AU2021100601A4 - A Pharmaceutical Composition for Treating Cancer Constructed by PD-L1 Antibody and Nintedanib - Google Patents
A Pharmaceutical Composition for Treating Cancer Constructed by PD-L1 Antibody and Nintedanib Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses a pharmaceutical composition for treating cancer, which is constructed
by PD-Li antibody and Nintedanib, belonging to the technical field of biomedicine. In
particular, a pharmaceutical composition for treating a subject with solid tumour is disclosed,
which comprises administering a therapeutically effective amount of PD-Li antibody and a
therapeutically effective amount of Nintedanib to the subject. A kit for the treatment of a
subject with solid tumour is also disclosed, including the application of therapeutically
effective amount of PD-Li antibody and Nintedanib to the subject, as well as an instruction for
effective administration. The combination of the two drugs can be uses as a valuable
therapeutic drug for clinical cancer patients, which can significantly inhibit the growth of
tumour and improve non-ideal anti-tumour effect of PD-Li antibody monotherapy in clinical
so as to enhance the effect of tumour immunotherapy.
1/6
2200- Control :
2000- Nintedanib
1800 - aPD-L1
E1600. - Nintedanib+aPD-L1
1400
E1200
01000
E
600
400
200
0 3 6 9 12 15
Days after treatment
Fig. 1 The tumour growth curve of LLC lung cancer model
25
0
e + Control
15 * aPD-L1
0
INintedanib
-- NintedanibeaPD-L1
101
0 3 6 9 12 15
Days after treatment
Fig. 2 A mouse weight diagram of LLC lung cancer model
Description
1/6
2200- Control : 2000- Nintedanib 1800 - aPD-L1 E1600. - Nintedanib+aPD-L1 1400 E1200 01000
E 600 400 200
0 3 6 9 12 15 Days after treatment
Fig. 1 The tumour growth curve of LLC lung cancer model
25
0
e + Control 15 * aPD-L1 0 INintedanib
-- NintedanibeaPD-L1 101 0 3 6 9 12 15 Days after treatment
Fig. 2 A mouse weight diagram of LLC lung cancer model
A Pharmaceutical Composition for Treating Cancer Constructed by PD-L1
Antibody and Nintedanib
[01] The invention relates to the technical field of biomedicine, in particular to a pharmaceutical composition for treating cancer, constructed by PD-Li antibody and Nintedanib.
[02] In the immune escape mechanism of tumour, there is a protein called PD-i (programmed cell death 1) on immune cells (T cells), and correspondingly, there is ligand PD-Li (programmed cell death-Ligand 1) on tumour cells. When PD-i and PD LI combine with each other, an inhibitive signal will be conducted, which will block the activation of immune cells, thus blocking the attack of immune cells on tumour cells. In view of this escape mechanism, PD-Li antibody is used in clinical treatment to target and compete for the binding of PD-Li and PD-1, thereby T cells are activated to exert immune function and eliminate tumour cells. As one of the effective immunotherapies in clinic, PD-Li antibody has achieved considerable curative effect in patients with melanoma, non-small cell lung cancer and urothelial cancer. However, at present, the response rates of PD-Li antibody alone in patients with many kinds of tumours or with middle and advanced tumours are low. Further, the effective rate of immunotherapy in cancer patients is only about 20%, and the response rate of combined chemotherapy is less than 50%. According to reports, the unsatisfactory effect of immunotherapy may be attributed to the existence of various immunosuppressive factors in tumour microenvironment that induce immune tolerance and immune escape. For example, in tumour microenvironment, collagen matrix will form a fibre barrier to prevent the infiltration of immune cells, and tumour vascular dysfunction will lead to hypoxia in tumour tissues, which will affect the effective recruitment of immune cells. In addition, a series of inhibitory inflammatory factors will be secreted to recruit regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and M2 macrophages, which can lead to poor efficacy of PD-Li antibody. Therefore, how to improve the effective rate of immunotherapy is an urgent problem to be solved.
[03] In order to solve the problems existing in the prior art, a pharmaceutical composition for treating cancer constructed by PD-Li antibody and Nintedanib is provided. Through the combination of PD-L I antibody and Nintedanib in the treatment of cancer, the problem of unsatisfactory anti-tumour effect of PD-Li antibody monotherapy in clinic is overcome.
[04] To achieve the above purpose, the present invention provides the following scheme.
[05] The pharmaceutical composition for treating a subject with solid tumour proposed in the invention is composed of an administration of a therapeutically effective amount of PD-Li antibody and Nintedanib to the subject.
[06] Preferably, the subject is composed of human subjects or animal model subjects.
[07] Furthermore, the solid tumour comprises lung cancer or colon cancer.
[08] It is preferred that the PD-Li antibody is administered by injection, and the Nintedanib is administered orally or intragastrically.
[09] The invention also provides a kit for the treatment of a subject with solid tumour, including the application of therapeutically effective amount of PD-Li antibody and Nintedanib to the subject, as well as an instruction for effective administration.
[010] Preferably, the PD-Li antibody and the Nintedanib are simultaneously and jointly administered to the subject according to the instructions.
[011] Following beneficial effects are further disclosed by the invention.
[012] Nintedanib, with chemical name of iH-indole-6-carboxylic acid, 2,3 dihydro-3- [[[4-[methyl [(4-methyl--piperazinyl) acetyl] amino] phenyl] amino] phenyl methylene]-2-oxy-methyl ester, (3Z)-, is an effective triple vascular kinase inhibitor, acting on VEGFR I/ 2 / 3, FGFR I / 2 / 3 and PDGFR a / . Nintedanib can inhibit VEGFR, which is expected to normalize the blood vessels of tumour. Besides, it can act on PDGFR to inhibit the formation of fibrous barrier of collagen matrix in tumour microenvironment, effectively increasing the infiltration and recruitment of immune cells, so as to enhance the efficacy of immunotherapy. Therefore, the invention combines PD-Li antibody and Nintedanib to treat tumour, and the mouse model experiment proves that the combination of PD-Li antibody and Nintedanib can inhibit tumour growth, prolong its survival time and normalize blood vessels in tumour microenvironment. It indicates that PD-Li antibody combined with Nintedanib can be used as a pharmaceutical composition for the treatment of tumour to significantly improve non-ideal anti-tumour effect of PD-Li antibody monotherapy in clinical and enhance the effect of tumour immunotherapy. In conclusion, the invention provides a valuable therapeutic drug composition for clinical treatment of tumour
[013] In order to explain the embodiments of the present invention or the technical scheme in the prior art more clearly, the figures needed in the embodiments will be briefly introduced below. Obviously, the figures in the following description are only some embodiments of the present invention, and for ordinary technicians in the field, other figures can be obtained according to these without paying creative labour.
[014] Figure 1 is the tumour growth curve of LLC lung cancer model.
[015] Figure 2 is a mouse weight diagram of LLC lung cancer model.
[016] Figure 3 is a mouse survival curve of LLC lung cancer model.
[017] Figure 4 is HE and Tunel immunofluorescence image of LLC lung cancer model.
[018] Figure 5 is an immunofluorescence image of CD31 (red) and a-SMA (green) in LLC lung cancer model.
[019] Figure 6 is a flow chart of tumour microenvironment of LLC lung cancer model.
[020] Figure 7 is the tumour growth curve of MC38 colon cancer model.
[021] Figure 8 is an excised tumour image of MC38 colon cancer model.
[022] Figure 9 is a tumour weight diagram of MC38 colon cancer model.
[023] Figure 10 is a mouse weight diagram of MC38 colon cancer model.
[024] Figure 11 is a mouse survival curve of MC38 colon cancer model.
Various exemplary embodiments of the present invention will now be described in
detail, which should not be regarded as a limitation of the present invention, but rather
as a more detailed description of certain aspects, characteristics and embodiments of
the present invention.
It should be understood that the terms described in the present invention are only for
describing specific embodiments, and are not intended to limit the present invention. In
addition, as for the numerical range in the present invention, it should be understood
that every intermediate value between the upper limit and the lower limit of the range
is also specifically disclosed. Intermediate values within any stated value or stated range
and every smaller range between any other stated value or intermediate values within
the stated range are also included in the present invention. The upper and lower limits
of these smaller ranges can be independently included or excluded from the range.
Unless otherwise stated, all technical and scientific terms used herein have the same
meanings as commonly understood by those skilled in the art to which the present
invention relates. Although the present invention only describes preferred methods and
materials, any methods and materials similar or equivalent to those described herein
may be used in the practice or testing of the present invention. All documents mentioned
in this specification are incorporated by reference to disclose and describe methods and/or materials related to the documents. In case of conflict with any incorporated documents, the contents of this specification shall prevail.
Without departing from the scope or spirit of the invention, it is obvious to those skilled
in the art that many modifications and changes can be made to the specific embodiments
of the specification of the invention. Other embodiments derived from the description
of the present invention will be apparent to the skilled person. The specification and
examples of this application are only exemplary.
As used herein, "including", "comprising", "having", "containing" and so on, are all
open terms, which means including but not limited to.
The reagents or materials used in the following embodiments can be obtained through
commercial channels unless otherwise specified.
Embodiment 1
1. 1.Experimental materials
SPF grade 18-20 g female C57BL/6 mice (6-8 weeks old) provided by Beijing Vital
River Laboratory Animal Technology Co., Ltd.
LLC cell strain (purchased from the cell bank of Chinese Academy of Sciences) and
MC38 cell strain (purchased from Wuhan Taikemei Biotechnology Co., Ltd.).
PD-Li antibody, purchased from Jiangsu Hengrui Medicine Co., Ltd. (PD-Li antibody
for mice is purchased from BioXcell).
2. Experimental methods
2.1 Tumour inhibition experiment and survival curve of LLC tumour and MC38 tumour
1) LLC cells (DMEM high-glucose complete medium) and MC38 cells (RMPI-1640
complete medium) were cultured to logarithmic growth stage at 37C, with 5% CO 2
. And then they were digested and counted for later use.
2) Shave the hair on the right back of the mouse, inject 1*106 LLC tumour cells (or
1*106 MC38 tumour cells) subcutaneously into the right lower back of the mouse, and
start drug joint intervention after the tumour volume grew to 100-150 mm 3 in about 7
9 days.
3) The mice were randomly divided into four groups.
Control group: normal saline with the same volume of that in Nintedanib group was
intragastrically administered and the same volume of sterile PBS was intraperitoneally
injected for the same days of that in PD-L antibody monotherapy group.
Nintedanib single drug group: 30 mg/kg of Nintedanib was given once a day for 10
consecutive days.
PD-Li antibody single drug group: PD-Li was injected intraperitoneally for three
times, once every three days.
Combined group: 30 mg/kg of Nintedanib was intragastrically administered and 10
mg/kg of PD-Li antibody was given by intraperitoneal injection.
The tumour volume and mouse weight were measured every three days. When the
tumour volume exceeded 2000 cm3, the mice were killed. Record the survival of each
group.
4) On the 10th day or so after drug administration (when the tumour grew to about 500
mm), three tumour-bearing mice were randomly selected from each group, and the
tumour was stripped, fixed and embedded. Then immunofluorescence staining (Tunel,
CD31 or SMA-a) and HE staining were performed.
) On the 10th day of administration, the mice were killed, the subcutaneous tumour
was taken out, and the tumour was reduced into small pieces, which were digested into
single cell suspension with type IV collagenase. Dividing the single cell suspension into
a plurality of flow tubes, centrifuging, discarding supernatant, adding fluorescent
labelled antibody mixed solution into the precipitate, and incubating for 30 minutes at
4 °C. The antibody was washed away with PBS, and the cells were resuspended with
300 1 PBS. The cells were detected by flow cytometry, and the results were analysed
by Flowjo software.
3. Results and analysis
3.1 PD-Li antibody combined with Nintedanib can inhibit the growth and prolong the
survival time of LLC tumour
As shown in Fig. 1, the tumour growth curve, it can be seen that single drug PD-Li
antibody has no obvious anti-tumour effect in LLC lung cancer model. As shown in the
mouse weight diagram of Fig. 2, it can be seen that the combination method of the two
drugs in the present invention has no additional toxic and side effects on the body and is very safe. As can be seen from the survival curve shown in Fig. 3, the combination of the two drugs can effectively prolong the survival time. As shown in Fig. 4, Tunel staining shows that the combination of the two drugs significantly increased the apoptosis area in tumour tissues.
3.2 Effect of PD-L antibody combined with Nintedanib on tumour microenvironment
of LLC lung cancer model
As shown in Fig. 5, Nintedanib combined with PD-Li antibody can normalize blood
vessels in tumour microenvironment. As shown in Fig,6, the infiltration of CD8' T cells
in tumour tissue can be increased after the combination of the two drugs.
3.3 Effect of PD-Li antibody combined with Nintedanib on MC38 tumour growth
It can be seen from the tumour growth curve shown in Fig. 7, the excised tumour image
shown in Fig. 8 and the tumour weight diagram shown in Fig. 9 that in MC38 colon
cancer model, although the single drug PD-Li antibody has a certain tumour inhibition
effect, the combined effect is better, and the tumour growth is significantly inhibited,
and even some tumour individuals are directly cured without recurrence. As can be seen
from the mouse weight chart shown in Fig. 10, the combined method of the two drugs
of the present invention has no additional toxic and side effects on the body and is very
safe. It can be seen from the mouse survival curve shown in Fig. I Ithat the combination
scheme of the two drugs of the present invention can effectively prolong the survival
time.
Through the above-mentioned experiments, the inventors revealed for the first time that
the effective dose of PD-Li antibody combined with the effective dose of Nintedanib has a significant effect in inhibiting the growth of tumours (lung cancer and colon cancer), and verified the mechanism of improving the immune efficacy, mainly studying the mechanism of the combination of the two drugs in normalizing blood vessels and enhancing infiltration of immune cells. The experimental results show that the combination of the two drugs can significantly inhibit the growth of tumour cells, prolong the survival time, normalize the blood vessels in tumour microenvironment, and increase the infiltration of CD8' T cells in tumour tissues. Therefore, the combination of PD-L I antibody and Nintedanib can be used for the treatment of people or animals with solid tumours, providing a new treatment method for clinical treatment of cancer (lung cancer and colon cancer).
[025] Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms, in keeping with the broad principles and the spirit of the invention described herein.
[026] The present invention and the described embodiments specifically include the best method known to the applicant of performing the invention. The present invention and the described preferred embodiments specifically include at least one feature that is industrially applicable
Claims (6)
1. A pharmaceutical composition for treating a subject with solid tumour, characterized by comprising an administration of a therapeutically effective amount of PD-Li antibody and Nintedanib to the subject.
2. The pharmaceutical composition for treating a subject with a solid tumour according to Claim 1, characterized in that the subject is composed of human subjects or animal model subjects.
3. The pharmaceutical composition for treating a subject suffering from a solid tumour according to Claim 1, characterized in that the solid tumour comprises lung cancer or colon cancer.
4. The pharmaceutical composition for treating a subject with a solid tumour according to Claim 1, characterized in that the PD-Li antibody is administered by injection, and the Nintedanib is administered orally or intragastrically.
5. A kit for the treatment of a subject with solid tumour, characterized by including the application of therapeutically effective amount of PD-Li antibody and Nintedanib to the subject, as well as an instruction for effective administration.
6. The kit for the treatment of a subject with solid tumour according to Claim 5, characterized in that the PD-Li antibody and the Nintedanib are simultaneously and jointly administered to the subject according to the instructions.
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