CN109893654A - The method of VEGFR inhibitor for treating tumour - Google Patents

The method of VEGFR inhibitor for treating tumour Download PDF

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Publication number
CN109893654A
CN109893654A CN201811502626.7A CN201811502626A CN109893654A CN 109893654 A CN109893654 A CN 109893654A CN 201811502626 A CN201811502626 A CN 201811502626A CN 109893654 A CN109893654 A CN 109893654A
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buddhist nun
once
antibody
days
cancer
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CN109893654B (en
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蒋家骅
杨昌永
张连山
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
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Abstract

The present invention relates to the methods of VEGFR inhibitor for treating tumour.Specifically, the purposes the present invention relates to VEGFR inhibitor in the drug of preparation treatment tumour, the VEGFR inhibitor is selected from his phenanthrene and replaces Buddhist nun, health Buddhist nun for Buddhist nun, Ah pa for VEGFR-2 inhibitor such as Buddhist nuns.

Description

The method of VEGFR inhibitor for treating tumour
Technical field
The present invention relates to the methods of VEGFR inhibitor for treating tumour.
Background technique
In recent years, treatment of cancer achieves significant progress, inhibits driving in Tumor Angiongesis and growth of cancer cells The targeted molecular therapy of the factor, and the immunomodulatory treatments of enhancing patient's anti-tumor immunity obtain criticizing for regulatory agency in succession It is quasi-.
Enzyme histidine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are in the new vessels of tumour generate Have extremely important effect, is the important target spot blocked in tumor angiogenesis.Small point disclosed in WO2005000232A Sub- tyrosine kinase inhibitor Ah pa combines for Buddhist nun (Apatinib) ATP for having VEGFR-2 in high selectivity competition cell Site blocks downstream signal transduction, inhibits tumor neovasculature generation, is finally reached the purpose for the treatment of tumour, and Ah pa replaces Buddhist nun Structural formula such as formula (I) shown in.
CN101676267A discloses a series of salt, such as mesylate, hydrochloride, maleate etc. that Ah pa replaces Buddhist nun. Presently commercially available Ah pa is that Ah pa replaces Buddhist nun's mesylate for Buddhist nun, daily oral primary, dose 850mg.
The monoclonal antibody of programmed cell death molecule -1 (PD-1), it is combined between PD-L1/PD-1 by blocking, maximum Patient itself is improved to limit to the immune system response of tumour, to achieve the purpose that kill tumour cell.At present There is transnational drugmaker, more families to be directed to the monoclonal antibody of PD-1/PD-L1 signal path in research and development, wherein the drug listed There are Nivolumab and Pembrolizumab, administration frequency is biweekly or once in three weeks.Anti- PD-1 provided by the invention is anti- Body, WO2017054646A disclose the sequence and preparation method of the antibody, which has been in third stage, safety Property is good, and the clinical study results registered have shown that it with certain antitumor action (Journal of Clinical Oncology[J].35(2017): e15572-e15572)。
Indoles amine-pyrroles -2,3- dioxygenase (Indoleamine-pyrrole-2,3-dioxygenase, IDO) is one Kind iron content ferroheme monomeric protein, IDO inhibitor have a good application prospect as drug in pharmaceuticals industry, patent application A kind of structure novel is provided in PCT/CN2016/079054 (applying date 2016.04.12, publication number WO2016169421A1) High-efficiency low-toxicity selective IDO inhibitor compound, have the effect of excellent and effect, especially excellent medicine generation, which absorbs, lives Property, entitled (the S) -2- of chemistry (4- (4- (4- (fluoro- 5H- imidazo [5, the 1-a] iso-indoles -5- base of 6-) piperidin-1-yl) benzene Base) -1H- pyrazol-1-yl) ethyl alcohol, shown in structure such as following formula (I)
The clinical research for having the antibody combined VEGFR inhibitor combination therapy cancer of anti-PD-1 at present is being carried out, example As CN106963948A discloses anti-PD-1 antibody and A Pa for the purposes of Buddhist nun's combination therapy colon cancer；CN105960415A is public The purposes of a kind of anti-PD-1 antibody and pazopanib combination treatment clear-cell carcinoma is opened；WO2016141218A discloses a kind of anti- PD-1 antibody and it is happy cut down for Buddhist nun be combined treatment thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, clear-cell carcinoma, carcinoma of endometrium, The purposes of glioblastoma and melanoma etc..But combined treatment is also needed to be optimized, to further improve Clinical Benefit and safety.
Summary of the invention
The present invention provides a kind of medication of VEGFR inhibitor for treating tumour for giving patient effective amounts, administration frequency Lower than once a day.
In one embodiment of the invention, wherein the administration frequency of VEGFR inhibitor be once two days, three days one It is secondary, once four days, once five days, once six days, weekly, weekly administration three days once a day, weekly administration one day four days Once, weekly administration five days is once a day or two weeks are discontinued one week.
In one embodiment of the invention, wherein the dosage of VEGFR inhibitor is selected from 100-800mg, preferably From 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg、425mg、450mg、475mg、500mg、525mg、550mg、 575mg、600mg、625mg、650mg、675mg、 700mg、725mg、750mg、775mg、800mg。
In one embodiment of the invention, wherein the VEGFR inhibitor is VEGFR-2 inhibitor.
In one embodiment of the invention, wherein the VEGFR-2 inhibitor is selected from: PAN-90806, Foretinib, he it is luxuriant and rich with fragrance for Buddhist nun (Tafetinib), health Buddhist nun for Buddhist nun (Kanitinib), Ah pa for Buddhist nun (Apatinib), Tanibirumab, peace sieve are vertical for Buddhist nun (Lucitanib), Vatalanib, Si Dinibu for Buddhist nun (Anlotinib), moral (Cediranib), Buddhist nun Theo sieve (Chiauranib), more Weis replace Buddhist nun (Dovitinib), the non-Buddhist nun of Donna (Donafenib), method rice It is rich for Buddhist nun for Buddhist nun (Famitinib), Sitravatinib, Telatinib (Telatinib), L-21649, TAS-115, card (Cabozantinib), thiophene Er Feini (Thiophenib), furan quinoline replace Buddhist nun (Fruquintinib), Bu Linibu (Brivanib), Suo Fan for Buddhist nun (Sulfatinib), Ramucirumab, Glesatinib, Nintedanib (Nintedanib), General quinoline for Buddhist nun (Puquitinib), Axitinib (Axitinib), EDP317, Sorafenib (Sorafenib), wheat he replace Buddhist nun (Metatinib), Tivozanib, Rui Gefeini (Regorafenib), Midostaurin, training azoles pa Buddhist nun (Pazopanib), HLX-06, Altiratinib, peaceful lattice for Buddhist nun (Ningetinib), Sutent (Sunitinib), AL-8326, The officinal salt of Rebastinib or the above drug.
In one embodiment of the invention, wherein the A Pa is selected from mesylate, maleic acid for Buddhist nun's officinal salt Salt, tartrate, succinate, acetate, two fluoroacetate, fumarate, citrate, citrate, benzene sulfonate, benzene Formates, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromate, sulfate and phosphate.
In one embodiment of the invention, above-mentioned VEGFR inhibitor can also be administered in combination with immunotherapeutic agent.
In one embodiment of the invention, above-mentioned immunotherapeutic agent is selected from the therapeutic agent for following target spot: PD- 1、PD-L1、CTLA-4、PD-L2、LAG3、TIM3、2B4、A2aR、B7H1、B7H3、B7H4、 BTLA、CD2、CD27、CD28、 CD30、CD40、CD70、CD80、CD86、CD137、CD160、 CD226、CD276、DR3、GAL9、GITR、HAVCR2、HVEM、 IDO1, IDO2, ICOS, KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagen structure), PS (phosphatidyl silk Propylhomoserin), OX-40, SLAM, TIGHT, VISTA, VTCN1 or any combination thereof.
In a preferred embodiment of the invention, above-mentioned VEGFR inhibitor and anti-PD-1 antibody or its antigen binding Segment is administered in combination.
In one embodiment of the invention, wherein the anti-PD-1 antibody or its antigen-binding fragment administration frequency are Once a day, once two days, once three days, once four days, once five days, once six days, weekly, biweekly.
In one embodiment of the invention, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage is selected from 1-10mg/kg preferably is selected from 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, most preferably 3mg/ kg。
In one embodiment of the invention, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage is selected from 50-600mg preferably is selected from 60mg, 100mg, 125mg, 150mg, 175mg, 200mg, 400mg, 600mg, most preferably 200mg.
In one embodiment of the invention, wherein the anti-PD-1 antibody or its antigen-binding fragment are selected from AMP- 224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、PF-06801591、 Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、 Pembrolizumab、LZM- 009, AK-103 and Nivolumab.
In one embodiment of the invention, wherein the light chain variable of the anti-PD-1 antibody or its antigen-binding fragment Area is comprising as described in LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively The heavy chain variable region of anti-PD-1 antibody include respectively as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR3.
Wherein, each CDR sequence is as shown in the table:
Title Sequence Number
HCDR1 SYMMS SEQID NO:1
HCDR2 TISGGGANTYYPDSVKG SEQID NO:2
HCDR3 QLYYFDY SEQID NO:3
LCDR1 LASQTIGTWLT SEQID NO:4
LCDR2 TATSLAD SEQID NO:5
LCDR3 QQVYSIPWT SEQID NO:6
In one embodiment of the invention, wherein the anti-PD-1 antibody is humanized antibody.
In one embodiment of the invention, wherein the light-chain variable sequence of the humanized antibody is such as SEQ Sequence shown in ID NO:10 or its variant；The variant preferably has the amino acid of 0-10 to change in light chain variable region；It is more excellent It is selected as the amino acid variation of A43S.Weight chain variabl area sequence is the sequence as shown in SEQ ID NO:9 or its variant；The variant It is preferred that thering is the amino acid of 0-10 to change in heavy chain variable region；The amino acid of more preferably G44R changes.
The humanized antibody is heavy, the variable region sequences of light chain are as follows:
Heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO:9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO:10
In one embodiment of the invention, wherein humanized antibody light chain's sequence is such as SEQ ID NO:8 institute The sequence shown or its variant；The variant preferably has the amino acid of 0-10 to change in light chain variable region；More preferably A43S's Amino acid variation.Sequence of heavy chain is the sequence as shown in SEQ ID NO:7 or its variant；The variant is preferably in heavy chain variable region There is the amino acid of 0-10 to change；The amino acid of more preferably G44R changes.
In one embodiment of the invention, wherein humanized antibody light chain's sequence is such as SEQ ID NO:8 Shown in sequence, sequence of heavy chain be the sequence as shown in SEQ ID NO:7.
Humanized antibody above-mentioned is heavy, the sequence of light chain is as follows:
Heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO:7
Light chain
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:8
In one embodiment of the invention, above-mentioned VEGFR inhibitor, anti-PD-1 antibody can also and IDO inhibitor Be administered in combination, when being administered in combination, VEGFR inhibitor administration frequency is unlimited, can be once a day, once two days, three days one It is secondary, once four days, once five days, once six days, weekly, weekly administration three days once a day, weekly administration one day four days Once, weekly administration five days is once a day or two weeks are discontinued one week.
In one embodiment of the invention, wherein IDO inhibitor is formula (I) compound represented or its is pharmaceutical Salt, solvated compounds or its stereoisomer,
In one embodiment of the invention, wherein the administration frequency of the IDO inhibitor be twice a day, one day one It is secondary, once two days, once three days, once four days, once five days, once six days, weekly.
In one embodiment of the invention, wherein it is 50-2000mg that the dosage of the IDO inhibitor, which is selected from, preferably 50mg、75mg、100mg、150mg、200mg、300mg、400mg、500mg、600mg、 700mg、750mg、800mg、900mg、 The more preferable 100mg, 200mg of 1000mg, 1200mg, 1500mg, 2000mg, 400mg, 800mg, 1000mg, 1200mg, 1500mg。
In a therapeutic scheme of the invention, VEGFR inhibitor for treating tumour is given, regulatory T cells can be reduced The quantity of (Regulatory T cells, abbreviation Tregs) increases CD8+The ratio of T cell and Treg.
In a therapeutic scheme of the invention, anti-PD-1 antibodies for antitumor therapy is given, regulatory T cell can be reduced Quantity, increase CD8+The ratio of T cell and Treg.
In a therapeutic scheme of the invention, anti-PD-1 antibody or its antigen fragment combine VEGFR inhibitor for treating tumour, The quantity of regulatory T cells can be reduced, CD8 is increased+The ratio of T cell and Treg.
Tumour of the present invention can be selected from gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical carcinoma, the carcinoma of the rectum, cancer of pancreas, brain Cancer, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritonaeum The renal tumor of tumour, melanoma, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process, head and neck neoplasm, white blood Disease, lymthoma, myeloma or non-small cell lung cancer；It is preferred that breast cancer, gastric cancer, intestinal cancer, colon cancer, kidney, melanoma or non-small Cell lung cancer.
The present invention also provides a kind of methods for reducing Treg, including giving the Ah pa of patient effective amounts in need for Buddhist nun.
The present invention also provides a kind of method for reducing Treg, the anti-PD-1 including giving patient effective amounts in need is anti- Body or its antigen-binding fragment.
The present invention also provides a kind of method for reducing Treg, including give the Ah pa of patient effective amounts in need for Buddhist nun and Anti- PD-1 antibody or its antigen-binding fragment.
In one embodiment of the invention, wherein the light chain variable of the anti-PD-1 antibody or its antigen-binding fragment Area is comprising as described in LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively The heavy chain variable region of anti-PD-1 antibody include respectively as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR3.
Wherein, each CDR sequence is as shown in the table:
Title Sequence Number
HCDR1 SYMMS SEQID NO:1
HCDR2 TISGGGANTYYPDSVKG SEQID NO:2
HCDR3 QLYYFDY SEQID NO:3
LCDR1 LASQTIGTWLT SEQID NO:4
LCDR2 TATSLAD SEQID NO:5
LCDR3 QQVYSIPWT SEQID NO:6
In one embodiment of the invention, wherein the anti-PD-1 antibody is humanized antibody.
In one embodiment of the invention, wherein the humanized antibody weight, the variable region sequences of light chain are as follows It is shown:
Heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO:9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO:10
In one embodiment of the invention, wherein humanized antibody weight, the sequence of light chain are as follows:
Heavy chain full length sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO:7
Light chain full length sequence
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:8
The present invention also provides a kind of medicine package boxes, and it includes have above-mentioned a effective amount of anti-PD-1 antibody or its antigen knot Close segment, VEGFR inhibitor and IDO inhibitor.
The present invention also provides a kind of pharmaceutical compositions, and it includes have above-mentioned a effective amount of anti-PD-1 antibody or its antigen knot Close segment, VEGFR inhibitor and IDO inhibitor and one or more pharmaceutical excipients, diluent or carrier.
The present invention also provides a kind of VEGFR inhibitor, anti-PD-1 antibody and IDO inhibitors to combine in preparation treatment tumour Purposes in drug.
The present invention also provides a kind of methods of VEGFR inhibitor, anti-PD-1 antibody and IDO inhibitor combination therapy tumour.
In one embodiment of the invention, wherein the VEGFR inhibitor is selected from: PAN-90806, Foretinib, he it is luxuriant and rich with fragrance for Buddhist nun (Tafetinib), health Buddhist nun for Buddhist nun (Kanitinib), Ah pa for Buddhist nun (Apatinib), Tanibirumab, peace sieve are vertical for Buddhist nun (Lucitanib), Vatalanib, Si Dinibu for Buddhist nun (Anlotinib), moral (Cediranib), Buddhist nun Theo sieve (Chiauranib), more Weis replace Buddhist nun (Dovitinib), the non-Buddhist nun of Donna (Donafenib), method rice It is rich for Buddhist nun for Buddhist nun (Famitinib), Sitravatinib, Telatinib (Telatinib), L-21649, TAS-115, card (Cabozantinib), thiophene Er Feini (Thiophenib), furan quinoline replace Buddhist nun (Fruquintinib), Bu Linibu (Brivanib), Suo Fan for Buddhist nun (Sulfatinib), Ramucirumab, Glesatinib, Nintedanib (Nintedanib), General quinoline for Buddhist nun (Puquitinib), Axitinib (Axitinib), EDP317, Sorafenib (Sorafenib), wheat he replace Buddhist nun (Metatinib), Tivozanib, Rui Gefeini (Regorafenib), Midostaurin, training azoles pa Buddhist nun (Pazopanib), HLX-06, Altiratinib, peaceful lattice for Buddhist nun (Ningetinib), Sutent (Sunitinib), AL-8326, The officinal salt of Rebastinib or the above drug.
In one embodiment of the invention, wherein the anti-PD-1 antibody or its antigen-binding fragment are selected from AMP- 224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、 PF-06801591、 Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、 Pembrolizumab、LZM- 009, AK-103 and Nivolumab.
In one embodiment of the invention, wherein the light chain variable of the anti-PD-1 antibody or its antigen-binding fragment Area is comprising as described in LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively The heavy chain variable region of anti-PD-1 antibody include respectively as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR3.
Wherein, each CDR sequence is as shown in the table:
Title Sequence Number
HCDR1 SYMMS SEQID NO:1
HCDR2 TISGGGANTYYPDSVKG SEQID NO:2
HCDR3 QLYYFDY SEQID NO:3
LCDR1 LASQTIGTWLT SEQID NO:4
LCDR2 TATSLAD SEQID NO:5
LCDR3 QQVYSIPWT SEQID NO:6
In one embodiment of the invention, wherein the anti-PD-1 antibody is humanized antibody.
In one embodiment of the invention, wherein the following institute of variable region sequences of humanized antibody weight, light chain Show:
Heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO:9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO:10
In one embodiment of the invention, wherein humanized antibody weight, the sequence of light chain are as follows:
Heavy chain full length sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGR FTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO:7
Light chain full length sequence
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:8
In one embodiment of the invention, wherein IDO inhibitor is formula (I) compound represented or its is pharmaceutical Salt, solvated compounds or its stereoisomer,
Tumour of the present invention can be selected from lung cancer, gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical carcinoma, the carcinoma of the rectum, pancreas Cancer, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovary The renal tumor of tumor, peritoneal tumor, melanoma, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process, incidence are swollen Tumor, leukaemia, lymthoma, myeloma；It is preferred that breast cancer, lung cancer, gastric cancer, intestinal cancer, colon cancer, kidney, melanoma.
The present invention also provides a kind of Ah pas to combine the purposes in the drug of preparation treatment tumour for Buddhist nun and immunotherapeutic agent.
Immunotherapeutic agent of the present invention can be selected from the therapeutic agent for following target spot: PD-1, PD-L1, CTLA-4, PD-L2(B7-DC、CD273)、LAG3、TIM3、2B4、A2aR、B7H1、B7H3、 B7H4、BTLA、CD2、CD27、CD28、 CD30、CD40、CD70、CD80、CD86、CD137、 CD160、CD226、CD276、DR3、GAL9、GITR、HAVCR2、HVEM、 IDO1, IDO2, ICOS, KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagen structure), PS (phosphatidyl silk Propylhomoserin), OX-40, SLAM, TIGHT, VISTA, VTCN1 or any combination thereof.The therapeutic agent preferred pin resists following target spot Body: PD-1, PD-L1, CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3,2B4, A2aR, B7H1, B7H3, B7H4, BTLA、CD2、CD27、CD28、 CD30、CD40、CD70、CD80、CD86、CD137、CD160、CD226、CD276、DR3、 GAL9, GITR, HAVCR2, HVEM, IDO1, IDO2, ICOS, KIR, LAIR1, LIGHT, MARCO are (huge with collagen structure Phagocyte receptor), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, VTCN1 or any combination thereof.Wherein PD-1 antibody is not that light chain variable region includes respectively as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 LCDR1, LCDR2 and LCDR3 and heavy chain variable region include respectively such as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 Shown in HCDR1, HCDR2 and HCDR3 antibody.
Tumour of the present invention can be selected from lung cancer, gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical carcinoma, the carcinoma of the rectum, pancreas Cancer, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovary The renal tumor of tumor, peritoneal tumor, melanoma, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process, incidence are swollen Tumor, leukaemia, lymthoma, myeloma；It is preferred that breast cancer, lung cancer, gastric cancer, intestinal cancer, colon cancer, kidney, melanoma.
In the present invention, VEGFR inhibitor and anti-PD-1 antibody or its antigen-binding fragment joint are used for the treatment of tumour When, the administration order of the two does not have any restrictions, can first give anti-PD-1 antibody, then give VEGFR inhibitor or first to VEGFR inhibitor is given, anti-PD-1 antibody is being given.
In the present invention, VEGFR inhibitor, anti-PD-1 antibody or its antigen-binding fragment and IDO inhibitor, which are combined, is used for When the treatment of tumour, the administration order of three does not have any restrictions.
United administration route of the present invention can be respectively selected from oral administration, parenteral, percutaneous dosing, the stomach Parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection.
Detailed description of the invention
One, term
In order to be easier to understand the present invention, certain technical and scientific terms are defined in detail below.Except obviously at this It is separately explicitly defined at it in file, otherwise all other technical and scientific term used herein all has belonging to the present invention The normally understood meaning of the those skilled in the art in field.
Term " humanized antibody (humanized antibody) ", also referred to as CDR grafted antibody (CDR-grafted Antibody), refer to the antibody variable region frame that the CDR sequence of mouse is transplanted to people, i.e., different types of human germline antibody The antibody generated in frame sequence.Chimeric antibody can be overcome due to carrying a large amount of murine protein ingredients, so that induction is strong Antibody variable antibody response.Such frame sequence can be from public DNA database or public affairs including germline antibody gene sequences The bibliography opened obtains.As people's heavy chain and the germline DNA sequence dna of light-chain variable region gene can be in " VBase " ethnic group system sequences Column database (can get) in internet www.mrccpe.com.ac.uk/vbase, and in Kabat, E.A. et al., 1991Sequences of Proteins of Immunological Interest is found in the 5th edition.At the present invention one In preferred embodiment, the CDR sequence of the PD-1 humanized antibody mouse is selected from SEQ ID NO:1, and 2,3,4,5,6.
Term " antigen-binding fragment ", refers to the Fab segment with antigen-binding activity, Fab ' segment, 2 segment of F (ab '), And the Fv segment sFv segment in conjunction with people PD-1；SEQ ID NO:1 to SEQ ID is selected from comprising antibody of the present invention One or more CDR regions in NO:6.Fv segment contains antibody heavy chain variable region and light chain variable region, but does not have constant region, and Minimum antibody fragment with whole antigen binding sites.Generally, Fv antibody also includes more between VH and VL structural domain Peptide linker, and structure needed for being capable of forming antigen binding.Two antibody variable regions can also be connected with different attachments At a polypeptide chain, referred to as single-chain antibody (single chain antibody) or scFv (sFv).Term of the invention " with PD-1 combination ", referring to can interact with people PD-1.Term " antigen binding site " of the invention refer to it is discontinuous on antigen, by The three-dimensional space site of antibody or antigen-binding fragment identification of the present invention.
Detailed description of the invention
The influence to mouse tumor volume is administered for Buddhist nun and PD-1 in Fig. 1 Ah pa alone or in combination.
The influence to mouse weight is administered for Buddhist nun and PD-1 in Fig. 2 Ah pa alone or in combination.
The influence to mouse tumor volume is administered for Buddhist nun, PD-1 and I DO inhibitor in Fig. 3 Ah pa alone or in combination
The influence to mouse weight is administered for Buddhist nun, PD-1 and I DO inhibitor in Fig. 4 Ah pa alone or in combination
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Embodiment 1
1, experiment purpose: this experiment inoculates the foundation of mouse MC38 tying colon-cancer cell in people's PD-1 transgenic mice and swells Tumor model evaluates drug combination by the size and mouse weight of tumour to antitumor action and its safety.Combination medicine Treatment is the anti-PD-1 antibody that doses are given in abdominal cavity, while the Ah pa of oral various dose replaces Buddhist nun's compound.
2, experimental material and method:
2.1 experimental animals and material:
People's PD-1 transgenic mice: it 70, is bred by Cephrim company animal center, 3 couples of original people PD-1 turn base Because mouse is purchased from the Isis company of Britain, SPF grades of raisings.
Solvent: 0.5% sodium carboxymethylcellulose+0.25% (v/v) polyoxyethylene sorbitan monoleate
Human IgG: it comes from serum (Sigma-Aldrich), product number: I4506-50MG
Anti- PD-1 antibody: SEQ ID NO:7 and SEQ ID NO:8 in its heavy, light chain sequence such as present invention, freeze-dried powder, After being dissolved in water, then with 5% glucose dilute, ultimate density 3mg/Ml, lot number P1512.
Methanesulfonic acid Ah pa replaces Buddhist nun: it is provided by Jiangsu Hengrui Medicine, it is poly- with 0.5% sodium carboxymethylcellulose+0.25% (v/v) Sorb ester 80 dilutes, ultimate density 20mg/mL, lot number 668170301
MC38 cell: DMEM culture medium, 10% fetal calf serum, 37 DEG C, 5%CO2Culture.Cell symbol of the selection for implantation Close following four standard: 1) fast-growth；2) passage number is few；3) inoculation the previous day replaces culture medium and 4) has high existence Power.
2.2 experimental methods:
MC38 cell is harvested on the day of inoculation, by cell (5x 105) it is inoculated in 70 people's PD-1 transgenic mice (male and female Having) right flank is subcutaneous, reach 100mm to mouse mean tumour volume3When left and right, 56 are chosen, is randomly divided into 8 groups, every group 7.Single dose is given according to scheme after grouping, anti-PD-1 antibody is injected intraperitoneally, then oral Ah pa carries out drug combination for Buddhist nun.Weekly Gross tumor volume is measured twice, is weighed, and data are recorded.
2.3 experimental groups and dosage regimen
Table 1: experimental group and dosage regimen
Note: it Q2Dx8: once two days, is administered 8 times；QDx21: it once a day, is administered 21 times；QWx3: weekly, administration 3 Week；QDx3for 3W: weekly administration three days, it is administered 3 weeks；Ip: intraperitoneal injection po: oral
3, data representation and statistical procedures
Weight, gross tumor volume and the knurl weight of groups of animals, data mean+SD (Mean ± SEM) expression, T- Test carries out statistical analysis to data.The weight of groups of animals as shown in Fig. 2, gross tumor volume result as shown in table 2 and Fig. 1, Tumor weight is as shown in table 3.Gross tumor volume calculation formula: volume=0.5236 × length × short × height
4, experimental result
2. gross tumor volume (mm of table3)
* p < 0.05 and following presentation have statistical significance.
3. tumor weight (g) of table
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 Group 8
Average value 1.290 1.194 0.827 0.560 0.839 0.575 0.328 0.153
Standard deviation 0.173 0.073 0.177 0.098 0.184 0.113 0.133 0.075
Embodiment 2
1, experiment purpose: this experiment inoculates the foundation of mouse MC38 tying colon-cancer cell in people's PD-1 transgenic mice and swells Tumor model evaluates drug combination by the size and mouse weight of tumour to antitumor action and its safety.Combination medicine Treatment is the anti-PD-1 antibody that doses are given in abdominal cavity, at the same the IDO inhibitor of oral doses and various dose Ah Pa replaces Buddhist nun's compound.
2, experimental material and method:
2.1 experimental animals and material:
People's PD-1 transgenic mice: it 55, is bred by Cephrim company animal center, 3 couples of original people PD-1 turn base Because mouse is purchased from the Isis company of Britain, SPF grades of raisings.
Solvent: 0.5% sodium carboxymethylcellulose
Human IgG: it comes from serum (Sigma-Aldrich), product number: I4506-50MG
Anti- PD-1 antibody: SEQ ID NO:7 and SEQ ID NO:8 in its heavy, light chain sequence such as present invention, freeze-dried powder, After being dissolved in water, then with 5% glucose dilute, ultimate density 3mg/Ml, lot number P1512.
Methanesulfonic acid Ah pa replaces Buddhist nun: it is provided by Jiangsu Hengrui Medicine, it is poly- with 0.5% sodium carboxymethylcellulose+0.25% (v/v) Sorb ester 80 dilutes, ultimate density 20mg/mL, lot number 668170301
IDO inhibitor: being provided by Jiangsu Hengrui Medicine, and ((((the fluoro- 5H- imidazo [5,1-a] of 6- is different by 4- by 4- by 4- by (S) -2- Indoles -5- base) piperidin-1-yl) phenyl) -1H- pyrazol-1-yl) ethyl alcohol, (the Shen referenced patent application PCT/CN2016/079054 Please day 2016.04.12, publication number WO2016169421A1) in embodiment 40,41 in method preparation), compound structure It is as follows:
MC38 cell: DMEM culture medium, 10% fetal calf serum, 37 DEG C, 5%CO2Culture.Cell symbol of the selection for implantation Close following four standard: 1) fast-growth；2) passage number is few；3) inoculation the previous day replaces culture medium and 4) has high existence Power.
2.2 experimental methods:
MC38 cell is harvested on the day of inoculation, by cell (5x 105) it is inoculated in 55 people's PD-1 transgenic mice (male and female Having) right flank is subcutaneous, reach 100mm to mouse mean tumour volume3When left and right, 42 are chosen, is randomly divided into 7 groups, every group 6 Only.Single dose is given according to scheme after grouping, anti-PD-1 antibody is injected intraperitoneally, then oral IDO inhibitor and A Pa combine for Buddhist nun Medication.Gross tumor volume is measured twice a week, is weighed, and data are recorded.
2.3 experimental groups and dosage regimen
Table 4: experimental group and dosage regimen
Note: it Q2Dx8: once two days, is administered 8 times；QDx21: it once a day, is administered 21 times；QDx3/week for 3W: every Week administration three days, is administered 3 weeks；BIDx21: it twice daily, is administered 21 days；Ip: intraperitoneal injection po: oral
3, data representation and statistical procedures
Weight, gross tumor volume and the knurl weight of groups of animals, data mean+SD (Mean ± SEM) expression, T- Test carries out statistical analysis to data.The weight of groups of animals as shown in figure 4, gross tumor volume result as shown in table 5 and Fig. 3. Gross tumor volume calculation formula: volume=0.5236 × length × short × height
4, experimental result
5. gross tumor volume (mm of table3)
A Pa is administered intermittently (QDx5 3W) and IDO inhibitor and the combination regimen on tumor growth suppression of PD-1 antibody for Buddhist nun System is obvious, and tumor killing effect is higher than Ah pa and is administered intermittently (Q2Dx10) and IDO inhibitor and PD-1 antibody combination scheme for Buddhist nun, Tumor killing effect is suitable for Buddhist nun's successive administration (QDx21) and PD-1 antibody combination with Ah pa.Two kinds of Ah pas are administered intermittently for Buddhist nun and PD- The combination of 1 antibody plays the role of inhibiting tumour growth, and tumor killing effect is higher than IDO inhibitor and PD-1 antibody is combined scheme.
Embodiment 3: flow cytometry tumor infiltrating lymphocyte
1, experiment purpose: this experiment inoculates the foundation of mouse MC38 tying colon-cancer cell in people's PD-1 transgenic mice and swells Tumor model passes through regulatory T cells in flow cytometry mouse tumor and spleen (Regulatory T cells, abbreviation ) and the expression of CD cell Tregs.
2, experimental material and method:
2.1 experimental animals and material:
People's PD-1 transgenic mice: it 70, is bred by Cephrim company animal center, 3 couples of original people PD-1 turn base Because mouse is purchased from the Isis company of Britain, SPF grades of raisings.
Solvent: 0.5% sodium carboxymethylcellulose+0.25% (v/v) polyoxyethylene sorbitan monoleate
Human IgG: it comes from serum (Sigma-Aldrich), product number: I4506-50MG
Anti- PD-1 antibody: SEQ ID NO:7 and SEQ ID NO:8 in its heavy, light chain sequence such as present invention, freeze-dried powder, After being dissolved in water, then with 5% glucose dilute, ultimate density 3mg/Ml, lot number P1512.
Methanesulfonic acid Ah pa replaces Buddhist nun: it is provided by Jiangsu Hengrui Medicine, it is poly- with 0.5% sodium carboxymethylcellulose+0.25% (v/v) Sorb ester 80 dilutes, ultimate density 20mg/mL, lot number 668170301
2.2 experimental methods:
2.2.1 experimental group and dosage regimen
It is same as Example 1, it is shown in Table 1.
2.2.2 harvest tissue/organ and preparation single cell suspension
In the 28th day (last time administration is one day after), every group of 5 mouse CO2It puts to death.Tumour and spleen are collected immediately, It weighs and records, then tumour and spleen are placed in RPMI-1640 culture medium on ice.Then by tumour and spleen section, It is transferred in the C separating pipe for being pre-loaded with 2.5mL premix synthase (Mittenyl Tumor/Spleen Isolation Kit), And to specifications in method at full-automatic tissue processor (model Miltenyi gentle MACS dissociator) Upper processing obtains single tumour or splenocyte suspension.
2.2.3 flow cytometry tumor infiltrating lymphocyte
2,000,000 single tumours or splenocyte and FcR blocking agent (BD Biosciences) are incubated for first, then and CD45+, CD3+, CD4+And CD8+The premix CD surface antigen buffer of (Biolegends Biosciences) mixes.It, will after washing The single suspension of cell is fixed overnight for 4 DEG C on ice with Foxp3 buffer.Second day, cell is washed using permeabilization buffer, is made With anti-Foxp3-APC monoclonal antibody (Biolegends Biosciences) cell inner dyeing Foxp3.After washing again, pass through FACSCanto II (BD Biosciences) analyzes suspension.It is analyzed with BD FACSDiva software (BD Biosciences) As a result.In CD45+CD8 is analyzed in hematopoietic cell group+And CD4+CD4 in group+Foxp3+The sum of cell, and with 2 × 106It indicates Living cells in tumour.
3, data representation and statistical procedures
Statistics between control group and treatment group or between treatment group uses one-way analysis of variance (ANOVA), with laggard Row Bonferroni's correction.It is analyzed using GraphPad Prism, p < 0.05 and following presentation have statistical significance.
4, experimental result
Expression of the 4.1:Treg in tumour and spleen CD4+ cell is shown in Table 5
Table 5.
Note: ip: intraperitoneal injection po: oral
Expression of the 4.2:CD cell in tumour is shown in Table 6
Table 6.
Note: ip: intraperitoneal injection po: oral
Expression of the 4.3:CD cell in spleen is shown in Table 7
Table 7.
Note: ip: intraperitoneal injection po: oral
It is compared with control group, anti-PD-1 antibody is applied alone to CD4 under the dosage of 3mg/kg+And CD8+T cell quantity is not obvious Influence, but anti-PD-1 antibody obviously lowers Treg quantity, increases CD8+The ratio of T cell and Treg.The dosage of 3mg/kg Under anti-PD-1 antibody be applied alone only reduce tumour in Treg, on the Treg in spleen without influence.
It is compared with control group, A Pa is applied alone for Buddhist nun to CD4 under the dosage of 100mg/kg+And CD8+T cell quantity is not obvious Influence, but Ah pa obviously lowers Treg quantity for Buddhist nun, increases CD8+The ratio of T cell and Treg.
A Pa is administered intermittently for Buddhist nun and (once a week, is administered three weeks；Three-times-weekly, it is administered three weeks) join with anti-PD-1 antibody With to CD4+And CD8+T cell quantity, CD8+The ratio of T cell and Treg do not influence significantly, but Ah pa continuously gives for Buddhist nun Medicine and the combination of anti-PD-1 antibody increase CD8+The ratio of T cell and Treg.
Embodiment 4: Ah pa treats the clinical research of gastric cancer administration frequency for Buddhist nun
1, compound
Commercially available methanesulfonic acid Ah pa replaces Buddhist nun's piece.
2, inclusion criteria
(1) the late gastric cancer patient for the second line treatment failure made a definite diagnosis through pathology or histology or gastroesophageal junction gland Cancer；(2) there is measurable lesion；(3) ECOG scores 0-2 points.
Note: (1) definition for the treatment of failure: tumor recurrence shifts after progression of disease or treatment end in therapeutic process, or There is not tolerable toxicity；(2) when the treatment of each line of progressive stage disease includes administration time >=1 period or is longer Between one or more chemotherapeutics；Allow early period carry out assisting/lower rectal cancer, if during auxiliary/lower rectal cancer or After the completion of person≤24 weeks in there is tumor recurrence transfer, then it is assumed that auxiliary/lower rectal cancer of early period be one for progress One line systemic chemotherapy (3) of phase disease allows the treatment of early period to be chemotherapy combined molecular targeted agents.
3, dosage regimen
This test will be grouped at random subject using district's groups method of randomization, will be tested according to the ratio of 1:1:1 Person is assigned randomly to 3 test groups.
A group: Ah pa replaces Buddhist nun's list medicine: 500mg, takes orally, and once a day, takes and stops within 5 days 2 days, 21 days are an observation period.Altogether It is included in subject and is no less than 20；
B group: Ah pa replaces Buddhist nun's list medicine: 500mg, takes orally, and once a day, takes and stops within 2 weeks 1 week, 21 days are an observation period.Altogether It is included in subject and is no less than 20；
C group: Ah pa replaces Buddhist nun's list medicine: 500mg, takes orally, and once a day, successive administration, 21 days are an observation period.It receives altogether Enter subject and is no less than 20；
4, efficacy analysis
Curative effect index: progression free survival phase (PFS) is defined as into group research to tumour progression/recurrence or because any The time of reason death.The subject of tumour progression/recurrence or death is not observed, Progression free survival/recurrence-free survival exists Last time effectively deletes mistake processing tumor evaluation day.
Secondary efficacy index:
1. Overall survival (OS): being defined as into group research to time dead for any reason.When last time contacts also The subject of survival, total existence delete mistake processing day in last time connection.
2. objective remission rate (ORR): complete incidence graph (CR)+part alleviates (PR), refer to using 1.1 editions standards of RECIST come The objective curative effect of tumour is evaluated, refers to percentage of the case load of CR and PR in evaluable curative effect patient.
3. disease control rate (DCR): (PR)+stable disease (SD) is alleviated in complete incidence graph (CR)+part, refers to CR, PR and SD Percentage of the case load of (>=4 weeks) in evaluable curative effect patient.
4. life quality scores (QoL): (referring to EORTC QLQ-C30 V3.0 and HCC-18).
Sequence table
<110>Hengrui Medicine Co., Ltd., Jiangsu Prov.
Suzhou Sheng Diya biological medicine Co., Ltd
<120>method of VEGFR inhibitor for treating tumour
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
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Ser Tyr Met Met Ser
1 5
<210> 2
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<213>source of mouse (Mus musculus)
<400> 2
Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys
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<210> 3
<211> 7
<212> PRT
<213>source of mouse (Mus musculus)
<400> 3
Gln Leu Tyr Tyr Phe Asp Tyr
1 5
<210> 4
<211> 11
<212> PRT
<213>source of mouse (Mus musculus)
<400> 4
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr
1 5 10
<210> 5
<211> 7
<212> PRT
<213>source of mouse (Mus musculus)
<400> 5
Thr Ala Thr Ser Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213>source of mouse (Mus musculus)
<400> 6
Gln Gln Val Tyr Ser Ile Pro Trp Thr
1 5
<210> 7
<211> 443
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(443)
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<400> 7
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 Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp 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 Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 8
<211> 214
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<213>artificial sequence (Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(214)
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<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
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<220>
<221> PEPTIDE
<222> (1)..(116)
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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 Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp 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 Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 10
<211> 107
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<221> PEPTIDE
<222> (1)..(10)
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105

Claims (24)

1. a kind for the treatment of method of tumour, it is characterised in that give the VEGFR inhibitor of patient effective amounts, administration frequency is lower than one It is primary.
2. method described in claim 1, wherein the administration frequency of VEGFR inhibitor be once two days, once three days, four days one It is secondary, once five days, once six days, weekly, weekly administration three days once a day, weekly administration four days once a day, weekly It is administered five days once a day or two weeks is discontinued one week.
3. method as claimed in claim 2, wherein the dosage of VEGFR inhibitor is selected from 100-800mg, preferably be selected from 100mg, 150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg。
4. method as claimed in claim 3, wherein the VEGFR inhibitor is VEGFR-2 inhibitor.
5. method as claimed in claim 4, wherein the VEGFR-2 inhibitor is selected from: PAN-90806, Foretinib, he is luxuriant and rich with fragrance Buddhist nun is replaced for Buddhist nun (Apatinib), Tanibirumab, peace sieve for Buddhist nun (Tafetinib), health Buddhist nun for Buddhist nun (Kanitinib), Ah pa (Anlotinib), moral is vertical replaces Buddhist nun (Lucitanib), Vatalanib, Si Dinibu (Cediranib), Theo Buddhist nun sieve (Chiauranib), more Weis for Buddhist nun (Dovitinib), the non-Buddhist nun of Donna (Donafenib), method rice for Buddhist nun (Famitinib), Sitravatinib, Telatinib (Telatinib), L-21649, TAS-115, card are rich for Buddhist nun (Cabozantinib), thiophene that Non- Buddhist nun (Thiophenib), furan quinoline replace Buddhist nun for Buddhist nun (Fruquintinib), Bu Linibu (Brivanib), Suo Fan (Sulfatinib), Ramucirumab, Glesatinib, Nintedanib (Nintedanib), general quinoline replace Buddhist nun (Puquitinib), Axitinib (Axitinib), EDP317, Sorafenib (Sorafenib), wheat he replace Buddhist nun (Metatinib), Tivozanib, Rui Gefeini (Regorafenib), Midostaurin, training azoles pa Buddhist nun (Pazopanib), HLX-06, Altiratinib, peaceful lattice for Buddhist nun (Ningetinib), Sutent (Sunitinib), AL-8326, The officinal salt of Rebastinib or the above drug.
6. method described in claim 5, wherein the A Pa is selected from mesylate, maleate, winestone for Buddhist nun's officinal salt Hydrochlorate, succinate, acetate, two fluoroacetate, fumarate, citrate, citrate, benzene sulfonate, benzoate, Naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromate, sulfate and phosphate.
7. method according to claim 1-6, it is characterised in that also and anti-PD-1 antibody or its antigen binding fragment Section is administered in combination.
8. according to the method described in claim 7, wherein the anti-PD-1 antibody or its antigen-binding fragment administration frequency are one It is once, once two days, once three days, once four days, once five days, once six days, weekly, biweekly.
9. according to the method described in claim 8, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage are selected from 1- 10mg/kg preferably is selected from 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, most preferably 3mg/kg.
10. according to the method described in claim 8, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage is selected from 50-600mg preferably is selected from 60mg, 100mg, 200mg, 400mg, 600mg, most preferably 200mg.
11. according to the method described in claim 8, wherein the anti-PD-1 antibody or its antigen-binding fragment be selected from AMP-224, GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、Pidilizumab、PF-06801591、 Genolimzumab、CA-170、MEDI-0680、JS-001、TSR-042、Camrelizumab、Pembrolizumab、LZM- 009, AK-103 and Nivolumab.
12. method according to any one of claims 8, wherein the light chain variable region of the anti-PD-1 antibody or its antigen-binding fragment includes Anti- PD- as described in LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively The heavy chain variable region of 1 antibody include respectively the HCDR1 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, HCDR2 and HCDR3.
13. method described in claim 12, wherein the anti-PD-1 antibody is humanized antibody.
14. method described in claim 13, wherein the light-chain variable sequence of the humanized antibody is such as SEQ ID NO: Sequence shown in 10 or its variant；The variant preferably has the amino acid of 0-10 to change in light chain variable region；More preferably The amino acid of A43S changes.Weight chain variabl area sequence is the sequence as shown in SEQ ID NO:9 or its variant；The variant is preferred There is the amino acid of 0-10 to change in heavy chain variable region；The amino acid of more preferably G44R changes.
15. method of claim 14, wherein humanized antibody light chain's sequence is the sequence as shown in SEQ ID NO:8 Column or its variant；The variant preferably has the amino acid of 0-10 to change in light chain variable region；The more preferably amino acid of A43S Variation.Sequence of heavy chain is the sequence as shown in SEQ ID NO:7 or its variant；The variant preferably has 0-10 in heavy chain variable region Amino acid variation；The amino acid of more preferably G44R changes.
16. method of claim 15, wherein humanized antibody light chain's sequence is as shown in SEQ ID NO:8 Sequence, sequence of heavy chain are the sequence as shown in SEQ ID NO:7.
17. the described in any item methods of claim 1-16, it is characterised in that be also administered in combination with IDO inhibitor.
18. method described in claim 17, wherein IDO inhibitor be formula (I) compound represented or its pharmaceutical salt, it is molten Immunomodulator compounds or its stereoisomer,
19. method of claim 18, wherein the administration frequency of the IDO inhibitor be twice a day, once a day, two It is once, once three days, once four days, once five days, once six days, weekly.
20. method of claim 18, wherein it is 50-2000mg that the dosage of the IDO inhibitor, which is selected from, preferably 50mg, 75mg、100mg、150mg、200mg、300mg、400mg、500mg、600mg、700mg、750mg、800mg、900mg、 The more preferable 100mg, 200mg of 1000mg, 1200mg, 1500mg, 2000mg, 300mg, 400mg, 600mg, 800mg, 1000mg, 1200mg、1500mg。
21. any one of claim 1-20 the method, wherein the tumour is selected from gastric cancer, intestinal cancer, colon cancer, breast cancer, palace Neck cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, Fallopian tube cneoplasms, ovarioncus, peritoneal tumor, melanoma, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney Property tumor, head and neck neoplasm, leukaemia, lymthoma, myeloma or non-small cell lung cancer；It is preferred that breast cancer, gastric cancer, intestinal cancer, colon Cancer, kidney, melanoma or non-small cell lung cancer.
22. the described in any item methods of claim 1-20, administration mode is oral, vein or subcutaneous administration.
23. a kind of medicine package box, it includes have the right to require a effective amount of anti-PD-1 antibody described in 1-20 any one or Its antigen-binding fragment, VEGFR inhibitor and IDO inhibitor.
24. a kind of pharmaceutical composition, it includes have the right to require a effective amount of anti-PD-1 antibody described in 1-20 any one or Its antigen-binding fragment, VEGFR inhibitor and IDO inhibitor and one or more pharmaceutical excipients, diluent or load Body.
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