JP2020505464A - ペプチド送達用の安定なエマルジョンを製造するための方法 - Google Patents
ペプチド送達用の安定なエマルジョンを製造するための方法 Download PDFInfo
- Publication number
- JP2020505464A JP2020505464A JP2019560481A JP2019560481A JP2020505464A JP 2020505464 A JP2020505464 A JP 2020505464A JP 2019560481 A JP2019560481 A JP 2019560481A JP 2019560481 A JP2019560481 A JP 2019560481A JP 2020505464 A JP2020505464 A JP 2020505464A
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- seq
- emulsion
- solution
- suspension
- 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.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 275
- 239000000839 emulsion Substances 0.000 title claims abstract description 93
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 17
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 83
- 239000000725 suspension Substances 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 50
- 239000002671 adjuvant Substances 0.000 claims abstract description 41
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims description 36
- 239000003921 oil Substances 0.000 claims description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000003995 emulsifying agent Substances 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 15
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- LUXUAZKGQZPOBZ-SAXJAHGMSA-N [(3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (Z)-octadec-9-enoate Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O LUXUAZKGQZPOBZ-SAXJAHGMSA-N 0.000 claims description 12
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019198 oils Nutrition 0.000 claims description 12
- 239000002480 mineral oil Substances 0.000 claims description 11
- 229940042472 mineral oil Drugs 0.000 claims description 11
- 235000010446 mineral oil Nutrition 0.000 claims description 11
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 claims description 9
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 9
- 239000012736 aqueous medium Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 150000002430 hydrocarbons Chemical class 0.000 claims description 7
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 7
- 239000001593 sorbitan monooleate Substances 0.000 claims description 7
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 7
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 7
- 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 claims description 6
- 125000001431 2-aminoisobutyric acid group Chemical group [#6]C([#6])(N*)C(*)=O 0.000 claims description 6
- 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 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- FUOOLUPWFVMBKG-UHFFFAOYSA-N alpha-amino-isobutyric acid Natural products CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 6
- 229940031439 squalene Drugs 0.000 claims description 6
- 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 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 108010074032 HLA-A2 Antigen Proteins 0.000 claims description 4
- 102000025850 HLA-A2 Antigen Human genes 0.000 claims description 4
- 238000002512 chemotherapy Methods 0.000 claims description 4
- 239000005662 Paraffin oil Substances 0.000 claims description 3
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 3
- 229940032094 squalane Drugs 0.000 claims description 3
- 238000002626 targeted therapy Methods 0.000 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- 238000009169 immunotherapy Methods 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 239000000243 solution Substances 0.000 description 75
- 230000008569 process Effects 0.000 description 18
- 238000003860 storage Methods 0.000 description 18
- 229960005486 vaccine Drugs 0.000 description 14
- 230000002776 aggregation Effects 0.000 description 13
- 238000004220 aggregation Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 230000003647 oxidation Effects 0.000 description 11
- 238000007254 oxidation reaction Methods 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 239000000427 antigen Substances 0.000 description 9
- 108091007433 antigens Proteins 0.000 description 9
- 102000036639 antigens Human genes 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000004945 emulsification Methods 0.000 description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 8
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 7
- 230000005847 immunogenicity Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 6
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000007762 w/o emulsion Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 5
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229940023041 peptide vaccine Drugs 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 3
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 3
- 229940045513 CTLA4 antagonist Drugs 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 3
- 102100037920 Insulin-like growth factor 2 mRNA-binding protein 3 Human genes 0.000 description 3
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 230000006240 deamidation Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- ZAJHBCDPAUKEPU-GIKXZWSFSA-N elpamotide Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCN=C(N)N)CC1=CC=CC=C1 ZAJHBCDPAUKEPU-GIKXZWSFSA-N 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 description 3
- 230000006919 peptide aggregation Effects 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 102000011251 ATP-dependent Clp protease proteolytic subunit Human genes 0.000 description 2
- 108050001496 ATP-dependent Clp protease proteolytic subunit Proteins 0.000 description 2
- 102100034357 Casein kinase I isoform alpha Human genes 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 2
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102100037753 DEP domain-containing protein 1A Human genes 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 102000004315 Forkhead Transcription Factors Human genes 0.000 description 2
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 102100031493 Growth arrest-specific protein 7 Human genes 0.000 description 2
- 102100039317 HAUS augmin-like complex subunit 3 Human genes 0.000 description 2
- 101710166951 HAUS augmin-like complex subunit 3 Proteins 0.000 description 2
- 108010075704 HLA-A Antigens Proteins 0.000 description 2
- 102000011786 HLA-A Antigens Human genes 0.000 description 2
- 101000950642 Homo sapiens DEP domain-containing protein 1A Proteins 0.000 description 2
- 101100452137 Homo sapiens IGF2BP3 gene Proteins 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-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
- 102100032129 Lymphocyte antigen 6K Human genes 0.000 description 2
- 101710158212 Lymphocyte antigen 6K Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102100023175 NADP-dependent malic enzyme Human genes 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 102000007982 Phosphoproteins Human genes 0.000 description 2
- 108010089430 Phosphoproteins Proteins 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000001772 anti-angiogenic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940001442 combination vaccine Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 108090000286 malate dehydrogenase (decarboxylating) Proteins 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000007764 o/w emulsion Substances 0.000 description 2
- 238000012510 peptide mapping method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000011127 radiochemotherapy Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- 238000003260 vortexing Methods 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N 2-Aminobutanoic acid Natural products CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 102000010825 Actinin Human genes 0.000 description 1
- 108010063503 Actinin Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 102100036360 Cadherin-3 Human genes 0.000 description 1
- 101710118321 Casein kinase I isoform alpha Proteins 0.000 description 1
- 102100025053 Cell division control protein 45 homolog Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 description 1
- 102100026245 E3 ubiquitin-protein ligase RNF43 Human genes 0.000 description 1
- 238000011510 Elispot assay Methods 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000007237 Forkhead Box Protein M1 Human genes 0.000 description 1
- 108010008599 Forkhead Box Protein M1 Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000021309 Germ cell tumor Diseases 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 102000010956 Glypican Human genes 0.000 description 1
- 108050001154 Glypican Proteins 0.000 description 1
- 102100032530 Glypican-3 Human genes 0.000 description 1
- 108050007237 Glypican-3 Proteins 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
- 101710135443 Growth arrest-specific protein 7 Proteins 0.000 description 1
- 108010091373 HA-1 antigen Proteins 0.000 description 1
- 108010013476 HLA-A24 Antigen Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 101000762242 Homo sapiens Cadherin-15 Proteins 0.000 description 1
- 101000714553 Homo sapiens Cadherin-3 Proteins 0.000 description 1
- 101000994700 Homo sapiens Casein kinase I isoform alpha Proteins 0.000 description 1
- 101000934421 Homo sapiens Cell division control protein 45 homolog Proteins 0.000 description 1
- 101000692702 Homo sapiens E3 ubiquitin-protein ligase RNF43 Proteins 0.000 description 1
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 1
- 101001027621 Homo sapiens Kinesin-like protein KIF20A Proteins 0.000 description 1
- 101001027631 Homo sapiens Kinesin-like protein KIF20B Proteins 0.000 description 1
- 101000801539 Homo sapiens Mitochondrial import receptor subunit TOM34 Proteins 0.000 description 1
- 101000619805 Homo sapiens Peroxiredoxin-5, mitochondrial Proteins 0.000 description 1
- 101001081189 Homo sapiens Rho GTPase-activating protein 45 Proteins 0.000 description 1
- 101000881168 Homo sapiens SPARC Proteins 0.000 description 1
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101150103227 IFN gene Proteins 0.000 description 1
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102400000022 Insulin-like growth factor II Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 102100037694 Kinesin-like protein KIF20A Human genes 0.000 description 1
- 102100037691 Kinesin-like protein KIF20B Human genes 0.000 description 1
- 102000019293 Kinesin-like proteins Human genes 0.000 description 1
- 108050006659 Kinesin-like proteins Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 102400000047 Minor histocompatibility antigen HA-1 Human genes 0.000 description 1
- 101800003181 Minor histocompatibility antigen HA-1 Proteins 0.000 description 1
- 102100033583 Mitochondrial import receptor subunit TOM34 Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 102000007456 Peroxiredoxin Human genes 0.000 description 1
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101001077668 Rattus norvegicus Serine protease inhibitor Kazal-type 1 Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 102100027748 Rho GTPase-activating protein 45 Human genes 0.000 description 1
- 102100037599 SPARC Human genes 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108050005900 Signal peptide peptidase-like 2a Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 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
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 1
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- -1 b-aminoalanine Chemical compound 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 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
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229940025708 injectable product Drugs 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 102000033952 mRNA binding proteins Human genes 0.000 description 1
- 108091000373 mRNA binding proteins Proteins 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 108030002458 peroxiredoxin Proteins 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000012301 transgenic model Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 239000012905 visible particle Substances 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
- A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00118—Cancer antigens from embryonic or fetal origin
- A61K39/001182—Carcinoembryonic antigen [CEA]
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001186—MAGE
-
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
-
- 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
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
-
- 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
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Developmental Biology & Embryology (AREA)
- Reproductive Health (AREA)
- Cell Biology (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- General Preparation And Processing Of Foods (AREA)
- Colloid Chemistry (AREA)
Abstract
Description
a)少なくとも3つの異なる溶液A、B及びCを準備する工程であって、
・溶液Aが、酸性の水性媒体であり、X及びaがそれぞれシクロヘキシルアラニン及びd-アラニンを表すペプチドaKXVAAWTLKAAa(配列番号1)を含み、
・溶液Bが、任意のペプチドを添加する前のpHが12.5から12.9の間である塩基性の水性媒体であり、ペプチドYLSGADLNL(配列番号8)を含み、
・溶液Cが、DMSOであり、ペプチドKVFGSLAFV(配列番号7)を含み、
・溶液A及び/又は溶液Bが、Bがα-アミノイソ酪酸を表すKLBPVQLWV(配列番号6)、SMPPPGTRV(配列番号5)、IMIGHLVGV(配列番号9)、LLTFWNPPV(配列番号4)、KVAEIVHFL(配列番号10)、RLLQETELV(配列番号2)及びYLQLVFGIEV(配列番号3)から選択される少なくとも3つの追加のペプチドを更に含む、工程と、
b)前記溶液を混合して懸濁液を形成する工程と、
c)前記懸濁液のpHを約7に調節する工程と
を含む方法によって調製される。
本発明の好適な実施形態によると、ペプチドは、腫瘍関連抗原(TAA)エピトープ、好ましくはHLA-A2結合TAAエピトープ及び/又はその類似体から選択されてもよい。
本発明に使用されるペプチド懸濁液は、それぞれ少なくとも2つの異なるペプチドを含有する少なくとも2つの異なる溶液を準備する工程を含むプロセスにより調製することができる。本発明のある実施形態によると、それぞれが少なくとも1つの特定のペプチドを含む、3つの異なる溶液A、B及びCが調製される。特に、溶液Aは酸性の水性媒体であり、溶液Bは塩基性の水性媒体であり、溶液Cは有機媒体、特に、DMSO(ジメチルスルホキシド)である。好適な実施形態において、溶液A、B及びCは、それぞれ、少なくともaKXVAAWTLKAAa(配列番号1)、YLSGADLNL(配列番号8)及びKVFGSLAFV(配列番号7)を含む。
a)少なくとも3つの異なる溶液A、B及びCを準備する工程であって、
・溶液Aが、X及びaがそれぞれシクロヘキシルアラニン及びd-アラニンを表すペプチドaKXVAAWTLKAAa(配列番号1)を含み、
・溶液Bが、ペプチドYLSGADLNL(配列番号8)を含み、
・溶液Cが、ペプチドKVFGSLAFV(配列番号7)を含み、
・溶液A及び/又は溶液Bが、Bがα-アミノイソ酪酸を表すKLBPVQLWV(配列番号6)、SMPPPGTRV(配列番号5)、IMIGHLVGV(配列番号9)、LLTFWNPPV(配列番号4)、KVAEIVHFL(配列番号10)、RLLQETELV(配列番号2)及びYLQLVFGIEV(配列番号3)から選択される少なくとも3つの追加のペプチドを更に含む、工程と、
b)前記溶液を混合して懸濁液を形成する工程と、
c)前記懸濁液のpHを約7に調節する工程と
を含む、ペプチド懸濁液を製造するための方法であって、
好ましくは、溶液BのpHは、任意のペプチドをそこに添加する前に12.5から12.9の間に調節される、方法に関する。
本発明は、その後、油中水型エマルジョンを得るようペプチド懸濁液をアジュバントと混合することで構成され、これは、樹状細胞へのペプチドの提示を促進すると考えられる。この種のエマルジョンでは、ペプチドを含有する水相は、油の連続相中に液滴の形態で閉じ込められ、これが、水中油型エマルジョンと比較した場合、デポーからの抗原のよりゆっくりとした放出、したがって、より強い長期免疫を可能にする。
本発明はまた、本発明による懸濁液の調製に続く、前記懸濁液の油中水型乳化剤との混合を含む、非経口投与用のエマルジョンを調製するためのプロセスに関する。
本発明による懸濁液の調製
標準的なBoc又はFmoc固相化学を使用してPolyPeptide社(サンディエゴ、CA)によって以下の10個のペプチドが合成された。
aKXVAAWTLKAAa(配列番号1)=MPS-7、
SMPPPGTRV(配列番号5)=MPS-103、
IMIGHLVGV(配列番号9)=MPS-214、
KVAEIVHFL(配列番号10)=MPS-215、
YLSGADLNL(配列番号8)=MPS-200、
KLBPVQLWV(配列番号6)=MPS-102、
LLTFWNPPV(配列番号4)=MPS-213、
RLLQETELV(配列番号2)=MPS-112、
YLQLVFGIEV(配列番号3)=MPS-106、及び
KVFGSLAFV(配列番号7)=MPS-216。
比較実験
水酸化ナトリウムの量を(WO2004/094454に記載されている)0.10Mから0.013Mに変動させたことを除いて実施例1に記載されている溶液2と同一のペプチド溶液を調製した。
懸濁液の安定性
以下に示されるとおり、ペプチド凝集の可能性を評価するためにさらなる試験を設定した。この方法は、ペプチド凝集を監視することができ、高感度で特異的で正確である。製造の間又は保存の間に起こる可能性のある構造的及び質量の改変又は変形を監視するのに適していた。液体クロマトグラフィー質量分析(LC-UV/MS)は、ペプチドの正体及びペプチド間の共有結合の不在を確実にするために行った。この方法は、いくらかのペプチド沈殿物が存在しているにもかかわらず、ペプチド間の凝集がないことを確認するために開発された。この目的は、さまざまな条件、-20℃、+5℃及び+25℃における9か月の保存の間に実施例1の懸濁液中に含まれるペプチド間にいくらか共有結合が構築され得るかを判断することであった。
カラム:Advance BioペプチドマッピングLCカラム、2.1×250mm、2.7μm、C18、120Å、Agilent参照番号651750-902
検出:215nm及び280nm
流量:0.3ml/分
注入量:5μl
ランタイム:100分
カラム温度:35℃±2℃
サンプル温度:5℃
ニードル洗浄:ジメチルスルホキシド(DMSO)中の0.1%トリフルオロ酢酸(TFA)
移動相:溶離液A:5%アセトニトリル中の0.2% TFA
溶離液B:95%アセトニトリル中の0.2% TFA
実施例1の懸濁液を含有する1バイアル(約1ml)の中身を10mlのメスフラスコに移し、DMSO中の0.1% TFAにより満杯にする。正確なサンプル質量を求めるためにサンプル採取の前後にバイアルを計量する。
本発明による必要に応じて調製されるW/Oエマルジョンの調製
注射可能な臨床上の生成物を調製するために、実施例1の懸濁液を、油中水型乳化混合物(SEPPIC社から供給されたMontanide(登録商標)ISA 51、バイアル中で暗所において2℃〜8℃で保存された)と1:1の質量比で混合することによって油中水型エマルジョンを形成し、これは、0.9mlのペプチド懸濁液及び1.1mlの乳化剤に相当する。特に、懸濁液及び乳化剤は、混合する直前に室温にし、それぞれシリンジに移した。エマルジョンを、これらのシリンジに連結されたプラスチックコネクターによって必要に応じて調製した。シリンジのプランジャーを交互にゆっくりとそれぞれ20回、その後、高速でそれぞれ40回押した。任意のシリンジから、1mlのこのエマルジョンを皮下経由で患者に注射することができる。
本発明によるすぐに使えるW/Oエマルジョンの調製
注射可能な臨床上の送達生成物を調製するために、実施例1の懸濁液を、油性アジュバント(SEPPIC社から供給されたMontanide(登録商標)ISA 51)と1:1の質量比で混合することによって油中水型エマルジョンを形成した。エマルジョンを調製するために、実行中に不活性ガスブランケットをもたらすよう、デバイスのミキサーバッグをまず窒素で膨らませた。5200gの乳化剤をろ過した後、無菌条件下において、軸流タービンを備えるAllegro(登録商標)ミキサーの混合チャンバーに移した。撹拌翼の回転速度を200rpmにセットした後、無菌条件下において、5200gの上記の懸濁液をゆっくりと(1分〜2分以内に)混合チャンバーに添加した。撹拌を5分間続けた。
さまざまな撹拌時間を使用したエマルジョンの調製
本発明によるエマルジョンを、さまざまな撹拌時間を使用して実施例5に記載されているとおりに調製した。各種ペプチドの最初の濃度を下の表に報告する。
エマルジョンの化学的安定性
実施例5に従って調製したエマルジョンに含まれるペプチドの化学的安定性を以下の方法によって評価する。
カラム:Advance BioペプチドマッピングLCカラム、2.1×250mm、2.7μm、C18、120Å、Agilent(登録商標)参照番号651750-902又は同等物
検出:215nm及び280nm
流量:0.3ml/分
注入量:5μl
ランタイム:100分
カラム温度:35℃±2℃
サンプル温度:5℃
ニードル洗浄:ジメチルスルホキシド(DMSO)中の0.1%トリフルオロ酢酸(TFA)
移動相:溶離液A:5%アセトニトリル中の0.2% TFA
溶離液B:95%アセトニトリル中の0.2% TFA
濃度(mg/g)=A/S×0.9X/10×5×1/W
式中、
A:サンプル溶液中のそれぞれのペプチドのピーク面積である
S:標準溶液中のそれぞれのペプチドのピーク面積である
W:g単位で表されるサンプル質量である
エマルジョンの物理的安定性
実施例5に記載されているとおりに調製したエマルジョンのさまざまなサンプルの液滴のサイズを、粒度計(Malvernマスターサイザー3000E光学システム)を使用したレーザー回折によって測定した。これらのサンプルを、ミキサーのさまざまな領域から回収した。その結果を、最大サイズの液滴のx%、すなわちDxとして表した。それらの概要を下記表に示す。
免疫原性
一部のペプチドは、実施例1に記載されているとおりに調製した懸濁液中で部分的に又は完全に沈殿すると確認した。
MPS-216 KVFGSLAFV(配列番号7)(33%の溶解度)
MPS-215 KVAEIVHFL(56%の溶解度)
MPS-106 YLQLVFGIEV(0%の溶解度)
比較実験
混合が回転子-固定子構成を有する高せん断ミキサー(Silverson(登録商標)Verso)によって行われたことを除いて、実施例1に記載されているとおりに調製した懸濁液を同じアジュバントと同じ比で混合した。2000rpm及び8000rpmの撹拌速度は、それぞれ15分間及び2分間を使用した。非常に粘稠なクリームが得られ、これは、注射可能な製品として使用することができなかった。5000rpm及び8000rpmで同じミキサーを用いて得た他のバッチはペプチド分解を引き起こしていた。特に、4℃における6週間の保存後にペプチドSMPPPGTRV(配列番号5)の8.5%の酸化が認められ、-20℃でも依然として2%の酸化が認められた。更に、ペプチドIMIGHLVGV(配列番号9)に関しては、4℃における6週間の保存後に16.5%の酸化が認められ、-20℃でも依然として4%の酸化が認められた。
Claims (15)
- すぐに使えるペプチドエマルジョンを工業規模で製造するための方法であって、少なくとも2つのペプチドの懸濁液を、低せん断条件下で、100rpmから1000rpmの間の回転速度で2分間から20分間、少なくとも1つのアジュバントと乳化する工程を含む、方法。
- 前記ペプチドが、少なくとも1つの可溶性ペプチド及び少なくとも1つの不溶性ペプチドを含むことを特徴とする、請求項1に記載の方法。
- 前記ペプチドが、ペプチドKVFGSLAFV(配列番号7)、ペプチドYLSGADLNL(配列番号8)、ペプチドKLBPVQLWV(配列番号6)(Bはα-アミノイソ酪酸を表す)、ペプチドSMPPPGTRV(配列番号5)、ペプチドIMIGHLVGV(配列番号9)、ペプチドLLTFWNPPV(配列番号4)、ペプチドRLLQETELV(配列番号2)、ペプチドaKXVAAWTLKAAa(配列番号1)(X及びaはそれぞれシクロヘキシルアラニン及びd-アラニンを表す)、ペプチドYLQLVFGIEV(配列番号3)並びにペプチドKVAEIVHFL(配列番号10)からなる群から選択されることを特徴とする、請求項1又は2に記載の方法。
- 前記懸濁液が、ペプチドKVFGSLAFV(配列番号7)、ペプチドYLSGADLNL(配列番号8)、ペプチドKLBPVQLWV(配列番号6)、ペプチドSMPPPGTRV(配列番号5)、ペプチドIMIGHLVGV(配列番号9)、ペプチドLLTFWNPPV(配列番号4)、ペプチドRLLQETELV(配列番号2)、ペプチドaKXVAAWTLKAAa(配列番号1)(X及びaはそれぞれシクロヘキシルアラニン及びd-アラニンを表す)、ペプチドYLQLVFGIEV(配列番号3)並びにペプチドKVAEIVHFL(配列番号10)の組合せを含むことを特徴とする、請求項3に記載の方法。
- 前記アジュバントが、炭化水素油と油中水型乳化剤の混合物からなることを特徴とする、請求項1から4のいずれか一項に記載の方法。
- 前記炭化水素油が、パラフィン油、植物油、スクアレン、スクアラン又は鉱油から選択され、前記油中水型乳化剤が、マンニドモノオレアート及びソルビタンモノオレアートから選択されることを特徴とする、請求項5に記載の方法。
- 前記アジュバントと前記ペプチド懸濁液との質量比は、10:1から1:10、好ましくは5:1から1:5、より好ましくは2:1から1:2の範囲であり、更に好ましくは1:1であることを特徴とする、請求項5又は6に記載の方法。
- 混合する工程のすべて又は一部が、不活性雰囲気下、好ましくは窒素下において行われることを特徴とする、請求項1から7のいずれか一項に記載の方法。
- 前記エマルジョンの体積が、5Lよりも大きい、好ましくは10L以上であることを特徴とする、請求項1から8のいずれか一項に記載の方法。
- 前記ペプチド懸濁液が、
a)少なくとも3つの異なる溶液A、B及びCを準備する工程であって、
・溶液Aが、酸性の水性媒体であり、ペプチドaKXVAAWTLKAAa(配列番号1)(X及びaはそれぞれシクロヘキシルアラニン及びd-アラニンを表す)を含み、
・溶液Bが、任意のペプチドを添加する前のpHが12.5から12.9の間である塩基性の水性媒体であり、ペプチドYLSGADLNL(配列番号8)を含み、
・溶液Cが、DMSOであり、ペプチドKVFGSLAFV(配列番号7)を含み、
・溶液A及び/又は溶液Bが、KLBPVQLWV(配列番号6)(Bはα-アミノイソ酪酸を表す)、SMPPPGTRV(配列番号5)、IMIGHLVGV(配列番号9)、LLTFWNPPV(配列番号4)、KVAEIVHFL(配列番号10)、RLLQETELV(配列番号2)及びYLQLVFGIEV(配列番号3)から選択される少なくとも3つの追加のペプチドを更に含む、工程と、
b)前記溶液を混合して懸濁液を形成する工程と、
c)前記懸濁液のpHを約7に調節する工程と
を含む方法によって調製されることを特徴とする、請求項3から8のいずれか一項に記載の方法。 - 前記溶液Aが、aKXVAAWTLKAAa(配列番号1)、SMPPPGTRV(配列番号5)、IMIGHLVGV(配列番号9)及びKVAEIVHFL(配列番号10)を含み、前記溶液Bが、YLSGADLNL(配列番号8)、KLBPVQLWV(配列番号6)、LLTFWNPPV(配列番号4)、RLLQETELV(配列番号2)及びYLQLVFGIEV(配列番号3)を含む、請求項10に記載の方法。
- 請求項1から11のいずれか一項に記載の方法により得ることが可能なすぐに使えるエマルジョン。
- 前記エマルジョン中のそれぞれのペプチドの量が、0.1mg/mlから10mg/ml、好ましくは0.5mg/mlから1mg/mlの範囲であり、前記エマルジョンの調製に使用された量と10%より大きく異ならないことを特徴とする、請求項12に記載のすぐに使えるエマルジョン。
- 前記エマルジョンのD50が10±2μmであることを特徴とする、請求項12又は13に記載のすぐに使えるエマルジョン。
- がんの処置において使用するための、好ましくはHLA-A2レセプターを発現する患者において使用するための、単独の又は化学療法、標的療法、放射線療法若しくはチェックポイント阻害剤等のその他の免疫療法と組み合わせた、請求項12から14のいずれか一項に記載のすぐに使えるエマルジョン。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17305079.0 | 2017-01-25 | ||
EP17305079 | 2017-01-25 | ||
PCT/EP2018/051647 WO2018138110A1 (en) | 2017-01-25 | 2018-01-24 | Method for manufacturing a stable emulsion for peptide delivery |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020505464A true JP2020505464A (ja) | 2020-02-20 |
JP7140778B2 JP7140778B2 (ja) | 2022-09-21 |
Family
ID=57965869
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019560481A Active JP7140778B2 (ja) | 2017-01-25 | 2018-01-24 | ペプチド送達用の安定なエマルジョンを製造するための方法 |
Country Status (23)
Country | Link |
---|---|
US (2) | US11325959B2 (ja) |
EP (2) | EP3573600B1 (ja) |
JP (1) | JP7140778B2 (ja) |
KR (1) | KR102577036B1 (ja) |
CN (2) | CN114917189B (ja) |
AR (1) | AR113209A1 (ja) |
AU (1) | AU2018213890B2 (ja) |
BR (1) | BR112019014917A2 (ja) |
CA (1) | CA3047492C (ja) |
DK (1) | DK3573600T3 (ja) |
ES (1) | ES2913268T3 (ja) |
HR (1) | HRP20220605T1 (ja) |
HU (1) | HUE058717T2 (ja) |
IL (1) | IL267237B1 (ja) |
LT (1) | LT3573600T (ja) |
MX (1) | MX2019008878A (ja) |
PL (1) | PL3573600T3 (ja) |
PT (1) | PT3573600T (ja) |
RS (1) | RS63259B1 (ja) |
SI (1) | SI3573600T1 (ja) |
TW (1) | TWI793099B (ja) |
WO (1) | WO2018138110A1 (ja) |
ZA (1) | ZA201905487B (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3047492C (en) | 2017-01-25 | 2024-01-02 | Ose Immunotherapeutics | Method for manufacturing a stable emulsion for peptide delivery |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006526628A (ja) * | 2003-04-18 | 2006-11-24 | アイディーエム ファーマ,インコーポレイティド | Hla−a2腫瘍関連抗原ペプチドおよび組成物 |
US20120195962A1 (en) * | 2009-08-18 | 2012-08-02 | Pevion Biotech Ag | Multiepitope Vaccine for Her2/Neu-Associated Cancers |
WO2016070928A1 (en) * | 2014-11-06 | 2016-05-12 | Orphan Synergy Europe - Pharma | Therapeutic multi-peptides t specific immune therapy for treatment of brain metastasis |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0717651A2 (pt) | 2006-10-17 | 2013-12-24 | Oncotherapy Science Inc | Vacinas de peptídeo para cânceres que expressam polipeptídeos mphosph1 ou depdc1 |
TWI615403B (zh) | 2007-02-21 | 2018-02-21 | 腫瘤療法 科學股份有限公司 | 表現腫瘤相關抗原之癌症的胜肽疫苗 |
CA2696701C (en) | 2007-08-20 | 2017-01-24 | Oncotherapy Science, Inc. | Cdca1 peptide and pharmaceutical agent comprising the same |
US20110104101A1 (en) | 2008-03-06 | 2011-05-05 | University Of Medicine And Dentistry Of New Jersey | Immunotherapy for Unresectable Pancreatic Cancer |
NZ592461A (en) | 2008-10-22 | 2012-12-21 | Oncotherapy Science Inc | Rab6kifl/kif20a epitope peptide and vaccines containing the same |
TWI507204B (zh) | 2009-05-26 | 2015-11-11 | Oncotherapy Science Inc | Cdc45l胜肽與含此胜肽之疫苗 |
TW201124530A (en) | 2009-12-01 | 2011-07-16 | Oncotherapy Science Inc | IMP-3 oligopeptides and vaccines including the same |
CN105601727B (zh) | 2010-03-11 | 2020-01-10 | 肿瘤疗法科学股份有限公司 | Hjurp肽及包含它们的疫苗 |
TW201216982A (en) | 2010-10-21 | 2012-05-01 | Oncotherapy Science Inc | WDHD1 peptides and vaccines including the same |
WO2012053200A1 (en) | 2010-10-21 | 2012-04-26 | Oncotherapy Science, Inc. | C18orf54 peptides and vaccines including the same |
KR102004900B1 (ko) | 2010-12-02 | 2019-07-29 | 온코세라피 사이언스 가부시키가이샤 | Tomm34 펩티드 및 이를 포함한 백신 |
TW201302800A (zh) | 2011-06-10 | 2013-01-16 | Oncotherapy Science Inc | Sema5b胜肽及含其之疫苗 |
EP2742133B1 (en) | 2011-08-12 | 2017-10-04 | Oncotherapy Science, Inc. | Mphosph1 peptides and vaccines including the same |
JP6124149B2 (ja) | 2011-10-28 | 2017-05-10 | オンコセラピー・サイエンス株式会社 | Topkペプチドおよびそれを含むワクチン |
PT2785375T (pt) | 2011-11-28 | 2020-10-29 | Merck Patent Gmbh | Anticorpos anti-pd-l1 e usos destes |
JP6283861B2 (ja) | 2012-09-11 | 2018-02-28 | オンコセラピー・サイエンス株式会社 | Ube2tペプチドおよびそれを含むワクチン |
WO2014047085A2 (en) | 2012-09-20 | 2014-03-27 | Rongfu Wang | Prostate-specific tumor antigen and uses thereof |
EP2956164A4 (en) | 2013-02-14 | 2016-08-31 | Immunocellular Therapeutics Ltd | OVARIAN CANCER VACCINES AND IMMUNIZATION METHODS |
WO2014136453A1 (en) | 2013-03-08 | 2014-09-12 | Oncotherapy Science, Inc. | C12orf48 PEPTIDES AND VACCINES CONTAINING THE SAME |
WO2014141652A1 (en) | 2013-03-11 | 2014-09-18 | Oncotherapy Science, Inc. | Smyd3 peptides and vaccines containing the same |
TWI658049B (zh) | 2013-03-12 | 2019-05-01 | 腫瘤療法 科學股份有限公司 | Kntc2胜肽及含此胜肽之疫苗 |
WO2014162962A1 (ja) | 2013-04-01 | 2014-10-09 | 学校法人 久留米大学 | 腫瘍抗原ペプチド |
GB2530236A (en) | 2014-04-11 | 2016-03-23 | Univ Nottingham Trent | PAP Peptide analogues |
AU2015247727A1 (en) | 2014-04-15 | 2016-11-03 | University Of Virginia Patent Foundation | Isolated T cell receptors and methods of use therefor |
EP2944652A1 (en) | 2014-05-13 | 2015-11-18 | Technische Universität München | Glypican-3-specific T-cell receptors and their uses for immunotherapy of hepatocellular carcinoma |
CA2990299C (en) * | 2015-06-29 | 2023-10-10 | Ose Immunotherapeutics | Method for inducing early t memory response with short peptides anti-tumor vaccine |
CA3047492C (en) | 2017-01-25 | 2024-01-02 | Ose Immunotherapeutics | Method for manufacturing a stable emulsion for peptide delivery |
JP6999035B2 (ja) | 2017-11-27 | 2022-01-18 | オーエスイー・イミュノセラピューティクス | 改良されたがんの処置 |
CA3122914A1 (en) | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Bifunctional anti-pd-1/sirp.alpha. molecule |
KR20210107058A (ko) | 2018-12-21 | 2021-08-31 | 오제 이뮈노테라프틱스 | 인간 pd-1에 대항하는 이작용성 분자 |
BR112021012037A2 (pt) | 2018-12-21 | 2021-11-03 | Ose Immunotherapeutics | Molécula anti-pd-1/il-7 bifuncional |
SG11202106347PA (en) | 2018-12-21 | 2021-07-29 | Ose Immunotherapeutics | Humanized anti-human-pd-1 antibody |
-
2018
- 2018-01-24 CA CA3047492A patent/CA3047492C/en active Active
- 2018-01-24 SI SI201830646T patent/SI3573600T1/sl unknown
- 2018-01-24 PL PL18710760T patent/PL3573600T3/pl unknown
- 2018-01-24 DK DK18710760.2T patent/DK3573600T3/da active
- 2018-01-24 MX MX2019008878A patent/MX2019008878A/es unknown
- 2018-01-24 WO PCT/EP2018/051647 patent/WO2018138110A1/en unknown
- 2018-01-24 RS RS20220413A patent/RS63259B1/sr unknown
- 2018-01-24 EP EP18710760.2A patent/EP3573600B1/en active Active
- 2018-01-24 EP EP22153774.9A patent/EP4029494A1/en active Pending
- 2018-01-24 JP JP2019560481A patent/JP7140778B2/ja active Active
- 2018-01-24 KR KR1020197024340A patent/KR102577036B1/ko active IP Right Grant
- 2018-01-24 HR HRP20220605TT patent/HRP20220605T1/hr unknown
- 2018-01-24 ES ES18710760T patent/ES2913268T3/es active Active
- 2018-01-24 LT LTEPPCT/EP2018/051647T patent/LT3573600T/lt unknown
- 2018-01-24 AU AU2018213890A patent/AU2018213890B2/en active Active
- 2018-01-24 BR BR112019014917-1A patent/BR112019014917A2/pt active Search and Examination
- 2018-01-24 CN CN202210293478.2A patent/CN114917189B/zh active Active
- 2018-01-24 US US16/477,534 patent/US11325959B2/en active Active
- 2018-01-24 HU HUE18710760A patent/HUE058717T2/hu unknown
- 2018-01-24 CN CN201880007527.3A patent/CN110191703B/zh active Active
- 2018-01-24 PT PT187107602T patent/PT3573600T/pt unknown
- 2018-01-24 IL IL267237A patent/IL267237B1/en unknown
- 2018-01-25 TW TW107102651A patent/TWI793099B/zh active
- 2018-01-25 AR ARP180100167A patent/AR113209A1/es unknown
-
2019
- 2019-08-20 ZA ZA2019/05487A patent/ZA201905487B/en unknown
-
2022
- 2022-05-04 US US17/736,113 patent/US11981713B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006526628A (ja) * | 2003-04-18 | 2006-11-24 | アイディーエム ファーマ,インコーポレイティド | Hla−a2腫瘍関連抗原ペプチドおよび組成物 |
US20120195962A1 (en) * | 2009-08-18 | 2012-08-02 | Pevion Biotech Ag | Multiepitope Vaccine for Her2/Neu-Associated Cancers |
WO2016070928A1 (en) * | 2014-11-06 | 2016-05-12 | Orphan Synergy Europe - Pharma | Therapeutic multi-peptides t specific immune therapy for treatment of brain metastasis |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Rarokar et al. | Nanostructured cubosomes in a thermoresponsive depot system: an alternative approach for the controlled delivery of docetaxel | |
AU2022221504A1 (en) | Compositions and methods for delivery of biomacromolecule agents | |
US20090263409A1 (en) | Cancer antigen peptide formulations | |
Rodrigues et al. | Characterization of lipid-based hexosomes as versatile vaccine carriers | |
Bobbala et al. | Novel injectable pentablock copolymer based thermoresponsive hydrogels for sustained release vaccines | |
Su et al. | Supramolecular co-assembly of self-adjuvanting nanofibrious peptide hydrogel enhances cancer vaccination by activating MyD88-dependent NF-κB signaling pathway without inflammation | |
US11981713B2 (en) | Method for manufacturing a stable emulsion for peptide delivery | |
JP2017510664A (ja) | 薬剤含有高分子微粒球製造方法 | |
EP3503877A1 (en) | Biodegradable polymer formulations for extended efficacy of botulinum toxin | |
US20220162382A1 (en) | Production of nanoparticles and microparticles | |
Mena-Hernández et al. | Preparation and evaluation of mebendazole microemulsion for intranasal delivery: an alternative approach for glioblastoma treatment | |
CN111093623A (zh) | 药物组合物、使用限定大小的脂质囊泡颗粒的制备方法及其用途 | |
Li et al. | Thermo-sensitive hydrogel-mediated locally sequential release of doxorubicin and palbociclib for chemo-immunotherapy of osteosarcoma | |
Gupta et al. | Nanoparticle formulation having ability to control the release of protein for drug delivery application | |
CN103784938A (zh) | 脉络膜血管新生的疫苗疗法 | |
Xie et al. | Bioresorbable Depot for Sustained Release of Immunostimulatory Resiquimod in Suppressing Both Primary Triple-Negative Breast Tumors and Metastatic Occurrence | |
TWI837189B (zh) | 包含內含藥物之脂質體組成物及鉑製劑之組合醫藥 | |
JP6671141B2 (ja) | 懸濁液剤 | |
JP2008174490A (ja) | 抗原性ペプチドを主成分とする薬剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210115 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220221 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220518 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220815 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220908 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7140778 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |