CN104623688B - It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease - Google Patents
It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease Download PDFInfo
- Publication number
- CN104623688B CN104623688B CN201510010040.9A CN201510010040A CN104623688B CN 104623688 B CN104623688 B CN 104623688B CN 201510010040 A CN201510010040 A CN 201510010040A CN 104623688 B CN104623688 B CN 104623688B
- Authority
- CN
- China
- Prior art keywords
- vaccine
- interleukin
- adjuvant
- mouse
- protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
It is to do any type of protein vaccine or coupling protein vaccine made of antigen with the natural or artificial synthesized intact proteins or protein fragments of interleukin-4 the invention discloses a kind of interleukin-4 therapeutic vaccine that can be used for treating human or animal's tumor disease；Or: any type of gene vaccine made of antigen gene or major antigen gene or fusion vaccine are done with the complete genome or genetic fragment of interleukin-4.The present invention carries out active immunity treatment to host using the form of IL-4 vaccine, generally, first immunisation is the effective time that can reach about 2~3 months, and secondary immunity is the effective treatment time that can reach about half a year, by 1~3 immunization therapy, that is, it can reach the purpose of rehabilitation.Compared with the directly anti-IL-4 Antybody therapy of application, there is the features such as number of applications is few, and dosage is low, in this way, treatment cost is not only greatly reduced, moreover, greatly reducing a possibility that generating allergic reaction.
Description
Technical field
This case is " to can be used for treating the interleukin-4 treatment of human or animal's immune related diseases for Chinese patent application
Property vaccine " (application number: divisional application 2011101749184).
Background technique
Up to the present, chronic biography caused by pathogen (virus, bacterium, helminth etc.) of the people to cytozoicus
It catches an illness and still lacks relatively effective treatment method, vaccine prevention effect is also undesirable.Theoretically, this kind of chronic infectious disease needs
Principal host, which generates the reaction of strong one kind (Th1) anti-infectious immunity, could remove pathogen, but it is strong how to induce body to generate
The reaction of Th1 anti-infectious immunity be still problem.It is found according to the long-term exploratory development of applicant, this kind of chronic infectious disease
Most of clinical onset stage all shows as very strong two classes (Th2) anti-infectious immunity reaction, i.e., with the reaction of Th2 anti-infectious immunity
Based on；And subclinical infection is then most of all shows as the reaction of very strong Th1 anti-infectious immunity, i.e., it is anti-with Th1 anti-infectious immunity
Based on answering.Further research has shown that a kind of generation with the reaction of two para-immunities is not synchronous generation, complementary shape
Formula, but mutually inhibit, the form risen one after another.IL-4 is the major cytokine that induction generates Th2 immune response, if
The content of IL-4 in host can be reduced, effectively Th2 can be inhibited to be immunoreacted, thus the generation for promoting Th1 to be immunoreacted.
It is demonstrated experimentally that injecting anti-IL-4 antibody to host can reach this purpose.But (IgG's partly declines since the half-life period of antibody is shorter
About 21-28 days phases), repeated multiple times injection is needed, not only increases cost, and easily cause allergic reaction.It is badly in need of a kind of cost
Technological means that is cheap and will not causing allergic reaction.
Summary of the invention
For the above-mentioned prior art, the present invention provides one kind to prepare simple, low in cost and safe and reliable can be used for
The interleukin-4 therapeutic vaccine for treating human or animal's immune related diseases.
The present invention is achieved by the following technical solutions:
The interleukin-4 therapeutic vaccine that can be used for treating human or animal's immune related diseases is the day with interleukin-4
(polypeptide or oligopeptides need further to divide greatly with other antigens before making vaccine for right or artificial synthesized intact proteins or protein fragments
It is sub to be mutually coupled) do any type of protein vaccine or coupling protein vaccine made of antigen；
Or: any shape made of antigen gene or major antigen gene is done with the complete genome or genetic fragment of interleukin-4
The gene vaccine or fusion vaccine of formula；
Or: with the complete genome of any carrier cloning IL-4 or genetic fragment, made with any expression system amplification gene
Gene vaccine, expression IL-4 intact proteins or protein fragments (polypeptide or oligopeptides) do any type of egg made of antigen
White vaccine or amalgamation protein vaccine；If selected expression vector belongs to live vector, live vector genetic engineering epidemic disease may be alternatively configured
Seedling.
Medically conventional vaccine adjuvant can be added in the vaccine.
Vaccine of the invention may not only be applied to the chronic infectious disease and parasitic disease for the treatment of human or animal, can also further push away
Extensively be applied to cancer, certain form of allergic reaction etc. in immune-related disease treatment.
It is different according to prepared vaccine form, the embodiment of vaccine of the invention can there are many: such as aluminium glue adjuvant, oil
The multitude of different ways such as subcutaneous injection, intracutaneous injection and intramuscular injection can be used in the vaccines such as adjuvant, Liposome Adjuvant；If it is
The different modes such as oral, sucking, collunarium, eye drip also can be used other than the above injection system in live vector vaccine.
The present invention be directed to defects existing in the prior art: " injecting anti-IL-4 antibody to host, need repeated multiple times note
Penetrate, not only increase cost, and easily cause allergic reaction ", and the technical solution proposed, it may be assumed that using the form of IL-4 vaccine
Active immunity treatment is carried out to host, generally, first immunisation is the effective time that can reach about 2~3 months, secondary immunity
The effective treatment time for reaching about half a year can reach the purpose of rehabilitation by 1~3 immunization therapy.It is anti-with directly application
IL-4 Antybody therapy is compared, and has the features such as number of applications is few, and dosage is low, in this way, treatment cost is not only greatly reduced, moreover,
Greatly reduce a possibility that generating allergic reaction.
Detailed description of the invention
Fig. 1: it is reacted first 3 weeks and 1 week subcutaneous (s.c.) to experiment BALB/c mouse respectively at induced hypersensitivity and is inoculated with embodiment 1
Prepared (seeing below embodiment 1) IL-4 genetic recombination oil-adjuvant vaccine, separately sets pET-32 carrier oil-adjuvant vaccine and physiology
Salt water immunized controls group.It was connect respectively with low dosage (5 μ g) chicken ovalbumin (OVA) aluminium glue vaccine abdominal cavity in the 0th week and the 3rd week
Kind, with sensitized mice, was instilled with high dose (80 μ g are dissolved in 50 μ l PBS) OVA by nostril in the 5th week, generated with inducing
Allergic reaction.As the result is shown: IL-4 genetic recombination oil-adjuvant vaccine immune group and pET-32 carrier oil-adjuvant vaccine group and physiology
Salt water immunized controls group is compared, and IL-4 genetic recombination oil-adjuvant vaccine can significantly reduce the generation of OVA-IgE specific antibody.
Fig. 2: experiment BALB/c mouse 3 weeks and 1 week abdominal cavity (i.p.) inoculation reality before Li Shiman parasite inoculation are given
The IL-4 genetic recombination aluminium glue vaccine that (sees below embodiment 1) prepared by example 1 is applied, pET-32 carrier aluminium glue vaccine and physiology are separately set
Salt water immunized controls group.Appropriate subcutaneous (s.c.) injection inoculation of Li Shiman helminth is in mouse hind leg foot pad.It is used weekly after inoculation
Lesion size at foot pad of calliper to measure, continues 8~10 weeks.The result shows that IL-4 genetic vaccine can significantly drop
The infection of low Li Shiman helminth.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Embodiment 1: the building and vaccine preparation of mouse IL-4 genetic vaccine
According to the full genome coded sequence of mouse IL-4, a pair of suitable primer of design expands IL- by RT-PCR method
4cDNA sequence.Then, by determined dna sequence, it was demonstrated that after the cDNA sequence expanded is accurate, then be cloned into
The suitable position of pET-32 fusion expression vector, and further by recombinant plasmid and pET-32 fusion expression vector blank control
Plasmid is transferred in appropriate expression coli strain, by scale fermentation, extraction purification IL-4 fusion protein and carrier pair
According to expressed sulphur hydrogen reduction albumen.By sulphur hydrogen reduction albumen and You Zuo expressed by purifying IL-4 fusion protein or vehicle Control
Agent or aluminium glue adjuvant etc. are by [content according to purifying IL-4 fusion protein is different, can to oil-adjuvant vaccine after proper proportion mixing
Oil/protein solution volume ratio is controlled in (1:1)~(3:1)；It, can be by aluminium glue/protein solution to aluminium glue Adjuvanted vaccines
Volume ratio control in (1:1)~(1:5)；It is required that IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen in every part vaccine
Amount be about 15-20 μ g；The volume of every part vaccine is about 0.1ml；Or prepared according to animal doctor's pharmacopeia operating instruction], further
Experiment vaccine is made in homogenate emulsification (carrying out by the operating instruction of refiner used).
The oil adjuvant is hard by 94% (V/V) mineral oil (No. 10 white oils), the Span-80 of 6% (V/V), 2% (g/V)
The pale yellow oily liquid that resin acid aluminium is formed after dissolving by heating；Oil adjuvant is that vaccine protein solution and oil adjuvant are formed through emulsification
Sticky milky water-in-oil type vaccine.Injection inoculation is generally used, is product commonly used in the prior art, is at present dynamic
Wider adjuvant is used in object inactivated vaccine.
The aluminium glue adjuvant is also that wider adjuvant is used in animal inactivated vaccine.
Embodiment 2: the safety testing of mouse IL-4 genetic vaccine and allergic reaction are tested
As described in Example 1, sulphur hydrogen reduction albumen expressed by purifying IL-4 fusion protein or vehicle Control is given birth to
It manages and is prepared by mixing into IL-4 amalgamation protein vaccine or load by the volume ratio of 1:1 with oil adjuvant or aluminium glue adjuvant after salt water suitably dilutes
Body compares sulphur hydrogen reduction protein vaccine.The IL-4 amalgamation protein vaccine prepared point low (0.1ml, about 1 part), in (0.25ml,
About 2.5 parts), high (0.5ml, about 5 parts) three various dose groups BALB/c mouse is immunized respectively, separately set pET-32 carrier epidemic disease
Seedling and saline control group, every group of 5 mouse, subcutaneous multi-point injection.Interval 3 weeks, carries out second respectively and third time is exempted from
Epidemic disease injection.Observed respectively after vaccine injection mouse have no adverse reaction, allergy, death phenomena such as.The result shows that: mouse inoculation epidemic disease
It physically well develops after seedling, the state of mind and appetite are normal, and inoculation position has the adverse reactions such as transient swelling, fever, especially exist
High dose group performance becomes apparent.For oil adjuvant seedling, high dose group mouse has slight granuloma since vaccine absorption is slower
Reaction.
Embodiment 3: the test of mouse IL-4 genetic vaccine enhancing anti-tumor activity
As described in Example 1, sulphur hydrogen reduction albumen expressed by the IL-4 fusion protein or vehicle Control by purifying is used
Physiological saline with aluminium glue adjuvant is mixed with experiment or control vaccine in the ratio of 1:1 after suitably diluting.It is required that every part vaccine
The amount of middle IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen is about 15~20 μ g；The volume of every part vaccine is about
0.1ml.To experiment mice respectively at tumour cell attack preceding 3 weeks and 1 week abdominal cavity (i.p.) inoculation embodiment 1 prepared by IL-4
Genetic recombination aluminium glue vaccine separately sets pET-32 carrier aluminium glue vaccine and physiological saline immunized controls group.Every 3 days after tumor inoculation
Check a tumour growth situation, experiment terminates for 60 days.The result shows that IL-4 genetic vaccine can significantly reduce tumour
Incidence (is shown in Table 1).
Table 1: (every group 10, data are survival to the test result of mouse IL-4 genetic vaccine enhancing anti-tumor activity
Rate %)
Embodiment 4: mouse IL-4 genetic vaccine reduces the test of recurrence rate after tumor operation
As described in Example 1, sulphur hydrogen reduction albumen expressed by the IL-4 fusion protein or vehicle Control by purifying is used
Physiological saline with aluminium glue adjuvant is mixed with experiment or control vaccine in the ratio of 1:1 after suitably diluting.It is required that every part vaccine
The amount of middle IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen is about 15-20 μ g；The volume of every part vaccine is about
0.1ml.To experiment mice after tumor operation the same day and IL-4 gene prepared by intraperitoneal inoculation embodiment 1 at the 14th day
Aluminium glue vaccine is recombinated, pET-32 carrier aluminium glue vaccine and physiological saline immunized controls group are separately set.It was checked after tumor operation every 3 days
Tumour growth situation, experiment terminate after 100 days.The result shows that IL-4 genetic vaccine can significantly reduce tumour
Recurrence rate (is shown in Table 2).Table 2: mouse IL-4 genetic vaccine enhance anti-tumor activity test result (every group 10, data
For survival rate %)
Embodiment 5: mouse IL-4 genetic vaccine inhibits the breathing anaphylactoid test of channel type
As described in Example 1, sulphur hydrogen reduction albumen expressed by the IL-4 fusion protein or vehicle Control by purifying is used
Physiological saline with oil adjuvant is mixed with experiment or control vaccine in the ratio of 1:1 after suitably diluting.It is required that in every part vaccine
The amount of IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen is about 15-20 μ g；The volume of every part vaccine is about 0.1ml.
IL-4 prepared by first 3 weeks and 1 week subcutaneous (s.c.) inoculation embodiments 1 is reacted respectively at induced hypersensitivity to experiment BALB/c mouse
Genetic recombination oil-adjuvant vaccine separately sets pET-32 carrier oil-adjuvant vaccine and physiological saline immunized controls group.In the 0th week and the 3rd
Week uses low dosage (5 μ g) chicken ovalbumin (OVA) aluminium glue vaccine intraperitoneal inoculation respectively, with sensitized mice, in the 5th week with high agent
Amount (80 μ g are dissolved in 50 μ l PBS) OVA is instilled by nostril, to induce generation allergic reaction.As the result is shown: IL-4 gene weight
Group oil-adjuvant vaccine immune group is compared with pET-32 carrier oil-adjuvant vaccine group and physiological saline immunized controls group, IL-4 gene weight
Group oil-adjuvant vaccine can significantly reduce generation (see attached drawing 1) and the pulmonary branches tracheae folliculus flushing liquor of OVA-IgE specific antibody
In acidophic cell quantity (being shown in Table 3), and significantly inhibit the hypertrophy of goblet cell and the degree of histocyte inflammation.
Table 3: mouse IL-4 genetic vaccine inhibits the secretion of acidophic cell in pulmonary branches tracheae folliculus
Embodiment 6: the test of mouse IL-4 genetic vaccine treatment murine chronic leishmaniasis
As described in Example 1, sulphur hydrogen reduction albumen expressed by the IL-4 fusion protein or vehicle Control by purifying is used
Physiological saline with aluminium glue adjuvant is mixed with experiment or control vaccine in the ratio of 1:1 after suitably diluting.It is required that every part vaccine
The amount of middle IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen is about 15-20 μ g；The volume of every part vaccine is about
0.1ml.To experiment BALB/c mouse before Li Shiman parasite inoculation 3 weeks and 1 week abdominal cavity (i.p.) inoculation 1 institute of embodiment
The IL-4 genetic recombination aluminium glue vaccine of preparation, separately sets pET-32 carrier aluminium glue vaccine and physiological saline immunized controls group.Appropriate benefit
Subcutaneous (s.c.) injection inoculation of assorted graceful helminth is in mouse hind leg foot pad.Weekly with the disease at foot pad of calliper to measure after inoculation
Become larger small, continues 8~10 weeks.The result shows that IL-4 genetic vaccine can significantly reduce Li Shiman helminth infection (see
Attached drawing 2).
Embodiment 7: mouse IL-4 genetic vaccine enhances the test of mouse prevention chronic tuberculosis disease
As described in Example 1, sulphur hydrogen reduction albumen expressed by the IL-4 fusion protein or vehicle Control by purifying is used
Physiological saline with aluminium glue adjuvant is mixed with experiment or control vaccine in the ratio of 1:1 after suitably diluting.It is required that every part vaccine
The amount of middle IL-4 fusion protein or vehicle Control sulphur hydrogen reduction albumen is about 15-20 μ g；The volume of every part vaccine is about
0.1ml.To experiment mice respectively at BCG vaccine (BCG) be inoculated with preceding 3 weeks and 1 week abdominal cavity (i.p.) inoculation embodiment 1 prepared by
IL-4 genetic recombination aluminium glue vaccine, separately sets pET-32 carrier aluminium glue vaccine and physiological saline immunized controls group.Appropriate BCG vaccine is given
Subcutaneous (s.c.) or vein (i.v.) injection inoculation of mouse.With the attack of high dose recombinant BCG, (i.v. is connect within 12~16 weeks after inoculation
Kind), then, mouse spleen is taken within 10~12 weeks, grinding, filtering, centrifugation take appropriate single cell suspension to be taped against in agar version, set
Enter to cultivate in 37 DEG C of incubators about 3 weeks, counts colony counts on each plate.The result shows that IL-4 genetic vaccine can
Significantly reduce the infection (being shown in Table 4) of BCG.
Table 4: (every group 10, count the test result of mouse IL-4 genetic vaccine enhancing mouse prevention chronic tuberculosis disease
According to for bacterium colony average on each plate)
Claims (1)
1. application of the interleukin-4 therapeutic vaccine in the drug of preparation treatment tumour, the interleukin-4 therapeutic vaccine
It is: interleukin-4 full-length gene is cloned into pET-32 expression vector, prepares IL4- sulphur hydrogen reduction fusion protein,
The volume ratio of the albumen and aluminium glue adjuvant volume ratio 1:1-1:5 prepare obtained vaccine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510010040.9A CN104623688B (en) | 2011-06-27 | 2011-06-27 | It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510010040.9A CN104623688B (en) | 2011-06-27 | 2011-06-27 | It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease |
| CN201110174918.4A CN102266551B (en) | 2011-06-27 | 2011-06-27 | Interleukin-4 therapeutic vaccine for treating immune related diseases of humans or animals |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110174918.4A Division CN102266551B (en) | 2011-06-27 | 2011-06-27 | Interleukin-4 therapeutic vaccine for treating immune related diseases of humans or animals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104623688A CN104623688A (en) | 2015-05-20 |
| CN104623688B true CN104623688B (en) | 2018-12-28 |
Family
ID=53203236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510010040.9A Active CN104623688B (en) | 2011-06-27 | 2011-06-27 | It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104623688B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1692942A (en) * | 2004-09-17 | 2005-11-09 | 四川大学 | Prepn. and application tech. for pig interleukin-4 gene anti-diseases prepns. |
-
2011
- 2011-06-27 CN CN201510010040.9A patent/CN104623688B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1692942A (en) * | 2004-09-17 | 2005-11-09 | 四川大学 | Prepn. and application tech. for pig interleukin-4 gene anti-diseases prepns. |
Non-Patent Citations (5)
| Title |
|---|
| Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine;Okada, H,et al;《Gene Therapy》;19990228;第6卷(第2期);219-228 * |
