CN112585163A - 靶向磷脂酰肌醇蛋白聚糖-2的高亲和力单克隆抗体及其用途 - Google Patents
靶向磷脂酰肌醇蛋白聚糖-2的高亲和力单克隆抗体及其用途 Download PDFInfo
- Publication number
- CN112585163A CN112585163A CN201980053942.7A CN201980053942A CN112585163A CN 112585163 A CN112585163 A CN 112585163A CN 201980053942 A CN201980053942 A CN 201980053942A CN 112585163 A CN112585163 A CN 112585163A
- Authority
- CN
- China
- Prior art keywords
- antibody
- antigen
- seq
- binding fragment
- monoclonal antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108050001154 Glypican Proteins 0.000 title claims abstract description 127
- 108050009388 Glypican-2 Proteins 0.000 title claims abstract description 120
- 230000008685 targeting Effects 0.000 title description 24
- 102000001992 Glypican-2 Human genes 0.000 title 1
- 230000027455 binding Effects 0.000 claims abstract description 167
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 144
- 239000000427 antigen Substances 0.000 claims abstract description 144
- 108091007433 antigens Proteins 0.000 claims abstract description 144
- 102000036639 antigens Human genes 0.000 claims abstract description 144
- 239000012634 fragment Substances 0.000 claims abstract description 128
- 102000010956 Glypican Human genes 0.000 claims abstract description 126
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims abstract description 111
- 206010029260 Neuroblastoma Diseases 0.000 claims abstract description 38
- 208000000172 Medulloblastoma Diseases 0.000 claims abstract description 18
- 201000000582 Retinoblastoma Diseases 0.000 claims abstract description 17
- 210000004027 cell Anatomy 0.000 claims description 134
- 150000007523 nucleic acids Chemical class 0.000 claims description 95
- 102000039446 nucleic acids Human genes 0.000 claims description 88
- 108020004707 nucleic acids Proteins 0.000 claims description 88
- 239000003814 drug Substances 0.000 claims description 76
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 73
- 201000011510 cancer Diseases 0.000 claims description 64
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 57
- 229940079593 drug Drugs 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 56
- 239000000611 antibody drug conjugate Substances 0.000 claims description 53
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 53
- 239000002105 nanoparticle Substances 0.000 claims description 51
- 108090000623 proteins and genes Proteins 0.000 claims description 51
- 102000004169 proteins and genes Human genes 0.000 claims description 50
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 claims description 44
- 229940127121 immunoconjugate Drugs 0.000 claims description 40
- 239000012636 effector Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 39
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 32
- 239000000562 conjugate Substances 0.000 claims description 29
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 claims description 27
- 230000014509 gene expression Effects 0.000 claims description 27
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 claims description 26
- 229940127089 cytotoxic agent Drugs 0.000 claims description 25
- 239000002502 liposome Substances 0.000 claims description 24
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 23
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 21
- 239000013598 vector Substances 0.000 claims description 21
- 102000004190 Enzymes Human genes 0.000 claims description 19
- 108090000790 Enzymes Proteins 0.000 claims description 19
- 239000003053 toxin Substances 0.000 claims description 19
- 231100000765 toxin Toxicity 0.000 claims description 19
- 108700012359 toxins Proteins 0.000 claims description 19
- 239000002254 cytotoxic agent Substances 0.000 claims description 18
- 230000011664 signaling Effects 0.000 claims description 18
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 15
- 108020001507 fusion proteins Proteins 0.000 claims description 15
- 102000037865 fusion proteins Human genes 0.000 claims description 15
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 11
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 11
- 208000008743 Desmoplastic Small Round Cell Tumor Diseases 0.000 claims description 11
- 206010064581 Desmoplastic small round cell tumour Diseases 0.000 claims description 11
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 11
- 206010065867 alveolar rhabdomyosarcoma Diseases 0.000 claims description 11
- 230000003834 intracellular effect Effects 0.000 claims description 11
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 9
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 9
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 9
- 208000011654 childhood malignant neoplasm Diseases 0.000 claims description 9
- 239000000693 micelle Substances 0.000 claims description 9
- 201000008968 osteosarcoma Diseases 0.000 claims description 9
- 102000016355 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Human genes 0.000 claims description 8
- 108010092372 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Proteins 0.000 claims description 8
- 206010027476 Metastases Diseases 0.000 claims description 8
- 230000009401 metastasis Effects 0.000 claims description 8
- 239000002088 nanocapsule Substances 0.000 claims description 8
- 239000002077 nanosphere Substances 0.000 claims description 8
- 229940044684 anti-microtubule agent Drugs 0.000 claims description 7
- 239000000412 dendrimer Substances 0.000 claims description 7
- 229920000736 dendritic polymer Polymers 0.000 claims description 7
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 claims description 7
- 108091008874 T cell receptors Proteins 0.000 claims description 6
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 6
- 238000001574 biopsy Methods 0.000 claims description 6
- 230000000139 costimulatory effect Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000004614 tumor growth Effects 0.000 claims description 6
- 239000003080 antimitotic agent Substances 0.000 claims description 5
- 230000004068 intracellular signaling Effects 0.000 claims description 5
- 102000005962 receptors Human genes 0.000 claims description 4
- 108020003175 receptors Proteins 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 claims description 3
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 claims description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 2
- 230000020411 cell activation Effects 0.000 claims description 2
- 230000002637 immunotoxin Effects 0.000 abstract description 45
- 229940051026 immunotoxin Drugs 0.000 abstract description 45
- 239000002596 immunotoxin Substances 0.000 abstract description 45
- 231100000608 immunotoxin Toxicity 0.000 abstract description 45
- 101000654403 Escherichia phage lambda Capsid assembly protease C Proteins 0.000 description 86
- 102100023849 Glycophorin-C Human genes 0.000 description 86
- 101000905336 Homo sapiens Glycophorin-C Proteins 0.000 description 86
- 102100025933 Cancer-associated gene 1 protein Human genes 0.000 description 83
- 235000018102 proteins Nutrition 0.000 description 47
- 102000004196 processed proteins & peptides Human genes 0.000 description 37
- 238000011282 treatment Methods 0.000 description 35
- 210000001519 tissue Anatomy 0.000 description 34
- 210000001744 T-lymphocyte Anatomy 0.000 description 33
- 229920001184 polypeptide Polymers 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 28
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 27
- 239000000523 sample Substances 0.000 description 27
- -1 radioisotopes Chemical class 0.000 description 24
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 23
- 229940024606 amino acid Drugs 0.000 description 23
- 150000001413 amino acids Chemical class 0.000 description 23
- 230000001225 therapeutic effect Effects 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 229940088598 enzyme Drugs 0.000 description 18
- 229940124597 therapeutic agent Drugs 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 17
- 239000002773 nucleotide Substances 0.000 description 16
- 125000003729 nucleotide group Chemical group 0.000 description 16
- 210000004881 tumor cell Anatomy 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 239000012472 biological sample Substances 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 230000000670 limiting effect Effects 0.000 description 13
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 12
- 102000016607 Diphtheria Toxin Human genes 0.000 description 12
- 108010053187 Diphtheria Toxin Proteins 0.000 description 12
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 12
- 239000002246 antineoplastic agent Substances 0.000 description 12
- 230000001472 cytotoxic effect Effects 0.000 description 11
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 10
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 10
- 231100000433 cytotoxic Toxicity 0.000 description 10
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 210000000952 spleen Anatomy 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 9
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 9
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 9
- 125000000524 functional group Chemical group 0.000 description 9
- 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 9
- 238000011580 nude mouse model Methods 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 238000010186 staining Methods 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 230000002285 radioactive effect Effects 0.000 description 8
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 8
- 229960004641 rituximab Drugs 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 7
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 238000003364 immunohistochemistry Methods 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 230000005291 magnetic effect Effects 0.000 description 7
- 239000003550 marker Substances 0.000 description 7
- 229920002857 polybutadiene Polymers 0.000 description 7
- 108010026333 seryl-proline Proteins 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 6
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 6
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 6
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 6
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 6
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 6
- 108010087924 alanylproline Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 229960002685 biotin Drugs 0.000 description 6
- 235000020958 biotin Nutrition 0.000 description 6
- 239000011616 biotin Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229960004679 doxorubicin Drugs 0.000 description 6
- 238000012377 drug delivery Methods 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 6
- 108010051242 phenylalanylserine Proteins 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 108010061238 threonyl-glycine Proteins 0.000 description 6
- 238000012384 transportation and delivery Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 5
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 5
- IICZCLFBILYRCU-WHFBIAKZSA-N Asn-Gly-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IICZCLFBILYRCU-WHFBIAKZSA-N 0.000 description 5
- KMCRKVOLRCOMBG-DJFWLOJKSA-N Asn-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KMCRKVOLRCOMBG-DJFWLOJKSA-N 0.000 description 5
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 5
- 102220644534 Cytoglobin_T2A_mutation Human genes 0.000 description 5
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 5
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 5
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 5
- VZSDQFZFTCVEGF-ZEWNOJEFSA-N Ile-Phe-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O VZSDQFZFTCVEGF-ZEWNOJEFSA-N 0.000 description 5
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 5
- QQUJSUFWEDZQQY-AVGNSLFASA-N Lys-Gln-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN QQUJSUFWEDZQQY-AVGNSLFASA-N 0.000 description 5
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 5
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 5
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 5
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 5
- 108010047495 alanylglycine Proteins 0.000 description 5
- 229960000548 alemtuzumab Drugs 0.000 description 5
- 229940045799 anthracyclines and related substance Drugs 0.000 description 5
- 108010008355 arginyl-glutamine Proteins 0.000 description 5
- 108010044540 auristatin Proteins 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 5
- 229930195731 calicheamicin Natural products 0.000 description 5
- 229960005395 cetuximab Drugs 0.000 description 5
- 230000009089 cytolysis Effects 0.000 description 5
- 239000002619 cytotoxin Substances 0.000 description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 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
- 230000004927 fusion Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 5
- 108010089804 glycyl-threonine Proteins 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 238000003018 immunoassay Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 108010057821 leucylproline Proteins 0.000 description 5
- 108010038320 lysylphenylalanine Proteins 0.000 description 5
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 5
- 125000006850 spacer group Chemical group 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 5
- 108010051110 tyrosyl-lysine Proteins 0.000 description 5
- 108010073969 valyllysine Proteins 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- AXAVXPMQTGXXJZ-UHFFFAOYSA-N 2-aminoacetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(O)=O.OCC(N)(CO)CO AXAVXPMQTGXXJZ-UHFFFAOYSA-N 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 4
- 108090001008 Avidin Proteins 0.000 description 4
- 241000251730 Chondrichthyes Species 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 4
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 4
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 4
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 4
- 101001014664 Homo sapiens Glypican-2 Proteins 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 108010065920 Insulin Lispro Proteins 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 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 4
- 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 4
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 108010090804 Streptavidin Proteins 0.000 description 4
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 4
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 4
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 4
- RZAGEHHVNYESNR-RNXOBYDBSA-N Tyr-Trp-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RZAGEHHVNYESNR-RNXOBYDBSA-N 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 238000001516 cell proliferation assay Methods 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 239000013068 control sample Substances 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 239000003431 cross linking reagent Substances 0.000 description 4
- 229960000975 daunorubicin Drugs 0.000 description 4
- 238000002405 diagnostic procedure Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 108010078144 glutaminyl-glycine Proteins 0.000 description 4
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 4
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 4
- 108010015792 glycyllysine Proteins 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 102000054842 human GPC2 Human genes 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000002147 killing effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 229950010159 nemorubicin Drugs 0.000 description 4
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 108010031719 prolyl-serine Proteins 0.000 description 4
- 238000003127 radioimmunoassay Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000010361 transduction Methods 0.000 description 4
- 230000026683 transduction Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- LGNCNVVZCUVPOT-FUVGGWJZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-methoxy-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 LGNCNVVZCUVPOT-FUVGGWJZSA-N 0.000 description 3
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(3r,4s,5s)-1-[(2s)-2-[(1r,2r)-3-[[(1s,2r)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 description 3
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 3
- 108010066676 Abrin Proteins 0.000 description 3
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 3
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 3
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 3
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 3
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 3
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 3
- 108030001720 Bontoxilysin Proteins 0.000 description 3
- 241000282832 Camelidae Species 0.000 description 3
- 108091026890 Coding region Proteins 0.000 description 3
- 239000004971 Cross linker Substances 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 101710112752 Cytotoxin Proteins 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 3
- LVNILKSSFHCSJZ-IHRRRGAJSA-N Gln-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LVNILKSSFHCSJZ-IHRRRGAJSA-N 0.000 description 3
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 3
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 3
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 3
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 3
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 3
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 3
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 3
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 3
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 3
- 108091005461 Nucleic proteins Proteins 0.000 description 3
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 3
- KWMZPPWYBVZIER-XGEHTFHBSA-N Pro-Ser-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWMZPPWYBVZIER-XGEHTFHBSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 102000016611 Proteoglycans Human genes 0.000 description 3
- 108010067787 Proteoglycans Proteins 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 108010039491 Ricin Proteins 0.000 description 3
- QGMLKFGTGXWAHF-IHRRRGAJSA-N Ser-Arg-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGMLKFGTGXWAHF-IHRRRGAJSA-N 0.000 description 3
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 3
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 3
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 3
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 3
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 3
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 3
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 3
- WNZRNOGHEONFMS-PXDAIIFMSA-N Trp-Ile-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WNZRNOGHEONFMS-PXDAIIFMSA-N 0.000 description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 3
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 108010005233 alanylglutamic acid Proteins 0.000 description 3
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 229940127093 camptothecin Drugs 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 3
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 3
- 239000005090 green fluorescent protein Substances 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000012933 kinetic analysis Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 229910052747 lanthanoid Inorganic materials 0.000 description 3
- 150000002602 lanthanoids Chemical class 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 3
- 231100001160 nonlethal Toxicity 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 229960003171 plicamycin Drugs 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 231100000167 toxic agent Toxicity 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229950007217 tremelimumab Drugs 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- GBABOYUKABKIAF-GHYRFKGUSA-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-GHYRFKGUSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 2
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 2
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 description 2
- SLURUCSFDHKXFR-WWMWMSKMSA-N (7s,9s)-7-[[(1s,3r,4as,9s,9ar,10as)-9-methoxy-1-methyl-3,4,4a,6,7,9,9a,10a-octahydro-1h-pyrano[1,2][1,3]oxazolo[3,4-b][1,4]oxazin-3-yl]oxy]-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=CC=CC(OC)=C2C(=O)C(C(O)=C23)=C1C(O)=C3C[C@@](O)(C(=O)CO)C[C@@H]2O[C@H]1C[C@@H]2N3CCO[C@H](OC)[C@H]3O[C@@H]2[C@H](C)O1 SLURUCSFDHKXFR-WWMWMSKMSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 2
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 2
- MVBWLRJESQOQTM-ACZMJKKPSA-N Ala-Gln-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O MVBWLRJESQOQTM-ACZMJKKPSA-N 0.000 description 2
