CN110691790A - 抗癌联合治疗 - Google Patents
抗癌联合治疗 Download PDFInfo
- Publication number
- CN110691790A CN110691790A CN201880036511.5A CN201880036511A CN110691790A CN 110691790 A CN110691790 A CN 110691790A CN 201880036511 A CN201880036511 A CN 201880036511A CN 110691790 A CN110691790 A CN 110691790A
- Authority
- CN
- China
- Prior art keywords
- ser
- compound
- val
- gly
- seq
- 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
- 238000002648 combination therapy Methods 0.000 title description 11
- 239000012635 anticancer drug combination Substances 0.000 title description 3
- 229940046044 combinations of antineoplastic agent Drugs 0.000 title description 3
- 230000027455 binding Effects 0.000 claims abstract description 171
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 84
- 238000011282 treatment Methods 0.000 claims abstract description 68
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims abstract description 45
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims abstract description 45
- 201000011510 cancer Diseases 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims description 145
- 108060003951 Immunoglobulin Proteins 0.000 claims description 104
- 102000018358 immunoglobulin Human genes 0.000 claims description 104
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 44
- 201000010099 disease Diseases 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 39
- 229940124060 PD-1 antagonist Drugs 0.000 claims description 36
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 29
- 230000001613 neoplastic effect Effects 0.000 claims description 25
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 24
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 24
- 230000003463 hyperproliferative effect Effects 0.000 claims description 17
- 229940126062 Compound A Drugs 0.000 claims description 16
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 16
- 108010071390 Serum Albumin Proteins 0.000 claims description 15
- 102000007562 Serum Albumin Human genes 0.000 claims description 15
- 229960003301 nivolumab Drugs 0.000 claims description 9
- 229960002621 pembrolizumab Drugs 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 7
- 229950010773 pidilizumab Drugs 0.000 claims description 6
- 229960000548 alemtuzumab Drugs 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 102100024952 Protein CBFA2T1 Human genes 0.000 claims 12
- 102100034608 Angiopoietin-2 Human genes 0.000 abstract description 34
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 abstract description 30
- 239000005557 antagonist Substances 0.000 abstract description 16
- 239000000427 antigen Substances 0.000 description 49
- 102000036639 antigens Human genes 0.000 description 49
- 108091007433 antigens Proteins 0.000 description 49
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 39
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 37
- 108010074708 B7-H1 Antigen Proteins 0.000 description 36
- 241000880493 Leptailurus serval Species 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 25
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 24
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 20
- 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 19
- 125000000539 amino acid group Chemical group 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- 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 16
- 101100372758 Danio rerio vegfaa gene Proteins 0.000 description 15
- 101150030763 Vegfa gene Proteins 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 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 14
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 13
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 11
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 10
- 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 10
- 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 10
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 10
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 10
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 10
- 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 10
- 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 10
- 238000009472 formulation Methods 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- 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 9
- 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 9
- 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 9
- 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 9
- 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 9
- 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 9
- 241000699670 Mus sp. Species 0.000 description 9
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 9
- 108010059993 Vancomycin Proteins 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 108010008355 arginyl-glutamine Proteins 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 208000020816 lung neoplasm Diseases 0.000 description 9
- 108010064235 lysylglycine Proteins 0.000 description 9
- 201000001441 melanoma Diseases 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 230000004614 tumor growth Effects 0.000 description 9
- 229960003165 vancomycin Drugs 0.000 description 9
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 9
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 9
- 229950000578 vatalanib Drugs 0.000 description 9
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 9
- 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 description 8
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 8
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 8
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- 201000005202 lung cancer Diseases 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 230000003442 weekly effect Effects 0.000 description 8
- 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 7
- 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 7
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 7
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 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 7
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 7
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 7
- 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 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 6
- 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 6
- 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 6
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 6
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 description 6
- 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 6
- 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 6
- XSLXHSYIVPGEER-KZVJFYERSA-N Thr-Ala-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XSLXHSYIVPGEER-KZVJFYERSA-N 0.000 description 6
- 108010041407 alanylaspartic acid Proteins 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 108010057821 leucylproline Proteins 0.000 description 6
- 206010061289 metastatic neoplasm Diseases 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 5
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 5
- KVWLTGNCJYDJET-LSJOCFKGSA-N Ala-Arg-His Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KVWLTGNCJYDJET-LSJOCFKGSA-N 0.000 description 5
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 5
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 5
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 5
- REAQAWSENITKJL-DDWPSWQVSA-N Ala-Met-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O REAQAWSENITKJL-DDWPSWQVSA-N 0.000 description 5
- AWNAEZICPNGAJK-FXQIFTODSA-N Ala-Met-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O AWNAEZICPNGAJK-FXQIFTODSA-N 0.000 description 5
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 5
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 5
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 5
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 5
- GCTANJIJJROSLH-GVARAGBVSA-N Ala-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C)N GCTANJIJJROSLH-GVARAGBVSA-N 0.000 description 5
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 5
- 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 5
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 5
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 5
- 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 5
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 5
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 5
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 5
- LRCIOEVFVGXZKB-BZSNNMDCSA-N Asn-Tyr-Tyr 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](CC1=CC=C(O)C=C1)C(O)=O LRCIOEVFVGXZKB-BZSNNMDCSA-N 0.000 description 5
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 5
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 5
- 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 5
- 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 5
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 5
- 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 5
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 5
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- 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 5
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 5
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 5
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 5
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 5
- SMLDOQHTOAAFJQ-WDSKDSINSA-N Gln-Gly-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SMLDOQHTOAAFJQ-WDSKDSINSA-N 0.000 description 5
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 5
- KPNWAJMEMRCLAL-GUBZILKMSA-N Gln-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KPNWAJMEMRCLAL-GUBZILKMSA-N 0.000 description 5
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 5
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 5
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 5
- 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 5
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 5
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 5
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 5
- 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 5
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 5
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 5
- NTNUEBVGKMVANB-NHCYSSNCSA-N Glu-Val-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O NTNUEBVGKMVANB-NHCYSSNCSA-N 0.000 description 5
- RMWAOBGCZZSJHE-UMNHJUIQSA-N Glu-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N RMWAOBGCZZSJHE-UMNHJUIQSA-N 0.000 description 5
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 5
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 5
- 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 5
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 5
- CQZDZKRHFWJXDF-WDSKDSINSA-N Gly-Gln-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CN CQZDZKRHFWJXDF-WDSKDSINSA-N 0.000 description 5
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 5
- 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 5
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 5
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 5
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 5
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 5
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 5
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 5
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 5
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 5
- WRDTXMBPHMBGIB-STECZYCISA-N Ile-Tyr-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=C(O)C=C1 WRDTXMBPHMBGIB-STECZYCISA-N 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 108010065920 Insulin Lispro Proteins 0.000 description 5
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 5
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 5
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 5
- 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 5
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 5
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 5
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 5
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 5
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 5
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu 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)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 5
- 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 5
- 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 5
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 5
- 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 5
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 5
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 5
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 5
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 5
- YFQSSOAGMZGXFT-MEYUZBJRSA-N Lys-Thr-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YFQSSOAGMZGXFT-MEYUZBJRSA-N 0.000 description 5
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 5
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 5
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 5
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 5
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 5
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 5
- YOFKMVUAZGPFCF-IHRRRGAJSA-N Phe-Met-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O YOFKMVUAZGPFCF-IHRRRGAJSA-N 0.000 description 5
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 5
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 5
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 5
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 5
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 5
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 5
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 5
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 5
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 5
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 5
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 5
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 5
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 5
- SQBLRDDJTUJDMV-ACZMJKKPSA-N Ser-Glu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQBLRDDJTUJDMV-ACZMJKKPSA-N 0.000 description 5
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 5
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 5
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 5
- 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 5
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 5
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 5
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 5
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 5
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 5
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 5
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 5
- 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 5
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 5
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 5
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 5
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 5
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 5
- 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 5
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 5
- 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 5
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 5
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 5
- 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 5
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 5
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 5
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 5
- 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 5
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 5
- 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 5
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 5
- 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 5
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 5
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 5
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 5
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu 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](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 5
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 5
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 5
- ZQGPWORGSNRQLN-NHCYSSNCSA-N Val-Asp-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZQGPWORGSNRQLN-NHCYSSNCSA-N 0.000 description 5
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 5
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 5
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 5
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 5
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 5
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 5
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 5
- 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 5
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 5
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 5
- 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 5
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 5
- 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 5
- 108010081404 acein-2 Proteins 0.000 description 5
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 5
- 108010087924 alanylproline Proteins 0.000 description 5
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 5
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 5
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 5
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 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 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 5
- 108010049041 glutamylalanine Proteins 0.000 description 5
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 5
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 5
- 108010089804 glycyl-threonine Proteins 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 108010015792 glycyllysine Proteins 0.000 description 5
- 108010077515 glycylproline Proteins 0.000 description 5
- 108010037850 glycylvaline Proteins 0.000 description 5
- 108010018006 histidylserine Proteins 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 5
- 108010017391 lysylvaline Proteins 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 108010070643 prolylglutamic acid Proteins 0.000 description 5
- 108010053725 prolylvaline Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 5
- 108010026333 seryl-proline Proteins 0.000 description 5
- -1 small molecule tyrosine kinase inhibitor Chemical class 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 108010080629 tryptophan-leucine Proteins 0.000 description 5
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 5
- 108010051110 tyrosyl-lysine Proteins 0.000 description 5
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 5
- 108010027345 wheylin-1 peptide Proteins 0.000 description 5
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 4
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 4
- 102100034594 Angiopoietin-1 Human genes 0.000 description 4
- 108010048036 Angiopoietin-2 Proteins 0.000 description 4
- RGKKALNPOYURGE-ZKWXMUAHSA-N Asp-Ala-Val Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O RGKKALNPOYURGE-ZKWXMUAHSA-N 0.000 description 4
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 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 4
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 4
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 4
- 101000924552 Homo sapiens Angiopoietin-1 Proteins 0.000 description 4
- 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 4
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 4
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 4
- ISHNZELVUVPCHY-ZETCQYMHSA-N Lys-Gly-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O ISHNZELVUVPCHY-ZETCQYMHSA-N 0.000 description 4
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 4
- TYYBJUYSTWJHGO-ZKWXMUAHSA-N Ser-Asn-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TYYBJUYSTWJHGO-ZKWXMUAHSA-N 0.000 description 4
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 4
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 4
- 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 4
- 108010090091 TIE-2 Receptor Proteins 0.000 description 4
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 4
- CNNVVEPJTFOGHI-ACRUOGEOSA-N Tyr-Lys-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CNNVVEPJTFOGHI-ACRUOGEOSA-N 0.000 description 4
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 4
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 4
- 208000009956 adenocarcinoma Diseases 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000002870 angiogenesis inducing agent Substances 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 108010059898 glycyl-tyrosyl-lysine Proteins 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 108010000761 leucylarginine Proteins 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 108010038745 tryptophylglycine Proteins 0.000 description 4
- 108010009962 valyltyrosine Proteins 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 3
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 3
- PLNJUJGNLDSFOP-UWJYBYFXSA-N Asp-Tyr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PLNJUJGNLDSFOP-UWJYBYFXSA-N 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 3
- 229940045513 CTLA4 antagonist Drugs 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 3
- RRIJEABIXPKSGP-FXQIFTODSA-N Cys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CS RRIJEABIXPKSGP-FXQIFTODSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 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 3
- 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 3
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 3
- 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 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- LLZLRXBTOOFODM-QSFUFRPTSA-N Ile-Asp-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N LLZLRXBTOOFODM-QSFUFRPTSA-N 0.000 description 3
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 3
- RIHIGSWBLHSGLV-CQDKDKBSSA-N Leu-Tyr-Ala 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](C)C(O)=O RIHIGSWBLHSGLV-CQDKDKBSSA-N 0.000 description 3
- DRCILAJNUJKAHC-SRVKXCTJSA-N Lys-Glu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DRCILAJNUJKAHC-SRVKXCTJSA-N 0.000 description 3
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 3
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- XWBJLKDCHJVKAK-KKUMJFAQSA-N Phe-Arg-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N XWBJLKDCHJVKAK-KKUMJFAQSA-N 0.000 description 3
- IPFXYNKCXYGSSV-KKUMJFAQSA-N Phe-Ser-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N IPFXYNKCXYGSSV-KKUMJFAQSA-N 0.000 description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 3
- 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 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- RRRRCRYTLZVCEN-HJGDQZAQSA-N Thr-Leu-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O RRRRCRYTLZVCEN-HJGDQZAQSA-N 0.000 description 3
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 3
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala 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(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 3
- SOEGLGLDSUHWTI-STECZYCISA-N Tyr-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 SOEGLGLDSUHWTI-STECZYCISA-N 0.000 description 3
- JXWGBRRVTRAZQA-ULQDDVLXSA-N Val-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N JXWGBRRVTRAZQA-ULQDDVLXSA-N 0.000 description 3
- 208000032594 Vascular Remodeling Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 102000025171 antigen binding proteins Human genes 0.000 description 3
- 108091000831 antigen binding proteins Proteins 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 230000024203 complement activation Effects 0.000 description 3
- 230000004154 complement system Effects 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 229950009791 durvalumab Drugs 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 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 3
- 108010073969 valyllysine Proteins 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 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 2
- WGDNWOMKBUXFHR-BQBZGAKWSA-N Ala-Gly-Arg Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N WGDNWOMKBUXFHR-BQBZGAKWSA-N 0.000 description 2
- NYDBKUNVSALYPX-NAKRPEOUSA-N Ala-Ile-Arg Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NYDBKUNVSALYPX-NAKRPEOUSA-N 0.000 description 2
- AJBVYEYZVYPFCF-CIUDSAMLSA-N Ala-Lys-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O AJBVYEYZVYPFCF-CIUDSAMLSA-N 0.000 description 2
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- PGNNQOJOEGFAOR-KWQFWETISA-N Ala-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 PGNNQOJOEGFAOR-KWQFWETISA-N 0.000 description 2
- NLYYHIKRBRMAJV-AEJSXWLSSA-N Ala-Val-Pro Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N NLYYHIKRBRMAJV-AEJSXWLSSA-N 0.000 description 2
- SKTGPBFTMNLIHQ-KKUMJFAQSA-N Arg-Glu-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SKTGPBFTMNLIHQ-KKUMJFAQSA-N 0.000 description 2
- ZDBWKBCKYJGKGP-DCAQKATOSA-N Arg-Leu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O ZDBWKBCKYJGKGP-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- VLIJAPRTSXSGFY-STQMWFEESA-N Arg-Tyr-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 VLIJAPRTSXSGFY-STQMWFEESA-N 0.000 description 2
- ZVTDYGWRRPMFCL-WFBYXXMGSA-N Asp-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N ZVTDYGWRRPMFCL-WFBYXXMGSA-N 0.000 description 2
- JDDYEZGPYBBPBN-JRQIVUDYSA-N Asp-Thr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JDDYEZGPYBBPBN-JRQIVUDYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 2
- 101100481404 Danio rerio tie1 gene Proteins 0.000 description 2
- 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 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- KHGGWBRVRPHFMH-PEFMBERDSA-N Gln-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](CCC(=O)N)N KHGGWBRVRPHFMH-PEFMBERDSA-N 0.000 description 2
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 2
- MIQCYAJSDGNCNK-BPUTZDHNSA-N Glu-Gln-Trp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MIQCYAJSDGNCNK-BPUTZDHNSA-N 0.000 description 2
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 2
- QLNKFGTZOBVMCS-JBACZVJFSA-N Glu-Tyr-Trp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QLNKFGTZOBVMCS-JBACZVJFSA-N 0.000 description 2
- 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 2
- DTPOVRRYXPJJAZ-FJXKBIBVSA-N Gly-Arg-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N DTPOVRRYXPJJAZ-FJXKBIBVSA-N 0.000 description 2
- HFXJIZNEXNIZIJ-BQBZGAKWSA-N Gly-Glu-Gln Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HFXJIZNEXNIZIJ-BQBZGAKWSA-N 0.000 description 2
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 2
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 2
- 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 2
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 2
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-N 0.000 description 2
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- NULSANWBUWLTKN-NAKRPEOUSA-N Ile-Arg-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N NULSANWBUWLTKN-NAKRPEOUSA-N 0.000 description 2
- GYAFMRQGWHXMII-IUKAMOBKSA-N Ile-Asp-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N GYAFMRQGWHXMII-IUKAMOBKSA-N 0.000 description 2
- RWYCOSAAAJBJQL-KCTSRDHCSA-N Ile-Gly-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RWYCOSAAAJBJQL-KCTSRDHCSA-N 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 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 2
- QUAAUWNLWMLERT-IHRRRGAJSA-N Leu-Arg-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(C)C)C(O)=O QUAAUWNLWMLERT-IHRRRGAJSA-N 0.000 description 2
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 2
- CUXRXAIAVYLVFD-ULQDDVLXSA-N Leu-Arg-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CUXRXAIAVYLVFD-ULQDDVLXSA-N 0.000 description 2
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 2
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 101100216078 Mus musculus Ang4 gene Proteins 0.000 description 2
- 101100481406 Mus musculus Tie1 gene Proteins 0.000 description 2
- 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 2
- 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 2
- 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 2
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 2
- AFNJAQVMTIQTCB-DLOVCJGASA-N Phe-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 AFNJAQVMTIQTCB-DLOVCJGASA-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
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 2
- UUHXBJHVTVGSKM-BQBZGAKWSA-N Pro-Gly-Asn Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UUHXBJHVTVGSKM-BQBZGAKWSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- GXXTUIUYTWGPMV-FXQIFTODSA-N Ser-Arg-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O GXXTUIUYTWGPMV-FXQIFTODSA-N 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- OHKLFYXEOGGGCK-ZLUOBGJFSA-N Ser-Asp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OHKLFYXEOGGGCK-ZLUOBGJFSA-N 0.000 description 2
- BTPAWKABYQMKKN-LKXGYXEUSA-N Ser-Asp-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BTPAWKABYQMKKN-LKXGYXEUSA-N 0.000 description 2
- 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 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
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 2
- VXYQOFXBIXKPCX-BQBZGAKWSA-N Ser-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N VXYQOFXBIXKPCX-BQBZGAKWSA-N 0.000 description 2
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 2
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-N 0.000 description 2
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 2
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 2
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 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
- URPSJRMWHQTARR-MBLNEYKQSA-N Thr-Ile-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O URPSJRMWHQTARR-MBLNEYKQSA-N 0.000 description 2
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 2
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 2
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 2
- BPGDJSUFQKWUBK-KJEVXHAQSA-N Thr-Val-Tyr Chemical compound C[C@@H](O)[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 BPGDJSUFQKWUBK-KJEVXHAQSA-N 0.000 description 2
- SLOYNOMYOAOUCX-BVSLBCMMSA-N Trp-Phe-Arg Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SLOYNOMYOAOUCX-BVSLBCMMSA-N 0.000 description 2
- NJLQMKZSXYQRTO-FHWLQOOXSA-N Tyr-Glu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NJLQMKZSXYQRTO-FHWLQOOXSA-N 0.000 description 2
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 2
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 2
- AGKDVLSDNSTLFA-UMNHJUIQSA-N Val-Gln-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N AGKDVLSDNSTLFA-UMNHJUIQSA-N 0.000 description 2
- 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 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000009824 affinity maturation Effects 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 230000006481 angiogenic pathway Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 229960002011 fludrocortisone Drugs 0.000 description 2
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 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 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 208000021039 metastatic melanoma Diseases 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 210000003668 pericyte Anatomy 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 238000009877 rendering Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 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 2
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-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
- 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
- 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 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- LFFOJBOTZUWINF-ZANVPECISA-N Ala-Trp-Gly Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O)=CNC2=C1 LFFOJBOTZUWINF-ZANVPECISA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 1
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- KNMRXHIAVXHCLW-ZLUOBGJFSA-N Asp-Asn-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O KNMRXHIAVXHCLW-ZLUOBGJFSA-N 0.000 description 1
- MFDPBZAFCRKYEY-LAEOZQHASA-N Asp-Val-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MFDPBZAFCRKYEY-LAEOZQHASA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- PYMDEDHDQYLBRT-DRIHCAFSSA-N Buserelin acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 PYMDEDHDQYLBRT-DRIHCAFSSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 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 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
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 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
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- WXOFKRKAHJQKLT-BQBZGAKWSA-N Cys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CS WXOFKRKAHJQKLT-BQBZGAKWSA-N 0.000 description 1
- 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 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 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 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 206010062878 Gastrooesophageal cancer Diseases 0.000 description 1
- IOFDDSNZJDIGPB-GVXVVHGQSA-N Gln-Leu-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IOFDDSNZJDIGPB-GVXVVHGQSA-N 0.000 description 1
- CGYDXNKRIMJMLV-GUBZILKMSA-N Glu-Arg-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O CGYDXNKRIMJMLV-GUBZILKMSA-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
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 1
- HHSKZJZWQFPSKN-AVGNSLFASA-N Glu-Tyr-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O HHSKZJZWQFPSKN-AVGNSLFASA-N 0.000 description 1
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 1
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 1
- UMRIXLHPZZIOML-OALUTQOASA-N Gly-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)CN UMRIXLHPZZIOML-OALUTQOASA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101000894590 Homo sapiens Uncharacterized protein C20orf85 Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 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 1
- 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 1
- HDODQNPMSHDXJT-GHCJXIJMSA-N Ile-Asn-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O HDODQNPMSHDXJT-GHCJXIJMSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- CDGLBYSAZFIIJO-RCOVLWMOSA-N Ile-Gly-Gly Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O CDGLBYSAZFIIJO-RCOVLWMOSA-N 0.000 description 1
- 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 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- IDGZVZJLYFTXSL-DCAQKATOSA-N Leu-Ser-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IDGZVZJLYFTXSL-DCAQKATOSA-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
- 108010000817 Leuprolide Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- CAODKDAPYGUMLK-FXQIFTODSA-N Met-Asn-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CAODKDAPYGUMLK-FXQIFTODSA-N 0.000 description 1
- MHQXIBRPDKXDGZ-ZFWWWQNUSA-N Met-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)[C@@H](N)CCSC)C(O)=O)=CNC2=C1 MHQXIBRPDKXDGZ-ZFWWWQNUSA-N 0.000 description 1
- MNGBICITWAPGAS-BPUTZDHNSA-N Met-Ser-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MNGBICITWAPGAS-BPUTZDHNSA-N 0.000 description 1
- VYXIKLFLGRTANT-HRCADAONSA-N Met-Tyr-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N VYXIKLFLGRTANT-HRCADAONSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 101000808007 Mus musculus Vascular endothelial growth factor A Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- 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 1
- RYJRPPUATSKNAY-STECZYCISA-N Pro-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]2CCCN2 RYJRPPUATSKNAY-STECZYCISA-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
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- BFZKMNSQCNVFGM-UCEYFQQTSA-N Sagopilone Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC=C)[C@@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@H]1C1=CC=C(SC(C)=N2)C2=C1 BFZKMNSQCNVFGM-UCEYFQQTSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000238370 Sepia Species 0.000 description 1
- DKKGAAJTDKHWOD-BIIVOSGPSA-N Ser-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)C(=O)O DKKGAAJTDKHWOD-BIIVOSGPSA-N 0.000 description 1
- OHKFXGKHSJKKAL-NRPADANISA-N Ser-Glu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OHKFXGKHSJKKAL-NRPADANISA-N 0.000 description 1
- AEGUWTFAQQWVLC-BQBZGAKWSA-N Ser-Gly-Arg Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O AEGUWTFAQQWVLC-BQBZGAKWSA-N 0.000 description 1
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- XZKQVQKUZMAADP-IMJSIDKUSA-N Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(O)=O XZKQVQKUZMAADP-IMJSIDKUSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 239000004268 Sodium erythorbin Substances 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
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102000012753 TIE-2 Receptor Human genes 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- BABINGWMZBWXIX-BPUTZDHNSA-N Trp-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N BABINGWMZBWXIX-BPUTZDHNSA-N 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 108091005906 Type I transmembrane proteins Proteins 0.000 description 1
- NSOMQRHZMJMZIE-GVARAGBVSA-N Tyr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NSOMQRHZMJMZIE-GVARAGBVSA-N 0.000 description 1
- UMXSDHPSMROQRB-YJRXYDGGSA-N Tyr-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O UMXSDHPSMROQRB-YJRXYDGGSA-N 0.000 description 1
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-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
- 102100021442 Uncharacterized protein C20orf85 Human genes 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 1
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 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 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000003838 adenosines Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000003443 bladder cell Anatomy 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
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960005064 buserelin acetate Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 108700008462 cetrorelix Proteins 0.000 description 1
- 229960003230 cetrorelix Drugs 0.000 description 1
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960004630 chlorambucil Drugs 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
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 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 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960005420 etoposide Drugs 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
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 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 1
- 229960002949 fluorouracil Drugs 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
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 201000006974 gastroesophageal cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 150000004676 glycans Chemical group 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 108700020746 histrelin Proteins 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229960000908 idarubicin 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
- 210000000987 immune system Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 229950005692 larotaxel Drugs 0.000 description 1
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229950007056 liarozole Drugs 0.000 description 1
- UGFHIPBXIWJXNA-UHFFFAOYSA-N liarozole Chemical compound ClC1=CC=CC(C(C=2C=C3NC=NC3=CC=2)N2C=NC=C2)=C1 UGFHIPBXIWJXNA-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000008443 lung non-squamous non-small cell carcinoma Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-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
- 229960001924 melphalan Drugs 0.000 description 1
- 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 1
- 239000012528 membrane Substances 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
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 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 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000017205 mitotic cell cycle checkpoint Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 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 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000002773 nucleotide Chemical group 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- VMZMNAABQBOLAK-DBILLSOUSA-N pasireotide Chemical compound C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 VMZMNAABQBOLAK-DBILLSOUSA-N 0.000 description 1
- 229960005415 pasireotide Drugs 0.000 description 1
- 108700017947 pasireotide Proteins 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 208000017805 post-transplant lymphoproliferative disease Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960000624 procarbazine Drugs 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
- 239000000047 product Substances 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010079317 prolyl-tyrosine Proteins 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229950007213 spartalizumab Drugs 0.000 description 1
- 230000000638 stimulation Effects 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
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229940066453 tecentriq 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
- 230000004797 therapeutic response Effects 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 210000003741 urothelium Anatomy 0.000 description 1
- 229950000449 vanucizumab Drugs 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 230000006426 vascular sprouting Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 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 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 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 1
- 229960004355 vindesine 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
- 229960000922 vinflunine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 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
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- 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
- C07K16/3023—Lung
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
-
- 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
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- 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
- C07K2317/565—Complementarity determining region [CDR]
-
- 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
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及某些双特异性VEGF和Ang2结合分子与PD1拮抗剂用于治疗癌症的联合用途。进一步涉及包含这样的结合分子和拮抗剂的药物组合物和试剂盒。
Description
发明领域
本发明涉及癌症治疗的联合治疗,并涉及用于这种联合治疗的化合物。用于联合的化合物是双特异性结合分子,如抗体衍生物和PD-1拮抗剂。
发明背景
血管生成是提供营养性血液供应的新血管的发生,是实体瘤生长和存活的先决条件。人们已经在癌症治疗中开辟了靶向参与血管生成途径的关键分子的途径。这些途径包括抑制血管内皮生长因子(VEGF)信号传导途径的模式,因为VEGF被认为是最有效的血管生成生长因子。
肺癌是癌症相关死亡的主要原因,其中2012年全世界有近160万例死亡,或者其占整个癌症死亡率的近20%Molina等人,Mayo Clin Proc.2008;83(5):584-594;Chan等人,Transl Lung Cancer Res.2014;(1):36-54)。最常见的肺癌类型是非小细胞肺癌(NSCLC),约占所有肺癌的85%(Chen等人Nat Rev Cancer 2014;14:535-546;Nawaz等人Nat RevDrug Discov.2016;15:229-230)。如今,NSCLC被理解为包括一组具有多种病理生理特征的异质性疾病,其中肺腺癌、鳞状细胞癌(SCC)和大细胞癌是最突出的亚型。
近年来,针对癌症,特别是针对NSCLC,除了化学疗法和放射疗法之外,已经为诊断时患有局部晚期或转移性疾病的患者开发了多种新的治疗选项。这些新的治疗方法是靶向治疗,涉及例如小分子抑制剂或受体单克隆抗体(mAb),其基于主要细胞信号传导和调控途径的改变-包括受体酪氨酸激酶(TK)(比如表皮生长因子受体(EGFR))的改变以及血管生成途径的改变-在肺癌中很常见。最近的工作大多集中在EGFR突变和受到EGFR酪氨酸激酶抑制剂和克唑替尼抑制的间变性淋巴瘤激酶(ALK)的异常融合上。还已经证明,靶向VEGF的单克隆抗体贝伐单抗与化学疗法的联用可以使结直肠癌(Hurwitz等人New Eng J Med 2004;350:2335-2342)或晚期非鳞状NSCLC(Sandler等人J Clin Oncol 2005 23(16s pt 1):2ss)患者的生存率显著提高。除了阻断直接参与VEGF途径的组分的疗法外,例如血管生成素2(Ang2),已成为癌症治疗中另一个引人注目的靶标;Ang2是Tie2受体酪氨酸激酶的配体,Tie2受体酪氨酸激酶通过启动其他血管生成因子(如VEGF)的功能来控制血管重塑。
WO2010/040508和Kienast等人(Clin Cancer Res;19(24),2013)公开了一种双特异性抗VEGF/抗Ang-2抗体——万古珠单抗(vanucizumab),及其在癌症治疗中的用途。
EP2694546B1和WO2012/131078A1涉及一种双特异性结合分子,其包含VEGF结合性免疫球蛋白单可变结构域和Ang2结合性免疫球蛋白单可变结构域,以及血清白蛋白结合性免疫球蛋白单可变结构域,其用于治疗癌症和其他疾病。
WO2016/170039A1涉及特异性结合血管生成素2的抗体与特异性结合程序性死亡1多肽(PD-1)的抗体的联合治疗。
WO2016/170040A1涉及特异性结合血管生成素2的抗体和特异性结合VEGF的抗体与特异性结合程序性死亡配体1(PD-L1)的抗体的联合治疗。
尽管存在上述所有方法,对于针对癌症患者的改进的治疗选项仍然存在需求。因此,本发明的目的是提供用于癌症治疗的药物组合物和方法,以改善治疗功效和适用性。
发明简述
本发明提供了一种用双特异性抗VEGF/抗Ang-2抗体与程序性死亡1蛋白(PD-1)的拮抗剂一起治疗患者的方法,PD-1是一种负向调控T细胞受体信号的免疫抑制蛋白。该治疗导致肿瘤生长显著降低,甚至导致肿瘤退缩(图1)。因此,本发明提供了包括双特异性抗VEGF/抗Ang-2抗体和PD-1拮抗剂的联合治疗。
在一个详细的方面,本发明涉及一种治疗和/或预防肿瘤性或过度增殖性疾病的方法,所述疾病特别是癌症或肿瘤疾病,所述方法包括对有此需要的患者施用
a)治疗有效量的化合物A,和
b)治疗有效量的化合物B,
其中
●化合物A是双特异性结合分子,其包含
○VEGF结合性免疫球蛋白单可变结构域,
○血清白蛋白结合性免疫球蛋白单可变结构域,和
○Ang2结合性免疫球蛋白单可变结构域
其中
○所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SYSMG(SEQ ID NO:1)
■CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2)
■CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3)
○所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SFGMS(SEQ ID NO:4)
■CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5)
■CDR3:GGSLSR(SEQ ID NO:6),
○所述Ang2结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:DYAIG(SEQ ID NO:7)
■CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8)
■CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ ID NO:9),并且
其中
●化合物B是PD-1拮抗剂。
在一个相关方面,本发明提供了各自用于治疗和/或预防肿瘤性或过度增殖性疾病的方法中的化合物A和化合物B,所述方法包括向有此需要的患者施用化合物A和化合物B。
本发明进一步涉及化合物A和化合物B各自在制备用于治疗和/或预防肿瘤性或过度增殖性疾病的药物组合物中的用途,其中化合物A和化合物B旨在或被提供为化合物A和化合物B的联合给药。
在另一方面,本发明公开了一种药物组合物,其包含
a)化合物A和
b)化合物B
其中
●化合物A是双特异性结合分子,其包含
○VEGF结合性免疫球蛋白单可变结构域,
○血清白蛋白结合性免疫球蛋白单可变结构域,和
○Ang2结合性免疫球蛋白单可变结构域,
其中
○所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SYSMG(SEQ ID NO:1)
■CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2)
■CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3)
○所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SFGMS(SEQ ID NO:4)
■CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5)
■CDR3:GGSLSR(SEQ ID NO:6),
○所述Ang2结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:DYAIG(SEQ ID NO:7)
■CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8)
■CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ ID NO:9),并且
其中
●化合物B是PD-1拮抗剂。
在一个另外的方面,本发明涉及一种试剂盒,其包含
a)包含化合物A的第一药物组合物,和
b)包含化合物B的第二药物组合物,
其中化合物A和化合物B如上定义。
附图说明
图1分别显示了使用与大鼠IgG2a抗鼠PD-1抗体EX 101359(克隆RMP1-14)(剂量:10mg/kg;时间表:每3-4天一次)联合的双特异性结合分子VEGFANGBII22(化合物A)(剂量:15mg/kg;日程:每3-4天一次)(A-B)和如WO2010/040508或Kienast等人(2013,上文)所定义的CrossMab抗VEGF/抗Ang-2抗体(万古珠单抗)(剂量:15mg/kg;日程:每3-4天一次)(C-D)治疗9个测试个体(空心三角,下线)后的肿瘤生长抑制,与9个未治疗个体(实心圆,上线)进行比较。对治疗个体进一步施用小分子酪氨酸激酶抑制剂瓦他拉尼(EXBF003)(剂量:100mg/kg;日程;每天一次),以模拟小鼠模型中抗VEGF活性。治疗在每只小鼠注射5x104LL/2皮下肿瘤细胞之后第5天开始。标明了到实验的第35天为止的肿瘤体积(mm3)(A,C)和相应的随机化相对肿瘤体积(B,D)。
