CN107149682A - A kind of targeting CD47 immunologic test point inhibitor medicaments composition and preparation method thereof - Google Patents
A kind of targeting CD47 immunologic test point inhibitor medicaments composition and preparation method thereof Download PDFInfo
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- CN107149682A CN107149682A CN201610125467.8A CN201610125467A CN107149682A CN 107149682 A CN107149682 A CN 107149682A CN 201610125467 A CN201610125467 A CN 201610125467A CN 107149682 A CN107149682 A CN 107149682A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
Abstract
The invention belongs to biological technical field, it is related to a kind of targeting CD47 preparation of immunologic test point inhibitor medicaments composition and application thereof.The present invention constitutes composition of medicine or drug compound preparation by the immunologic test point inhibitor and cell autophagy inhibitor for targetting CD47.Described cell autophagy inhibitor can strengthen targeting CD47 fragmentation effect of the medicine for tumour cell, so as to strengthen the antitumor curative effect of such medicine；The drug regimen compound preparation of described cell autophagy inhibitor and targeting CD47, the Targeting Effect and the sealing effect and antitumous effect for CD47 sites of medicine can be strengthened, while ensureing the stability and targeting of former targeting CD47 immunologic test point inhibitor.The preparation can be used for the diagnosis, detection and treatment of all kinds of tumours.The preparation technology of said preparation is simple, wide adaptability, available for mass producing.
Description
Technical field
The invention belongs to biological technical field, it is related to the immunologic test point inhibitor medicaments of novel targeted CD47 a kind of
Composition and its production and use, especially a kind of targeting CD47 immunologic test point inhibitor and one kind
Or various kinds of cell autophagy inhibitor combine the novel compound medicine to be formed or pharmaceutical composition and preparation method thereof and
Purposes.
Background technology
(integrin associated protein, integrin associated are also known as prior art discloses CD47
Protein IAP), it is a kind of cell transmembrane albumen in tumor cell surface height expression, it includes five cross-films
Domain and an Ig spline structures domain；In immune cell, CD47 part is mainly Signal Regulation egg
White α (SIRP α, also known as MyD-1)；CD47 by and its part combination adjust cell migration, phagocytosis
Activity and immune homeostasis；In body immune system, CD47 plays the part of a class " not eating me " signal, can pass through
Ig spline structures domain and SIRP α NH2Terminal domains combination can produce the signal for suppressing macrophage phagocytosis,
And then inhibitory action is produced to body inherent immunity system.At present to target CD47 drug research it is more be
CD47 and the combination of its part are blocked, so that the combination for getting rid of CD47 and its part is produced to inherent immunity system
Raw inhibitory action.Existing medicine has anti-CD47 monoclonal antibodies, SIRP α albumen, SIRP α/MyD-1/
CD172-Fc fusion proteins etc..
CD47 is used as " not eating a me " signal so that tumour cell can escape body immune system to it
Phagocytosis.Targeting CD47 SIRP α-Fc fusion proteins can block CD47 and the combination of its part for a long time,
About the research discovery to different human leukemia cell's Nude Mouse Models, the monoclonal antibody for targetting CD47 passes through resistance
Disconnected CD47-SIRP α combination, activation body to the removing of the leukaemia of transplanting (Chao MP,
Alizadeh AA,Tang C,Myklebust JH,Varghese B,et al.Cell 2010
142:699-713).The studies have shown that of cancer cell Weissman group blood sources and that non-blood is originated
CD47 expression is some higher in tumor stem cell, and it is tumor patient to further point out CD47 high expression
One poor prognosis factor.Because CD47 is in the overexpression of tumor cell surface, it is suppressed that macrophage is to swollen
The removing of oncocyte, so as to improve the survival rate of tumour cell in vivo.Van groups are prominent in homologous SIRP α
The research of modification mouse Transplanted tumor model finds that SIRP alpha signals have no effect on the transfer and growth of tumour in itself, but
CD47-SIRP α combine after but seriously undermined monoclonal antibody treatment drug effect (Zhao XW, Van Beek EM,
Schornagel K,Van der Maaden H,Van Houdt M,et al.Proc.Natl.Acad.Sci.
USA 2011 108:18342–47)；These results are targeting CD47-SIRP α treatment malignant tumours or increasing
The drug effect of strong monoclonal antibody provides theoretical foundation.
Studies have found that CD47 can improve the efficiency that medicine is passed into tumor microenvironment, and particularly, Rodriguez
Group in recombinant C D47 protein bindings to nanoparticle, improve in vivo the half-life period of nanoparticle in the circulating cycle and
Cytotoxic drug passs drug effect rate into tumour；Pass through Fc γ R suppression bodies pair with reference to the CD47 of nanoparticle
The removing of nanoparticle, this is combined with the CD47-SIRP α being noted above weakens antibody-mediated oncotherapy
Effect it is consistent (Rodriguez PL, Harada T, Christian DA, Pantano DA, Tsai RK,
Discher DE.Science 2013 339:971–75)；It is another to there is research erythrocyte membrane to wrap up nanoparticle
Afterwards, find this phagocytosis that can suppress body to nanoparticle, and this inhibitory action be CD47 according to
Bad (Hu C-MJ, Fang RH, Luk BT, Chen KN, Carpenter C, et al.Nanoscale
2013 5:2664–68)；These results show that targetting CD47 is likely to become the effective means for improving and passing drug effect rate.
Cell autophagy (autophagy) is also known as II type programmed death (the programmed cell of type II
Death), be evolution conservative in eucaryote body responsible intracellular matter turnover significant process, can decompose carefully
Intracellular is damaged or unnecessary organelle and the albumen of aging generation nucleotides, and the small-molecule substance such as amino acid supplies cell
The new protein of synthesis, and the stabilization of intracellular microenvironment can be maintained.Research finds cell autophagy and a variety of diseases,
The occurrence and development of especially tumour are in close relations.Lysosome intracavitary is transported to not according to intracellular substrate
Together, mammalian cell autophagy can be divided into three kinds of modes：Big autophagy (macroautophagy), small autophagy
(microautophagy) and molecular chaperones mediation autophagy (chaperone-mediated
autophagy,CMA).Wherein, big autophagy mainly has following characteristics：(1) evolution is rapid；(2) certainly
The inducibility bitten；(3) batch is degraded；(4) non-selectivity swallows；(5) conservative of autophagy；Other two
The main distinction for planting autophagy and big autophagy is：Small autophagy is lysosome membrane self-deformation, and then parcel phagocytosis is thin
Substrate in endochylema；And the autophagy of molecular chaperones mediation then can selectively protein degradation.
Research discloses autophagy can change and various stimulation generation stress reactions to cell to external environment condition, and cell exists
The autophagy of reduced levels can occur under growth conditions, also referred to as basic autophagy, however, once stimulated by the external world,
Such as starvation, anoxic, high temperature, high-cell density or growth factor are deprived, and the level of cell autophagy will be fast
Speed up-regulation, such as in the case where nutriment lacks, non-viable non-apoptotic cell device produces amino in cell autophagy energy decomposer
Acid etc. synthesizes new protein for cell, maintains survival [1. the Piacentini M, D'Eletto of cell
M,Falasca L,et al.2011；78:197-246；②Cook KL,Shajahan AN,Clarke
R.2011；11(8):1283-94.；③Wirawan E,VandenBerghe T,Lippens S,et
al.2012；22(1):43-61.].However, as one kind of apoptosis, cell autophagy can lead to
Crossing number of ways either directly or indirectly causes cell death, and this killing may be by inducing cell apoptosis, bad
Extremely, the mechanism such as aging occurs, it is also possible to cell is directly occurred autophagy death [DentonD, Nicolson
S,Kumar S.Cell Death Differ.2012；19(1):87-95.].
Current targeting CD47 fusion protein formulations are prepared by traditional preparation process, there are feelings of missing the target
Condition, and therapeutic effect has much room for improvement.So far, there is not yet cell autophagy inhibitor is with targetting merging for CD47
Albumen constitutes the report of new formulation.
The content of the invention
The purpose of the present invention is that the defect for overcoming prior art presses down there is provided the immunologic test point of targeting CD47 a kind of
Preparation medicine composition and its production and use.The key technical problem that the present invention is solved is to prepare a kind of target
To CD47, and can notable killing tumor cell immunologic test point inhibitor medicaments composition, while ensureing former
Target the stability and targeting of CD47 immunologic test point inhibitor.
The present invention solves the problems, such as that the scheme of this technology is, by by targeting CD47 immunologic test point inhibitor and carefully
Born of the same parents' autophagy inhibitor constitutes composition of medicine or drug compound preparation.
In the present invention, cell autophagy inhibitor includes but is not limited to chloroquine (CQ), and 3-MA irrigates graceful penicillin,
Bava Lip river mycin A-1, ammonium chloride and LY294002；Preferred chloroquine in embodiments of the invention；
In the present invention, targeting CD47 immunologic test point inhibitor medicaments include but is not limited to：Anti- CD47 Dan Ke
Grand antibody, SIRP α albumen, SIRP α/MyD-1/CD172-Fc fusion proteins etc.；In embodiments of the invention
It is preferred that SIRP α-Fc (MyD-1-Fc) fusion protein, especially recombined human SIRP α/CD172-Fc
(MyD-1/CD172-Fc) fusion protein；
In the present invention, described cell autophagy inhibitor can strengthen targeting CD47 medicine for tumour cell
Fragmentation effect, so as to strengthen the antitumor curative effect of such medicine；Described cell autophagy inhibitor and targeting CD47
Drug regimen be compound preparation, can strengthen medicine Targeting Effect and for CD47 sites closing imitate
Fruit and antitumous effect.
In the present invention, pharmaceutical composition can be made with targetting CD47 medicine in cell autophagy inhibitor, using sequence
Passing through the mode used strengthens the antitumor curative effect of targeting CD47 medicines.
The composition being made up of the immunologic test point inhibitor for targetting CD47 with cell autophagy inhibitor of the present invention
Or compound preparation can be used for the tumour for the treatment of to include but is not limited to：Non-small cell lung cancer, ED-SCLC, pouring
Bar knurl, chronic myelogenous granulocytic leukemia, acute myeloid granulocytic leukemia, the white blood of acute lymphoblastic system granulocyte
Disease, breast cancer, melanoma；The fusion protein of the invention for further carrying out targeting CD47 is to non-small cell lung
The influence experiment of cancer cell autophagy level, targets the fusion protein of CD47 fusion protein formulations and targeting CD47
External rush phagocytosis comparative test and target CD47 fusion protein formulations and merge egg with targetting CD47
White cylinder therapeutic effect comparative experiments and the albumen of the fusion protein formulations and common targeting CD47 that target CD47
Cylinder therapeutic effect comparative experiments；As a result, it was confirmed that the fusion protein substantially can cause lung carcinoma cell to produce
Cell autophagy (such as Figure 1A, shown in B) and autophagy stream (as shown in Figure 1 C)；The fusion protein formulations have
Stronger rush macrophage phagocytosis, is compared with fusion protein (MyD-1-Fc) is used alone, and promotees phagocytosis effect
Fruit significantly improves, it was demonstrated that the antitumor action of novel targeted CD47 fusion protein in vivo, and and cell
New formulation, which is made, in autophagy inhibitor can significantly improve antitumous effect；The fusion protein formulations have stronger
Antitumor action, is compared with common targeting CD47 fusion protein, promotees antitumous effect and significantly improve (as schemed
Shown in 4A, B).
The combination being made up of the immunologic test point inhibitor for targetting CD47 with cell autophagy inhibitor of the present invention
Thing or compound preparation can use the diagnosis and detection of above-mentioned all kinds of tumours.
The invention provides prepare to be made up of with cell autophagy inhibitor the immunologic test point inhibitor for targetting CD47
Composition or compound preparation method, including the configuration of 1) autophagy inhibitor medicine；2) target
To the preparation of CD47 mother liquid medicines；3) preparation of targeting CD47 immunologic test point inhibitor medicaments composition
.The preparation technology of said preparation is simple, wide adaptability, available for mass producing.
Brief description of the drawings
Fig. 1 shows that targeting CD47 fusion protein causes non-small cell lung cancer cell to produce cell autophagy,
Wherein, A：Laser confocal fluorescence microscope observes the generation of autophagosome, B：Electron microscope observation is certainly
Bite the generation and distribution of body, C：Laser confocal fluorescence microscope detects the whole process of autophagy stream.
Fig. 2 is that the fusion protein formulations for targetting CD47 promote phagocytosis of the macrophage to non-small cell lung cancer cell.