| Fusion Protein of Interleukin 4 and Pseudomonas Exotoxin with High Cytotoxicity to Cancer Cells;ZHANG Yu_Jian，等;《生物工程学报》;20041130;第20卷(第6期);862-867 * |
| IL-4与肿瘤免疫;付体辉;《上海免疫学杂志》;19931231;第13卷(第3期);176-178 * |
| IL-4基因转染瘤苗体内抗肿瘤转移;曹雪涛等;《中华微生物学和免疫学杂志》;19950228;第15卷(第1期);53-57 * |
| IL-4抗肿瘤作用及其机理的研究进展;于益芝;《国外医学免疫学分册》;19931231(第4期);208-212 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104623688A (en) | 2015-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Taslimi et al. | Leishmaniasis and various immunotherapeutic approaches | |
| CN101166559B (en) | Immunogenic substances comprising a polyinosinic acid - polycytidilic acid based adjuvant | |
| Siddiqui et al. | Enhancement of Sm-p80 (large subunit of calpain) induced protective immunity against Schistosoma mansoni through co-delivery of interleukin-2 and interleukin-12 in a DNA vaccine formulation | |
| Zhang et al. | Evaluation of the immune response induced by multiantigenic DNA vaccine encoding SAG1 and ROP2 of Toxoplasma gondii and the adjuvant properties of murine interleukin-12 plasmid in BALB/c mice | |
| CN103768595B (en) | Zoledronic acid adjuvant and the vaccine containing zoledronic acid adjuvant | |
| Cecílio et al. | Vaccines for human leishmaniasis: where do we stand and what is still missing | |
| Jiang et al. | Low-molecular-weight polysaccharides from Agaricus blazei Murrill modulate the Th1 response in cancer immunity | |
| JP7203015B2 (en) | immunogenic composition | |
| Jin et al. | Induction of potent cellular immune response in mice by hepatitis C virus NS3 protein with double‐stranded RNA | |
| Ennis et al. | Cytotoxic T lymphocytes induced in mice by inactivated influenza virus vaccine | |
| CN1909925B (en) | Immunologic adjuvant | |
| CN102127554B (en) | Japanese encephalitis particle vaccine and preparation method and application thereof | |
| CN102266551B (en) | Interleukin-4 therapeutic vaccine for treating immune related diseases of humans or animals | |
| CN102337289A (en) | Prokaryotic expression of enterovirus 71 type VP1 (virus protein 1) and vaccine containing VP1 | |
| CN104623688B (en) | It can be used for treating the interleukin-4 therapeutic vaccine of human or animal's tumor disease | |
| Rezvan et al. | Leishmania mexicana Gp63 cDNA using gene gun induced higher immunity to L. mexicana infection compared to soluble Leishmania antigen in BALB/C | |
| CN101575608A (en) | Recombinant combined DNA vaccine aiming to avian influenza virus | |
| CN105263518B (en) | Novel vaccines composition comprising immunostimulatory oligonucleotide | |
| CN107281474A (en) | Strengthen the New Immunity Strategy and immune composition of anti tumor immune response | |
| ES2546301T3 (en) | Composition containing Leishmania Lip2a | |
| CN114829608A (en) | Fusion gene, recombinant novel coronavirus high-efficiency immune DNA vaccine, and construction method and application thereof | |
| CN104623647A (en) | Therapeutic interleukin-4 vaccine capable of treating human or animal chronic tuberculosis | |
| CN102000330B (en) | Nucleic acid vaccine adjuvant and construction method thereof | |
| CN105727278B (en) | A kind of sore mouth virus recombinant protein antigen vaccine and preparation method thereof | |
| EP3752181A1 (en) | Immunotherapy of leishmaniasis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191018 Address after: 250101 Shandong Province Jinan Hi-tech Zone Comprehensive Bonded Zone Gangxing No.3 Road North Section 1 Jinan Yaogu R&D Platform Zone Building B 0323 Patentee after: Ji'nan Bao Bao Biotechnology Co., Ltd. Address before: 250022 sunshine new road, Lixia District, Shandong City, Ji'nan province 100D3-3-702 Patentee before: Liu Yong Qing |
|
| TR01 | Transfer of patent right |