JP5222134B2 - Her−2ペプチド - Google Patents
Her−2ペプチド Download PDFInfo
- Publication number
- JP5222134B2 JP5222134B2 JP2008517193A JP2008517193A JP5222134B2 JP 5222134 B2 JP5222134 B2 JP 5222134B2 JP 2008517193 A JP2008517193 A JP 2008517193A JP 2008517193 A JP2008517193 A JP 2008517193A JP 5222134 B2 JP5222134 B2 JP 5222134B2
- Authority
- JP
- Japan
- Prior art keywords
- epitope
- chimeric peptide
- peptide
- linker
- sequence
- 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.)
- Active
Links
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 title claims abstract description 180
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims abstract description 178
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 229960005486 vaccine Drugs 0.000 claims abstract description 18
- 108091006116 chimeric peptides Proteins 0.000 claims description 76
- 150000001413 amino acids Chemical class 0.000 claims description 34
- 208000026310 Breast neoplasm Diseases 0.000 claims description 25
- 206010006187 Breast cancer Diseases 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 10
- 230000028993 immune response Effects 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 24
- 230000002018 overexpression Effects 0.000 abstract description 9
- 210000000987 immune system Anatomy 0.000 abstract description 3
- 230000036210 malignancy Effects 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 94
- 210000004027 cell Anatomy 0.000 description 77
- 241000699670 Mus sp. Species 0.000 description 40
- 102000004196 processed proteins & peptides Human genes 0.000 description 36
- 235000001014 amino acid Nutrition 0.000 description 31
- 230000027455 binding Effects 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 28
- 229960000575 trastuzumab Drugs 0.000 description 26
- 241000699666 Mus <mouse, genus> Species 0.000 description 20
- 102000040430 polynucleotide Human genes 0.000 description 16
- 108091033319 polynucleotide Proteins 0.000 description 16
- 239000002157 polynucleotide Substances 0.000 description 16
- 210000003719 b-lymphocyte Anatomy 0.000 description 12
- 230000003053 immunization Effects 0.000 description 12
- 230000002163 immunogen Effects 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- 238000002649 immunization Methods 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229940022353 herceptin Drugs 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 230000005847 immunogenicity Effects 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 238000006664 bond formation reaction Methods 0.000 description 8
- 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 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000283707 Capra Species 0.000 description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- 241000699660 Mus musculus Species 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000011830 transgenic mouse model Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 101100501691 Rattus norvegicus Erbb2 gene Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 229960002087 pertuzumab Drugs 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 239000012981 Hank's balanced salt solution Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000005875 antibody response Effects 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- -1 Leu amino acid Chemical class 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000009260 cross reactivity Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 229940023041 peptide vaccine Drugs 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 238000013519 translation Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011651 chromium Substances 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000010188 recombinant method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- 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 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 238000005515 capillary zone electrophoresis Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229940030156 cell vaccine Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000007796 conventional method 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
- 230000009089 cytolysis Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000008348 humoral response Effects 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- WTKQMHWYSBWUBE-UHFFFAOYSA-N (3-nitropyridin-2-yl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CN=C1SCl WTKQMHWYSBWUBE-UHFFFAOYSA-N 0.000 description 1
- UHPQFNXOFFPHJW-UHFFFAOYSA-N (4-methylphenyl)-phenylmethanamine Chemical compound C1=CC(C)=CC=C1C(N)C1=CC=CC=C1 UHPQFNXOFFPHJW-UHFFFAOYSA-N 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- VUCNQOPCYRJCGQ-UHFFFAOYSA-N 2-[4-(hydroxymethyl)phenoxy]acetic acid Chemical compound OCC1=CC=C(OCC(O)=O)C=C1 VUCNQOPCYRJCGQ-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- HQFLTUZKIRYQSP-UHFFFAOYSA-N 3-ethyl-2h-1,3-benzothiazole-6-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=C2N(CC)CSC2=C1 HQFLTUZKIRYQSP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 238000011603 BDIX rat Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 101150104494 CAV1 gene Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010060123 Conjugate Vaccines Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 102100035149 Cytosolic endo-beta-N-acetylglucosaminidase Human genes 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 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
- 101710144190 Endo-beta-N-acetylglucosaminidase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 206010073094 Intraductal proliferative breast lesion Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-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
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 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
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 229920000057 Mannan Polymers 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000982698 Prorodonopsis coli Species 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101100163901 Rattus norvegicus Asic2 gene Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 239000012722 SDS sample buffer Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 241000701093 Suid alphaherpesvirus 1 Species 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000007097 Urinary Bladder 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
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108010059722 Viral Fusion Proteins Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- WRYNUJYAXVDTCB-UHFFFAOYSA-M acetyloxymercury Chemical compound CC(=O)O[Hg] WRYNUJYAXVDTCB-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical class N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 229960004405 aprotinin 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
- 229910052786 argon Inorganic materials 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
- JTMZBRWRXFAITF-UHFFFAOYSA-N azane;(7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound [NH4+].C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C JTMZBRWRXFAITF-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 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
- 229910021538 borax Inorganic materials 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 239000012267 brine Substances 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
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000001142 circular dichroism spectrum Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940031670 conjugate vaccine Drugs 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001378 electrochemiluminescence detection Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000002523 gelfiltration Methods 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
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment 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
- 102000045108 human EGFR Human genes 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 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 1
- 230000036212 malign transformation Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 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
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 230000036278 prepulse Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 229940076009 protein stimulant Drugs 0.000 description 1
- 229940023143 protein vaccine Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005748 tumor development Effects 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
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- 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
- 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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/82—Translation products from oncogenes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Mycology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Marine Sciences & Fisheries (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
本出願は、2005年6月15日に出願され、表題「HER-2 Peptides」の米国仮出願第60/690,574号(この全体が、本明細書に参考として援用される)への優先権およびあらゆるほかの利益を主張する。
本出願に記載する研究は、少なくとも一部は、米国国立衛生研究所(the National Institute of Health)からの援助 NIH 5ROI CA 84356による支援を受けている。米国連邦政府は、本発明に関して一定の権利を有する。
現在、乳癌治療の最も一般的なアプローチは、手術、化学的介入および/または放射線療法を含む。癌が被定義領域に限定されなければ、手術のみで癌を除去することはできない。それ故、手術部位付近にあり、手術を免れた癌細胞を破壊するために、手術後、放射線治療を施すことが多い。こうした治療の副作用としては、皮膚の過敏性または痒み、免疫系への干渉、時として、吐き気、および希に、肺の患部が繊維性になる放射線肺線維症が挙げられる。化学療法が手術後に用いられることもある。化学療法には、癌細胞に対して傷害性である薬物が用いられる。これは、完全に選択的なシステムではないので、正常な細胞にも影響を及ぼす。負の副作用としては、悪心、疲労、脱毛、食欲不振および下痢が挙げられる。
Hudziak,R.M.ら、Mol.Cell.Biol.,1989,9:11−65−72 Tagliabue,E.ら、Int.J.Cancer,1991,47:933−7 Drebin,J.A.ら、Proc.Natil.Acad.Scie.USA,1986,83:9129−33 Drebin,J.A.ら、Oncogene,1988,2:273−7 Katsumata,M.ら、Nat.Med.,1995,1:644−8. Baselga,J.ら、J.Clin.Oncol.,1996,14:737−44 Pegram,M.D.ら、J.Clin.Oncol.,1988,16:2659−71 Bernards,R.ら、Proc.Natl.Acad.Sci.USA,1987,84:6854−8 Gu,X.G.ら、Cancer Res.,1998,58:3385−90 Esserman,L.J.,Cancer Immunol.Immunother.,1999,47:337−42 Cefai.D.ら、Int.J.Cancer,1999,83:393−400
実施形態に従って、HER−2 Bエピトープを提供する。該エピトープは、
さて、本発明の特定の実施形態を随時参照しながら本発明を説明する。しかし、本発明は、種々の形態で具体化することができ、本明細書に記載する実施形態に限定されると解釈すべきではない。むしろ、これらの実施形態は、本開示が、詳細、且つ、完全になるように、ならびに当業者に本発明の範囲を十分に知らせるために提供するものである。
免疫化および動物。雌ニュージーランド白ウサギを、Mochican Valley Rabbitry(オハイオ州、Loudenville)から入手した。ウサギを、CFA中で乳化させた合計1gのペプチドで、多数の部位に皮下免疫した。初回免疫の3および6週間後、続いてブースター注射(PBS中、1mgおよび500μg)を施した。血清を採取し、30分間、56℃に加熱することにより補体を不活性化した。血清アリコートを−5から−15℃で保管した。抗体を硫酸アンモニウム沈殿法によって精製した:硫酸アンモニウム飽和溶液(SAS)の保存溶液を調製し、オートクレーブで処理し、4℃に冷却した。冷室内で攪拌しながら35% v/vまでSASをゆっくりと添加することにより、抗体を沈殿させた。サンプルを14,000×gで20分間、遠心分離し、上清を−20℃で保存した。1/2原体積のペレットを0.1M PBSで溶解した。その後、画分をSlide−a−lyzerカセット(Pierce)内に配置し、>200体積のpH8の0.15M NaClの頻繁な交換により透析した。数滴の0.1M NaOHでその食塩水をpH8にした。IgG濃度を、放射免疫拡散(RID)(英国、The Binding Site)により決定した。モノクローナル抗体は、Oncogene Scienceから購入した。
2つの天然ジスルフィド結合が組み込まれている配座HER−2細胞エピトープは、強化された腫瘍細胞結合を示す。
新規HER−2 B細胞エピトープの設計および合成
表1に示すような4つの新規構築物を合成のために選択した。4つすべての構築物が、トラスツズマブと接触する3つの領域のうちの少なくとも1つの領域を含有する。HER−2 Bエピトープを、MVFプロミスカスThエピトープと共直線的に合成した。ペプチド合成は、Fmoc/t−But化学を用いて行った。エピトープ563−598についての3つのジスルフィド結合の形成は、図2に示す差次的保護システイン残基を使用して達成した。第一のジスルフィド結合は、ヨウ素酸化を用いて形成する。水の添加により、Acm除去、およびC567とC584の間のジスルフィド結合の付随的形成を増進する。C563とC576の間の最後のジスルフィド結合は、シリルクロライド−スルホキシド法を用いて形成する。
HER−2ペプチドの免疫原性
表1に記載した4つの構築物の免疫原性は、ジスルフィド結合構築物と線状構築物の両方を使用し、FBV/nマウス(n=4〜9)週齢6〜8週の群に免疫することにより判定した。563−598環化および非環化構築物の両方が、高度に免疫原性であった(図3A)。第三回免疫の3週後には、すべてのマウスが、120,000より高い力価を有し、環化構築物(MVF563SS)での2匹のマウスは、250,000より高い力価を有した。585−598構築物は、最小の免疫原性であることが判明し(図3B)、第三回免疫の3週間後、環化(SS)群と線状(NC)群の両方からの1匹のマウスだけが、120,000より高い力価を有し、平均力価は、約58,000であった。597−626ペプチド構築物と613−626ペプチド構築物の両方が、高度に免疫原性であった(図3C、D)。環化形の597−626を受けた3匹のマウスは、120,000より高い力価を有したが、線状形を受けたいずれのマウスも、120,000より高い力価を有さなかった。
ヘルセプチン結合ペプチドとヘルセプチン(トラスツズマブ)の交差反応性
ELISAにより、トラスツズマブ結合部位からの配座ペプチドがヘルセプチンを認識できるかどうかを試験した。図4に示すように、563−626の結合領域内の様々なペプチドが、トラスツズマブと結合した。最大の結合は、3つのジスルフィド対合を有する環化エピトープ563−598で発生した。この結果は、グリコシル化に起因するHER−2への抗体のFACS結合とは対照的である。
ペプチド抗体とHER−2タンパク質の交差反応性
ヘルセプチン−ペプチドエピトープにより惹起された抗体が、HER−2受容体を認識するそれらの能力に差を示すかどうかを判定するために、HER−2過剰発現ヒト乳癌細胞系統BT474へのFBV/n精製抗体の結合を試験した。図5C、Dは、597−626構築物と613−626構築物の両方が、正常マウス抗体に比べてシフトしていることを示している。しかし、563−598および585−598構築物は、正常マウス抗体と比較して殆どシフトを示さなかった(図5A、B)。563−598は、HER−2がトラスツズマブと共に作る3つの構築物のうちの2つを含有する。トラスツズマブとの最後の接点を含む597−626エピトープは、天然タンパク質を認識する11のアミノ酸から成る(図5C)。この配列613−626のさらに短いバージョンも、同様に天然タンパク質を認識する(図5D)。エピトープ563−598および585−598の認識の欠如についての尤もらしい説明は、残基571−573に潜在的グリコシル化部位(NGS)があり、その大きな嵩高い糖部分が立体的に干渉し、そのエピトープの結合を妨げるということである。
腫瘍攻撃
B細胞エピトープワクチンへの配座拘束の導入に随伴する潜在的な臨床的利点をさらに良好に理解するために、FVB/nマウスとneu−Nトランスジェニックマウスの両方を、neu−Nトランスジェニックマウスから単離した自然発生***腫瘍から採取した腫瘍細胞系統NT2.5で攻撃した。neu過剰発現の結果として、これらのマウスは、ヒト乳癌患者において観察されるものと同様の様式で自然発生乳腺癌を発症し、従って、ヒト乳癌研究の適するモデルである。FVB/nマウスの群を、最終免疫の2週間後に5×106のNT2.5細胞で皮下攻撃した(下腹部)。第55日まで週に2度、腫瘍測定を行った。腫瘍体積は、(長いほうの測定値×短いほうの測定値2)/2の式によって計算した。第30日の後、FBV/nマウスの腫瘍は退縮し始める(これは、腫瘍の拒絶を示す)ことに留意すること。FBV/nマウスを使用するその後の腫瘍研究に関しては、第30日まで腫瘍を測定した。563−598NCおよびSS構築物で免疫したマウスは、第30日に、それぞれ、166.517および173.7292mm3の平均腫瘍体積を有し、一方、免疫しなかったマウスは、346.6563mm3の平均腫瘍体積を有した(データは示さない)。第33日には、613−626および585−598CYCで免疫したマウスは、免疫しなかったマウスとMVFで免疫したマウスの両方と比較して、腫瘍体積の低減を示した。トラスツズマブB細胞エピトープで免疫したマウスの腫瘍負荷の低減の点で何らかの適度な成功があるように見えるが、ほぼすべてのマウスが腫瘍を発症した。
新規ペルツズマブ結合配座B細胞エピトープの設計および評価
表2に記載する3つのペプチド配列は、ペルツズマブ結合部位に類似した抗体を惹起する最小配列をさらに描写するために設計した。これらの複合配座ペプチドエピトープを合成し、首尾よく精製し、適正なジスルフィド対合で環化した。エピトープ266−296(Cys268−Cys295間のSH結合)、エピトープ298−333(Cys299−Cys311間のSH結合)およびエピトープ315−333(Cys315−Cys331間のSH結合)により、最小ペルツズマブ結合エピトープを描写することができよう。
Claims (26)
- 第2のキメラペプチドをさらに含む請求項1に記載の組成物であって、該第2のキメラペプチドは、HER−2Bエピトープと、Thエピトープと、該HER−2Bエピトープを該Thエピトープに連結するリンカーとを含み、第2のキメラペプチドの該HER−2
Bエピトープは、請求項1に記載のキメラペプチドのHER−2Bエピトープとは異なる、組成物。 - 前記HER−2 Bエピトープのうちの少なくとも1つ、前記Thエピトープまたは前記リンカーが、レトロ−インベルソ形である、請求項1に記載の組成物。
- 前記リンカーが、2から15個のアミノ酸を含む、請求項1に記載の組成物。
- 前記被験者が、ヒトであり、かつ乳癌、卵巣癌、肺癌、前立腺癌および大腸癌のうちの1つを有する、または乳癌、卵巣癌、肺癌、前立腺癌および大腸癌のうちの1つについての素因を有する、請求項9に記載の組成物。
- 前記癌が、乳癌である、請求項10に記載の組成物。
- 前記医薬組成物が、キメラペプチドの混合物をさらに含み;
該混合物が、2つまたはそれ以上のキメラペプチドを含み;および
該2つまたはそれ以上のキメラペプチドの各々が、前記HER−2 Bエピトープと、前記Tヘルパー(Th)エピトープと、該HER−2 Bエピトープを該Thエピトープに連結する前記リンカーとを含み、該2つまたはそれ以上のキメラペプチドの各々のHER−2 Bエピトープが、互いに異なる、
請求項9に記載の組成物。 - 少なくとも1つの追加のHER−2 Bエピトープと、Tヘルパー(Th)エピトープと、該追加のHER−2 Bエピトープを該Thエピトープに連結するリンカーとをさらに含み、該少なくとも1つの追加のHER−2 Bエピトープが、前記HER−2 Bエピトープとは異なる、請求項13に記載のワクチン。
- 第2のキメラペプチドをさらに含む請求項13に記載のワクチンであって、該第2のキメラペプチドは、HER−2Bエピトープと、Thエピトープと該HER−2Bエピトープを該Thエピトープに連結するリンカーとを含み、第2のキメラペプチドの該HER−2
Bエピトープは、請求項1に記載のHER−2Bエピトープとは異なる、ワクチン。 - 前記リンカーは2〜15アミノ酸を含む、請求項13に記載のワクチン。
- 第2のキメラペプチドをさらに含む請求項8に記載の組成物であって、該第2のキメラペプチドは、HER−2Bエピトープと、Thエピトープと該HER−2Bエピトープを該Thエピトープに連結するリンカーとを含み、第2のキメラペプチドの該HER−2 Bエピトープは、請求項8に記載のHER−2Bエピトープとは異なる、組成物。
- 前記リンカーは2〜15アミノ酸を含む、請求項8に記載の組成物。
- 第2のキメラペプチドをさらに含む請求項9に記載の医薬組成物であって、該第2のキメラペプチドは、HER−2Bエピトープと、Thエピトープと該HER−2Bエピトープを該Thエピトープに連結するリンカーとを含み、第2のキメラペプチドの該HER−2
Bエピトープは、請求項9に記載のHER−2Bエピトープとは異なる、医薬組成物。 - 前記リンカーが、2から15個のアミノ酸を含む、請求項9に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US69057405P | 2005-06-15 | 2005-06-15 | |
US60/690,574 | 2005-06-15 | ||
PCT/US2006/023672 WO2006138675A2 (en) | 2005-06-15 | 2006-06-15 | Her-2 peptides |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012093680A Division JP5542865B2 (ja) | 2005-06-15 | 2012-04-17 | Her−2ペプチド |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2009500298A JP2009500298A (ja) | 2009-01-08 |
JP2009500298A5 JP2009500298A5 (ja) | 2009-07-30 |
JP5222134B2 true JP5222134B2 (ja) | 2013-06-26 |
Family
ID=37571268
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008517193A Active JP5222134B2 (ja) | 2005-06-15 | 2006-06-15 | Her−2ペプチド |
JP2012093680A Active JP5542865B2 (ja) | 2005-06-15 | 2012-04-17 | Her−2ペプチド |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012093680A Active JP5542865B2 (ja) | 2005-06-15 | 2012-04-17 | Her−2ペプチド |
Country Status (7)
Country | Link |
---|---|
US (3) | US7691396B2 (ja) |
EP (1) | EP1912680B1 (ja) |
JP (2) | JP5222134B2 (ja) |
AU (1) | AU2006261342B2 (ja) |
CA (1) | CA2612394C (ja) |
ES (1) | ES2531483T3 (ja) |
WO (1) | WO2006138675A2 (ja) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7060284B1 (en) * | 1999-08-03 | 2006-06-13 | The Ohio State University | Polypeptides and polynucleotides for enhancing immune reactivity to HER-2 protein |
ES2531483T3 (es) | 2005-06-15 | 2015-03-16 | The Ohio State University Research Foundation | Péptidos HER-2 |
US8945573B2 (en) * | 2005-09-08 | 2015-02-03 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Targeted identification of immunogenic peptides |
WO2008097229A1 (en) * | 2007-02-09 | 2008-08-14 | The Government Of The Usa As Represented By The Secretary Of The Dept. Of Health And Human Services | Method for spectroscopic quantitation of her-2 in biological samples |
KR20110008227A (ko) * | 2008-04-22 | 2011-01-26 | 케메탈 푸테 코포레이션 | 고순도 수산화리튬 및 염화수소산의 제조 방법 |
US20100234283A1 (en) | 2009-02-04 | 2010-09-16 | The Ohio State University Research Foundation | Immunogenic epitopes, peptidomimetics, and anti-peptide antibodies, and methods of their use |
US9125848B2 (en) | 2010-06-10 | 2015-09-08 | The Cleveland Clinic Foundation | Alpha lactalbumin immunization methods |
KR101893473B1 (ko) * | 2010-09-28 | 2018-08-30 | 노노 인코포레이티드 | 신경계 질병을 치료하는 nd2 펩티드 및 방법 |
JP2015520129A (ja) * | 2012-04-16 | 2015-07-16 | ザ クリーブランド クリニック ファウンデーション | 多価乳がんワクチン |
WO2014131019A2 (en) | 2013-02-25 | 2014-08-28 | Ohio State Innovation Foundation | Her-1, her-3 and igf-1r compositions and uses thereof |
CN105017425B (zh) * | 2014-04-30 | 2018-02-16 | 京天成生物技术(北京)有限公司 | 抗her2中和活性单克隆抗体及其应用 |
US20180327453A1 (en) * | 2015-11-06 | 2018-11-15 | Evorx Technologies, Inc. | Her-2-specific cyclized supr peptides |
WO2018145020A1 (en) | 2017-02-03 | 2018-08-09 | The Medical College Of Wisconsin, Inc. | Kras peptide vaccine compositions and method of use |
EP3600398B1 (en) * | 2017-03-28 | 2023-09-13 | Ohio State Innovation Foundation | Human pd1 peptide vaccines and uses thereof |
US20200179500A1 (en) * | 2018-12-05 | 2020-06-11 | Wayne State University | Methods and immunogenic compositions relating to her2 with selective sequence modifications |
WO2020191434A1 (en) * | 2019-03-22 | 2020-10-01 | Olivia Newton-John Cancer Research Institute | Anti-her2 binding molecules |
WO2023161526A1 (en) | 2022-02-28 | 2023-08-31 | Tridem Bioscience Gmbh & Co Kg | A CONJUGATE CONSISTING OF OR COMPRISING AT LEAST A ß-GLUCAN OR A MANNAN |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989006692A1 (en) * | 1988-01-12 | 1989-07-27 | Genentech, Inc. | Method of treating tumor cells by inhibiting growth factor receptor function |
EP0474727B1 (en) * | 1989-05-19 | 1997-07-23 | Genentech, Inc. | Her2 extracellular domain |
ES2070492T3 (es) * | 1990-01-26 | 1995-06-01 | Washington Res Found | Reactividad inmunitaria para oncogenes expresados activos para diagnostico y tratamiento de estados malignos. |
IL101943A0 (en) * | 1991-05-24 | 1992-12-30 | Genentech Inc | Structure,production and use of heregulin |
DE69327599T2 (de) | 1992-06-25 | 2000-08-10 | Smithkline Beecham Biolog | Adjuvantien enthaltende Impfstoffzusammensetzung |
ES2225825T3 (es) | 1992-09-28 | 2005-03-16 | Wyeth Holdings Corporation | Procedimiento de mejora de las respuestas inmunitarias mediadas por celulas. |
CA2145391A1 (en) | 1992-09-30 | 1994-04-14 | Vernon C. Stevens | Vaccines and antigenic conjugates |
