CN106075432A - Pick up calcium associating adjuvant and the vaccine containing pick up calcium associating adjuvant - Google Patents
Pick up calcium associating adjuvant and the vaccine containing pick up calcium associating adjuvant Download PDFInfo
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- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
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Abstract
Pick up calcium associating adjuvant be pick up calcium adjuvant (polyinosini kanamycin calcium chloride) be that core is combined other immunopotentiating agents and further worked in coordination with the adjuvant of enhancing human body immunity.Other immunity promote agent and include various Toll-like receptor part, mineral salt, suspended particulates cleaning agent, emulsifying agent, saponifier, granule releasing agent, human cell factor, chemotactic factor, activating ligands, DC costimulatory molecules, bacterial exotoxin CT, LT (modified), liposome especially cationic-liposome, PD1/PD L1, TIM 3 blocking antibody, activate the CTLA4 of T cell, promotes other metal cations such as zinc, magnesium etc. beyond cell transfecting formulations PEI, PEG and deliming；The vaccine of pick up calcium associating adjuvant refer to the vaccine containing pick up calcium associating adjuvant include the people of prevention, treatment, muscle or mucosal immunity with and anti-cell for animals in infect and anti-tumor vaccine.Pick up calcium associating adjuvant itself is immunopotentiating agent, can the antitumor of separately made various dosage forms and anti-virus formulation.
Description
The present invention relates to Medical Immunology field, particularly relate to vaccine adjuvant and the vaccine containing this adjuvant.New adjuvant pick up calcium
The composition of associating adjuvant: (poly I: C-kanamycin-calcium chloride english abbreviation is: PICKCa) with pick up calcium adjuvant
Combine other immunopotentiating agents (pick up calcium associating adjuvant) for core, as the application in preparing immunological adjuvant, to be relatively used alone
Pick up calcium adjuvant further promotes the nonspecific immunity of body and the adjuvant of specific immunity.Pick up calcium associating adjuvant can not only
Improve the immunogenicity of antigen further, have more the effect changing immunization type further, make preventative vaccine be transformed into and have concurrently
Therapeutic and preventative vaccine, to improve anti-various intracellular infections (virus and intracellular infection further under secured premise
Antibacterial, parasite etc.), the effect of anti-various tumors.In pick up calcium adjuvant, various compositions are to be compounded in one by chemical bonds such as hydrogen bonds
Rising, in pick up calcium associating adjuvant, pick up calcium adjuvant is chemically bound together the most completely with other immunopotentiating agent, and
It it is the effect focusing on being reached to improve further immunity cure diseases by the immune system of different mechanism combined stimulation bodies.
Pick up calcium adjuvant and the vaccine containing this adjuvant we successively obtain three patents from 20th century the nineties (first be
I individually invention former patent " poly I: C compound immunologic adjuvant and the vaccine containing this adjuvant " (ZL93 1 05862.7) with
And patent " comprising adjuvant immunity material based on the polyinosinic acid-polycytidylicacid " (ZL 2,006 8 of application is combined thereafter with Li Lietao
0000776.7), " containing adjuvant mucosal immunity material based on polyinosinic acid-polycytidylicacid " (ZL 2,006 8 0001059.6), 30
Nian Laiyi at home and abroad achieves a series of impressive progress (vast stretch of wooded country is auspicious in the Internet).Adjuvant substance in these patents is polyinosine
Acid poly-kanamycin-calcium chloride english abbreviation is PICKCa and the various antigen vaccines containing this adjuvant substance.
The present invention is the further development to pick up calcium adjuvant, i.e. pick up calcium adjuvant combines other immunopotentiating agents on foundation for security
Adjuvant effect is made to improve further.Other immunopotentiating agents include various Toll-like receptor agonist, mineral salt such as aluminium adjuvant, hang
Floating microgranule cleaning agent such as MF59, ASO3, AFO3, emulsifying agent, saponifier QS21, ISCOM, GLA-SE, granule
Releasing agent such as nanoparticles, PLGA, VLP, Liposomes, Virosomes, human cell factor, chemotactic factor, live
Change part, DC costimulatory molecules, IL-12, IL-15, GM-CSF, MCP-1, CD40L, DEC-205, bacterial exotoxin
CT, LT (modified), liposome especially cationic-liposome such as DOTIM, DC-Chol, CCS, diC14 miaow, DOTAP,
DDA, PD1/PD-L1, TIM-3 blocking antibody, the CTLA4 of activation T cell, promotion cell transfecting formulations such as PEI,
Metal ion such as zinc, magnesium etc. beyond PEG and deliming ion；The vaccine of pick up calcium associating adjuvant refers to combine containing pick up calcium
The vaccine of adjuvant include prevention with or treatment use, people with or live vaccine and have and improve further anti-various intracellular infections (disease
Poison and the antibacterial of intracellular infection, parasite etc.) effect of anti-various tumors.Pick up calcium associating adjuvant itself i.e. has immunity rush
Enter effect can non-specifically resist various intracellular infection (virus and the antibacterial of intracellular infection, parasite etc.) and resist various
The effect of tumor, infects and antineoplastic injection, spray, unguentum etc. in various anti-cell can be manufactured separately into.Pick up calcium is combined
Adjuvant is the kind new medicine all not having both at home and abroad, and pick up calcium of the present invention associating adjuvant and injection, spray, unguentum etc. fall within state
Inside and outside the kind new medicine that all do not has.