图2显示了用对照/同种型抗体、抗PD1抗体(剂量:10mg/kg;日程:每3-4天一次)、VEGFANGBII22(剂量:15mg/kg;日程:每3-4天一次)、瓦他拉尼(剂量:100mg/kg;日程;每天一次)、瓦他拉尼加抗PD1抗体、瓦他拉尼加抗PD1抗体加VEGFANGBII22、或抗PD1抗体加VEGFANGBII22治疗的小鼠的平均生存期。每个治疗组由10只荷瘤随机化个体小鼠组成。治疗在每只小鼠个体注射5x 104LL/2皮下肿瘤细胞之后第3天开始。
发明详述
本发明涉及方法、用于特定用途的化合物、化合物的用途、药物组合物和试剂盒,它们均涉及化合物A和化合物B的联合治疗或联合提供,其中
●化合物A是双特异性结合分子,其包含
○VEGF结合性免疫球蛋白单可变结构域,
○血清白蛋白结合性免疫球蛋白单可变结构域,和
○Ang2结合性免疫球蛋白单可变结构域
其中
○所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SYSMG(SEQ ID NO:1)
■CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2)
■CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3)
○所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
■CDR1:SFGMS(SEQ ID NO:4)
■CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5)
■CDR3:GGSLSR(SEQ ID NO:6),
○所述Ang2结合性免疫球蛋白单可变结构域具有下列
CDR序列:
■CDR1:DYAIG(SEQ ID NO:7)
■CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8)
■CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ ID NO:9),并且
其中
●化合物B是PD-1拮抗剂。
本发明人惊奇地发现,与仅使用化合物A或仅使用化合物B的疗法相比,化合物A和化合物B的联合导致肿瘤生长显著减弱或甚至缩小。化合物A和B协同作用,并且可以使癌症减轻。
根据本发明的化合物A是双特异性抗VEGF/抗Ang-2结合分子。抗血管生成治疗已成为几种类型的肿瘤的重要治疗选项。这些治疗当前聚焦于通过中和VEGF或其受体来阻断VEGF途径(Ferrara等人,Nat Rev Drug Discov.2004;3(5):391-400)。在小鼠中的最近研究表明,血管生成素2(Ang2)(Tie2受体的配体)通过启用其他血管生成因子(比如VEGF)的功能来控制血管重塑。Ang2主要由内皮细胞表达,受缺氧和其他血管生成因子强烈诱导,并已被证明其调节肿瘤血管的可塑性,使血管对VEGF和FGF2有反应(Augustin等人,Nat RevMol Cell Biol.2009;10(3):165-77)。与此作用一致,Ang2的缺失或抑制导致血管生成减少(Gale等人,Dev Cell.2002;3(3):302-4)(Falcon等人,Am J Pathol.2009;175(5):2159-70)。据报道患有结肠直肠癌、NSCLC和黑色素瘤的患者Ang2血清浓度升高(Goede等人,Br J Cancer.2010 Oct 26;103(9):1407-14),(Park等人,Chest.2007;132(1):200-6),(Helfrich等人,Clin Cancer Res.2009 15;15(4):1384-92)。在CRC癌症中,Ang2血清水平与抗VEGF疗法的治疗反应相关。
Ang2是Tie2受体酪氨酸激酶的一种分泌的66kDa配体(Augustin等人,Nat RevMol Cell Biol.2009;10(3):165-77)。Ang2由N端卷曲螺旋结构域和C端纤维蛋白原样结构域组成,后者是Tie2相互作用必需的。Ang2主要由内皮细胞表达,并受缺氧和其他血管生成因子(包括VEGF)强烈诱导。Tie2发现于内皮细胞、造血干细胞和肿瘤细胞上。Ang2-Tie2已被证明其调节肿瘤血管的可塑性,使血管对VEGF和FGF2有反应。
Ang-Tie系统由2种受体(Tie1和Tie2)和3种配体(Ang1、Ang2和Ang4)组成(Augustin等人,Nat Rev Mol Cell Biol.2009;10(3):165-77)。Tie2、Ang1和Ang2是该家族中研究最多的成员,Tie1是孤儿受体,Ang4在血管重塑中的作用仍然需要确定。在Tie2结合和激活后,Ang2和Ang1介导相反的功能。Ang2介导的Tie2激活导致内皮细胞活化、周细胞解离、血管渗漏和诱导血管发芽。与Ang2相反,Ang1信号传导通过募集周细胞维持血管完整性,从而维持内皮细胞静止。
可以根据本发明使用的双特异性抗VEGF/抗Ang-2结合分子,在例如WO2012/131078中有公开,将其通过提述并入本文。
根据本发明的化合物B是针对蛋白质程序性死亡1蛋白(PD-1)家族成员的拮抗剂,比如PD-1本身或其配体之一PD-L1或PD-L2。PD-1已知是一种负调节TCR信号的免疫抑制蛋白(Ishida,Y.等人(1992)EMBO J.11:3887-3895;Blank,C.等人(2006)Immunol.Immunother.56(6):739-745)。PD-1和PD-L1之间的相互作用可发挥免疫检查点的作用,可导致例如肿瘤浸润淋巴细胞减少、T细胞受体介导的增殖降低和/或癌性细胞的免疫逃避(Dong等人(2003)J.Mol.Med.81:281-7;Blank等人(2005)CancerImmunol.Immunother.54:307-314;Konishi等人(2004)Clin.Cancer Res.10:5094-100)。通过抑制PD-1与PD-L1或PD-L2的局部相互作用可以逆转免疫抑制,并且当PD-1与PD-L2的相互作用也被阻断时,效果是累加性的(Iwai等人(2002)Proc.Nat’l.Acad.Sci USA 99:12293-7;Brown等人(2003)J.Immunol.170:1257-66)。
PD-1是T细胞调节因子的CD28/CTLA-4这一大家族的一种抑制性成员。CD28家族的其他成员包括CD28、CTLA-4、ICOS和BTLA。PD-1被认为以单体形式存在,其缺乏其他CD28家族成员特征性的未配对半胱氨酸残基。PD-1表达于活化的B细胞、T细胞和单核细胞上(Okazaki等人(2002)Curr Opin Immunol 14:391779-82;Bennett等人(2003)J.Immunol.170:711-8)。已经鉴定了PD-1的两种配体——PD-L1(B7-H1)和PD-L2(B7-DC),已经证明,它们在与PD-1结合时下调T细胞活化(Freeman等人(2000)J.Exp.Med.192:1027-34;Carter等人(2002)Eur.J.Immunol.32:634-43)。PD-L1和PD-L2两者都是与PD-1结合的B7同源物。PD-L1大量存在于多种人类癌症中(Dong等人,(2002)Nat.Med.8:787-9)。
PD-1基因编码一个55kDa I型跨膜蛋白,该蛋白是Ig基因超家族的一部分(Agata等人,(1996)Int Immunol 8:765-72)。完整的PD-1序列可以GenBank登录号U64863找到。PD-1尽管与CTLA-4在结构上相似,但缺乏对于B7-1和B7-2结合重要的MYPPY基序(SEQ IDNO:10)。
鉴于上述情况,近年来已经开发了作为PD-1拮抗剂的单克隆抗体用于治疗,更精确地说,用于治疗包括癌症和传染病在内的各种疾病(例如,WO2006/121168;WO2015/112900)。根据本发明可以使用任何一种这样的抗体。
本发明人惊奇地发现,与仅用化合物A或仅用化合物B治疗相比,用如上/下文定义的化合物A和化合物B的联合治疗个体导致显著更强的肿瘤体积减小甚至缩小。而且,当与用万古珠单抗和相同的PD-1拮抗剂治疗个体相比时,用包含如上/下定义的化合物A和化合物B的组合物治疗甚至导致肿瘤缩小(实施例1;图1)。化合物A和化合物B两者都是根据本发明的活性剂。
本发明意义上的PD-1拮抗剂是抑制PD-1与其受体或配体相互作用的化合物。
优选地,PD-1拮抗剂是PD-1的抑制剂或PD-L1的抑制剂。PD-1拮抗剂可优选为抗PD-1抗体或抗PD-L1抗体,更优选为人源化或全人源抗PD-1抗体或人源化或全人抗PD-L1抗体。这些抗体中的任何一种可以是重组人抗体。
本文中的术语“抗体”以最广义的方式加以使用,并且涵盖各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)、单链抗体、单结构域抗体和片段化抗体(也称为抗体片段),比如Fab、F(ab)2、F(ab’)2、Fab'、单链可变片段(scFv)或抗体的抗原结合结构域,只要它们表现出期望的抗原结合活性即可。
抗体可以具有通常由抗体的Fc部分(抗体恒定区)介导的效应子功能,比如ADCC或CDC,或者,抗体可以由于例如缺乏Fc部分或具有封闭的、掩蔽的Fc部分而不具有效应子功能,所述封闭的、掩蔽的Fc部分实质上是未被免疫细胞或免疫系统成分如补体系统识别或未被充分识别的Fc部分。
抗体或其片段可为任何类型,例如IgA、IgD、IgE、IgG、IgM。优选的是IgG。
如本文中使用的术语“单克隆抗体”或“单克隆抗体组合物”是指具有单氨基酸组成的抗体分子制剂。
“重组抗体”是由重组工程改造的宿主细胞产生的抗体。重组抗体任选地经过分离或纯化。
“人抗体”是具有这样的氨基酸序列的抗体,所述氨基酸序列对应于人细胞产生的抗体或衍生自利用人抗体库或其他的人抗体编码序列的非人来源的抗体的氨基酸序列。人抗体的这个定义明确排除包含非人的(non-human)抗原结合残基的人源化抗体。
如本文中使用的,术语“重组人抗体”预期包括通过重组手段制备、表达、产生或分离的所有人抗体,比如从宿主细胞(比如NS0或CHO细胞)或从对于人免疫球蛋白基因而言为转基因的动物(例如小鼠)中分离的抗体或使用转染到宿主细胞中的重组表达载体表达的抗体。这样的重组人抗体具有处于重排形式的可变区和恒定区。已经对根据本发明的重组人抗体进行了体内体细胞超突变。因此,重组抗体的VH和VL区的氨基酸序列是这样的序列,尽管其衍生自人种系VH和VL序列并与之相关,但可能并不天然存在于体内人抗体种系库中。
“人源化”抗体是指包含来自非人高变区(HVR)的氨基酸残基和来自人FR的氨基酸残基的嵌合抗体。在某些实施方案中,人源化抗体将包含至少一个(通常两个)可变结构域中的基本上所有的可变结构域,其中所有或基本上所有的HVR(例如,互补决定区(CDR))对应于非人抗体的HVR,并且所有或基本上全部框架区(FR)对应于人抗体的FR。人源化抗体任选地可以包含衍生自人抗体的抗体恒定区的至少一部分。抗体例如非人抗体的“人源化形式”是指经过人源化的抗体。
多肽(比如本发明的免疫球蛋白、抗体、免疫球蛋白单可变结构域,或通常地抗原结合分子或其片段)的“结合”意味着对某种表位、抗原或蛋白质(或对其至少一部分、片段或表位)“具有亲和力”或“具有特异性”。
通常,术语“特异性”是指特定抗原结合分子或抗原结合蛋白(比如本发明的免疫球蛋白单可变结构域)分子能够结合的不同类型的抗原或表位的数目。可以基于其亲和力和/或亲合力来确定抗原结合分子的特异性。亲和力由抗原与抗原结合蛋白的解离平衡常数(KD)表示,其为表位与抗原结合蛋白上的抗原结合位点之间结合强度的量度:KD的值越小,表位与抗原结合分子之间的结合强度越强(或者,亲和力也可以表示为亲和常数(KA),其为1/KD)。正如技术人员将清楚的(例如,基于本文中的进一步公开),取决于感兴趣的特定抗原,亲和力可以以本身已知的方式来加以测定。亲合力是包含它的抗原结合分子(比如免疫球蛋白、抗体、免疫球蛋白单可变结构域或多肽)与相关抗原之间结合强度的量度。亲合力与表位和抗原结合分子上的其抗原结合位点之间的亲和力以及抗原结合分子上存在的相关结合位点的数目两者都有关。
例如,天然抗体是单特异性的。如本文中使用的术语“单特异性抗体”表示具有一个或多个各自与相同抗原的相同表位结合的结合位点的抗体。“多特异性抗体”结合两个或更多个不同的表位(例如,两个、三个、四个或更多个不同的表位)。所述表位可以在相同或不同的抗原上。多特异性抗体的例子是结合两个不同的表位的“双特异性抗体”。当抗体具有多于一种的特异性时,所识别的表位可以与单一抗原或多于与一种的抗原相关联。
表位是被抗体或抗原结合模块结合的抗原区域。术语“表位”包括能够与抗体或抗原结合模块特异性结合的任何多肽决定簇。在某些实施方案中,表位决定簇包括分子的化学活性表面基团,比如氨基酸、聚糖侧链、磷酰基或磺酰基,并且在某些实施方案中,可以具有特定的三维结构特征和/或特定的电荷特征。构象和非构象表位的区别在于,在变性溶剂的存在下,与前者的结合的结合丧失,而与后者的结合未丧失。如本文中使用的,术语“结合”和“特异性结合”是指在体外测定法中抗体或抗原结合模块与抗原表位的结合,优选在等离子体共振测定(GE-Healthcare Uppsala,Sweden)中与纯化的野生型抗原的结合。
根据本发明的结合分子(例如抗体)(包括化合物A或化合物B的抗体)与抗原的结合亲和力由术语ka(抗体的抗体/抗原复合物结合的速率常数)、kD(解离常数)和KD(kD/ka)定义。在一个实施方案中,结合或特异性结合表示10-8mol/l或更小的结合亲和力(KD),在一个实施方案中为10-8M至10-13mol/l。因此,根据本发明的多特异性抗体以10-8mol/l或更小的结合亲和力(KD),例如以10-8至10-13mol/l的结合亲和力(KD)与对其特异的每种抗原特异性结合。在一个实施方案中,结合亲和力(KD)为10-9至10-13mol/l。
如本文中使用的表述“可变结构域”或“可变区”或Fv表示直接参与抗体抗原结合的一对轻链与重链中的每一者。轻链的可变结构域缩写为“VL”,重链的可变结构域缩写为“VH”。可变轻链和重链结构域具有相同的一般结构,并且每个结构域包含四个框架(FR)区,FR区的序列高度保守,通过三个HVR(或CDR)连接。框架区采用β-片层构象,并且CDR可形成连接β-片层结构的环。每条链中的CDR通过框架区保持在其三维结构中,并与来自另一条链的CDR一起形成抗原结合位点。抗体的重链和轻链CDR3区在根据本发明的抗体的结合特异性/亲和力中发挥特别重要的作用,并因此提供本发明的进一步目的。
如在本申请中使用的,术语“恒定结构域”或“恒定区”表示除可变区之外的抗体的结构域的总和。恒定区不直接参与抗原结合,但表现出各种效应子功能。
如本文中公开的抗体中使用的,“恒定结构域”优选地是人来源的,其来自人抗体亚类IgG1、IgG2、IgG3或IgG4的恒定重链区和/或恒定轻链κ或λ区。这样的恒定结构域和区域在现有技术中是熟知的,例如由Kabat等人描述(“Sequence of proteins ofimmunological interest”,US Public Health Services,NIH Bethesda,MD,PublicationNo.91)。
抗体的“Fc部分”不直接参与抗体抗原结合,但表现出各种效应子功能。“抗体的Fc部分”是技术人员熟知的术语,并且是根据抗体的木瓜蛋白酶切割定义的。根据其重链恒定区的氨基酸序列,将抗体或免疫球蛋白分为类别IgA、IgD、IgE、IgG和IgM,其中一些可进一步分为亚类(同种型),例如IgG1、IgG2、IgG3和IgG4、IgA1和IgA2。根据重链恒定区,不同类别的免疫球蛋白分别称为α、δ、ε、γ和μ。基于补体激活、Clq结合和Fc受体结合,抗体的Fc部分直接参与ADCC(抗体依赖性细胞介导的细胞毒性)和CDC(补体依赖性细胞毒性)。通过补体因子C1q与大多数IgG抗体亚类的Fc部分结合而启动补体激活(CDC)。虽然抗体对补体系统的影响取决于某些条件,但与C1q的结合是由Fc部分中定义的结合位点引起的。这样的结合位点在现有技术中是已知的,并且例如描述于Boackle,R.J.等人,Nature 282(1979)742-743;Lukas,T.J.等人,J.Immunol.127(1981)2555-2560;Brunhouse,R.和Cebra,J.J.,Mol.Immunol.16(1979)907-917;Burton,D.R.等人,Nature 288(1980)338-344;Thommesen,J.E.等人,Mol.Immunol.37(2000)995-1004;Idusogie,E.E.等人,J.Immunol.164(2000)4178-4184;Hezareh,M.等人,J.Virology 75(2001)12161-12168;Morgan,A.等人,Immunology 86(1995)319-324;EP 0 307 434。这样的结合位点是例如L234、L235、D270、N297、E318、K320、K322、P331和P329(根据Kabat E.A.的EU索引编号,参见下文)。抗体亚类IgG1、IgG2和IgG3通常显示补体激活以及C1q和C3结合,而IgG4不激活补体系统并且不结合C1q和C3。
关于化合物A,术语“双特异性结合分子”是指包含至少一个Ang2结合分子(或“Ang2结合组分”)和至少一个VEGF结合分子(或“VEGF结合组分”)的分子。双特异性结合分子可包含多于一个的Ang2结合分子和/或多于一个的VEGF结合分子,即在双特异性结合分子包含双互补位(如下定义)的Ang2结合分子和/或双互补位的VEGF结合分子的情况下,所述Ang2结合分子和/或VEGF结合分子在与Ang2或与VEGF结合的分子的一部分中,即分别在其“Ang2结合组分”(或抗Ang2组分)或“VEGF结合组分”(或抗VEGF组分)中。然而,在此上下文中,词语“双特异性”不应被解释为从双特异性结合分子中排除对VEGF和Ang2以外的分子具有结合特异性的其他结合组分。这样的其他结合组分的非限制性实例是与血清白蛋白结合的结合组分。
除非另有说明,否则术语“VEGF结合分子”或“Ang2结合分子”包括如本文中定义的抗VEGF或抗Ang2抗体、抗VEGF抗体或抗Ang2抗体片段、“抗VEGF抗体样分子”或“抗Ang2抗体样分子”或具有这些中的任一者的缀合物。抗体包括但不限于单克隆抗体和嵌合单克隆抗体。术语“抗体”涵盖完整的免疫球蛋白,如通过在宿主细胞中重组表达产生的单克隆抗体,也涵盖抗体片段或“抗体样分子”,包括:单链抗体和线性抗体,所谓的“SMIP”(“小模块免疫药物”),例如在WO2002/056910中描述的;抗体样分子包括本文中定义的免疫球蛋白单可变结构域。抗体样分子的其他实例是免疫球蛋白超家族抗体(IgSF)或CDR移植分子。
“Ang2结合分子”或“VEGF结合分子”各自指单价靶结合分子(即与相应靶的一个表位结合的分子)以及二价或多价结合分子(即与多于一个表位结合的结合分子,例如下文定义的“双互补位”分子)二者。包含多于一个Ang2(或VEGF)结合性免疫球蛋白单可变结构域的Ang2(或VEGF)结合分子也被称为“格式化”(formatted)的结合分子,它们在靶结合组分内除了免疫球蛋白单可变结构域外,还可以包含具有效应子功能的接头和/或模块,例如半衰期延长模块,如白蛋白结合性免疫球蛋白单可变结构域;和/或融合伴侣,如血清白蛋白和/或附接的聚合物,如PEG。
如本文中使用的,术语“双互补位Ang2(或VEGF)结合分子”或“双互补位免疫球蛋白单可变结构域”是指这样的结合分子,其包含如本文中定义的第一免疫球蛋白单可变结构域和第二免疫球蛋白单可变结构域,其中这两种分子与相应抗原的两个非重叠的表位结合。双互补位结合分子由相对于表位具有不同特异性的免疫球蛋白单可变结构域组成。
格式化的结合分子也可以包含两个相同的免疫球蛋白单可变结构域或两个不同的、但识别相应抗原的相同或重叠表位的免疫球蛋白单可变结构域,尽管这是较不优选的。在这样的情况下,对于VEGF,两个免疫球蛋白单可变结构域可以结合在形成VEGF二聚体的两个单体的每一个中的相同或重叠表位。
可以使用本身已知的任何适合的体外测定法、基于细胞的测定法、体内测定法和/或动物模型或其任何组合来测试本发明的双特异性结合分子和包含它的组合物的功效,这取决于特定的疾病或感兴趣的疾患。适合的测定法和动物模型对技术人员将是清楚的,并且例如包括EP 2 694 546B1中描述的测定法。
除非另有说明,否则术语“免疫球蛋白”和“免疫球蛋白序列”,无论在本文中用于指重链抗体还是指常规的4链抗体,都作为一般性的术语使用,包括全尺寸抗体、抗体的单独的链、以及抗体的所有部分、结构域或片段(分别包括但不限于抗原结合结构域或片段,比如VHH结构域或VH/VL结构域)。另外,除非上下文需要更有限的解释,否则如本文中使用的术语“序列”(例如,术语如“免疫球蛋白序列”、“抗体序列”、“(单)可变结构域序列”、“VHH序列”或“蛋白质序列”)通常应当理解为包括相关的氨基酸序列以及编码所述氨基酸序列的核酸序列或核苷酸序列两者。
如本文中使用的,术语“结构域(多肽或蛋白质的)”是指折叠的蛋白质结构,其具有保留独立于蛋白质的其余部分的其三级结构的能力。通常,结构域负责蛋白质的某种独立的功能特性,并且在许多情况下,可以被添加、去除或转移至其他蛋白质,而不丧失蛋白质的剩余部分和/或结构域的功能。
如本文中使用的,术语“免疫球蛋白结构域”是指抗体链(例如像常规4链抗体或重链抗体的链)的球状区域,或指基本上由这样的球状区域组成的多肽。免疫球蛋白结构域的特征在于,它们保留了抗体分子的免疫球蛋白折叠特征,其由排列在两个β片层中的任选地通过保守的二硫键稳定化的约7条反平行β链的2层夹层组成。免疫球蛋白结构域包含一个或多个可变结构域,即一个或多个免疫球蛋白可变结构域。
如本文中使用的,术语“免疫球蛋白可变结构域”是指基本上由四个“框架区”组成的免疫球蛋白结构域,所述框架区在本领域中并且在下文中分别被称为“框架区1”或“FR1”;“框架区2”或“FR2”;“框架区3”或“FR3”;和“框架区4”或“FR4”;所述框架区被三个“互补决定区”或“CDR”中断,所述互补决定区在本领域中并且在下文中分别被称为“互补决定区1”或“CDR1”;“互补决定区2”或“CDR2”;和“互补决定区3”或“CDR3”。因此,免疫球蛋白可变结构域的一般结构或序列可以指示如下:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。通过携带抗原结合位点,免疫球蛋白可变结构域赋予抗体针对抗原的特异性。本发明的分子包括免疫球蛋白单可变结构域,如VHH。
如本文中使用的,术语“免疫球蛋白单可变结构域”是指能够与抗原表位特异性结合而不与另外的免疫球蛋白可变结构域配对的免疫球蛋白可变结构域。本发明含义上的免疫球蛋白单可变结构域的一个实例是“结构域抗体”,比如免疫球蛋白单可变结构域VH和VL(VH结构域和VL结构域)。免疫球蛋白单可变结构域的另一个实例是骆驼科动物的“VHH结构域”(或简称为“VHH”),如下文所述。
鉴于以上定义,常规4链抗体(比如IgG、IgM、IgA、IgD或IgE分子;本领域已知)或Fab片段、F(ab’)2片段、Fv片段(比如二硫键连接的Fv或scFv片段)或衍生自此类常规4链抗体的双抗体(均为本领域已知)的抗原结合结构域通常不被视为免疫球蛋白单可变结构域,因为在这些情况下,通常通过一个(单个)免疫球蛋白结构域不发生与抗原的相应表位结合,而是通过一对(相关的)免疫球蛋白结构域,如轻链和重链可变结构域,即通过免疫球蛋白结构域的VH-VL对发生结合,所述各免疫球蛋白结构域共同地与相应抗原的表位结合。
“VHH结构域”,也称为VHH、VHH结构域、VHH抗体片段和VHH抗体,其最初被描述为“重链抗体”(即“缺失轻链的抗体”;Hamers-Casterman C,Atarhouch T,Muyldermans S,Robinson G,Hamers C,Songa EB,Bendahman N,Hamers R.:“Naturally occurringantibodies devoid of light chains”;Nature 363,446-448(1993))的抗原结合免疫球蛋白(可变)结构域。选择术语“VHH结构域”是为了区分这些可变结构域与常规4链抗体中存在的重链可变结构域(在本文中称为“VH结构域”或“VH结构域”)和常规4链抗体中存在的轻链可变结构域(在本文中称为“VL结构域”或“VL结构域”)。VHH结构域可以与表位特异性结合,而无需另外的抗原结合结构域(与常规4链抗体中的VH或VL结构域相反,在常规4链抗体的情况下,VL结构域与VH结构域一起识别表位)。VHH结构域是由单个免疫球蛋白结构域形成的、小型、强大而有效的抗原识别单位。
在本发明的上下文中,VHH结构域、VHH、VHH结构域、VHH抗体片段、VHH抗体等术语可互换使用,代表免疫球蛋白单可变结构域(具有结构FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4,并且与表位特异性结合而无需第二免疫球蛋白可变结构域的存在),并且其通过如例如WO2009/109635的图1中定义的所谓的“标志残基”与VH结构域区分开。
如在例如Riechmann和Muyldermans,J.Immunol.Methods 231,25-38(1999)的图2中所示,应用于来自骆驼科的VHH结构域,根据由Kabat等人(“Sequence of proteins ofimmunological interest”,US Public Health Services,NIH Bethesda,Md.,Publication No.91)给出的VH结构域的通用编号将免疫球蛋白单可变结构域(例如VHH)的氨基酸残基编号。根据这个编号法
-FR1包含1-30位的氨基酸残基,
-CDR1包含31-35位的氨基酸残基,
-FR2包含36-49位的氨基酸,
-CDR2包含50-65位的氨基酸残基,
-FR3包含66-94位的氨基酸残基,
-CDR3包含95-102位的氨基酸残基,并且
-FR4包含103-113位的氨基酸残基。
然而,应该注意的是-正如本领域熟知的VH结构域和VHH结构域一样,每个CDR中的氨基酸残基总数可以变化,并且可能不对应于Kabat编号所指示的氨基酸残基总数(即,在实际序列中根据Kabat编号的一个或多个位置可能不被占据,或者实际序列可能含有的氨基酸残基比Kabat编号所允许的数目多一个或多个)。这意味着,一般而言,根据Kabat的编号可能对应于,也可能不对应于实际序列中的氨基酸残基的实际编号。
针对VH结构域的氨基酸残基编号的替代方法是本领域已知的,这样的方法也可以以类似的方式应用于VHH结构域。然而,在本说明书、权利要求书和附图中,除非另有说明,否则将遵循如上所述的根据Kabat并应用于VHH结构域的编号。
VHH结构域中的氨基酸残基总数通常在110至120的范围,常常为112至115。然而必须指出,更小和更长的序列也可以适用于本文所述的目的。
根据本发明优选实施方案,免疫球蛋白单可变结构域,例如VHH和结构域抗体具有许多独特的结构特征和功能特性,这使其非常有利于在治疗中用作功能性抗原结合分子。具体而言,但不限于此,VHH结构域(实质上已经被“设计”为在功能上与抗原结合而不与轻链可变结构域配对)可以用作单个相对较小的功能性抗原结合结构单元。
EP 2 694 546 B1中详细公开了关于免疫球蛋白单可变结构域的优点和关于获得VHH的更多细节和信息。
本发明的免疫球蛋白单可变结构域不限于其所获子的特定生物学来源或特定的制备方法。在WO2006/040153和WO2006/122786中描述了用于获得与特定抗原或表位结合的VHH结构域的适合方法和技术。
根据特定实施方案,本发明的免疫球蛋白单可变结构域是具有与天然存在的VHH结构域的氨基酸序列基本上对应但是已经被“人源化”或“序列优化”(任选地在亲和力成熟之后)的氨基酸序列的VHH结构域,即通过用来自人的常规4链抗体的重链可变结构域中的相应位置存在的一个或多个氨基酸残基替换所述天然存在的VHH序列的氨基酸序列中的一个或多个氨基酸残基。这可以使用本领域已知的方法来执行,所述方法可以通过技术人员常规地加以使用。
人源化VHH结构域可包含一个或多个完整的人框架区序列,在一个更具体的实施方案中,可包含衍生自人种系Vh3序列DP-29、DP-47、DP-51或其部分或与其高度同源,任选地其与JH序列,如JH5结合。因此,人源化方案可以包括以单独的或联合的种系VH基因(比如DP 47、DP 29和DP 51)的相应框架1、2和3(FR1、FR2和FR3)残基替换任何VHH残基。本发明的免疫球蛋白单可变结构域的适合框架区(FR)可以选自例如在WO2006/004678中所述的那些,并且特别包括所谓的“KERE”和“GLEW”类。实例为在约44至47位具有氨基酸序列G-L-E-W的免疫球蛋白单可变结构域,以及它们各自的人源化对应物。人源化VHH结构域可以包含一个或多个完整的人框架区序列。
举例来说,属于103P、R、S-基团和/或GLEW-基团(如下定义)的VHH的一种人源化取代是108Q至108L。免疫球蛋白单可变结构域的人源化方法是本领域已知的。
具有对于治疗应用而言改善的性质(例如增强的亲和力或降低的免疫原性)的结合免疫球蛋白单可变结构域可以通过本领域已知的技术从单独的结合分子获得,这样的技术例如亲和力成熟(例如,从合成的、随机的或天然存在的免疫球蛋白序列出发)、CDR移植、人源化、结合源自不同免疫球蛋白序列的片段、使用重叠引物的PCR组装以及技术人员熟知的用于工程化免疫球蛋白序列的类似技术;或前述技术的任何适当组合,也称为“序列优化”,如本文所述。可以参考例如标准手册以及进一步的描述和实施例。
根据上文,在优选的、实施方案中,化合物A的免疫球蛋白单可变结构域是VHH结构域。更优选地,化合物A选自具有以下氨基酸序列的化合物:
DVQLVESGGGLVQPGGSLRLSCAASGRTFSSYSMGWFRQAPGKEREFVVAISKGGYKYDAVSLEGRFTISRDNAKNTVYLQINSLRPEDTAVYYCASSRAYGSSRLRLADTYEYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAVSGITLDDYAIGWFRQAPGKEREGVSAIRSSGGSTYYADSVKGRFTISSDNSKNTVYLQMNSLRPEDTAVYYCAAVPAGRLRYGEQWYPIYEYDAWGQGTLVTVSS
(SEQ ID NO:11);
EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYSMGWFRQAPGKEREFVVAISKGGYKYDAVSLEGRFTISRDNAKNTVYLQINSLRPEDTAVYYCASSRAYGSSRLRLADTYEYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAVSGITLDDYAIGWFRQAPGKEREGVSAIRSSGGSTYYADSVKGRFTISSDNSKNTVYLQMNSLRPEDTAVYYCAAVPAGRLRYGEQWYPIYEYDAWGQGTLVTVSS
(SEQ ID NO:12);和
VQLVESGGGLVQPGGSLRLSCAASGRTFSSYSMGWFRQAPGKEREFVVAISKGGYKYDAVSLEGRFTISRDNAKNTVYLQINSLRPEDTAVYYCASSRAYGSSRLRLADTYEYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAVSGITLDDYAIGWFRQAPGKEREGVSAIRSSGGSTYYADSVKGRFTISSDNSKNTVYLQMNSLRPEDTAVYYCAAVPAGRLRYGEQWYPIYEYDAWGQGTLVTVSS
(SEQ ID NO:13)。
上文显示的三个序列几乎完全相同——除了N端序列之外,可以对N端序列进行改变或修饰,以使序列最佳地适应于选择的表达系统(表达载体,宿主细胞)或其他需要。因此,本领域技术人员清楚的是,其他基本上由上述序列组成、但是具有轻微修饰,例如不改变所得多肽的结合亲和力的氨基酸变化、缺失或添加的多肽,也可用作根据本发明的药物组合制剂的“化合物A”。
在另一个实施方案中,本发明的与VEGF和/或与Ang2结合性免疫球蛋白单可变结构域的类别的代表具有这样的氨基酸序列:其对应于天然存在的VH结构域经过“骆驼化”,即通过将来自常规4链抗体的天然存在的可变重链氨基酸序列中的一个或多个氨基酸残基替换为存在于重链抗体VHH结构域相应位置的一个或多个氨基酸残基,而得到的氨基酸序列。这可以按照本身已知的方式进行,本领域技术人员对此是清楚的,并且可以另外参考WO1994/04678。这样的骆驼化可优先在VH-VL界面上的氨基酸位置和所谓“骆驼科标志”(Camelidae Hallmark)残基的氨基酸位置处发生(例如还参见例如WO1994/04678)。这样的“人源化”和“骆驼化”技术以及与其一致的优选框架区序列的详细描述可另行参见,例如,WO2006/040153的第98页和WO2006/122786的第107页。
本发明及其所有实施方案意义上的PD-1拮抗剂是抑制PD-1与其受体相互作用的化合物。PD-1拮抗剂是本领域熟知的,例如,综述于Li等人,Int.J.Mol.Sci.2016,17,1151(通过提述并入本文)。根据本发明可以使用任何PD-1拮抗剂,尤其是抗体,比如Li等人公开的那些以及下文公开的其他抗体。优选地,本发明的PD-1拮抗剂及其所有实施方案选自下组,该组由以下抗体组成:
-派姆单抗(pembrolizumab)(抗PD-1抗体);
-纳武单抗(nivolumab)(抗PD-1抗体);
-皮地利珠单抗(pidilizumab)(抗PD-1抗体);
-PDR-001(抗PD-1抗体);
-如下文公开的PD1-1、PD1-2、PD1-3、PD1-4和PD1-5(抗PD-1抗体)
-阿特珠单抗(抗PD-L1抗体);
-阿维鲁单抗(avelumab)(抗PD-L1抗体);
-德瓦鲁单抗(durvalumab)(抗PD-L1抗体)。
派姆单抗(以前也被称为拉姆布罗力珠单抗(lambrolizumab);商品名Keytruda;也被称为MK-3475)(公开于例如Hamid,O.等人(2013)New England Journal of Medicine369(2):134-44),是与PD-1结合的人源化IgG4单克隆抗体;它在C228P处包含被设计为防止Fc介导的细胞毒性的突变。派姆单抗公开于例如US 8,354,509和WO2009/114335中。它已获得FDA批准用于治疗不可切除的或转移的黑色素瘤患者和转移性NSCLC患者。
纳武单抗(CAS登记号:946414-94-4;BMS-936558或MDX1106b)是一种完全的人IgG4单克隆抗体,可特异性阻断PD-1,缺乏可检测的抗体依赖性细胞毒性(ADCC)。纳武单抗例如公开于US 8,008,449和WO2006/121168中。它已获得FDA批准用于治疗不可切除或转移的黑色素瘤、转移性NSCLC和晚期肾细胞癌患者。
皮地利珠单抗(CT-011;Cure Tech)是与PD-1结合的人源化IgG1k单克隆抗体。皮地利珠单抗公开于例如WO2009/101611中。
PDR-001或PDR001是一种高亲和力的阻断配体的人源化抗PD-1IgG4抗体,其阻断PD-L1和PD-L2与PD-1的结合。PDR-001公开于WO2015/112900和WO2017/019896中。
抗体PD1-1至PD1-5是由表1所示的序列定义的抗体分子,其中HC表示(全长)重链,LC表示(全长)轻链:
表1:
具体地说,上文所述的抗PD-1抗体分子具有:
(PD1-1:)包含氨基酸序列SEQ ID NO:14的重链和包含氨基酸序列SEQ ID NO:15的轻链;或
(PD1-2:)包含氨基酸序列SEQ ID NO:16的重链和包含氨基酸序列SEQ ID NO:17的轻链;或
(PD1-3:)包含氨基酸序列SEQ ID NO:18的重链和包含氨基酸序列SEQ ID NO:19的轻链;或
(PD1-4:)包含氨基酸序列SEQ ID NO:20的重链和包含氨基酸序列SEQ ID NO:21的轻链;或
(PD1-5:)包含氨基酸序列SEQ ID NO:22的重链和包含氨基酸序列SEQ ID NO:23的轻链。
阿特珠单抗(Tecentriq,也称为MPDL3280A)是靶向PD-L1的噬菌体衍生的人IgG1k单克隆抗体,并且描述于例如Deng等人mAbs 2016;8:593-603。它已被FDA批准用于治疗尿路上皮癌患者。
阿维鲁单抗是全人抗PD-L1 IgG1单克隆抗体,并且描述于例如Boyerinas等人Cancer Immunol.Res.2015;3:1148-1157。
德瓦鲁单抗(MEDI4736)是对PD-L1具有高度特异性的人IgG1k单克隆抗体,并且描述于例如Stewart等人,Cancer Immunol.Res.2015;3:1052-1062或Ibrahim等人,Semin.Oncol.2015;42:474-483。
其他PD-1拮抗剂由Li等人公开(上文),或在临床试验中是已知的,比如AMP-224、MEDI0680(AMP-514)、REGN2810、BMS-936559、JS001-PD-1、SHR-1210、BMS-936559、TSR-042、JNJ-63723283、MEDI4736、MPDL3280A和MSB0010718C,可以用作上述拮抗剂的替代或补充。
本文中使用的INN旨在还包括与起始抗体具有相同或基本相同氨基酸序列的所有生物相似抗体,包括但不限于根据美国法典第42篇第262节(k)和其他司法管辖区中的等效法规授权的那些生物相似抗体。
上面列出的PD-1拮抗剂以其各自的制造、治疗用途和性质在本领域中是已知的。
在一个实施方案中,PD-1拮抗剂是派姆单抗。
在另一个实施方案中,PD-1拮抗剂是纳武单抗。
在另一个实施方案中,PD-1拮抗剂是皮地利珠单抗。
在另一个实施方案中,PD-1拮抗剂是阿特珠单抗。
在另一个实施方案中,PD-1拮抗剂是阿维鲁单抗。
在另一个实施方案中,PD-1拮抗剂是德瓦鲁单抗。
在另一个实施方案中,PD-1拮抗剂是PDR-001。
在另一个实施方案中,PD-1拮抗剂是PD1-1。
在另一个实施方案中,PD-1拮抗剂是PD1-2。
在另一个实施方案中,PD-1拮抗剂是PD1-3。
在另一个实施方案中,PD-1拮抗剂是PD1-4。
在另一个实施方案中,PD-1拮抗剂是PD1-5。
在本发明内应理解的是,根据本发明使用的组合制剂、组合物、试剂盒、方法、用途或化合物可设想活性剂或成分的同时、并行、序贯、连续、交替或分开施用。可以理解的是,可以施用从属或独立地配制的双特异性结合分子和PD-1拮抗剂,例如像双特异性结合分子和PD-1拮抗剂既可以作为同一个药物组合物/剂型的一部分也可以优选地以分开的药物组合物/剂型施用。
在此上下文中,本发明意义的“组合制剂”或“组合”包括但不限于由多于一种的活性剂的混合或组合而产生的产物,并且包括固定的和非固定的(例如游离的)组合制剂(包括试剂盒)和用途,例如像组分或药剂的同时、并行、序贯、连续、交替或分开使用。术语“固定组合制剂”是指将活性剂都以单一实体或剂量的形式同时施用于患者。术语“非固定组合制剂”是指在没有特定时间限制的情况下同时、并行或序贯地将活性剂都作为单独的实体施用于患者,其中这样的施用提供了两种化合物在患者体内的治疗有效水平。后者也适用于鸡尾酒疗法,例如三种或更多种活性剂的施用。
可以通过共同施用活性组分或药剂来进行双特异性结合分子/化合物A和PD-1拮抗剂/化合物B的施用,比如通过以一种单一的或两种分开的制剂或剂型同时或并行地施用它们。或者,可以通过例如以两种分开的制剂或剂型序贯或交替施用活性组分或药剂来进行双特异性结合分子和PD-1拮抗剂的施用。
例如,同时施用包括基本上同时施用。这种施用形式也可以称为“伴随”(concomitant)施用。并行(concurrent)施用包括在同一个总体时间段内(例如在同一天,但不一定在同一时间)施用活性剂。交替施用包括在一段时间内,例如在几天或一周的过程中施用一种药剂,然后在随后的一段时间内,例如在几天或一周的过程中施用另一种药剂,然后将该模式重复一个或多个周期。序贯或连续施用包括在第一时间段内(例如在几天或一周的过程中)使用一个或多个剂量施用一种药剂,然后在第二时间段内(例如在几天或一周的过程中)使用一个或多个剂量施用另一种药剂。也可以采用重叠的日程,其包括在治疗期间的不同日施用活性剂,而不一定按照规则的顺序。也可以采用这些通用指南的变化形式,例如根据所使用的药剂和受试者的状况。
因此,在优选实施方案中,在根据本发明的方法中,本文所述的化合物A与本文所述的化合物B同时、并行、序贯、连续、交替或分开施用。在类似的优选实施方案中,用于根据本发明的方法中的本文所述的化合物A与本文所述的化合物B同时、并行、序贯、连续、交替或分开施用。在相关的优选实施方案中,用于根据本发明的方法中的本文所述的化合物B与本文所述的化合物A同时、并行、序贯、连续、交替或分开施用。在一个另外的优选实施方案中,提供了本文所述的化合物A的用途,其中化合物A与化合物B同时、并行、序贯、连续、交替或分开施用。在一个另外的相关的优选实施方案中,提供了本文所述的化合物B的用途,其中化合物B与化合物A同时、并行、序贯、连续、交替或分开施用。在另一个实施方案中,提供了根据本发明的试剂盒,其中将第一药物组合物与第二药物组合物同时、并行、序贯、连续、交替或分开施用。
分开或同时施用的化合物A、化合物B或两者的优选施用途径包括但不限于口服、经肠、肠胃外(例如,肌内、腹膜内、静脉内、经皮或皮下注射或植入)、经鼻、阴道、直肠或局部施用。在优选实施方案中,施用途径是静脉内施用,特别是静脉内输注或注射。本发明化合物可以单独或一起配制成适合的剂量单位制剂,其中含有适用于每种给药途径的常规的无毒的药学上可接受的载体、赋形剂和/或媒介物。更优选地,制剂包括固体、半固体或液体剂型,比如冻干制剂、液体溶液(例如可注射和可输注的溶液)、分散体或混悬剂、脂质体和栓剂。优选方式取决于预期的给药方式和治疗应用。特别优选的实施方案包括液体制剂和冻干制剂。在冻干制剂的情况下,冻干物可以在液体中,优选在水中复原。
本文所述的化合物可以按每天一次、每周5次、每周3次、每周2次、每周一次、每2周一次、每3周一次、每4周一次施用。优选的给药间隔包括每周一次和每2周一次。
优选地,化合物A和B每周一次通过静脉内输注给药。
给药方案可包括长期治疗。“长期”是指持续至少两周,并且优选持续数周、数月或数年。鉴于本文的教导,本领域普通技术人员仅使用常规实验即可确定该剂量方案的必要修改。参见Remington’s Pharmaceutical Sciences(Martin,E.W.,第4版),MackPublishing Co.,Easton,PA。在发生任何并发症的情况下,也可以由个体医师调整剂量。给药可以是每天一次、每两天一次、每三天一次、每四天一次、每周一天、每周两天、每两周一天、每三周一天等等。
可以按适当时间间隔以单剂量或分次剂量以治疗有效量施用本文所述的化合物。治疗有效量是指在实现期望的治疗结果所必需的剂量和时间段内有效的量,并且是预防、改善或治疗疾病或疾患必需的最小量。根据本发明的化合物的治疗有效量可以根据个体的疾病状态、年龄、性别和体重等因素以及化合物以在个体中引出期望应答的能力而变化。治疗有效量还是化合物的治疗有益效果超过任何毒性或有害作用的量。相对于未治疗的受试者或相对于待治疗的同一位受试者的先前未治疗时期,治疗有效剂量优选地抑制可测量参数,例如肿瘤生长率的至少约20%,更优选至少约40%,甚至更优选至少约60%,再更优选至少约80%。
可以按照在单一疗法中治疗有效的这样的剂量,或以低于或高于单一疗法中使用的剂量的这样的剂量来施用活性化合物,但是当联合时产生期望的(联合)治疗有效量。用于治疗所需的本发明的双特异性结合分子的量可适合于所选择的特定结合分子、给药途径、被治疗病症的性质以及患者的年龄和状况,并且最终将由主治医师或临床医师判定。同样,可以根据靶细胞、肿瘤、组织、移植物或器官来调整本发明结合分子的剂量。
可通过每次施用固定量或推注来施用化合物A或化合物B的期望剂量,以在患者体内达到设定的血药浓度。
如本文所述,可通过以约0.1至30mg/kg患者体重,例如约0.5至25mg/kg患者体重、约1至20mg/kg患者体重、约2至5mg/kg患者体重或约3mg/kg患者体重的剂量注射(例如皮下或静脉内)施用化合物B(PD-1拮抗剂)。
PD-1拮抗剂的剂量和治疗方案可以由技术人员确定。本发明PD-1拮抗剂的优选剂量方案包括l mg/kg宿主体重或3mg/kg宿主体重,静脉内给药,其中抗体使用如下的给药方案之一给药:(i)每四周一次,六个剂量,然后每三个月一次;(ii)每三周一次;(iii)一次3mg/kg宿主体重,随后l mg/kg宿主体重,每三周一次。在某些实施方案中,通过以约1至40mg/kg宿主体重,例如1至30mg/kg宿主体重,例如,约5至25mg/kg宿主体重、约10至20mg/kg宿主体重、约1至5mg/kg宿主体重、1至10mg/kg宿主体重、5至15mg/kg宿主体重、10至20mg/kg宿主体重、15至25mg/kg宿主体重或约3mg/kg宿主体重的剂量注射(例如皮下或静脉内)施用PD-1拮抗剂。给药方案可以从例如每周一次到每2、3或4周一次的范围变化。在一个实施方案中,以约10至20mg/kg宿主体重的剂量每隔一周施用PD-1拮抗剂。可以大于20mg/min,例如20-40mg/min,典型地大于或等于40mg/min的速率通过静脉内输注来施用抗体分子,以达到约35至440mg/m2,通常为约70至310mg/m2,更通常为约110至130mg/m2的剂量。在实施方案中,约110至130mg/m2的输注速率实现约3mg/kg宿主体重的水平。在其他实施方案中,可以小于10mg/min,例如小于或等于5mg/min的速率通过静脉内输注来施用抗体分子,以达到约1至100mg/m2,例如,约5至50mg/m2、约7至25mg/m2或约10mg/m2的剂量。在一些实施方案中,经过约30分钟的时间输注抗体。要注意的是,剂量值可以随着待减轻病症的类型和严重性而变化。还应理解的是,对于任何特定的受试者,应根据个体需要和施用组合物或监督其施用的人的专业判断,随时间调整具体的剂量方案,并且本文列出的剂量范围仅仅是示例性的,并不意图限制要求保护的组合物的范围或实践。
化合物A和化合物B分开或一起的给药方案可以从例如每周一次到每2、3或4周一次的范围变化。在某个实施方案中,化合物A、化合物B或两者的施用量或剂量较低(例如,低至少20%、至少30%、至少40%或至少50%)。在其他实施方案中,产生期望的作用(例如治疗过度增殖性或肿瘤性疾病)的化合物A、化合物B或两者的量或剂量较低(例如低至少20%、至少30%、至少40%、或至少50%)。
根据本发明的方法、化合物、供使用的化合物、化合物的用途、药物组合物和试剂盒包括向受试者施用如本文所述的双特异性抗体分子和抗PD-1抗体分子的组合制剂。
根据待治疗的癌性疾病,本文中定义的联合治疗可单独使用或与一种或多种另外的治疗剂进一步组合使用,所述治疗剂尤其选自抑制血管生成、信号转导途径或癌细胞中的有丝分裂检查点的化学治疗剂或治疗活性化合物。
另外的治疗剂可以与任选的相同药物制剂的组分同时施用,或者在施用结合分子和/或PD1拮抗剂之前或之后施用。
化学治疗剂可以选自激素、激素类似物和抗激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、氟维司群、醋酸甲地孕酮、氟他胺、尼鲁米特、比卡鲁胺、醋酸环丙孕酮、非那雄胺、醋酸布舍瑞林、氟氢可的松、氟甲睾酮、甲羟孕酮、曲肽、阿佐昔芬、帕瑞肽、伐普肽)、芳香化酶抑制剂(例如阿那曲唑、来曲唑、利阿唑、依西美坦、阿他美坦、福美司坦)、LHRH激动剂和拮抗剂(例如醋酸戈舍瑞林、亮丙瑞林、阿巴瑞克、西曲瑞克、地洛瑞林、组氨瑞林、曲普瑞林)、抗代谢药(例如抗叶酸剂,如甲氨蝶呤、培美曲塞、嘧啶类似物如5氟尿嘧啶、卡培他滨、地西他滨、奈拉滨和吉西他滨、嘌呤和腺苷类似物如巯基嘌呤、硫鸟嘌呤、克拉屈滨和喷司他丁、阿糖胞苷、氟达拉滨);抗肿瘤抗生素(例如蒽环类,如多柔比星、柔红霉素、表柔比星和伊达比星、丝裂霉素C、博来霉素、放线菌素D、普卡霉素、米托蒽醌、匹杉琼、链脲菌素);铂衍生物(例如顺铂、奥沙利铂、卡铂、洛铂、沙铂);烷化剂(例如雌莫司汀、双氯乙基甲胺、美法仑、苯丁酸氮芥、白舒非、达卡巴嗪、环磷酰胺、异环磷酰胺、羟基脲、替莫唑胺、亚硝基脲如卡莫司汀和洛莫司汀、噻替派);抗有丝分裂剂(例如长春花生物碱,如长春碱、长春地辛、长春瑞滨、长春氟宁和长春新碱;和紫杉烷类,如紫杉醇、多西他赛及其制剂、拉洛他赛;司莫紫杉醇和埃博霉素类,如伊沙匹隆、帕土匹龙、ZK-EPO);拓扑异构酶抑制剂(例如表鬼臼毒素,如依托泊苷和磷酸依托泊苷、替尼泊苷、安吖啶、托泊替康、伊立替康)和其他化学治疗剂,如氨磷汀、阿那格雷、干扰素α、丙卡巴肼、米托坦和泊非美(porfimer)、贝沙罗汀、塞来昔布。
在优选实施方案中,涉及化合物A和化合物B的治疗进一步包括“铂双联”疗法,即用(i)铂化合物(比如顺铂或卡铂)加上(ii)第三代化疗剂(比如多西他赛、紫杉醇、长春瑞滨或吉西他滨)进行治疗。
在另一个优选实施方案中,将涉及化合物A和化合物B的治疗与癌细胞靶向治疗联合。
在某些实施方案中,用本文中公开的联合治疗进行治疗的肿瘤性或过度增殖性疾病,特别是癌症或肿瘤疾病,包括但不限于实体瘤、血液癌症(例如白血病、淋巴瘤、骨髓瘤,例如多发性骨髓瘤)和转移灶。在一个实施方案中,癌症是实体瘤。实体瘤的例子包括恶性肿瘤,例如肉瘤和癌,例如各种器官系统的腺癌,比如影响肺、乳腺、卵巢、淋巴、胃肠道(例如结肠)、肛门、生殖器和泌尿生殖道(例如肾、泌尿道上皮、膀胱细胞、前列腺)、咽、CNS(例如脑、神经或神经胶质细胞)、头颈部、皮肤(例如黑色素瘤)和胰腺的腺癌,以及包括恶性肿瘤的腺癌,比如结肠癌、直肠癌、肾细胞癌、肝癌、非小细胞肺癌、小肠癌和食道癌。癌症可以是早期、中期、晚期或转移癌。
如本文中使用的,“过度增殖性疾病”是指细胞生长超过正常水平的状况。例如,过度增殖性疾病或疾患包括恶性疾病(例如,食道癌、结肠癌、胆管癌)和非恶性疾病(例如,动脉粥样硬化、良性增生、良性前列腺肥大)。
在一个实施方案中,癌症选自肺癌(例如NSCLC(例如具有鳞状和/或非鳞状组织学的NSCLC,或NSCLC腺癌))、黑色素瘤(例如晚期黑色素瘤)、肾癌(例如肾细胞癌)、肝癌、骨髓瘤(例如多发性骨髓瘤)、前列腺癌、乳腺癌(例如,不表达雌激素受体、孕酮受体或Her2/neu中的一种或两种或全部的乳腺癌,例如三阴性乳腺癌)、结直肠癌、胰腺癌、头颈癌(例如头颈鳞状细胞癌(HNSCC)、肛门癌、胃食管癌、甲状腺癌、宫颈癌、淋巴增殖性疾病(例如,移植后淋巴增殖性疾病)或血液癌症、T细胞淋巴瘤、B细胞淋巴瘤、非霍奇金淋巴瘤或白血病(例如髓性白血病或淋巴性白血病)。
在另一个实施方案中,所述癌症选自癌(例如,晚期或转移癌)、黑色素瘤或肺癌,例如NSCLC。
在一个实施方案中,癌症是肺癌,例如NSCLC或小细胞肺癌。在优选实施方案中,癌症是NSCLC。
在可与本发明的任何方面和实施方案联合的特别优选的实施方案中,根据本发明的联合治疗用于治疗患有局部晚期或转移性非鳞状NSCLC而无EGFR突变或ALK易位的患者。其中,任选地,根据他/她的PD-L1表达状态,例如高或低PD-L1表达状态选择患者。治疗可以是一线治疗,即针对疾病(NSCLC)的第一治疗。因此,当根据本发明进行治疗时,患者可能未曾经历化学疗法或放射疗法,特别是未进行NSCLC的治疗。通过在对患者进行任何癌症治疗之前确定PD-L1表达状态,可以获得可靠的结果。
可以如Han等人(Journal of Pathology and Translational Medicine 2017;51:40-48)或通过Wang等人(OncoTargets and Therapy 2016:9 5023–5039)所述比如通过使用免疫组织化学确定PD-L1表达状态。待治疗患者的肿瘤活检样品可以用于PD-L1表达状态的确定。在使用多于一个活检的情况下,可以使用来自个体患者的单个肿瘤活检或多个活检,优选地,根据本发明,使用具有最高PD-L1表达的活检来确定PD-L1表达状态。可以确定PD-L1在细胞表面(膜)或细胞质上的表达,其仅由肿瘤细胞和/或由肿瘤微环境中的其他细胞(例如免疫细胞)表达。考虑PD-L1阳性表达的阈值可以是例如在细胞(例如肿瘤和/或免疫细胞)中至少1%、至少5%或至少10%的PD-L1表达,其中通过免疫组织化学确定的细胞中PD-L1表达≥1%、≥5%或≥10%的样品可以被认为是PD-L1“阳性”。在优选实施方案中,确定了在肿瘤细胞或免疫细胞上更优选在肿瘤细胞上的PD-L1表达状态,其中1%至5%的细胞的PD-L1表达被认为是低PD-L1表达,并且大于5%的细胞,例如>5%至40%的细胞的PD-L1表达被认为是高PD-L1表达,如上文所述,优选地例如通过如Han等人或Wang等人所述的免疫组织化学确定。待治疗患者可以是低PD-L1表达的患者、高PD-L1表达的患者、排除了高PD-L1表达的患者的低PD-L1表达的患者或排除了低PD-L1表达的患者的高PD-L1表达的患者。
在一个实施方案中,癌症是黑色素瘤,例如晚期黑色素瘤。在一个实施方案中,癌症是对其他疗法无反应的晚期或不可切除的黑色素瘤。在其他实施方案中,癌症是具有BRAF突变(例如BRAF V600突变)的黑色素瘤。
在另一个实施方案中,癌症是肝癌,例如有或没有病毒感染(例如慢性病毒性肝炎)的晚期肝癌。
在另一个实施方案中,癌症是前列腺癌,例如晚期前列腺癌。
在又另一个实施方案中,癌症是骨髓瘤,例如多发性骨髓瘤。
在又另一个实施方案中,癌症是肾癌,例如肾细胞癌(RCC)(例如转移性RCC或肾透明细胞癌(CCRCC))。
如上所述,本发明涉及包含如本文中定义的化合物A和化合物B的药物组合物,并且涉及试剂盒,其包含:包含如本文中定义的化合物A的第一药物组合物,和包含如本文中定义的化合物B的第二药物组合物。
如本文中定义的术语“药物组合物”是指其为这样的形式的制剂,所述形式允许其中所含的活性成分的生物活性是有效的,并且所述制剂不含另外的对该组合物所施用的受试者具有不可接受的毒性的组分。可以通过本领域已知的多种方法施用本发明药物组合物。正如本领域技术人员将理解,施用途径和/或方式将视期望的结果而变化。
无论选择的施用途径如何,都通过本领域技术人员已知的常规方法将用于本发明联合治疗和/或药物组合物的化合物、本发明的第一药物组合物和第二药物组合物配制成药学上可接受的剂型。
如本文中定义的试剂盒可包含含有第一药物组合物和/或第二药物组合物的一个适合的容器或几个适合的容器,其中第一药物组合物和第二药物组合物可容纳在相同容器中或不同容器中。试剂盒可用于本发明的任何方法或任何用途中。
优选地,根据本发明的试剂盒进一步包括包装说明书,其包括关于在治疗和/或预防在有此需要的患者中的肿瘤性或过度增殖性疾病(优选癌症或肿瘤疾病,特别是NSCLC)中使用化合物A和/或化合物B的可读指令。指令可提供如上所述关于本发明方法及其任何优选实施方案的进一步详情。
当在权利要求书和/或说明书中与术语“包括”一起使用时,使用词语“一个/一种”(“a”)或“一个/一种”(“an”)可以表示“一个/一种”(“one”),但是它也与“一个/种或多个/种”、“至少一个/种”、“一个/种或多个/种”的含义一致。
如本文中使用的,“约”是指在给定测量精度的性质的情况下对于所测量的量的可接受的误差程度。示例性误差程度在给定值或值范围的20%之内,通常在10%之内,更通常在5%之内。
如本文中使用的,术语“治疗”(“treating”或“treatment”)表示治愈已经存在的疾病状态或病症或增加从疾病状态或病症中恢复的可能性。治疗还可以包括抑制,即阻止疾病状态或病症的发展,以及改善,即引起疾病的消退或延缓疾病的进展。治疗可以是缓解疾病症状而没有治愈患者。
如本文中使用的,术语“预防”(“preventing”或“prevention”)并不意味着完全停止发生在患者或受试者中的疾病状态或病症,而是还可以指降低产生疾病状态或病症的风险。
通过以下实施例进一步展示本发明,而不必不限于本发明的这些实施方案。本身或与上面的详述结合的实施例或其部分,包括化合物、剂量和给药途径以及治疗组合,构成本发明的一部分。
实施例
缩略语和缩写
CD 分化簇
DMEM 达尔伯克改良伊格尔培养基
FCS 胎牛血清
ID 识别码
i.p. 腹膜内
LAG-3 淋巴细胞活化基因3
M 摩尔
MEM 最小必需培养基
PBS 磷酸盐缓冲盐水
PD-1 程序性细胞死亡1
PD-L1 程序性细胞死亡配体1
PD-L2 程序性细胞死亡配体2
Q3or4d 每3或4天一次(每周两次)
R 缓解
TGI 肿瘤生长抑制,根据以下公式计算:
TGI=100x{1-[(治疗最后一天–治疗第1天)/(对照最后一天–对照第1天)]}
TIL 肿瘤浸润淋巴细胞
实施例1
测试化合物
这些实验使用了大鼠IgG2a抗鼠PD-1抗体EX101359(克隆RMP1-14)(10mg/kg)、双特异性VEGF和Ang2结合蛋白VEGFANGBII22(具有上文和SEQ ID NO:11、12和13中定义的结构/序列)、小分子TKI瓦他拉尼和CrossMab抗体万古珠单抗(抗人VEGF-A和抗人/鼠Ang-2)。对于对照组,使用与PD-1抗体大鼠IgG2a(EX101362)对应的同种型(10mg/kg),即具有相似序列但不与PD-1结合的抗体。所有抗体均用1x PBS稀释,并从BioXcell,West Lebanon,NH,USA订购。
细胞
LL/2(LLC1)是鼠肺癌细胞系,购自美国典型培养物保藏中心(ATCC)(CRL-1642)。将细胞在37℃和5%CO2的T175组织培养瓶中培养。使用的培养基是补充有10%FCS(优级胎牛血清;目录号SH30071.03;Thermo Scientific)的DMEM。每隔两三天以1:4/1:6的比率分离培养基。
小鼠
C57BL/6NTac是具有完全免疫能力的小鼠品系,由Taconic Denmark提供。将7周龄雌性小鼠从Taconic运到当地的动物设施。到达动物设施之后,让小鼠适应条件至少5天,然后再用于实验。在21.5+/-1.5C的温度和55+/-10%的湿度的标准化条件下,将它们分成10组。随意提供标准化饮食(PROVIMI KLIBA)和高压灭菌自来水。使用在异氟烷麻醉下植入的皮下微芯片来标识每只小鼠。动物在研究中全程带有笼卡,笼卡上显示研究编号、动物识别号、抗体和化合物以及剂量水平、给药途径及日程。
肿瘤的建立、随机化
通过计算机程序SEPIA将动物随机分到不同的组中。为建立皮下肿瘤模型,收获LL/2细胞,重悬于PBS/5%FCS中,并以5x 105/ml与Matrigel Matrix(不含生长因子,Corning,Tewksbury,MA,USA)以1:2混合。每只小鼠注射100μl的含有5x 104个细胞的细胞悬浮液(第5天)。
测试化合物的施用
将抗体在PBS中稀释至1mg/mL,以10ml/kg的体积腹膜内注射。稀释液在4℃下最多保存5天。在细胞注射后3天开始治疗(第1天)。将瓦他拉尼悬浮在5%的Natrosol溶液(羟乙基纤维素)中,并通过管饲针(Infusionskanüle Olive A,Acufirm,No.14 64ll-1)进行胃内给药。给药量为每kg体重10ml。每24小时给药一次。为了制备悬浮液,将化合物加入到Natrosol溶液中并将混合物搅拌过夜。有时需要超声处理。将溶液在黑暗中在室温下保持最多1周。
表2:治疗组
监测肿瘤生长和疾病进展
每周三次(周一、周三和周五)用卡尺测量肿瘤直径。从治疗开始之后的第14天至第28天,每天测量所有肿瘤。根据公式“肿瘤体积=长度*直径2*pi/6”计算每个肿瘤的体积[单位mm3]。为了监测治疗的副作用,每天检查小鼠的异常情况,并且每周测量体重至少三次。当肿瘤达到1500mm3的大小或肿瘤坏死大于肿瘤表面的1/3时,处死动物。另外,出于伦理学原因,对体重减轻>18%的动物实施了安乐死。肿瘤生长抑制(TGI)值计算如下:
TGI=100x{1-[(治疗最后一天–治疗第1天)/(对照最后一天–对照第1天)]}
统计分析–抗肿瘤功效
为了评价肿瘤抑制的统计显著性,基于作用只有在一个方向上可测量(即预期肿瘤抑制而不是肿瘤刺激)的假设,进行了单尾非参数Mann-Whitney-Wilcoxon U检验。在这种情况下,U检验根据特定日期的绝对体积比较两组个体肿瘤的排名(两个组之间的成对比较)。在实验的第17天进行分析。使用Bonferroni-Holm校正,调整从U检验获得的p值。按照惯例,p值≤0.05指示差异的显著性。
结果
同位素对照组的小鼠用EX101362腹膜内治疗每周两次。在治疗期间,肿瘤从中位体积41mm3增长到1275mm3的体积。每周两次腹膜内施用10mg/kg抗鼠PD-1抗体EX101359治疗。与同种型对照相比,EX101359治疗降低了肿瘤生长(中位TGI=51%)。
单独用VEGFANGBII22治疗产生49%的TGI。单独用瓦他拉尼治疗产生54%的TGI。用瓦他拉尼、VEGFANGBII22和抗PD1联合治疗产生79%的TGI。
仅用万古珠单抗治疗产生64%的TGI。用瓦他拉尼、万古珠单抗和抗PD1联合治疗产生81%的TGI。
进一步的联合结果和对比化合物的结果如图1所示。
结论
在这项研究中,抗PD1、瓦他拉尼(靶向VEGFR)、VEGFANGBII22和万古珠单抗的单一疗法显示出最小至中等的抗肿瘤反应,TGI值分别为51%、54%、49%和64%。抗PD1+瓦他拉尼+VEGFANGBII22、或抗PD1+瓦他拉尼+万古珠单抗的三药联合明显更有效,TGI值为79%和81%。通过分析个体肿瘤的反应曲线,抗PD1+瓦他拉尼+VEGFANGBII22的三药联合脱颖而出,因为其中被治疗的肿瘤之一显示缩小,而抗PD1+瓦他拉尼+万古珠单抗治疗组中的所有肿瘤均显示肿瘤生长降低。
与同种型对照和单一疗法相比,三药联合显示出更好的抗肿瘤作用。抗PD1+瓦他拉尼+VEGFANGBII22的三药联合甚至在一个被治疗的个体中诱导了肿瘤缩小。在本实验中,所有治疗均耐受良好。
根据上文应当理解的是,将这些结果转移至人类的疗法后,化合物VEGFANGBII22将包括抗Ang2以及抗VEGF活性,因为这种化合物与人VEGF结合。因此,在上述实验中将不需要另外使用抗VEGF剂诸如瓦他拉尼。因此,以上数据表明,用VEGFANGBII22+PD1拮抗剂(比如抗PD1抗体)治疗人,将对人患者产生有用的治疗作用。
实施例2
基本上如实施例1中所述建立进一步的实验,比较单一疗法与VEGFANGBII22+抗PD1抗体+瓦他拉尼三药联合(其中瓦他拉尼在小鼠中再次模拟了抗VEGF活性,所述活性预期不会来自VEGFANGBII22,因为该化合物的VEGF结合组分不与小鼠VEGF结合)。
再次确定了TGI值,施用三联组合时达到80%。与此相对的是,通过单一疗法,TGI值达到22%(抗PD-1抗体)、27%(VEGFANGBII22的抗Ang2活性)和43%(瓦他拉尼)。
另外,确定了各治疗组内的小鼠的生存期。从图2可以看出,只有用VEGFANGBII22、瓦他拉尼和PD1拮抗剂治疗才能提供显著超过30天极限的生存期。这再次提示,提议的治疗可预期同样在人类中实现优异效果(同样,应理解的是,抗VEGF活性将由VEGFANGBII22组分提供,因此不需要添加瓦他拉尼)。
序列表
<110> 勃林格殷格翰国际有限公司
<120> 抗癌联合治疗
<130> 12-0421-WO-1
<160> 23
<170> BiSSAP 1.3.6
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 1
Ser Tyr Ser Met Gly
1 5
<210> 2
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 2
Ala Ile Ser Lys Gly Gly Tyr Lys Tyr Asp Ala Val Ser Leu Glu Gly
1 5 10 15
<210> 3
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 3
Ser Arg Ala Tyr Gly Ser Ser Arg Leu Arg Leu Ala Asp Thr Tyr Glu
1 5 10 15
Tyr
<210> 4
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 4
Ser Phe Gly Met Ser
1 5
<210> 5
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 5
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 6
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 6
Gly Gly Ser Leu Ser Arg
1 5
<210> 7
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 7
Asp Tyr Ala Ile Gly
1 5
<210> 8
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 8
Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 9
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> CDR序列
<400> 9
Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp Tyr Pro Ile Tyr
1 5 10 15
Glu Tyr Asp Ala
20
<210> 10
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 结合基序肽序列
<400> 10
Met Tyr Pro Pro Tyr
1 5
<210> 11
<211> 387
<212> PRT
<213> 人工序列
<220>
<223> 双特异性抗VEGF抗Ang2结合分子
<400> 11
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Val Ala Ile Ser Lys Gly Gly Tyr Lys Tyr Asp Ala Val Ser Leu Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Ile Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ser Arg Ala Tyr Gly Ser Ser Arg Leu Arg Leu Ala Asp Thr Tyr
100 105 110
Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
130 135 140
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
145 150 155 160
Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
165 170 175
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr
180 185 190
Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Thr Leu Asp
275 280 285
Asp Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
290 295 300
Gly Val Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr
325 330 335
Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Ala Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp
355 360 365
Tyr Pro Ile Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr
370 375 380
Val Ser Ser
385
<210> 12
<211> 387
<212> PRT
<213> 人工序列
<220>
<223> 双特异性抗VEGF抗Ang2结合分子
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Val Ala Ile Ser Lys Gly Gly Tyr Lys Tyr Asp Ala Val Ser Leu Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Ile Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ser Arg Ala Tyr Gly Ser Ser Arg Leu Arg Leu Ala Asp Thr Tyr
100 105 110
Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
130 135 140
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
145 150 155 160
Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
165 170 175
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr
180 185 190
Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
195 200 205
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Thr Leu Asp
275 280 285
Asp Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
290 295 300
Gly Val Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr
325 330 335
Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Ala Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp
355 360 365
Tyr Pro Ile Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr
370 375 380
Val Ser Ser
385
<210> 13
<211> 386
<212> PRT
<213> 人工序列
<220>
<223> 双特异性抗VEGF抗Ang2结合分子
<400> 13
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ser
20 25 30
Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Val
35 40 45
Ala Ile Ser Lys Gly Gly Tyr Lys Tyr Asp Ala Val Ser Leu Glu Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Ile Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ser
85 90 95
Ser Arg Ala Tyr Gly Ser Ser Arg Leu Arg Leu Ala Asp Thr Tyr Glu
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
145 150 155 160
Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
165 170 175
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
195 200 205
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Thr Leu Asp Asp
275 280 285
Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly
290 295 300
Val Ser Ala Ile Arg Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser
305 310 315 320
Val Lys Gly Arg Phe Thr Ile Ser Ser Asp Asn Ser Lys Asn Thr Val
325 330 335
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Ala Ala Val Pro Ala Gly Arg Leu Arg Tyr Gly Glu Gln Trp Tyr
355 360 365
Pro Ile Tyr Glu Tyr Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val
370 375 380
Ser Ser
385
<210> 14
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> PD1-1的HC
<400> 14
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ala Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Ser Ser Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Asn Val Asn Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 15
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> PD1-1的LC
<400> 15
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Glu Asn Ile Asp Thr Ser
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 16
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> PD1-2的HC
<400> 16
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ala Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Ser Ser Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Asn Pro Asn Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 17
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> PD1-2的LC
<400> 17
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Glu Asn Ile Asp Thr Ser
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 18
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> PD1-3的HC
<400> 18
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Lys Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Ser Ser Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Asn Val Asn Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 19
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> PD1-3的LC
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Glu Asn Ile Asp Val Ser
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 20
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> PD1-4的HC
<400> 20
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Lys Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Ser Ser Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Asn Val Asn Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 21
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> PD1-4的LC
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Glu Asn Ile Asp Val Ser
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 22
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> PD1-5的HC
<400> 22
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Lys Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Gly Gly Gly Gly Asp Thr Tyr Tyr Ser Ser Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Ser Asn Val Asn Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 23
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> PD1-5的LC
<400> 23
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Glu Asn Ile Asp Val Ser
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (32)
1.一种治疗或预防肿瘤性或过度增殖性疾病的方法,其包括对有此需要的患者施用
a)治疗有效量的化合物A,和
b)治疗有效量的化合物B,
其中
化合物A是双特异性结合分子,其包含
VEGF结合性免疫球蛋白单可变结构域,
血清白蛋白结合性免疫球蛋白单可变结构域,和
Ang2结合性免疫球蛋白单可变结构域,
其中
所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SYSMG(SEQ ID NO:1)
CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2),
CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3);
所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SFGMS(SEQ ID NO:4),
CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5),
CDR3:GGSLSR(SEQ ID NO:6);
所述Ang2结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:DYAIG(SEQ ID NO:7),
CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8),
CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ IDNO:9);并且
其中
化合物B是PD-1拮抗剂。
2.根据权利要求1的方法,其中肿瘤性或过度增殖性疾病是癌症或肿瘤疾病。
3.根据权利要求1或2的方法,其中肿瘤性或过度增殖性疾病是非小细胞肺癌(NSCLC)。
4.根据权利要求1-3中任一项的方法,其中化合物A的所述免疫球蛋白单可变结构域是VHH结构域。
5.根据权利要求1-4中任一项的方法,其中化合物A具有根据SEQ ID NO:11、SEQ IDNO:12或SEQ ID NO:13的氨基酸序列。
6.根据权利要求1至5中任一项的方法,其中PD-1拮抗剂是抗PD-1抗体或抗PD-L1抗体。
7.根据权利要求6的方法,其中抗PD-1抗体选自下组:派姆单抗、纳武单抗、皮地利珠单抗、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
8.根据权利要求6的方法,其中抗PD-L1抗体选自下组:阿特珠单抗、阿维鲁单抗和德瓦鲁单抗。
9.根据权利要求1至8中任一项所述的方法,其中,将化合物A与化合物B同时、并行、序贯、连续、交替或分开施用。
10.如权利要求1、4或5任一项中定义的化合物A,其用于治疗或预防肿瘤性或过度增殖性疾病的方法中,所述疾病优选癌症或肿瘤疾病,特别优选NSCLC,所述方法包括将化合物A与化合物B联合施用于有此需要的患者,其中化合物B如权利要求1和6至8任一项中定义。
11.根据权利要求10的用途限定的化合物A,其中化合物A与化合物B同时、并行、序贯、连续、交替或分开施用。
12.如权利要求1和6至8任一项中定义的化合物B,其用于治疗或预防肿瘤性或过度增殖性疾病的方法中,所述疾病尤其是癌症或肿瘤疾病,特别是NSCLC,所述方法包括将化合物B与化合物A联合施用于有此需要的患者,其中化合物A如权利要求1、4或5任一项中定义。
13.根据权利要求12的用途限定的化合物B,其中化合物B与化合物A同时、并行、序贯、连续、交替或分开施用。
14.如权利要求1、4或5中任一项定义的化合物A在制备用于治疗或预防肿瘤性或过度增殖性疾病,优选癌症或肿瘤疾病,更优选NSCLC的药物组合物中的用途,其中化合物A与化合物B联合使用,其中化合物B如权利要求1和6至8任一项中定义。
15.根据权利要求14的化合物A的用途,其中化合物A与化合物B同时、并行、序贯、连续、交替或分开施用。
16.如权利要求1和6至8中任一项定义的化合物B在制备用于治疗或预防肿瘤性或过度增殖性疾病,优选癌症或肿瘤疾病,更优选NSCLC的药物组合物中的用途,其中化合物B与化合物A联合使用,其中化合物A如权利要求1、4或5任一项中定义。
17.根据权利要求16的化合物B的用途,其中化合物B与化合物A同时、并行、序贯、连续、交替或分开施用。
18.一种药物组合物,其包含
a)化合物A,和
b)化合物B
其中
化合物A是双特异性结合分子,其包含
VEGF结合性免疫球蛋白单可变结构域,
血清白蛋白结合性免疫球蛋白单可变结构域,和
Ang2结合性免疫球蛋白单可变结构域,
其中
所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SYSMG(SEQ ID NO:1)
CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2),
CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3);
所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SFGMS(SEQ ID NO:4),
CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5),
CDR3:GGSLSR(SEQ ID NO:6);
所述Ang2结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:DYAIG(SEQ ID NO:7),
CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8),
CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ ID NO:9);并且
其中
化合物B是PD-1拮抗剂。
19.根据权利要求18的药物组合物,其中化合物A的所述免疫球蛋白单可变结构域是VHH结构域。
20.根据权利要求18或19的药物组合物,其中化合物A具有根据SEQ ID NO:11、SEQ IDNO:12或SEQ ID NO:13的氨基酸序列。
21.根据权利要求18至20中任一项的药物组合物,其中PD-1拮抗剂是抗PD-1抗体或抗PD-L1抗体。
22.根据权利要求21的药物组合物,其中抗PD-1抗体选自下组:派姆单抗、纳武单抗、皮地利珠单抗、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
23.根据权利要求22的药物组合物,其中抗PD-L1抗体选自下组:阿特珠单抗、阿维鲁单抗和德瓦鲁单抗。
24.根据权利要求18至23中任一项的药物组合物,进一步包含一种或多种药学上可接受的载体、赋形剂和/或媒介物。
25.根据权利要求18至24中任一项的药物组合物,其用于治疗和预防肿瘤性或过度增殖性疾病的方法中,所述疾病优选癌症或肿瘤疾病,更优选NSCLC。
26.一种试剂盒,其包含
a)包含化合物A的第一药物组合物,和
b)包含化合物B的第二药物组合物,
其中
化合物A是双特异性结合分子,其包含
VEGF结合性免疫球蛋白单可变结构域,
血清白蛋白结合性免疫球蛋白单可变结构域,和
Ang2结合性免疫球蛋白单可变结构域,其中
所述VEGF结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SYSMG(SEQ ID NO:1)
CDR2:AISKGGYKYDAVSLEG(SEQ ID NO:2),
CDR3:SRAYGSSRLRLADTYEY(SEQ ID NO:3);
所述血清白蛋白结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:SFGMS(SEQ ID NO:4),
CDR2:SISGSGSDTLYADSVKG(SEQ ID NO:5),
CDR3:GGSLSR(SEQ ID NO:6);
所述Ang2结合性免疫球蛋白单可变结构域具有下列CDR序列:
CDR1:DYAIG(SEQ ID NO:7),
CDR2:AIRSSGGSTYYADSVKG(SEQ ID NO:8),
CDR3:VPAGRLRYGEQWYPIYEYDA(SEQ ID NO:9);并且
其中
化合物B是PD-1拮抗剂。
27.根据权利要求26的试剂盒,其中化合物A的所述免疫球蛋白单可变结构域是VHH结构域。
28.根据权利要求26或27的试剂盒,其中化合物A具有根据SEQ ID NO:11、SEQ ID NO:12或SEQ ID NO:13的氨基酸序列。
29.根据权利要求26至28中任一项的试剂盒,其中PD-1拮抗剂是抗PD-1抗体或抗PD-L1抗体。
30.根据权利要求29的试剂盒,其中抗PD-1抗体选自下组:派姆单抗、纳武单抗、皮地利珠单抗、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
31.根据权利要求29的试剂盒,其中抗PD-L1抗体选自下组:阿特珠单抗、阿维鲁单抗和德瓦鲁单抗。
32.根据权利要求26至31中任一项的试剂盒,进一步包括包装说明书,其包括关于在治疗或预防在有此需要的患者中的肿瘤性或过度增殖性疾病(优选癌症或肿瘤疾病,特别优选NSCLC)中对患者同时、并行、序贯、连续、交替或分开给药的可读性说明。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17174323 | 2017-06-02 | ||
EP17174323.0 | 2017-06-02 | ||
EP17196949.6 | 2017-10-17 | ||
EP17196949 | 2017-10-17 | ||
PCT/EP2018/064445 WO2018220169A1 (en) | 2017-06-02 | 2018-06-01 | Anti-cancer combination therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110691790A true CN110691790A (zh) | 2020-01-14 |
Family
ID=62386492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880036511.5A Pending CN110691790A (zh) | 2017-06-02 | 2018-06-01 | 抗癌联合治疗 |
Country Status (13)
Country | Link |
---|---|
US (2) | US11198726B2 (zh) |
EP (1) | EP3630822A1 (zh) |
JP (1) | JP2020521797A (zh) |
KR (1) | KR20200013231A (zh) |
CN (1) | CN110691790A (zh) |
AU (1) | AU2018277227A1 (zh) |
BR (1) | BR112019022074A2 (zh) |
CA (1) | CA3061053A1 (zh) |
CL (1) | CL2019003430A1 (zh) |
IL (1) | IL270905A (zh) |
MX (1) | MX2019014199A (zh) |
PH (1) | PH12019502692A1 (zh) |
WO (1) | WO2018220169A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20170080584A (ko) | 2014-11-10 | 2017-07-10 | 에프. 호프만-라 로슈 아게 | 이중특이적 항체 및 안과학에서 이의 사용 방법 |
CA2963719A1 (en) | 2014-11-10 | 2016-05-19 | F. Hoffmann-La Roche Ag | Anti-il-1beta antibodies and methods of use |
MX2017005642A (es) * | 2014-11-10 | 2017-07-24 | Hoffmann La Roche | Anticuerpos anti-angiopoyetina 2 (ang2) y metodos de uso. |
KR20200013231A (ko) * | 2017-06-02 | 2020-02-06 | 베링거 인겔하임 인터내셔날 게엠베하 | 항암 조합 요법 |
WO2021209458A1 (en) | 2020-04-14 | 2021-10-21 | Ares Trading S.A. | Combination treatment of cancer |
CN116507627A (zh) | 2020-11-02 | 2023-07-28 | 勃林格殷格翰国际有限公司 | 作为egfr抑制剂的经取代1h-吡唑并[4,3-c]吡啶及衍生物 |
KR20230104653A (ko) | 2020-11-04 | 2023-07-10 | 하이델베르크 파마 리서치 게엠베하 | 암 요법에 사용하기 위한 면역 체크포인트 억제제 및 항체-아마톡신 접합체의 조합물을 포함하는 조성물 |
JP2024512478A (ja) | 2021-03-19 | 2024-03-19 | ハイデルベルク ファルマ リサーチ ゲゼルシャフト ミット ベシュレンクテル ハフツング | Bリンパ球特異的アマトキシン抗体コンジュゲート |
WO2024094688A1 (en) | 2022-11-01 | 2024-05-10 | Heidelberg Pharma Research Gmbh | Anti-gucy2c antibody and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103562222A (zh) * | 2011-04-01 | 2014-02-05 | 勃林格殷格翰国际有限公司 | 结合VEGF和Ang2的双特异性结合分子 |
WO2016170039A1 (en) * | 2015-04-23 | 2016-10-27 | F. Hoffmann-La Roche Ag | Combination therapy of antibody binding to angiopoietin 2 with antibody binding to programmed death 1 polypeptide |
WO2016170040A1 (en) * | 2015-04-23 | 2016-10-27 | F. Hoffmann-La Roche Ag | Combination therapy of antibody binding to angiopoietin 2 with antibody binding to programmed death ligand 1 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3101690B2 (ja) | 1987-03-18 | 2000-10-23 | エス・ビィ・2・インコーポレイテッド | 変性抗体の、または変性抗体に関する改良 |
ATE452207T1 (de) | 1992-08-21 | 2010-01-15 | Univ Bruxelles | Immunoglobuline ohne leichte ketten |
KR100927261B1 (ko) | 2001-01-17 | 2009-11-18 | 트루비온 파마슈티칼스, 인코포레이티드 | 결합 도메인-면역글로불린 융합 단백질 |
US20050284249A1 (en) | 2004-06-29 | 2005-12-29 | Arnone David F | Worm type gear mover assembly |
WO2006040153A2 (en) | 2004-10-13 | 2006-04-20 | Ablynx N.V. | Single domain camelide anti -amyloid beta antibodies and polypeptides comprising the same for the treatment and diagnosis of degenarative neural diseases such as alzheimer's disease |
EP2418278A3 (en) | 2005-05-09 | 2012-07-04 | Ono Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
DK1888640T3 (da) | 2005-05-18 | 2012-06-18 | Ablynx Nv | Forbedrede nanobodies mod tumornekrosefaktor-alfa |
EP3222634A1 (en) | 2007-06-18 | 2017-09-27 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
PT2242773T (pt) | 2008-02-11 | 2017-09-15 | Cure Tech Ltd | Anticorpos monoclonais para o tratamento de tumores |
WO2009109635A2 (en) | 2008-03-05 | 2009-09-11 | Ablynx Nv | Novel antigen binding dimer-complexes, methods of making and uses thereof |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
US8268314B2 (en) | 2008-10-08 | 2012-09-18 | Hoffmann-La Roche Inc. | Bispecific anti-VEGF/anti-ANG-2 antibodies |
SI2831111T1 (sl) * | 2012-03-30 | 2019-06-28 | Boehringer Ingelheim International Gmbh | Ang2-vezavne molekule |
BR112015006363A2 (pt) * | 2012-09-28 | 2017-08-08 | Boehringer Ingelheim Int | combinações farmacêuticas compreendendo ligantes angiopoietina-2/dll4 duplos e agentes anti-vegf-r |
WO2014049100A1 (en) * | 2012-09-28 | 2014-04-03 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations comprising dual angiopoietin-2 / dll4 binders and anti-vegf agents |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
JP6878405B2 (ja) | 2015-07-29 | 2021-05-26 | ノバルティス アーゲー | Pd−1に対する抗体分子を含む組み合わせ治療 |
US10894823B2 (en) * | 2016-03-24 | 2021-01-19 | Gensun Biopharma Inc. | Trispecific inhibitors for cancer treatment |
AU2017266298B2 (en) * | 2016-05-18 | 2024-01-04 | Boehringer Ingelheim International Gmbh | Anti PD-1 and anti-LAG3 antibodies for cancer treatment |
KR20200013231A (ko) * | 2017-06-02 | 2020-02-06 | 베링거 인겔하임 인터내셔날 게엠베하 | 항암 조합 요법 |
US10793634B2 (en) * | 2017-06-09 | 2020-10-06 | Boehringer Ingelheim International Gmbh | Anti-TrkB antibodies |
-
2018
- 2018-06-01 KR KR1020197035427A patent/KR20200013231A/ko active Search and Examination
- 2018-06-01 US US15/995,375 patent/US11198726B2/en active Active
- 2018-06-01 WO PCT/EP2018/064445 patent/WO2018220169A1/en active Application Filing
- 2018-06-01 MX MX2019014199A patent/MX2019014199A/es unknown
- 2018-06-01 CA CA3061053A patent/CA3061053A1/en active Pending
- 2018-06-01 EP EP18727819.7A patent/EP3630822A1/en not_active Ceased
- 2018-06-01 BR BR112019022074-7A patent/BR112019022074A2/pt unknown
- 2018-06-01 AU AU2018277227A patent/AU2018277227A1/en not_active Abandoned
- 2018-06-01 JP JP2019566199A patent/JP2020521797A/ja active Pending
- 2018-06-01 CN CN201880036511.5A patent/CN110691790A/zh active Pending
-
2019
- 2019-11-25 CL CL2019003430A patent/CL2019003430A1/es unknown
- 2019-11-25 IL IL270905A patent/IL270905A/en unknown
- 2019-11-28 PH PH12019502692A patent/PH12019502692A1/en unknown
-
2021
- 2021-11-08 US US17/520,748 patent/US20220340651A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103562222A (zh) * | 2011-04-01 | 2014-02-05 | 勃林格殷格翰国际有限公司 | 结合VEGF和Ang2的双特异性结合分子 |
WO2016170039A1 (en) * | 2015-04-23 | 2016-10-27 | F. Hoffmann-La Roche Ag | Combination therapy of antibody binding to angiopoietin 2 with antibody binding to programmed death 1 polypeptide |
WO2016170040A1 (en) * | 2015-04-23 | 2016-10-27 | F. Hoffmann-La Roche Ag | Combination therapy of antibody binding to angiopoietin 2 with antibody binding to programmed death ligand 1 |
Non-Patent Citations (1)
Title |
---|
ZHUANSUN Y等: "Anti-PD-1/PD-L1 antibody versus conventional chemotherapy for previously-treated, advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials" * |
Also Published As
Publication number | Publication date |
---|---|
US20220340651A1 (en) | 2022-10-27 |
KR20200013231A (ko) | 2020-02-06 |
EP3630822A1 (en) | 2020-04-08 |
CA3061053A1 (en) | 2018-12-06 |
US11198726B2 (en) | 2021-12-14 |
IL270905A (en) | 2020-01-30 |
JP2020521797A (ja) | 2020-07-27 |
BR112019022074A2 (pt) | 2020-05-12 |
WO2018220169A1 (en) | 2018-12-06 |
AU2018277227A1 (en) | 2019-10-31 |
CL2019003430A1 (es) | 2020-05-08 |
US20180346559A1 (en) | 2018-12-06 |
PH12019502692A1 (en) | 2020-07-13 |
MX2019014199A (es) | 2020-01-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220340651A1 (en) | Anti cancer combination therapy | |
TWI762484B (zh) | 抗pd1抗體分子、其製造方法及其用於癌症治療之用途 | |
CN105636986B (zh) | 包含vegf拮抗剂和抗-ctla-4抗体的组合的方法和组合物 | |
US11685787B2 (en) | Treatment of cancer with anti-GITR agonist antibodies | |
EP4001308A1 (en) | Anti-tigit antibodies and application thereof | |
CN116057070A (zh) | 抗cd40结合分子和包括其的双特异性抗体 | |
KR20160106074A (ko) | 신규 항-네트린-1 항체 | |
JP2022521305A (ja) | 抗pd-l1抗体及びその使用 | |
US20240010729A1 (en) | Combination therapy of a pd-1 antagonist and lag3 antagonist and lenvatinib or a pharmaceutically acceptable salt thereof for treating patients with cancer | |
EP3687573A1 (en) | Anti igf, anti pd-1 anti-cancer combination therapy | |
CN109195626B (zh) | 结合死亡受体4和死亡受体5的抗体 | |
JP2020515594A (ja) | Erbb−2、erbb−2/erbb−3陽性腫瘍を有する個体の処置のための、erb−2及びerbb−3の細胞外部分上のエピトープに結合する抗原結合部位を含むerbb−2標的化剤及び二重特異性抗体 | |
US20230416388A1 (en) | Treatment of cancer with anti-gitr agonist antibodies | |
US20240059771A1 (en) | Anti-cldn-18.2 antibody and use thereof | |
WO2021013207A1 (zh) | 用于治疗egfr高表达的癌症的多变剂量方法 | |
US20240052065A1 (en) | Binding molecules for the treatment of cancer | |
JP2024054284A (ja) | ガンの処置のための結合分子 | |
CN116806226A (zh) | 用于治疗癌症患者的pd-1拮抗剂和vegfr-2的拮抗剂的联合疗法 |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200114 |
|
WD01 | Invention patent application deemed withdrawn after publication |