Fig. 3 is the suppression of targeting CD47 fusion protein and its preparation to the growth of transplanted tumor in nude mice,
Wherein, A：Target the influence of CD47 fusion protein and its preparation to tumor volume growth, B：Targeting
Influence of the CD47 fusion protein and its preparation to tumor weight.
Life of Fig. 4 targetings CD47 fusion protein formulations and common targeting the CD47 albumen to transplanted tumor in nude mice
Long suppression,
Wherein, A：The albumen of the fusion protein formulations and common targeting CD47 that target CD47 is given birth to gross tumor volume
Long influence, B：CD47 fusion protein formulations and common targeting CD47 albumen are targetted to tumor weight
Influence.
Embodiment
Embodiment 1
1) configuration of autophagy inhibitor medicine
(1) preparation of chloroquine solution：Take appropriate chloroquine to be dissolved in 0.01M PBS (pH=7.4) and be made into 10mmol/L
Storing liquid, with being stored in 4 DEG C after 0.1 μm of filter filtration sterilization, experiment in vitro room dilution 500-1000
It is used to suppress cell autophagy again；
(2) preparation of ammonium chloride solution：Take appropriate ammonium chloride to be dissolved in 0.01M PBS (pH=7.4) and be made into 0.4mol/L
Storing liquid, with being stored in 4 DEG C after 0.1 μm of filter filtration sterilization, 50-80 times is diluted during experiment in vitro
For suppressing cell autophagy；
(3) preparation of 3-MA solution：Take appropriate 3-MA to be dissolved in 0.01M PBS (pH=7.4) and be configured to 200mM
Storing liquid, with being stored in -20 DEG C after 0.1 μm of filter filtration sterilization, 2mM is diluted to during experiment in vitro
For suppressing cell autophagy；(4) preparation of LY294002 solution：Appropriate LY294002 is taken to be dissolved in 0.01M PBS
(pH=7.4) 20mM storing liquid is configured to, with being stored in -20 DEG C after 0.1 μm of filter filtration sterilization,
20 μM are diluted to during experiment in vitro is used to suppress cell autophagy；
2) preparation of CD47 mother liquid medicines is targetted
Targeting CD47 medicine can be obtained by R＆D companies, weigh 10mg targeting CD47 albumen or fusion protein
Freeze-dried powder, in the PBS solution for being dissolved in 1ml 0.02M pH=7.4, be sufficiently stirred for and with 0.1 μm of sterile filter
Device is filtered, and concentration is 10mg/mL, and 4 DEG C of preservations are diluted to 10 μ g/ml during in vitro test；
3) preparation of novel targeted CD47 immunologic test point inhibitor medicaments composition
The immunologic test point inhibitor for targetting CD47 is prepared into cell autophagy inhibitor and will target the new of CD47
Type pharmaceutical composition：The mother liquid medicine and chloroquine solution of targetting CD47 are pressed 1:1 mixing so that targeting CD47
Fusion protein concentration 1mg/mL, the concentration of chloroquine is 1mmol/L.100 times are diluted during experiment in vitro：
4) influence of the targeting CD47 fusion protein to non-small cell lung cancer cell autophagy level
Above-mentioned targeting CD47 fusion protein (MyD-1-Fc) is pressed into volume 1:100 are added in culture medium,
Using laser confocal fluorescence microscope, electron microscope and observation and the detection fusion egg respectively such as protein imprinted
Influence to non-small cell lung cancer cell autophagy level in vain, test result indicates that, the fusion protein can substantially draw
Play lung carcinoma cell and produce cell autophagy (Figure 1A, B) and autophagy stream (Fig. 1 C).
5) the external rush phagocytosis of fusion protein of the targeting CD47 fusion protein formulations with targetting CD47 is compared
Non-small cell lung cancer cell is marked using CFSE, and macrophage and non-small cell lung cancer cell are co-cultured,
Above-mentioned targeting CD47 fusion protein formulations (MyD-1-Fc+CQ) are pressed volume 1:100 are added in culture medium,
Observe the influence that fusion protein formulations swallow non-small cell lung cancer cell to macrophage.Laser co-focusing fluorescence shows
Micro mirror observe result as shown in Fig. 2 test result indicates that, the fusion protein formulations have stronger rush macrophage
Phagocytosis, is compared with the fusion protein (MyD-1-Fc) is used alone, and is promoted phagocytosis effect and is significantly improved.
6) cylinder therapeutic effect of fusion protein of the targeting CD47 fusion protein formulations with targetting CD47 is compared
By above-mentioned targeting CD47 fusion protein formulations (MyD-1-Fc+CQ) and targeting CD47 fusion protein
(MyD-1-Fc) with the dosage of 100 every mouse of μ L by being injected intraperitoneally in Mice Body, 2 times a week, even
After continuous treatment 4 weeks, tumour growth volume line chart as shown in Fig. 2 test result indicates that, the fusion protein system
Agent has stronger antitumor action (Fig. 3 A, B), is compared with the fusion protein is used alone, promotees antitumor effect
Fruit significantly improves (Fig. 3 A, B).Demonstrate the antitumor work of novel targeted CD47 fusion protein in vivo
With, and new formulation is made with cell autophagy inhibitor can significantly improve antitumous effect.
7) targeting CD47 fusion protein formulations are compared with the cylinder therapeutic effect of common targeting CD47 albumen
By the albumen of above-mentioned targeting CD47 fusion protein formulations (MyD-1-Fc+CQ) and common targeting CD47
(B6H12) 2 times a week, continuously controlled with the dosage of 100 every mouse of μ L by being injected intraperitoneally in Mice Body
Treat after 4 weeks, tumour growth volume line chart as shown in Fig. 2 test result indicates that, the fusion protein formulations have
Stronger antitumor action (Fig. 4 A), is compared with common targeting CD47 fusion protein, promotees antitumous effect
Significantly improve (Fig. 4 A, B).
Claims (9)
1. a kind of targeting CD47 immunologic test point inhibitor medicaments composition, it is characterised in that by targetting
CD47 immunologic test point inhibitor constitutes composition of medicine or drug compound preparation with cell autophagy inhibitor.
2. the immunologic test point inhibitor medicaments composition of the targeting CD47 as described in claim 1, it is special
Levy and be, described cell autophagy inhibitor is selected from chloroquine (CQ), 3-MA irrigates graceful penicillin, and Bava Lip river is mould
Plain A-1, ammonium chloride or LY294002.
3. the immunologic test point inhibitor medicaments composition of the targeting CD47 as described in claim 1, it is special
Levy and be, described targeting CD47 immunologic test point inhibitor medicaments are selected from：Anti- CD47 monoclonal antibodies,
SIRP α albumen or SIRP α/MyD-1/CD172-Fc fusion proteins.
4. the immunologic test point inhibitor medicaments composition of the targeting CD47 as described in claim 1, it is special
Levy and be, described cell autophagy inhibitor is chloroquine.
5. the immunologic test point inhibitor medicaments composition of the targeting CD47 as described in claim 1, it is special
Levy and be, described targeting CD47 immunologic test point inhibitor medicaments are SIRP α-Fc (MyD-1-Fc)
Fusion protein.
6. the immunologic test point inhibitor medicaments composition of the targeting CD47 as described in claim 5, it is special
Levy and be, described SIRP α-Fc (MyD-1-Fc) fusion protein is recombined human SIRP α/CD172-Fc
(MyD-1/CD172-Fc) fusion protein.
7. the immunologic test point inhibitor medicaments composition of the targeting CD47 described in claim 1 is for making
The Targeting Effect of standby enhancing tumor and the sealing effect to CD47 sites and antitumous effect
Purposes in medicine.
8. the purposes as described in claim 7, it is characterised in that the combination medicine in described pharmaceutical composition
Thing is sequential to be used.
9. the purposes as described in claim 7, it is characterised in that described tumour is, non-small cell lung cancer,
ED-SCLC, lymthoma, chronic myelogenous granulocytic leukemia, acute myeloid granulocytic leukemia, acute pouring
Bar system granulocytic leukemia, breast cancer or melanoma.
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| CN110981942A (en) * | 2019-12-11 | 2020-04-10 | 中国药科大学 | Polypeptide RS-17 with anti-CD47 immune checkpoint antagonistic activity and application thereof |
| CN111909276A (en) * | 2019-05-10 | 2020-11-10 | 复旦大学 | Fusion protein and application thereof |
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| CN110981942A (en) * | 2019-12-11 | 2020-04-10 | 中国药科大学 | Polypeptide RS-17 with anti-CD47 immune checkpoint antagonistic activity and application thereof |
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