CN114042154A - Application of medicine composition in preparing anti-tumor combination therapy medicine - Google Patents
Application of medicine composition in preparing anti-tumor combination therapy medicine Download PDFInfo
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Abstract
The invention discloses application of a drug combination in preparation of an anti-tumor combination therapy drug, and relates to the technical field of biological medicines. The medicine composition comprises: polypeptides and/or antibodies that inhibit PD-1 or inhibit PD-L1, and traditional Chinese medicine components; the Chinese medicinal component is lycorine or its salt, or its hydrate. The inventor finds that the traditional Chinese medicine component lycorine jointly inhibits PD-1 or inhibits polypeptide and/or antibody of PD-L1 to obtain a synergistic antitumor effect in vivo and obviously improves the immune microenvironment. This provides a favorable premise for preparing anti-tumor combination therapy medicines, and also provides a potential strategy for jointly enhancing the PD-1/PD-L1 antibody.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of a medicine composition in preparing an anti-tumor combination therapy medicine.
Background
Malignant tumor is one of the diseases which have the greatest threat to the health of people in China. Malignant tumors seriously affect the healthy life of citizens and also bring serious challenges to the operation of urban medical systems and the development of socioeconomic performance, so that the search for novel and efficient tumor treatment strategies is particularly important.
Immunotherapy represented by programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoint inhibitors attracts attention, and compared with traditional chemotherapy, the immunotherapy remarkably improves the survival of tumor patients, but the problem of low clinical response rate and the like is increasingly prominent, and a novel effective combination strategy needs to be searched urgently. With the intensive research on tumor immune microenvironment, inhibitory immune microenvironment and variable tumor immune escape mechanisms are important reasons for poor clinical response of PD-1/PD-L1 antibody. An increasing number of studies have shown that Myeloid Derived Suppressor Cells (MDSCs) promote immune evasion in tumors by inhibiting T cell proliferation and function. MDSCs are mainly divided into two distinct subgroups: single-core like MDSCs (M-MDSCs) and multi-core like MDSCs (PMN-MDSCs). Targeting MDSCs aims to unlock immunosuppressive microenvironments, promote infiltration and priming of T cells, and is key to enhancing the response rate and clinical efficacy of PD-1/PD-L1 immunotherapy.
The traditional Chinese medicine has unique advantages in the aspects of tumor resistance and immunoregulation, can generate an anti-tumor effect through multiple mechanisms and enhance the immune function of a patient, and has great potential in the aspects of prolonging the life cycle of a tumor patient, improving the life quality of the patient and the like. Lycorine is an isoquinoline alkaloid derivative extracted and separated from lycoris radiata of lycoris and is one of main effective components of lycoris radiata, and reported anti-tumor effects of lycorine comprise inhibiting growth, invasion and metastasis of tumor cells such as colon cancer, lung cancer, multiple myeloma and the like, inducing apoptosis of the tumor cells, reversing tumor resistance and the like. The lycorine has rich resources and better druggability, and has great potential value in antitumor research.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide application of a medicine composition in preparing an anti-tumor combined treatment medicine, and the inventor finds that the traditional Chinese medicine component lycorine combined with polypeptide and/or antibody for inhibiting PD-1 or PD-L1 obtains a synergistic anti-tumor effect in vivo and obviously improves the immune microenvironment. This provides a favorable premise for preparing anti-tumor combination therapy medicines, and also provides a potential strategy for jointly enhancing the PD-1/PD-L1 antibody.
The invention is realized by the following steps:
the invention provides an application of a drug combination in preparing an anti-tumor combined treatment drug, wherein the drug combination comprises the following components:
polypeptide and/or antibody for inhibiting PD-1 or PD-L1, and Chinese medicinal components;
the Chinese medicinal component is lycorine or its salt, or its hydrate.
The salt can be lycorine any pharmaceutically acceptable salt, such as hydrochloride, carbonate, etc.
The invention provides a combined treatment scheme comprising a polypeptide and/or antibody inhibiting PD-1 or inhibiting PD-L1 and lycorine, aiming at treating tumor patients which are relatively insensitive to the treatment of the PD-L1 antibody. The inventor finds that the combined treatment medicine consisting of the polypeptide and/or the antibody inhibiting PD-1 or PD-L1 and lycorine has better anti-tumor effect than the treatment of the polypeptide or the antibody inhibiting PD-1 or PD-L1 alone. The combined treatment medicine has better tumor inhibition effect than single use of lycorine, and has no influence on the body weight of mice.
The main mechanisms of the combination therapy are: lycorine reduces infiltration of myeloid-derived suppressor cells (MDSCs) in the tumor immune microenvironment, and relieves the inhibitory effect on T cells, thereby enhancing the therapeutic effect of PD-L1 antibody.
The hydrate may be a hydrate containing one crystal water.
In other embodiments, the above combination therapy further comprises pharmaceutically acceptable additives or adjuvants. In an alternative embodiment, the above-mentioned combination therapy is in a dosage form selected from the group consisting of tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.
In an alternative embodiment, the combination therapy may further comprise other combinations of the presently disclosed pharmaceutical compounds with at least one of the following drugs or therapies:
chemotherapeutic drugs, radiation therapy, photosensitizers, photothermal agents, immunotherapy.
In a preferred embodiment of the present invention, the tumor includes, but is not limited to, colon cancer, rectal cancer, colorectal cancer, lung cancer, stomach cancer, liver cancer, pancreatic cancer, breast cancer, kidney cancer, fibrosarcoma, cholangiocarcinoma, esophageal cancer, ovarian cancer, bladder cancer, malignant melanoma, or glioma. In other embodiments, partial or total inhibition of other solid tumors by the combination therapy is also contemplated by those skilled in the art.
In an optional embodiment, the pharmaceutical composition can also be a peptide inhibiting PD-L1 and a herbal medicine component.
In an optional embodiment, the pharmaceutical composition can also be a functional fragment inhibiting PD-L1 and a traditional Chinese medicine component. The functional fragment is any one of VHH, F (ab ') 2, Fab', Fab, Fv and scFv of the PD-L1 antibody.
Functional fragments of the above antibodies typically have the same binding specificity as the antibody from which they are derived. It will be readily understood by those skilled in the art from the disclosure of the present invention that functional fragments of the above antibodies can be obtained by methods such as enzymatic digestion (including pepsin or papain) and/or by chemical reduction cleavage of disulfide bonds. The above-described functional fragments are readily available to the skilled person on the basis of the prior art disclosing the structure of the intact antibody.
Functional fragments of the above antibodies can also be obtained by recombinant genetic techniques known to those skilled in the art or synthesized by, for example, automated peptide synthesizers, such as those sold by Applied BioSystems and the like.
In a preferred embodiment of the invention, the PD-L1 antibody includes, but is not limited to, adonitab, Devolumab, Adriazumab, BMS-936559, CX-072, SHR-1316, M-7824, LY-3300054, FAZ-053, KN-035, CA-170, CK-301, CS-1001, HLX-10, MCLA-145, MSB-2311 or MEDI-4736.
In a preferred embodiment of the present invention, the PD-L1 antibody is selected from the group consisting of alemtuzumab, dewaluzumab, or aveluzumab.
PD-1 monoclonal antibody selected from pembrolizumab (also known as Pabollizumab), nivolumab (nivolumab), cimirapril mab (cemipimab), Terepril mab (toreplimab), Cedilizumab (sintillizab), Carrilizumab (camrelizumab), or Tirellizumab (tiselizumab).
The PD-1 antibody of the therapeutic drug includes but is not limited to the monoclonal antibody types listed above, and various inhibitors targeting PD-1 should also be within the scope of the present invention.
In a preferred embodiment of the present invention, the anti-tumor is to reduce infiltration of bone marrow-derived suppressor cells in a tumor immune microenvironment, thereby relieving the suppression of T cells by the suppressor cells.
The invention also provides an anti-tumor combination therapy medicament, which comprises a medicament combination, wherein the medicament combination comprises: a first component and a traditional Chinese medicine component; the first component is polypeptide and/or antibody which inhibits PD-1 or inhibits PD-L1; the antibody is PD-1 antibody or PD-L1 antibody.
The Chinese medicinal component is lycorine or its salt, or its hydrate; and the mixing mass ratio of the first component to the traditional Chinese medicine components is 3.7-5.0: 10-20. Under the mixing proportion, the lycorine can better relieve the inhibiting effect of bone marrow-derived inhibitory cells (MDSCs) on T cells, thereby enhancing the curative effect of the PD-L1 antibody.
The dosage form of the combination therapy medicine is selected from tablets, pills, powder, suspension, gel, emulsion, cream, granules, nano particles, capsules, suppositories, injection, spray or injection.
The invention has the following beneficial effects:
the present invention provides a combination treatment regimen comprising a polypeptide and/or antibody that inhibits PD-1 or inhibits PD-L1, and lycorine. The inventor finds that the combined treatment medicine consisting of the polypeptide and/or the antibody inhibiting PD-1 or PD-L1 and lycorine has better anti-tumor effect than the treatment with the PD-L1 antibody alone. The combined treatment medicine has better tumor inhibition effect than single use of lycorine, and has no influence on the body weight of mice.
This provides a favorable premise for preparing anti-tumor combination therapy medicines, and also provides a potential strategy for jointly enhancing the PD-1/PD-L1 antibody.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a graph showing the results of pharmacodynamic evaluation of a mouse model of subcutaneous transplantation tumor;
FIG. 2 is a graph showing the results of studies on the effect of lycorine in combination with PD-L1 antibody on immune microenvironment.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the skill of the art. Such techniques are well explained in the literature, e.g. "molecular cloning: a Laboratory Manual, second edition (Sambrook et al, 1989); oligonucleotide Synthesis (oligo Synthesis) (eds. m.j. goal, 1984); animal Cell Culture (Animal Cell Culture), ed.r.i. freshney, 1987; methods in Enzymology (Methods in Enzymology), Handbook of Experimental Immunology (Handbook of Experimental Immunology) (ed. D.M.Weir and C.C.Black well), Gene Transfer Vectors for Mammalian Cells (ed. J.M.Miller and M.P.Calos) (ed. J.M.and M.P.Calos) (ed. 1987), Methods in Current Generation (Current Protocols in Molecular Biology) (ed. F.M.Ausubel.et al, 1987), PCR, Polymerase Chain Reaction (ed. PCR: The Polymerase Chain Reaction) (ed. Mullis et al, 1994), and Methods in Current Immunology (ed. J.1991).
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
In this example, a mouse model of subcutaneous transplantation tumor was established and corresponding pharmacodynamic evaluations were performed.
C57BL/6 female mice (six weeks old) were purchased from the australian university animal center and the experiments will be completed at this central SPF-scale laboratory. Relevant studies will be approved by the central animal ethics laboratory committee. The specific animal experimental protocol is as follows:
mice with substantially consistent body weight, viability, etc. were selected for the experiment, and the expected body weight range when inoculated with cells was 18-22 g. MC38 cells (from American Type Culture Collection (Rockville, Md., USA)) were taken in logarithmic growth phase, PBS was resuspended to appropriate concentration, and subcutaneous tumors were constructed at 100 ten thousand per injection subcutaneously into the right back of mice. Tumors were measured starting 6 days after the tumor growth (volume: length: width: height/2), and then more homogeneous tumor volumes (80-100 mm) were taken 10 days later3) The mice of (1) were administered, the body weights of all animals were weighed before the start of administration, and the tumor volume was measured, and the mice were randomly divided into a blank control group, a lycorine administration group, a PD-L1 antibody monotherapy group, and a PD-L1 antibody combination lycorine group, each group containing 8 animals, according to the tumor size and the mouse body weight. Lycorine was purchased from Olympic corporation of the Beijing century, PD-L1 antibody (clone:10F.9G2, Bio XCell), and from Cibotai-NaoboAnd (4) a driver.
After grouping, the corresponding administration dose of lycorine is 10mg/kg, and the lycorine is administered by intraperitoneal injection for a period from one time per day to mouse sacrifice. The PD-L1 antibody is administered at a dose of 75 μ g/mouse by intraperitoneal injection, once every three days for four times. The control group was administered with an equal volume of physiological saline in the same administration manner for 21 consecutive days. The body weight, the intake water intake, the defecation, the hair color, the activity, the mental state and the like of the experimental animal are regularly detected, and the tumor volume and the body weight of the mouse are observed and recorded every other day. The formula for calculating the tumor volume is as follows: length, width, height/2.
Experimental results referring to fig. 1, a in fig. 1 is a statistical result graph of tumor volume, B is a statistical result graph of mouse body weight, and C is a photograph actually taken of a mouse tumor. The anti PD-L1 is a PD-L1 antibody, the Lycorine is Lycorine, and the Lycorine and the anti PD-L1 are combined.
The results show that: the combined administration of the PD-L1 antibody and lycorine remarkably enhances the inhibition effect of the PD-L1 antibody alone on the tumor cell MC 38. The combined administration had more excellent antitumor effect and significantly smaller tumor volume (A, C) than the PD-L1 antibody alone, while having no effect on the body weight of the mice (B).
Example 2
In this example, the research on the effect of lycorine in combination with PD-L1 antibody on the improvement of immune microenvironment was carried out.
After the mice in example 1 were sacrificed, the tumor tissue was dissected out and single cell suspension was prepared for flow cytometry detection. Analyzing the abundance change of each group of immune cells by adopting a flow cytometer: the number of myeloid immunocytes was examined by staining anti-CD45 (immunocytes), anti-CD11b (myeloid immunocytes), anti-Ly6G (inhibitory cells derived from polynuclear bone marrow), and anti-Ly6C (inhibitory cells derived from mononuclear bone marrow). Removing cell fragments, selecting single cell clusters, trapping CD45, CD11b, Ly6G and Ly6C positive cells, and analyzing abundance change of each group; analysis of other immune cell abundance changes: anti-CD45 (immune cell), anti-CD3 (lymphoid immune cell), anti-CD8(CD 8)+T cells), anti-CD4(CD 4)+T cell) staining assayTumor infiltration CD4, CD8 positive T cells, and Treg cells. Removing cell debris, selecting single cell mass, and trapping CD45 and CD3 positive cells, wherein in the full positive cell mass, the CD8 positive cells are trapped as CD8+T cells, analyzing abundance changes of each group; the circled CD4 positive cell is CD4+T cells, and analyzing the abundance change of each group.
Experimental results as shown with reference to figure 2, the combined treatment regimen comprising PD-L1 antibody and lycorine significantly improved the immune microenvironment compared to administration of PD-L1 antibody alone. Specifically, the combination group significantly reduced infiltration of M-MDSCs (E), reduced infiltration of bone marrow cells (C), and increased CD3 in tumor tissues, as compared to PD-L1 antibody alone+T cell, CD4+T cells and CD8+Infiltration of T cells (B, C). *: p<0.05。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of a pharmaceutical combination for the manufacture of a combination therapeutic against tumors, said pharmaceutical combination comprising:
polypeptide and/or antibody for inhibiting PD-1 or PD-L1, and Chinese medicinal components;
the traditional Chinese medicine component is lycorine or salt thereof or hydrate thereof; the antibody is a PD-1 antibody or a PD-L1 antibody.
2. The use of claim 1, wherein the tumor is colon cancer, rectal cancer, colorectal cancer, lung cancer, stomach cancer, liver cancer, pancreatic cancer, breast cancer, kidney cancer, fibrosarcoma, cholangiocarcinoma, esophageal cancer, ovarian cancer, bladder cancer, malignant melanoma, or glioma.
3. The use of claim 1 or 2, wherein the PD-L1 antibody is selected from the group consisting of atilizumab, dewaluzumab, aralizumab, BMS-936559, CX-072, SHR-1316, M-7824, LY-3300054, FAZ-053, KN-035, CA-170, CK-301, CS-1001, HLX-10, MCLA-145, MSB-2311, and MEDI-4736.
4. The use of claim 3, wherein the PD-L1 antibody is selected from the group consisting of amiritumab, Devolumab, and Arvelizumab.
5. The use according to claim 1 or 2, wherein the PD-1 antibody is selected from pembrolizumab, nivolumab, cimiralizumab, terliplizumab, certolizumab, carlelizumab, or tiragluzumab.
6. The use of claim 1, wherein the anti-tumor is the removal of the inhibitory effect of suppressor cells on T cells by reducing infiltration of bone marrow-derived suppressor cells in a tumor-immune microenvironment.
7. An anti-tumor combination therapy comprising a pharmaceutical combination comprising: a first component and a traditional Chinese medicine component; the first component is a polypeptide and/or antibody that inhibits PD-1 or inhibits PD-L1; the antibody is a PD-1 antibody or a PD-L1 antibody;
the traditional Chinese medicine component is lycorine or salt thereof or hydrate thereof.
8. The anti-tumor combination therapy medicament according to claim 7, wherein the mixing mass ratio of the first component to the traditional Chinese medicine components is 3.7-5.0: 10-20.
9. The anti-tumor combination therapy according to claim 7 or 8, wherein the combination therapy further comprises pharmaceutically acceptable additives or adjuvants.
10. The anti-tumor combination therapy according to claim 9, wherein the formulation of the combination therapy is selected from the group consisting of tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.
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