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 2
- JDIQCVUDDFENPU-ZKWXMUAHSA-N Ala-His-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CNC=N1 JDIQCVUDDFENPU-ZKWXMUAHSA-N 0.000 description 2
- LXAARTARZJJCMB-CIQUZCHMSA-N Ala-Ile-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LXAARTARZJJCMB-CIQUZCHMSA-N 0.000 description 2
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 2
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 2
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 2
- KRQSPVKUISQQFS-FJXKBIBVSA-N Arg-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N KRQSPVKUISQQFS-FJXKBIBVSA-N 0.000 description 2
- YKZJPIPFKGYHKY-DCAQKATOSA-N Arg-Leu-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKZJPIPFKGYHKY-DCAQKATOSA-N 0.000 description 2
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 2
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 2
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 2
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 2
- WHLDJYNHXOMGMU-JYJNAYRXSA-N Arg-Val-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 WHLDJYNHXOMGMU-JYJNAYRXSA-N 0.000 description 2
- ANAHQDPQQBDOBM-UHFFFAOYSA-N Arg-Val-Tyr Natural products CC(C)C(NC(=O)C(N)CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O ANAHQDPQQBDOBM-UHFFFAOYSA-N 0.000 description 2
- CTQIOCMSIJATNX-WHFBIAKZSA-N Asn-Gly-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O CTQIOCMSIJATNX-WHFBIAKZSA-N 0.000 description 2
- DDPXDCKYWDGZAL-BQBZGAKWSA-N Asn-Gly-Arg Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N DDPXDCKYWDGZAL-BQBZGAKWSA-N 0.000 description 2
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 2
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 2
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 2
- OMMIEVATLAGRCK-BYPYZUCNSA-N Asp-Gly-Gly Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)NCC(O)=O OMMIEVATLAGRCK-BYPYZUCNSA-N 0.000 description 2
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 2
- BPHKULHWEIUDOB-FXQIFTODSA-N Cys-Gln-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BPHKULHWEIUDOB-FXQIFTODSA-N 0.000 description 2
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- DXMPMSWUZVNBSG-QEJZJMRPSA-N Gln-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N DXMPMSWUZVNBSG-QEJZJMRPSA-N 0.000 description 2
- RKAQZCDMSUQTSS-FXQIFTODSA-N Gln-Asp-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RKAQZCDMSUQTSS-FXQIFTODSA-N 0.000 description 2
- QKCZZAZNMMVICF-DCAQKATOSA-N Gln-Leu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O QKCZZAZNMMVICF-DCAQKATOSA-N 0.000 description 2
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 2
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 2
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 2
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 2
- NLKVNZUFDPWPNL-YUMQZZPRSA-N Glu-Arg-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O NLKVNZUFDPWPNL-YUMQZZPRSA-N 0.000 description 2
- KKCUFHUTMKQQCF-SRVKXCTJSA-N Glu-Arg-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O KKCUFHUTMKQQCF-SRVKXCTJSA-N 0.000 description 2
- PCBBLFVHTYNQGG-LAEOZQHASA-N Glu-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N PCBBLFVHTYNQGG-LAEOZQHASA-N 0.000 description 2
- OXEMJGCAJFFREE-FXQIFTODSA-N Glu-Gln-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O OXEMJGCAJFFREE-FXQIFTODSA-N 0.000 description 2
- LYCDZGLXQBPNQU-WDSKDSINSA-N Glu-Gly-Cys Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CS)C(O)=O LYCDZGLXQBPNQU-WDSKDSINSA-N 0.000 description 2
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 2
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 2
- TWYFJOHWGCCRIR-DCAQKATOSA-N Glu-Pro-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYFJOHWGCCRIR-DCAQKATOSA-N 0.000 description 2
- UDEPRBFQTWGLCW-CIUDSAMLSA-N Glu-Pro-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O UDEPRBFQTWGLCW-CIUDSAMLSA-N 0.000 description 2
- RGJKYNUINKGPJN-RWRJDSDZSA-N Glu-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(=O)O)N RGJKYNUINKGPJN-RWRJDSDZSA-N 0.000 description 2
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 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
- OGCIHJPYKVSMTE-YUMQZZPRSA-N Gly-Arg-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O OGCIHJPYKVSMTE-YUMQZZPRSA-N 0.000 description 2
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 2
- JSNNHGHYGYMVCK-XVKPBYJWSA-N Gly-Glu-Val Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O JSNNHGHYGYMVCK-XVKPBYJWSA-N 0.000 description 2
- UFPXDFOYHVEIPI-BYPYZUCNSA-N Gly-Gly-Asp Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O UFPXDFOYHVEIPI-BYPYZUCNSA-N 0.000 description 2
- FXGRXIATVXUAHO-WEDXCCLWSA-N Gly-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN FXGRXIATVXUAHO-WEDXCCLWSA-N 0.000 description 2
- JJGBXTYGTKWGAT-YUMQZZPRSA-N Gly-Pro-Glu Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O JJGBXTYGTKWGAT-YUMQZZPRSA-N 0.000 description 2
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 2
- KBBFOULZCHWGJX-KBPBESRZSA-N Gly-Tyr-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)CN)O KBBFOULZCHWGJX-KBPBESRZSA-N 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101000589301 Homo sapiens Natural cytotoxicity triggering receptor 1 Proteins 0.000 description 2
- 101000589305 Homo sapiens Natural cytotoxicity triggering receptor 2 Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 101000777646 Homo sapiens Uncharacterized protein encoded by LINC01587 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- KIAOPHMUNPPGEN-PEXQALLHSA-N Ile-Gly-His Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KIAOPHMUNPPGEN-PEXQALLHSA-N 0.000 description 2
- PFPUFNLHBXKPHY-HTFCKZLJSA-N Ile-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)O)N PFPUFNLHBXKPHY-HTFCKZLJSA-N 0.000 description 2
- NPAYJTAXWXJKLO-NAKRPEOUSA-N Ile-Met-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N NPAYJTAXWXJKLO-NAKRPEOUSA-N 0.000 description 2
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- MMEDVBWCMGRKKC-GARJFASQSA-N Leu-Asp-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N MMEDVBWCMGRKKC-GARJFASQSA-N 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 2
- DZQMXBALGUHGJT-GUBZILKMSA-N Leu-Glu-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O DZQMXBALGUHGJT-GUBZILKMSA-N 0.000 description 2
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 2
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 2
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 2
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 2
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 2
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 2
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 2
- YLMIDMSLKLRNHX-HSCHXYMDSA-N Leu-Trp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YLMIDMSLKLRNHX-HSCHXYMDSA-N 0.000 description 2
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 2
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YORIKIDJCPKBON-YUMQZZPRSA-N Met-Glu-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YORIKIDJCPKBON-YUMQZZPRSA-N 0.000 description 2
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 101100337459 Mus musculus Gpc2 gene Proteins 0.000 description 2
- 108010046068 N-Acetyllactosamine Synthase Proteins 0.000 description 2
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical group CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 2
- 108010047562 NGR peptide Proteins 0.000 description 2
- 102100032851 Natural cytotoxicity triggering receptor 2 Human genes 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- QPVFUAUFEBPIPT-CDMKHQONSA-N Phe-Gly-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O QPVFUAUFEBPIPT-CDMKHQONSA-N 0.000 description 2
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 2
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 2
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 2
- 108010004729 Phycoerythrin Proteins 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 2
- OCSACVPBMIYNJE-GUBZILKMSA-N Pro-Arg-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O OCSACVPBMIYNJE-GUBZILKMSA-N 0.000 description 2
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 2
- XKHCJJPNXFBADI-DCAQKATOSA-N Pro-Asp-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O XKHCJJPNXFBADI-DCAQKATOSA-N 0.000 description 2
- DEDANIDYQAPTFI-IHRRRGAJSA-N Pro-Asp-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O DEDANIDYQAPTFI-IHRRRGAJSA-N 0.000 description 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 2
- XQSREVQDGCPFRJ-STQMWFEESA-N Pro-Gly-Phe Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XQSREVQDGCPFRJ-STQMWFEESA-N 0.000 description 2
- HAEGAELAYWSUNC-WPRPVWTQSA-N Pro-Gly-Val Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HAEGAELAYWSUNC-WPRPVWTQSA-N 0.000 description 2
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 2
- MCWHYUWXVNRXFV-RWMBFGLXSA-N Pro-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 MCWHYUWXVNRXFV-RWMBFGLXSA-N 0.000 description 2
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 2
- QUBVFEANYYWBTM-VEVYYDQMSA-N Pro-Thr-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUBVFEANYYWBTM-VEVYYDQMSA-N 0.000 description 2
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 2
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 2
- KNZQGAUEYZJUSQ-ZLUOBGJFSA-N Ser-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N KNZQGAUEYZJUSQ-ZLUOBGJFSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 2
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 2
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 2
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 2
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 2
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 2
- OGXQLUCMJZSJPW-LYSGOOTNSA-N Trp-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O OGXQLUCMJZSJPW-LYSGOOTNSA-N 0.000 description 2
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 2
- SGFIXFAHVWJKTD-KJEVXHAQSA-N Tyr-Arg-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SGFIXFAHVWJKTD-KJEVXHAQSA-N 0.000 description 2
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 2
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- 102100031590 Uncharacterized protein encoded by LINC01587 Human genes 0.000 description 2
- IQQYYFPCWKWUHW-YDHLFZDLSA-N Val-Asn-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N IQQYYFPCWKWUHW-YDHLFZDLSA-N 0.000 description 2
- BRPKEERLGYNCNC-NHCYSSNCSA-N Val-Glu-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N BRPKEERLGYNCNC-NHCYSSNCSA-N 0.000 description 2
- JZWZACGUZVCQPS-RNJOBUHISA-N Val-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N JZWZACGUZVCQPS-RNJOBUHISA-N 0.000 description 2
- QPPZEDOTPZOSEC-RCWTZXSCSA-N Val-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](C(C)C)N)O QPPZEDOTPZOSEC-RCWTZXSCSA-N 0.000 description 2
- MJOUSKQHAIARKI-JYJNAYRXSA-N Val-Phe-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 MJOUSKQHAIARKI-JYJNAYRXSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 230000001946 anti-microtubular Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940125644 antibody drug Drugs 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 108010068380 arginylarginine Proteins 0.000 description 2
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 2
- 108010093581 aspartyl-proline Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 102000005936 beta-Galactosidase Human genes 0.000 description 2
- 238000005415 bioluminescence Methods 0.000 description 2
- 230000029918 bioluminescence Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 238000002619 cancer immunotherapy Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 208000025997 central nervous system neoplasm Diseases 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000005081 chemiluminescent agent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 238000011961 computed axial tomography Methods 0.000 description 2
- 239000000599 controlled substance Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229960004397 cyclophosphamide Drugs 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
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- 229940039227 diagnostic agent Drugs 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 2
- 229930188854 dolastatin Natural products 0.000 description 2
- 229960005501 duocarmycin Drugs 0.000 description 2
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 2
- 229930184221 duocarmycin Natural products 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 229950001109 galiximab Drugs 0.000 description 2
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 2
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 2
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 108010036413 histidylglycine Proteins 0.000 description 2
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 108010034529 leucyl-lysine Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 125000005439 maleimidyl group Chemical class C1(C=CC(N1*)=O)=O 0.000 description 2
- 229950001869 mapatumumab Drugs 0.000 description 2
- 229950008001 matuzumab Drugs 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical class CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 229950010203 nimotuzumab Drugs 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 150000002482 oligosaccharides Polymers 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 229940127084 other anti-cancer agent Drugs 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229950010773 pidilizumab Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 108010025826 prolyl-leucyl-arginine Proteins 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 108010071207 serylmethionine Proteins 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000000779 thoracic wall Anatomy 0.000 description 2
- 229950004742 tigatuzumab Drugs 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 108010084932 tryptophyl-proline Proteins 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 2
- LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 1
- ZADWXFSZEAPBJS-SNVBAGLBSA-N (2r)-2-amino-3-(1-methylindol-3-yl)propanoic acid Chemical compound C1=CC=C2N(C)C=C(C[C@@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-SNVBAGLBSA-N 0.000 description 1
- KYYLBTDGVAUNBT-VANKVMQKSA-N (2r,3s,4s,5r)-2-azido-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@](O)(C=O)N=[N+]=[N-] KYYLBTDGVAUNBT-VANKVMQKSA-N 0.000 description 1
- PKOHVHWNGUHYRE-ZFWWWQNUSA-N (2s)-1-[2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)NCC(=O)N1CCC[C@H]1C(O)=O PKOHVHWNGUHYRE-ZFWWWQNUSA-N 0.000 description 1
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical compound SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- 206010000077 Abdominal mass Diseases 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 1
- WJRXVTCKASUIFF-FXQIFTODSA-N Ala-Cys-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WJRXVTCKASUIFF-FXQIFTODSA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- FBHOPGDGELNWRH-DRZSPHRISA-N Ala-Glu-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FBHOPGDGELNWRH-DRZSPHRISA-N 0.000 description 1
- ZPXCNXMJEZKRLU-LSJOCFKGSA-N Ala-His-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 ZPXCNXMJEZKRLU-LSJOCFKGSA-N 0.000 description 1
- LBFXVAXPDOBRKU-LKTVYLICSA-N Ala-His-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LBFXVAXPDOBRKU-LKTVYLICSA-N 0.000 description 1
- XCZXVTHYGSMQGH-NAKRPEOUSA-N Ala-Ile-Met Chemical compound C[C@H]([NH3+])C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C([O-])=O XCZXVTHYGSMQGH-NAKRPEOUSA-N 0.000 description 1
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 1
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 1
- PEIBBAXIKUAYGN-UBHSHLNASA-N Ala-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 PEIBBAXIKUAYGN-UBHSHLNASA-N 0.000 description 1
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- XQNRANMFRPCFFW-GCJQMDKQSA-N Ala-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C)N)O XQNRANMFRPCFFW-GCJQMDKQSA-N 0.000 description 1
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 1
- ISCYZXFOCXWUJU-KZVJFYERSA-N Ala-Thr-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O ISCYZXFOCXWUJU-KZVJFYERSA-N 0.000 description 1
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 1
- QRIYOHQJRDHFKF-UWJYBYFXSA-N Ala-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 QRIYOHQJRDHFKF-UWJYBYFXSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 101000878595 Arabidopsis thaliana Squalene synthase 1 Proteins 0.000 description 1
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 1
- DCGLNNVKIZXQOJ-FXQIFTODSA-N Arg-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N DCGLNNVKIZXQOJ-FXQIFTODSA-N 0.000 description 1
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 1
- TTXYKSADPSNOIF-IHRRRGAJSA-N Arg-Asp-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O TTXYKSADPSNOIF-IHRRRGAJSA-N 0.000 description 1
- YSUVMPICYVWRBX-VEVYYDQMSA-N Arg-Asp-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YSUVMPICYVWRBX-VEVYYDQMSA-N 0.000 description 1
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 1
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 1
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- HAVKMRGWNXMCDR-STQMWFEESA-N Arg-Gly-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HAVKMRGWNXMCDR-STQMWFEESA-N 0.000 description 1
- ZATRYQNPUHGXCU-DTWKUNHWSA-N Arg-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZATRYQNPUHGXCU-DTWKUNHWSA-N 0.000 description 1
- VRZDJJWOFXMFRO-ZFWWWQNUSA-N Arg-Gly-Trp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O VRZDJJWOFXMFRO-ZFWWWQNUSA-N 0.000 description 1
- UBCPNBUIQNMDNH-NAKRPEOUSA-N Arg-Ile-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O UBCPNBUIQNMDNH-NAKRPEOUSA-N 0.000 description 1
- NVUIWHJLPSZZQC-CYDGBPFRSA-N Arg-Ile-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NVUIWHJLPSZZQC-CYDGBPFRSA-N 0.000 description 1
- UZGFHWIJWPUPOH-IHRRRGAJSA-N Arg-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UZGFHWIJWPUPOH-IHRRRGAJSA-N 0.000 description 1
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 1
- PAPSMOYMQDWIOR-AVGNSLFASA-N Arg-Lys-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O PAPSMOYMQDWIOR-AVGNSLFASA-N 0.000 description 1
- MNBHKGYCLBUIBC-UFYCRDLUSA-N Arg-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCNC(N)=N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MNBHKGYCLBUIBC-UFYCRDLUSA-N 0.000 description 1
- XSPKAHFVDKRGRL-DCAQKATOSA-N Arg-Pro-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XSPKAHFVDKRGRL-DCAQKATOSA-N 0.000 description 1
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
- VUGWHBXPMAHEGZ-SRVKXCTJSA-N Arg-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N VUGWHBXPMAHEGZ-SRVKXCTJSA-N 0.000 description 1
- WCZXPVPHUMYLMS-VEVYYDQMSA-N Arg-Thr-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O WCZXPVPHUMYLMS-VEVYYDQMSA-N 0.000 description 1
- WOZDCBHUGJVJPL-AVGNSLFASA-N Arg-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N WOZDCBHUGJVJPL-AVGNSLFASA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 1
- GJFYPBDMUGGLFR-NKWVEPMBSA-N Asn-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC(=O)N)N)C(=O)O GJFYPBDMUGGLFR-NKWVEPMBSA-N 0.000 description 1
- UHGUKCOQUNPSKK-CIUDSAMLSA-N Asn-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N UHGUKCOQUNPSKK-CIUDSAMLSA-N 0.000 description 1
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 1
- KYQJHBWHRASMKG-ZLUOBGJFSA-N Asn-Ser-Cys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O KYQJHBWHRASMKG-ZLUOBGJFSA-N 0.000 description 1
- MYTHOBCLNIOFBL-SRVKXCTJSA-N Asn-Ser-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MYTHOBCLNIOFBL-SRVKXCTJSA-N 0.000 description 1
- KTDWFWNZLLFEFU-KKUMJFAQSA-N Asn-Tyr-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O KTDWFWNZLLFEFU-KKUMJFAQSA-N 0.000 description 1
- DXHINQUXBZNUCF-MELADBBJSA-N Asn-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O DXHINQUXBZNUCF-MELADBBJSA-N 0.000 description 1
- HPNDBHLITCHRSO-WHFBIAKZSA-N Asp-Ala-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)NCC(O)=O HPNDBHLITCHRSO-WHFBIAKZSA-N 0.000 description 1
- PBVLJOIPOGUQQP-CIUDSAMLSA-N Asp-Ala-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O PBVLJOIPOGUQQP-CIUDSAMLSA-N 0.000 description 1
- KVMPVNGOKHTUHZ-GCJQMDKQSA-N Asp-Ala-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KVMPVNGOKHTUHZ-GCJQMDKQSA-N 0.000 description 1
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- MUWDILPCTSMUHI-ZLUOBGJFSA-N Asp-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)C(=O)O MUWDILPCTSMUHI-ZLUOBGJFSA-N 0.000 description 1
- PJERDVUTUDZPGX-ZKWXMUAHSA-N Asp-Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CC(O)=O PJERDVUTUDZPGX-ZKWXMUAHSA-N 0.000 description 1
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 1
- WBDWQKRLTVCDSY-WHFBIAKZSA-N Asp-Gly-Asp Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O WBDWQKRLTVCDSY-WHFBIAKZSA-N 0.000 description 1
- BIVYLQMZPHDUIH-WHFBIAKZSA-N Asp-Gly-Cys Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)C(=O)O BIVYLQMZPHDUIH-WHFBIAKZSA-N 0.000 description 1
- QCVXMEHGFUMKCO-YUMQZZPRSA-N Asp-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O QCVXMEHGFUMKCO-YUMQZZPRSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- PYXXJFRXIYAESU-PCBIJLKTSA-N Asp-Ile-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PYXXJFRXIYAESU-PCBIJLKTSA-N 0.000 description 1
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 1
- FQHBAQLBIXLWAG-DCAQKATOSA-N Asp-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N FQHBAQLBIXLWAG-DCAQKATOSA-N 0.000 description 1
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 1
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 1
- HJZLUGQGJWXJCJ-CIUDSAMLSA-N Asp-Pro-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O HJZLUGQGJWXJCJ-CIUDSAMLSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- ZQFRDAZBTSFGGW-SRVKXCTJSA-N Asp-Ser-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZQFRDAZBTSFGGW-SRVKXCTJSA-N 0.000 description 1
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 1
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 101000669426 Aspergillus restrictus Ribonuclease mitogillin Proteins 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 229940125565 BMS-986016 Drugs 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 102100035337 Bone marrow proteoglycan Human genes 0.000 description 1
- 101710134771 Bone marrow proteoglycan Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- PRVVCRZLTJNPCS-FXQIFTODSA-N Cys-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N PRVVCRZLTJNPCS-FXQIFTODSA-N 0.000 description 1
- OIMUAKUQOUEPCZ-WHFBIAKZSA-N Cys-Asn-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIMUAKUQOUEPCZ-WHFBIAKZSA-N 0.000 description 1
- YKKHFPGOZXQAGK-QWRGUYRKSA-N Cys-Gly-Tyr Chemical compound SC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YKKHFPGOZXQAGK-QWRGUYRKSA-N 0.000 description 1
- XVLMKWWVBNESPX-XVYDVKMFSA-N Cys-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CS)N XVLMKWWVBNESPX-XVYDVKMFSA-N 0.000 description 1
- RRJOQIBQVZDVCW-SRVKXCTJSA-N Cys-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CS)N RRJOQIBQVZDVCW-SRVKXCTJSA-N 0.000 description 1
- WTNLLMQAFPOCTJ-GARJFASQSA-N Cys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CS)N)C(=O)O WTNLLMQAFPOCTJ-GARJFASQSA-N 0.000 description 1
- XLLSMEFANRROJE-GUBZILKMSA-N Cys-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N XLLSMEFANRROJE-GUBZILKMSA-N 0.000 description 1
- ABLQPNMKLMFDQU-BIIVOSGPSA-N Cys-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CS)N)C(=O)O ABLQPNMKLMFDQU-BIIVOSGPSA-N 0.000 description 1
- ALNKNYKSZPSLBD-ZDLURKLDSA-N Cys-Thr-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ALNKNYKSZPSLBD-ZDLURKLDSA-N 0.000 description 1
- WTXCNOPZMQRTNN-BWBBJGPYSA-N Cys-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)O WTXCNOPZMQRTNN-BWBBJGPYSA-N 0.000 description 1
- MHYHLWUGWUBUHF-GUBZILKMSA-N Cys-Val-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N MHYHLWUGWUBUHF-GUBZILKMSA-N 0.000 description 1
- DGQJGBDBFVGLGL-ZKWXMUAHSA-N Cys-Val-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N DGQJGBDBFVGLGL-ZKWXMUAHSA-N 0.000 description 1
- 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 1
- 230000004543 DNA replication Effects 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- XPDXVDYUQZHFPV-UHFFFAOYSA-N Dansyl Chloride Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(Cl)(=O)=O XPDXVDYUQZHFPV-UHFFFAOYSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- JHKFWJUVTLNOJZ-UHFFFAOYSA-N Dolabellin Natural products COC(=O)C1=CSC(C(OC(=O)C(C)C(CCCC(C)(Cl)Cl)OC(=O)C=2N=C(SC=2)C(O)CO)C(C)C)=N1 JHKFWJUVTLNOJZ-UHFFFAOYSA-N 0.000 description 1
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108091092566 Extrachromosomal DNA Proteins 0.000 description 1
- 102100035427 Forkhead box protein O1 Human genes 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- INKFLNZBTSNFON-CIUDSAMLSA-N Gln-Ala-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O INKFLNZBTSNFON-CIUDSAMLSA-N 0.000 description 1
- TWHDOEYLXXQYOZ-FXQIFTODSA-N Gln-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N TWHDOEYLXXQYOZ-FXQIFTODSA-N 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 1
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 1
- LGIKBBLQVSWUGK-DCAQKATOSA-N Gln-Leu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LGIKBBLQVSWUGK-DCAQKATOSA-N 0.000 description 1
- CAXXTYYGFYTBPV-IUCAKERBSA-N Gln-Leu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CAXXTYYGFYTBPV-IUCAKERBSA-N 0.000 description 1
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 1
- UESYBOXFJWJVSB-AVGNSLFASA-N Gln-Phe-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O UESYBOXFJWJVSB-AVGNSLFASA-N 0.000 description 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- MQJDLNRXBOELJW-KKUMJFAQSA-N Gln-Pro-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O MQJDLNRXBOELJW-KKUMJFAQSA-N 0.000 description 1
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 1
- OACQOWPRWGNKTP-AVGNSLFASA-N Gln-Tyr-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O OACQOWPRWGNKTP-AVGNSLFASA-N 0.000 description 1
- UQKVUFGUSVYJMQ-IRIUXVKKSA-N Gln-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCC(=O)N)N)O UQKVUFGUSVYJMQ-IRIUXVKKSA-N 0.000 description 1
- VDMABHYXBULDGN-LAEOZQHASA-N Gln-Val-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O VDMABHYXBULDGN-LAEOZQHASA-N 0.000 description 1
- SDSMVVSHLAAOJL-UKJIMTQDSA-N Gln-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N SDSMVVSHLAAOJL-UKJIMTQDSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- RDDSZZJOKDVPAE-ACZMJKKPSA-N Glu-Asn-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDDSZZJOKDVPAE-ACZMJKKPSA-N 0.000 description 1
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 1
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 1
- XKPOCESCRTVRPL-KBIXCLLPSA-N Glu-Cys-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XKPOCESCRTVRPL-KBIXCLLPSA-N 0.000 description 1
- RQNYYRHRKSVKAB-GUBZILKMSA-N Glu-Cys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O RQNYYRHRKSVKAB-GUBZILKMSA-N 0.000 description 1
- QQLBPVKLJBAXBS-FXQIFTODSA-N Glu-Glu-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QQLBPVKLJBAXBS-FXQIFTODSA-N 0.000 description 1
- PXXGVUVQWQGGIG-YUMQZZPRSA-N Glu-Gly-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N PXXGVUVQWQGGIG-YUMQZZPRSA-N 0.000 description 1
- OAGVHWYIBZMWLA-YFKPBYRVSA-N Glu-Gly-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(O)=O OAGVHWYIBZMWLA-YFKPBYRVSA-N 0.000 description 1
- ZHNHJYYFCGUZNQ-KBIXCLLPSA-N Glu-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O ZHNHJYYFCGUZNQ-KBIXCLLPSA-N 0.000 description 1
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 1
- PJBVXVBTTFZPHJ-GUBZILKMSA-N Glu-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N PJBVXVBTTFZPHJ-GUBZILKMSA-N 0.000 description 1
- DNPCBMNFQVTHMA-DCAQKATOSA-N Glu-Leu-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O DNPCBMNFQVTHMA-DCAQKATOSA-N 0.000 description 1
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 1
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 1
- KXTAGESXNQEZKB-DZKIICNBSA-N Glu-Phe-Val Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 KXTAGESXNQEZKB-DZKIICNBSA-N 0.000 description 1
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-N 0.000 description 1
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 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
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- PYTZFYUXZZHOAD-WHFBIAKZSA-N Gly-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CN PYTZFYUXZZHOAD-WHFBIAKZSA-N 0.000 description 1
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 1
- CLODWIOAKCSBAN-BQBZGAKWSA-N Gly-Arg-Asp Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O CLODWIOAKCSBAN-BQBZGAKWSA-N 0.000 description 1
- JPXNYFOHTHSREU-UWVGGRQHSA-N Gly-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN JPXNYFOHTHSREU-UWVGGRQHSA-N 0.000 description 1
- OVSKVOOUFAKODB-UWVGGRQHSA-N Gly-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OVSKVOOUFAKODB-UWVGGRQHSA-N 0.000 description 1
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 1
- OCDLPQDYTJPWNG-YUMQZZPRSA-N Gly-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN OCDLPQDYTJPWNG-YUMQZZPRSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 1
- LXXLEUBUOMCAMR-NKWVEPMBSA-N Gly-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)CN)C(=O)O LXXLEUBUOMCAMR-NKWVEPMBSA-N 0.000 description 1
- TZOVVRJYUDETQG-RCOVLWMOSA-N Gly-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN TZOVVRJYUDETQG-RCOVLWMOSA-N 0.000 description 1
- XXGQRGQPGFYECI-WDSKDSINSA-N Gly-Cys-Glu Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(O)=O XXGQRGQPGFYECI-WDSKDSINSA-N 0.000 description 1
- CEXINUGNTZFNRY-BYPYZUCNSA-N Gly-Cys-Gly Chemical compound [NH3+]CC(=O)N[C@@H](CS)C(=O)NCC([O-])=O CEXINUGNTZFNRY-BYPYZUCNSA-N 0.000 description 1
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 1
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 1
- QPDUVFSVVAOUHE-XVKPBYJWSA-N Gly-Gln-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)CN)C(O)=O QPDUVFSVVAOUHE-XVKPBYJWSA-N 0.000 description 1
- MOJKRXIRAZPZLW-WDSKDSINSA-N Gly-Glu-Ala Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MOJKRXIRAZPZLW-WDSKDSINSA-N 0.000 description 1
- ZQIMMEYPEXIYBB-IUCAKERBSA-N Gly-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN ZQIMMEYPEXIYBB-IUCAKERBSA-N 0.000 description 1
- LHRXAHLCRMQBGJ-RYUDHWBXSA-N Gly-Glu-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN LHRXAHLCRMQBGJ-RYUDHWBXSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- NSTUFLGQJCOCDL-UWVGGRQHSA-N Gly-Leu-Arg Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NSTUFLGQJCOCDL-UWVGGRQHSA-N 0.000 description 1
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- LLWQVJNHMYBLLK-CDMKHQONSA-N Gly-Thr-Phe Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LLWQVJNHMYBLLK-CDMKHQONSA-N 0.000 description 1
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 235000005612 Grewia tenax Nutrition 0.000 description 1
- 244000041633 Grewia tenax Species 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000123599 Hemiscylliidae Species 0.000 description 1
- HDXNWVLQSQFJOX-SRVKXCTJSA-N His-Arg-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HDXNWVLQSQFJOX-SRVKXCTJSA-N 0.000 description 1
- MWXBCJKQRQFVOO-DCAQKATOSA-N His-Cys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CN=CN1)N MWXBCJKQRQFVOO-DCAQKATOSA-N 0.000 description 1
- UPGJWSUYENXOPV-HGNGGELXSA-N His-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N UPGJWSUYENXOPV-HGNGGELXSA-N 0.000 description 1
- CHZRWFUGWRTUOD-IUCAKERBSA-N His-Gly-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N CHZRWFUGWRTUOD-IUCAKERBSA-N 0.000 description 1
- NQKRILCJYCASDV-QWRGUYRKSA-N His-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 NQKRILCJYCASDV-QWRGUYRKSA-N 0.000 description 1
- LJUIEESLIAZSFR-SRVKXCTJSA-N His-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N LJUIEESLIAZSFR-SRVKXCTJSA-N 0.000 description 1
- FCPSGEVYIVXPPO-QTKMDUPCSA-N His-Thr-Arg Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FCPSGEVYIVXPPO-QTKMDUPCSA-N 0.000 description 1
- ZNTSGDNUITWTRA-WDSOQIARSA-N His-Trp-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O ZNTSGDNUITWTRA-WDSOQIARSA-N 0.000 description 1
- WSAILOWUJZEAGC-DCAQKATOSA-N His-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N WSAILOWUJZEAGC-DCAQKATOSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 101000877727 Homo sapiens Forkhead box protein O1 Proteins 0.000 description 1
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 1
- 101001040711 Homo sapiens Glypican-5 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- WZPIKDWQVRTATP-SYWGBEHUSA-N Ile-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 WZPIKDWQVRTATP-SYWGBEHUSA-N 0.000 description 1
- FVEWRQXNISSYFO-ZPFDUUQYSA-N Ile-Arg-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N FVEWRQXNISSYFO-ZPFDUUQYSA-N 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- CWJQMCPYXNVMBS-STECZYCISA-N Ile-Arg-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N CWJQMCPYXNVMBS-STECZYCISA-N 0.000 description 1
- QYZYJFXHXYUZMZ-UGYAYLCHSA-N Ile-Asn-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N QYZYJFXHXYUZMZ-UGYAYLCHSA-N 0.000 description 1
- UKTUOMWSJPXODT-GUDRVLHUSA-N Ile-Asn-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N UKTUOMWSJPXODT-GUDRVLHUSA-N 0.000 description 1
- NKRJALPCDNXULF-BYULHYEWSA-N Ile-Asp-Gly Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O NKRJALPCDNXULF-BYULHYEWSA-N 0.000 description 1
- ZDNORQNHCJUVOV-KBIXCLLPSA-N Ile-Gln-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O ZDNORQNHCJUVOV-KBIXCLLPSA-N 0.000 description 1
- OONBGFHNQVSUBF-KBIXCLLPSA-N Ile-Gln-Cys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(O)=O OONBGFHNQVSUBF-KBIXCLLPSA-N 0.000 description 1
- WNQKUUQIVDDAFA-ZPFDUUQYSA-N Ile-Gln-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N WNQKUUQIVDDAFA-ZPFDUUQYSA-N 0.000 description 1
- LPXHYGGZJOCAFR-MNXVOIDGSA-N Ile-Glu-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N LPXHYGGZJOCAFR-MNXVOIDGSA-N 0.000 description 1
- MQFGXJNSUJTXDT-QSFUFRPTSA-N Ile-Gly-Ile Chemical compound N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)O MQFGXJNSUJTXDT-QSFUFRPTSA-N 0.000 description 1
- LWWILHPVAKKLQS-QXEWZRGKSA-N Ile-Gly-Met Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)O)N LWWILHPVAKKLQS-QXEWZRGKSA-N 0.000 description 1
- UAQSZXGJGLHMNV-XEGUGMAKSA-N Ile-Gly-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N UAQSZXGJGLHMNV-XEGUGMAKSA-N 0.000 description 1
- TVYWVSJGSHQWMT-AJNGGQMLSA-N Ile-Leu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N TVYWVSJGSHQWMT-AJNGGQMLSA-N 0.000 description 1
- RQQCJTLBSJMVCR-DSYPUSFNSA-N Ile-Leu-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RQQCJTLBSJMVCR-DSYPUSFNSA-N 0.000 description 1
- XDUVMJCBYUKNFJ-MXAVVETBSA-N Ile-Lys-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N XDUVMJCBYUKNFJ-MXAVVETBSA-N 0.000 description 1
- LRAUKBMYHHNADU-DKIMLUQUSA-N Ile-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)CC)CC1=CC=CC=C1 LRAUKBMYHHNADU-DKIMLUQUSA-N 0.000 description 1
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 1
- YBKKLDBBPFIXBQ-MBLNEYKQSA-N Ile-Thr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)O)N YBKKLDBBPFIXBQ-MBLNEYKQSA-N 0.000 description 1
- REXAUQBGSGDEJY-IGISWZIWSA-N Ile-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N REXAUQBGSGDEJY-IGISWZIWSA-N 0.000 description 1
- JERJIYYCOGBAIJ-OBAATPRFSA-N Ile-Tyr-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JERJIYYCOGBAIJ-OBAATPRFSA-N 0.000 description 1
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 1
- JZBVBOKASHNXAD-NAKRPEOUSA-N Ile-Val-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N JZBVBOKASHNXAD-NAKRPEOUSA-N 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 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
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 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
- 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
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- 241000282852 Lama guanicoe Species 0.000 description 1
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 1
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 1
- OXKYZSRZKBTVEY-ZPFDUUQYSA-N Leu-Asn-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OXKYZSRZKBTVEY-ZPFDUUQYSA-N 0.000 description 1
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 1
- RVVBWTWPNFDYBE-SRVKXCTJSA-N Leu-Glu-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RVVBWTWPNFDYBE-SRVKXCTJSA-N 0.000 description 1
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 1
- KVMULWOHPPMHHE-DCAQKATOSA-N Leu-Glu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KVMULWOHPPMHHE-DCAQKATOSA-N 0.000 description 1
- NEEOBPIXKWSBRF-IUCAKERBSA-N Leu-Glu-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O NEEOBPIXKWSBRF-IUCAKERBSA-N 0.000 description 1
- BABSVXFGKFLIGW-UWVGGRQHSA-N Leu-Gly-Arg Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N BABSVXFGKFLIGW-UWVGGRQHSA-N 0.000 description 1
- PBGDOSARRIJMEV-DLOVCJGASA-N Leu-His-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O PBGDOSARRIJMEV-DLOVCJGASA-N 0.000 description 1
- XQXGNBFMAXWIGI-MXAVVETBSA-N Leu-His-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 XQXGNBFMAXWIGI-MXAVVETBSA-N 0.000 description 1
- UCNNZELZXFXXJQ-BZSNNMDCSA-N Leu-Leu-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UCNNZELZXFXXJQ-BZSNNMDCSA-N 0.000 description 1
- FKQPWMZLIIATBA-AJNGGQMLSA-N Leu-Lys-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FKQPWMZLIIATBA-AJNGGQMLSA-N 0.000 description 1
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 1
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 1
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 1
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 1
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 1
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 1
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 1
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 1
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- NTXYXFDMIHXTHE-WDSOQIARSA-N Leu-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 NTXYXFDMIHXTHE-WDSOQIARSA-N 0.000 description 1
- 241001490312 Lithops pseudotruncatella Species 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- GAOJCVKPIGHTGO-UWVGGRQHSA-N Lys-Arg-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O GAOJCVKPIGHTGO-UWVGGRQHSA-N 0.000 description 1
- NCTDKZKNBDZDOL-GARJFASQSA-N Lys-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)C(=O)O NCTDKZKNBDZDOL-GARJFASQSA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- XTONYTDATVADQH-CIUDSAMLSA-N Lys-Cys-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O XTONYTDATVADQH-CIUDSAMLSA-N 0.000 description 1
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 1
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 1
- UETQMSASAVBGJY-QWRGUYRKSA-N Lys-Gly-His Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 UETQMSASAVBGJY-QWRGUYRKSA-N 0.000 description 1
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 1
- PRSBSVAVOQOAMI-BJDJZHNGSA-N Lys-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN PRSBSVAVOQOAMI-BJDJZHNGSA-N 0.000 description 1
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 1
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 0.000 description 1
- PFZWARWVRNTPBR-IHPCNDPISA-N Lys-Leu-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N PFZWARWVRNTPBR-IHPCNDPISA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 1
- TVOOGUNBIWAURO-KATARQTJSA-N Lys-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N)O TVOOGUNBIWAURO-KATARQTJSA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- SUZVLFWOCKHWET-CQDKDKBSSA-N Lys-Tyr-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O SUZVLFWOCKHWET-CQDKDKBSSA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 1
- 241001441512 Maytenus serrata Species 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- QXEVZBXTDTVPCP-GMOBBJLQSA-N Met-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCSC)N QXEVZBXTDTVPCP-GMOBBJLQSA-N 0.000 description 1
- YLLWCSDBVGZLOW-CIUDSAMLSA-N Met-Gln-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O YLLWCSDBVGZLOW-CIUDSAMLSA-N 0.000 description 1
- PHWSCIFNNLLUFJ-NHCYSSNCSA-N Met-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N PHWSCIFNNLLUFJ-NHCYSSNCSA-N 0.000 description 1
- UZWMJZSOXGOVIN-LURJTMIESA-N Met-Gly-Gly Chemical compound CSCC[C@H](N)C(=O)NCC(=O)NCC(O)=O UZWMJZSOXGOVIN-LURJTMIESA-N 0.000 description 1
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 1
- CQRGINSEMFBACV-WPRPVWTQSA-N Met-Val-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O CQRGINSEMFBACV-WPRPVWTQSA-N 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 101100181099 Mus musculus Klra1 gene Proteins 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 108010065395 Neuropep-1 Proteins 0.000 description 1
- 101100067989 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cpc-2 gene Proteins 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000042387 PAX family Human genes 0.000 description 1
- 108091061489 PAX family Proteins 0.000 description 1
- 101150112800 PE35 gene Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- MDHZEOMXGNBSIL-DLOVCJGASA-N Phe-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N MDHZEOMXGNBSIL-DLOVCJGASA-N 0.000 description 1
- HHOOEUSPFGPZFP-QWRGUYRKSA-N Phe-Asn-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O HHOOEUSPFGPZFP-QWRGUYRKSA-N 0.000 description 1
- FMMIYCMOVGXZIP-AVGNSLFASA-N Phe-Glu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O FMMIYCMOVGXZIP-AVGNSLFASA-N 0.000 description 1
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 1
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 1
- RMKGXGPQIPLTFC-KKUMJFAQSA-N Phe-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RMKGXGPQIPLTFC-KKUMJFAQSA-N 0.000 description 1
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 1
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- DZZCICYRSZASNF-FXQIFTODSA-N Pro-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 DZZCICYRSZASNF-FXQIFTODSA-N 0.000 description 1
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 1
- CQZNGNCAIXMAIQ-UBHSHLNASA-N Pro-Ala-Phe Chemical compound C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O CQZNGNCAIXMAIQ-UBHSHLNASA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- LNLNHXIQPGKRJQ-SRVKXCTJSA-N Pro-Arg-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1 LNLNHXIQPGKRJQ-SRVKXCTJSA-N 0.000 description 1
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 1
- WECYCNFPGZLOOU-FXQIFTODSA-N Pro-Asn-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O WECYCNFPGZLOOU-FXQIFTODSA-N 0.000 description 1
- JFNPBBOGGNMSRX-CIUDSAMLSA-N Pro-Gln-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O JFNPBBOGGNMSRX-CIUDSAMLSA-N 0.000 description 1
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 description 1
- FKLSMYYLJHYPHH-UWVGGRQHSA-N Pro-Gly-Leu Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O FKLSMYYLJHYPHH-UWVGGRQHSA-N 0.000 description 1
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 1
- HFNPOYOKIPGAEI-SRVKXCTJSA-N Pro-Leu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 HFNPOYOKIPGAEI-SRVKXCTJSA-N 0.000 description 1
- FKYKZHOKDOPHSA-DCAQKATOSA-N Pro-Leu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FKYKZHOKDOPHSA-DCAQKATOSA-N 0.000 description 1
- VWHJZETTZDAGOM-XUXIUFHCSA-N Pro-Lys-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VWHJZETTZDAGOM-XUXIUFHCSA-N 0.000 description 1
- CGSOWZUPLOKYOR-AVGNSLFASA-N Pro-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 CGSOWZUPLOKYOR-AVGNSLFASA-N 0.000 description 1
- ITUDDXVFGFEKPD-NAKRPEOUSA-N Pro-Ser-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ITUDDXVFGFEKPD-NAKRPEOUSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- DCHQYSOGURGJST-FJXKBIBVSA-N Pro-Thr-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O DCHQYSOGURGJST-FJXKBIBVSA-N 0.000 description 1
- CHYAYDLYYIJCKY-OSUNSFLBSA-N Pro-Thr-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CHYAYDLYYIJCKY-OSUNSFLBSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940127180 SS1P Drugs 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 1
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 1
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 1
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 1
- SNVIOQXAHVORQM-WDSKDSINSA-N Ser-Gly-Gln Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O SNVIOQXAHVORQM-WDSKDSINSA-N 0.000 description 1
- LQESNKGTTNHZPZ-GHCJXIJMSA-N Ser-Ile-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O LQESNKGTTNHZPZ-GHCJXIJMSA-N 0.000 description 1
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- DYEGLQRVMBWQLD-IXOXFDKPSA-N Ser-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CO)N)O DYEGLQRVMBWQLD-IXOXFDKPSA-N 0.000 description 1
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 1
- PCMZJFMUYWIERL-ZKWXMUAHSA-N Ser-Val-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMZJFMUYWIERL-ZKWXMUAHSA-N 0.000 description 1
- BEBVVQPDSHHWQL-NRPADANISA-N Ser-Val-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O BEBVVQPDSHHWQL-NRPADANISA-N 0.000 description 1
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 229940126624 Tacatuzumab tetraxetan Drugs 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 1
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 1
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 1
- TZKPNGDGUVREEB-FOHZUACHSA-N Thr-Asn-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O TZKPNGDGUVREEB-FOHZUACHSA-N 0.000 description 1
- NRUPKQSXTJNQGD-XGEHTFHBSA-N Thr-Cys-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NRUPKQSXTJNQGD-XGEHTFHBSA-N 0.000 description 1
- LYGKYFKSZTUXGZ-ZDLURKLDSA-N Thr-Cys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)NCC(O)=O LYGKYFKSZTUXGZ-ZDLURKLDSA-N 0.000 description 1
- UZJDBCHMIQXLOQ-HEIBUPTGSA-N Thr-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O UZJDBCHMIQXLOQ-HEIBUPTGSA-N 0.000 description 1
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 1
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 1
- XFTYVCHLARBHBQ-FOHZUACHSA-N Thr-Gly-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XFTYVCHLARBHBQ-FOHZUACHSA-N 0.000 description 1
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- ZSPQUTWLWGWTPS-HJGDQZAQSA-N Thr-Lys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZSPQUTWLWGWTPS-HJGDQZAQSA-N 0.000 description 1
- CJXURNZYNHCYFD-WDCWCFNPSA-N Thr-Lys-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CJXURNZYNHCYFD-WDCWCFNPSA-N 0.000 description 1
- WRUWXBBEFUTJOU-XGEHTFHBSA-N Thr-Met-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N)O WRUWXBBEFUTJOU-XGEHTFHBSA-N 0.000 description 1
- WYLAVUAWOUVUCA-XVSYOHENSA-N Thr-Phe-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WYLAVUAWOUVUCA-XVSYOHENSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 1
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 1
- AHERARIZBPOMNU-KATARQTJSA-N Thr-Ser-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O AHERARIZBPOMNU-KATARQTJSA-N 0.000 description 1
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 1
- RVMNUBQWPVOUKH-HEIBUPTGSA-N Thr-Ser-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMNUBQWPVOUKH-HEIBUPTGSA-N 0.000 description 1
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 1
- BZTSQFWJNJYZSX-JRQIVUDYSA-N Thr-Tyr-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O BZTSQFWJNJYZSX-JRQIVUDYSA-N 0.000 description 1
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 1
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 1
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- VZBWRZGNEPBRDE-HZUKXOBISA-N Trp-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N VZBWRZGNEPBRDE-HZUKXOBISA-N 0.000 description 1
- PHNBFZBKLWEBJN-BPUTZDHNSA-N Trp-Glu-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PHNBFZBKLWEBJN-BPUTZDHNSA-N 0.000 description 1
- IVBJBFSWJDNQFW-XIRDDKMYSA-N Trp-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IVBJBFSWJDNQFW-XIRDDKMYSA-N 0.000 description 1
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 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
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- JONPRIHUYSPIMA-UWJYBYFXSA-N Tyr-Ala-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JONPRIHUYSPIMA-UWJYBYFXSA-N 0.000 description 1
- MTEQZJFSEMXXRK-CFMVVWHZSA-N Tyr-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N MTEQZJFSEMXXRK-CFMVVWHZSA-N 0.000 description 1
- TZXFLDNBYYGLKA-BZSNNMDCSA-N Tyr-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 TZXFLDNBYYGLKA-BZSNNMDCSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- YLRLHDFMMWDYTK-KKUMJFAQSA-N Tyr-Cys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLRLHDFMMWDYTK-KKUMJFAQSA-N 0.000 description 1
- QOEZFICGUZTRFX-IHRRRGAJSA-N Tyr-Cys-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O QOEZFICGUZTRFX-IHRRRGAJSA-N 0.000 description 1
- RYSNTWVRSLCAJZ-RYUDHWBXSA-N Tyr-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RYSNTWVRSLCAJZ-RYUDHWBXSA-N 0.000 description 1
- RIJPHPUJRLEOAK-JYJNAYRXSA-N Tyr-Gln-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O RIJPHPUJRLEOAK-JYJNAYRXSA-N 0.000 description 1
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 1
- USYGMBIIUDLYHJ-GVARAGBVSA-N Tyr-Ile-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 USYGMBIIUDLYHJ-GVARAGBVSA-N 0.000 description 1
- YMUQBRQQCPQEQN-CXTHYWKRSA-N Tyr-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N YMUQBRQQCPQEQN-CXTHYWKRSA-N 0.000 description 1
- BYAKMYBZADCNMN-JYJNAYRXSA-N Tyr-Lys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O BYAKMYBZADCNMN-JYJNAYRXSA-N 0.000 description 1
- YSGAPESOXHFTQY-IHRRRGAJSA-N Tyr-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N YSGAPESOXHFTQY-IHRRRGAJSA-N 0.000 description 1
- XDGPTBVOSHKDFT-KKUMJFAQSA-N Tyr-Met-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XDGPTBVOSHKDFT-KKUMJFAQSA-N 0.000 description 1
- QFXVAFIHVWXXBJ-AVGNSLFASA-N Tyr-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O QFXVAFIHVWXXBJ-AVGNSLFASA-N 0.000 description 1
- KLQPIEVIKOQRAW-IZPVPAKOSA-N Tyr-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O KLQPIEVIKOQRAW-IZPVPAKOSA-N 0.000 description 1
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 1
- KSGKJSFPWSMJHK-JNPHEJMOSA-N Tyr-Tyr-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KSGKJSFPWSMJHK-JNPHEJMOSA-N 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 1
- IJGPOONOTBNTFS-GVXVVHGQSA-N Val-Lys-Glu Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O IJGPOONOTBNTFS-GVXVVHGQSA-N 0.000 description 1
- JVGHIFMSFBZDHH-WPRPVWTQSA-N Val-Met-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)O)N JVGHIFMSFBZDHH-WPRPVWTQSA-N 0.000 description 1
- XBJKAZATRJBDCU-GUBZILKMSA-N Val-Pro-Ala Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O XBJKAZATRJBDCU-GUBZILKMSA-N 0.000 description 1
- YTNGABPUXFEOGU-SRVKXCTJSA-N Val-Pro-Arg Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O YTNGABPUXFEOGU-SRVKXCTJSA-N 0.000 description 1
- SJRUJQFQVLMZFW-WPRPVWTQSA-N Val-Pro-Gly Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SJRUJQFQVLMZFW-WPRPVWTQSA-N 0.000 description 1
- AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 1
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 1
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 1
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 1
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- JHKFWJUVTLNOJZ-ZSGPHXLJSA-N [(2r,3s)-7,7-dichloro-1-[(1s)-1-(4-methoxycarbonyl-1,3-thiazol-2-yl)-2-methylpropoxy]-2-methyl-1-oxooctan-3-yl] 2-[(1r)-1,2-dihydroxyethyl]-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1=CSC([C@@H](OC(=O)[C@H](C)[C@H](CCCC(C)(Cl)Cl)OC(=O)C=2N=C(SC=2)[C@H](O)CO)C(C)C)=N1 JHKFWJUVTLNOJZ-ZSGPHXLJSA-N 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Chemical class 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010028939 alanyl-alanyl-lysyl-alanine Proteins 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000001745 anti-biotin effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229950003145 apolizumab Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000008135 aqueous vehicle 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
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010091092 arginyl-glycyl-proline Proteins 0.000 description 1
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 1
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000004009 axon guidance Effects 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000028600 axonogenesis Effects 0.000 description 1
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 229950007843 bavituximab Drugs 0.000 description 1
- 229960003270 belimumab Drugs 0.000 description 1
- 230000008901 benefit 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
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-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
- 229940108502 bicnu Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical class NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000002967 competitive immunoassay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229950007276 conatumumab Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 108010069495 cysteinyltyrosine Proteins 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229950007409 dacetuzumab Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 229950008962 detumomab Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940042396 direct acting antivirals thiosemicarbazones Drugs 0.000 description 1
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 229950000006 ecromeximab Drugs 0.000 description 1
- 238000004993 emission spectroscopy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 239000012645 endogenous antigen Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229950009760 epratuzumab Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229950008579 ertumaxomab Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- 229960005420 etoposide Drugs 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000011347 external beam therapy Methods 0.000 description 1
- 229950009929 farletuzumab Drugs 0.000 description 1
- 229950008085 figitumumab Drugs 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 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
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 1
- 108010079547 glutamylmethionine Proteins 0.000 description 1
- KZNQNBZMBZJQJO-YFKPBYRVSA-N glyclproline Chemical compound NCC(=O)N1CCC[C@H]1C(O)=O KZNQNBZMBZJQJO-YFKPBYRVSA-N 0.000 description 1
- JYPCXBJRLBHWME-UHFFFAOYSA-N glycyl-L-prolyl-L-arginine Natural products NCC(=O)N1CCCC1C(=O)NC(CCCN=C(N)N)C(O)=O JYPCXBJRLBHWME-UHFFFAOYSA-N 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010025801 glycyl-prolyl-arginine Proteins 0.000 description 1
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 108010025306 histidylleucine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000045108 human EGFR Human genes 0.000 description 1
- 102000048373 human GPC3 Human genes 0.000 description 1
- 102000043997 human GPC5 Human genes 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229940096120 hydrea Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 229950009034 indoximod Drugs 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000012444 intercalating antibiotic Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 108010073093 leucyl-glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000002865 local sequence alignment Methods 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000003986 lysosome degradation Effects 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229950005555 metelimumab Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 108010093470 monomethyl auristatin E Proteins 0.000 description 1
- 108010059074 monomethylauristatin F Proteins 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- ZTLGJPIZUOVDMT-UHFFFAOYSA-N n,n-dichlorotriazin-4-amine Chemical compound ClN(Cl)C1=CC=NN=N1 ZTLGJPIZUOVDMT-UHFFFAOYSA-N 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- MGPASPKEZKCJFU-DYDAQHSGSA-N n-[(3r,4r,5s,6r)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]hexadecanamide Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MGPASPKEZKCJFU-DYDAQHSGSA-N 0.000 description 1
- 229950003027 nacolomab tafenatox Drugs 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000001178 neural stem cell Anatomy 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- 229950008516 olaratumab Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- 210000003800 pharynx Anatomy 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
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000771 poly (alkylcyanoacrylate) Polymers 0.000 description 1
- 229920001432 poly(L-lactide) Polymers 0.000 description 1
- 229920000962 poly(amidoamine) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder 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
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000013390 scatchard method Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229950001603 taplitumomab paptox 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
- 210000001550 testis Anatomy 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 150000003584 thiosemicarbazones Chemical class 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 210000005010 torso Anatomy 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- PYHOFAHZHOBVGV-UHFFFAOYSA-N triazane Chemical compound NNN PYHOFAHZHOBVGV-UHFFFAOYSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229950005972 urelumab Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229950000815 veltuzumab Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229950003511 votumumab Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 108010000998 wheylin-2 peptide Proteins 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464474—Proteoglycans, e.g. glypican, brevican or CSPG4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6829—Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3053—Skin, nerves, brain
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/5748—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncogenic proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/47—Brain; Nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Mycology (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Urology & Nephrology (AREA)
- General Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Plant Pathology (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
Abstract
描述了以高亲和力结合磷脂酰肌醇蛋白聚糖‑2(GPC2)的单克隆抗体。进一步描述了包括公开的抗体或其抗原结合片段的免疫毒素和嵌合抗原受体(CAR)。在某些情况下,抗体或抗原结合片段是人源化的。公开的GPC2特异性抗体和偶联物可用于例如,诊断或治疗GPC2阳性癌症,包括神经母细胞瘤、髓母细胞瘤和视网膜母细胞瘤。
Description
相关申请的交叉引用
本申请要求2018年8月8日提交的美国临时申请号62/716,169的权益,该临时申请的全部内容通过引用并入本文。
技术领域
本公开涉及特异性结合磷脂酰肌醇蛋白聚糖-2的单克隆抗体及其用途,例如用于治疗儿科癌症。
致谢政府支持
本发明是在国立卫生研究院授予的项目编号Z01 BC010891的政府支持下完成的。政府对本发明享有一定的权利。
背景技术
神经母细胞瘤是儿童最常见的颅外实体瘤。它来自交感神经系统的神经内分泌组织,占美国儿童期癌症的8-10%(Maris and Hogarty,Lancet 369:2106-2120,2007)。神经母细胞瘤是一种复杂的异质性疾病,即使使用密集的多模式治疗,近50%的患者具有高风险表型,其特征是癌症广泛传播且长期生存率较差(Yu et al.,New Engl JMed 363:1324-1334,2010)。接受标准疗法的患者中约有45%复发并最终死于转移性疾病(Matthay etal.,NewEnglJMed341:1165-1173,1999)。因此,迫切需要安全且有效地治疗神经母细胞瘤。
治疗神经母细胞瘤和其他致命实体瘤的最困难挑战之一是缺乏肿瘤特异性靶标。已经表明,磷脂酰肌醇蛋白聚糖-2(GPC2)mRNA在神经母细胞瘤和其他儿科癌症中高表达(Orentas et al.,Front Oncol 2:194,2012)。GPC2属于六成员人类磷脂酰肌醇蛋白聚糖蛋白家族,它们通过糖基磷脂酰肌醇(GPI)锚附着到细胞表面(Filmus et al.,GenomeBiol 9:224,2008)。不同于其他已知的磷脂酰肌醇蛋白聚糖,GPC2在神经系统中独特表达(Stipp et al.,JCellBiol 124:149-160,1994),参与细胞粘附并被认为调节轴突的生长和引导。
发明内容
本公开描述了通过小鼠杂交瘤技术分离的两种高亲和力GPC2特异性单克隆抗体。GPC2抗体(称为CT3和CT5)特异性结合GPC2,但不特异性结合其他磷脂酰肌醇蛋白聚糖。由公开的抗体组成的免疫毒素和嵌合抗原受体(CAR)T细胞能够有效杀死GPC2阳性肿瘤细胞。
本文提供了结合(例如特异性结合)GPC2的单克隆抗体(或抗原结合片段)。在一些实施方案中,单克隆抗体或抗原结合片段包括CT3或CT5的互补决定区(CDR)序列。本文还提供了包含公开的单克隆抗体或抗原结合片段的偶联物。在一些实例中,提供了包括本文公开的单克隆抗体或抗原结合片段的免疫偶联物、CAR、多特异性抗体、抗体-药物偶联物(ADC)、抗体-纳米颗粒、偶联物或融合蛋白。本公开内容还提供了包括GPC特异性单克隆抗体或抗原结合片段和药学上可接受的运载体(carrier)的组合物。
本文还提供了编码本文公开的GPC2特异性单克隆抗体或抗原结合片段、免疫偶联物、CAR、多特异性抗体和融合蛋白的核酸分子和载体(vector)。
还提供了编码GPC2特异性CAR和截短的人表皮生长因子受体(huEGFRt)的核酸构建体。编码的CAR包括与细胞外铰链区、跨膜区、细胞内共刺激结构域和细胞内信号传导结构域融合的GPC2特异性单克隆抗体片段(例如scFv)。huEGFRt包含两个EGFR细胞外结构域(结构域III和结构域IV)和EGFR跨膜结构域,但缺少两个膜远端细胞外结构域和所有细胞内结构域。在一些实施方案中,所述核酸分子在5'至3'方向上包括编码第一信号序列的核酸;编码GPC2特异性抗体或其抗原结合片段的核酸;编码细胞外铰链区的核酸;编码跨膜结构域的核酸;编码细胞内共刺激结构域的核酸;编码细胞内信号传导结构域的核酸;编码自切割2A肽的核酸;编码第二信号序列的核酸;以及编码huEGFRt的核酸。还提供了载体,例如病毒载体,其包括本文公开的核酸分子。还公开了共表达所公开的CAR和huEGFRt的分离细胞,例如T淋巴细胞。
还提供了治疗受试者中的GPC2阳性癌症的方法,以及抑制受试者中的GPC2阳性癌症的肿瘤生长或转移的方法。在一些实施方案中,该方法包括向受试者施用本文公开的单克隆抗体或抗原结合片段,或向受试者施用包含本文公开的单克隆抗体或抗原结合片段的免疫偶联物、CAR、ADC、多特异性抗体、抗体-纳米颗粒偶联物或融合蛋白。
本文进一步提供了检测样品中GPC2表达的方法。在一些实施方案中,该方法包括将样品与本文公开的单克隆抗体或抗原结合片段接触,并检测抗体与样品的结合。
还提供了诊断受试者患有GPC2阳性癌症的方法。在一些实施方案中,该方法包括将从受试者获得的样品与本文公开的单克隆抗体或抗原结合片段接触,并检测抗体与样品的结合。
从下面参照附图进行的详细描述,本公开的前述和其他目的和特征将变得更加明显。
附图说明
图1A:CT3和CT5与GPC2和其他磷脂酰肌醇蛋白聚糖蛋白的结合的ELISA分析。两种抗体都特异性结合GPC2。
图1B:CT3与人磷脂酰肌醇蛋白聚糖蛋白(huGPC1、huGPC2、huGPC3、huGPC4、huGPC5和huGPC6)和小鼠GPC2(msGPC2)的结合的ELISA分析。CT3抗体特异性结合人GPC2。
图1C:针对CT3抗体与人GPC2之间相互作用的八隅体动力学分析。CT3以高亲和力(KD=0.5nM)结合GPC2。
图2A:通过流式细胞术确定的GPC2阳性神经母细胞瘤细胞系LAN1和IMR5的细胞表面GPC2表达。白色峰代表同种型对照抗体对细胞表面的染色,黑色峰代表CT5抗体对细胞表面的染色。10μg/ml下的CT5用于染色。
图2B:CT3抗体与细胞表面上的人GPC2的特异性结合。不表达GPC2的A431细胞用作对照。G10是GPC2过表达的A431细胞系。F8是GPC2过表达的IMR5细胞系。标记为“1”的峰代表同种型对照抗体对细胞表面的染色,标记为“2”的峰代表抗GPC2抗体CT3对细胞表面的染色。CT3特异性识别在细胞表面上表达的GPC2。
图3:人神经母细胞瘤肿瘤中的GPC2表达。如通过免疫组织化学测定的,GPC2在神经母细胞瘤(i至iv)和正常神经(v和vi)组织中的表达。用1μg/ml CT3抗体标记组织。
图4:人髓母细胞瘤肿瘤中的GPC2表达。通过免疫组织化学测定,GPC2在成神经管细胞瘤肿瘤(i至iv)和正常脑组织(v和vi)中的表达。用1μg/ml CT3抗体标记组织。
图5:GPC2在人视网膜母细胞瘤肿瘤中的表达。通过免疫组织化学测定,GPC2在视网膜母细胞瘤肿瘤(i至iv)和癌旁眼(v和vi)组织中的表达。用1μg/ml CT3抗体标记组织。
图6:GPC2在人正常组织中的表达。如通过免疫组织化学测定的,GPC2在人正常组织(包括脑、心脏、肺、肝、胃、小肠、结肠、胰腺、脾脏、肾脏和皮肤)中的表达。用1μg/ml CT3抗体标记组织。在任何正常组织中均未检测到明显的GPC2染色。
图7A-7E:靶向GPC2的CT3 CAR T细胞杀死神经母细胞瘤细胞。(图7A)使用T2A核糖体跳跃序列表达靶向GPC2的CT3 CAR连同截短的人EGFR(huEGFRt)的慢病毒构建体的示意图。(图7B)使用流式细胞术通过检测huEGFRt表达来分析在慢病毒颗粒转导的人T细胞上的CT3 CAR表达。(图7C-7E)在细胞测定中靶向GPC2的CAR T细胞的细胞溶解活性。表达荧光素酶的SKNBE2(图7C)、NBEB(图7D)和LAN1(图7E)神经母细胞瘤细胞与空白对照品(mock)或CT3 CAR转导的T细胞以指定的效应器(E):靶(T)比共培养20小时,并使用基于发光的细胞溶解测定法测量特异性裂解。CT3 CART细胞诱导表达GPC2的神经母细胞瘤细胞有效裂解。
图8A-8D:与GPC2阳性细胞(G10、IMR5、F8)和GPC2阴性细胞(A431)以指定的E:T比共同培养20小时后,靶向GPC2的CAR T细胞的细胞溶解活性。使用基于发光的细胞溶解测定法测量特异性裂解。hCT3#1、#2和#3代表具有不同人源化CT3抗体的三种CAR版本(在本文中分别如SEQ ID NO:10、11和21所示)。CT3和人源化CT3(hCT3)CAR T细胞可有效裂解GPC2阳性肿瘤细胞,但不会裂解GPC2阴性A431细胞。
图9A-9B:(图9A)用静脉内尾静脉注射空白对照T细胞(空白对照品),250万、500万和1000万(CT3)CAR T细胞处理的IMR5荷瘤NSG小鼠的实验示意图。在CAR T细胞输注后第0天(输注)、第3天、第11天、第10天和第28天通过生物发光成像监测肿瘤负荷。(图9B)CT3CAR使转移性IMR5神经母细胞瘤肿瘤消退。剂量低至250万CT3 CAR T细胞可获得部分缓解,而500万和1000万CT3 CAR T细胞组均可获得完全缓解。
图10:处理2-4周后,检测小鼠脾脏中CAR载体阳性细胞。处理后第34天(2.5M#737)、第14天(5M#733)和第28天(10M#742)收获脾脏。处理后一个月,小鼠脾脏中存在的CT3CAR T细胞占总小鼠脾脏细胞的21.2%至41.2%。
图11A-11G:CT3-PE38和CT3-T20免疫毒素的表征。(图11A)使用Octet Red96e系统将人GPC2-His(250ng/ml)加载到Ni-NTA生物传感器上。以100nM加入免疫毒素(CT3-PE38和CT3-T20)以确定结合的亲和力。缔合发生600秒,解离发生1800秒。CT3-PE38和CT3-T20对人GPC2的亲和力(KD)被确定为分别为0.22nM和0.16nM。(图11B-11C)使用阴离子交换和尺寸排阻色谱法纯化CT3-PE38免疫毒素。Tris-甘氨酸4-20%凝胶用于评估蛋白质洗脱过程中的馏分纯度。图11B代表从Qseph和MonoQ柱洗脱液中选择的馏分。图11C代表来自TSK柱洗脱的馏分。(图11D-11E)使用阴离子交换和尺寸排阻色谱法纯化CT3-T20免疫毒素。Tris-甘氨酸4-20%凝胶用于评估蛋白质洗脱过程中的馏分纯度。图11D代表从Qseph和MonoQ柱洗脱液中选择的馏分。图11E代表来自TSK柱洗脱的馏分。(图11F-11G)CT3-PE38(图11F)和CT3-T20(图11G)免疫毒素选择性杀死表达GPC2的细胞系。使用不同浓度的免疫毒素孵育细胞三天,然后使用WST-8细胞增殖测定法确定细胞数。当计算细胞增殖的抑制时,未处理的孔中的细胞增殖设定为100%。用CT3-PE38和CT3-T20处理导致抑制GPC2阳性细胞,包括G10、F8和IMR5。抗原低的IMR32和抗原阴性的A431细胞未显示抑制作用。
图12A-12C:sCT3-PE38免疫毒素的表征。(图12A-12B)使用阴离子交换和尺寸排阻色谱法纯化sCT3-PE38免疫毒素。Tris-甘氨酸4-20%凝胶用于评估蛋白质洗脱过程中的馏分纯度。图12A代表从Qseph和MonoQ柱洗脱液中选择的馏分。图12B代表来自两个独立的TSK色谱柱运行的馏分。(图12C)sCT3-PE38免疫毒素选择性杀死表达GPC2的细胞系。使用不同浓度的免疫毒素孵育细胞三天,然后使用WST-8细胞增殖测定法确定细胞数。当计算细胞增殖的抑制时,未处理的孔中的细胞增殖设定为100%。sCT3-PE38处理导致抑制GPC2阳性细胞,包括G10、F8、IMR5和SKNBE。抗原阴性的A431和SKNAS细胞显示没有被sCT3-PE38抑制。
图13:将基质胶中的一千万个F8细胞注射到裸鼠的右背侧。当平均肿瘤体积达到100mm3时,开始使用PBS、CT3-PE38(0.25mg/kg)或CT3-T20(2mg/kg)处理。箭头指示处理天数。使用双因素ANOVA检验确定肿瘤体积的显著性,****p<0.0001,n=5。还测量了处理小鼠的体重。基于CT3的免疫毒素在裸鼠中耐受良好,并显著抑制F8皮下异种移植。
图14A-14B:将基质胶中的两千万个G10细胞注射到裸鼠的右背侧。当平均肿瘤体积达到100mm3时,开始使用PBS、CT3-PE38(0.25mg/kg)或CT3-T20(6mg/kg)处理。箭头指示处理天数。评估了肿瘤体积(图14A)、体重(图14A)和存活率(图14B)。当肿瘤超过1500mm3或肿瘤开始溃烂时,对小鼠实施安乐死。与PBS处理组为21天相比,免疫毒素组的平均生存期为28天。使用Mantel-Cox检验确定Kaplan-Meier生存曲线的显著性,*p<0.05,n=5。基于CT3的免疫毒素处理导致G10皮下异种移植模型中裸鼠的存活率提高。剂量高达6mg/kg的小鼠对CT3-T20的耐受性良好。
图15A-15B:通过尾静脉将五百万个IMR5细胞注射到裸鼠中。用PBS或CT3-T20(4mg/kg)处理小鼠。箭头指示处理天数。在注射100μl的xenolight D-荧光素(30mg/ml)后,用IVIS Lumina系列III测定辐射率(图15A)。在IMR5转移模型中,用CT3-T20免疫毒素进行的处理可减轻肿瘤负荷,但未显著改变体重(图15B)。
序列表
如37C.F.R.1.822所定义,随附序列表中列出的核酸和氨基酸序列使用核苷酸碱基的标准字母缩写和氨基酸的三字母代码显示。每个核苷酸序列仅显示一条链,但是互补链应理解为包括对显示链的任何提及。序列表以ASCII文本文件的形式提交,创建于2019年8月1日,26.6Kb,通过引用并入本文。在随附的序列表中:
SEQ ID NO:1是CT3 VH结构域的核苷酸序列。
SEQ ID NO:2是CT3 VH结构域的氨基酸序列。
SEQ ID NO:3是CT3 VL结构域的核苷酸序列。
SEQ ID NO:4是CT3 VL结构域的氨基酸序列。
SEQ ID NO:5是CT5 VH结构域的核苷酸序列。
SEQ ID NO:6是CT5 VH结构域的氨基酸序列。
SEQ ID NO:7是CT5 VL结构域的核苷酸序列。
SEQ ID NO:8是CT5 VL结构域的氨基酸序列。
SEQ ID NO:9是CT3 scFv的氨基酸序列。
SEQ ID NO:10是人源化CT3 scFv(hCT3-1)的氨基酸序列。
SEQ ID NO:11是人源化CT3 scFv(hCT3-2)的氨基酸序列。
SEQ ID NO:12是sCT3 scFv的氨基酸序列,其包含CT3的CDR序列和来自鼠抗体SS1的框架序列。
SEQ ID NO:13是肽新表位的氨基酸序列。
SEQ ID NO:14是GM-CSF受体信号序列的氨基酸序列。
SEQ ID NO:15是CD8α铰链区的氨基酸序列。
SEQ ID NO:16是CD8α跨膜结构域的氨基酸序列。
SEQ ID NO:17是4-1BB的氨基酸序列。
SEQ ID NO:18是CD3ζ的氨基酸序列。
SEQ ID NO:19是T2A自切割肽序列的氨基酸序列。
SEQ ID NO:20是截短的人表皮生长因子受体(huEGFRt)的氨基酸序列。
SEQ ID NO:21是人源化CT3 scFv(hCT3-3)的氨基酸序列。
SEQ ID NO:22是PE38的氨基酸序列。
SEQ ID NO:23是T20的氨基酸序列。
具体实施方式
I.缩写
ADC 抗体-药物偶联物
ADCC 抗体依赖性细胞介导的细胞毒性
CAR 嵌合抗原受体
CDR 互补决定区
CTL 细胞毒性T淋巴细胞
EF1 延伸因子1
EGF 表皮生长因子
EGFR 表皮生长因子受体
ELISA 酶联免疫吸附测定
FACS 荧光激活细胞分选
GMCSFRss 粒细胞-巨噬细胞集落刺激因子受体信号
序列
GPC2 磷脂酰肌醇蛋白聚糖-2
GPI 糖基磷脂酰肌醇
hFc 人Fc
huEGFRt 截短的人表皮生长因子受体
Ig 免疫球蛋白
IL 白介素
i.p. 腹膜内
i.v. 静脉内
mFc 鼠Fc
PE 假单胞菌外毒素
s.c. 皮下
scFv 单链可变片段
VH或VH 可变重链
VL或VL 可变轻链
II.术语和方法
除非另有说明,否则根据常规用法使用技术术语。分子生物学中常用术语的定义可以在Benjamin Lewin,Genes V,由Oxford University Press出版,1994(ISBN 0-19-854287-9);Kendrew等人(编辑),The Encyclopedia ofMolecular Biology,由BlackwellScience Ltd.出版,1994(ISBN 0-632-02182-9);和RobertA.Meyers(编辑),MolecularBiology and Biotechnology:a Comprehensive Desk Reference,由VCH Publishers,Inc.出版,1995(ISBN 1-56081-569-8)中找到。
为了促进审阅本公开的各种实施方案,提供了以下对特定术语的解释:
4-1BB:由T细胞受体(TCR)激活的淋巴细胞以及包括自然杀伤细胞的其他细胞表达的共刺激分子。4-1BB的连接诱导信号传导级联,其导致细胞因子产生、抗凋亡分子的表达和增强的免疫应答。4-1BB的示例性氨基酸序列在本文如SEQ ID NO:17所示。
急性淋巴细胞白血病(ALL):白血病的急性形式,以淋巴母细胞过量产生为特征。ALL在儿童期最常见,在2-5岁时达到峰值。
抗体:一种多肽配体,其包含至少一个识别和结合(例如特异性识别和特异性结合)抗原表位的可变区。哺乳动物免疫球蛋白分子由重(H)链和轻(L)链组成,它们各自具有可变区,分别称为可变重链(VH)区和可变轻链(VL)区。VH区和VL区共同负责结合抗体识别的抗原。哺乳动物免疫球蛋白有五种主要的重链类别(或同种型),其决定了抗体分子的功能活性:IgM、IgD、IgG、IgA和IgE。在哺乳动物中未发现的抗体同种型包括IgX、IgY、IgW和IgNAR。IgY是由鸟类和爬行动物产生的一抗,在功能上与哺乳动物IgG和IgE有些相似。IgW和IgNAR抗体由软骨鱼类产生,而IgX抗体则在两栖动物中发现。
抗体可变区包含“框架”区和高变区,称为“互补决定区”或“CDR”。CDR主要负责与抗原表位的结合。抗体的框架区用于在三维空间中定位和对齐CDR。给定CDR的氨基酸序列边界可以使用许多众所周知的编号方案中的任何一种容易地确定,包括Kabat et al.(Sequences ofProteins ofImmunological Interest,U.S.Department of Health andHuman Services,1991;“Kabat”编号方案)、Chothia et al.(参见Chothia and Lesk,JMol Biol196:901-917,1987;Chothia et al.,Nature 342:877,1989;and Al-Lazikaniet al.,JMB273,927-948,1997;“Chothia”编号方案)、Kunik et al.(参见Kunik et al.,PLoS Comput Biol8:e1002388,2012;and Kunik et al.,Nucleic Acids Res 40(WebServer issue):W521-524,2012;“Paratome CDRs”)和ImMunoGeneTics(IMGT)数据库(参加Lefranc,Nucleic Acids Res 29:207-9,2001;“IMGT”编号方案)描述的那些。Kabat、Paratome和IMGT数据库是在线维护的。
“单结构域抗体”是指具有单个结构域(可变结构域)的抗体,其能够在不存在其他抗体结构域的情况下特异性结合抗原或抗原表位。单结构域抗体包括例如,VH结构域抗体、VNAR抗体、骆驼科VHH抗体和VL结构域抗体。VNAR抗体由软骨鱼类产生,例如铰口鲨、斑纹须鲨、白斑角鲨和竹鲨。骆驼科VHH抗体是由几种物种产生的,包括骆驼、美洲驼、羊驼、单峰骆驼和原驼,它们产生的天然缺乏轻链的重链抗体。
“单克隆抗体”是由淋巴细胞的单个克隆或已经转染了单个抗体的编码序列的细胞产生的抗体。单克隆抗体通过本领域技术人员已知的方法产生。单克隆抗体包括人源化单克隆抗体。
“嵌合抗体”具有来自一种物种(例如人)的框架残基和来自另一物种的CDR(通常,其赋予抗原结合)。
“人源化”抗体是免疫球蛋白,其包括人框架区和来自非人(例如小鼠、兔、大鼠、鲨鱼或合成的)免疫球蛋白的一个或更多个CDR。提供CDR的非人免疫球蛋白称为“供体”,而提供框架的人免疫球蛋白称为“受体”。在一个实施方案中,所有CDR都来自人源化免疫球蛋白中的供体免疫球蛋白。恒定区不必存在,但是如果存在,则它们必须与人免疫球蛋白恒定区基本相同,即,至少约85-90%,例如约95%或更高的同一性。因此,除可能的CDR外,人源化免疫球蛋白的所有部分与天然人免疫球蛋白序列的相应部分基本相同。人源化抗体结合与提供CDR的供体抗体相同的抗原。人源化或其他单克隆抗体可具有其他保守氨基酸替换,这些替换对抗原结合或其他免疫球蛋白功能基本上没有影响。
抗体-药物偶联物(ADC):包括与药物(例如细胞毒性剂)偶联的抗体(或抗体的抗原结合片段)的分子。通过抗体与细胞表面上表达的肿瘤抗原的特异性结合,ADC可用于将药物特异性靶向癌细胞。与ADC一起使用的示例性药物包括抗微管药(例如,美登素类化合物、澳瑞他汀(auristatin)E和澳瑞他汀F)和链间交联剂(例如,吡咯并苯并二氮杂卓;PDB)。
抗微管剂:通过停止有丝分裂阻止细胞生长的一种类型的药物。抗微管剂,也称为“抗有丝分裂剂”,用于治疗癌症。
结合亲和力:抗体对抗原的亲和力。在一个实施方案中,亲和力是通过Frankel etal.,Mol.Immunol.,16:101-106,1979描述的Scatchard方法的改进来计算的。在另一个实施方案中,结合亲和力通过抗原/抗体解离速率来测量。在另一个实施方案中,通过竞争放射免疫测定法测量高结合亲和力。在另一个实施方案中,通过ELISA测量结合亲和力。在其他实施方案中,抗体亲和力通过流式细胞术或通过表面等离激元参照来测量。“特异性结合”抗原(例如GPC2)的抗体是以高亲和力结合抗原并且不显著结合其他不相关抗原的抗体。
双特异性抗体:重组蛋白,其包含两种不同单克隆抗体的抗原结合片段,因此能够结合两种不同抗原。在一些实施方案中,双特异性抗体通过同时靶向例如CTL(例如,CTL受体组分如CD3)或效应器自然杀伤(NK)细胞和肿瘤抗原两者而用于癌症免疫疗法。类似地,多特异性抗体是重组蛋白,其包括至少两种不同的单克隆抗体,例如两种、三种或四种不同的单克隆抗体的抗原结合片段。
化学治疗剂:在治疗以异常细胞生长为特征的疾病中具有治疗作用的任何化学试剂。这样的疾病包括肿瘤、赘生物和癌症以及以增生性生长为特征的疾病,例如银屑病。在一个实施方案中,化学治疗剂是一种用于治疗神经母细胞瘤的药物。在一个实施方案中,化学治疗剂是一种放射性化合物。本领域技术人员可以容易地确定所使用的化学治疗剂(参见例如,Slapak and Kufe,Principles of Cancer Therapy,Chapter 86in Harrison'sPrinciples ofInternal Medicine,14th edition;Perry et al.,Chemotherapy,Ch.17inAbeloff,Clinical Oncology 2nd ed.,Churchill Livingstone,Inc;Baltzer,L.,Berkery,R.(eds.):Oncology Pocket Guide to Chemotherapy,2nded.St.Louis,Mosby-Year Book,1995;Fischer,D.S.,Knobf,M.F.,Durivage,H.J.(eds):The Cancer Chemotherapy Handbook,4th ed.St.Louis,Mosby-Year Book,1993)。联合化疗是施用多于一种药剂治疗癌症。一个实例是结合GPC2的抗体的施用与放射性或化学化合物联合使用。
嵌合抗原受体(CAR):嵌合分子,其包括抗原结合部分(例如scFv)和信号传导结构域,例如来自T细胞受体的信号传导结构域(例如CD3ζ)。通常,CAR由抗原结合部分、跨膜结构域和内结构域组成。内结构域通常包括具有基于免疫受体酪氨酸的激活基序(ITAM),例如CD3ζ或FcεRIγ的信号传导链。在一些情况下,内结构域还包括至少一个另外的共刺激结构域的细胞内部分,例如CD28、4-1BB(CD137)、ICOS、OX40(CD134)、CD27和/或DAP10。
互补决定区(CDR):定义抗体的结合亲和力和特异性的高变氨基酸序列区域。哺乳动物免疫球蛋白的轻链和重链各具有三个CDR,分别称为L-CDR1、L-CDR2、L-CDR3和H-CDR1、H-CDR2、H-CDR3。
偶联物:在本公开的上下文中,“偶联物”是共价连接到效应器分子或第二蛋白质(例如,第二抗体)的抗体或抗体片段(例如,抗原结合片段)。效应器分子可以是例如,药物、毒素、治疗剂、可检测标签、蛋白质、核酸、脂质、纳米颗粒、碳水化合物或重组病毒。抗体偶联物通常被称为“免疫偶联物”。当偶联物包含与药物连接的抗体(例如,细胞毒性剂)时,该偶联物通常被称为“抗体-药物偶联物”或“ADC”。其他抗体偶联物包括例如,多特异性(例如,双特异性或三特异性)抗体和嵌合抗原受体(CAR)。
保守变体:“保守”氨基酸替换是基本上不影响或降低蛋白质的亲和力(例如抗体对GPC2)的那些替换。例如,特异性结合GPC2的单克隆抗体可以包括至多约1个、至多约2个、至多约5个、和至多约10个或至多约15个保守替换并特异性结合GPC2多肽。术语“保守变体”还包括使用替换的氨基酸代替未替换的母体氨基酸,条件是抗体特异性结合GPC2。非保守替换是降低活性或与GPC2结合的那些。
提供功能上相似的氨基酸的保守氨基酸替换表是本领域普通技术人员众所周知的。以下六组是被认为是彼此的保守替换的氨基酸的实例:
1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T);
2)天冬氨酸(D)、谷氨酸(E);
3)天冬酰胺(N)、谷氨酰胺(Q);
4)精氨酸(R)、赖氨酸(K);
5)异亮氨酸(I)、亮氨酸(L)、蛋氨酸(M)、缬氨酸(V);和
6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
接触:置于直接物理缔合中;包括固体和液体形式两者。
细胞毒性剂:杀死细胞的任何药物或化合物。
细胞毒性:分子对旨在靶向的细胞的毒性(例如,免疫毒素),与生物体其余部分的细胞相反。相反,在一个实施方案中,术语“毒性”是指免疫毒素对除那些旨在被免疫毒素的靶向部分靶向的细胞以外的细胞的毒性,而术语“动物毒性”是指免疫毒素对动物的毒性而不是免疫毒素对除旨在被免疫毒素靶向的那些细胞以外的细胞的毒性。
促结缔组织增生型小圆细胞瘤(DRCT):软组织肉瘤主要发生在儿童时期,尤其是在男孩中。DRCT是一种侵袭性和罕见的癌症类型,主要以腹部肿块的形式出现,但也可以在淋巴结、腹部衬壁、隔膜、脾脏、肝脏、胸壁、头骨、脊髓、肠道、膀胱、脑、肺、睾丸、卵巢和骨盆中发现。
诊断:识别病理状况(例如神经母细胞瘤)的存在或性质。诊断方法的敏感性和特异性不同。诊断测定的“敏感性”是测试阳性的患病个体的百分比(真实阳性的百分比)。诊断测定的“特异性”是一减去假阳性率,其中假阳性率定义为那些没有疾病且测试阳性的患病个体的比例。尽管特定的诊断方法可能无法提供对状况的明确诊断,但只要该方法提供有助于诊断的阳性指示就足够了。“预后”是病理状况例如神经母细胞瘤发展的可能性(例如,严重程度)。
药物:用于治疗、改善或预防受试者的疾病或状况的任何化合物。在本文的一些实施方案中,药物是抗癌剂,例如细胞毒性剂,例如抗有丝分裂剂或抗微管剂。
效应器分子:嵌合分子的一部分,旨在对嵌合分子靶向的细胞产生期望作用。效应器分子也称为效应器部分(EM)、治疗剂或诊断剂,或类似术语。治疗剂(或药物)包括诸如核酸、蛋白质、肽、氨基酸或衍生物、糖蛋白、放射性同位素、脂质、碳水化合物或重组病毒的化合物。核酸治疗和诊断部分包括反义核酸、用于与单链或双链DNA共价交联的衍生寡核苷酸以及形成三链体的寡核苷酸。或者,与靶向部分例如抗GPC2抗体连接的分子可以是封装系统,例如含有治疗组合物例如药物,核酸(例如反义核酸)的脂质体或胶束,或另一种可避免直接暴露于循环系统的治疗部分。制备附着于抗体的脂质体的手段是本领域技术人员众所周知的(参见,例如,美国专利号4,957,735;和Connor et al.,Pharm Ther 28:341-365,1985)。诊断剂或部分包括放射性同位素和其他可检测标签。可用于此类目的的可检测标签在本领域中也是众所周知的,包括放射性同位素,例如35S、11C、13N、15O、18F、19F、99mTc、131I、3H、14C、15N、90Y、99Tc、111In和125I、荧光团、化学发光剂和酶。
表位:抗原决定簇。这些是分子上具有抗原性(即引起特异性免疫应答)的特定化学基团或肽序列。抗体特异性结合多肽(例如GPC2)上的特定抗原表位。
尤文氏肉瘤:骨或软组织中发现的一种罕见类型的恶性肿瘤。尤文氏肉瘤是一种小的蓝色圆形细胞瘤。
框架区:插入CDR之间的氨基酸序列。框架区包括可变轻和可变重框架区。框架区用于将CDR保持在用于抗原结合的适当方向上。
融合蛋白:一种蛋白质,其包含至少两种不同(异源)蛋白质的一部分。
磷脂酰肌醇蛋白聚糖-2(GPC2):通过GPI锚附着在细胞表面的硫酸乙酰肝素(HS)蛋白聚糖的六成员磷脂酰肌醇蛋白聚糖家族成员(Filmus et al.,Genome Biol9:224,2008)。GPC2在神经系统中独特表达(Stipp et al.,J Cell Biol 124:149-160,1994),参与细胞粘附并被认为调节轴突的生长和引导。另外,GPC2 mRNA在神经母细胞瘤和其他儿科癌症中高度表达(Orentas et al.,Front Oncol 2:194,2012)。GPC2也称为大脑蛋白聚糖蛋白聚糖和磷脂酰肌醇蛋白聚糖蛋白聚糖2。GPC2基因组、mRNA和蛋白质序列是可公开获得的(参见例如,NCBI基因ID 221914)。
GPC2-阳性癌:过表达GPC2的癌症。GPC2阳性癌的实例包括但不限于神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
异源的:源于单独的遗传来源或物种。
免疫应答:免疫系统细胞(例如,B细胞、T细胞或单核细胞)对刺激的应答。在一个实施方案中,该应答对特定抗原是特异性的(“抗原特异性应答”)。在一个实施方案中,免疫应答是T细胞应答,例如CD4+应答或CD8+应答。在另一个实施方案中,该反应是B细胞应答,并导致特异性抗体的产生。
免疫偶联物:效应器分子与抗体或其功能片段的共价连接。效应器分子可以是可检测标签或免疫毒素。毒素的具体非限制性实例包括但不限于相思豆毒蛋白、蓖麻毒蛋白、假单胞菌外毒素(PE,例如PE35、PE37、PE38和PE40)、白喉毒素(DT)、肉毒杆菌毒素或其修饰毒素或其他直接或间接抑制细胞生长或杀死细胞的毒剂。例如,PE和DT是高毒性化合物,通常会因肝毒性导致死亡。然而,可以通过去除毒素的天然靶向成分(例如,PE的结构域Ia和DT的B链)并将其替换为不同的靶向部分(例如抗体),将PE和DT修饰成一种用作免疫毒素的形式。“嵌合分子”是与效应器分子偶联(conjugated、coupled)的靶向部分,例如配体或抗体。术语“偶联”或“连接”是指使两个多肽成为一个连续的多肽分子。在一个实施方案中,抗体连接至效应器分子。在另一个实施方案中,与效应器分子连接的抗体进一步与脂质或其他分子连接为蛋白质或肽,以增加其在体内的半衰期。连接可以通过化学或重组手段进行。在一个实施方案中,连接是化学的,其中抗体部分和效应器分子之间的反应已经产生了在两个分子之间形成的共价键以形成一个分子。肽接头(短肽序列)可以任选地包含在抗体和效应器分子之间。由于免疫偶联物最初是由具有独立功能的两个分子(例如抗体和效应器分子)制备的,因此它们有时也称为“嵌合分子”。因此,如本文所用,术语“嵌合分子”是指与效应器分子偶联(conjugated、coupled)的靶向部分,例如配体或抗体。
免疫脂质体:脂质体,其表面偶联有抗体或抗体片段。免疫脂质体可以将细胞毒性剂或其他药物携带到靶向抗体的细胞(例如肿瘤细胞)。
链间交联剂:一种类型细胞毒性药物,其能够在DNA的两条链之间共价结合从而阻止DNA复制和/或转录。
分离的:“分离的”生物成分,例如核酸、蛋白质(包括抗体)或细胞器,已与天然存在该成分的环境(例如细胞)中的其他生物成分基本分离或从其中纯化,即其他染色体和染色体外DNA和RNA、蛋白质和细胞器。已被“分离”的核酸分子和蛋白质包括通过标准纯化方法纯化的核酸分子和蛋白质。该术语还涵盖通过在宿主细胞中重组表达制备的核酸和蛋白质,以及化学合成的核酸。
标签:直接或间接偶联于另一种分子(例如抗体(例如本文提供的一种抗体)或蛋白质)的可检测化合物或组合物,以促进该分子的检测。标记的具体的非限制性实例包括荧光标签、酶键和放射性同位素。在一个实例中,“标记的抗体”是指在抗体中掺入另一分子。例如,标签是可检测的标志物,例如放射性标记的氨基酸的掺入或通过标记的亲和素可检测到的生物素基部分的多肽的附着(例如,含有荧光标志物的链霉亲和素或可通过光学或比色法检测的酶活性)。可以使用多种标记多肽和糖蛋白的方法。用于多肽的标签的实例包括但不限于以下:放射性同位素或放射性核苷酸(例如5S、11C、13N、15O、18F、19F、99mTc、131I、3H、14C、15N、90Y、99Tc、111In和125I)、荧光标签(例如,异硫氰酸荧光素(FITC)、若丹明、镧系元素荧光粉)、酶标签(例如,辣根过氧化物酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶)、化学发光标志物、生物素基、被二级报告分子识别的预定的多肽表位(例如,亮氨酸拉链对序列、二抗的结合位点、金属结合结构域、表位标签)或磁性试剂,例如钆螯合物。在一些实施方案中,标签通过各种长度的间隔臂附着以减少潜在的空间位阻。
接头:在一些情况下,接头是抗体结合片段(例如,Fv片段)内的肽,其用于将可变重链间接结合至可变轻链。“接头”也可以指用于将靶向部分(例如抗体)与效应器分子(例如,细胞毒素或可检测标签)连接的肽。
术语“偶联”、“连接(joining)”、“结合”或“连接(linking)”是指使两个多肽成为一个连续的多肽分子,或将放射性核素或其他分子共价附着到多肽,例如scFv。在特定的上下文中,该术语包括提及将配体(例如抗体部分)连接至效应器分子。连接可以通过化学或重组手段进行。“化学手段”是指抗体部分和效应器分子之间的反应,使得在两个分子之间形成共价键以形成一个分子。
髓母细胞瘤:小脑中形成的一种快速增长型癌症。髓母细胞瘤倾向于通过脑脊液扩散到脊髓或大脑其他部位。它们也可能扩散到身体的其他部位,但这很罕见。髓母细胞瘤最常见于儿童和青壮年。它们是一种类型的中枢神经系统胚胎肿瘤。
瘤形成、恶性肿瘤、癌症或肿瘤:赘生物是由过度的细胞分裂导致的组织或细胞的异常生长。赘生物生长可产生肿瘤。个体中肿瘤的数量是“肿瘤负荷”,其可以用肿瘤的数量、体积或重量来衡量。不转移的肿瘤称为“良性”。侵入周围组织和/或可以转移的肿瘤被称为“恶性”。
神经母细胞瘤:由胚胎神经干细胞引起的实体瘤。神经母细胞瘤通常发生在肾上腺及其周围,但也可以发生在发现有交感神经组织的任何地方,例如在脊柱附近的腹部、胸部、颈部或神经组织中。神经母细胞瘤通常发生在5岁以下的儿童中。
可操作地连接:当第一核酸序列与第二核酸序列处于功能关系时,第一核酸序列与第二核酸序列可操作地连接。例如,如果启动子影响编码序列的转录或表达,则将启动子与编码序列可操作地连接。通常,可操作地连接的DNA序列是连续的,并且在需要连接两个蛋白质编码区的情况下,在同一阅读框中。
骨肉瘤:在骨骼中发现的一种类型癌性肿瘤。骨肉瘤是一种侵袭性癌症,起源于间充质来源的原始转化细胞。这种类型的癌症在儿童和青壮年中最普遍。
儿科癌症:一种在0至14岁的儿童中发展的癌症。儿科癌症的主要类型包括,例如,神经母细胞瘤、急性淋巴细胞白血病(ALL)、胚胎性横纹肌肉瘤(ERMS)、肺泡横纹肌肉瘤(ARMS)、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤(DRCT)、骨肉瘤、脑和其他中枢神经系统肿瘤(例如髓母细胞瘤)、Wilm肿瘤、非霍奇金淋巴瘤和视网膜母细胞瘤。
药剂:当适当地施用于受试者或细胞时能够诱导期望的治疗或预防作用的化学化合物或组合物。
药学上可接受的运载体:使用的药学上可接受的运载体是常规的。Remington’sPharmaceutical Sciences,by E.W.Martin,Mack Publishing Co.,Easton,PA,15thEdition,1975描述了适用于本文公开的抗体的药物递送的组合物和制剂。
通常,运载体的性质将取决于所采用的特定施用方式。例如,肠胃外制剂通常包含可注射的流体,其包括药学和生理学上可接受的流体,例如水、生理盐水、平衡盐溶液、葡萄糖水溶液、甘油等作为溶媒。对于固体组合物(例如散剂、丸剂、片剂或胶囊剂形式),常规的无毒固体运载体可以包括例如,药物级的甘露醇、乳糖、淀粉或硬脂酸镁。除生物中性运载体外,待施用的药物组合物还可包含少量的无毒辅助物质,例如润湿剂或乳化剂、防腐剂和pH缓冲剂等,例如乙酸钠或脱水山梨糖醇单月桂酸酯。
预防、治疗或改善疾病:“预防”疾病是指抑制疾病的全面发展。“治疗”是指改善疾病或病理状况开始发展后的体征或症状的治疗干预,例如减轻肿瘤负荷或减少转移瘤大小的数量。“改善”是指疾病,例如癌症的体征或症状的数量或严重程度的降低。
纯化的:术语“纯化的”不需要绝对的纯度;相反,它旨在作为一个相对术语。因此,例如,纯化的肽制品是其中肽或蛋白质比在其天然环境中在细胞内存在的肽或蛋白质更富集的肽制品。在一个实施方案中,纯化制剂使得蛋白质或肽占制剂的总肽或蛋白质含量的至少50%。基本上纯化表示从其他蛋白质或细胞成分中纯化。基本上纯化的蛋白质的纯度为至少60%、70%、80%、90%、95%或98%。因此,在一个具体的非限制性实例中,基本上纯化的蛋白质90%不含其他蛋白质或细胞成分。
吡咯并苯并二氮杂卓(PBD):最初在链霉菌属(Streptomyces)物种中发现的一类序列选择性DNA小沟结合交联剂。PDB比全身化疗药物有效得多。PBD的作用机制与其在DNA小沟中形成加合物的能力有关,从而干扰DNA加工。在本公开的上下文中,PBD包括天然产生和分离的PBD、化学合成的天然存在的PBD和化学合成的非天然存在的PBD。PBD还包括单体、二聚和混合PBD(有关综述,参见Gerratana,Med ResRev 32(2):254-293,2012)。
重组体:重组核酸或蛋白质是具有非天然存在的序列或具有由两个否则分离的序列片段的人工组合制成的序列的重组核酸或蛋白质。通常通过化学合成或通过人工操作分离的核酸片段,例如通过基因工程技术,来实现这种人工组合。
视网膜母细胞瘤:在视网膜组织中形成的一种类型的癌症。视网膜母细胞瘤通常发生在5岁以下的儿童中。它可以是遗传的或非遗传的(散发性的)。
横纹肌肉瘤(RMS):骨骼肌起源的软组织恶性肿瘤。横纹肌肉瘤最常见的原发部位是头部和颈部(例如,脑膜旁(parameningeal)、眼眶、咽等)、泌尿生殖道和四肢。其他较不常见的原发部位包括躯干、胸壁、腹部(包括腹膜后腔和胆道)以及会阴/肛门区域。至少有两种类型的RMS;最常见的形式是肺泡RMS(ARMS)和胚胎组织学RMS(ERMS)。约20%的横纹肌肉瘤儿童患有ARMS亚型。在青少年以及原发部位涉及四肢、躯干和会阴/肛周区域的患者中,注意到这种亚型的频率增加。ARMS与编码涉及13号染色体上的FKHR和PAX家族成员的融合基因的染色体易位相关。胚胎亚型是儿童中最频繁观察到的亚型,占儿童横纹肌肉瘤的约60-70%。具有胚胎组织学的肿瘤通常出现在头颈部区域或泌尿生殖道中,尽管它们可能发生在任何原发部位。ERMS的特征是诊断时低龄化、杂合性丢失和基因组印记改变。
样品(或生物样品):从受试者获得的包含基因组DNA、RNA(包括mRNA)、蛋白质或其组合的生物样本。实例包括但不限于外周血、组织、细胞、尿液、唾液、组织活检、细针抽吸、手术标本和尸检材料。在一个实例中,样品包括肿瘤活检。
序列同一性:氨基酸或核酸序列之间的相似性以序列之间的相似性表示,否则称为序列同一性。序列同一性经常用百分比同一性(或相似性或同源性)来衡量;百分比越高,两个序列相似性越大。当使用标准方法比对时,多肽或核酸分子的同源物或变体将具有相对高程度的序列同一性。
用于比较的序列比对方法是本领域众所周知的。各种程序和比对算法描述在:Smith和Waterman,Adv.Appl.Math.2:482,1981;Needleman和Wunsch,J.Mol.Biol.48:443,1970;Pearson和Lipman,Proc.Natl.Acad.Sci.U.S.A.85:2444,1988;Higgins和Sharp,Gene73:237,1988;Higgins和Sharp,CABIOS 5:151,1989;Corpet et al.,NucleicAcidsResearch16:10881,1988;和Pearson和Lipman,Proc.Natl.Acad.Sci.U.S.A.85:2444,1988.Altschul et al.,Nature Genet.6:119,1994中,提出了序列比对方法和同源性计算的详细考虑。
NCBI局部序列比对检索基本工具(BLAST)(Altschul et al.,J.Mol.Biol.215:403,1990)可从包括美国国家生物技术信息中心(NCBI,Bethesda,Md)的多种资源获得,也可在互联网上获得,用于与序列分析程序blastp、blastn、blastx、tblastn和tblastx结合使用。互联网的NCBI网站上提供了有关如何使用此程序确定序列同一性的说明。
特异性结合GPC2多肽的抗体的VH的同源物和变体通常特征在于具有使用NCBIBlast 2.0(缺口blastp设置为默认参数),在与抗体的氨基酸序列进行的全长比对中计算的至少约75%,例如至少约80%、90%、95%、96%、97%、98%或99%的序列同一性。为了比较大于约30个氨基酸的氨基酸序列,使用默认BLOSUM62矩阵设置为默认参数,采用Blast 2序列函数(缺口存在成本为11,且每个残基缺口成本为1)。比对短肽(少于约30个氨基酸)时,应使用Blast 2序列功能进行比对,采用PAM30矩阵设置为默认参数(开放缺口9、延伸缺口1罚分)。当通过这种方法评估时,与参考序列具有甚至更高相似性的蛋白质将显示出增加的同一性百分比,例如至少80%、至少85%、至少90%、至少95%、至少98%或至少99%的序列同一性。当比较少于整个序列的序列同一性时,同源物和变体通常在10-20个氨基酸的短窗口内具有至少80%的序列同一性,并且取决于它们与参考序列的相似性可能具有至少85%或至少90%或95%的序列同一性。在这样的短窗口上确定序列同一性的方法可在互联网上的NCBI网站上获得。本领域的技术人员将理解,提供这些序列同一性范围仅用于指导;完全有可能获得超出所提供范围的非常重要的同源物。
小分子:通常具有小于约1000道尔顿,或在一些实施方案中小于约500道尔顿的分子量的分子,其中该分子能够在某种可测量的程度上调节靶分子的活性。
受试者:活的多细胞脊椎动物生物体,包括人类和兽医受试者的类别,包括人类和非人类哺乳动物。
合成的:在实验室中通过人工手段产生的,例如可以在实验室中化学合成合成的核酸或蛋白质(例如,抗体)。
治疗有效量:一定量的特定物质,足以在被治疗的受试者中获得期望的效果。例如,这可以是抑制或压制肿瘤生长所需的量。在一个实施方案中,治疗有效量是消除、减小肿瘤大小或防止肿瘤转移所需的量。当施用于受试者时,通常将使用达到靶组织浓度(例如,在肿瘤中)的剂量,其已被证实实现期望的体外作用。
毒素:对细胞具有细胞毒性的分子。毒素包括相思豆毒蛋白、蓖麻毒蛋白、假单胞菌外毒素(PE)、白喉毒素(DT)、肉毒杆菌毒素、皂角素、局限曲菌素或白树毒素或其修饰毒素。例如,PE和DT是高毒性化合物,通常会因肝毒性导致死亡。然而,可以通过去除毒素的天然靶向成分(例如,PE的结构域Ia或DT的B链)并将其替换为不同的靶向部分(例如抗体),将PE和DT修饰成用作免疫毒素的形式。
载体:引入宿主细胞的核酸分子,从而产生转化的宿主细胞。载体可以包括允许其在宿主细胞中复制的核酸序列,例如复制起点。载体还可以包括一个或更多个可选择的标记基因和本领域已知的其他遗传因子。在一些实施方案中,载体是病毒载体,例如慢病毒载体。
除非另外说明,否则在此使用的所有技术和科学术语具有与由本公开所属领域的普通技术人员通常所理解的相同的含义。除非上下文另有明确规定,否则单数术语“a”、“an”和“the”包括复数指示物。“包括A或B”是指包括A或B、或A和B。还应理解,针对核酸或多肽给出的所有碱基大小或氨基酸大小以及所有分子量或分子量值均为近似值,并提供用于描述。虽然与本文所述的那些相似或等同的方法和材料可用于本公开的实践或测试,但下面描述合适的方法和材料。本文提及的所有出版物、专利申请、专利和其他参考文献都通过引用其全部内容并入。在发生冲突的情况下,以本说明书(包括术语解释)为准。另外,材料、方法和实施例仅是说明性的而不旨在是限制性的。
III.磷脂酰肌醇蛋白聚糖-2(GPC2)特异的单克隆抗体
本文公开了高亲和力的抗GPC2单克隆抗体。从小鼠杂交瘤中分离出抗体CT3和CT5,发现它们特异性结合GPC2;这些抗体不是磷脂酰肌醇蛋白聚糖家族的其他蛋白质。抗GPC2抗体结合GPC2阳性的神经母细胞瘤、髓母细胞瘤和视网膜母细胞瘤肿瘤细胞,但不结合正常(健康)组织。基于GPC2特异性抗体的CAR表现出对表达GPC2的神经母细胞瘤肿瘤细胞的优异杀伤作用。基于工程化CT3抗体的免疫毒素抑制多种表达GPC2的细胞系的增殖。公开的抗体对GPC2和表达GPC2的肿瘤的特异性使这些抗体成为治疗儿科癌症的极佳疗法,包括神经母细胞瘤、髓母细胞瘤和视网膜母细胞瘤。公开的抗体也可用于检测表达GPC2的细胞和诊断GPC2阳性肿瘤。
下面提供CT3和CT4的VH和VL结构域的核苷酸和氨基酸序列,并在本文中如SEQ IDNO:1-8所示。表1-4列出了使用Kabat、IMGT或Paratome或所有这三种的组合确定的CDR1、CDR2和CDR3的氨基酸位置。本领域技术人员可以使用替代的编号方案,例如Chothia编号方案,容易地确定CDR边界。
CT3 VHDNA(SEQ ID NO:1)
GAGGTCCAGCTGCAACAGTCTGGACCTGAACTGGTGAAGCCTGGGGCTTCAGTAAAGATGTCCTGCAAGGCTTCTAGATTCACATTCACTGACTACAACATACACTGGGTGAAGCAGAGCCCTGGAAAGACCCTTGAATGGATTGGATATATTAACCCTAACAATGGTGATATTTTCTACAAACAGAAGTTCAATGGCAAGGCCACATTGACTATAAACAAGTCCTCCAACACAGCCTACATGGAGCTCCGCAGCCTGACATCGGAGGATTCTGCAGTCTATTACTGTGTAAGATCCTCTAATATTCGTTATACTTTCGACAGGTTCTTCGATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCACT3VH蛋白质(SEQ ID NO:2)
EVQLQQSGPELVKPGASVKMSCKASRFTFTDYNIHWVKQSPGKTLEWIGYINPNNGDIFYKQKFNGKATLTINKSSNTAYMELRSLTSEDSAVYYCVRSSNIRYTFDRFFDVWGTGTTVTVSS
表1.CDR在CT3 VH结构域中的位置(SEQ ID NO:2)
方案 | CDR1 | CDR2 | CDR3 |
Kabat | 31-35 | 50-66 | 99-112 |
IMGT | 26-33 | 51-58 | 97-112 |
Paratome | 26-35 | 47-61 | 97-112 |
组合的 | 26-35 | 47-66 | 97-112 |
CT3 VLDNA(SEQ ID NO:3)
GAAAATGTGCTCACCCAGTCTCCAGCAATCATGTCTGCATCTCTAGGGGAGAAGGTCACCATGAGCTGCAGGGCCAGCTCAAGTGTAAATTACATTTACTGGTACCAGCAGAAGTCAGATGCCTCCCCCAAACTATGGATTTATTACACATCCAACCTGGCTCCTGGAGTCCCAGCTCGCTTCAGTGGCAGTGGGTCTGGGAACTCTTATTCTCTCACAATCAGCAGCATGGAGGGTGAAGATGCTGCCACTTATTACTGCCAGCAGTTTTCTAGTTCCCCATCCACGTTCGGTACTGGGACCAAGCTGGAGCTGAAA
CT3 VL蛋白质(SEQ ID NO:4)
ENVLTQSPAIMSASLGEKVTMSCRASSSVNYIYWYQQKSDASPKLWIYYTSNLAPGVPARFSGSGSGNSYSLTISSMEGEDAATYYCQQFSSSPSTFGTGTKLELK
表2.CDR在CT3 VL结构域中的位置(SEQ ID NO:4)
方案 | CDR1 | CDR2 | CDR3 |
Kabat | 24-33 | 49-55 | 88-96 |
IMGT | 27-31 | 49-51 | 88-96 |
Paratome | 27-33 | 45-55 | 88-95 |
组合的 | 24-33 | 45-55 | 88-96 |
CT5 VHDNA(SEQ ID NO:5)
GAGGTGAAACTGGTGGAGTCTGGAGGAGGCTTGGTACAGTCTGGGCGTTCTCTGAGACTCTCCTGTGCAACTTCTGGATTCACCTTCAGTGATTTCTACATGGAGTGGGTCCGCCAAGCTCCAGGGAAGGGACTGGAGTGGATTGTTGCAAGTAGAGACAAAGCTAATGATTATACAACAGCGTATAGTGCATCTGTGAAGGGTCGGTTCATCGTCTCCAGAGACACTTCCCAAAGCATCCTCTACCTTCAGATGAATGCCCTGAGAGCTGAGGACACTGCCATTTATTACTGTGTAAGAGATTTCTATGATTACGACGAGGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCT
CT5 VH蛋白质(SEQ ID NO:6)
EVKLVESGGGLVQSGRSLRLSCATSGFTFSDFYMEWVRQAPGKGLEWIVASRDKANDYTTAYSASVKGRFIVSRDTSQSILYLQMNALRAEDTAIYYCVRDFYDYDEAYWGQGTLVTVS
表3.CDR在CT5 VH结构域中的位置(SEQ ID NO:6)
方案 | CDR1 | CDR2 | CDR3 |
Kabat | 31-35 | 50-68 | 101-109 |
IMGT | 26-33 | 51-60 | 99-109 |
Paratome | 27-35 | 47-62 | 99-109 |
组合的 | 26-35 | 47-68 | 99-109 |
CT5 VLDNA(SEQ ID NO:7)
GACATCCAGATGACTCAGTCTCCGTCCTCACTGTCTGCCTCTCTGGGAGGTACAGTCACCATCACTTGCAAGGCAAGCGAAGACATTAACAACTATATAGCTTGGTACCAACACAAGCCTGGAAAAGGTCCTCGGCTGCTCATACAATACACATCTACATTACAGCCAGGCATCCCATCAAGGTTCAGTGGAAGTGGGTCTGGGCGAGATTATTCCCTCAGCATCAGCAACCTGGAGCCTGAAGATATTGCAACTTATTATTGTCTACAGTATGATATTCTGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
CT5 VL蛋白质(SEQ ID NO:8)
DIQMTQSPSSLSASLGGTVTITCKASEDINNYIAWYQHKPGKGPRLLIQYTSTLQPGIPSRFSGSGSGRDYSLSISNLEPEDIATYYCLQYDILWTFGGGTKLEIK
表4.CDR在CT5 VL结构域中的位置(SEQ ID NO:8)
方案 | CDR1 | CDR2 | CDR3 |
Kabat | 24-34 | 50-56 | 89-96 |
IMGT | 27-32 | 50-52 | 89-96 |
Paratome | 27-34 | 46-56 | 89-95 |
组合的 | 24-34 | 46-56 | 89-96 |
本文还公开了基于CT3的scFv分子。在下面的氨基酸序列中,组合的Kabat/IMGT/Paratome CDR以粗体显示,框架残基以正常字体显示,并且位于VH和VL结构域之间的(G3S)4接头序列带有下划线。CT3 scFv包含来自原始CT3抗体的CDR和框架序列。hCT3-1、hCT3-2和hCT3-3 scFv分子包括CT3的CDR序列和人框架序列。sCT3 scFv包括CT3的CDR序列和鼠抗体SS1的框架序列(参见美国专利号6,809,184;Chowdhury和Pastan,NatBiotechnol 17:568-572,199;Pastan等人,NatRev Cancer 6:559-565,2006)。
CT3 scFv(SEQ ID NO:9)
粗体=组合的Kabat/IMGT/Paratome CDRs
带下划线的=接头
正常字体=CT3框架
hCT3-1 scFv(SEQ ID NO:10)
粗体=组合的Kabat/IMGT/Paratome CDRs
带下划线的=接头
正常字体=人框架
hCT3-2 scFv(SEQ ID NO:11)
粗体=组合的Kabat/IMGT/Paratome CDRs
带下划线的=接头
正常字体=人框架
hCT3-3 scFv(SEQ ID NO:21)
粗体=组合的Kabat/IMGT/Paratome CDRs
带下划线的=接头
正常字体=人框架
sCT3(带有SS1框架的CT3;SEQ ID NO:12)
粗体=组合的Kabat/IMGT/Paratome CDRs
带下划线的=接头
正常字体=SS1(鼠)框架
本文提供了结合(例如特异性结合)GPC2的分离的单克隆抗体,或其抗原结合片段。单克隆抗体或抗原结合片段包括可变重(VH)结构域和可变轻(VL)结构域。在一些实施方案中,单克隆抗体或抗原结合片段包括本文SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、或SEQ ID NO:8所示的氨基酸序列的至少一部分,例如来自SEQ ID NO:2、SEQ ID NO:4、SEQID NO:6、或SEQ ID NO:8的一个或更多个(例如所有三个)CDR序列。在一些实例中,CDR位置是IMGT、Kabat、Paratome、Chothia或其一种或更多种的组合确定的。
在一些实施方案中,抗体的VH结构域(或抗原结合片段)包含SEQ ID NO:2的CDR序列,且抗体的VL结构域(或其抗原结合片段)包含SEQ ID NO:4的CDR序列。在一些实例中,使用Kabat、IMGT、Paratome或Chothia编号方案或其组合来确定CDR序列。在特定实例中,使用Kabat、IMGT和Paratome的组合确定CDR序列。
在一些实施方案中,抗体的VH结构域(或抗原结合片段)包含SEQ ID NO:6的CDR序列,且抗体的VL结构域(或其抗原结合片段)包含SEQ ID NO:8的CDR序列。在一些实例中,使用Kabat、IMGT、Paratome或Chothia编号方案或其组合来确定CDR序列。在特定实例中,使用Kabat、IMGT和Paratome的组合确定CDR序列。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:2的残基31-35、50-66和99-112。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:4的残基24-33、49-55和88-96。在一些实例中,VH结构域包含SEQ ID NO:2的残基31-35、50-66和99-112且VL结构域包含SEQ ID NO:4的残基24-33、49-55和88-96。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:6的残基31-35、50-68和101-109。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:8的残基24-34、50-56和89-96。在一些实例中,VH结构域包含SEQ ID NO:6的残基31-35、50-68和101-109且VL结构域包含SEQ ID NO:8的残基24-34、50-56和89-96。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:2的残基26-33、51-58和97-112。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:4的残基27-31、49-51和88-96。在一些实例中,VH结构域包含SEQ ID NO:2的残基26-33、51-58和97-112且VL结构域包含SEQ ID NO:4的残基27-31、49-51和88-96。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:6的残基26-33、51-60和99-109。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:8的残基27-32、50-52和89-96。在一些实例中,VH结构域包含SEQ ID NO:6的残基26-33、51-60和99-109且VL结构域包含SEQ ID NO:8的残基27-32、50-52和89-96。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:2的残基26-35、47-61和97-112。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:4的残基27-33、45-55和88-95。在一些实例中,VH结构域包含SEQ ID NO:2的残基26-35、47-61和97-112且VL结构域包含SEQ ID NO:4的残基27-33、45-55和88-95。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:6的残基27-35、47-62和99-109。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:8的残基27-34、46-56和89-95。在一些实例中,VH结构域包含SEQ ID NO:6的残基27-35、47-62和99-109且VL结构域包含SEQ ID NO:8的残基27-34、46-56和89-95。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:2的残基26-35、47-66和97-112。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:4的残基24-33、45-55和88-96。在一些实例中,VH结构域包含SEQ ID NO:2的残基26-35、47-66和97-112且VL结构域包含SEQ ID NO:4的残基24-33、45-55和88-96。
在一些实施方案中,抗体或抗原结合片段的VH结构域包含SEQ ID NO:6的残基26-35、47-68和99-109。在一些实施方案中,抗体或抗原结合片段的VL结构域包含SEQ ID NO:8的残基27-34、46-56和89-96。在一些实例中,VH结构域包含SEQ ID NO:6的残基26-35、47-68和99-109且VL结构域包含SEQ ID NO:8的残基27-34、46-56和89-96。
在一些实施方案中,VH结构域的氨基酸序列与SEQ ID NO:2具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性和/或VL结构域的氨基酸序列与SEQ ID NO:4具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实例中,VH结构域的氨基酸序列包含SEQ IDNO:2或由其组成和/或VL结构域的氨基酸序列包含SEQ ID NO:4或由其组成。
在一些实施方案中,VH结构域的氨基酸序列与SEQ ID NO:6具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性和/或VL结构域的氨基酸序列与SEQ ID NO:8具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实例中,VH结构域的氨基酸序列包含SEQ IDNO:6或由其组成和/或VL结构域的氨基酸序列包含SEQ ID NO:8或由其组成。
在一些实施方案中,单克隆抗体或抗原结合片段是人源化的、嵌合或合成的单克隆抗体或抗原结合片段。
在一些实例中,单克隆抗体是IgG。在其他实例中,单克隆抗体是IgA、IgD、IgE或IgM。
在一些实施方案中,抗原结合片段是单链可变片段(scFv)、Fab片段、Fab’片段、F(ab)’2片段或二硫键稳定的可变片段(dsFv)。在一些实例中,抗原结合片段是scFv。在特定的实例中,scFv包含与SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、或SEQID NO:21具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的氨基酸序列。在非限制性实例中,scFv包含SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、或SEQ ID NO:21的氨基酸序列或由其组成。
本文还提供了嵌合抗原受体(CAR),其包括本文公开的单克隆抗体或抗原结合片段。在一些实施方案中,CAR进一步包括铰链区、跨膜结构域、共刺激信号传导部分、信号传导结构域或其任何组合。还提供了表达GPC2特异性CAR的细胞。在一些实例中,细胞是T淋巴细胞,例如CTL。第V节进一步描述了CAR和表达CAR的T细胞。
本文还提供了免疫偶联物,其包括本文公开的单克隆抗体或抗原结合片段和效应器分子。在一些实施方案中,效应器分子是毒素,例如但不限于假单胞菌外毒素或其变体,例如PE38。在其他实施方案中,效应器分子是可检测标签,例如但不限于荧光团、酶或放射性同位素。免疫偶联物在第IV节中进一步描述。
本文还提供了抗体-药物偶联物(ADC),其包括与本文公开的单克隆抗体或抗原结合片段偶联的药物。在一些实施方案中,药物是小分子,例如抗微管剂、抗有丝分裂剂和/或细胞毒性剂。第VI节将进一步描述ADC。
本文还提供了多特异性抗体,其包括本文公开的单克隆抗体或其抗原结合片段和至少一种另外的单克隆抗体或其抗原结合片段。在一些实施方案中,多特异性抗体是双特异性抗体。在其他实施方案中,多特异性抗体是三特异性抗体。在一些实施方案中,至少一种另外的单克隆抗体或其抗原结合片段特异性结合T细胞受体或天然杀伤(NK)细胞活化受体的组分。多特异性抗体在第VII节中进一步描述。
本文还提供了抗体-纳米颗粒偶联物,其包括与本文公开的单克隆抗体或抗原结合片段偶联的纳米颗粒。在一些实施方案中,纳米颗粒包括聚合物纳米颗粒、纳米球、纳米胶囊、脂质体、树枝状分子、聚合物胶束或类脂囊泡。在一些实施方案中,纳米颗粒包括细胞毒性剂。抗体-纳米颗粒偶联物在第VIII节中进一步描述。
本文还提供了融合蛋白,其包括本文公开的单克隆抗体或抗原结合片段和异源蛋白质或肽。在一些实施方案中,异源蛋白质是Fc蛋白质。在一些实例中,Fc蛋白质是小鼠Fc或人Fc蛋白。在一些实施方案中,异源肽对人不是内源的(例如,异源肽是肽新表位)。
包括药学上可接受的运载体和单克隆抗体或抗原结合片段、CAR、分离细胞(例如表达CAR的细胞,例如CAR T细胞)、免疫偶联物、ADC、多特异性抗体、抗体-纳米颗粒偶联物、或本文公开的融合蛋白的组合物被本公开内容进一步提供。
还提供了编码本文公开的单克隆抗体或抗原结合片段的核酸分子。还提供了编码本文公开的CAR、免疫偶联物、多特异性抗体或融合蛋白的核酸分子。在一些实施方案中,核酸分子可操作地连接至启动子。本文进一步提供了包含核酸分子的载体。
在一些实施方案中,VH结构域的核苷酸序列与SEQ ID NO:1具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实施方案中,VL结构域的核苷酸序列与SEQ ID NO:3具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实例中,VH结构域的核苷酸序列包含SEQ ID NO:1或由其组成且VL结构域的核苷酸序列包含SEQ ID NO:3或由其组成。
在一些实施方案中,VH结构域的核苷酸序列与SEQ ID NO:5具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实施方案中,VL结构域的核苷酸序列与SEQ ID NO:7具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%同一性。在一些实例中,VH结构域的核苷酸序列包含SEQ ID NO:5或由其组成且VL结构域的核苷酸序列包含SEQ ID NO:7或由其组成。
在一些实施方案中,本文提供了表达CAR和截短的人EGFR(huEGFRt)的核酸构建体。在一些实施方案中,核酸在5'至3'方向上包括:编码第一粒细胞-巨噬细胞集落刺激因子受体信号序列(GMCSFRss)的核酸;编码本文公开的GPC2特异性单克隆抗体或其抗原结合片段的核酸;编码细胞外铰链区的核酸;编码跨膜结构域的核酸;编码细胞内共刺激结构域的核酸;编码细胞内信号传导结构域的核酸;编码自切割2A肽的核酸;编码第二GMCSFRss的核酸;以及编码截短的人表皮生长因子受体(huEGFRt)的核酸。在一些实例中,核酸还包括编码第一GMCSFRss的核酸的人延伸因子1(EF1α)启动子序列5’。在一些实例中,铰链区包括CD8α铰链区。在一些实例中,跨膜结构域包含CD8α跨膜结构域。在一些实例中,共刺激信号传导部分包括4-1BB信号传导部分。在一些实例中,信号传导结构域包括CD3ζ信号传导结构域。在一些实例中,抗原结合片段是单链可变片段(scFv)。在特定的非限制性实例中,scFv包含SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、或SEQ ID NO:21的氨基酸序列。
还提供了共表达本文公开的CPC2特异性CAR和huEGFRt的分离细胞。在一些实例中,细胞是细胞毒性T淋巴细胞(CTL)。
IV.免疫偶联物
所公开的单克隆抗体可以与治疗剂或效应器分子偶联。免疫偶联物包括但不限于,其中治疗剂与抗体共价连接的分子。治疗剂是具有针对特定靶分子或带有靶分子的细胞的特定生物学活性的试剂。本领域技术人员将理解,治疗剂可以包括各种药物,例如长春碱、道诺霉素等,细胞毒素,例如天然或修饰的假单胞菌外毒素或白喉毒素,包含药理组合物的包囊剂(例如脂质体),放射性剂,例如125I、32P、14C、3H和35S和其他标签、靶部分和配体。
特定治疗剂的选择取决于特定的靶分子或细胞以及期望的生物学效应。因此,例如,治疗剂可以是用于引起特定靶细胞(例如肿瘤细胞)死亡的细胞毒素。相反,在需要引起非致命性生物反应的情况下,可以将治疗剂与非致命性药理剂或含有非致命性药理剂的脂质体偶联。
使用本文所述的治疗剂和抗体,技术人员可以容易地构建各种包含功能上等同的核酸的克隆,例如序列不同但其编码相同效应器部分或抗体序列的核酸。因此,本公开提供了编码抗体及其偶联物和融合蛋白的核酸。
可以使用本领域技术人员已知的多种手段将效应器分子与目的抗体连接。可使用共价和非共价附着手段。将效应器分子附着到抗体的程序根据效应器的化学结构而变化。多肽通常包含各种官能团;例如羧酸(COOH)、游离胺(-NH2)或巯基(-SH)基团,其可用于与抗体上的合适官能团反应以导致效应器分子的结合。或者,将抗体衍生化以暴露或附着其他反应性官能团。衍生化可以涉及许多已知接头分子中的任一种的附着。接头可以是用于将抗体连接至效应器分子的任何分子。接头能够与抗体和效应器分子形成共价键。合适的接头是本领域技术人员众所周知的,包括但不限于直链或支链碳接头、杂环碳接头或肽接头。在抗体和效应器分子是多肽时,接头可以通过它们的侧基(例如通过与半胱氨酸的二硫键)连接至组成氨基酸或连接至末端氨基酸的α碳氨基和羧基。
在某些情况下,当免疫偶联物到达其靶位点时,希望从抗体中释放效应器分子。因此,在这些情况下,免疫偶联物将包含在靶位点附近可切割的连接。可以通过酶活性或免疫偶联物在靶细胞内部或靶位点附近所经历的条件来促进接头的切割以从抗体中释放效应器分子。
鉴于已经报道了将各种放射诊断化合物、放射治疗化合物、标签(例如酶或荧光分子)、药物、毒素和其他试剂附着于抗体的许多方法,本领域技术人员能够确定将给定试剂附着于抗体或其他多肽的合适方法。
本文公开的抗体可以被衍生化或连接至另一分子(例如,另一种肽或蛋白质)。通常,抗体或其部分被衍生化,使得与靶抗原的结合不受衍生化或标记的不利影响。例如,抗体可以功能性连接(通过化学偶联、遗传融合、非共价结合或其他方式)与一个或更多个其他分子实体,例如另一种抗体(例如双特异性抗体或双抗体)、检测剂、可以介导抗体或抗体部分与另一种分子(例如,链霉亲和素核区域或聚组氨酸标签)结合的药物剂和/或蛋白质或肽。
一种类型的衍生化抗体通过将两种或更多种抗体(相同类型或不同类型,例如以生成双特异性抗体)交联而产生。合适的交联剂包括异双官能的那些,具有被适当的间隔基(例如,间马来酰亚胺基苯甲酰基-N-羟基琥珀酰亚胺酯)隔开的两个不同的反应性基团或同双官能的的那些(例如,辛二酸二琥珀酰亚胺酯)。这样的接头是可商购的。
抗体可以与可检测的标志物偶联;例如,能够通过ELISA、分光光度法、流式细胞仪、显微镜或诊断成像技术(例如,计算机断层扫描(CT)、计算机轴向断层(CAT)扫描、磁共振成像(MRI)、核磁共振成像NMRI)、磁共振断层扫描(MTR)、超声、光纤检查和腹腔镜检查)进行检测的可检测标志物。可检测标志物的具体非限制性实例包括荧光团、化学发光剂、酶键、放射性同位素和重金属或化合物(例如,用于通过MRI检测的超顺磁性氧化铁纳米晶体)。例如,有用的可检测标志物包括荧光化合物,包括荧光素、异硫氰酸荧光素、若丹明、5-二甲胺-1-萘磺酰氯、藻红蛋白、镧系元素荧光粉等。也可以使用生物发光标志物,例如荧光素酶、绿色荧光蛋白(GFP)和黄色荧光蛋白(YFP)。抗体或抗原结合片段也可以与可用于检测的酶偶联,例如辣根过氧化物酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶、葡萄糖氧化酶等。当抗体或抗原结合片段与可检测的酶偶联时,可以通过添加酶用于产生可识别的反应产物的其他试剂进行检测。例如,当存在辣根过氧化物酶试剂时,添加过氧化氢和二氨基联苯胺导致有色反应产物,其在视觉上是可检测的。抗体或抗原结合片段也可以与生物素偶联,并通过间接测量抗生物素蛋白或链霉亲和素结合来检测。应当注意,抗生物素蛋白本身可以与酶或荧光标签偶联。
可以用诸如钆的磁性试剂标记抗体。抗体也可以用镧系元素(例如铕和镝)和锰进行标记。顺磁性颗粒如超顺磁性氧化铁也可用作标签。抗体也可以用次级报告分子识别的预定多肽表位标记(例如亮氨酸拉链对序列、二抗的结合位点、金属结合结构域、表位标签)。在一些实施方案中,标签通过各种长度的间隔臂附着以减少潜在的空间位阻。
抗体也可以用放射性标记的氨基酸标记。放射性标记可用于诊断和治疗目的。例如,放射性标签可以用于通过X射线、发射光谱或其他诊断技术来检测靶抗原的表达。多肽标签的实例包括但不限于,以下放射性同位素或放射性核苷酸:3H、14C、15N、35S、90Y、99Tc、111In、125I、131I。
抗体也可以用化学基团例如聚乙二醇(PEG)、甲基或乙基或碳水化合物基团衍生。这些基团可用于改善抗体的生物学特性,例如增加血清半衰期或增加组织结合。
毒素可与本文所述的单克隆抗体一起使用以产生免疫毒素。示例性毒素包括蓖麻毒蛋白、相思豆毒蛋白、白喉毒素及其亚基,以及肉毒杆菌毒素A至F。这些毒素可容易地从商业来源获得(例如,Sigma Chemical Company,St.Louis,MO)。预期的毒素也包括本文所述毒素的变体(参见,例如,参见美国专利号5,079,163和4,689,401)。在一个实施方案中,该毒素是假单胞菌外毒素(PE)(美国专利号5,602,095)。如本文所用,“假单胞菌外毒素”是指全长天然(天然存在的)PE或已被修饰的PE。此类修饰可包括但不限于结构域Ia的消除,结构域Ib、II和III中的各种氨基酸缺失、单个氨基酸替换以及在羧基末端添加一个或更多个序列(例如,参见,Siegall et al.,J.Biol.Chem.264:14256-14261,1989)。
与本文所述的单克隆抗体一起使用的PE可以包括天然序列、天然序列的细胞毒性片段以及天然PE及其细胞毒性片段的保守修饰的变体。PE的细胞毒性片段包括在靶细胞中有或没有后续蛋白水解或其他加工的细胞毒性的那些。PE的细胞毒性片段包括PE40、PE38和PE35。对于PE及其变体的附加描述,参见,例如,美国专利号4,892,827;5,512,658;5,602,095;5,608,039;5,821,238;和5,854,044;美国专利申请公开号2015/0099707;PCT公开号WO 99/51643和WO 2014/052064;Pai et al.,Proc.Natl.Acad.Sci.USA 88:3358-3362,1991;Kondo et al.,J.Biol.Chem.263:9470-9475,1988;Pastan et al.,Biochim.Biophys.Acta 1333:C1-C6,1997。
本文还考虑了蛋白酶抗性PE变体和免疫原性降低的PE变体,例如但不限于PE-LR、PE-6X、PE-8X、PE-LR/6X和PE-LR/8X(参见例如,Weldon et al.,Blood113(16):3792-3800,2009;Onda et al.,Proc Natl Acad Sci USA 105(32):11311-11316,2008;和PCTPublication Nos.WO 2007/016150,WO 2009/032954和WO 2011/032022,将其通过引用并入本文)。
在一些实例中,PE是抗溶酶体降解的变体,例如PE-LR(Weldon et al.,Blood113(16):3792-3800,2009;PCT公开号WO 2009/032954)。在其他实例中,PE是命名为PE-LR/6X的变体(PCT公开号WO 2011/032022)。在其他实例中,PE变体是免疫原性降低的PE。在其他实例中,PE是命名为PE-LR/8M的变体(PCT公开号WO2011/032022)。
PE的修饰可能发生在任何先前描述的变体中,包括PE的细胞毒性片段(例如,PE38、PE-LR和PE-LR/8M)。修饰的PE可包括任何替换(多个),例如对PE的一个或更多个T细胞表位和/或B细胞表位内的一个或更多个氨基酸残基,或一个或更多个T细胞和/或B-细胞表位的缺失(参见,例如,美国专利申请公开号2015/0099707)。
PE的预期形式还包括PE的去免疫形式,例如缺失结构域II的版本(例如,PE24)。PE的去免疫形式描述于例如,PCT公开号WO 2005/052006、WO 2007/016150、WO 2007/014743、WO 2007/031741、WO 2009/32954、WO 2011/32022、WO 2012/154530和WO 2012/170617中。
本文所述的抗体还可用于将许多不同的诊断或治疗化合物靶向于在其表面上表达肿瘤或病毒抗原的细胞。因此,本公开的抗体可以直接或经由接头附着至药物,所述药物将直接递送至表达细胞的细胞表面抗原。这可以出于治疗、诊断或研究目的进行。治疗剂包括诸如核酸、蛋白质、肽、氨基酸或衍生物、糖蛋白、放射性同位素、脂质、碳水化合物或重组病毒的化合物。核酸治疗和诊断部分包括反义核酸、用于与单链或双链DNA共价交联的衍生寡核苷酸以及形成三链体的寡核苷酸。
或者,与抗体连接的分子可以是封装系统,例如含有治疗组合物例如药物、核酸(例如反义核酸)的纳米颗粒、脂质体或胶束,或另一种优选可避免直接暴露于循环系统的治疗部分。制备附着于抗体的脂质体的手段是本领域技术人员众所周知的(参见,例如,美国专利号4,957,735;Connor et al.,Pharm.Ther.28:341-365,1985)。
本文所述的抗体也可以共价或非共价连接至可检测标签。适用于这种用途的可检测标签包括可通过光谱、光化学、生物化学、免疫化学、电、光学或化学手段检测的任何组合物。有用的标签包括磁珠、荧光染料(例如异硫氰酸荧光素、德克萨斯红、若丹明、绿色荧光蛋白等)、放射性标签(例如3H、125I、35S、14C或32P)、酶(例如辣根过氧化物酶、碱性磷酸酶和ELISA中常用的其他酶)和比色标签(例如,胶体金或有色玻璃或塑料(例如,聚苯乙烯、聚丙烯、乳胶等)珠。
检测此类标签的手段是本领域技术人员众所周知的。因此,例如,可以使用照相底片或闪烁计数器来检测放射性标签,可以使用光检测器来检测发射的照明来检测荧光标志物。通常通过向酶提供底物并检测由于酶在底物上的作用而产生的反应产物来检测酶标签,并且比色标签通过简单地可视化有色标签来检测。
V.嵌合抗原受体(CAR)
所公开的单克隆抗体还可以用于产生CAR(也称为嵌合T细胞受体、人工T细胞受体或嵌合免疫受体)和/或经工程改造以表达CAR的细胞毒性T淋巴细胞(CTL)。通常,CAR包含结合部分、胞外铰链和间隔区元件、跨膜区和执行信号传导功能的内结构域(Cartellieriet al.,JBiomedBiotechnol 2010:956304,2010;Dai et al.,JNatl CancerInst108(7):djv439,2016)。在许多情况下,结合部分是单克隆抗体例如scFv或单结构域抗体的抗原结合片段。间隔区/铰链区通常包括来自IgG亚类的序列,例如IgG1、IgG4、IgD和CD8结构域。跨膜结构域可以衍生自多种不同的T细胞蛋白,例如CD3ζ、CD4、CD8或CD28。几种不同的内结构域已用于产生CAR。例如,内结构域可以由具有ITAM的信号传导链组成,例如CD3ζ或FcεRIγ。在一些情况下,内结构域还包括至少一个另外的共刺激结构域的细胞内部分,例如CD28、4-1BB(CD137、TNFRSF9)、OX-40(CD134)、ICOS、CD27和/或DAP10。
表达CAR的CTL可用于靶向特定的细胞类型,例如GPC2阳性肿瘤细胞。因此,本文公开的单克隆抗体可用于工程化表达含有GPC2特异性单克隆抗体(或其片段)的CAR的的CTL,从而将工程化的CTL靶向表达GPC2的肿瘤细胞。工程化的T细胞先前已用于某些类型的癌症的过继性治疗(参见,例如,Park et al.,Mol Ther 15(4):825-833,2007)。与基于CTL的标准免疫疗法相比,表达CAR的T细胞的使用更为普遍,因为表达CAR的CTL是不受HLA限制的,因此可用于患有表达靶抗原的肿瘤的任何患者。
因此,本文提供了包括GPC2特异性抗体的CAR。还提供了分离的编码CAR的核酸分子和载体,以及表达CAR的宿主细胞,例如CTL。表达由GPC2特异性单克隆抗体组成的CAR的CTL可用于治疗表达GPC2的癌症。在本文的一些实施方案中,CAR是双特异性CAR。
在某些情况下,期望在将表达CAR的T细胞输注到患者体内后调节它们的激活和扩增。如Rodgers et al.(Proc NatlAcad Sci USA 113(4):E459-E468,2016)所述,已经开发出几种策略来在体内将表达CAR的T细胞模块化,包括使用介导表达CAR的T细胞与靶向肿瘤细胞之间的相互作用的基于抗体的开关。基于抗体的开关由已嫁接有肽新表位(PNE)的肿瘤抗原特异性抗体组成。可切换的CAR T(sCAR-T)细胞旨在与PNE特异性结合。由于sCAR-T细胞不结合内源性抗原,因此必须存在开关才能对其进行激活。
因此,本文提供了基于抗体的开关,其包括与异源肽(例如PNE)融合的本文公开的GPC2特异性抗体。在一些实施方案中,异源肽对人不是内源的(例如,它是在人蛋白质组中未发现的肽)。在一些实例中,异源肽的长度为约8个氨基酸至约20个氨基酸,例如长度为约10至约18个氨基酸,例如长度为约12至约16个氨基酸,例如长度为约14个氨基酸。在特定实例中,异源肽的长度为约8、9、10、11、12、13、14、15、16、17、18、19或20个氨基酸。在特定的非限制性实例中,PNE包含NYHLENEVARLKKL(SEQ ID NO:13)或由其组成。
在一些实施方案中,CAR包括信号肽序列,例如在抗原结合结构域的N末端。信号肽序列可以是任何合适的信号肽序列,例如来自粒细胞-巨噬细胞集落刺激因子受体(GMCSFR)、免疫球蛋白轻链κ或IL-2的信号序列。尽管信号肽序列可以促进CAR在细胞表面上的表达,但是为了使CAR起作用,在表达的CAR中信号肽序列的存在不是必需的。在CAR在细胞表面上表达时,信号肽序列可以从CAR上切割下来。因此,在一些实施方案中,CAR缺乏信号肽序列。
在一些实施方案中,本文公开的CAR从也表达人EGFR(huEGFRt)的截短形式的构建体(例如从慢病毒载体)表达。CAR和huEGFRt被自我切割的肽序列(例如T2A)分开,使得在转导的细胞中表达后,CAR就会从huEGFRt上切割下来。
在本文公开的一些实施方案中,CAR构建体在N末端至C末端方向上编码以下氨基酸序列:
GMCSFRss:MLLLVTSLLLCELPHPAFLLIP(SEQ ID NO:14)
NdeI:HM
抗原结合:GPC2-特异性scFv(例如SEQ ID NO:9-12中的任一个)
SpeI:TS
CD8α铰链:TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:15)
CD8αTM:IYIWAPLAGTCGVLLLSLVIT(SEQ ID NO:16)
4-1BB:KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:17)
CD3ζ:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:18)
T2A:EGRGSLLTCGDVEENPGP(SEQ ID NO:19)
GMCSFRss:MLLLVTSLLLCELPHPAFLLIP(SEQ ID NO:14)
huEGFRt:
RKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM(SEQ ID NO:20)
人表皮生长因子受体由四个胞外结构域、跨膜结构域和三个胞内结构域组成。在以下N末端至C末端顺序中发现EGFR结构域:结构域I-结构域II-结构域III-结构域IV-跨膜(TM)结构域-近膜结构域-酪氨酸激酶结构域-C末端尾。结构域I和结构域III是富含亮氨酸的结构域,其参与配体结合。结构域II和结构域IV是富含半胱氨酸的结构域,并且不与EGFR配体接触。结构域II介导具有与其他EGFR家族成员相似结构域的同源或异源二聚体的形成,且结构域IV可与结构域II形成二硫键。EGFR TM结构域单次通过细胞膜,且可能在蛋白质二聚化中起作用。胞内结构域包括介导EGFR信号转导的近膜结构域、酪氨酸激酶结构域和C末端尾(Wee和Wang,Cancers 9(52),doi:10.3390/cancers9050052;Ferguson,AnnuRev Biophys 37:353-373,2008;Wang et al.,Blood 118(5):1255-1263,2011)。
人EGFR的截短形式,在本文中称为“huEGFRt”,仅包括结构域III、结构域IV和TM结构域。因此,huEGFRt缺乏结构域I、结构域II和所有三个胞内结构域。huEGFRt无法结合EGF,并且缺乏信号传导活性。然而,该分子保留结合特定EGFR特异性单克隆抗体,例如FDA批准的西妥昔单抗的能力(PCT公开号WO 2011/056894,其通过引用并入本文)。
用本文公开的编码huEGFRt和肿瘤抗原特异性CAR的构建体(例如慢病毒载体)转导T细胞可以使用标记的EGFR单克隆抗体西妥昔单抗(ERBITUXTM)选择转导的T细胞。例如,西妥昔单抗可以用生物素标记,并且可以使用可商购的抗生物素磁珠选择转导的T细胞(例如来自Miltenyi Biotec)。huEGFRt的共表达还允许在体内跟踪过继性转移的表达CAR的T细胞。此外,西妥昔单抗与表达huEGFRt的T细胞的结合诱导ADCC效应器细胞的细胞毒性,从而提供在体内消除转导的T细胞的机制(Wang et al.,Blood 118(5):1255-1263,2011),例如在治疗结束时。
VI.抗体-药物偶联物(ADC)
ADC是由肿瘤抗原特异性抗体(或其抗原结合片段)和药物组成的化合物,通常为细胞毒性剂,例如抗微管剂或交联剂。由于ADC能够特异性地靶向癌细胞,因此该药物的功效可能比用于标准化疗的药物更有效。目前与ADC一起使用的最常见的细胞毒性药物的IC50强度比传统化疗药物的更有效100到1000倍。常见的细胞毒性药物包括抗微管药,例如美登素类化合物和澳瑞他汀类(例如澳瑞他汀E和澳瑞他汀F)。与ADC一起使用的其他细胞毒素包括吡咯并苯并二氮杂卓(PDB),其共价结合DNA的小沟以形成链间交联。在许多情况下,ADC包含1:2至1:4比例的抗体与药物(Bander,ClinicalAdvances in Hematology&Oncology 10(8;suppl 10):3-7,2012)。
抗体和药物可以通过可切割或不可切割的接头连接。然而,在某些情况下,期望具有在循环中稳定的接头,以防止细胞毒性药物的全身释放,这可能导致明显的脱靶毒性。不可切割的接头防止在ADC被靶细胞内化之前的细胞毒性剂的释放。一旦处于溶酶体中,溶酶体蛋白酶对抗体的消化导致细胞毒性剂的释放(Bander,ClinicalAdvances inHematology&Oncology 10(8;suppl 10):3-7,2012)。
药物与单克隆抗体的位点特异性和稳定偶联的一种方法是通过聚糖工程。单克隆抗体在每条重链的CH2结构域的Asn297残基处具有一个保守的N-连接的寡糖链(Qasba etal.,Biotechnol Prog 24:520-526,2008)。使用突变β1,4-半乳糖基转移酶(Y289L-Gal-T1;美国专利申请公开号2007/0258986和2006/0084162,通过引用并入本文),将2-酮-半乳糖转移至抗体重链上的游离GlcNAc残基以提供用于偶联的化学处理。
基于末端半乳糖残基,附着至单克隆抗体的寡糖链可分为三类-完全半乳糖基化(两个半乳糖残基;IgG-G2),一个半乳糖残基(IgG-G1)或完全去半乳糖基化(IgG-G0)。用β1,4-半乳糖苷酶处理单克隆抗体将抗体转化为IgG-G0糖型。突变β1,4-半乳糖基转移酶能够将2-酮-半乳糖或2-叠氮基-半乳糖从它们各自的UDP衍生物转移至IgG-G1和IgG-G0糖型上的GlcNAc残基。转移的糖上的化学处理使得能够通过聚糖残基将多种分子与单克隆抗体偶联(Qasba et al.,BiotechnolProg24:520-526,2008)。
本文提供的ADC包括与结合(例如特异性结合)GPC2的单克隆抗体偶联的药物(例如,细胞毒性剂)。在一些实施方案中,药物是小分子。在一些实例中,药物是交联剂、抗微管剂和/或抗有丝分裂剂,或适合于介导杀死肿瘤细胞的任何细胞毒性剂。示例性细胞毒性剂包括但不限于,PDB、澳瑞他汀、美登素类化合物、尾海兔素、卡里奇霉素、奈莫柔比星及其衍生物、PNU-159682、蒽环类药物、长春花生物碱、紫杉烷、单端孢霉烯、CC1065、喜树碱、依利奈法德、康普瑞汀、尾海兔素、倍癌霉素(duocarmycin)、烯二炔、格尔德霉素、吡咯并-苯并二氮杂卓二聚体、嘌呤霉素、tubulysin、哈米特林、剪接抑素(spliceostatin)或普拉地内酯(pladienolide)、以及具有细胞毒性的立体异构体、电子等排体、类似物及其衍生物。
在一些实施方案中,ADC包括吡咯并苯并二氮杂卓(PBD)。天然产物安曲霉素(PBD)于1965年首次报道(Leimgruber et al.,JAm Chem Soc,87:5793-5795,1965;Leimgruberet al.,JAm Chem Soc,87:5791-5793,1965)。自那时以来,已经报道了许多PBD,既有天然存在的也有合成类似物(Gerratana,MedRes Rev 32(2):254-293,2012;以及美国专利号6,884,799;7,049,311;7,067,511;7,265,105;7,511,032;7,528,126;和7,557,099)。作为一个实例,PDB二聚体识别并结合特定的DNA序列,并已证实可用作细胞毒性剂。PBD二聚体已经与抗体偶联,并且所得ADC显示出具有抗癌特性(参见,例如,US 2010/0203007)。PBD二聚体上的示例性连接位点包括五元吡咯环,PBD单元之间的系链和N10-C11亚胺基(参见WO2009/016516;US 2009/304710;US 2010/047257;US 2009/036431;US 2011/0256157;和WO2011/130598)。
在一些实施方案中,ADC包含偶联至一个或更多个美登素类化合物分子的抗体。美登素类化合物是美登素的衍生物,并且是通过抑制微管蛋白聚合而起作用的有丝分裂抑制剂。美登素最初是从东非灌木齿叶美登木中分离得到的(美国专利号3,896,111)。随后,发现某些微生物也产生美登素类化合物,例如美登醇和C-3美登醇酯(美国专利号4,151,042)。合成的美登素类化合物公开在例如,美国专利号4,137,230;4,248,870;4,256,746;4,260,608;4,265,814;4,294,757;4,307,016;4,308,268;4,308,269;4,309,428;4,313,946;4,315,929;4,317,821;4,322,348;4,331,598;4,361,650;4,364,866;4,424,219;4,450,254;4,362,663;和4,371,533中。
在一些实施方案中,ADC包括与尾海兔素或澳瑞他汀或其类似物或衍生物偶联的抗体(参见美国专利号5,635,483;5,780,588;5,767,237;和6,124,431)。澳瑞他汀类是海洋软体动物化合物尾海兔素-10的衍生物。已经证实尾海兔素和澳瑞他汀干扰微管动力学、GTP水解以及核和细胞分裂(Woyke et al.,Antimicrob Agents and Chemother45(12):3580-3584,2001)并具有抗癌作用(美国专利号5,663,149)和抗真菌活性(Pettit et al.,AntimicrobAgents Chemother 42:2961-2965,1998)。示例性的尾海兔素和澳瑞他汀包括但不限于,尾海兔素10、澳瑞他汀E、澳瑞他汀F、澳瑞他汀EB(AEB)、澳瑞他汀EFP(AEFP)、MMAD(单甲基澳瑞他汀D或单甲基尾海兔素10)、MMAF(单甲基澳瑞他汀F或N-甲基缬氨酸-缬氨酸-海兔异亮氨酸(dolaisoleuine)-海兔脯氨酸(dolaproine)-苯丙氨酸)、MMAE(单甲基澳瑞他汀E或N-甲基缬氨酸-缬氨酸-海兔异亮氨酸-海兔脯氨酸-去甲麻黄碱)、5-苯甲酰基戊酸-AE酯(AEVB)和其他澳瑞他汀类(参见例如,美国公开号2013/0129753)。
在一些实施方案中,ADC包含偶联至一个或更多个卡里奇霉素(calicheamicin)分子的抗体。卡里奇霉素抗生素家族及其类似物能够在亚皮摩尔浓度下产生双链DNA断裂(Hinman et al.,Cancer Res 53:3336-3342,1993;Lode et al.,Cancer Res 58:2925-2928,1998)。在美国专利号5,712,374;5,714,586;5,739,116;和5,767,285中描述了用于制备具有卡里奇霉素药物部分的ADC的示例性方法。
在一些实施方案中,ADC包括蒽环类。蒽环类是具有细胞毒性活性的抗生素化合物。人们认为,蒽环类可以通过多种不同的机制杀死细胞,包括将药物分子插入细胞的DNA中,从而抑制DNA依赖性核酸合成;诱导产生自由基,然后自由基与细胞大分子发生反应,从而损坏细胞;和/或药物分子与细胞膜的相互作用。非限制性示例性蒽环类包括阿霉素、表柔比星、伊达比星、道诺霉素、柔红霉素、阿霉素、表柔比星、奈莫柔比星、戊柔比星和米托蒽醌及其衍生物。例如,PNU-159682是奈莫柔比星的有效代谢产物(或衍生物)(Quintieri etal.,Clin Cancer Res 11(4):1608-1617,2005)。奈莫柔比星是阿霉素的半合成类似物,在阿霉素的糖苷氨基上具有2-甲氧基吗啉基(Grandi et al.,Cancer TreatRev 17:133,1990;Ripamonti et al.,BrJCancer 65:703-707,1992)。
在一些实施方案中,ADC可以进一步包括接头。在一些实例中,接头是可用于将一个或更多个药物部分连接至抗体以形成ADC的双官能或多官能部分。在一些实施方案中,使用具有反应性官能团的接头制备ADC,所述反应性官能团用于共价附着到药物和抗体。例如,抗体的半胱氨酸硫醇可与接头或药物接头中间体的反应性官能团形成键以形成ADC。
在一些实例中,接头具有能够与抗体上存在的游离半胱氨酸反应以形成共价键的官能团。具有这种反应性官能团的示例性接头包括马来酰亚胺、卤代乙酰胺、β-卤代乙酰基、活化的酯,例如琥珀酰亚胺酯、4-硝基苯基酯、五氟苯基酯、四氟苯基酯、酸酐、酰氯、磺酰氯、异氰酸酯和异硫氰酸酯。
在一些实例中,接头具有能够与抗体上存在的亲电子基团反应的官能团。这种亲电子基团的实例包括但不限于,醛和酮羰基。在某些情况下,接头的反应性官能团的杂原子可与抗体上的亲电子基团反应并与抗体单元形成共价键。非限制性实例包括酰肼、肟、氨基、肼、缩氨基硫脲、联氨羧酸酯和芳酰肼。
在一些实例中,接头是可切割的接头,其促进药物的释放。可切割的接头的实例包括酸不稳定的接头(例如,包含腙)、蛋白酶敏感的接头(例如,肽酶敏感的)、光不稳定的接头和含二硫键的接头(Chari et al.,CancerRes 52:127-131,1992;U.S.Patent No.5,208,020)。
本文公开的ADC可单独或与另一种治疗剂组合和/或与用于治疗癌症的任何标准疗法组合用于治疗GPC2阳性癌症(例如,用于肿瘤的外科切除、化学疗法或放射疗法)。
VII.多特异性抗体
多特异性抗体是由两种或更多种不同单克隆抗体的抗原结合片段组成的重组蛋白。例如,双特异性抗体由两种不同单克隆抗体的抗原结合片段组成。因此,双特异性抗体结合两种不同的抗原,且三特异性抗体结合三种不同的抗原。多特异性抗体通过同时靶向例如CTL(例如,CTL受体组分如CD3)或效应器自然杀伤(NK)细胞和至少一种肿瘤抗原而用于癌症免疫疗法。本文公开的GPC2特异性单克隆抗体可用于产生靶向GPC2和CTL二者、或靶向GPC2和NK细胞的多特异性(例如,双特异性或三特异性)抗体,从而提供治疗表达GPC2的癌症的手段。
双特异性T细胞衔接子(BiTE)是一种类型的双特异性单克隆抗体,其是靶向肿瘤抗原的第一单链可变片段(scFv)和结合T细胞(例如结合T细胞上的CD3)的第二scFv的融合体。在本文的一些实施方案中,BiTE的结合部分之一(例如scFv分子之一)对GPC2具有特异性。
双特异性杀伤细胞衔接子(BiKE)是一种类型的双特异性单克隆抗体,其是靶向肿瘤抗原的第一scFv和结合NK细胞激活受体(例如,CD16)的第二scFv的融合体。
本文提供了包含GPC2特异性单克隆抗体的多特异性(例如,三特异性或双特异性)单克隆抗体。在一些实施方案中,多特异性单克隆抗体还包含特异性结合T细胞受体的组分(例如CD3)的单克隆抗体或其抗原结合片段。在其他实施方案中,多特异性单克隆抗体还包含特异性结合NK细胞激活受体(例如CD16、Ly49或CD94)的单克隆抗体或其抗原结合片段。还提供了编码多特异性抗体的分离的核酸分子和载体,以及包含核酸分子或载体的宿主细胞。包含GPC2特异性抗体的多特异性抗体可以用于治疗表达GPC2的癌症。因此,本文提供了通过选择患有表达GPC2的癌症的受试者并向该受试者施用治疗有效量的靶向GPC2的多特异性抗体来治疗患有癌症的受试者的方法。
VIII.抗体-纳米颗粒偶联物
本文公开的单克隆抗体可以与多种不同类型的纳米颗粒偶联,以通过抗体与在肿瘤表面上表达的肿瘤特异性抗原(例如GPC2)的结合而将细胞毒性剂或其他抗癌剂直接递送至肿瘤细胞。纳米颗粒的使用减少了脱靶副作用,并且还可以改善药物生物利用度并减少达到治疗效果所需的药物剂量。可以调整纳米颗粒制剂以适合要在纳米颗粒内携带或封装的药物。例如,可以将疏水性分子掺入纳米颗粒的核内,而将亲水性药物携带在由聚合物或脂质壳保护的水性核内。纳米颗粒的实例包括但不限于纳米球、纳米胶囊、脂质体、树枝状分子、聚合物胶束、脂囊泡和聚合物纳米颗粒(Fay和Scott,Immunotherapy 3(3):381-394,2011)。
脂质体目前是用于药物递送的最常见的纳米颗粒类型之一。与脂质体偶联的抗体通常被称为“免疫脂质体”。免疫脂质体的脂质体组分通常是一个或更多个同心磷脂双层的脂质囊泡。在某些情况下,磷脂由亲水性头基和两个疏水性链组成,以使疏水性和亲水性药物都能封装。常规脂质体通过网状内皮系统(RES)的巨噬细胞从循环中迅速除去。为了产生长循环脂质体,可以调节脂质体的组成、大小和电荷。脂质体的表面也可以被修饰,例如用糖脂或唾液酸。例如,包含聚乙二醇(PEG)可显著增加循环半衰期。在本领域中已经描述了用作药物递送剂的脂质体,包括用于制备免疫脂质体的脂质体(参见,例如,Paszko和Senge,CurrMed Chem 19(31)5239-5277,2012;Immordino et al.,Int J Nanomedicine 1(3):297-315,2006;美国专利申请公开号2011/0268655;2010/00329981)。
类脂囊泡是基于非离子表面活性剂的囊泡,其具有类似于脂质体的结构。类脂囊泡的膜仅由非离子表面活性剂组成,例如聚甘油基烷基醚或N-棕榈酰基氨基葡萄糖。类脂囊泡范围从小的单层颗粒到大的多层颗粒。这些纳米颗粒是单分散的、水溶性的、化学稳定的,具有低毒性,是可生物降解的和非免疫原性的,并增加了封装药物的生物利用度。
树枝状分子包括一系列支链聚合物复合物。这些纳米颗粒是水溶性的、生物相容性的,并且对于人类使用是足够非免疫原性的。通常,树枝状分子由引发剂核组成,其被接枝到该核上的所选聚合物层包围,形成支化的大分子复合物。树枝状分子通常使用诸如聚(酰胺基胺)或聚(L-赖氨酸)的聚合物生产。树枝状分子已经用于多种治疗和诊断应用,包括用于递送DNA、RNA、生物成像造影剂和化学治疗剂。
聚合物胶束由两亲性共聚物(由亲水性和疏水性单体单元组成)的聚集体组成,其组装成疏水核,并被暴露于水性环境的亲水性聚合物链的电晕所包围。在许多情况下,用于制备聚合物胶束的聚合物是异双官能共聚物,由形成颗粒核的PEG亲水性嵌段、聚(乙烯基吡咯烷酮)和疏水性聚(L-丙交酯)或聚(L-赖氨酸)组成。聚合物胶束可用于运载溶解性较差的药物。这些纳米颗粒已用于封装许多抗癌药物,包括阿霉素和喜树碱。阳离子胶束也已经被开发来携带DNA或RNA分子。
聚合物纳米颗粒包括纳米球和纳米胶囊。纳米球由聚合物的固体基质组成,而纳米胶囊包含水性核。选择的制剂通常取决于待携带/封装的治疗剂的溶解度;水溶性差的药物更容易封装在纳米球中,而水溶性和不稳定药物(例如DNA和蛋白质)更容易封装在纳米胶囊中。用于生产这些纳米颗粒的聚合物包括,例如,聚(丙烯酰胺)、聚(酯)、聚(氰基丙烯酸烷基酯)、聚(乳酸)(PLA)、聚(乙醇酸)(PGA)和聚(D,L-乳酸-co-乙醇酸)(PLGA)。
可以根据本领域已知的标准方法将抗体(或其片段)偶联至合适的纳米颗粒。例如,偶联可以是共价的或非共价的。在其中纳米颗粒是脂质体的一些实施方案中,抗体通过PEG链附着至空间稳定的长循环脂质体。抗体或抗体片段与脂质体的偶联也可以涉及硫酯键,例如通过硫醇和马来酰亚胺基团的反应。交联剂可用于产生巯基基团以使抗体附着于纳米颗粒(Paszko和Senge,CurrMed Chem 19(31)5239-5277,2012)。
IX.组合物和使用方法
提供了包括一种或更多种公开的单克隆抗体的组合物,所述单克隆抗体结合(例如特异性结合)运载体中的GPC2。还提供了包含ADC、CAR(和包含CAR的CTL)、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体和免疫偶联物的组合物。组合物可以单位剂型制备,以施用于受试者。施用的量和时机由临床治疗医师决定是否达到期望的结局。抗体、ADC、CAR、CTL、多特异性抗体、抗体-纳米颗粒偶联物、免疫脂质体或免疫偶联物可被配制用于全身或局部(例如瘤内)施用。在一个实例中,将抗体配制用于肠胃外施用,例如静脉内施用。
用于施用的组合物可以包括抗体、ADC、CAR、CTL、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体或免疫偶联物在药学上可接受的运载体(例如水性运载体)中的溶液。可以使用多种水性运载体,例如缓冲盐水等。这些溶液是无菌的,通常没有不期望的物质。这些组合物可以通过常规的、众所周知的灭菌技术进行灭菌。组合物可包含近似生理条件所需的药学上可接受的辅助物质,例如pH调节剂和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这些制剂中抗体的浓度可以在很大范围内变化,并且将根据所选择的特定施用方式和受试者的需要,主要基于体液量、粘度、体重等来选择。
用于静脉内施用的典型药物组合物每天每位受试者包含约0.1至10mg抗体(或ADC、CAR、多特异性抗体、抗体-纳米颗粒偶联物或免疫偶联物)。可使用每天每位受试者0.1至约100mg的剂量,特别是如果将药剂施用到隐蔽的部位,而不是进入循环系统或淋巴系统,例如进入体腔或器官的内腔。用于制备可施用的组合物的实际方法对本领域技术人员而言是已知的或显而易见的,并且在诸如Remington's Pharmaceutical Science,19thed.,Mack Publishing Company,Easton,PA(1995)的出版物中有更详细的描述。
抗体(或其他治疗性分子)可以冻干形式提供,并在施用前用无菌水再水化,尽管它们也以已知浓度的无菌溶液形式提供。然后将抗体溶液添加到含有0.9%氯化钠、USP的输液袋中,在某些情况下以0.5至15mg/kg体重的剂量施用。自1997年RITUXANTM获批以来,抗体药物的施用领域已有相当丰富的经验,抗体药物已在美国上市。抗体、ADC、CAR、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体或免疫偶联物可以通过缓慢输注来给药,而不是通过静脉推注或团注来施用。在一个实例中,施用较高的负载剂量,随后以较低的水平施用维持剂量。例如,可以在约90分钟的时间内输注4mg/kg的初始负载剂量,如果先前的剂量耐受良好,则可以在30分钟时间内输注2mg/kg的每周维持剂量时间为4-8周。
控释肠胃外制剂可以制成植入物、油性注射剂或颗粒系统。对于蛋白质递送系统的广泛概述,参见Banga,A.J.,Therapeutic Peptides and Proteins:Formulation,Processing,andDelivery Systems,Technomic Publishing Company,Inc.,Lancaster,PA,(1995)。颗粒系统包括例如,微球、微粒、微胶囊、纳米胶囊、纳米球和纳米颗粒。微胶囊含有治疗性蛋白质,例如细胞毒素或药物,作为中心核。在微球中,治疗剂分散在整个颗粒中。小于约1μm的颗粒、微球和微胶囊通常分别称为纳米颗粒、纳米球和纳米胶囊。毛细管的直径为约5μm,使得只有纳米颗粒可以静脉内施用。微粒的直径通常为约100μm,可通过皮下或肌肉内施用。参见例如,Kreuter,J.,Colloidal Drug Delivery Systems,J.Kreuter,ed.,Marcel Dekker,Inc.,New York,NY,pp.219-342(1994);和Tice&Tabibi,Treatise onControlledDrugDelivery,A.Kydonieus,ed.,Marcel Dekker,Inc.New York,NY,pp.315-339,(1992)。
聚合物可用于离子控制释放本文公开的基于抗体的组合物。用于受控药物递送的各种可降解和不可降解的聚合物基质是本领域已知的(Langer,Accounts Chem.Res.26:537-542,1993)。例如,嵌段共聚物泊洛沙姆407在低温下以粘性但可流动的液体形式存在,但在体温下形成半固体凝胶。已证明它是用于配制和持续递送重组白介素-2和脲酶的有效溶媒(Johnston et al.,Pharm.Res.9:425-434,1992;和Pec et al.,J.Parent.Sci.Tech.44(2):58-65,1990)。另外,羟基磷灰石已被用作微运载体,用于蛋白质的控制释放(Ijntema et al.,Int.J.Pharm.112:215-224,1994)。在另一方面,脂质体可用于脂质胶囊包裹的药物的控制释放以及药物靶向(Betageri et al.,LiposomeDrugDelivery Systems,Technomic Publishing Co.,Inc.,Lancaster,PA(1993))。用于治疗性蛋白质的受控递送的许多其他系统是已知的(参见美国专利号5,055,303;5,188,837;4,235,871;4,501,728;4,837,028;4,957,735;5,019,369;5,055,303;5,514,670;5,413,797;5,268,164;5,004,697;4,902,505;5,506,206;5,271,961;5,254,342和5,534,496)。
A.治疗方法
可以施用本文公开的抗体、组合物、CAR(和表达CAR的CTL)、ADC、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体和免疫偶联物以减缓或抑制肿瘤细胞的生长或抑制肿瘤细胞的转移,例如GPC2阳性癌症。在这些应用中,将治疗有效量的组合物以足以抑制癌细胞的生长、复制或转移、或抑制癌症的体征或症状的量施用于受试者。因此,在一些实例中,公开的方法将原发性肿瘤和/或转移的大小、重量和/或体积减少至少20%、至少25%、至少50%、至少75%、至少80%、至少90%、至少95%、至少99%、甚至100%。因此,在一些实例中,公开的方法将转移的数量减少至少20%、至少25%、至少50%、至少75%、至少80%、至少90%、至少95%、至少99%、或甚至100%。合适的受试者可能包括那些被诊断出患有表达GPC2的癌症的受试者,例如但不限于神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
本文提供了通过向受试者施用治疗有效量的GPC2特异性抗体、免疫偶联物、CAR(例如,表达CAR的CTL)、ADC、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体或本文公开的组合物来治疗受试者中的GPC2阳性癌症的方法。本文还提供了通过向受试者施用治疗有效量的GPC2特异性抗体、免疫偶联物、CAR(例如,表达CAR的CTL)、ADC、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体或本文公开的组合物来抑制受试者中的GPC2阳性癌症的肿瘤生长或转移的方法。在一些实施方案中,GPC2阳性癌症是神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
GPC2特异性单克隆抗体(或其片段)、ADC、CAR(例如,表达CAR的CTL)、多特异性(例如,双特异性或三特异性)抗体、免疫偶联物、免疫脂质体或本文公开的组合物的治疗有效量将取决于疾病的严重程度、疾病的类型以及患者健康的一般状况。基于抗体的组合物的治疗有效量是提供症状(多个)的主观缓解或如临床医生或其他合格观察员所指出的客观可识别的改善的量。
施用本文公开的GPC2特异性抗体、ADC、CAR、免疫偶联物、多特异性(例如双特异性或三特异性)抗体、抗体-纳米颗粒偶联物、免疫脂质体和组合物也可以伴随施用其他抗癌剂或治疗性治疗(例如手术切除肿瘤)。任何合适的抗癌剂可以与本文公开的抗体、组合物和免疫偶联物联合施用(例如序贯地或同时地)。示例性的抗癌剂包括但不限于化学治疗剂,诸如例如有丝分裂抑制剂、烷基化剂、抗代谢物、嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、抗存活剂、生物反应调节剂,抗激素(例如抗雄激素)和抗血管生成剂。其他抗癌治疗包括放射治疗和其他特异性靶向癌细胞的抗体。
烷基化剂的非限制性实例包括氮芥(例如,二氯甲基二乙胺、环磷酰胺、美法仑、尿嘧啶氮芥或苯丁酸氮芥)、烷基磺酸酯(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、链脲菌素或达卡巴嗪)。
抗代谢物的非限制性实例包括叶酸类似物(例如甲氨蝶呤)、嘧啶类似物(例如,5-FU或阿糖胞苷)和嘌呤类似物,例如巯基嘌呤或硫代鸟嘌呤。
天然产物的非限制性实例包括长春花生物碱(例如,长春碱、长春新碱或长春地辛)、表鬼臼毒素(例如,依托泊苷或替尼泊苷)、抗生素(例如,放线菌素、柔红霉素、阿霉素、博来霉素、普卡霉素、或丝裂霉素C)和酶(例如,L-天冬酰胺酶)。
其他试剂的非限制性实例包括铂配位复合物(例如顺式二胺-二氯铂II、也称为顺铂)、取代的尿素(例如羟基脲)、甲基肼衍生物(例如,丙卡巴肼)和肾上腺皮质激素抑制剂(例如,米托坦和氨鲁米特)。
激素和拮抗剂的非限制性实例包括肾上腺皮质类固醇(例如,泼尼松)、孕激素(例如,己酸羟孕酮、乙酸甲羟孕酮和乙酸甲地孕酮)、雌激素(例如,二乙基己烯雌酚和炔雌醇)、抗雌激素(例如,他莫昔芬)和雄激素(例如,丙酸睾丸酮和氟甲睾酮)。通常使用的化疗药物的实例包括阿霉素(Adriamycin)、马法兰(Alkeran)、阿糖胞苷(Ara-C)、BiCNU、白消安(Busulfan)、CCNU、卡铂、顺铂、环磷酰胺(Cytoxan)、柔红霉素(Daunorubicin)、DTIC、5-FU、氟达拉滨(Fludarabine)、羟基脲(Hydrea)、伊达比星(ldarubicin)、异环磷酰胺(lfosfamide)、甲氨蝶呤(Methotrexate)、光辉霉素(Mithramycin)、丝裂霉素(Mitomycin)、米托蒽醌(Mitoxantrone)、氮芥(Nitrogen Mustard)、紫杉醇(Taxol)(或其他紫杉烷(taxanes),例如多西他赛(docetaxel))、长春花碱(Velban)、长春新碱(Vincristine)、VP-16,而一些较新的药物包括吉西他滨(Gemcitabine)(Gemzar)、赫赛汀(Herceptin)、伊立替康(lrinotecan)(Camptosar、CPT-11)、克拉屈滨(Leustatin)、长春瑞滨(Navelbine)、利妥昔单抗(Rituxan)STI-571、泰索帝(Taxotere)、托泊替康(Topotecan)(Hycamtin)、希罗达(Xeloda)(卡培他滨(Capecitabine))、Zevelin和骨化三醇(calcitriol)。
可以使用的免疫调节剂的非限制性实例包括AS-101(Wyeth-Ayerst Labs.)、溴匹立明(Upjohn)、γ干扰素(Genentech)、GM-CSF(粒细胞巨噬细胞集落刺激因子;GeneticsInstitute)、IL-2(Cetus或Hoffman-LaRoche)、人免疫球蛋白(Cutter Biological)、IMREG(来自New Orleans,La.的Imreg)、SK&F 106528和TNF(肿瘤坏死因子;Genentech)。
可与本文公开的抗体、组合物和免疫偶联物一起使用的其他生物制剂(例如单克隆抗体)的非限制性实例包括拮抗PD-1或PD-L1的抗体,例如阿替利珠单抗(Atezolizumab)、MPDL3280A、BNS-936558(纳武单抗)、帕博利珠单抗(Pembrolizumab)、匹地利珠单抗(Pidilizumab)、CT011、AMP-224、AMP-514、MEDI-0680、BMS-936559、BMS935559、MEDI-4736、MPDL-3280A、MSB-0010718C、MGA-271、吲哚莫德(Indoximod)、Epacadostat、BMS-986016、MEDI-4736、MEDI-4737、MK-4166、BMS-663513、PF-05082566(PF-2566)、利鲁单抗(Lirilumab)和度伐利尤单抗(Durvalumab)。在一些实例中,所施用的另外的治疗剂是3F8、阿巴伏单抗(Abagovomab)、阿德木单抗(Adecatumumab)、阿夫土珠(Afutuzumab)、培化阿珠单抗(Alacizumab)、阿仑单抗(Alemtuzumab)、喷替酸阿妥莫单抗(Altumomabpentetate)、麻安莫单抗(Anatumomab mafenatox)、阿泊珠单抗(Apolizumab)、阿西莫单抗(Arcitumomab)、巴维昔单抗(Bavituximab)、贝妥莫单抗(Bectumomab)、贝利尤单抗(Belimumab)、贝西洛索单抗(Besilesomab)、贝伐珠单抗(Bevacizumab)、莫比伐珠单抗(Bivatuzumab mertansine)、贝林妥欧单抗(Blinatumomab)、维布妥昔单抗(Brentuximabvedotin)、莫坎妥珠单抗(Cantuzumab mertansine)、卡罗单抗喷地肽(Capromabpendetide)、卡妥索单抗(Catumaxomab)、CC49、西妥昔单抗(Cetuximab)、泊西他珠单抗(Citatuzumab bogatox)、西妥木单抗(Cixutumumab)、泰坦-克利妥珠单抗(Clivatuzumabtetraxetan)、可那木单抗(Conatumumab)、达曲珠单抗(Dacetuzumab)、地莫单抗(Detumomab)、依美昔单抗(Ecromeximab)、依库珠单抗(Eculizumab)、依决洛单抗(Edrecolomab)、依帕珠单抗(Epratuzumab)、厄妥索单抗(Ertumaxomab)、埃达珠单抗(Etaracizumab)、法妥组单抗(Farletuzumab)、芬妥木单抗(Figitumumab)、加利昔单抗(Galiximab)、吉妥珠单抗(Gemtuzumab ozogamicum)、吉妥昔单抗(Girentuximab)、Glembatumumab vedotin、替伊莫单抗(Ibritumomab tiuxetan)、伊戈伏单抗(Igovomab)、英西单抗(Imciromab)、英妥木单抗(Intetumumab)、奥英妥珠单抗(Inotuzumabozogamicin)、伊匹单抗(Ipilimumab)、伊妥木单抗(Iratumumab)、拉贝珠单抗(Labetuzumab)、来沙木单抗(Lexatumumab)、林妥珠单抗(Lintuzumab)、莫星-洛沃妥珠单抗(Lorvotuzumab mertansine)、卢卡木单抗(Lucatumumab)、鲁昔单抗(Lumiliximab)、马帕木单抗(Mapatumumab)、马妥珠单抗(Matuzumab)、美泊利单抗(Mepolizumab)、美替木单抗(Metelimumab)、米拉组单(Milatuzumab)、米妥莫单抗(Mitumomab)、莫罗木单抗(Morolimumab)、他那可单抗(Nacolomab tafenatox)、埃托-那普妥莫单抗(Naptumomabestafenatox)、耐昔妥珠单抗(Necitumumab)、尼妥珠单抗(Nimotuzumab)、巯诺莫单抗(Nofetumomab merpentan)、奥法木单抗(Ofatumumab)、奥拉单抗(Olaratumab)、莫妥组单抗(Oportuzumab monatox)、奥瑞戈单抗(Oregovomab)、帕尼单抗(Panitumumab)、培妥木单抗(Pemtumomab)、帕妥珠单抗(Pertuzumab)、平妥单抗(Pintumomab)、普托木单抗(Pritumumab)、雷莫芦单抗(Ramucirumab)、利妥木单抗(Rilotumumab)、利妥昔单抗(Rituximab)、罗妥木单抗(Robatumumab)、标喷地肽沙妥莫单抗(Satumomab pendetide)、西罗珠单抗(Sibrotuzumab)、索耐珠单抗(Sonepcizumab)、替珠单抗(Tacatuzumabtetraxetan)、帕他普莫单抗(Taplitumomab paptox)、替妥莫单抗(Tenatumomab)、TGN1412、替西木单抗(Ticilimumab)、曲美木单抗(tremelimumab)、替加组单抗(Tigatuzumab)、TNX-650、曲妥珠单抗(Trastuzumab)、替西木单抗(Tremelimumab)、西莫白介素单抗(Tucotuzumab celmoleukin)、维妥珠单抗(Veltuzumab)、伏洛昔单抗(Volociximab)、伏妥莫单抗(Votumumab)、和扎鲁木单抗(Zalutumumab)中的一种或多种。用于一些类型的癌症的另一示例性治疗是外科手术治疗,例如外科手术切除癌症或其一部分。治疗的另一实例是放射疗法,例如在手术切除之前向肿瘤部位施用放射性物质或能量(例如外射束治疗)以帮助根除肿瘤或使其缩小。
本文还提供了试剂盒,其包括GPC2特异性单克隆抗体或抗原结合片段、CAR、分离细胞、免疫偶联物、ADC、多特异性抗体、抗体-纳米颗粒偶联物、融合蛋白或本文公开的组合物和用于治疗癌症的第二治疗剂。在一些实例中,第二治疗剂是放射性或化学化合物。
B.诊断和检测方法
本文提供了用于体外或体内检测GPC2蛋白的方法。在某些情况下,在生物样品中检测GPC2表达。样品可以是任何样品,包括但不限于用于活检、尸检和病理标本的组织。生物样品还包括组织切片,例如,出于组织学目的而采取的冷冻切片。生物样品还包括体液,例如血液、血清、血浆、痰、脊髓液或尿液。生物样品通常获自哺乳动物,例如人或非人灵长类动物。
本文提供了通过使受试者的样品与本文公开的GPC2特异性单克隆抗体接触和检测抗体与样品的结合来确定受试者是否患有GPC2阳性癌症的方法。与抗体与对照样品的结合相比,抗体与样品的结合的增加鉴定出该受试者患有GPC2阳性癌症。
在另一个实施方案中,提供了一种通过将来自诊断出患有GPC2阳性癌症的受试者的样品与本文公开的GPC2特异性单克隆抗体接触和检测抗体与样品的结合来确认受试者中GPC2阳性癌症的诊断的方法。与抗体与对照样品的结合相比,抗体与样品的结合的增加证实了受试者中GPC2阳性癌症的诊断。
在公开的方法的一些实例中,单克隆抗体被直接标记。
在其他实例中,该方法进一步包括将特异性结合单克隆抗体的第二抗体与样品接触;和检测第二抗体的结合。与第二抗体与对照样品的结合相比,第二抗体与样品的结合的增加检测了受试者中的GPC2阳性癌症或证实了受试者中的GPC2阳性癌症的诊断。
在某些情况下,癌症是神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
在一些实例中,对照样品是来自没有癌症的受试者的样品。在特定的实例中,样品是血液或组织样品。
在诊断和检测方法的一些实施方案中,结合(例如特异性结合)GPC2的抗体直接用可检测标记物标记。在另一个实施方案中,结合(例如,特异性结合)GPC2(第一抗体)的抗体未被标记,并且可以结合特异性结合GPC2的抗体的第二抗体或其他分子被标记。如本领域技术人员所公知的,选择能够特异性结合第一抗体的特定种类和类别的第二抗体。例如,如果第一抗体是人IgG,则第二抗体可以是抗人IgG。可以与抗体结合的其他分子包括但不限于,蛋白A和蛋白G,两者均可商购。
抗体或二抗的合适标记包括各种酶、辅基、荧光材料、发光材料、磁性试剂和放射性物质。合适的酶的非限制性实例包括辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶或乙酰胆碱酯酶。合适的辅基复合物的非限制性实例包括链霉亲和素/生物素和抗生物素蛋白/生物素。合适的荧光材料的非限制性实例包括伞形酮、荧光素、异硫氰酸荧光素、若丹明、二氯三嗪胺荧光素、丹磺酰氯或藻红蛋白。非限制性示例性发光材料是鲁米诺;非限制性示例性磁性剂是钆,并且非限制性示例性放射性标记包括125I、131I、35S或3H。
在替代的实施方案中,可以利用标记有可检测物质的GPC2蛋白标准品和特异性结合GPC2的未标记抗体,通过竞争免疫测定法在生物样品中测定GPC2。在该测定中,将生物学样品,标记的GPC2蛋白标准品和特异性结合GPC2的抗体合并在一起,并确定与未标记的抗体结合的标记的GPC2蛋白标准品的量。生物样品中GPC2的量与特异性结合GPC2的抗体结合的标记GPC2蛋白标准品的量成反比。
本文公开的免疫测定和方法可以用于多种目的。在一实施方案中,特异性结合的抗体可用于检测细胞培养物中细胞中GPC2的产生。在另一个实施方案中,该抗体可以用于检测生物学样品如组织样品或血液或血清样品中GPC2的量。在一些实例中,GPC2是细胞表面GPC2。在其他实例中,GPC2蛋白是可溶的(例如在细胞培养上清液中或在体液样品中,例如血液或血清样品中)。
在一个实施方案中,提供了一种试剂盒,用于检测生物样品,例如血液样品或组织样品中的GPC2。例如,为了确认受试者中的癌症诊断,可以进行活检以获得用于组织学检查的组织样品。用于检测多肽的试剂盒可以包括特异性结合GPC2的单克隆抗体,例如本文公开的任何单克隆抗体。在另一个实施方案中,抗体被标记(例如,用荧光、放射性或酶标记物)。
在一个实施方案中,试剂盒包括公开使用结合GPC2的抗体的手段的说明材料。指导材料可以电子形式(例如,计算机软盘或光盘)书写,也可以是可视的(例如,视频文件)。试剂盒还可以包括附加组件,以方便针对特定应用设计试剂盒。因此,例如,试剂盒可另外包含检测标记物的手段(例如用于酶标记物的酶底物、用于检测荧光标记物的滤波器组、合适的第二标记物,例如第二抗体等)。试剂盒可另外包括常规用于实施特定方法的缓冲液和其他试剂。此类试剂盒和适当的内容物是本领域技术人员众所周知的。
在一实施方案中,诊断试剂盒包括免疫测定。尽管免疫测定的细节可能随所采用的特定形式而变化,但是检测生物样品中GPC2的方法通常包括以下步骤:将生物样品与在免疫反应条件下与GPC2特异性反应的抗体接触。使抗体在免疫反应性条件下特异性结合以形成免疫复合物,并直接或间接检测免疫复合物(结合的抗体)的存在。
本文公开的抗体还可以用于免疫测定,例如但不限于放射免疫测定(RIA)、ELISA或免疫组织化学测定。抗体也可以用于荧光激活细胞分选(FACS)。FACS采用多个颜色通道、低角度和钝角光散射检测通道和阻抗通道以及其他更复杂的检测级别,以分离或分类细胞(参见美国专利号5,061,620)。如本文所公开的,结合GPC2的任何单克隆抗体都可以用于这些测定中。因此,该抗体可以用于常规的免疫测定中,包括但不限于ELISA、RIA、FACS、组织免疫组织化学、蛋白质印迹或免疫沉淀。
提供以下实施例以说明某些特定特征和/或实施方案。这些实施例不应被解释为将本公开限制为所描述的特定特征或实施方案。
实施例
实施例1:高亲和力GPC2特异性抗体的分离与表征
使用小鼠杂交瘤技术分离GPC2特异性单克隆抗体。为了免疫,合成对应于细胞表面蛋白GPC2的C末端的50聚体肽(残基504-553)。将另外的半胱氨酸残基引入到肽的N末端。因此,认为针对该肽产生的单克隆抗体(mAb)结合膜结合的GPC2的C末端。将三只C57BL/6小鼠免疫3次,并用肽-KLH偶联物加强免疫。用两只最好的小鼠进行脾细胞融合。在十个克隆中分离出两种抗体CT3和CT5,并将其同型化为IgG1κ。CT3和CT5的VH和VL结构域的核苷酸和氨基酸序列在本文中如SEQ ID NO:1-8所示。表1-4中显示了每个结构域中CDR序列的位置(参见以上第III节)。
使用重组人和/或小鼠磷脂酰肌醇蛋白聚糖蛋白进行ELISA以测定两种抗体的结合特异性。如图1A所示,CT3和CT5仅结合人GPC2,而不结合人GPC3、GPC5或GPC6。进一步评估CT3与人GPC蛋白和小鼠GPC2结合的能力。如图1B所示,CT3抗体仅特异性结合人GPC2。进行八隅体动力学分析以测量CT3抗体与人GPC2的结合亲和力。如图1C所示,CT3以高亲和力(KD=0.5nM)结合GPC2。
通过流式细胞术进一步评估CT3和CT5抗体,以确定它们是否可以结合细胞表面表达的GPC2。在第一项研究中,测试了CT5与两种表达GPC2的神经母细胞瘤细胞系LAN1和IMR5的结合。结果证明CT5抗体在两种神经母细胞瘤细胞系上均结合了GPC2(图2A)。第二项研究测量了CT3与GPC2阴性A431细胞、GPC2阳性G10细胞(过表达GPC2的A431细胞系)、IMR5细胞和F8细胞(过表达GPC2的IMR5细胞系)的结合。如图2B所示,CT3抗体特异性识别在所有三个GPC2阳性细胞系的细胞表面上表达的GPC2。
为了评估CT3和CT5抗体在免疫组织化学中的应用,使用CT3抗体检查神经母细胞瘤或非恶性疾病患者的人体组织中的GPC2表达。在所有实验中,组织均用1μg/ml CT3抗体标记。如图3所示,GPC2标记在源自神经母细胞瘤(i-iv)的患者的样本中是明显的,但是在来自非恶性疾病(v和vi)的患者的正常外周神经中基本上不可检测。神经母细胞瘤肿瘤组织在25例病例中有23例(92%)表现出强烈的GPC2染色。还使用CT3抗体评估了其他儿科癌症(包括髓母细胞瘤和视网膜母细胞瘤)中的GPC2表达。如图4所示,在20例髓母细胞瘤(i至iv)病例中有10例(50%)发现了强烈的GPC2表达,而在正常脑样本(v和vi)中未检测到染色。与癌旁的正常角膜和视网膜组织相比,近80%的视网膜母细胞瘤样本(14例中的11例)显示出高水平的GPC2表达(图5)。为了进一步分析正常人组织中的GPC2表达,用CT3抗体探测了FDA推荐的人正常组织阵列。在包括诸如脑、心脏、肺和肝的重要器官的正常组织中未观察到显著的GPC2染色(图6)。这些结果表明GPC2的肿瘤特异性表达和这些抗体作为神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤和其他癌症的诊断工具的潜在用途。
为了探索抗GPC2 mAb的治疗应用,使用CT3抗体的单链可变片段(scFv)构建了嵌合抗原受体(CAR)。在5'至3'方向上包含的CAR核酸构建体:编码第一个GMCSFR信号序列的核酸;编码CT3 scFv的核酸;编码CD8α细胞外铰链区的核酸;编码CD8跨膜(TM)结构域的核酸;编码4-1BB细胞内共刺激结构域的核酸;编码CD3ζ细胞内信号传导结构域的核酸;编码自切割T2A肽的核酸;编码第二GMCSFR信号序列的核酸;和编码huEGFRt的核酸(图7A)。如图7B所示,CT3 CAR在人T细胞中的转导效率为56%。即使效应器:靶比率(E:T)低至5.5:1,CT3CAR T细胞也有效地裂解三种GPC2阳性神经母细胞瘤细胞系(SKNBE2、NBEB和LAN1)(图7C-7E)。相比之下,在神经母细胞瘤细胞中模拟转导的T细胞介导的杀伤作用最小。
为了使CT3抗体人源化以用于治疗癌症患者的临床应用,将CT3 CDR移植到人框架序列。人源化的scFv构建体包含CT3(参见表1和2)和人框架序列的组合的(Kabat/IMGT/Paratome)CDR。VH和VL结构域由(G3S)4接头分隔。产生了三个克隆:hCT3-1(SEQ ID NO:10)、hCT3(SEQ ID NO:11)和hCT3-3(SEQ ID NO:21)。表达人源化CT3抗体的CAR T细胞表现出与针对GPC2阳性肿瘤细胞(G10、IMR5和F8;图8B-8D)的原始基于CT3的CAR T细胞相当的有效杀伤活性,但不针对GPC2阴性A431细胞(图8A)。数据未根据其转导效率进行归一化。如果通过其转导效率标准化,则人源化CT3衍生的CAR T细胞比原始CT3 CAR T细胞更具活性,因为与原始CT3 CAR相比,人源化CT3 CAR具有降低的转导效率。
还在鼠神经母细胞瘤模型中测试了CT3 CAR T细胞。在第0天,向NSG小鼠施用700万个IMR5-luc肿瘤细胞。在第35天,通过尾静脉注射向IMR5荷瘤NSG小鼠施用空白对照T细胞,或250万、500万或1000万CT3 CAR T细胞(图9A)。在CAR T细胞输注当天以及CAR T细胞输注后第3、11、19和28天,通过生物发光成像监测肿瘤负荷(图9B)。CT3 CAR T细胞以较高的剂量(500万和1000万)显著抑制小鼠中的神经母细胞瘤生长,而低剂量(250万)抑制肿瘤生长。在2-4周的治疗后,通过测量小鼠脾脏中的CAR载体阳性细胞来评估靶向GPC2的CAR T细胞在体内的持久性。具体地,在第34天,收获用250万CAR T细胞治疗的小鼠脾脏,在第14天,收获用500万CAR T细胞治疗的小鼠的脾脏,在第28天,收获用1000万CAR T细胞治疗的小鼠的脾脏。如图10所示,从分别用250万、500万和1000万CAR T细胞治疗的小鼠中收获的41.2%,26.54%和21.2%的细胞分别被鉴定为CAR T细胞,这表明CAR T细胞在治疗后在小鼠脾脏中仍然存在至少一个月。
为了测试免疫毒素形式的CT3抗体,将CT3 CDR移植到小鼠抗体SS1的框架序列上(参见Chowdhury和Pastan,Nat Biotechnol 17:568-572,1999;Pastan et al.,Nat RevCancer 6:559-565,2006)。已产生SS1P免疫毒素,并已在治疗间皮瘤、卵巢癌和胰腺癌的临床试验中进行测试。scFv包含CT3的组合(Kabat/IMGT/Paratome)CDR,SS1的框架残基和VH和VL结构域之间的(G3S)4接头。所得的scFv被称为sCT3(SEQ ID NO:12)。产生了包含sCT3scFv和截短的假单胞菌外毒素(PE38)的免疫毒素。图12A-12B示出了sCT3-PE38免疫毒素的产生。它的纯度和产率与SS1P相似。测试了sCT3-PE38杀死表达GPC2的细胞的能力。将细胞使用不同浓度的免疫毒素孵育三天,然后使用WST-8细胞增殖测定法确定细胞数。当计算细胞增殖的抑制时,未处理的孔中的细胞增殖设定为100%。sCT3-PE38免疫毒素杀死GPC2阳性肿瘤细胞系,但不会杀死GPC2阴性细胞(图12C)。这些结果证明由sCT3-PE38引起的细胞抑制是抗原依赖性的。
使用SEQ ID NO:9的CT3 scFv开发了另外两种靶向GPC2的免疫毒素,和任一种PE38(SEQ ID NO:22)、或T20(SEQ ID NO:23)作为毒素。进行八隅体动力学分析以评估靶向GPC2的免疫毒素与人GPC2的结合。使用Octet Red96e系统将人GPC2-His(250ng/ml)加载到Ni-NTA生物传感器上。以100nM加入免疫毒素(CT3-PE38和CT3-T20)以确定结合的亲和力。缔合发生600秒,解离发生1800秒。CT3-PE38和CT3-T20对人GPC2的亲和力(KD)被确定为分别为0.22nM和0.16nM(图11A)。由于其对人GPC2的高度亲和力,CT3非常适合免疫毒素的开发。Tris-甘氨酸4-20%凝胶用于评估CT3-PE38洗脱过程中的馏分纯度(图11B-11C)和CT3-T20(图11D-11E)免疫毒素。然后分析两种免疫毒素杀死表达GPC2的细胞系的能力。将细胞使用不同浓度的免疫毒素孵育三天,并使用WST-8细胞增殖测定法确定细胞数。用CT3-PE38(图11F)和CT3-T20(图11G)处理导致GPC2阳性的G10、F8和IMR5细胞的抑制。相比之下,抗原低的IMR32和抗原阴性的A431细胞未显示抑制作用。
接下来,进行实验以评估在表达GPC2的肿瘤动物模型中靶向GPC2的免疫毒素。将基质胶中的一千万个F8细胞注射到裸鼠的右背侧。当平均肿瘤体积达到100mm3时,开始使用PBS、CT3-PE38(0.25mg/kg)或CT3-T20(2mg/kg)进行治疗。用任一种免疫毒素进行的治疗均导致肿瘤体积显著减少(p<0.0001),并且免疫毒素具有良好耐受性(图13)。
在另一项研究中,将基质胶中的两百万个G10细胞注射到裸鼠的右背侧。当平均肿瘤体积达到100mm3时,开始使用PBS、CT3-PE38(0.25mg/kg)或CT3-T20(6mg/kg)进行治疗。当肿瘤超过1500mm3或肿瘤开始溃烂时,对小鼠实施安乐死。与PBS治疗组为21天相比,免疫毒素组的平均生存期为28天。基于CT3的免疫毒素治疗导致G10皮下异种移植模型中裸鼠的存活率显著提高(p<0.05)(图14B)。剂量高达6mg/kg的小鼠对CT3-T20的耐受性良好(图14A)。
在第三项研究中,通过尾静脉将五百万个IMR5细胞注射到裸鼠中。用PBS或CT3-T20(4mg/kg)处理小鼠。在注射100μl的xenolight D-荧光素(30mg/ml)后,用IVIS Lumina系列III测定辐射率(图15A)。用CT3-T20免疫毒素治疗导致IMR5转移模型中肿瘤负荷减小(图15B)。
鉴于可以应用公开的主题的原理的许多可能的实施方案,应当认识到,图示的实施方案仅是公开的实例,而不应被视为对公开的范围的限制。相反,公开的范围由以下权利要求书限定。因此,我们要求所有落入这些权利要求的范围和精神内。
序列表
<110> 美国政府(由卫生和人类服务部的部长所代表)
<120> 靶向磷脂酰肌醇蛋白聚糖-2的高亲和力单克隆抗体及其用途
<130> 4239-101087-02
<150> US 62/716,169
<151> 2018-08-08
<160> 23
<170> PatentIn version 3.5
<210> 1
<211> 369
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 1
gaggtccagc tgcaacagtc tggacctgaa ctggtgaagc ctggggcttc agtaaagatg 60
tcctgcaagg cttctagatt cacattcact gactacaaca tacactgggt gaagcagagc 120
cctggaaaga cccttgaatg gattggatat attaacccta acaatggtga tattttctac 180
aaacagaagt tcaatggcaa ggccacattg actataaaca agtcctccaa cacagcctac 240
atggagctcc gcagcctgac atcggaggat tctgcagtct attactgtgt aagatcctct 300
aatattcgtt atactttcga caggttcttc gatgtctggg gcacagggac cacggtcacc 360
gtctcctca 369
<210> 2
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 2
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp Tyr
20 25 30
Asn Ile His Trp Val Lys Gln Ser Pro Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys Phe
50 55 60
Asn Gly Lys Ala Thr Leu Thr Ile Asn Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp Val
100 105 110
Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 3
<211> 318
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 3
gaaaatgtgc tcacccagtc tccagcaatc atgtctgcat ctctagggga gaaggtcacc 60
atgagctgca gggccagctc aagtgtaaat tacatttact ggtaccagca gaagtcagat 120
gcctccccca aactatggat ttattacaca tccaacctgg ctcctggagt cccagctcgc 180
ttcagtggca gtgggtctgg gaactcttat tctctcacaa tcagcagcat ggagggtgaa 240
gatgctgcca cttattactg ccagcagttt tctagttccc catccacgtt cggtactggg 300
accaagctgg agctgaaa 318
<210> 4
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 4
Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Arg Ala Ser Ser Ser Val Asn Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Ser Asp Ala Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Tyr Thr Ser Asn Leu Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Gly Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Ser Ser Pro Ser Thr
85 90 95
Phe Gly Thr Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 5
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 5
gaggtgaaac tggtggagtc tggaggaggc ttggtacagt ctgggcgttc tctgagactc 60
tcctgtgcaa cttctggatt caccttcagt gatttctaca tggagtgggt ccgccaagct 120
ccagggaagg gactggagtg gattgttgca agtagagaca aagctaatga ttatacaaca 180
gcgtatagtg catctgtgaa gggtcggttc atcgtctcca gagacacttc ccaaagcatc 240
ctctaccttc agatgaatgc cctgagagct gaggacactg ccatttatta ctgtgtaaga 300
gatttctatg attacgacga ggcttactgg ggccaaggga ctctggtcac tgtctct 357
<210> 6
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 6
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Phe
20 25 30
Tyr Met Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Val Ala Ser Arg Asp Lys Ala Asn Asp Tyr Thr Thr Ala Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Ile Val Ser Arg Asp Thr Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Thr Ala Ile Tyr
85 90 95
Tyr Cys Val Arg Asp Phe Tyr Asp Tyr Asp Glu Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser
115
<210> 7
<211> 318
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 7
gacatccaga tgactcagtc tccgtcctca ctgtctgcct ctctgggagg tacagtcacc 60
atcacttgca aggcaagcga agacattaac aactatatag cttggtacca acacaagcct 120
ggaaaaggtc ctcggctgct catacaatac acatctacat tacagccagg catcccatca 180
aggttcagtg gaagtgggtc tgggcgagat tattccctca gcatcagcaa cctggagcct 240
gaagatattg caacttatta ttgtctacag tatgatattc tgtggacgtt cggtggaggc 300
accaagctgg aaatcaaa 318
<210> 8
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Gly Thr Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Asn Asn Tyr
20 25 30
Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
35 40 45
Gln Tyr Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Ser Leu Ser Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ile Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 9
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp Tyr
20 25 30
Asn Ile His Trp Val Lys Gln Ser Pro Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys Phe
50 55 60
Asn Gly Lys Ala Thr Leu Thr Ile Asn Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp Val
100 105 110
Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Asn Val Leu Thr Gln
130 135 140
Ser Pro Ala Ile Met Ser Ala Ser Leu Gly Glu Lys Val Thr Met Ser
145 150 155 160
Cys Arg Ala Ser Ser Ser Val Asn Tyr Ile Tyr Trp Tyr Gln Gln Lys
165 170 175
Ser Asp Ala Ser Pro Lys Leu Trp Ile Tyr Tyr Thr Ser Asn Leu Ala
180 185 190
Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr
195 200 205
Ser Leu Thr Ile Ser Ser Met Glu Gly Glu Asp Ala Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Phe Ser Ser Ser Pro Ser Thr Phe Gly Thr Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys
<210> 10
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser
130 135 140
Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys
145 150 155 160
Arg Ala Ser Ser Ser Val Asn Tyr Ile Tyr Trp Tyr Leu Gln Lys Pro
165 170 175
Gly Gln Ser Pro Gln Leu Trp Ile Tyr Tyr Thr Ser Asn Leu Ala Pro
180 185 190
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
210 215 220
Gln Gln Phe Ser Ser Ser Pro Ser Thr Phe Gly Gln Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 11
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys Phe
50 55 60
Asn Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser
130 135 140
Pro Ala Phe Leu Ser Val Thr Pro Gly Glu Lys Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Ser Ser Val Asn Tyr Ile Tyr Trp Tyr Gln Gln Lys Pro
165 170 175
Asp Gln Ala Pro Lys Leu Trp Ile Tyr Tyr Thr Ser Asn Leu Ala Pro
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Phe Ser Ser Ser Pro Ser Thr Phe Gly Gln Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 12
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 12
Met Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly
1 5 10 15
Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp
20 25 30
Tyr Asn Ile His Trp Val Lys Gln Ser His Gly Lys Cys Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys
50 55 60
Phe Asn Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
65 70 75 80
Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe
85 90 95
Cys Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr
130 135 140
Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met
145 150 155 160
Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Ile Tyr Trp Tyr Gln Gln
165 170 175
Lys Ser Gly Thr Ser Pro Lys Leu Trp Ile Tyr Tyr Thr Ser Asn Leu
180 185 190
Ala Pro Gly Val Pro Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser
195 200 205
Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu Asp Asp Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Phe Ser Ser Ser Pro Ser Thr Phe Gly Cys Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys
245
<210> 13
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 13
Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu
1 5 10
<210> 14
<211> 22
<212> PRT
<213> 智人
<400> 14
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro
20
<210> 15
<211> 45
<212> PRT
<213> 智人
<400> 15
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 16
<211> 21
<212> PRT
<213> 智人
<400> 16
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr
20
<210> 17
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 17
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 18
<211> 112
<212> PRT
<213> 智人
<400> 18
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 19
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 19
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 20
<211> 335
<212> PRT
<213> 智人
<400> 20
Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu
1 5 10 15
Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile
20 25 30
Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe
35 40 45
Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr
50 55 60
Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn
65 70 75 80
Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg
85 90 95
Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile
100 105 110
Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val
115 120 125
Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp
130 135 140
Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn
145 150 155 160
Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu
165 170 175
Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser
180 185 190
Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu
195 200 205
Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln
210 215 220
Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly
225 230 235 240
Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro
245 250 255
His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr
260 265 270
Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His
275 280 285
Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro
290 295 300
Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala
305 310 315 320
Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met
325 330 335
<210> 21
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Arg Phe Thr Phe Thr Asp Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Asp Ile Phe Tyr Lys Gln Lys Phe
50 55 60
Asn Gly Lys Ala Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Ser Asn Ile Arg Tyr Thr Phe Asp Arg Phe Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Ser Ser Val Asn Tyr Ile Tyr Trp Tyr Gln Gln Lys Ser
165 170 175
Gly Lys Ala Pro Lys Leu Trp Ile Tyr Tyr Thr Ser Asn Leu Ala Pro
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Phe Ser Ser Ser Pro Ser Thr Phe Gly Gln Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 22
<211> 355
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 22
Ser Ala Ala Lys Ala Ser Gly Gly Pro Glu Gly Gly Ser Leu Ala Ala
1 5 10 15
Leu Thr Ala His Gln Ala Cys His Leu Pro Leu Glu Thr Phe Thr Arg
20 25 30
His Arg Gln Pro Arg Gly Trp Glu Gln Leu Glu Gln Cys Gly Tyr Pro
35 40 45
Val Gln Arg Leu Val Ala Leu Tyr Leu Ala Ala Arg Leu Ser Trp Asn
50 55 60
Gln Val Asp Gln Val Ile Arg Asn Ala Leu Ala Ser Pro Gly Ser Gly
65 70 75 80
Gly Asp Leu Gly Glu Ala Ile Arg Glu Gln Pro Glu Gln Ala Arg Leu
85 90 95
Ala Leu Thr Leu Ala Ala Ala Glu Ser Glu Arg Phe Val Arg Gln Gly
100 105 110
Thr Gly Asn Asp Glu Ala Gly Ala Ala Asn Gly Pro Ala Asp Ser Gly
115 120 125
Asp Ala Leu Leu Glu Arg Asn Tyr Pro Thr Gly Ala Glu Phe Leu Gly
130 135 140
Asp Gly Gly Asp Val Ser Phe Ser Thr Arg Gly Thr Gln Asn Trp Thr
145 150 155 160
Val Glu Arg Leu Leu Gln Ala His Arg Gln Leu Glu Glu Arg Gly Tyr
165 170 175
Val Phe Val Gly Tyr His Gly Thr Phe Leu Glu Ala Ala Gln Ser Ile
180 185 190
Val Phe Gly Gly Val Arg Ala Arg Ser Gln Asp Leu Asp Ala Ile Trp
195 200 205
Arg Gly Phe Tyr Ile Ala Gly Asp Pro Ala Leu Ala Tyr Gly Tyr Ala
210 215 220
Gln Asp Gln Glu Pro Asp Ala Arg Gly Arg Ile Arg Asn Gly Ala Leu
225 230 235 240
Leu Arg Val Tyr Val Pro Arg Ser Ser Leu Pro Gly Phe Tyr Arg Thr
245 250 255
Ser Leu Thr Leu Ala Ala Pro Glu Ala Ala Gly Glu Val Glu Arg Leu
260 265 270
Ile Gly His Pro Leu Pro Leu Arg Leu Asp Ala Ile Thr Gly Pro Glu
275 280 285
Glu Glu Gly Gly Arg Leu Glu Thr Ile Leu Gly Trp Pro Leu Ala Glu
290 295 300
Arg Thr Val Val Ile Pro Ser Ala Ile Pro Thr Asp Pro Arg Asn Val
305 310 315 320
Gly Gly Asp Leu Asp Pro Ser Ser Ile Pro Asp Lys Glu Gln Ala Ile
325 330 335
Ser Ala Leu Pro Asp Tyr Ala Ser Gln Pro Gly Lys Pro Pro Arg Glu
340 345 350
Asp Leu Lys
355
<210> 23
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
Lys Leu Lys Ala Ser Gly Gly Arg His Arg Gln Pro Arg Gly Trp Glu
1 5 10 15
Gln Leu Gly Gly Gly Gly Gly Ser Pro Thr Gly Ala Glu Phe Leu Gly
20 25 30
Asp Gly Gly Asp Val Ser Phe Ser Thr Arg Gly Thr Gln Asn Trp Thr
35 40 45
Val Glu Arg Leu Leu Gln Ala His Ala Gln Leu Glu Glu Arg Gly Tyr
50 55 60
Val Phe Val Gly Tyr His Gly Thr Ala Leu Glu Ala Ala Gln Ser Ile
65 70 75 80
Val Phe Gly Gly Val Arg Ala Arg Ser Gln Asp Leu Asp Ala Ile Trp
85 90 95
Arg Gly Phe Tyr Ile Ala Gly Asp Pro Ala His Ala Tyr Gly Tyr Ala
100 105 110
Gln Asp Gln Glu Pro Asp Ala Arg Gly Arg Ile Ala Asn Gly Ala Leu
115 120 125
Leu Arg Val Tyr Val Pro Ala Ser Ser Leu Pro Gly Phe Tyr Arg Thr
130 135 140
Ser Leu Thr Leu Ala Ala Pro Glu Ala Ala Gly Glu Val Glu Arg Leu
145 150 155 160
Ile Gly His Pro Leu Pro Leu Arg Leu Asp Ala Ile Thr Gly Pro Glu
165 170 175
Glu Glu Gly Gly Arg Glu Glu Thr Ile Leu Gly Trp Pro Leu Ala Glu
180 185 190
Arg Thr Val Val Ile Pro Ser Ala Ile Pro Thr Asp Pro Arg Asn Val
195 200 205
Gly Gly Asp Leu Asp Pro Ser Ser Ile Pro Asp Lys Glu Gln Ala Ile
210 215 220
Ser Ala Leu Pro Asp Tyr Ala Ser Gln Pro Gly Lys Pro Pro Arg Glu
225 230 235 240
Asp Leu Lys
Claims (65)
1.一种结合磷脂酰肌醇蛋白聚糖-2(GPC2)的单克隆抗体或其抗原结合片段,其包含可变重链(VH)结构域和可变轻链(VL)结构域,其中:
所述VH结构域包含SEQ ID NO:2的CDR序列且所述VL结构域包含SEQ ID NO:4的CDR序列;或
所述VH结构域包含SEQ ID NO:6的CDR序列且所述VL结构域包含SEQ ID NO:8的CDR序列。
2.根据权利要求1所述的单克隆抗体或抗原结合片段,其中所述CDR序列是使用Kabat、IMGT或Paratome编号方案或Kabat、IMGT和Paratome编号方案的组合定义的。
3.根据权利要求1或权利要求2所述的单克隆抗体或抗原结合片段,其中:
所述VH结构域包含SEQ ID NO:2的残基31-35、50-66和99-112且所述VL结构域包含SEQID NO:4的残基24-33、49-55和88-96;或
所述VH结构域包含SEQ ID NO:6的残基31-35、50-68和101-109且所述VL结构域包含SEQ ID NO:8的残基24-34、50-56和89-96。
4.根据权利要求1或权利要求2所述的单克隆抗体或抗原结合片段,其中:
所述VH结构域包含SEQ ID NO:2的残基26-33、51-58和97-112且所述VL结构域包含SEQID NO:4的残基27-31、49-51和88-96;或
所述VH结构域包含SEQ ID NO:6的残基26-33、51-60和99-109且所述VL结构域包含SEQID NO:8的残基27-32、50-52和89-96。
5.根据权利要求1或权利要求2所述的单克隆抗体或抗原结合片段,其中:
所述VH结构域包含SEQ ID NO:2的残基26-35、47-61和97-112且所述VL结构域包含SEQID NO:4的残基27-33、45-55和88-95;或
所述VH结构域包含SEQ ID NO:6的残基27-35、47-62和99-109且所述VL结构域包含SEQID NO:8的残基27-34、46-56和89-95。
6.根据权利要求1或权利要求2所述的单克隆抗体或抗原结合片段,其中:
所述VH结构域包含SEQ ID NO:2的残基26-35、47-66和97-112且所述VL结构域包含SEQID NO:4的残基24-33、45-55和88-96;或
所述VH结构域包含SEQ ID NO:6的残基26-35、47-68和99-109且所述VL结构域包含SEQID NO:8的残基27-34、46-56和89-96。
7.根据权利要求1-6中任一项所述的单克隆抗体或抗原结合片段,其中VH结构域的氨基酸序列与SEQ ID NO:2具有至少95%同一性和/或所述VL结构域的氨基酸序列与SEQ IDNO:4具有至少95%同一性。
8.根据权利要求1-7中任一项所述的单克隆抗体或抗原结合片段,其中所述VH结构域的氨基酸序列包含SEQ ID NO:2或由其组成和/或所述VL结构域的氨基酸序列包含SEQ IDNO:4或由其组成。
9.根据权利要求1-6中任一项所述的单克隆抗体或抗原结合片段,其中VH结构域的氨基酸序列与SEQ ID NO:6具有至少95%同一性和/或所述VL结构域的氨基酸序列与SEQ IDNO:8具有至少95%同一性。
10.根据权利要求1-7中任一项所述的单克隆抗体或抗原结合片段,其中所述VH结构域的氨基酸序列包含SEQ ID NO:6或由其组成和/或所述VL结构域的氨基酸序列包含SEQ IDNO:8或由其组成。
11.根据权利要求1-10中任一项所述的单克隆抗体或抗原结合片段,其为人源化单克隆抗体或抗原结合片段。
12.根据权利要求1-11中任一项所述的抗原结合片段,其中所述抗原结合片段是单链可变片段(scFv)、Fab片段、Fab'片段、F(ab)’2片段或二硫键稳定的可变片段(dsFv)。
13.根据权利要求12所述的抗原结合片段,其为scFv。
14.根据权利要求13所述的抗原结合片段,其中所述scFv包含SEQ ID NO:9、SEQ IDNO:10、SEQ ID NO:11、SEQ ID NO:12、或SEQ ID NO:21的氨基酸序列。
15.一种嵌合抗原受体(CAR),其包含根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段。
16.根据权利要求15所述的CAR,其进一步包含铰链区、跨膜结构域、共刺激信号传导部分、信号传导结构域或其任何组合。
17.根据权利要求16所述的CAR,其中所述铰链区包括CD8α铰链区。
18.根据权利要求16或权利要求17所述的CAR,其中所述跨膜结构域包含CD8α跨膜结构域。
19.根据权利要求16-18中任一项所述的CAR,其中所述共刺激信号传导部分包括4-1BB信号传导部分。
20.根据权利要求16-19中任一项所述的CAR,其中所述信号传导结构域包括CD3ζ信号传导结构域。
21.根据权利要求15-20中任一项所述的CAR,其中所述抗原结合片段是包含SEQ IDNO:9、SEQ ID NO:10、SEQ ID NO:11、或SEQ ID NO:21的氨基酸序列的scFv。
22.一种分离细胞,其表达权利要求15-21中任一项所述的CAR。
23.根据权利要求22所述的分离细胞,其是细胞毒性T淋巴细胞(CTL)。
24.一种免疫偶联物,其包含根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段和效应器分子。
25.根据权利要求24所述的免疫偶联物,其中所述效应器分子是毒素。
26.根据权利要求25所述的免疫偶联物,其中所述毒素是假单胞菌外毒素或其变体。
27.根据权利要求26所述的免疫偶联物,其中所述假单胞菌外毒素变体是PE38。
28.根据权利要求24所述的免疫偶联物,其中所述效应器分子是可检测标记物。
29.根据权利要求28所述的免疫偶联物,其中所述可检测标记物包括荧光团、酶或放射性同位素。
30.一种抗体-药物偶联物(ADC),其包含与权利要求1-14中任一项所述的单克隆抗体或抗原结合片段偶联的药物。
31.根据权利要求30所述的ADC,其中所述药物是小分子。
32.根据权利要求30或权利要求31所述的ADC,其中所述药物是抗微管剂、抗有丝分裂剂和/或细胞毒性剂。
33.一种多特异性抗体,其包含根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段和至少一种另外的单克隆抗体或其抗原结合片段。
34.根据权利要求33所述的多特异性抗体,其是双特异性抗体。
35.根据权利要求33所述的多特异性抗体,其是三特异性抗体。
36.根据权利要求33-35中任一项所述的多特异性抗体,其中所述至少一种另外的单克隆抗体或其抗原结合片段特异性结合T细胞受体或天然杀伤(NK)细胞激活受体的组分。
37.一种抗体-纳米颗粒偶联物,其包含与权利要求1-14中任一项所述的单克隆抗体或抗原结合片段偶联的纳米颗粒。
38.根据权利要求37所述的抗体-纳米颗粒偶联物,其中所述纳米颗粒包括聚合物纳米颗粒、纳米球、纳米胶囊、脂质体、树枝状分子、聚合物胶束或类脂囊泡。
39.根据权利要求37或权利要求38所述的抗体-纳米颗粒偶联物,其中所述纳米颗粒包含细胞毒性剂。
40.一种融合蛋白,其包含根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段和异源蛋白或肽。
41.根据权利要求40所述的融合蛋白,其中所述异源蛋白是Fc蛋白。
42.一种核酸分子,其编码根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段、根据权利要求15-21中任一项所述的CAR、根据权利要求24-29中任一项所述的免疫偶联物、根据权利要求33-36中任一项所述的多特异性抗体、或根据权利要求40或权利要求41所述的融合蛋白。
43.根据权利要求42所述的核酸分子,其可操作地连接至启动子。
44.一种载体,其包含权利要求42或权利要求43所述的核酸分子。
45.一种编码嵌合抗原受体(CAR)的核酸分子,其在5'到3'方向包含:
编码第一粒细胞-巨噬细胞集落刺激因子受体信号序列(GMCSFRss)的核酸;
编码根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段的核酸;
编码细胞外铰链区的核酸;
编码跨膜结构域的核酸;
编码细胞内共刺激结构域的核酸;
编码细胞内信号传导结构域的核酸;
编码自切割2A肽的核酸;
编码第二GMCSFRss的核酸;和
编码截短的人表皮生长因子受体(huEGFRt)的核酸。
46.根据权利要求45所述的核酸分子,其进一步包含编码所述第一GMCSFRss的核酸的人延伸因子1α(EF1α)启动子序列5’。
47.根据权利要求45或权利要求46所述的核酸分子,其中所述抗原结合片段是单链可变片段(scFv)。
48.一种载体,其包含根据权利要求45-47中任一项所述的核酸分子。
49.根据权利要求48所述的载体,其中所述载体是慢病毒载体。
50.一种分离宿主细胞,其包含权利要求45-47中任一项所述的核酸分子或权利要求48或权利要求49所述的载体。
51.一种组合物,其包含药学上可接受的运载体和根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段、根据权利要求15-21中任一项所述的CAR、根据权利要求22或权利要求23所述的分离细胞、根据权利要求24-29中任一项所述的免疫偶联物、根据权利要求30-32中任一项所述的ADC、根据权利要求33-36中任一项所述的多特异性抗体、根据权利要求37-39中任一项所述的抗体-纳米颗粒偶联物、或根据权利要求40或权利要求41所述的融合蛋白。
52.一种治疗受试者中的GPC2阳性癌症的方法,其包括向所述受试者施用根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段、根据权利要求15-21中任一项所述的CAR、根据权利要求22或权利要求23所述的分离细胞、根据权利要求24-29中任一项所述的免疫偶联物、根据权利要求30-32中任一项所述的ADC、根据权利要求33-36中任一项所述的多特异性抗体、根据权利要求37-39中任一项所述的抗体-纳米颗粒偶联物、根据权利要求40或权利要求41所述的融合蛋白、或根据权利要求51所述的组合物。
53.一种抑制受试者中的GPC2阳性癌症的肿瘤生长或转移的方法,其包括向所述受试者施用根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段、根据权利要求15-21中任一项所述的CAR、根据权利要求22或权利要求23所述的分离细胞、根据权利要求24-29中任一项所述的免疫偶联物、根据权利要求30-32中任一项所述的ADC、根据权利要求33-36中任一项所述的多特异性抗体、根据权利要求37-39中任一项所述的抗体-纳米颗粒偶联物、根据权利要求40或权利要求41所述的融合蛋白、或根据权利要求51所述的组合物。
54.根据权利要求52或权利要求53所述的方法,其中所述GPC2阳性癌症是儿科癌症。
55.根据权利要求52-54中任一项所述的方法,其中所述GPC2阳性癌症是神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
56.一种检测样品中GPC2表达的方法,包括:
将所述样品与根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段接触;和
检测所述抗体与所述样品的结合,从而检测所述样品中GPC2的表达。
57.根据权利要求56所述的方法,其中所述单克隆抗体或抗原结合片段被直接标记。
58.根据权利要求56所述的方法,进一步包括:
将所述单克隆抗体或抗原结合片段与第二抗体接触,和
检测所述第二抗体与所述单克隆抗体或抗原结合片段的结合,从而检测所述样品中GPC2的表达。
59.根据权利要求56-58中任一项所述的方法,其中所述样品获自怀疑患有GPC2阳性癌症的受试者。
60.根据权利要求56-59中任一项所述的方法,其中所述样品是肿瘤活检物。
61.一种诊断受试者患有GPC2阳性癌症的方法,包括:
将从所述受试者获得的样品与根据权利要求1-14中任一项所述的单克隆抗体或抗原结合片段接触;和
检测所述抗体与所述样品的结合,从而诊断所述受试者为患有GPC2阳性癌症。
62.根据权利要求61所述的方法,其中所述单克隆抗体或抗原结合片段被直接标记。
63.根据权利要求61所述的方法,进一步包括:
将所述单克隆抗体或抗原结合片段与第二抗体接触,和
检测所述第二抗体与所述单克隆抗体或抗原结合片段的结合,从而诊断所述受试者为患有GPC2阳性癌症。
64.根据权利要求61-63中任一项所述的方法,其中所述样品是肿瘤活检物。
65.根据权利要求61-64中任一项所述的方法,其中所述GPC2阳性癌症是神经母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、急性淋巴细胞白血病、胚胎性横纹肌肉瘤、肺泡横纹肌肉瘤、尤文氏肉瘤、促结缔组织增生型小圆细胞瘤或骨肉瘤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862716169P | 2018-08-08 | 2018-08-08 | |
US62/716,169 | 2018-08-08 | ||
PCT/US2019/045338 WO2020033430A1 (en) | 2018-08-08 | 2019-08-06 | High affinity monoclonal antibodies targeting glypican-2 and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112585163A true CN112585163A (zh) | 2021-03-30 |
Family
ID=67777401
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980053942.7A Pending CN112585163A (zh) | 2018-08-08 | 2019-08-06 | 靶向磷脂酰肌醇蛋白聚糖-2的高亲和力单克隆抗体及其用途 |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP3833684A1 (zh) |
CN (1) | CN112585163A (zh) |
AU (1) | AU2019317565A1 (zh) |
CA (1) | CA3106544A1 (zh) |
WO (1) | WO2020033430A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3999546A1 (en) * | 2019-07-19 | 2022-05-25 | The Children's Hospital of Philadelphia | Chimeric antigen receptors containing glypican 2 binding domains |
TW202144432A (zh) * | 2020-03-12 | 2021-12-01 | 大陸商南京傳奇生物科技有限公司 | 磷脂醯肌醇蛋白聚糖-2結合部分、嵌合抗原受體及其用途 |
WO2023158986A1 (en) | 2022-02-15 | 2023-08-24 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cd28 hinge and transmembrane containing chimeric antigen receptors targeting gpc2 and use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017083296A1 (en) * | 2015-11-09 | 2017-05-18 | The Children's Hospital Of Philadelphia | Glypican 2 as a cancer marker and therapeutic target |
WO2018026533A1 (en) * | 2016-08-02 | 2018-02-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (gpc2) and use thereof |
CN108174604A (zh) * | 2015-08-07 | 2018-06-15 | 西雅图儿童医院(Dba西雅图儿童研究所) | 用于实体瘤靶向的双特异性car t细胞 |
Family Cites Families (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US4957735A (en) | 1984-06-12 | 1990-09-18 | The University Of Tennessee Research Corporation | Target-sensitive immunoliposomes- preparation and characterization |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US5079163A (en) | 1985-03-29 | 1992-01-07 | Cetus Corporation | Recombinant ricin toxin fragments |
US4689401A (en) | 1986-03-06 | 1987-08-25 | Cetus Corporation | Method of recovering microbially produced recombinant ricin toxin a chain |
US4902505A (en) | 1986-07-30 | 1990-02-20 | Alkermes | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
US4892827A (en) | 1986-09-24 | 1990-01-09 | The United States Of America As Represented By The Department Of Health And Human Services | Recombinant pseudomonas exotoxins: construction of an active immunotoxin with low side effects |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5004697A (en) | 1987-08-17 | 1991-04-02 | Univ. Of Ca | Cationized antibodies for delivery through the blood-brain barrier |
US5055303A (en) | 1989-01-31 | 1991-10-08 | Kv Pharmaceutical Company | Solid controlled release bioadherent emulsions |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5271961A (en) | 1989-11-06 | 1993-12-21 | Alkermes Controlled Therapeutics, Inc. | Method for producing protein microspheres |
US5188837A (en) | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
US5061620A (en) | 1990-03-30 | 1991-10-29 | Systemix, Inc. | Human hematopoietic stem cell |
US5268164A (en) | 1990-04-23 | 1993-12-07 | Alkermes, Inc. | Increasing blood-brain barrier permeability with permeabilizer peptides |
DK0531434T3 (da) | 1990-05-11 | 2000-01-31 | Us Health | Forbedrede Pseudomonas-exotoksiner med lav dyretoksicitet og høj cytocidal aktivitet |
US5608039A (en) | 1990-10-12 | 1997-03-04 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Single chain B3 antibody fusion proteins and their uses |
US5254342A (en) | 1991-09-30 | 1993-10-19 | University Of Southern California | Compositions and methods for enhanced transepithelial and transendothelial transport or active agents |
WO1993017668A1 (en) | 1992-03-12 | 1993-09-16 | Alkermes Controlled Therapeutics, Inc. | Controlled release acth containing microspheres |
ATE314475T1 (de) | 1992-06-18 | 2006-01-15 | Us Gov Health & Human Serv | Rekombinantes pseudomonas exotoxin mit gesteigerter aktivität |
US5534496A (en) | 1992-07-07 | 1996-07-09 | University Of Southern California | Methods and compositions to enhance epithelial drug transport |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US5514670A (en) | 1993-08-13 | 1996-05-07 | Pharmos Corporation | Submicron emulsions for delivery of peptides |
JP3469580B2 (ja) | 1993-10-01 | 2003-11-25 | 帝国臓器製薬株式会社 | 新規なペプチド誘導体 |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US6809184B1 (en) | 1997-12-01 | 2004-10-26 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Antibodies, including FV molecules, and immunoconjugates having high binding affinity for mesothelin and methods for their use |
US6296843B1 (en) | 1998-04-03 | 2001-10-02 | The Penn State Research Foundation | Mutagenized IL 13-based chimeric molecules |
EP1109812B1 (en) | 1998-08-27 | 2005-05-04 | Spirogen Limited | Pyrrolobenzodiazepines |
AU2004204463B2 (en) | 2003-01-10 | 2009-02-12 | Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services National Institutes Of Health | Catalytic domains of beta(1,4)-galactosyltransferase I having altered donor and acceptor specificities, domains that promote in vitro protein folding, and methods for their use |
ATE421967T1 (de) | 2003-03-31 | 2009-02-15 | Council Scient Ind Res | Nichtvernetzende pyrroloä2,1-cüä1, 4übenzodiazepine als potentielle antitumor- agentien und ihre herstellung |
EP1675857B1 (en) | 2003-10-22 | 2011-07-13 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
US20070258986A1 (en) | 2003-11-19 | 2007-11-08 | Govt of the US as represented by the secretary, | Targeted Delivery System for Bioactive Agents |
WO2005052006A2 (en) | 2003-11-25 | 2005-06-09 | The Government Of The United States, As Represented By The Secretary Of Health And Human Services | Mutated anti-cd22 antibodies and immunoconjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
EP3006456B1 (en) | 2005-07-29 | 2018-09-19 | The Government of the United States of America, as represented by the Secretary of Health and Human Services | Mutated pseudomonas exotoxins with reduced antigenicity |
TW200726776A (en) | 2005-07-29 | 2007-07-16 | Friedrich Alexander University Of Erlangen Nuremberg | CD33-specific single-chain immunotoxin and methods of use |
WO2007031741A1 (en) | 2005-09-14 | 2007-03-22 | Cambridge Antibody Technology Limited | Pseudomonas exotoxin a cd4+ t-cell epitopes |
ATE527262T1 (de) | 2006-01-25 | 2011-10-15 | Sanofi Sa | Neue tomaymycin derivate enhaltende zytotoxische mittel |
CA2658276A1 (en) | 2006-07-18 | 2008-01-24 | Sanofi-Aventis | Antagonist antibody for the treatment of cancer |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
US20090175784A1 (en) | 2007-05-11 | 2009-07-09 | Joshua Goldstein | Anti-Alpha V Immunoliposome Composition, Methods, and Uses |
US7628445B2 (en) | 2007-07-06 | 2009-12-08 | Ford Global Technologies, Llc | Striker reinforcement for hydroformed automotive door frame |
PT2019104E (pt) | 2007-07-19 | 2013-12-03 | Sanofi Sa | Agentes citotóxicos compreendendo novos derivados de tomaimicina e sua utilização terapêutica |
PL2197903T3 (pl) | 2007-09-04 | 2015-03-31 | Us Gov Health & Human Services | Delecje w domenie ii egzotoksyny a psuedomonas zmniejszające toksyczność niespecyficzną |
US8426402B2 (en) | 2009-02-05 | 2013-04-23 | Immunogen, Inc. | Benzodiazepine derivatives |
AU2010292069B2 (en) | 2009-09-11 | 2015-08-13 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Improved Pseudomonas Exotoxin A with reduced immunogenicity |
DK2496698T3 (en) | 2009-11-03 | 2019-04-15 | Hope City | TRUNCATED EPIDERIMAL GROWTH FACTOR RECEPTOR (EGFRt) FOR TRUNCATED T-CELL SELECTION |
MA34277B1 (fr) | 2010-04-15 | 2013-06-01 | Spirogen Developments Sarl | Pyrrolobenzodiazépines et conjugués de celles-ci |
SG194787A1 (en) | 2011-05-06 | 2013-12-30 | Us Gov Health & Human Serv | Recombinant immunotoxin targeting mesothelin |
WO2012170617A1 (en) | 2011-06-09 | 2012-12-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Pseudomonas exotoxin a with less immunogenic t cell and/or b cell epitopes |
PE20190515A1 (es) | 2011-11-17 | 2019-04-10 | Pfizer | Peptidos modificados de auristatina y conjugados anticuerpo-farmaco de los mismos |
WO2014052064A1 (en) | 2012-09-27 | 2014-04-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mesothelin antibodies and methods for eliciting potent antitumor activity |
WO2015051199A2 (en) | 2013-10-06 | 2015-04-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Modified pseudomonas exotoxin a |
-
2019
- 2019-08-06 EP EP19759784.2A patent/EP3833684A1/en active Pending
- 2019-08-06 WO PCT/US2019/045338 patent/WO2020033430A1/en unknown
- 2019-08-06 CA CA3106544A patent/CA3106544A1/en active Pending
- 2019-08-06 CN CN201980053942.7A patent/CN112585163A/zh active Pending
- 2019-08-06 AU AU2019317565A patent/AU2019317565A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108174604A (zh) * | 2015-08-07 | 2018-06-15 | 西雅图儿童医院(Dba西雅图儿童研究所) | 用于实体瘤靶向的双特异性car t细胞 |
WO2017083296A1 (en) * | 2015-11-09 | 2017-05-18 | The Children's Hospital Of Philadelphia | Glypican 2 as a cancer marker and therapeutic target |
WO2018026533A1 (en) * | 2016-08-02 | 2018-02-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (gpc2) and use thereof |
Also Published As
Publication number | Publication date |
---|---|
EP3833684A1 (en) | 2021-06-16 |
US20210292428A1 (en) | 2021-09-23 |
WO2020033430A1 (en) | 2020-02-13 |
CA3106544A1 (en) | 2020-02-13 |
AU2019317565A1 (en) | 2021-02-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210324074A1 (en) | Affinity matured cd22-specific monoclonal antibody and uses thereof | |
US20220380471A1 (en) | High affinity nanobodies targeting b7-h3 (cd276) for treating multiple solid tumors | |
US11066479B2 (en) | Monoclonal antibodies targeting glypican-2 (GPC2) and use thereof | |
WO2017196847A1 (en) | Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens | |
US20220064324A1 (en) | Cross species single domain antibodies targeting mesothelin for treating solid tumors | |
US20220098323A1 (en) | High affinity monoclonal antibodies targeting glypican-1 and methods of use | |
EP3559038B1 (en) | Human monoclonal antibodies specific for flt3 and uses thereof | |
WO2017214182A1 (en) | Fully human antibody targeting pdi for cancer immunotherapy | |
CN112585163A (zh) | 靶向磷脂酰肌醇蛋白聚糖-2的高亲和力单克隆抗体及其用途 | |
CN114269783A (zh) | 结合egfrviii的单克隆抗体及其应用 | |
US12012463B2 (en) | High affinity monoclonal antibodies targeting glypican-2 and uses thereof | |
AU2022291120A1 (en) | Cross species single domain antibodies targeting pd-l1 for treating solid tumors | |
WO2024097660A2 (en) | Monoclonal antibodies specific for fas ligand and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |