CN114159557A - Combined medicine composition for treating tumor diseases and application thereof - Google Patents
Combined medicine composition for treating tumor diseases and application thereof Download PDFInfo
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- CN114159557A CN114159557A CN202111318017.8A CN202111318017A CN114159557A CN 114159557 A CN114159557 A CN 114159557A CN 202111318017 A CN202111318017 A CN 202111318017A CN 114159557 A CN114159557 A CN 114159557A
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- monoclonal antibody
- dfpd1
- metastatic
- nimotuzumab
- cancer
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Abstract
The invention relates to the field of biological medicines, and particularly provides a combined medicine composition for treating tumor diseases, which comprises an anti-PD-1 monoclonal antibody taking PD-1 as a target point and an anti-EGFR monoclonal antibody taking EGFR as a target point. The invention combines anti-PD-1 monoclonal antibody and anti-EGFR monoclonal antibody, so that the drug safety is higher, the treatment response duration is effectively improved, the progression-free survival period and the total survival period of a cancer patient are prolonged, the health condition and the survival quality of the patient are improved, and the combined drug composition can be used for treating non-small cell lung cancer, metastatic non-small cell lung cancer, glioma, colorectal cancer, liver cancer, hepatocellular carcinoma, metastatic hepatocellular carcinoma, HER2 negative metastatic breast cancer, metastatic gastric adenocarcinoma, metastatic colorectal cancer, metastatic melanoma, metastatic renal cell carcinoma, advanced esophageal squamous cell carcinoma, advanced squamous non-small cell lung cancer or advanced head and neck squamous cell carcinoma.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a combined medicine composition for treating tumor diseases and application thereof.
Background
Immunotherapy is a popular field of tumor therapy, and the PD-1 target is the current popular target for immunotherapy. PD-1 is a key immune checkpoint receptor expressed on the surface of activated T cells, and after encountering PD-L1 and PD-L2 ligand molecules on the surface of tumor cells, the activation of the T cells is inhibited, the invaded tumor cells escape the monitoring of the immune system, while the inhibition of the activation of the T cells by the tumor cells is relieved by adopting an anti-PD-1 monoclonal antibody inhibitor, and the T cells of the autoimmune system of a patient are activated in a large quantity, so that the tumor cells are killed. At present, a plurality of monoclonal antibody medicines taking PD-1 as a target point are on the market at home and abroad, and simultaneously, a plurality of anti-PD-1 monoclonal antibodies are in the stage of preclinical research or clinical test, for example, the patent application No. CN201510312910.8 discloses an anti-PD-1 monoclonal antibody and an obtaining method thereof, the anti-PD-1 monoclonal antibody disclosed by the patent has been reported to the clinical research at present, and the safety and the effectiveness in vivo of the anti-PD-1 monoclonal antibody are verified through preclinical data. However, in order to further improve the cancer treatment effect, the research of the anti-PD-1 monoclonal antibody combined drug becomes a new research hotspot.
There are many drugs that can be administered in combination with anti-PD-1 mab that are currently available, but there is no case where the administration of anti-PD-1 mab in combination with anti-EGFR mab is approved for marketing. EGFR (epidermal Growth Factor receptor) is a receptor for cell proliferation and signaling by the Epidermal Growth Factor (EGF). EGFR is overexpressed in various solid tumors, such as head and neck cancer, lung cancer and colorectal cancer, and EGFR overexpression is observed. Overexpression of EGFR is highly correlated with high invasiveness, high metastasis and poor prognosis of tumors. Currently, many monoclonal antibodies targeting EGFR are marketed, such as Cetuximab (Cetuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), etc., but how to further improve the cancer treatment effect of anti-EGFR monoclonal antibodies on the basis of anti-EGFR monoclonal antibodies is the research direction of many drug enterprises.
Therefore, in order to improve the treatment effect of the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody on cancer under the large environment with high research and development heat of antibody combination, the invention needs to develop a composition for treating tumor diseases by combining the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody.
Disclosure of Invention
In order to solve the problem that the combined medicine of the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody is not approved to be on the market in the prior art, and in order to improve the research and development progress of antibody medicines as soon as possible and improve the cancer treatment effect of the anti-PD-1 monoclonal antibody, the development of the monoclonal antibody combined medicine with clinical value is urgently needed, so the invention discloses a combined medicine composition for treating tumor diseases and application thereof.
The specific technical scheme of the invention is as follows:
the invention provides a combined medicine composition for treating tumor diseases, which comprises an anti-PD-1 monoclonal antibody taking PD-1 as a target spot and an anti-EGFR monoclonal antibody taking EGFR as a target spot.
Further, the anti-PD-1 monoclonal antibodies comprise DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12, DFPD1-13, Nivolumab, Pembrolizumab, Terepritumomab, Cedilitumumab, Tirilizumab, Rilizumab, Peraprimab or Serpalizumab.
Further, the anti-EGFR monoclonal antibody includes cetuximab, nimotuzumab, and panitumumab.
Further, the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody are administered in a manner that includes simultaneous, concurrent, sequential, alternating, or separate administration;
preferably, the administration is sequential.
Further, the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody are both administered by intravenous infusion.
Further, the anti-PD-1 monoclonal antibody is DFPD1-10, the DFPD1-10 comprises a light chain variable region shown as SEQ ID No. 3 and a heavy chain variable region shown as SEQ ID No. 1;
the dosage of the DFPD1-10 is 100-300 mg;
preferably, the dosage of DFPD1-10 is 200 mg.
Further, the anti-EGFR monoclonal antibody is nimotuzumab; the dosage of the nimotuzumab is 100 mg-500 mg;
preferably, the amount of the nimotuzumab is 200 mg;
preferably, the amount of the nimotuzumab is 400 mg.
Further, the administration period of DFPD1-10 is once every two weeks, and the administration period of nimotuzumab is once a week.
The invention also provides the application of the combined medicine composition in preparing a medicine for treating tumor diseases;
preferably, the neoplastic disease comprises non-small cell lung cancer, glioma, colorectal cancer, liver cancer, HER2 negative metastatic breast cancer, metastatic gastric adenocarcinoma, metastatic melanoma, metastatic renal cell carcinoma, advanced esophageal squamous carcinoma, advanced head and neck squamous carcinoma;
preferably, the tumor diseases comprise advanced esophageal squamous carcinoma, non-small cell lung cancer and advanced head and neck squamous carcinoma.
The invention has the following beneficial effects: the invention combines the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody, so that the drug safety is higher, the treatment response duration is effectively improved, the progression-free survival period and the total survival period of a cancer patient are prolonged, and the health condition and the survival quality of the patient are improved.
Drawings
FIG. 1 is a graph showing the tumor volume growth in the FaDu head and neck squamous cell carcinoma model for the combination of Experimental example 1;
FIG. 2 is a graph showing the inhibition of tumor weight in FaDu head and neck squamous cell carcinoma model by the combination of Experimental example 1.
Detailed Description
The present invention will be described in further detail with reference to the following examples.
Example 1
The embodiment 1 of the invention provides a combined medicine composition for treating tumor diseases, which comprises an anti-PD-1 monoclonal antibody taking PD-1 as a target point and an anti-EGFR monoclonal antibody taking EGFR as a target point.
The anti-PD-1 monoclonal antibodies comprise DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12, DFPD1-13, Nivolumab, Pembrolizumab, Terepril monoclonal antibody, Cedilitumumab, Triralizumab ozolomide, Carrilizumab, Pleazeprizumab or Serpalizumab.
Wherein, Nivolumab, Pembrolizumab, Tereprinizumab, Cedilizumab, Tirilizumab, Carrilizumab, Pleurotizumab or Serpalizumab are all products which are on the market.
Wherein, DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12 and DFPD1-13 are monoclonal antibodies against PD-1 provided by application number CN201510312910.8, and DFPD1-9 comprises a light chain variable region shown as SEQ ID No. 2 and a heavy chain variable region shown as SEQ ID No. 1; DFPD1-10 includes the light chain variable region as shown in SEQ ID No. 3 and the heavy chain variable region as shown in SEQ ID No. 1; DFPD1-11 includes the light chain variable region as shown in SEQ ID No. 2 and the heavy chain variable region as shown in SEQ ID No. 4; DFPD1-12 includes the light chain variable region as shown in SEQ ID No. 2 and the heavy chain variable region as shown in SEQ ID No. 5; DFPD1-13 comprises a light chain variable region as shown in SEQ ID No. 3 and a heavy chain variable region as shown in SEQ ID No. 4, and the specific sequences are as follows:
1, the sequence is as follows:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNYGMHWVRQAPGKGLEWV AVIWYDSSRKYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNN DYWGQGTLVTVSS;
2, the sequence is as follows:
DIQMTQSPSSLSASVGDRVTITCRASQSIHNYLDWYQQKPGKAPKLLIYN ASTRATGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQELHLPLTFGQGTKVE IK;
3, SEQ ID No. 3, the sequence is as follows:
DIQMTQSPSSLSASVGDRVTITCRASQSVSNYLDWYQQKPGKAPKLLIYD ASTRATGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNMQLPLTFGQGTKV EIK;
SEQ ID No. 4, the sequence is as follows:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNNGMHWVRQAPGKGLEWV AVIWYDSSRKYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNN DYWGQGTLVTVSS;
SEQ ID No. 5, the sequence is as follows:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNYGMHWVRQAPGKGLEWV AVIWYDGSKKYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNN DYWGQGTLVTVSS。
in addition, the anti-PD-1 monoclonal antibody also includes heavy chain constant regions and light chain constant regions, the heavy chain constant regions and light chain constant regions having the same sequences as the heavy chain constant regions and light chain constant regions of the anti-PD-1 monoclonal antibody provided in patent application No. CN 201510312910.8.
anti-EGFR monoclonal antibodies include cetuximab, nimotuzumab, and panitumumab.
The anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody are administered in a manner that includes simultaneous, concurrent, sequential, alternating, or separate administration.
The anti-PD-1 monoclonal antibody, the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody are all intravenously infused.
Example 2
Embodiment 2 of the present invention provides a combination drug composition for treating tumor diseases based on embodiment 1, which comprises an anti-PD-1 monoclonal antibody targeting PD-1 and an anti-EGFR monoclonal antibody targeting EGFR.
The anti-PD-1 monoclonal antibody is DFPD1-10, and DFPD1-10 comprises a light chain variable region shown as SEQ ID No. 3 and a heavy chain variable region shown as SEQ ID No. 1.
The anti-EGFR monoclonal antibody is nimotuzumab.
DFPD1-10 and nimotuzumab were administered sequentially.
Both DFPD1-10 and nimotuzumab were administered intravenously.
The dosage of DFPD1-10 is 100 mg;
the usage amount of the nimotuzumab is 100 mg;
the dosing cycle for DFPD1-10 was once every two weeks and for nimotuzumab was once a week.
Example 3
The embodiment 3 of the invention further limits the dosage of DFPD1-10 to 200mg on the basis of the embodiment 2; the amount of nimotuzumab used was 200mg, and the remaining protocol was the same as in example 2.
Example 4
The embodiment 4 of the invention further limits the dosage of DFPD1-10 to 200mg on the basis of the embodiment 2; the amount of nimotuzumab used was 400mg, and the remaining protocol was the same as in example 2.
Example 5
The embodiment 5 of the invention further limits the modification of the dosage of DFPD1-10 to 300mg on the basis of the embodiment 2; the amount of nimotuzumab used was 500mg, and the remaining protocol was the same as in example 2.
Example 6
Embodiment 6 of the present invention further provides the use of the combination composition in the preparation of a medicament for treating neoplastic diseases, on the basis of the above embodiments 1 to 5;
the tumor diseases include non-small cell lung cancer, glioma, colorectal cancer, liver cancer, HER2 negative metastatic breast cancer, metastatic gastric adenocarcinoma, metastatic melanoma, metastatic renal cell carcinoma, advanced esophageal squamous cell carcinoma, and advanced head and neck squamous cell carcinoma.
Non-small cell lung cancer including, but not limited to, metastatic non-small cell lung cancer, advanced squamous non-small cell lung cancer; colorectal cancer including but not limited to metastatic colorectal cancer; liver cancers include, but are not limited to, hepatocellular carcinoma and metastatic stem cell carcinoma.
Example 7
Example 8 of the present invention further defines the tumor diseases including late esophageal squamous cell carcinoma, non-small cell lung cancer, and late head and neck squamous cell carcinoma on the basis of the above example 7. Non-small cell lung cancer includes, but is not limited to, metastatic non-small cell lung cancer, advanced squamous non-small cell lung cancer.
Experimental example 1: in vivo efficacy experiment of combined drug composition on FaDu head and neck squamous cell carcinoma tumor model
1. Test medicine
Test drug 1: the anti-PD-1 monoclonal antibody is DFPD1-10 (numbered JY034), and the DFPD1-10 comprises a light chain variable region shown as SEQ ID No:3 and a heavy chain variable region shown as SEQ ID No: 1.
Production unit: beijing Oriental Baitai Biotechnology GmbH;
quantity: 10ml, 10mg/ml, 3 bottles, 300mg totally;
the characteristics are as follows: a liquid;
test drug 2: opdivo (Nivolumab);
the purchasing manufacturer: baishimei noble treasure;
quantity: 100mg/10ml, 1 piece;
the characteristics are as follows: a liquid;
test drug 3: taixinsheng (nimuzumab injection);
providing a unit: beijing Oriental Baitai Biotechnology GmbH;
quantity: about 10ml (49mg), 4.9mg/ml, 1 vial;
the characteristics are as follows: a liquid;
2. experimental animals:
species lines: musmululus, NCG;
sex: male;
weight: 18-22 g;
quantity: 105 pieces of the Chinese character 'pin';
experimental animal providers: jiangsu Jiejiaokang Biotech limited;
producing license numbers: SCXK (su) 2018-;
quality certification number: 202013758.
3. the experimental method comprises the following steps:
3.1 cell culture
FaDu tumor cells (YK-CL-222) were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin and 2mM glutamine at 37 ℃ in a 5% CO2 incubator, and were bottled for passage every 3 to 4 days after the cells were confluent, and tumor cells in logarithmic growth phase were used for in vivo tumor inoculation.
3.2 tumor cell inoculation and grouping
PBMC (human peripheral blood mononuclear cells) derived from normal human peripheral blood (Donor #: SLB200234) were inoculated into tumor-bearing mice at 2X 10 days before the FaDu tumor cells were inoculated6A/only; PBS resuspended FaDu tumor cells at a concentration of 5X 107Perml, inoculated subcutaneously in the right flank of the experimental animal, 100. mu.l/body, and the tumor growth reached 53mm3The medicine is administered in groups on the left and right (on the same day)PG-D0), 8 groups of 10 individuals each, and the specific dosing schedule is shown in Table 1.
3.3 measurement and Experimental indices of mouse body weight
Tumor volume was measured 2 times per week using a vernier caliper and mouse body weight was weighed with an electronic balance to measure the long and short diameters of the tumor, the volume calculation formula was: volume is 0.5 x long diameter x short diameter2. The T/C value was calculated from the tumor volume, where T is the mean Relative Tumor Volume (RTV) of each subject treatment group, C is the mean Relative Tumor Volume (RTV) of the control group, and RTV is the ratio of tumor volume after and before administration. Tumor growth inhibition ratio TGITV (%) (1-T/C) × 100%.
At the end of the experiment, the animals were euthanized, the tumors were peeled off, weighed, placed in order for photography, and the tumor weight inhibition ratio TGITW (%) was calculated as (1-T/C) × 100%, where T/C is the treatment group TW average/control group TW average.
In principle, the evaluation criteria are: T/C (%) > 40% is ineffective; T/C (%) < 40%, and P <0.05 is effective by statistical treatment.
3.4 dosing regimens
Table 1 dosing schedule
Note: the administration volume of each group is 10 mul/g according to the weight of the animal, and the administration amount can be adjusted when the weight is reduced by 15-20%;
i.p.: performing intraperitoneal injection; tiw x 3 ks: three times per week for a total of 9 times; biw x 3 wks: twice weekly for 6 times.
3.5 statistical analysis
Statistical analysis between groups was performed on tumor volume, tumor weight using IBM SPSS Statistics 22.0 statistical software using One-Way ANOVA test, and a significant difference was considered to be present when p < 0.05.
3.6 tumor growth inhibition results are shown in Table 2 below:
TABLE 2 tumor suppression of PBMC humanized head and neck squamous carcinoma FaDu model animals by test substances
Note: One-Way ANOVA One-Way analysis of variance was performed on each group and multiple comparisons were performed afterwards using Bonferroni;a.mean ± standard error;b.comparing with an Isotype group;c.comparison with the Opdivo group;d.compared with the taixinsheng group;e.compared with the JY034 low dose + Taoxin group. No significant statistical differences were seen among the treatment groups (p)>0.05)。
3.7 tumor weight results are shown in Table 3 below:
TABLE 3 tumor suppression of PBMC humanized head and neck squamous carcinoma FaDu model animals
Note: One-Way ANOVA One-Way analysis of variance was performed on each group and multiple comparisons were performed afterwards using Bonferroni;a.mean ± standard error;b.comparing with an Isotype group;c.comparison with the Opdivo group;d.compared with the taixinsheng group;e.compared with the JY034 low dose + Taoxin group. No significant statistical differences were seen among the treatment groups (p)>0.05)。
In conclusion, through the data and the data shown in fig. 1 and fig. 2, in the PBMC humanized head and neck squamous cell carcinoma FaDu model, the combination therapy of the test drug JY034 and Taoxin produces a definite anti-tumor effect, the drug effect is superior to that of JY034 or Taoxin single-drug therapy, and the anti-tumor effect in each treatment group is optimal.
Experimental example 2: safety test of anti-PD-1 monoclonal antibody
1. The test drugs are:
the anti-PD-1 monoclonal antibody is DFPD1-10 (numbered JY034), and the DFPD1-10 comprises a light chain variable region shown as SEQ ID No:3 and a heavy chain variable region shown as SEQ ID No: 1.
Production and supply unit: beijing Oriental Baitai Biotechnology GmbH
Specification: 12 mL/tube, 40 mL/tube;
protein concentration/content: 14.2 mg/mL.
2. Laboratory animal
Species & strain: cynomolgus monkey (Macacafasacularis)
Animal grade: common stage
Number of animals: 40 animals (20/sex).
Administration start age (D1): the regimen requires that the animals be 2.5-5 years of age at the start of dosing, that the male be 3.5-4.8 years of age and that the female be 2.8-3.6 years of age at the start of actual dosing.
Initial body weight of administration (D-1): the scheme requires 2-5 kg; actual male body weight: 2.76-4.55 kg, female body weight: 2.12-3.24 kg.
The experimental animal source is as follows: guangxi Xiongsen Primates laboratory animals Breeding and development Co., Ltd
Animal production license: SCXK (cinnamon) 2016-
The qualification certificate of the experimental animal is numbered: 0002908, 0002916, 0002917
Issuing unit: guangxi Zhuang autonomous region science and technology hall
3. The administration route is as follows: and (4) performing intravenous injection.
4. Frequency and period of administration: the administration was 1 time per week for 13 weeks, and 14 times in total. Recovery period was 6 weeks from the last dose.
5. The experimental method comprises the following steps: 40 cynomolgus monkeys were used in the test, and randomly divided into 1-4 groups by gender zone, which were the adjuvant control group and the low, medium and high dose groups of the test article, 5/gender/group. JY034 preparation buffer solution is given to the auxiliary material control group animals; the animals in the low, medium and high dose groups of the test article are respectively administered with 5, 15 and 50mg/kg of JY034, the administration concentrations are respectively 0.5, 1.5 and 5mg/mL, and the administration volumes are all 10 mL/kg. The administration route is intravenous infusion administration, the administration speed is about 0.5mL/kg/min, the administration is performed 1 time per week, the administration is performed for 13 weeks continuously, and the administration is performed 14 times in total; and blood was collected at different time points before and after the first, 5 th, and 13 th administrations for pharmacokinetic analysis. On the day following the last drug (D93) and at the end of the 6 weeks of recovery (D134), animals were euthanized, all animals were subjected to gross anatomical observation and bone marrow smear, major organs were weighed, visceral volume and brain ratios were calculated and pathological examination of various tissues was performed.
6. The experimental results are as follows: under the test condition, JY034 was administered to cynomolgus monkeys by repeated intravenous infusion at 5, 15 and 50mg/kg doses, 1 time per week, 13 weeks and 14 times in total, and the cytokines IL-6, MCP-1 and IP-10 related to immune function were increased in the animals in each dose group division, and no systemic toxic reaction was observed.
Experimental example 3: clinical experiments of single anti-PD-1 monoclonal antibody and combined nimotuzumab for treating advanced solid tumors
1. The name of the test drug:
(1) the anti-PD-1 monoclonal antibody is DFPD1-10, and DFPD1-10 comprises a light chain variable region shown as SEQ ID No. 3 and a heavy chain variable region shown as SEQ ID No. 1.
The preparation formulation is as follows: injection preparation
Specification: 100 mg/bottle (10mL)
The manufacturer: beijing Oriental Baitai Biotechnology GmbH;
(2) nimotuzumab injection, trade name: taixin sheng
The preparation formulation is as follows: injection preparation
Specification: 50 mg/bottle (10mL)
The manufacturer: baitai biological pharmaceuticals Co.
2. Target population: patients with advanced esophageal squamous carcinoma, squamous non-small cell lung cancer, and head and neck squamous carcinoma;
sample size: phase1 a: the single-dose increasing stage is planned to 9-18 patients; planning 45-90 patients in a single-dose expansion stage; phase1 b: combining an anti-PD-1 monoclonal antibody and the nimotuzumab in a dose increasing stage to be administered to 6-20 patients; the anti-PD-1 monoclonal antibody and the nimotuzumab dose expansion stage are planned to 45-90 subjects.
Co-planning into groups: 105-218 patients.
3. Subjects must meet all of the following conditions to be eligible for this study:
(1) the purpose of the test is fully understood, and the researchers judge that the test scheme can be complied with and voluntarily sign written informed consent.
(2) The male and the female can use the male and the female when signing an informed consent, wherein the age is more than or equal to 18 years old.
(3) The subject can provide Tumor tissue and blood samples for Tumor Mutational Burden (TMB), PD-L1 expression level determination. Note: it is recommended to provide formalin fixed paraffin embedded tumor tissue specimens (FFPE) or unstained freshly cut serial tissue sections (slides) collected at non-radiation sites within 6 months prior to the first study, and also to provide a report of the pathology associated with the specimens. Freshly collected specimens, resection, hollow core biopsy, resection, incision, punch or jaw biopsy are all within acceptable limits (with freshly obtained tissue being preferred). No needle-aspirate samples (i.e., samples lacking intact tissue structures that provide only cell suspensions and/or cell smears), brush-on samples, cell pellet samples from pleural or peritoneal effusions were accepted.
(4) Histologically or cytologically confirmed advanced solid tumors:
Phase1a part A:advanced esophageal squamous carcinoma, squamous non-small cell lung cancer or head and neck squamous carcinoma with histologically or cytologically confirmed lack of standard therapy, refusal to receive standard therapy, ineffective or intolerant standard therapy;
Phase1a part B:
(ii) esophageal squamous carcinoma cohort: (ii) has histologically or cytologically proven locally advanced, recurrent metastatic esophageal squamous carcinoma that is inoperable or unsuitable for local treatment, failing at least first-line chemotherapy;
cohort of squamous non-small cell lung cancers: (ii) a locally advanced, relapsed metastatic squamous non-small cell lung cancer, histologically or cytologically proven to be inoperable or unsuitable for local treatment, that has failed at least first-line chemotherapy;
③ treatment of squamous carcinoma of head and neck: (ii) has histologically or cytologically proven locally advanced, recurrent metastatic head and neck squamous carcinoma that is inoperable or unsuitable for local treatment, squamous non-small cell lung carcinoma that failed at least first-line chemotherapy;
Phase1b:patients with histologically or cytologically proven locally advanced, recurrent metastatic esophageal squamous carcinoma, squamous non-small cell lung cancer, or squamous carcinoma of the head and neck that are inoperable or unsuitable for topical treatment, failed at least first-line chemotherapy, or are intolerant to first-line platinum-containing chemotherapy;
note: patients with tumor progression within 6 months after curative radical chemoradiotherapy or adjuvant, neoadjuvant chemotherapy treatment can also be considered as first-line chemotherapy failure.
(5) The presence of at least one measurable tumor lesion (recistv 1.1);
(6) ECOG score 0 or 1 within 7 days before treatment initiation;
(7) the estimated survival time is more than or equal to 3 months;
(8) the functions of main organs and bone marrow are basically normal, and no transfusion, no hematopoietic stimulating factors (including G-CSF, GM-CSF, EPO, TPO and the like) and no infusion of human albumin preparation are required within 14 days before screening. Laboratory examination results were within 7 days before treatment initiation:
coagulation function INR is less than or equal to 1.5 × ULN, aPTT is less than or equal to 1.5 × ULN (if a subject is receiving anticoagulation treatment, only PT or aPTT is in the expected treatment range of the application of anticoagulation medicine);
the liver and kidney functions of the testee meet the following conditions: total bilirubin is less than or equal to 1.5 × ULN, AST and ALT are less than or equal to 2.5 × ULN (if liver metastasis is present, less than or equal to 5 × ULN); blood creatinine is less than or equal to 1.5 multiplied by ULN;
③ the blood routine satisfies: the neutrophil count is more than or equal to 1.5 multiplied by 109L, platelet is more than or equal to 100109The ratio of the hemoglobin to the hemoglobin is more than or equal to 9 g/dL.
(9) Adverse events from previous treatments returned to < CTCAE grade 1 (except for hair loss).
(10) HIV detection negative in the screening period.
(11) Effective contraceptive measures were taken throughout the study period until 12 weeks after the last dose.
4. And (3) experimental design:
the test is designed as a multicenter, open, dose escalation and dose extension phase I clinical test, comprising two parts, phase1a and phase1b, with the primary objective of determining the safety, efficacy, PK/PD profile of anti-PD-1 monoclonal antibody single drugs and combined nimotuzumab in patients with advanced solid tumors.
Phase1a partA: 3 doses of anti-PD-1 monoclonal antibody 1mg/kg, 3mg/kg, 10mg/kg were selected for the single up-dosing phase of anti-PD-1 monoclonal antibody, and DLT was assessed using a conventional "3 + 3" up-dosing test within 28 days after the first dose, followed by Q2W until intolerable toxicity or disease progression. The trial was run incrementally from low to high dose, with the next dose being run incrementally if 1 subject in a dose group had a DLT, and the previous dose group being considered as the MTD if 2 subjects had a DLT.
Phase1a partB: and (3) the single dose expansion stage of the anti-PD-1 monoclonal antibody is respectively used for 15-30 cases of the group of late esophageal squamous cell carcinoma, late squamous non-small cell lung cancer and late head and neck squamous cell carcinoma, if no DLT appears in the partA, the anti-PD-1 monoclonal antibody 200mg Q2W is used for administration in the part, and the administration is continued until intolerable toxicity or disease progression.
After the test for phase1a is completed, the test for phase1b can be initiated at the appropriate time to evaluate the safety and preliminary efficacy of the anti-PD-1 monoclonal antibody in combination with nimotuzumab.
Phase1b partA: the anti-PD-1 mab was combined with a dose escalation phase of nimotuzumab to select 2 doses of nimotuzumab, tentatively administered with nimotuzumab 200mg and 400mg QW, respectively, in combination with anti-PD-1 mab 200mgQ2W, each dose being combined into 3-10 patients. The first 3 patients in each dose group were observed and evaluated for DLT within 14 days after the first dose, followed by administration of 200mg and 400mg of nimotuzumab, 200mg of Q2W, in combination with the anti-PD-1 monoclonal antibody; the next 7 patients were dosed directly with nimotuzumab 200mg and 400mg QW in combination with anti-PD-1 monoclonal antibody 200mg Q2W until intolerable toxicity or disease progression.
Phase1b partB: the anti-PD-1 monoclonal antibody is combined with a nimotuzumab dose expansion stage, one administration dose RP2D QW of the nimotuzumab is selected from a phase1b partA part, and is combined with 200mg of the anti-PD-1 monoclonal antibody to be administered as Q2W, 15-30 cases of advanced esophageal squamous cell carcinoma, advanced squamous non-small cell lung cancer and advanced head and neck squamous cell carcinoma are respectively organized, and the administration is continued until the intolerable toxicity or disease progression.
5. The administration scheme is as follows:
phase1a was dosed as a single anti-PD-1 monoclonal antibody at a dose shown in 4, experimental design, Phase1a partA first dose (C1D1) followed by DLT observation over 28 days, followed by a dosing cycle of every 2 weeks with D1 dosing; phase1a partB was intended to be administered with 200mg of Q2W as anti-PD-1 monoclonal antibody. The time for the first intravenous infusion of the anti-PD-1 monoclonal antibody is 60 +/-15 min. If the first infusion is well tolerated, the time for the second infusion can be shortened to 30 + -10 min. All subsequent infusions can be completed in 30min if the patient also has good tolerance to a 30 minute infusion. Dose adjustments were not made during the course of the experiment against the monoclonal antibody anti-PD-1.
Phase1b was administered with anti-PD-1 monoclonal antibody in combination with nimotuzumab at a dose shown in 4, experimental design, Phase1b partA first time (C1D1) after which DLT was observed within 14 days, followed by a dosing cycle of every 2 weeks, nimotuzumab D1 and D8 administered every week, anti-PD-1 monoclonal antibody administered at D1; the planned dose of Phase1b partB was 200mg Q2W of anti-PD-1 monoclonal antibody, and nimotuzumab was given the recommended dose QW of RP2D according to the partA fraction. The patient is given the anti-PD-1 monoclonal antibody injection at intervals of at least 10min before the nimotuzumab injection. The time for the first intravenous infusion of the anti-PD-1 monoclonal antibody and the nimotuzumab is 60 +/-15 min. If the first infusion is well tolerated, the time for the second infusion can be shortened to 30 + -10 min. All subsequent infusions can be completed in 30min if the patient also has good tolerance to a 30 minute infusion.
The present invention is not limited to the above-described preferred embodiments, and any other various products can be obtained by anyone in the light of the present invention, regardless of any changes in shape or structure, and all within the same or similar protection scope as the present application.
Sequence listing
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85 90 95
Ala Thr Asn Asn Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 5
<211> 113
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asn Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
Claims (10)
1. A combined medicine composition for treating tumor diseases is characterized by comprising an anti-PD-1 monoclonal antibody taking PD-1 as a target point and an anti-EGFR monoclonal antibody taking EGFR as a target point.
2. The combination composition of claim 1, wherein the anti-PD-1 monoclonal antibody comprises DFPD1-9, DFPD1-10, DFPD1-11, DFPD1-12, DFPD1-13, Nivolumab, Pembrolizumab, teripril mab, fiducizumab, tirlizumab, palivizumab, perapril mab, or serpalizumab.
3. The combination composition of claim 2, wherein the anti-EGFR monoclonal antibody comprises cetuximab, nimotuzumab and panitumumab.
4. The combination composition of claim 1, wherein the anti-PD-1 monoclonal antibody and the anti-EGFR monoclonal antibody are administered in a manner comprising simultaneous, concurrent, sequential, alternating, or separate administration;
preferably, the administration is sequential.
5. The combination composition of claim 1, wherein said anti-PD-1 monoclonal antibody and said anti-EGFR monoclonal antibody are both administered by intravenous infusion.
6. The combination composition of claim 3, wherein the anti-PD-1 monoclonal antibody is DFPD1-10, and the DFPD1-10 comprises a light chain variable region as set forth in SEQ ID No. 3 and a heavy chain variable region as set forth in SEQ ID No. 1;
the dosage of the DFPD1-10 is 100-300 mg;
preferably, the dosage of DFPD1-10 is 200 mg.
7. The combination composition of claim 6, wherein the anti-EGFR monoclonal antibody is nimotuzumab; the dosage of the nimotuzumab is 100 mg-500 mg;
preferably, the amount of the nimotuzumab is 200 mg;
preferably, the amount of the nimotuzumab is 400 mg.
8. The combination composition of claim 7, wherein the administration period of DFPD1-10 is once every two weeks and the administration period of nimotuzumab is once a week.
9. Use of a combination according to claim 1 for the preparation of a medicament for the treatment of a neoplastic disease;
preferably, the neoplastic disease includes non-small cell lung cancer, glioma, colorectal cancer, liver cancer, HER2 negative metastatic breast cancer, metastatic gastric adenocarcinoma, metastatic melanoma, metastatic renal cell carcinoma, advanced esophageal squamous cell carcinoma, advanced head and neck squamous cell carcinoma.
10. The use of claim 9, wherein the neoplastic disease comprises advanced esophageal squamous carcinoma, non-small cell lung cancer, advanced head and neck squamous carcinoma.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023208001A1 (en) * | 2022-04-26 | 2023-11-02 | 上海君实生物医药科技股份有限公司 | Combination of anti-pd-1 antibody and anti-egfr antibody, and use thereof in treatment of head and neck squamous cell carcinoma |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061597A (en) * | 2015-06-09 | 2015-11-18 | 北京东方百泰生物科技有限公司 | Anti-PD-1 monoclonal antibody and obtaining method thereof |
CN107034235A (en) * | 2017-05-19 | 2017-08-11 | 尹荣 | Joint targeting PD 1 and EGFR mosaic antigens T cells tumour immunity method |
CN110036030A (en) * | 2016-09-26 | 2019-07-19 | 英克隆有限责任公司 | The combination treatment of cancer |
CN110835375A (en) * | 2018-08-16 | 2020-02-25 | 上海洛启生物医药技术有限公司 | anti-PD-1/EGFR bispecific antibody and application thereof |
CN112203688A (en) * | 2018-05-31 | 2021-01-08 | 小野药品工业株式会社 | Biomarkers for determining the effectiveness of immune checkpoint inhibitors |
CN113134080A (en) * | 2020-01-17 | 2021-07-20 | 嘉和生物药业有限公司 | Application of anti-PD-1 antibody and furoquintinib combination in preparation of medicine for treating cancer |
-
2021
- 2021-11-09 CN CN202111318017.8A patent/CN114159557A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061597A (en) * | 2015-06-09 | 2015-11-18 | 北京东方百泰生物科技有限公司 | Anti-PD-1 monoclonal antibody and obtaining method thereof |
CN110036030A (en) * | 2016-09-26 | 2019-07-19 | 英克隆有限责任公司 | The combination treatment of cancer |
CN107034235A (en) * | 2017-05-19 | 2017-08-11 | 尹荣 | Joint targeting PD 1 and EGFR mosaic antigens T cells tumour immunity method |
CN112203688A (en) * | 2018-05-31 | 2021-01-08 | 小野药品工业株式会社 | Biomarkers for determining the effectiveness of immune checkpoint inhibitors |
CN110835375A (en) * | 2018-08-16 | 2020-02-25 | 上海洛启生物医药技术有限公司 | anti-PD-1/EGFR bispecific antibody and application thereof |
CN113134080A (en) * | 2020-01-17 | 2021-07-20 | 嘉和生物药业有限公司 | Application of anti-PD-1 antibody and furoquintinib combination in preparation of medicine for treating cancer |
WO2021143799A1 (en) * | 2020-01-17 | 2021-07-22 | 嘉和生物药业有限公司 | Use of anti-pd-1 antibody in combination with fruquintinib in preparation of medicaments for treating cancer |
Non-Patent Citations (3)
Title |
---|
BASTOS, B.等: "Synergistic Combination of PD-1 and EGFR Antibodies: A Proposed Phase 1 Clinical Trial Using Nivolumab and Cetuximab", 《INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY, BIOLOGY, PHYSICS》, vol. 94, no. 4, 15 March 2016 (2016-03-15) * |
罗详冲;李高峰;: "PD-1抑制剂卡瑞利珠单抗在晚期恶性肿瘤中的应用进展", 解放军医学杂志, no. 06, 28 June 2020 (2020-06-28) * |
苏宁;梁继珍;许育花;刘燕;薛丽京;谢亚琳;张贤兰;岑文昌;: "PD-L1蛋白在晚期肺腺癌中的表达及其与EGFR基因状态的关系", 临床肺科杂志, no. 11, 18 October 2018 (2018-10-18) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023208001A1 (en) * | 2022-04-26 | 2023-11-02 | 上海君实生物医药科技股份有限公司 | Combination of anti-pd-1 antibody and anti-egfr antibody, and use thereof in treatment of head and neck squamous cell carcinoma |
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