CN107383174A - A kind of tumor suppression peptide and application thereof that can be specifically bound with PD 1 - Google Patents
A kind of tumor suppression peptide and application thereof that can be specifically bound with PD 1 Download PDFInfo
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- CN107383174A CN107383174A CN201710720200.8A CN201710720200A CN107383174A CN 107383174 A CN107383174 A CN 107383174A CN 201710720200 A CN201710720200 A CN 201710720200A CN 107383174 A CN107383174 A CN 107383174A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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Abstract
The present invention relates to a kind of tumor suppression peptide and application thereof that can be specifically bound with PD 1, the peptide for inhibiting can combine the extracellular region of the protein receptors of PD 1, and the albumen of PD 1 can be effectively closed in protein level and cellular level, prevent the albumen of PD 1 and part PD L1 combination.Described polypeptide has good bioactivity.The polypeptide can be individually or with that in the diagnosis and examination of the anti-monoclonal antibodies of PD 1 or the united immunotherapy of tumors of other antineoplastics and the positive tumor patients of PD 1, i.e., can apply to treat in the preparations of medicine such as tumour, autoimmune disease.
Description
Technical field
The present invention relates to disease treatment technical field, and in particular to a kind of tumor suppression peptide that can be specifically bound with PD-1
And application thereof.
Background technology
Body T cell is immunized serves important function in the generation, evolution of control tumour.Wherein tumor by local soaks
Lubricant nature CD 8+T lymphocytes have played key effect in antitumor immunity of organism response.Discovered in recent years, tumor patient body
Immunosuppression mechanism inside be present, hinder removing of the body to tumour, cause tumour to be colonized for a long time, show as T lymphocyte functions
Obstacle weakens with multiplication capacity.PD-1 has been acknowledged as the surface marker of debilitating T lymphocytes.PD-1/PD-L1 is blocked to lead to
Road can partly recover the function of debilitating T cell.Known PD-1 (programmed death 1) programmed death acceptor 1,
It is a kind of important immunosuppression molecule.For CD28 superfamily members, it is initially the mouse Tcell hybridoma from apoptosis
2B4.11, which is cloned, to be come.Immunological regulation using PD-1 as target spot moves to antitumor, anti-infective, anti-autoimmune disease and organ
Planting survival etc. has important meaning.Its part PD-L1 can also be used as target spot, and corresponding antibody can also play identical work
With.
Apoptosis albumen -1 (programmed death-1, PD-1) and its part (PD-L1) inhibitor are
Immune Sentinel point monoclonal antibody medicine, range, depth and the persistence of its response are very rare, are that tumour immunotherapy is ground in recent years
The focus studied carefully.The Buddhist nun listed lies prostrate monoclonal antibody (nivolumab) and Pan Li pearls monoclonal antibody (pembrolizumab) belongs to PD-1 suppression
Agent, it is mainly used in the treatment of melanoma and non-small cell lung cancer, the effect of to clear-cell carcinoma, carcinoma of urinary bladder, Hodgkin lymphoma etc.
Also it is preferable.
At present, the main inhibitor of apoptosis albumen -1 is monoclonal antibody, does anti-PD-1 antibody earliest
It is curetech companies, he combines with teva has pushed anti-PD-1 antibody to the second stage of clinic, but due to strategic cooperation unsuccessfully etc.
Reason, the clinical test of the medicine have stopped.Then, the small wild pharmacy of Japan and BMS develop jointly anti-PD-1 antibody
Nivolumab, the medicine list in Japan, turn into the monoclonal antibody medicine of first pd-1 drug targets in the world.BMS is current
In U. S. application BLA, it is contemplated that listing in the recent period.In addition, BMS companies are laid out for a long time in tumour immunity field, first anti-immunity inspection
Point antibody-anti-CTLA-4 antibody is exactly the product of the said firm.In addition, Roche, GSK stare at this drug target of PD-1, it is anti-
PD-1 antibody all comes into clinical investigation phase.BMS is laid out for a long time in immunotherapy of tumors field, and its anti-CTLA-4 resists
Good sales volume is obtained after body listing.But I had never expected that Merck ＆ Co., Inc. catches up from behind, September Keytruda takes the lead in granted.Just
It is based on the huge market prospects of PD-1 inhibitor, current major medicine enterprise enters on a large scale one after another.
According to the space structure design polypeptide of albumen, studied at present so as to suppress the function of albumen in three-dimensional structure
Focus, and also there are multiple products to list.High investment and uncertainty based on the research of PD-1 antibody, for PD-1 spy
The research of different in nature peptide for inhibiting and a new research direction.
The content of the invention
The defects of for prior art, the present inventor are found that a kind of small peptide suppresses by the work of lot of experiments and hardships
Agent, it has significant inhibitory action to PD-1, can be used as treating and/or prevent the pharmaceutical activity of the disease relevant with PD-1 into
Point.Therefore, it is an object of the invention to provide a kind of small peptide inhibitor and application thereof.
To realize the purpose of the present invention, the present invention uses following technical scheme:
On the one hand a kind of CAD preparation method of peptide for inhibiting is provided, the computer software is applicant
The peptide designer of Independent Development Design, the design method are that to set length be the random short of 25-150 amino acid
Peptide makes it in the surface migration of PD-1 protein moleculars, and changes peptide fragment and PD-1 relative position by electric charge, quickly calculates the peptide
The active force of each atom and protein surface adjacent atom in section, and energy variation caused by mobile, torsion peptide fragment；And repeatedly
The more various possible combinations of optimization, select minimum energy, as determining conformation.According to Condensate Composed of Interactive Atoms distance and
Spatial relationship show that polypeptide obtains with the binding site of PD-1 molecules, the atomic radical and the mode of action of participation, final screening
10 associativities and inhibition highest suppress peptide sequence, finally determine that 1 peptide for inhibiting has best suppression using Bioexperiment
Effect processed.
In still further aspect, the present invention provides a kind of small peptide inhibitor, is SEQ ID NO in its sequence:Amino shown in 1
Acid sequence.
Preferably, the sequence of the small peptide inhibitor is modified in N sections using amidatioon, C-terminal connection cholesterol modification.
Still further aspect of the present invention, there is provided a kind of peptide for inhibiting-nano-particles reinforcement system, prepare and repair in the following manner
Decorations:
(1) peptide for inhibiting:Prepared by Fmoc/ t-Butyl strategies and HOBt/TBTU/NMM the method chemical synthesis being coupled (
Directly it can be synthesized by biotech firm)；
(2) synthesis of 60nm gold nanos microballoon:Utilize Chinese catalpa lemon acid sodium reduction one-step synthesis 18nm gold grains；
(3) synthesis of gold nanorods:Gold nanorods are synthesized using seed mediated growth method；
(4) the surface polypeptide modification of nanogold particle；
(5) sign of nanogold particle after modifying:The physicochemical properties of gold grain through modification can be by measuring its light
Spectrum and Zeta- potentials characterize.
In yet another aspect, the invention provides pharmaceutical composition, it includes the anti-PD-1 inhibitor of the present invention, Yi Jike
Pharmaceutical carrier.
In yet another aspect, the invention provides for treating or preventing cancer or infectious disease in object in need
The method of disease, it includes the polypeptide/of the present invention or pharmaceutical composition being administered to the object.
In yet another aspect, the invention provides in object in need strengthen T cell immune response method,
It includes the polypeptide/of the present invention or pharmaceutical composition being administered to the object.In some embodiments, the enhancing T is thin
The cell factor that born of the same parents' immune response includes enhancing T cell produces, and preferably described cell factor includes IL-2 and/or IFN-γ.
In some preferred embodiments, the cell factor of the enhancing T cell, which produces, includes the T cell that anti-cd 3 antibodies stimulate
Cell factor produces.In other preferred embodiments, the object is cancer patient, such as PD-L1 positive cancers are suffered from
Person, preferably lung cancer and melanoma patient.
In yet another aspect, the invention provides the method for promoting T cell activation in object in need, it is wrapped
Include and the polypeptide/of the present invention or pharmaceutical composition are administered to the object.Preferably, methods described is also included anti-cd 3 antibodies
It is administered to the object.
In yet another aspect, the invention provides for eliminating suppressions of the PD-L1 to T cell activation in object in need
The method of system, it includes the polypeptide/of the present invention or pharmaceutical composition being administered to the object.Preferably, methods described is also wrapped
Include and anti-cd 3 antibodies are administered to the object.
In yet another aspect, the invention provides the method (preferably external) for promoting T cell activation, it includes making this hair
Bright polypeptide or pharmaceutical composition is in contact with T cell.Preferably, methods described also includes making anti-cd 3 antibodies with T cell connect
Touch.
In yet another aspect, the invention provides the method for eliminating suppression of the PD-L1 to T cell activation is (preferably external
), it includes making the polypeptide/of the present invention or pharmaceutical composition be in contact with T cell.Preferably, methods described also includes making to resist
CD3 antibody is in contact with T cell.
The positive effect of the present invention is：Polypeptide of the present invention its with PD-1 albumen there is high affinity
(affinity KD<1×10-12M), the extracellular region of PD-1 protein receptors can be combined, and can had in protein level and cellular level
Effect closing PD-1 albumen, prevents PD-1 albumen and part PD-L1 combination.Described polypeptide has good bioactivity.Should
Polypeptide can be individually or positive with anti-PD-1 monoclonal antibodies or the united immunotherapy of tumors of other antineoplastics and PD-1
In the diagnosis and examination of tumour patient, i.e., it can apply to treat in the preparations of medicine such as tumour, autoimmune disease.
Brief description of the drawings
Fig. 1 is gross tumor volume and administration time graph of a relation in embodiment 4.
Embodiment
The present invention is described in detail with reference to embodiment, but they are not the further limitations to the present invention.
Embodiment one:The acquisition of peptide for inhibiting
Inventor designs according to the computer-implemented method peptide designer of self-designed peptide for inhibiting
Corresponding peptide for inhibiting, the design method are that the random small peptide for setting length to be 25-150 amino acid makes it in PD-1 albumen point
The migration of sublist face, and peptide fragment and PD-1 relative position are changed by electric charge, quickly calculate each atom and albumen on the peptide fragment
The active force of surface adjacent atom, and energy variation caused by mobile, torsion peptide fragment；And optimize repeatedly more various possible
Combination, minimum energy is selected, determines conformation the most.Distance and spatial relationship according to Condensate Composed of Interactive Atoms show that polypeptide is same
The binding site of PD-1 molecules, the atomic group participated in and the mode of action, final screening obtain 10 associativities and inhibition
Highest suppresses peptide sequence, finally determines that 1 peptide for inhibiting has best inhibition using Bioexperiment.Other 9 effects
It is not particularly pertinent numerous to list herein.Peptide sequence with preferable inhibition is：
KWQEEGQAIHSTNLTQYPHRSGLRVGCHDWRTWPHNYPCGALPRKNYSLFPQDHTPCYIWYYSPDLQHMPNNVKHNS
SRSPDLLASKPPVTESPWWHIDTQMSGYMA.It is specific binding and PD-1 protein receptor wherein at the three of underscore
Extracellular region, disulfide bond is formed between the 11st amino acid and the 77th amino acids.
Measure of the peptide for inhibiting of embodiment 2 to PD-1 affinity
(1) by polypeptide with 1 × PBS be configured to concentration be 1mg/mL solution, anti-PD-1 polypeptide is configured to 100 μ g/
ML solution, 2.5 μ L are taken to be dropped on the SPR chips (being purchased from Plexera companies, Kx5 type SPR standard configurations substrate) of carboxylated,
Polypeptide is fixed on SPR chips by the specific reaction of streptavidin and biotin.By concentration it is successively then 0.1 μ
G/mL, 1 μ g/mL, 10 μ g/mL, 50 μ g/mL PD-1 solution (1 × PBS dilutions) as mobile phase by chip surface, with reference to
Time 150s, Dissociation time 130s, live again time 200s.Using 1 × PBS as dissociation solution, using 0.5% phosphoric acid as living again
Liquid.The combination dissociation curve of polypeptide and TNF-α is recorded on the type SPR instrument (Plexera) of K × 5.
(2) with polypeptide described in Langmuir formula fittings and PD-1 SPR curves.Be computed obtaining balance combination/
Dissociation constant.The equilibrium dissociation constant KD values of the polypeptide and PD-1 are 0.12 × 10-12M, show the polypeptide and PD-1 combination
It is very capable.
The biological activity detection of the peptide inhibitor of embodiment 3
(1) selection is deposited in China Committee for Culture Collection of Microorganisms's common micro-organisms center with registration number 10298
JurKat/PD-1/NFAT cells as target cell, shine 2.5 × 10 using DMEM/F12+10%FBS culture mediums4Individual/hole,
The even density in the holes of 100 μ 1/ is spread into 96 orifice plates (corning), 37 DEG C of 5%CO2It is incubated overnight in incubator；
(2) prepare various concentrations polypeptide solution using 1640+10% hyclone culture mediums and be diluted to 1 μ g/mL, Ran Houxiang
Lower 10 times of doubling dilutions, 7 concentration points, suck the DMEM/F12+10%FBS culture mediums in above-mentioned 96 orifice plate, more by what is prepared
Inhibitor peptides solution is added in 96 orifice plates according to the holes of 50 μ 1/；
(3) target cell suspension is prepared using 1640+10% hyclone culture mediums, and according to 5 × 104Individual/hole, 50 μ l/
The even density in hole is spread into above-mentioned 96 orifice plate, in 37 DEG C of 5%CO2It is incubated 6 hours in incubator；
(4) relative chemical flat light emission value (rlu) is read using chemiluminescence on M200 or Pherastar ELIASAs,
The biological activity of peptide inhibitor is calculated by data processing, peptide inhibitor median effective dose concentration is calculated according to four parametric regressions
EC50 is 0.016 μ g/ml.
Embodiment 4 uses antidepressants antibody processing vivo tumor model
Peptide for inhibiting is modified in N sections using amidatioon respectively using this area conventional practices, C-terminal connection cholesterol is repaiied
Decorations, are named as PD-1-YZL-C；
Peptide for inhibiting-nano-particles reinforcement system is prepared in addition, prepares and modifies in the following manner, and methods described is this
The conventional operating method in field:(1) peptide for inhibiting:By directly being synthesized by biotech firm；(2) synthesis of 60nm gold nanos microballoon:
Utilize Chinese catalpa lemon acid sodium reduction one-step synthesis 18nm gold grains；(3) synthesis of gold nanorods:Jenner is synthesized using seed mediated growth method
Rice rod；(4) the surface polypeptide modification of nanogold particle.It is named as PD-1-YZL-NM.
The mouse of cancerous tumour is implanted with processing in peptide for inhibiting to be influenceed with examining inside antibodies on tumor growth.According to
Female AJ mouse between 6-8 week old are randomly divided into 6 groups by body weight.The 0th day by be dissolved in 200 μ l DMEM culture mediums 2 ×
106Individual SA1/N fibrosarcoma cells are subcutaneously implanted mouse on right side.Mouse is handled with PBS control or 1mg/kg peptide for inhibiting.
It is administered with the about 20 μ l PBS for containing peptide for inhibiting or control by intraperitoneal injection to animal dosage within 1st, 4,8 and 11 day.Every group
Comprising 10 animals, each group composition is as follows:(1) PBS control group, (2) peptide for inhibiting；(3)PD-1-YZL-C；(4)PD-1-YZL-
NM.Tumour growth is monitored twice a week to mouse, continues about 6 weeks.It is (high that three-dimensional measurement is carried out to tumour using electronic caliper
Degree X width X length) and calculate gross tumor volume.When tumour reaches tumour terminal (1500mm3) or show that the body weight more than 15% subtracts
Mouse is put to death when few.As a result it is shown in Fig. 1.Inhibitor polypeptide is up to tumour terminal volume (1500mm3) average time
Extended to from 25 days of control group 50 days.Thus, peptide for inhibiting processing has inhibition inside directly to tumour growth.Using
PD-1-YZL-C and PD-1-YZL-NM is substantially similar to peptide for inhibiting effect, and it is up to tumour terminal volume (1500mm3) it is flat
The equal time extended to 55 days from 25 days of control group.Improved compared with peptide for inhibiting.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not limited by embodiment
System, it is other it is any without departing from the present invention Spirit Essences with made under principle change, modification, combine, replacement, simplification should be
Equivalence replacement mode, is included within protection scope of the present invention.
Sequence table
<110>Suzhou Li Hao bio tech ltd
<120>A kind of tumor suppression peptide and application thereof that can be specifically bound with PD-1
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 107
<212> PRT
<213>Artificial peptide (2 Ambystoma laterale x Ambystoma jeffersonianum)
<400> 1
Lys Trp Gln Glu Glu Gly Gln Ala Ile His Ser Thr Asn Leu Thr Gln
1 5 10 15
Tyr Pro His Arg Ser Gly Leu Arg Val Gly Cys His Asp Trp Arg Thr
20 25 30
Trp Pro His Asn Tyr Pro Cys Gly Ala Leu Pro Arg Lys Asn Tyr Ser
35 40 45
Leu Phe Pro Gln Asp His Thr Pro Cys Tyr Ile Trp Tyr Tyr Ser Pro
50 55 60
Asp Leu Gln His Met Pro Asn Asn Val Lys His Asn Ser Ser Arg Ser
65 70 75 80
Pro Asp Leu Leu Ala Ser Lys Pro Pro Val Thr Glu Ser Pro Trp Trp
85 90 95
His Ile Asp Thr Gln Met Ser Gly Tyr Met Ala
100 105
Claims (7)
- A kind of 1. tumor suppression peptide, it is characterised in that：It can be specifically bound with PD-1.
- 2. peptide for inhibiting as claimed in claim 1, it is characterised in that：The suppression peptide amino acid sequence such as SEQ ID NO：1 institute Show.
- A kind of 3. peptide for inhibiting modified peptides, it is characterised in that：Peptide for inhibiting in claim 2 is modified, used respectively in N-terminal Amidatioon is modified, and C-terminal connection cholesterol modification, is named as PD-1-YZL-C.
- 4. a kind of peptide for inhibiting-nano-particles reinforcement system, is in the following manner modified the peptide for inhibiting of claim 2： (1) peptide for inhibiting:By directly being synthesized by biotech firm;The synthesis of (2) 60 nm gold nano microballoons:Utilize Chinese catalpa lemon acid sodium reduction The nm gold grains of one-step synthesis 18；(3) synthesis of gold nanorods:Gold nanorods are synthesized using seed mediated growth method；(4) nanogold The surface polypeptide modification of grain, the product of acquisition are named as PD-1-YZL-NM.
- 5. the hybrid system described in any described peptide for inhibiting of claim 1-3 or claim 4 is preparing suppression PD-1 work Purposes in the medicine of property.
- 6. the hybrid system described in any described peptide for inhibiting of claim 1-2 or claim 4 is preparing suppression cancer Purposes in medicine.
- A kind of 7. method for suppressing cancer, it is characterised in that：Using the tumor suppression peptide or power described in claim any one of 1-2 Profit requires peptide for inhibiting-nano-particles reinforcement system described in peptide for inhibiting modified peptides or claim 4 described in 3.
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| CN109265533A (en) * | 2018-10-30 | 2019-01-25 | 苏州立豪生物科技有限公司 | A kind of improved tumor suppression peptide and application thereof that can be specifically bound with PD-1 |
| WO2019168524A1 (en) * | 2018-02-27 | 2019-09-06 | Leidos, Inc. | Pd-1 peptide inhibitors |
| CN110478472A (en) * | 2019-09-29 | 2019-11-22 | 北京鼎成肽源生物技术有限公司 | PD-1 sealer and its application |
| US10799581B2 (en) | 2016-09-15 | 2020-10-13 | Leidos, Inc. | PD-1 peptide inhibitors |
| US10799555B2 (en) | 2016-09-15 | 2020-10-13 | Leidos, Inc. | PD-1 peptide inhibitors |
| CN113336824A (en) * | 2021-04-30 | 2021-09-03 | 重庆理工大学 | Application of polypeptide as PD-1/PD-L1 protein-protein interaction (PPI) regulator |
| US11338040B2 (en) | 2020-06-04 | 2022-05-24 | Leidos, Inc. | Immunomodulatory compounds |
| US11987646B2 (en) | 2020-10-12 | 2024-05-21 | Leidos, Inc. | Immunomodulatory peptides |
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| US10799581B2 (en) | 2016-09-15 | 2020-10-13 | Leidos, Inc. | PD-1 peptide inhibitors |
| US11793856B2 (en) | 2016-09-15 | 2023-10-24 | Leidos, Inc. | PD-1 peptide inhibitors |
| US10799555B2 (en) | 2016-09-15 | 2020-10-13 | Leidos, Inc. | PD-1 peptide inhibitors |
| WO2019168524A1 (en) * | 2018-02-27 | 2019-09-06 | Leidos, Inc. | Pd-1 peptide inhibitors |
| CN111548408A (en) * | 2018-10-30 | 2020-08-18 | 苏州立豪生物科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN111647064A (en) * | 2018-10-30 | 2020-09-11 | 苏州立豪生物科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN111647065A (en) * | 2018-10-30 | 2020-09-11 | 苏州立豪生物科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN109265533A (en) * | 2018-10-30 | 2019-01-25 | 苏州立豪生物科技有限公司 | A kind of improved tumor suppression peptide and application thereof that can be specifically bound with PD-1 |
| CN111548407A (en) * | 2018-10-30 | 2020-08-18 | 苏州立豪生物科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN109265533B (en) * | 2018-10-30 | 2020-11-17 | 广东赛尔生物科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN111548408B (en) * | 2018-10-30 | 2021-08-03 | 德琪(浙江)医药科技有限公司 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN111647065B (en) * | 2018-10-30 | 2021-10-08 | 北京永恩堂医学研究院 | Improved tumor inhibiting peptide capable of being specifically combined with PD-1 and application thereof |
| CN110478472B (en) * | 2019-09-29 | 2020-08-28 | 北京鼎成肽源生物技术有限公司 | PD-1 sealant and application thereof |
| CN110478472A (en) * | 2019-09-29 | 2019-11-22 | 北京鼎成肽源生物技术有限公司 | PD-1 sealer and its application |
| US11338040B2 (en) | 2020-06-04 | 2022-05-24 | Leidos, Inc. | Immunomodulatory compounds |
| US11987646B2 (en) | 2020-10-12 | 2024-05-21 | Leidos, Inc. | Immunomodulatory peptides |
| CN113336824A (en) * | 2021-04-30 | 2021-09-03 | 重庆理工大学 | Application of polypeptide as PD-1/PD-L1 protein-protein interaction (PPI) regulator |
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| CN107383174B (en) | 2019-01-18 |
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