US5801005A (en) * | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) * | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
EP1167377B2 (en) | 1994-07-15 | 2012-08-08 | University of Iowa Research Foundation | Immunomodulatory oligonucleotides |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
US6410022B1 (en) | 1995-05-01 | 2002-06-25 | Avant Immunotherapeutics, Inc. | Modulation of cholesteryl ester transfer protein (CETP) activity |
NZ331596A (en) | 1996-04-03 | 1999-07-29 | Pepresearch A S | Non-dendritic backbone peptide carrier |
EP1106183A3 (en) | 1996-10-18 | 2001-09-12 | Genentech, Inc. | Antibodies to erbB2 and their therapeutic uses |
CN1181422A (zh) * | 1996-10-31 | 1998-05-13 | 上海市肿瘤研究所 | 与生长因子受体结合的多肽所构建的基因转移载体 |
JP2001513369A (ja) | 1997-08-11 | 2001-09-04 | アラーガン・セイルズ・インコーポレイテッド | 改善された生物適合性を有する無菌の生物侵食性の移植デバイスおよび方法 |
ZA9811162B (en) | 1997-12-12 | 2000-06-07 | Genentech Inc | Treatment with anti-ERBB2 antibodies. |
EP0953823A2 (en) | 1998-05-01 | 1999-11-03 | Aisin Cosmos R & D Co. Ltd. | Micro yaw rate sensors |
WO2000034337A1 (en) | 1998-12-10 | 2000-06-15 | Tsukuba Research Laboratory, Toagosei Co., Ltd. | Humanized monoclonal antibodies against vascular endothelial cell growth factor |
SI1187632T1 (sl) * | 1999-05-14 | 2009-04-30 | Genentech Inc | Zdravljenje z anti-ErbB2 protitelesi |
US7060284B1 (en) * | 1999-08-03 | 2006-06-13 | The Ohio State University | Polypeptides and polynucleotides for enhancing immune reactivity to HER-2 protein |
US20030235594A1 (en) * | 1999-09-14 | 2003-12-25 | Antigen Express, Inc. | Ii-Key/antigenic epitope hybrid peptide vaccines |
US6432409B1 (en) * | 1999-09-14 | 2002-08-13 | Antigen Express, Inc. | Hybrid peptides modulate the immune response |
US20020193329A1 (en) * | 2000-08-14 | 2002-12-19 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of Her-2/neu-associated malignancies |
GB0213878D0 (en) * | 2002-06-17 | 2002-07-31 | Protherics Plc | Use |
WO2004030616A2 (en) * | 2002-09-17 | 2004-04-15 | Antigen Express, Inc. | Ii-KEY/ANTIGENIC EPITOPE HYBRID PEPTIDE VACCINES |
PT1601770E (pt) * | 2003-03-04 | 2009-12-07 | Intercell Ag | Antigénios de streptococcus pyogenes |
AU2004249340B2 (en) * | 2003-06-25 | 2011-04-21 | Ottawa Hospital Research Institute | Use of cardiotrophin to modulate stem cell proliferation |
ATE474589T1 (de) * | 2003-10-29 | 2010-08-15 | Univ Ramot | Angiogene peptide und ihre verwendungen |
ES2541779T3 (es) | 2004-02-05 | 2015-07-24 | The Ohio State University Research Foundation | Péptidos VEGF quiméricos |
SE527089C2 (sv) | 2004-10-19 | 2005-12-20 | Mia Kumm | Anordning och system för ventilation av tunnel vid brand |
RU2007127719A (ru) * | 2004-12-20 | 2009-01-27 | Адзиномото Ко., Инк. (Jp) | Мутантный белок, имеющий пептидсинтезирующую активность |
ES2531483T3 (es) * | 2005-06-15 | 2015-03-16 | The Ohio State University Research Foundation | Péptidos HER-2 |
US20100234283A1 (en) * | 2009-02-04 | 2010-09-16 | The Ohio State University Research Foundation | Immunogenic epitopes, peptidomimetics, and anti-peptide antibodies, and methods of their use |
JP5510272B2 (ja) | 2010-06-21 | 2014-06-04 | 株式会社リコー | 画像形成装置 |
-
2006
- 2006-06-15 ES ES06785065.1T patent/ES2531483T3/es active Active
- 2006-06-15 US US11/424,526 patent/US7691396B2/en active Active
- 2006-06-15 CA CA2612394A patent/CA2612394C/en active Active
- 2006-06-15 WO PCT/US2006/023672 patent/WO2006138675A2/en active Application Filing
- 2006-06-15 AU AU2006261342A patent/AU2006261342B2/en active Active
- 2006-06-15 EP EP06785065.1A patent/EP1912680B1/en active Active
- 2006-06-15 JP JP2008517193A patent/JP5222134B2/ja active Active
-
2010
- 2010-02-01 US US12/697,578 patent/US8470333B2/en active Active
-
2012
- 2012-04-17 JP JP2012093680A patent/JP5542865B2/ja active Active
-
2013
- 2013-05-30 US US13/905,996 patent/US9452204B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
WO2006138675A2 (en) | 2006-12-28 |
ES2531483T3 (es) | 2015-03-16 |
JP2009500298A (ja) | 2009-01-08 |
AU2006261342B2 (en) | 2012-02-02 |
US20140010831A1 (en) | 2014-01-09 |
WO2006138675A9 (en) | 2010-01-28 |
US8470333B2 (en) | 2013-06-25 |
US20110086055A1 (en) | 2011-04-14 |
EP1912680A4 (en) | 2010-09-22 |
EP1912680B1 (en) | 2014-11-26 |
US9452204B2 (en) | 2016-09-27 |
JP2012136555A (ja) | 2012-07-19 |
US20070060516A1 (en) | 2007-03-15 |
CA2612394A1 (en) | 2006-12-28 |
CA2612394C (en) | 2017-02-21 |
AU2006261342A1 (en) | 2006-12-28 |
JP5542865B2 (ja) | 2014-07-09 |
US7691396B2 (en) | 2010-04-06 |
EP1912680A2 (en) | 2008-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5222134B2 (ja) | Her−2ペプチド | |
JP4658423B2 (ja) | Her−2タンパク質に対する免疫反応性を増強するためのポリペプチドおよびポリヌクレオチド | |
US10166276B2 (en) | Compositions and methods for treatment of non-hodgkins lymphoma | |
KR100731820B1 (ko) | 치료적 백신화를 위한 새로운 방법 | |
US10800834B2 (en) | HER-1, HER-3 and IGF-1R compositions and uses thereof | |
US9504738B2 (en) | Immunogenic epitopes, peptidomimetics, and anti-peptide antibodies, and methods of their use | |
US8080253B2 (en) | Chimeric VEGF peptides | |
AU766898B2 (en) | Tumor associated antigen 791Tgp72 | |
JP2003529370A (ja) | 血管浸透性に対する有害な作用を有さないve−カドヘリンに対する拮抗薬抗体 | |
US20080107662A1 (en) | Immunogenic Peptides, Nucleic Acids Encoding The Same And Use Thereof In Cancer Treatment And Diagnosis | |
US7485621B2 (en) | Tumor tag and the use thereof | |
US20210253646A1 (en) | Vaccine vector encoding mutated gnaq for treatment of uveal melanoma and cancers having oncogenic mutations on gnaq and gna11 proteins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090601 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090601 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090713 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20090713 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20111017 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120112 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120119 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120417 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121023 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130116 |
|
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: 20130212 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130308 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160315 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 5222134 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |