CN109893654B - Methods of treating tumors with VEGFR inhibitors - Google Patents
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Abstract
The present invention relates to methods of treating tumors with VEGFR inhibitors. Specifically, the invention relates to an application of a VEGFR inhibitor in preparing a medicine for treating tumors, wherein the VEGFR inhibitor is selected from VEGFR-2 inhibitors such as tafenib, cantinib and apatinib.
Description
Technical Field
The present invention relates to methods of treating tumors with VEGFR inhibitors.
Background
In recent years, significant advances have been made in cancer treatment, with regulatory approval continuing from molecularly targeted therapies that inhibit tumor angiogenesis and intrinsic drivers of cancer cell growth, as well as immunomodulatory therapies that enhance patient immunity against tumors.
The enzyme-induced tyrosine kinase Vascular Endothelial Growth Factor (VEGF) and the receptor thereof (VEGFR) play an extremely important role in the angiogenesis of tumor angiogenesis and are important targets for blocking the angiogenesis of tumor angiogenesis. The small molecule tyrosine kinase inhibitor Apatinib (Apatinib) disclosed in WO2005000232A has the advantages of high selectivity competition for ATP binding sites of VEGFR-2 in cells, blocking down-stream signal transduction, and inhibiting generation of tumor neovascularization, and finally achieves the purpose of treating tumors, wherein the structural formula of the Apatinib is shown as the formula (I).
CN101676267A discloses a series of salts of apatinib, such as mesylate, hydrochloride, maleate, etc. Apatinib currently marketed is apatinib mesylate, which is administered orally once daily at a dose of 850 mg.
The monoclonal antibody of programmed death molecule-1 (PD-1) can block the combination between PD-L1 and PD-1, and can maximally raise the immune system reaction of patient to tumor so as to attain the goal of killing tumor cell. Monoclonal antibodies against the PD-1/PD-L1 signaling pathway are currently developed by several pharmaceutical companies, among which Nivolumab and Pembrolizumab are marketed as drugs administered at a frequency of once every two or once every three weeks. The anti-PD-1 antibody provided by the invention, WO2017054646A discloses the sequence and the preparation method of the antibody, the anti-PD-1 antibody is in Clinical stage III, the safety is good, and the reported Clinical research results show that the anti-PD-1 antibody has a certain anti-tumor effect (Journal of Clinical Oncology [ J ] 35(2017): e15572-e 15572).
Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a monomeric protein containing iron heme, and an IDO inhibitor has good application prospect in the pharmaceutical industry as a medicament, and a high-efficiency low-toxicity selective IDO inhibitor compound with a novel structure is provided in the patent application PCT/CN2016/079054 (application No. 2016.04.12, publication No. WO2016169421A1), has excellent effects and effects, particularly excellent drug absorption activity, the chemical name of the compound is (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidine-1-yl) phenyl) -1H-pyrazole-1-yl) ethanol, and the structure of the compound is shown in the following formula (I).
Clinical studies on the combination of anti-PD-1 antibodies with VEGFR inhibitors for the treatment of cancer are currently under development, for example CN106963948A discloses the use of anti-PD-1 antibodies in combination with apatinib for the treatment of colon cancer; CN105960415A discloses the use of an anti-PD-1 antibody in combination with axitinib for the treatment of renal cell carcinoma; WO2016141218A discloses the use of an anti-PD-1 antibody in combination with lenvatinib for the treatment of thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma, glioblastoma, melanoma and the like. There is a need to further optimize the combination treatment regimen in order to further improve clinical benefit and safety.
Disclosure of Invention
The present invention provides a method of administering to a patient an effective amount of a VEGFR inhibitor for treating a tumor at a frequency of less than once a day.
In one embodiment of the present invention, wherein the VEGFR inhibitor is administered once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every three days and once every three days, once every four days and once every four days, once every five days and once every five days, or twice a week without dosing for one week.
In one embodiment of the invention, wherein the VEGFR inhibitor is administered in a dose selected from the group consisting of 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, 800 mg.
In one embodiment of the present invention, wherein said VEGFR inhibitor is a VEGFR-2 inhibitor.
In one embodiment of the present invention, wherein said VEGFR-2 inhibitor is selected from the group consisting of: PAN-90806, Foretinib, Tafinitib (Tafetinib), cantinib (Kanitinib), Apatinib (Apatinib), Tanibirumab, Anlotinib (Anlotinib), Delitinib (Lucitinib), Vatalanib, Cediranib (Cediranib), Sevoranib (Chiaurantib), Dovirinib (Dovitinib), Donafenib (Donafenib), Famitiniib (Famitiniib), Sitravatinib, Teratinib (Telatinib), L-21649, TAS-115, Cabovatinib (Cabozantinib), Thiofinib (Thiophib), Fuquninib (Fruquintinib), britinib (Brivanib), Sovatinib (Sulfatinib), Ramucirumab, Glesatinib, Nintedanib (Nintedanib), Proquintinib (Puquitinib), Axitinib (Axitinib), EDP317, Sorafenib (Sorafenib), Metatinib (Metatinib), Tivozanib, Regorafenib (Regorafenib), Midostaurin, Pazopanib (Pazopanib), HLX-06, Altiratinib, Ningetinib (Nigeritinib), Sunitinib (Sunitinib), AL-8326, Rebastinib or pharmaceutically acceptable salts thereof.
In one embodiment of the present invention, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate.
In one embodiment of the present invention, the VEGFR inhibitor described above may also be administered in combination with an immunotherapeutic agent.
In one embodiment of the invention, the above immunotherapeutic agent is selected from the group consisting of therapeutic agents directed against the following targets: 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 (phosphatidylserine), OX-40, SLAM, ht, VISTA, VTCN1, or any combination thereof.
In a preferred embodiment of the present invention, the VEGFR inhibitor described above is administered in combination with an anti-PD-1 antibody or antigen-binding fragment thereof.
In one embodiment of the present invention, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks.
In one embodiment of the invention, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 1-10mg/kg, preferably 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, and most preferably 3 mg/kg.
In one embodiment of the invention, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 50-600mg, preferably from 60mg, 100mg, 125mg, 150mg, 175mg, 200mg, 400mg, 600mg, and most preferably 200 mg.
In one embodiment of the invention, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 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 present invention, the heavy chain variable region of the anti-PD-1 antibody, wherein the light chain variable region of the anti-PD-1 antibody or the antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.
Wherein, the CDR sequences are shown in the following table:
| name (R) | Sequence of | Numbering |
| 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 present invention, wherein said anti-PD-1 antibody is a humanized antibody.
In one embodiment of the present invention, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO. 10 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region; more preferably the amino acid change of A43S. The heavy chain variable region sequence is shown as SEQ ID NO. 9 or the variant thereof; the variant preferably has 0-10 amino acid changes in the heavy chain variable region; more preferably the amino acid change of G44R.
The variable region sequences of the heavy chain and the light chain of the humanized antibody are shown as follows:
heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO：9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10
In one embodiment of the invention, wherein the humanized antibody light chain sequence is that shown as SEQ ID NO. 8 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region; more preferably the amino acid change of A43S. The heavy chain sequence is shown as SEQ ID NO. 7 or the variant thereof; the variant preferably has 0-10 amino acid changes in the heavy chain variable region; more preferably the amino acid change of G44R.
In one embodiment of the present invention, the humanized antibody light chain sequence is shown as SEQ ID NO. 8, and the heavy chain sequence is shown as SEQ ID NO. 7.
The sequences of the heavy and light chains of the humanized antibodies are shown below:
heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO：7
Light chain
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
In one embodiment of the present invention, the VEGFR inhibitor, the anti-PD-1 antibody described above may also be administered in combination with an IDO inhibitor, and when administered in combination, the VEGFR inhibitor may be administered at an unlimited frequency, and may be administered once a day, once two days, once three days, once four days, once five days, once six days, once a week, once a day for three days for a week, once a day for four days for a week, once a day for five days for a week, or for two weeks, for one week off.
In one embodiment of the present invention, wherein the IDO inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
in one embodiment of the present invention, wherein the frequency of administration of said IDO inhibitor is twice a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week.
In one embodiment of the invention, wherein the dose of the IDO inhibitor is selected from the group consisting of 50-2000mg, preferably 50mg, 75mg, 100mg, 150mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg, 1200mg, 1500mg, 2000mg more preferably 100mg, 200mg, 400mg, 800mg, 1000mg, 1200mg, 1500 mg.
In one embodiment of the present invention, VEGFR inhibitors are administered to treat tumors to decrease the number of Regulatory T cells (Tregs) and increase CD8+Ratio of T cells to tregs.
In one treatment regimen of the invention, the administration of an anti-PD-1 antibody to treat a tumor can decrease the number of regulatory T cells and increase CD8+Ratio of T cells to tregs.
In one treatment scheme of the invention, the anti-PD-1 antibody or the antigen fragment thereof is combined with a VEGFR inhibitor to treat tumors, so that the number of regulatory T cells can be reduced, and the CD8 can be increased+Ratio of T cells to tregs.
The tumor of the invention can be selected from gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma or non-small cell lung cancer; preferably breast cancer, gastric cancer, intestinal cancer, colon cancer, renal cancer, melanoma or non-small cell lung cancer.
The present invention also provides a method of reducing Treg comprising administering to a patient in need thereof an effective amount of apatinib.
The invention also provides a method of reducing tregs comprising administering to a patient in need thereof an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof.
The invention also provides a method of reducing Treg comprising administering to a patient in need thereof an effective amount of apatinib and an anti-PD-1 antibody or antigen-binding fragment thereof.
In one embodiment of the present invention, the heavy chain variable region of the anti-PD-1 antibody, wherein the light chain variable region of the anti-PD-1 antibody or the antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.
Wherein, the CDR sequences are shown in the following table:
| name (R) | Sequence of | Numbering |
| 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 present invention, wherein said anti-PD-1 antibody is a humanized antibody.
In one embodiment of the present invention, the sequences of the variable regions of the heavy and light chains of the humanized antibody are as follows:
heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO：9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10
In one embodiment of the present invention, wherein the sequences of the heavy and light chains of the humanized antibody are as follows:
full length sequence of heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO：7
Full length light chain sequence
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
The invention also provides a pharmaceutical packaging box, which comprises the effective dose of the anti-PD-1 antibody or the antigen binding fragment thereof, the VEGFR inhibitor and the IDO inhibitor.
The present invention also provides a pharmaceutical composition comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof, a VEGFR inhibitor, and an IDO inhibitor as described above, in combination with one or more pharmaceutically acceptable excipients, diluents, or carriers.
The invention also provides an application of the combination of the VEGFR inhibitor, the anti-PD-1 antibody and the IDO inhibitor in preparing a medicament for treating tumors.
The invention also provides a method for treating tumors by combining the VEGFR inhibitor, the anti-PD-1 antibody and the IDO inhibitor.
In one embodiment of the present invention, wherein the VEGFR inhibitor is selected from the group consisting of: PAN-90806, Foretinib, Tafinitib (Tafetinib), cantinib (Kanitinib), Apatinib (Apatinib), Tanibirumab, Anlotinib (Anlotinib), Delitinib (Lucitinib), Vatalanib, Cediranib (Cediranib), Sevoranib (Chiaurantib), Dovirinib (Dovitinib), Donafenib (Donafenib), Famitiniib (Famitiniib), Sitravatinib, Teratinib (Telatinib), L-21649, TAS-115, Cabovatinib (Cabozantinib), Thiofinib (Thiophib), Fuquninib (Fruquintinib), britinib (Brivanib), Sovatinib (Sulfatinib), Ramucirumab, Glesatinib, Nintedanib (Nintedanib), Proquintinib (Puquitinib), Axitinib (Axitinib), EDP317, Sorafenib (Sorafenib), Metatinib (Metatinib), Tivozanib, Regorafenib (Regorafenib), Midostaurin, Pazopanib (Pazopanib), HLX-06, Altiratinib, Ningetinib (Nigeritinib), Sunitinib (Sunitinib), AL-8326, Rebastinib or pharmaceutically acceptable salts thereof.
In one embodiment of the invention, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 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 present invention, the heavy chain variable region of the anti-PD-1 antibody, wherein the light chain variable region of the anti-PD-1 antibody or the antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.
Wherein, the CDR sequences are shown in the following table:
| name (R) | Sequence of | Numbering |
| 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 present invention, wherein said anti-PD-1 antibody is a humanized antibody.
In one embodiment of the present invention, wherein the variable region sequences of the heavy and light chains of the humanized antibody are as follows:
heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSS
SEQID NO：9
Light chain variable region
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10
In one embodiment of the present invention, wherein the sequences of the heavy and light chains of the humanized antibody are as follows:
full length sequence of heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISG GGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK
SEQID NO：7
Full length light chain sequence
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLA DGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
In one embodiment of the present invention, wherein the IDO inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
the tumor can be selected from lung cancer, gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumor, leukemia, lymphoma and myeloma; preferably breast cancer, lung cancer, gastric cancer, intestinal cancer, colon cancer, renal cancer, and melanoma.
The invention also provides an application of the combination of apatinib and an immunotherapeutic agent in preparing a medicament for treating tumors.
The immunotherapeutic agent of the invention may be selected from therapeutic agents directed against the following targets: 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, cr2, HVEM, IDO1, IDO2, ICOS, KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagen structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, VTCN1, or any combination thereof. The therapeutic agent is preferably an antibody directed against the following targets: 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, cr2, HVEM, IDO1, IDO2, ICOS, KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collagen structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, VTCN1, or any combination thereof. Wherein the PD-1 antibody is not an antibody in which the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, and the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.
The tumor can be selected from lung cancer, gastric cancer, intestinal cancer, colon cancer, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumor, leukemia, lymphoma and myeloma; preferably breast cancer, lung cancer, gastric cancer, intestinal cancer, colon cancer, renal cancer, and melanoma.
In the present invention, when the VEGFR inhibitor and the anti-PD-1 antibody or an antigen-binding fragment thereof are used in combination for the treatment of tumors, the order of administration of the two is not limited at all, and the anti-PD-1 antibody may be administered first and then the VEGFR inhibitor or the VEGFR inhibitor may be administered first and then the anti-PD-1 antibody may be administered.
In the present invention, when the VEGFR inhibitor, the anti-PD-1 antibody or an antigen-binding fragment thereof, and the IDO inhibitor are used in combination for the treatment of tumors, the order of administration of the three is not limited at all.
The routes of administration of the combination of the present invention may be selected from oral, parenteral, including but not limited to intravenous, subcutaneous, intramuscular, and transdermal administration, respectively.
Detailed Description
Term of
In order that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless clearly defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "humanized antibody", also known as CDR-grafted antibody (CDR), refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. Can overcome the strong antibody variable antibody reaction induced by the chimeric antibody because of carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of genes such as the human heavy and light chain variable regions can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/VBase), as well as in Kabat, E.A. et al, 1991Sequences of Proteins of Immunological Interest, 5 th edition. In a preferred embodiment of the invention, the CDR sequences of the mouse humanized antibody of PD-1 are selected from SEQ ID NO 1, 2,3, 4, 5, 6.
The term "antigen-binding fragment" refers to Fab fragments, Fab 'fragments, F (ab') 2 fragments, and Fv fragments sFv fragments that bind to human PD-1, having antigen-binding activity; comprising one or more CDR regions of an antibody of the invention selected from SEQ ID NO 1 to SEQ ID NO 6. The Fv fragment contains the variable regions of the antibody heavy and light chains, but lacks the constant region, and has the smallest antibody fragment with the entire antigen-binding site. Generally, Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding. Two antibody variable regions can also be joined together with different linkers into a single polypeptide chain, known as single chain antibodies (scFv) or single chain fv (sFv). The term "binds to PD-1" in the context of the present invention means capable of interacting with human PD-1. The term "antigen binding site" of the present invention refers to a three-dimensional spatial site that is not antigenically contiguous and is recognized by an antibody or antigen binding fragment of the present invention.
Drawings
FIG. 1 Effect of Apatinib and PD-1, administered alone or in combination, on tumor volume in mice.
FIG. 2. Effect of Apatinib and PD-1, alone or in combination, on mouse body weight.
FIG. 3 Effect of Apatinib, PD-1 and I DO inhibitors alone or in combination on tumor volume in mice
FIG. 4 Effect of Apatinib, PD-1 and I DO inhibitors alone or in combination on mouse body weight
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Example 1
1. Purpose of the experiment: in the experiment, a mouse MC38 knot intestinal cancer cell is subcutaneously inoculated on a human PD-1 transgenic mouse to establish a tumor model, and the anti-tumor effect and safety of the combined medicament are evaluated according to the size of the tumor and the weight of the mouse. Combination therapy is given intraperitoneally at a dose of anti-PD-1 antibody, while oral administration of varying doses of apatinib compound.
2. Experimental materials and methods:
2.1 Experimental animals and materials:
human PD-1 transgenic mice: 70 mice were bred by the animal center of Cephrim, and the original 3-human PD-1 transgenic mice were purchased from Isis, Inc., UK, on SPF scale.
Solvent: 0.5% sodium carboxymethylcellulose + 0.25% (v/v) polysorbate 80
Human IgG: from serum (Sigma-Aldrich), product number: i4506-50MG
anti-PD-1 antibody: the sequences of heavy chains and light chains are shown as SEQ ID NO:7 and SEQ ID NO: lyophilized powder, dissolved in water, was then diluted with 5% glucose to a final concentration of 3mg/Ml, lot number P1512.
Apatinib mesylate: is provided by Jiangsu Henry medicine and is diluted by 0.5 percent of sodium carboxymethylcellulose and 0.25 percent (v/v) of polysorbate 80, the final concentration is 20mg/mL, and the batch number is 668170301
MC38 cells: DMEM medium, 10% fetal bovine serum, 37 ℃, 5% CO2And (5) culturing. The cells selected for implantation meet the following four criteria: 1) fast growth; 2) the number of passages is small; 3) medium was changed the day before inoculation and 4) high viability.
2.2 Experimental methods:
MC38 cells were harvested on the day of seeding (5X 10)5) Inoculating into the right flank of 70 human PD-1 transgenic mice (both male and female), and allowing the average tumor volume of the mice to reach 100mm3On the left and right sides, 56 were selected and randomly divided into 8 groups of 7. After grouping, a single dose of the anti-PD-1 antibody is given for intraperitoneal injection according to a scheme, and then the apatinib is orally taken for combined administration. Tumor volume was measured twice weekly, body weight was weighed and data was recorded.
2.3 Experimental groups and dosing regimens
Table 1: experimental groups and dosing regimens
Note: q2Dx 8: once every two days, 8 times of administration; QDx 21: once a day, 21 times of administration; QWx 3: once a week for 3 weeks; QDx3for 3W: three days per week for 3 weeks; ip: intraperitoneal injection of po: is administered orally
3. Data expression and statistical processing
Body weight, tumor volume and tumor weight of each group of animals, data were expressed as Mean ± standard deviation (Mean ± SEM), and data were statistically analyzed by T-test. The body weights of the animals in each group are shown in FIG. 2, the tumor volume results are shown in Table 2 and FIG. 1, and the tumor weights are shown in Table 3. Tumor volume calculation formula: volume is 0.5236 Xlong Xshort Xhigh
4. Results of the experiment
TABLE 2 tumor volume (mm)3)
P <0.05 and below indicates statistical significance.
TABLE 3 tumor weight (g)
| Group 1 | |
Group 3 | |
Group 5 | |
Group 7 | |
|
| Mean value of | 1.290 | 1.194 | 0.827 | 0.560 | 0.839 | 0.575 | 0.328 | 0.153 |
| Standard deviation of | 0.173 | 0.073 | 0.177 | 0.098 | 0.184 | 0.113 | 0.133 | 0.075 |
Example 2
1. Purpose of the experiment: in the experiment, a mouse MC38 knot intestinal cancer cell is subcutaneously inoculated on a human PD-1 transgenic mouse to establish a tumor model, and the anti-tumor effect and safety of the combined medicament are evaluated according to the size of the tumor and the weight of the mouse. Combination therapy is the intraperitoneal administration of a dose of anti-PD-1 antibody, with the oral administration of a dose of IDO inhibitor and a different dose of apatinib compound.
2. Experimental materials and methods:
2.1 Experimental animals and materials:
human PD-1 transgenic mice: 55 mice were bred by the animal center of Cephrim, and primary 3-human PD-1 transgenic mice were purchased from Isis, Inc., UK, on SPF scale.
Solvent: 0.5% sodium carboxymethylcellulose
Human IgG: from serum (Sigma-Aldrich), product number: i4506-50MG
anti-PD-1 antibody: the sequences of heavy chains and light chains are shown as SEQ ID NO:7 and SEQ ID NO: lyophilized powder, dissolved in water, was then diluted with 5% glucose to a final concentration of 3mg/Ml, lot number P1512.
Apatinib mesylate: is provided by Jiangsu Henry medicine and is diluted by 0.5 percent of sodium carboxymethylcellulose and 0.25 percent (v/v) of polysorbate 80, the final concentration is 20mg/mL, and the batch number is 668170301
IDO inhibitors: provided by Jiangsu Henry medicine, (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol, prepared by the method of examples 40, 41 in reference patent application PCT/CN2016/079054 (application date 2016.04.12, publication number WO2016169421A1), the compound having the following structure:
MC38 cells: DMEM medium, 10% fetal bovine serum, 37 ℃, 5% CO2And (5) culturing. The cells selected for implantation meet the following four criteria: 1) fast growth; 2) the number of passages is small; 3) medium was changed the day before inoculation and 4) high viability.
2.2 Experimental methods:
MC38 cells were harvested on the day of seeding (5X 10)5) Inoculating into the right flank of 55 human PD-1 transgenic mice (both male and female), and allowing the average tumor volume of the mice to reach 100mm3On the left and right sides, 42 were selected and randomly divided into 7 groups of 6. After grouping, a single dose of the anti-PD-1 antibody is given for intraperitoneal injection according to a scheme, and an IDO inhibitor and apatinib are taken orally for combined administration. Tumor volume was measured twice weekly, body weight was weighed and data was recorded.
2.3 Experimental groups and dosing regimens
Table 4: experimental groups and dosing regimens
Note: q2Dx 8: once every two days, 8 times of administration; QDx 21: once a day, 21 times of administration; QDx3/week for 3W: three days per week for 3 weeks; BIDx 21: twice daily for 21 days; ip: intraperitoneal injection of po: is administered orally
3. Data expression and statistical processing
Body weight, tumor volume and tumor weight of each group of animals, data were expressed as Mean ± standard deviation (Mean ± SEM), and data were statistically analyzed by T-test. The body weights of the animals in each group are shown in fig. 4, and the results of tumor volumes are shown in table 5 and fig. 3. Tumor volume calculation formula: volume is 0.5236 Xlong Xshort Xhigh
4. Results of the experiment
TABLE 5 tumor volume (mm)3)
The combination scheme of the apatinib intermittent administration (QDx 53W) and the IDO inhibitor and the PD-1 antibody has obvious tumor growth inhibition effect, the tumor inhibition effect is higher than that of the combination scheme of the apatinib intermittent administration (Q2Dx10), the IDO inhibitor and the PD-1 antibody, and the tumor inhibition effect is equivalent to that of the combination scheme of the apatinib continuous administration (QDx21) and the PD-1 antibody. The two apatinib intermittent administration and PD-1 antibody combination have the effect of inhibiting tumor growth, and the tumor inhibition effect is higher than that of the IDO inhibitor and PD-1 antibody combination scheme.
Example 3: flow cytometry analysis of tumor infiltrating lymphocytes
1. Purpose of the experiment: in the experiment, a mouse MC38 knot intestinal cancer cell is subcutaneously inoculated to a human PD-1 transgenic mouse to establish a tumor model, and the expression conditions of Regulatory T cells (Tregs for short) and CD cells in the tumor and spleen of the mouse are analyzed by flow cytometry.
2. Experimental materials and methods:
2.1 Experimental animals and materials:
human PD-1 transgenic mice: 70 mice were bred by the animal center of Cephrim, and the original 3-human PD-1 transgenic mice were purchased from Isis, Inc., UK, on SPF scale.
Solvent: 0.5% sodium carboxymethylcellulose + 0.25% (v/v) polysorbate 80
Human IgG: from serum (Sigma-Aldrich), product number: i4506-50MG
anti-PD-1 antibody: the sequences of heavy chains and light chains are shown as SEQ ID NO:7 and SEQ ID NO: lyophilized powder, dissolved in water, was then diluted with 5% glucose to a final concentration of 3mg/Ml, lot number P1512.
Apatinib mesylate: is provided by Jiangsu Henry medicine and is diluted by 0.5 percent of sodium carboxymethylcellulose and 0.25 percent (v/v) of polysorbate 80, the final concentration is 20mg/mL, and the batch number is 668170301
2.2 Experimental methods:
2.2.1 Experimental groups and dosing regimens
Same as example 1, see table 1.
2.2.2 harvesting of tissues/organs and preparation of Single cell suspensions
On day 28 (one day after the last dose), 5 mice per group were CO administered2And (6) killing. Tumors and spleens were immediately collected, weighed and recorded, and then placed in RPMI-1640 medium on ice. The Tumor and Spleen were then sectioned, transferred to a C Isolation tube previously loaded with 2.5mL of pre-mix enzyme (Mittenyl Tumor/Spleen Isolation Kit), and processed on a fully automated tissue processor (model Miltenyi genetic MACS Dissociator) as described in the instructions to obtain a single Tumor or Spleen cell suspension.
2.2.3 flow cytometry analysis of tumor infiltrating lymphocytes
200 million individual tumors or splenocytes were first incubated with FcR blockers (BD Biosciences) followed by CD45+，CD3+，CD4+And CD8+(biolegens Biosciences) was mixed with a pre-mixed CD surface antigen buffer. Washing machineAfter washing, the cell individual suspensions were fixed overnight on ice at 4 ℃ in Foxp3 buffer. The following day, cells were washed with permeabilization buffer and stained for Foxp3 intracellularly using anti-Foxp 3-APC monoclonal antibody (biolegens Biosciences). After washing again, the suspension was analyzed by facscan II (BD Biosciences). The results were analyzed with BD FACSDiva software (BD Biosciences). In CD45+Analysis of CD8 in hematopoietic cell populations+And CD4+CD4 in a population+Foxp3+Total number of cells, and 2X 106Indicating living cells in the tumor.
3. Data expression and statistical processing
Statistics between control and treatment groups or between treatment groups were analyzed using one-way analysis of variance (ANOVA), followed by Bonferroni's correction. Analysis was performed using GraphPad Prism, with p <0.05 and below indicating statistical significance.
4. Results of the experiment
4.1: expression of tregs in tumor and spleen CD4+ cells is shown in table 5
Table 5.
Note: ip: intraperitoneal injection of po: is administered orally
4.2: expression of CD cells in tumors is shown in Table 6
Table 6.
Note: ip: intraperitoneal injection of po: is administered orally
4.3: expression of CD cells in spleen is shown in Table 7
Table 7.
Note: ip: intraperitoneal injection of po: is administered orally
anti-PD-1 antibody alone versus CD4 at a dose of 3mg/kg compared to control+And CD8+T cell number had no significant effect, but anti-PD-1 antibody significantly reduced the Treg number and increased CD8+Ratio of T cells to tregs. The anti-PD-1 antibody alone at a dose of 3mg/kg reduced Tregs in the tumor and had no effect on Tregs in the spleen.
Papanicnib single dose versus CD4 at a dose of 100mg/kg compared to control+And CD8+T cell number had no significant effect, but apatinib significantly reduced Treg number and increased CD8+Ratio of T cells to tregs.
Intermittent dosing of apatinib (once weekly, three weeks; three times weekly, three weeks) in combination with anti-PD-1 antibody to CD4+And CD8+Number of T cells, CD8+There was no significant effect on the ratio of T cells to tregs, but continuous apatinib administration in combination with anti-PD-1 antibody increased CD8+Ratio of T cells to tregs.
Example 4: clinical research on drug administration frequency of apatinib for treating gastric cancer
1. Compound (I)
Commercially available apatinib mesylate tablets.
2. Group entry criteria
(1) Pathologically or histologically confirmed secondary treatment failed advanced gastric cancer patients or gastroesophageal junction adenocarcinoma; (2) has measurable lesions; (3) ECOG score 0-2.
Note: (1) definition of treatment failure: recurrence and metastasis of tumor after disease progression or treatment is finished in the treatment process, or intolerable toxicity appears; (2) treatment of each line of progressive disease includes administration of one or more chemotherapeutic agents for a period of time greater than or equal to 1 cycle or longer; allowing prior adjuvant/neoadjuvant therapy, considering the prior adjuvant/neoadjuvant therapy as a first-line systemic chemotherapy for advanced disease if recurrent metastasis of the tumor occurs during or within 24 weeks after completion of the adjuvant/neoadjuvant therapy (3) allowing the prior therapy to be a chemotherapeutic combination molecular targeted drug.
3. Dosing regimens
The test will use the block randomization method to randomly group the subjects into 3 test groups at a ratio of 1:1: 1.
Group A: apatinib single drug: 500mg, orally administered once a day for 5 days and 2 days, 21 days being an observation period. Not less than 20 subjects are admitted in total;
group B: apatinib single drug: 500mg, orally administered once a day for 2 weeks for 1 week, with 21 days as an observation period. Not less than 20 subjects are admitted in total;
group C: apatinib single drug: 500mg, orally administered once a day, continuously administered for 21 days as an observation period. Not less than 20 subjects are admitted in total;
4. analysis of efficacy
The main curative effect indexes are as follows: progression Free Survival (PFS), defined as the time to tumor progression/recurrence or death from any cause, in the study cohort. Subjects with no observed tumor progression/recurrence or death, progression free/recurrence free survival were censored on the last day of effective tumor assessment.
Secondary efficacy index:
1. overall Survival (OS): defined as the time from study enrollment to death by any cause. Subjects who were still alive at the last contact, all survived the last contact date for the deletion treatment.
2. Objective Remission Rate (ORR): complete Remission (CR) + Partial Remission (PR), refers to the objective efficacy of tumors assessed using RECIST version 1.1 criteria, and refers to the percentage of cases of CR and PR among patients with evaluable efficacy.
3. Disease Control Rate (DCR): complete Remission (CR) + Partial Remission (PR) + Stable Disease (SD), refers to the percentage of cases in CR, PR and SD (> 4 weeks) among patients with evaluable efficacy.
4. Quality of life score (QoL): (see EORTC QLQ-C30V 3.0 and HCC-18).
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Claims (18)
1. Use of a VEGFR inhibitor, an anti-PD-1 antibody or an antigen binding fragment thereof, an IDO inhibitor in combination for the manufacture of a medicament for the treatment of colon cancer, liver cancer, lymphoma or stomach cancer, characterized in that an effective amount of the VEGFR inhibitor is administered to a patient less frequently than once a day, the VEGFR inhibitor is apatinib, the IDO inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
the anti-PD-1 antibody or the antigen binding fragment thereof is a humanized antibody, the light chain sequence of the humanized antibody is the sequence shown as SEQ ID NO. 8, and the heavy chain sequence is the sequence shown as SEQ ID NO. 7.
2. The use of claim 1, wherein the VEGFR inhibitor is administered once a day, once three days, once four days, once five days, once six days, once a week, once a day three days a week, once a day four days a week, once a day five days a week, or once a week two weeks off for one week.
3. The use of claim 2, wherein the VEGFR inhibitor is administered at a dose selected from the group consisting of 100 and 800 mg.
4. The use of claim 2, wherein the VEGFR inhibitor is administered in a dose selected from the group consisting of 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600 mg.
5. The use of claim 1, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate.
6. The use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks.
7. The use according to claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 1-10 mg/kg.
8. The use of claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, and 10 mg/kg.
9. The use according to claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 3 mg/kg.
10. The use according to claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose selected from the group consisting of 50-600 mg.
11. The use of claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in an amount selected from the group consisting of 60mg, 100mg, 200mg, 400mg, and 600 mg.
12. The use of claim 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg.
13. The use of claim 1, wherein the frequency of administration of the IDO inhibitor is twice a day, once two days, once three days, once four days, once five days, once six days, once a week.
14. The use of claim 1, wherein the dose of the IDO inhibitor is selected from 50-2000 mg.
15. The use of claim 1, wherein the dose of the IDO inhibitor is selected from the group consisting of 50mg, 75mg, 100mg, 150mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg, 1200mg, 1500mg, 2000 mg.
16. The use of claim 1, wherein the dose of the IDO inhibitor is selected from the group consisting of 100mg, 200mg, 300mg, 400mg, 600mg, 800mg, 1000mg, 1200mg, 1500 mg.
17. The use according to any one of claims 1 to 16, which is administered orally, intravenously or subcutaneously.
18. A pharmaceutical composition comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof according to any one of claims 1-16, a VEGFR inhibitor and an IDO inhibitor, in combination with one or more pharmaceutically acceptable excipients, diluents, or carriers.
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|---|---|---|---|---|
| AU2019375808A1 (en) * | 2018-11-06 | 2021-06-17 | Jiangsu Hengrui Medicine Co., Ltd. | Use of anti-PD-1 antibody in combination with famitinib in preparation of drug for treating tumors |
| CN112168961A (en) * | 2019-07-03 | 2021-01-05 | 正大天晴药业集团南京顺欣制药有限公司 | Combined pharmaceutical composition for treating colorectal cancer |
| CN112294817B (en) * | 2019-08-02 | 2022-08-16 | 薪火炙药(北京)科技有限公司 | Use of dormitotinib for treating diseases related to high uric acid |
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| EP4017495A4 (en) * | 2019-08-23 | 2023-08-30 | Spectrum Pharmaceuticals, Inc. | Poziotinib combination with vegfr2 inhibitors and methods of use thereof |
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| CN113262223A (en) * | 2020-02-17 | 2021-08-17 | 上海交通大学医学院 | Application of nilotinib and pharmaceutically acceptable salt thereof in preparation of medicines for treating multiple myeloma |
| CN115052605B (en) * | 2020-03-09 | 2024-07-05 | 和记黄埔医药（上海）有限公司 | Pharmaceutical combinations of anti-PD-1 antibodies and multi-receptor tyrosine kinase inhibitors and methods of use thereof |
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| CA3181598A1 (en) * | 2020-04-30 | 2021-11-04 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Combination drug for treating kidney cancer |
| CN113925865A (en) * | 2020-06-29 | 2022-01-14 | 上海市胸科医院 | Synergistic combination of anrotinib combined with immune checkpoint inhibitor for treatment of advanced lung cancer |
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| EP4212160A4 (en) * | 2020-09-09 | 2024-10-09 | Shenzhen Chipscreen Biosciences Co Ltd | Use of chiauranib in combination with immune checkpoint inhibitor in antitumor therapy |
| CN115227812A (en) * | 2021-04-22 | 2022-10-25 | 上海君实生物医药科技股份有限公司 | Use of anti-PD-1 antibody in combination with first-line chemotherapy for treating advanced NSCLC |
| CN117377492A (en) * | 2021-05-26 | 2024-01-09 | 深圳微芯生物科技股份有限公司 | Pharmaceutical composition containing protein kinase inhibitor and medical application thereof |
| CN118103066A (en) * | 2021-09-26 | 2024-05-28 | 正大天晴药业集团股份有限公司 | Use of anti-CD 40 antibodies |
| CN114028586A (en) * | 2021-11-25 | 2022-02-11 | 南昌大学附属口腔医院(江西省口腔医院) | Method for researching antitumor effect of apatinib based on PDX model |
| WO2023193705A1 (en) * | 2022-04-07 | 2023-10-12 | 深圳微芯生物科技股份有限公司 | Use of chiauranib in resisting pancreatic cancer |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
| WO2017054646A1 (en) * | 2015-09-28 | 2017-04-06 | 江苏恒瑞医药股份有限公司 | Stable anti-pd-1 antibody pharmaceutical preparation and application thereof in medicine |
| CN106963948A (en) * | 2017-05-12 | 2017-07-21 | 顾艳宏 | A Pa is combined the application in colon cancer drug is prepared for Buddhist nun with the antibody of Anti PD 1 |
| CN106999574A (en) * | 2014-10-10 | 2017-08-01 | 伊黛拉制药有限公司 | Use TLR9 activators and treatment of the checkpoint inhibitor to cancer |
-
2018
- 2018-12-10 CN CN201811502626.7A patent/CN109893654B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999574A (en) * | 2014-10-10 | 2017-08-01 | 伊黛拉制药有限公司 | Use TLR9 activators and treatment of the checkpoint inhibitor to cancer |
| WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
| WO2017054646A1 (en) * | 2015-09-28 | 2017-04-06 | 江苏恒瑞医药股份有限公司 | Stable anti-pd-1 antibody pharmaceutical preparation and application thereof in medicine |
| CN106963948A (en) * | 2017-05-12 | 2017-07-21 | 顾艳宏 | A Pa is combined the application in colon cancer drug is prepared for Buddhist nun with the antibody of Anti PD 1 |
Non-Patent Citations (3)
| Title |
|---|
| A phase 1 study of intermittently administered pazopanib in combination with continuous daily dosing of lapatinib in patients with solid tumors;H. Henary等;《Cancer Chemotherapy and Pharmacology》;20150706;第76卷;第597–603页摘要、介绍、研究设计、剂量递增和剂量限制毒性、表2、4部分 * |
| H. Henary等.A phase 1 study of intermittently administered pazopanib in combination with continuous daily dosing of lapatinib in patients with solid tumors.《Cancer Chemotherapy and Pharmacology》.2015,第76卷第597–603页摘要、介绍、研究设计、剂量递增和剂量限制毒性、表2、4部分. * |
| INCYTE CORPORATION.Progression-Free Survival Data from ECHO-202 Trial of Incyte’s Epacadostat in Combination with Merck’s KEYTRUDA® (pembrolizumab) Underscore Durability of Response in Patients with Advanced Melanoma.《businesswire https://www.businesswire.com/news/home/20170909005016/en/》.2017,第2页1-3段、第5页第2段-第7页第3段. * |
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