 200 residues, 20 to 100 residues, 50 to 500 residues 50 to 400 residues, 50 to 300 residues, 50 to 200 residues, 50 to 100 residues, 100 to 500 residues, 100 to 400 residues, 100 to 300 residues or 100 to 250.
- said heterologous sequence comprises or consists of one or several antigen(s), each antigen comprising one or several epitope(s) as defined herein.
- an antigen is defined as a peptidic sequence which is able to elicit an immune response, in particular a T cell immune response, against one or several epitopes contained in this sequence.
- An antigen is either a full-length antigenic peptidic sequence of cellular or viral origin, a fragment of this sequence able to elicit an immune response, in particular a T cell immune response, against an antigenic determinant contained in this fragment, or a synthetic, non-natural sequence which carries epitope(s) consisting of several parts of the antigenic peptidic sequence fused together, provided that the synthetic polypeptide comprising this non-natural sequence is able to elicit a T cell immune response, against an antigenic determinant contained in this sequence.
- said heterologous sequence bears, comprises or consists of at least one epitope(s), preferably at least one CD8(+) epitope(s) and/or at least one CD4(+) epitope(s).
- at least it is meant one or a plurality of epitopes.
- An epitope is defined herein as any amino acid sequence involved in the elicitation or induction of a cell-mediated immune response, especially a T cell immune response, and is either linear or conformational.
- epitopes described herein include those which are processed by APC (Antigen Presenting Cells) in a host, especially T epitopes recognized in association with class I MHC (Major Histocompatibility Complex) molecules, such as epitopes the target cells of which are CD8(+) T lymphocytes, or T epitopes recognized in association with class II MHC molecules, such as those which target cells are CD4(+) T lymphocytes.
- APC Antigen Presenting Cells
- T epitopes recognized in association with class I MHC (Major Histocompatibility Complex) molecules such as epitopes the target cells of which are CD8(+) T lymphocytes, or T epitopes recognized in association with class II MHC molecules, such as those which target cells are CD4(+) T lymphocytes.
- Epitopes within the present invention have preferably a size ranging from 9 to 17, preferably 9 to 12, residues.
- Epitopes described herein include also B epitopes involved in humoral response.
- said heterologous sequence comprises or consists of at least one antigen or at least one epitope, said at least one antigens or at least one epitope being of cellular origin.
- said at least one antigen or at least one epitope originates from a prokaryote or eukaryote cell.
- said at least one antigen or at least one epitope originates from a virus, a bacterium, a fungus or a parasite, such as, but not limited to, Bordetella, Chlamydia, Plasmodium, Candida, Leishmania, Leptospirosis , Mmycobacterium tuberculosis, parvovirus , distemper virus, adenovirus , parainfluenza virus , influenza virus, coronavirus, Herpesvirus , calicivirus or panleukopenia Virus.
- a virus a bacterium, a fungus or a parasite
- Bordetella Chlamydia
- Plasmodium Plasmodium
- Candida Leishmania
- Leptospirosis Mmycobacterium tuberculosis
- parvovirus parvovirus
- distemper virus adenovirus
- parainfluenza virus influenza virus
- coronavirus Herpesvirus
- Herpesvirus
- heterologous sequence comprises or consists of more than one epitope or more than one antigen
- these epitopes or antigens originate from the same virus, the same bacterium, the same fungus or the same parasite.
- the heterologous polypeptide comprises or consists of more than one epitope or more than one antigen
- these epitopes or antigens originate from different organisms, such as different viruses, different bacteria, different fungi or different parasites.
- said at least one antigen or at least one epitope originates from mammalian cell.
- said at least one antigen or at least one epitope is from a tumour antigen -i.e., a polypeptide expressed by tumour or by cancerous cells-, the tumour being self or induced by a pathogen.
- the tumour antigen is self, preferably of human origin.
- tumour antigen encompasses the following groups of tumour antigens, and the heterologous polypeptide contained in the chimeric protein of the invention may be chosen in at least one of the following groups: (a) oncofetal tumour antigens, (b) oncoviral tumour antigens, (c) overexpressed/accumulated tumour antigens, expressed in a wide variety of normal tissues and overexpressed in tumours, (d) shared tumour-specific antigens or cancer- Testis antigens, expressed in many tumours but not in normal tissues (including BAGE family, GAGE family, MAGE family, SAGE family and XAGE family), (e) lineage-restricted tumour antigens, (f) mutated tumour antigens, resulting from point mutations in genes that are ubiquitously expressed; and (g) differentiation tumour antigens, expressed in the normal tissue of origin of the tumours but which are not tumour-specific.
- a heterologous sequence encodes several antigens
- these antigens are either fused or separated by peptide linkers or at least two of said antigens are fused whereas at least two of said antigens are separated by a linker.
- said peptide linker has a size ranging from 2 to 10 residues.
- the linkers may be added to separate antigens and/or to improve immune response.
- the expression "fused to" when reference is made to a peptidic sequence means that each peptidic part (e.g., the sequence derived from a CyaA protein and the heterologous sequence) are covalently linked together by a peptide bond.
- active agents relates to an immunogenic active component in that it resembles a disease-causing pathogen or infectious agent, and/or is made from attenuated, weakened, killed and/or recombinant forms of the same, its cells, tissues, DNA, RNA, toxins, proteins subunits, particles, and/or one of its surface proteins, tumor antigens , and combination thereof such that it provokes an immune response to that pathogen or infectious agent.
- the active agent may comprise a killed, but previously virulent, microorganism that has been destroyed.
- active agents are for example , but not limited to influenza, cholera, polio, hepatitis A, and rabies vaccines.
- Other active agents may contain living attenuated microorganisms and/or modified living virus, which either use living active agent that have been cultivated under conditions that disable their virulent properties, or use closely related but less dangerous organisms to produce a broad immune response. Examples include, but are not limited to , yellow fever, measles, mumps, rubella, whooping cough, porcine reproductive and respiratory syndrome (PRRS), distemper, canine adenovirus Type 2, parainfluenza, and kennel cough (e.g., coronavirus) vaccines.
- Some active agents are also bacterial or protozoan parasite in nature, such as, but not limited to, Mycoplasma hyopneumoniae, Bordetella bronchiseptica, Bordetella pertusis, Mycobacterium tuberculosis, Salmonella typhi (typhoid), Staphylococcus aureus, Staphylococcus pseudintermedius, Leptospira interrogans, Leptospira grippotyphosa, Leptospira Pomona, Leptospira spirochete , Leishmania and Streptococcus suis.
- Suitable active agents include toxoids made from inactivated toxic compounds that cause illness rather than the microorganism itself. Such examples are, but not limited to, Cryptosporidiosis, neosporosis, toxoplasmosis, tetanus and diphtheria toxoid-based vaccines. Protein subunit active agents can also be used, in which a fragment of the microorganism is used to create an immune response. Examples include , but are not limited to, subunit vaccines against HPV, hepatitis B, and the hemagglutinin and neuraminidase subunits of the influenza virus.
- Active agents can also be formulated using viral or bacterial DNA to provoke an immune response.
- most current vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic active agents using synthetic peptides, carbohydrates, or antigens can also be used.
- Suitable immunogenic compositions can be monovalent or polyvalent.
- the at least one active agent and the polypeptide heterologous sequence here above defined are antigens from the same pathogen.
- the active antigen can be an inactivated Bordetella bacteria and the heterologous sequence fused with adenylate cyclase toxin (CyaA) is a fragment of a self-associating tip complex protein from the type III secretion system (T3SS) from Bordetella such as Bsp 22 (e.g. Bordetella bronchiseptica, accession number WP003809882.1) or the P36 protein from Leishmania infantum (Accession number XP001470319.2, SEQ. ID NO :7).
- T3SS type III secretion system
- the immunogenic composition of present invention eventually also comprises a suitable pharmaceutical vehicle, which is, for example , selected from buffering agents, saline, phosphate buffered saline, dextrose, glycerol, water, ethanol and the like, stabilizers, preservatives, adjuvant, surfactants and/or immunomodulatory substances (such as cytokines or chemokines) and/or growth factors such as GM-CSF and combinations thereof.
- a suitable pharmaceutical vehicle which is, for example , selected from buffering agents, saline, phosphate buffered saline, dextrose, glycerol, water, ethanol and the like, stabilizers, preservatives, adjuvant, surfactants and/or immunomodulatory substances (such as cytokines or chemokines) and/or growth factors such as GM-CSF and combinations thereof.
- Stabilizers are used to help the immunogenic composition to maintain its effectiveness during storage.
- the composition stability is essential, particularly where the cold chain is unreliable.
- Stabilizing agents include for example , but not limited to, MgCI2 MgS04, lactose-sorbitol and sorbitol-gelatin.
- Preservatives are added to the immunogenic composition to prevent bacterial and fungal growth. They include a variety of substances, for example, but not limited to antibiotics, thiomersal, formaldehyde, or phenol derivatives.
- Adjuvants are known in the art and include for example , but not limited to , Complete Freund's Adjuvant (CFA), Incomplete Freund's Adjuvant (IFA), montanide ISA (incomplete seppic adjuvant), muramyl peptides such as muramyl dipeptide (MDP) MDP-Lys (L18) (N.sup..alpha.-acetylemuramyl-L-alanyl-D-isoglutaminyl-N.sup.esteoroyl-L-- lysine), zinc sulphate, colloidal iron hydroxide, calcium phosphate or calcium chloride, CpG oligodeoxynucleotides (CPG ODN) such as CPG ODN 1826 and CPG ODN 2007, MF59 which is a detergent stabilized oil-in water emulsion containing 5% squalene (w/v), 0.5% TweenTM 80 (w/v) and 0.5% Span (w/v)
- At least one adjuvant is chosen among molecules which have the capacity to activate T-cell immune response.
- Preferred adjuvants are the ones that bind or are agonist to PRR (Pathogen Recognition Receptors) and even more preferably to TLR (Toll like receptor) 3, 4, 7, 8 and/or 9 on immune cells (such as APC).
- the adjuvant is a TLR ligand, in particular a TLR ligand selected from the group consisting of TLR ligands of class 3, such as poly-ICLC, TLR ligands of class 4, such as MPL TLR ligands of class 9, such as CpG, and TLR ligands of class 7/8, such as Imiquimod.
- adjuvants examples include Imiquimod and Poly-ICLC.
- a commercially available drug based on Imiquimod is AldaraTM (sold as a cream containing 5% Imiquimod)
- Poly-ICLC can be purchased from Oncovir Inc, (WA, US) as HiltonolTM.
- the immunogenic composition of the invention can be injected in a human and/or non human animal by different routes: subcutaneous (s.c), intradermal (i.d.), intramuscular (i.m.) or intravenous (i.v.) injection, oral administration and mucosal administration, especially intranasal administration or inhalation.
- immunogenic composition(s) defined herein is/are administered intradermally.
- the immunogenic composition of the invention may be in a solid form (capsule, powder, tablet, pill, suppository, quick release tablet, gastro-resistant tablet, delayed release tablet), a powder form, preferably after lyophilization (lyophilized form or lyophilized powder form) which needs to be reconstituted for example with diluents(s) before injection, or in a liquid form, such as an injectable solution or injectable suspension.
- a solid form capsule, powder, tablet, pill, suppository, quick release tablet, gastro-resistant tablet, delayed release tablet
- a powder form preferably after lyophilization (lyophilized form or lyophilized powder form) which needs to be reconstituted for example with diluents(s) before injection, or in a liquid form, such as an injectable solution or injectable suspension.
- the immunogenic composition of the invention is for use in the prophylaxis and/or treatment of a pathogen infection.
- the immunogenic composition of the present invention is for use in the prophylaxis and/or treatment of an oncogenic based disorder.
- the invention also relates to a method for the therapeutic treatment of a human and/or a non human animal presenting a pathogen infection or suspected to be infected with a pathogen comprising (a) the administration of an effective amount of an immunogenic composition of the present invention into said human and/or non human animal, possibly as multiple administered doses, and (b) the follow up of the condition of said human and/or non human animal.
- the invention also relates to a method to prevent a pathogen infection of a human and/or of a non human animal comprising (a) the administration of an effective amount of an immunogenic composition of the present invention into said human and/or non human animal, possibly as multiple administered doses, and (b) the follow up of the condition of said human and/or non human animal, possibly as multiple administered doses.
- the invention also relates to a method for the therapeutic treatment of a human and/or of a non human animal suffering from tumor disorders comprising (a) the administration of an effective amount of an immunogenic composition of the present invention into said human and/or non human animal, possibly as multiple administered doses, and (b) the follow up of the condition of said human and/or non human animal.
- An "effective amount" of the immunogenic composition of the invention meant that is sufficient to prevent or inhibit the pathogen infection or the growth of cancer cells.
- the doses used for the administration can be adapted as a function of various parameters, in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
- the form of the immunogenic composition, the route of administration, the dosage and the regimen depend on the condition to be treated, the severity of the illness, the age, weight, and sex of the subject, etc.
- the amount of active agent present in the immunogenic compositions of the present invention will vary depending upon the particular active agent used, as well as the intended subject for administration of the composition, and route of administration...
- the immunogenic composition of the present invention will comprise from about 0.01% to about 90% by weight of the active agent, preferably from about 10% to about 60% and more preferably, from about 30% to about 50%, based upon the total weight of the immunogenic composition taken as 100% by weight.
- the immunogenic compositions will also comprise from about 0.5% to about 80% by weight of the polypeptide disclosed previously or of the polynucleotide encoding thereof, preferably from about 10% to about 60% by weight and more preferably, from about 30 to about 50%, based upon the total weight of the immunogenic composition taken as 100% by weight.
- the weight ratio of the polypeptide or the nucleic acid encoding thereof, to active agent in the immunogenic composition will be from about 1: 1 to about 50:1, preferably from about 10: 1 to about 30: 1, and more preferably from about 20: 1 to about 40: 1.
- a therapeutic treatment according to the invention aims at improving the clinical condition of a human and/or a non human animal in need thereof, who has been diagnosed as being infected or suspected to be infected by a pathogen or as suffering from a pathological state.
- this treatment aims at the elimination of the causative agent or organism of the disease, or at lowering the abundance of said agent or organism.
- the treatment may result in a significant decrease of the viral load in the targeted tissues of the host that is less than what can be detected when measured.
- the treatment may result at lowering the size or the development of the tumour(s), or at eradicating the tumour cells, or at reducing the number of tumour cells at a level which is less than what can be detected when measured.
- the therapeutic treatment also aims at improving the clinical status of the human and/or non human animal, by eliminating or lowering the symptoms associated with the pathogen infection or the tumour disorders, and preferably aims at restoring health.
- a prophylactic treatment of a human and/or a non human animal aims at preventing the pathogen infection of said human and/or non human animal, or preventing the apparition or development of neoplastic tumoral disorders, or preventing the occurrence of a pathological state in said human and/or non human animal.
- the prophylactic treatment encompasses vaccination.
- Therapeutic and prophylactic treatments, using a composition of the invention are based on the elicitation of an efficient immune response, preferably a cellular immune response, against the epitope(s) contained in the heterologous polypeptide in the host.
- non human animal encompasses, and preferably is a non human mammal such as for example a canine, a feline, a bovine, an ovine, a porcine, a camelid and/or an equine.
- Example 1 Construction, production and purification of CyaA protein.
- Antigens The synthetic peptides corresponding to antigens such as Bsp22 of Bordetella Bronchiseptica (Accession number WP003809882.1, SEQ ID NO:6) and Leishmania infantum P36 protein (Gonzales-Aseguinolaza et al., Eur. J. Biochem. 259: 909-916, Accession number XP001470319.2, SEQ ID NO :7) were purchased from Polypeptide (Strasbourg, France).
- Recombinant CyaA protein comprising the antigens such as Bsp22 (CyaA-Bsp22, SEQ ID NO:9) or Leishmania infantum P36 (CyaA-P36, SEQ ID NO:10) genetically link to the N- terminal part of Bordetella Bronchiseptica CyaA protein which is the polypeptide from residues 374 to 1706 .
- CyaA proteins were produced in E. coli XLl-Blue (Stratagen, an Agilent Technologies Company, USA) transformed with appropriate pT7CACTl-derived constructs as in described in Osicka R. et al. (2000, Infect. Immun., 68: 247-256).
- Exponential 500-ml cultures were grown at 37°C and induced by isopropyl l-thio- -D-galactopyranoside (IPTG, 1 mM) for 4 h before the cells were washed with 50 mM Tris-HCI (pH 8.0), 150 mM NaCI, resuspended in 50 mM Tris-HCI (pH 8.0), 0.2 mM CaCI2, and disrupted by sonication. Upon centrifugation at 25,000 x g for 20 min, the insoluble cell pellets were resuspended in 8 M urea, 50 mM Tris-HCI (pH 8.0), 50 mM NaCI, 0.2 mM CaCI2.
- mice Six week old female BALB/c mice (Janvier Labs, France) were immunized with two doses of subcutaneous Injections in the upper back at 3-weeks intervals of either 250 ⁇ (1 ⁇ 2 of a canine dose of Bronchicine Cae, Zoetis) (Group 1), 250 ⁇ (1 ⁇ 4 of a canine dose of Bronchicine Cae, Zoetis) plus 75 ⁇ g of CyaA-Bsp22 as described in Example 1 (SEQJDNO: 9)(in Urea 2.4M) (Group 2) and 2.4M Urea for control mice (Group 3).
- mice per group were challenged by instillation into the left nostril under ether anesthesia of 50 ⁇ of Bordetella Bronchiseptica suspension as defined hereabove and equivalent to a total of approximately 2xl0 8 colony forming units [CFU]).
- the survival curve was determined with the Kaplan Meier method.
- Beagle dogs were purchased from a licensed kennel for animal breeding and husbandry (CEDS,
- Bordetella bronchiseptica All dogs were dewormed and vaccinated against canine distemper virus, parvovirus, leptospirosis, infectious canine hepatitis and parainfluenza virus. They were housed in an accredited class II facility and were provided commercial dog food (VetCare
- Dogs were randomly allocated to two groups, following an equivalent ratio of male vs female in each group.
- the control group was composed of 5 puppies and the vaccinated group composed of 20 puppies divided in two groups: one group of 10 puppies received two doses of canine Bronchicine Cae as recommended by the manufactor Zoetis (Group 1) and a group of 10 puppies received the same dose of canine Bronchicine Cae plus 300 ⁇ g of CyaA-Bsp22 as described in Example 1 (in Urea 2.4M) (Group 2) . All dogs received two parenteral vaccine injections at 10 weeks of age (2 weeks after their arrival) and three weeks later.
- the control group received the same amount of excipient and adjuvant as in the vaccine formulation. All dogs were infected by Bordetella bronchiseptica four weeks after the second vaccine injection. All puppies were exposed to an aerosol of 1 ml of challenge preparation (8 xlO 9 CFU/ml during 15 min using a nebuliser (OMRON, compAir Pro C900). Puppies were slightly tranquilized with an intramuscular injection of a mix of butorphenol (0.3mg/kg) and acepromazine (O.Olmg/kg) 10 min before the aerosol nebulization.
- Example 3 Leishmania infection challenge
- mice Six week old female BALB/c mice (Janvier Labs, France) were immunized with three doses of subcutaneous Injections in the upper back at 21 days of intervals of either 250 ⁇ (1 ⁇ 2 of a canine dose of CaniLeish, Virbac) ( Group 1) ,250 ⁇ (1 ⁇ 4 of a canine dose of CaniLeish, Virbac) plus 75 ⁇ g of CyaA- P36 as obtained in Example 1 (in Urea 2.4M) (Group 2) and 2.4M Urea for control mice (Group 3).
- mice per group were challenged intradermally in their left hind footpad with 1 10 7 stationnary phase promastigotes of L. infantum (strain MHOM/BR/2001/HP-EMO or strain MHOM/BR/1970/BH46).
- mice were euthanized and spleen, liver, infected pawsi's draining lymph nodes (dLN) and bone marrow (BM) were collected to evaluate the parasite burden and visceral lesions in the animals.
- dLN infected pawsi's draining lymph nodes
- BM bone marrow
- the liver, spleen, dLN and BM were collected for parasite quantification.
- the limiting-dilution technique was used according to the technique previously described (Martins et al., 2013).
- Example 4 Profile of dog immune response after vaccination with an ⁇ -Leishmania infantum vaccine combined with CyaA
- Beagle dogs were purchased from a licensed kennel for animal breeding and husbandry (CEDS, Centre d'Elevage du Domaine de Souches, France). Specific pathogen-free puppies were five month old at their arrival. All dogs were dewormed and vaccinated against canine distemper virus, parvovirus, leptospirosis, infectious canine hepatitis and parainfluenza virus. They were housed in an accredited class II facility and were provided commercial dog food (VetCare Nutrition, Royal Canin) and tap water ad libitum.
- Dogs were randomly allocated to two groups, following an equivalent ratio of male vs female in each group: one group of 10 dogs received doses of Canileish as recommended by the manufacturer Virbac (Group 1) and the second group of 10 dogs received doses of Canisleish plus 150 ⁇ g of empty CyaA (in Urea 2.4M) (Group 2).
- a longitudinal immunological follow-up was performed at different time point after vaccine injection.
- the humoral immune response against vaccine Ags (ESP Ags from leishmania infantum, LiESP) was quantified by ELISA at each vaccination time and 10 days after the last vaccine injection.
- the specific cellular immune response against LiESP Ag was quantified by IFNg ELISpot at day 0, day 21, day 42 and day 52.
- the macrophage activity against leishmania parasites was determined with the CMLA assay at day 0 and day 52.
- Example 5 Profile of the immune response of dogs infected by Leishmania infantum after vaccination with anti-Leishmania vaccine combined with CyaA
- Beagle dogs were purchased from a licensed kennel for animal breeding and husbandry (CEDS, Centre d'Elevage du Domaine de Souches, France). Specific pathogen-free puppies were five month old at their arrival. All dogs were dewormed and vaccinated against canine distemper virus, parvovirus, leptospirosis, infectious canine hepatitis and parainfluenza virus. They were housed in an accredited class II facility and were provided commercial dog food (VetCare Nutrition, Royal Canin) and tap water ad libitum.
- the 30 infected dogs were randomly allocated to three groups, following an equivalent ratio of male vs female in each group: one group of 10 dogs received doses of Canileish (Virbac, Group 1), the second group of 10 dogs received doses of Canileish plus 150 ⁇ g of empty CyaA (in Urea 2.4M) (Group 2) the third group was the control group. This group received the same amount of excipient and adjuvant as in the vaccine formulation. All dogs received three parenteral vaccine injections at three weeks interval.
- a longitudinal follow-up was performed at different time point after vaccine injections to monitor the profile of the immune response specific for Leishmania Ags.
- the humoral immune response against vaccine Ags was quantified by ELISA at the day of the first vaccination (W26), at the day of the third vaccination injection, then at W36, W60 and W78.
- Isotype of specific Abs IgGl vs lgG2
- the immune response against Leishmania infantum was determined using the IFAT test (BVT France).
- the specific cellular immune response against LiESP Ag was quantified by IFNg ELISpot and the macrophage activity against L infantum was determined with the CM LA assay at the day of the first vaccination, at the day of the third vaccination injection, then at W36, W60 and W78. After infection, a clinical follow-up was performed daily to detect any clinical signs. In addition, on W26, W36, W60 and W78, biochemical analysis (total protein and Albumin/Globulin ratio) and haematological analysis (white blood cell and red blood cell counts, haematocrit, platelet count) were also performed. Evolution of infection was controlled by qPCR on bone marrow samples at W36, W60 and W78. Results: The group of dogs that received the combination of leishmania vaccine plus CyaA displays a stronger Th-1 response against L infantum Ags than the group that received the leishmania vaccine alone.
- Example 6 Profile of dog immune response after vaccination with anti-Leptospirosis vaccine combined with CyaA
- Beagle dogs were purchased from a licensed kennel for animal breeding and husbandry (CEDS, Centre d'Elevage du Domaine de Souches, France). Specific pathogen-free puppies were eight weeks old at their arrival. All dogs were dewormed and vaccinated against canine distemper virus, parvovirus, infectious canine hepatitis and parainfluenza virus. They were housed in an accredited class II facility and were provided commercial dog food (VetCare Nutrition, Junior 10kg, Royal Canin) and tap water ad libitum.
- Dogs were randomly allocated to two groups, following an equivalent ratio of male vs female in each group: one group of 10 puppies received doses of Leptospirosis vaccine as recommended by the manufacturer Virbac (Canigen L) (Group 1) and the second group of 10 puppies received doses of Canigen L plus 150 ⁇ g of empty CyaA (in Urea 2.4M) (Group 2).
- a longitudinal immunological follow-up was performed at different time point after vaccine injection.
- the humoral immune response against leptospira serovars present in the vaccine was quantified by MAT (micro-agglutination test) at each vaccination time and 10 days after the last vaccine injection.
- Isotype of specific Abs IgGl vs lgG2 was determined by ELISA.
- the specific cellular immune response against leptospira Ags was quantified by IFNg ELISpot at each vaccination time and 10 days after the last vaccine injection.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP2016002451 | 2016-11-17 | ||
PCT/EP2017/001341 WO2018091142A1 (en) | 2016-11-17 | 2017-11-16 | Cyaa polypeptides as immune enhancer |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3541412A1 true EP3541412A1 (de) | 2019-09-25 |
Family
ID=67623394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17809185.6A Withdrawn EP3541412A1 (de) | 2016-11-17 | 2017-11-16 | Cyaa-polypeptide als immunomodulatorenverstärker |
Country Status (1)
Country | Link |
---|---|
EP (1) | EP3541412A1 (de) |
-
2017
- 2017-11-16 EP EP17809185.6A patent/EP3541412A1/de not_active Withdrawn
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10441648B2 (en) | Mycobacterium antigenic composition | |
Goodwin et al. | Brucellosis vaccines for livestock | |
MX2012000158A (es) | Vacunas y composiciones contra streptococcus pneumoniae. | |
Estein et al. | The polymeric antigen BLSOmp31 confers protection against Brucella ovis infection in rams | |
US8425913B2 (en) | Immunogenic agents against Burkholderia pseudomallei and/or Burkholderia mallei, comprising lipopolysaccharide, capsular polysaccharide and/or proteins from Burkholderia pseudomallei | |
TW201309327A (zh) | 疫苗 | |
Lu et al. | Improved efficacy of DNA vaccination against prostate carcinoma by boosting with recombinant protein vaccine and by introduction of a novel adjuvant epitope | |
JP2004507453A (ja) | 組換え細胞内病原体ワクチンおよび使用のための方法 | |
US20210040162A1 (en) | Immunogenic compositions comprising mycobacterium bovis surface proteins and uses thereof | |
US20090087456A1 (en) | Adjuvanted vaccine | |
EP3541412A1 (de) | Cyaa-polypeptide als immunomodulatorenverstärker | |
WO2018091142A1 (en) | Cyaa polypeptides as immune enhancer | |
US11833197B2 (en) | Immunotherapy of leishmaniasis | |
WO2022236370A1 (en) | Immunogenic composition | |
US20180133301A1 (en) | Immunogenic and vaccine compositions for use against bordetella bronchiseptica infection | |
EP3323426A1 (de) | Immunogen- und impfstoffzusammensetzungen zur verwendung gegen bordetella-bronchiseptica-infektion | |
WO2018091613A1 (en) | Immunogenic and vaccine compositions for use against bordetella bronchiseptica infection | |
AU2017387570A1 (en) | Immunogenic composition comprising CyaA-derived polypeptide promoting a TH1/TH17-oriented immune response |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20190606 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20200108 |