CN116196415B - Mixed formulations for sensitizing PD-1 antibodies and methods of use thereof - Google Patents
Mixed formulations for sensitizing PD-1 antibodies and methods of use thereof Download PDFInfo
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Abstract
The invention discloses a mixed preparation for sensitization of PD-1 antibodies and a use method thereof, and relates to the technical field of medicines. The pharmaceutical composition comprises a PD-1 antibody, a PRMT5 inhibitor, and a PARP inhibitor, and one or more pharmaceutically acceptable excipients, diluents, or carriers. The two-drug combination treatment scheme of the PD-1 antibody combined with the PRMT5 or the three-drug combination treatment scheme of the PD-1 antibody combined with the PRMT5 and the RAPR inhibitor provided by the invention enables some patients which are ineffective to the PD-1 antibody to benefit from the combination treatment, and can effectively enhance the effect of the PD-1 antibody.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a mixed preparation for sensitization of PD-1 antibodies and a use method thereof.
Background
Immunotherapy has achieved some progress in the treatment of a variety of solid tumors. A significant portion of tumor patients remain insensitive to immunotherapy. Research shows that the infiltration degree of immune cells in tumor tissues can reflect the effect of immunotherapy to a certain extent. Tumors in which immune cells infiltrate more in the tumor microenvironment are called "hot tumors", whereas they are called "cold tumors". Patients with cold tumors have no significant increase in immune cell infiltration inside the tumor after treatment with PD-1 antibodies, which is a significant cause of immunotherapy failure. Therefore, how to convert a "cold tumor" into a "hot tumor" is a problem that needs to be solved in the art. The invention aims to provide a combined treatment scheme for treating insensitive tumors by using PD-1 antibodies, in particular to a two-drug combined treatment scheme for treating various solid tumors with unstable chromatin by using PD-1 antibodies combined with PRMT5 or a three-drug combined treatment scheme for treating PD-1 antibodies combined with PRMT5 and an RAPR inhibitor, so that some patients which are not effective for the PD-1 antibodies can benefit from the combined treatment scheme.
Disclosure of Invention
The invention aims to provide a mixed preparation for sensitization of PD-1 antibodies and a using method thereof, and provides a two-drug combination treatment scheme of PD-1 antibodies combined with PRMT5 or a three-drug combination treatment scheme of PD-1 antibodies combined with PRMT5 and an RAPR inhibitor, so that some patients who are ineffective to PD-1 antibodies can benefit from the combination treatment, and the effect of the PD-1 antibodies can be effectively enhanced.
The technical scheme adopted by the invention for achieving the purpose is as follows:
a pharmaceutical composition comprising a PD-1 antibody, a PRMT5 inhibitor and a PARP inhibitor, and one or more pharmaceutically acceptable excipients, diluents or carriers. The invention provides a two-drug combination scheme of combining a PD-1 antibody with PRMT5 or a three-drug combination scheme of combining a PD-1 antibody with PRMT5 and a RAPR inhibitor, and the biological activity analysis shows that LLY-283 and PD-1 combined drugs have stronger inhibition effect on murine cell line 4T1 subcutaneous tumor, and the effect is obviously superior to that of single drugs, and the effects are additive or synergistic. Meanwhile, after biological activity analysis, the combined drug of LLY-283, olaparib and PD-1 has stronger inhibition effect on the mouse cell line EMT6 subcutaneous tumor, and the effect is obviously superior to that of single drug, and has additive or synergistic enhancement effect; compared with the traditional treatment with the Olaparib single drug, the method can effectively reduce the action concentration of Olaparib, obviously inhibit tumor proliferation, and avoid or reduce the occurrence of recurrent and acquired drug resistant events caused by the treatment with only the single drug. The anti-tumor pharmaceutical composition provided by the invention has clear components and simple preparation process, can be independently used for treating tumors, and can be matched with radiotherapy and operation. The anti-tumor pharmaceutical composition provides a new thought for anti-tumor treatment or prevention, and has a huge application prospect.
Preferably, the PARP inhibitor is selected from one of Olaparib, veliparib, talazoparib, niraparib, rucaparib.
Preferably, the PRMT5 inhibitor is selected from one of GSK3326595, AMG-193, MRTX1719, TNG-908, PF-069399999, PRT543, PRT811, SH-3765, onametostat, SCR-6920, SKL27969, SYHX2001, AGX323, BRD0639, C220, DS-437, DW14800, GSK3203591, GSK3235025, JBI-778, LLY-283, MRTX9768, MS4322, MS4369, MS4370, PF-06855800.
Preferably, PD-1 antibodies include, but are not limited to, yu Terui p Li Shan antibodies (toripalimab), and a variety of different inhibitors targeting PD-1 are also within the scope of the invention.
Preferably, the dosage range of the PD-1 antibody is selected from 10-100 mg in vivo; further, it may be 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg.
Preferably, the dose range of the PRMT5 inhibitor is selected from 10-100 mg in vivo; further, it may be 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg.
Preferably, the dose range of the PAPR inhibitor is selected from 10-100 mg in vivo; further, it may be 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg.
Preferably, the combined route of administration is selected from the group consisting of oral administration, parenteral administration, transdermal administration, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection.
Preferably, the PRMT5 inhibitor may be administered once a day, twice a day, three times a day, once a week, once a two weeks, once a three weeks, or once a month; the frequency of administration of PARP inhibitors may be once daily, twice daily, three times daily, once a week, once a three week, or once a month.
It is a further object of the present invention to provide the use of a PD-1 antibody in combination with PRMT5 in the manufacture of a medicament for the prevention or treatment of solid tumors.
It is a further object of the present invention to provide the use of a PD-1 antibody in combination with a PRMT5 and RAPR inhibitor in the manufacture of a medicament for the prevention or treatment of solid tumors.
Preferably, a solid tumor refers to a chromatin-unstable solid tumor.
In particular, solid tumors include benign solid tumors and malignant solid tumors.
Further, benign solid tumors mainly comprise hamartoma, smooth myoma, hemangioma, lymphangioma, various adenomas, adenomatous polyps and the like; malignant solid tumors include Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, breast cancer, ovarian cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, also head and neck malignant tumor, urinary system malignant tumor, endometrial cancer, cervical cancer, osteosarcoma, chondrosarcoma, ewing's sarcoma, thyroid cancer, hepatoblastoma, nephroblastoma, etc.
The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more therapeutic agents.
The term "combination" as used herein refers to a mode of administration wherein at least one dose of a PRMT5 inhibitor and at least one dose of a PD-1 antibody, or at least one dose of a PARP inhibitor and at least one dose of a PD-1 antibody, or at least one dose of a PRMT5 inhibitor and at least one dose of a PARP inhibitor and at least one dose of a PD-1 antibody are administered over a period of time. The period of time may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. Such a period includes treatment in which the PRMT5 inhibitor, the PARP inhibitor and the PD-1 antibody are administered by the same route of administration or by different routes of administration.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a pharmaceutical composition for preventing or treating solid tumors, in particular to a pharmaceutical composition which combines two drugs of PD-1 antibody combined with PRMT5 or three drugs of PD-1 antibody combined with PRMT5 and RAPR inhibitor, and provides a new drug choice for tumor drug treatment. The PRMT5 inhibitor can effectively increase the curative effect of the PD-1 antibody after biological activity analysis. Meanwhile, the combination of the PRMT5 inhibitor and the PARP inhibitor can effectively increase the curative effect of the PD-1 antibody after biological activity analysis; compared with the traditional single-drug treatment, the method can effectively reduce the action concentration of the single drug, obviously inhibit the proliferation of tumors, and avoid or reduce the occurrence of recurrent and acquired drug-resistant events caused by the single-drug treatment; the combined therapy also provides a new thought for the treatment scheme of patients who are invalid to PD-1 antibodies, provides a new theoretical support for the design and development of medicines, and has great value in the aspects of research and treatment of tumors.
Therefore, the invention provides a mixed preparation for sensitization of PD-1 antibodies and a using method thereof, and provides a two-drug combination treatment scheme of PD-1 antibodies combined with PRMT5 or a three-drug combination treatment scheme of PD-1 antibodies combined with PRMT5 and RAPR inhibitors, so that some patients who are ineffective to PD-1 antibodies can benefit from the combination treatment, and the effect of the PD-1 antibodies can be effectively enhanced.
Drawings
FIG. 1 is the effect of PRMT5 inhibitors on the increase of PD-1 antibodies in a murine cell line 4T1 in a BALB/C mouse model with subcutaneous tumor;
FIG. 2 is the effect of PRMT5 inhibitor in combination with PARP inhibitor to increase PD-1 antibodies in a murine cell line EMT6 subcutaneously tumor-bearing BALB/C mouse model;
FIG. 3 is the effect of shikonin derivatives on increasing PD-1 antibodies in a murine cell line EMT6 in a BALB/C mouse model with subcutaneous tumor.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the following describes in detail various embodiments of the present invention with reference to the embodiments. However, those of ordinary skill in the art will understand that in various embodiments of the present invention, numerous technical details have been set forth in order to provide a better understanding of the present application. However, the technical solutions claimed in the present application can be implemented without these technical details and with various changes and modifications based on the following embodiments.
Example 1:
in vivo efficacy studies of PRMT5 inhibitor and PD-1 antibody in combination with each alone in BALB/C mouse model of murine cell line 4T1 subcutaneous tumor:
1. test agent
Drug name: PRMT5 inhibitor LLY-283, PD-1 antibodies.
2. Experimental animal
BALB/c mice, 6-8 weeks old, females, feeding environment: SPF stage.
Feeding environment: temperature: controlling the temperature to be 20-26 ℃; relative humidity: controlling the relative humidity to be 40% -70%; illumination: automatic illumination, and light and shade alternate every 12 h.
3. Experimental procedure
4T1 cell resuspension at 1:1 PBS and matrigel (2×10) 5 ) (RPMI 1640, 10% fetal bovine serum, 1% P/S (PB 180120), 37 ℃,5% CO 2 Culture), subcutaneous tumor-bearing was performed subcutaneously on right rib sections of 24 BALB/c nude mice. When the average tumor volume of the mice reaches 100-150 mm 3 At this time, the random number was divided into 4 groups of 6. After grouping, 0.5% sodium carboxymethylcellulose/saline (group 1), LLY-283 (group 2), PD-1 antibody (group 3), LLY-283+pd-1 antibody (group 4) were orally administered according to the protocol; the experimental groupings and dosing regimens are shown in table 1. Tumor volumes were measured 1 time every two days, weighed, and data recorded. The tumor volume (V) was calculated as:
V＝0.52×a×b 2 wherein a and b respectively represent length and width.
Table 1 experimental groupings and dosing regimens
Note that: QDx15: stopping for 4 days after 3 days, and administering 15 times; QDx10: starting administration after 5 days, and administering for 10 times every two days; po: oral administration; i.p.: intraperitoneal injection.
The test results are shown in FIG. 1. From the analysis in the figure, the PRMT5 inhibitor and the PD-1 antibody are combined, the tumor volume is obviously lower than that of each single administration, and the PRMT5 inhibitor can effectively increase the curative effect of the PD-1 antibody, and the combined use of the PRMT5 inhibitor and the PD-1 antibody has better in vivo pharmacodynamic effect in a BALB/C mouse model of murine cell line 4T1 subcutaneous tumor.
4. Compatibility calculation method
Calculating q value according to the gold equation, q=e A+B /(E A +E B -E A ×E B ) Is used for judging whether the effect of the two medicines after compatibility is better than that of single administration. If q<0.55, the two drugs act as significant antagonism; q is more than or equal to 0.55<0.85, the two drugs act as antagonism; q is more than or equal to 0.85<1.15, the two medicines are added singly; q is more than or equal to 1.15<20, the two medicines act as synergistic enhancement; q is more than or equal to 20, and the actions of the two medicines are obviously enhanced.
From the analysis of the data in fig. 1, it is clear that the tumor volume reduction rates of group 2, group 3 and group 4 are 45.45%, 34.06% and 74.33% respectively after 35d administration, and q= 74.33%/(45.45% +34.06% -45.45% ×34.06%) =1.16 according to the golden formula, and q <20 is 1.15.ltoreq.q <20, indicating that the tumor inhibition effect of the compatibility of LLY-283 and PD-1 antibodies is synergistically enhanced.
Example 2:
in vivo efficacy studies in three drug combinations of PRMT5 inhibitor in combination with PARP inhibitor and PD-1 antibody, each alone, on a murine cell line EMT6, a BALB/C mouse model of subcutaneous tumor-bearing:
1. test agent
Drug name: PRMT5 inhibitor LLY-283, PARP inhibitor Olaparib, PD-1 antibody.
2. Experimental animal
BALB/c mice, 6-8 weeks old, females, feeding environment: SPF stage.
Feeding environment: temperature: controlling the temperature to be 20-26 ℃; relative humidity: controlling the relative humidity to be 40% -70%; illumination: automatic illumination, and light and shade alternate every 12 h.
3. Experimental procedure
EMT6 cells were resuspended in PBS (4X 10) 5 ) (high sugar DMEM Medium, 10% fetal bovine serum, 1% P/S (PB 180120), 37 ℃ C., 5% CO) 2 Culture), subcutaneous tumor-bearing was performed subcutaneously on the right rib of 64 BALB/c nude mice. When the average tumor volume of the mice reaches 100-150 mm 3 At this time, the random groups were 8, 8 each. After grouping, 0.5% sodium carboxymethylcellulose in saline/saline (group 1), LLY-283 (group 2), PD-1 antibody (group 3), olaparib (group 4), LLY-283+pd-1 antibody (group 5), olaparib+pd-1 antibody (group 6), LLY-283+olaparib (group 7), LLY-283+olaparib+pd-1 antibody (group 8) were orally administered according to the protocol; the experimental groupings and dosing regimens are shown in table 1. Tumor volumes were measured 1 time every two days, weighed, and data recorded. The tumor volume (V) was calculated as:
V＝0.52×a×b 2 wherein a and b respectively represent length and width.
Table 2 experimental groupings and dosing regimens
Note that: QDx15: once a day, 15 times of administration; QDx7: stopping for 4 days after 3 days, and administering for 7 times; QDx5: dosing every two days, 5 times; po: oral administration; i.p.: intraperitoneal injection.
The test results are shown in fig. 2. From the analysis in the figure, the PRMT5 inhibitor combined PARP inhibitor and PD-1 antibody combined administration group has a tumor volume which is obviously lower than that of the respective single administration and the two-to-two combination administration, which indicates that the PRMT5 inhibitor and PARP inhibitor combined can effectively increase the curative effect of the PD-1 antibody, and the in vivo efficacy effect of the PRMT5 inhibitor and PARP inhibitor combined in a BALB/C mouse model of murine cell line 4T1 subcutaneous tumor is better.
4. Compatibility calculation method
Calculating q value according to the gold equation, q=e A+B /(E A +E B -E A ×E B ) Is used for judging whether the effect of the two medicines after compatibility is better than that of single administration. If q<0.55, the two drugs act as significant antagonism; q is more than or equal to 0.55<0.85, the two drugs act as antagonism; 0.85 percent or lessq<1.15, the two medicines are added singly; q is more than or equal to 1.15<20, the two medicines act as synergistic enhancement; q is more than or equal to 20, and the actions of the two medicines are obviously enhanced.
From the analysis of the data in fig. 2, the tumor volume reduction rates of group 2, group 3, group 4, group 5, group 6, group 7, and group 8 were 29.67%, 19.36%, 48.51%, and 82.20%, respectively, compared to the control group after 21d of administration.
Compared with group 5, group 6 and group 8, q= 82.20%/(29.67% +19.36% -29.67% ×19.36%) =1.90 according to the golden formula, conforming to 1.15.ltoreq.q <20;
compared with group 5, group 7 and group 8, q= 82.20%/(29.67% +48.51% -29.67% ×48.51%) =1.29 according to the golden formula, conforming to 1.15.ltoreq.q <20;
compared with group 6, group 7 and group 8, q= 82.20%/(19.36% +48.51% -19.36% ×48.51%) =1.41 according to the golden formula, conforming to 1.15.ltoreq.q <20;
the above results indicate that the inhibition effect of the compatibility of LLY-283, olaparib and PD-1 antibodies on tumors is synergistically enhanced.
Example 3:
the chemical structure of shikonin derivative is shown as formula I:
I。
the invention also aims at providing the application of the PD-1 antibody in combination with shikonin derivatives shown in the formula I in preparing medicines for preventing or treating solid tumors.
The preparation method of the shikonin derivative comprises the following steps: the shikonin derivative is prepared by adopting chromen card to carry out chemical modification on shikonin through esterification reaction. According to the invention, the chromene card is adopted to carry out chemical modification on shikonin which is a natural plant extract, so that the biological activity of shikonin derivatives is further improved, and compared with single medicine or certain other combined medicines, the provided medicine composition combined with the shikonin derivatives has remarkable synergistic effect in inhibiting solid tumors such as benign or malignant tumors, the shikonin derivatives can effectively increase the curative effect of the PD-1 antibodies, and the combined use of the shikonin derivatives and the shikonin derivatives has better in-vivo pharmacodynamic effect in a BALB/C mouse model of 4T1 subcutaneous tumor-bearing of a murine cell line; and simultaneously improves the drug resistance of single drug treatment.
Specifically, the preparation method of the shikonin derivative comprises the following steps:
dissolving chromene card, DCC and DMAP in anhydrous dichloromethane, stirring for 10-15 min, then adding shikonin, placing the reaction system in an ice bath, stirring for reaction for 10-15 h, and monitoring by TLC to confirm whether the reaction is finished; after the reaction is finished, the reaction system is placed in a refrigerator at the temperature of minus 20 ℃, frozen overnight, quickly filtered, the filtrate is concentrated at low temperature by a rotary evaporator, and the shikonin derivative is obtained by thin layer chromatography separation by taking a mixed solvent of ethyl acetate/petroleum ether (v/v, 1:6-8) as a developing agent.
Preferably, the mole ratio of chromene card, DCC and DMAP is 1:1.5-2:0.2-0.3; the solid-to-liquid ratio of chromene card to anhydrous dichloromethane is 2-3 g/1 mL; the molar ratio of shikonin to chromene is 0.8-0.9:1.
In this example, shikonin derivatives were prepared as follows:
dissolving chromene card, DCC and DMAP (the mol ratio of the chromene card to the DCC is 1:1.8:0.24) in anhydrous dichloromethane (the solid-liquid ratio of the chromene card to the anhydrous dichloromethane is 2.6g:1 mL), stirring for 12min, then adding shikonin (the mol ratio of the chromene card to the DCC is 0.85:1), placing the reaction system in an ice bath, stirring for reaction for 12h, and monitoring by TLC to confirm whether the reaction is finished; after the reaction is finished, the reaction system is placed in a refrigerator at the temperature of minus 20 ℃, frozen overnight, quickly filtered, the filtrate is concentrated at low temperature by a rotary evaporator, and the shikonin derivative is obtained by thin layer chromatography separation by taking a mixed solvent of ethyl acetate/petroleum ether (v/v, 1:7.5) as a developing agent. 1 H NMR(500 MHz, CDCl 3 ) δ 12.62 (s, 1H, -OH), 12.49 (s, 1H, -OH), 8.09 – 7.40 (4H, Ar-H), 7.61 (dd, 2H,Ar-H), 7.82、7.43、5.21 (3H, CH=C), 5.45 (m, 1H, -CH), 2.21、2.40(2H,-CH 2 ), 1.77 (s, 3H, -CH 3 ), 1.65 (s, 3H, -CH 3 )。
Combination of shikonin derivatives with PD-1 antibodies study of in vivo pharmacodynamic effects in BALB/C mouse model of murine cell line EMT6 subcutaneous tumor-bearing, each alone:
1. test agent
Drug name: shikonin derivative and PD-1 antibody prepared in this example.
2. Experimental animal
BALB/c mice, 6-8 weeks old, females, feeding environment: SPF stage.
Feeding environment: temperature: controlling the temperature to be 20-26 ℃; relative humidity: controlling the relative humidity to be 40% -70%; illumination: automatic illumination, and light and shade alternate every 12 h.
3. Experimental procedure
EMT6 cells were resuspended in PBS (4X 10) 5 ) (high sugar DMEM Medium, 10% fetal bovine serum, 1% P/S (PB 180120), 37 ℃ C., 5% CO) 2 Culture), subcutaneous tumor-bearing was performed subcutaneously on right rib sections of 32 BALB/c nude mice. When the average tumor volume of the mice reaches 100-150 mm 3 At this time, the random number was divided into 4 groups of 8. After grouping, 0.5% sodium carboxymethylcellulose/physiological saline (group 1), PD-1 antibody (group 2), shikonin derivative (group 3), shikonin derivative+pd-1 antibody (group 4) were orally administered according to the protocol; the experimental groupings and dosing regimens are shown in table 3. Tumor volumes were measured 1 time every two days, weighed, and data recorded. The tumor volume (V) was calculated as:
V＝0.52×a×b 2 wherein a and b respectively represent length and width.
Table 3 experimental groupings and dosing regimens
Note that: QDx15: stopping for 4 days after 3 days, and administering 15 times; QDx7: stopping for 4 days after 3 days, and administering for 7 times; po: oral administration; i.p.: intraperitoneal injection.
The test results are shown in FIG. 3. From the analysis in the figure, the tumor volume of the combination administration group of shikonin derivative and PD-1 antibody is obviously lower than that of the combination administration group of shikonin derivative and PD-1 antibody, which indicates that shikonin derivative can effectively increase the curative effect of PD-1 antibody, and the combination use of shikonin derivative and PD-1 antibody has better in vivo pharmacodynamic effect in a BALB/C mouse model of murine cell line 4T1 subcutaneous tumor.
4. Compatibility calculation method
Calculating q value according to the gold equation, q=e A+B /(E A +E B -E A ×E B ) Is used for judging whether the effect of the two medicines after compatibility is better than that of single administration. If q<0.55, the two drugs act as significant antagonism; q is more than or equal to 0.55<0.85, the two drugs act as antagonism; q is more than or equal to 0.85<1.15, the two medicines are added singly; q is more than or equal to 1.15<20, the two medicines act as synergistic enhancement; q is more than or equal to 20, and the actions of the two medicines are obviously enhanced.
From the analysis of the data in fig. 3, it is found that after 21d administration, the tumor volume reduction rates of group 2, group 3 and group 4 are 19.47%, 18.54% and 77.22%, respectively, and q=77.22%/(19.47% +18.54% -19.47% ×18.54%) =2.24, according to the gold formula, and 1.15.ltoreq.q <20, indicating that the tumor inhibition effect of the combination of shikonin derivative and PD-1 antibody is synergistic.
The conventional technology in the above embodiments is known to those skilled in the art, and thus is not described in detail herein.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (4)
1. A mixed formulation for sensitizing a PD-1 antibody comprising a PD-1 antibody and shikonin derivative represented by formula I:
I。
2. the cocktail for sensitizing PD-1 antibodies according to claim 1, wherein said PD-1 antibodies comprise terlipressin Li Shan antibodies.
3. Use of a PD-1 antibody in combination with shikonin derivatives of formula I for the manufacture of a medicament for the prevention or treatment of solid tumors:
I。
4. the use of claim 3, wherein the solid tumor comprises a benign solid tumor or a malignant solid tumor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2022115611765 | 2022-12-07 | ||
| CN202211561176 | 2022-12-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116196415A CN116196415A (en) | 2023-06-02 |
| CN116196415B true CN116196415B (en) | 2023-08-01 |
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| KR20080041441A (en) * | 2006-11-07 | 2008-05-13 | 한국생명공학연구원 | Composition containing extracts of zanthoxylum piperitum dc or compounds isolated therefrom for the prevention and treatment of cardiovascular diseases |
| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN107743495A (en) * | 2015-03-23 | 2018-02-27 | 拜耳制药股份公司 | Anti- CEACAM6 antibody and application thereof |
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| US9949961B2 (en) * | 2013-03-14 | 2018-04-24 | Rahimdzhan Roziev | Agent for the prophylaxis and/or treatment of neoplastic diseases |
| EP3519051B1 (en) * | 2016-09-27 | 2021-09-22 | Beigene, Ltd. | Treatment of cancers using combination comprising parp inhibitors |
| TW201922282A (en) * | 2017-10-13 | 2019-06-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | Combination use of PD-1 antibody and epigenetic modulating agent in the preparation of a medicament for the treatment of tumor |
| US20200048716A1 (en) * | 2017-11-03 | 2020-02-13 | Twister Biotech, Inc | Using minivectors to treat ovarian cancer |
| US20190112671A1 (en) * | 2017-12-01 | 2019-04-18 | Florida State University Research Foundation, Inc. | Breast Cancer Immunotherapy and Methods |
| CN111714629B (en) * | 2020-05-13 | 2023-09-26 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Application of pharmaceutical composition in preparation of medicaments for treating tumors insensitive to PD-1 antibody immunotherapy |
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| KR20080041441A (en) * | 2006-11-07 | 2008-05-13 | 한국생명공학연구원 | Composition containing extracts of zanthoxylum piperitum dc or compounds isolated therefrom for the prevention and treatment of cardiovascular diseases |
| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN107743495A (en) * | 2015-03-23 | 2018-02-27 | 拜耳制药股份公司 | Anti- CEACAM6 antibody and application thereof |
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