It is a lot of to obtain the example of preferable immunne response associating adjuvant application, if complete Freund's adjuvant (FCA) is exactly to exempt from
Epidemic disease regulator tubercule bacillus and W/O Emulsion use in conjunction cause Th1 and Th2 response.Zamene and the success of MOD use in conjunction；
Liposome can be combined with various immune modulatory molecules MPL, MDP, QuiA；MPL and QS21 combines.CPG and aluminum
Adjuvant use in conjunction has synergism, promotes the humoral immunization of restructuring hepatitis C antigen, and aluminium adjuvant is as the delivery system of CPG
System makes the efficient immunological effect of CPG give full play to.
The formula of adjuvant should be to be used in combination with immunomodulator and carrier by adjuvant, makes immunocompetence reach optimum, and root
The immunity needed for enhancing body of the different immunopotentiating agent use in conjunction is selected according to genesis mechanism and the mechanism of action of adjuvant of disease
Response.Immunopotentiating agent comprises multiple, is promoted the immunoreation of body by different mechanism and channel, and suitable use in conjunction makes
Adjuvant effect becomes apparent from.Substantial amounts of preclinical test and clinical testing data show that TLR receptor stimulating agent is potent vaccine assistant
Agent, Toll-like receptor finds 13 kinds in white mice, finds 11 kinds in human body.Human Toll-like receptor 1,2,4,5,6
Identify extracellular and express the microbe composition at cell surface, such as: Toll-like receptor 2,4 identifies that the lipoprotein of antibacterial and fat are many
Sugar.Toll-like receptor 3,7,8,9 identifies virus or the nucleic acid of antibacterial and at endosome and lysosome.Toll-like receptor can be known
The most various different microorganisms compositions, through its important signal conduction, first cause nonspecific immune reaction, then send out
Dynamic specific immune response, produces cytokine and chemotactic factor makes T cells break up.Toll-like receptor is tied with virulence factor
Close also generation inflammatory tissue and make B cell core intrinsic factor kB (NF-kB) and interferon regulatory factor activation, induction immunity, inflammatory
Gene releaser inflammatory chemokine and 1 type interferon (IFN1).The signal of Toll-like receptor is conducted through dependence and non-dependent marrow sample divides
Change the factor (MyD88) two kinds of paths.TLR1,2,4,5,6,7,8,9 are to rely on marrow sample differentiation factor (MyD88)
Path；TLR3,4 it is that non-dependent marrow sample differentiation factor (MyD88) path or TRIF are (containing inducement interferon-β joint
Toll-like receptor region) path.TIR (Toll/ interleukin 1 receptor) territory containing adaptor protein, such as: MyD88,
Under TRIF, TIRAP (the Toll/ interleukin 1 receptor containing adaptor protein), TRAM (relevant TRIF linkers)
Trip signal conduction plays mastery reaction to inducing specific immunity.
Part TLR and part thereof
Adjuvant or immunopotentiating agent that some vaccines only use single target spot can not induce the immunity of being effectively protected property of generation anti-
Should.In addition to above-mentioned pick up calcium associating adjuvant content, it is also possible to combine adjuvant effect mechanism according to pathogenic mechanism and pick up calcium, add
As PD-1/PD-L1 antibody removes the exhaustion to T cell and the immunosuppressant to tumor, add the CTLA4 as activated T cell
And promote that accelerator such as PEI, PEG etc. of cell transfecting become associating adjuvant component, more can reach target purpose.For this
Present invention provide the technical scheme that
1. one kind is that core combines other immunity with (pick up calcium adjuvant) containing the poly I: C of kanamycin and calcium ion
Accelerator works in coordination with enhancing human body immunity excitor substance pick up calcium associating adjuvant as the application in preparing immunological adjuvant.
2. according to a kind of vaccine containing pick up calcium associating adjuvant described in right 1.It is characterized in that described adjuvant is containing skin
Card calcium associating adjuvant, described vaccine infects (virus and the antibacterial of intracellular infection, parasite etc.) in including various anti-cell
Vaccine and various anti-tumor vaccine.For vivo immunization, mucosa-immune, local immunity.
3. containing pick up calcium associating adjuvant in the application prepared in the preventative and therapeutic vaccine of mammal or people,
Including vivo immunization, mucosa-immune, local immunity.
4. according to described in right 1 with containing pick up calcium associating adjuvant immunologic stimulant stimulated in vitro immunity stem cell, such as external thorn
Sharp DC-CIK cell, NK cell, TCL/TCR-T/CAR-T cell make amplification, ripe and load tumor or infectant resist
Former feedback is internal to reach the immune effect infected in strengthening antitumor, anti-cell.It is characterized in that described immunologic stimulant contains
Skin ammonia calcium is had to combine adjuvant.
5. combine the adjuvant application as non-specific promotion immunity of organisms itself, including system according to described in right 1 with pick up calcium
Standby one-tenth aqueous injection and the application of various unguentum.It is characterized in that described immunostimulant or immunopotentiating agent contain the associating of skin ammonia calcium
Adjuvant.
6., according to claim 1 to 5, no matter pick up calcium combines adjuvant or the vaccine containing pick up calcium associating adjuvant by appointing
What approach (respiratory tract, intestinal, muscle, subcutaneous, external etc.) or with any immunity dosage form (aqueous injection, lyophilized formulations, breast
Agent, unguentum, inhalant, capsule, enema etc.) to immunity of organism or direct killing to reach anti-tumor intracellular infection mesh
Be the scope of the invention.
Illustrate necessity of the present invention below in conjunction with example, i.e. the mechanism of action and be relatively used alone skin ammonia calcium adjuvant and vaccine thereof enter one
The immune effect of step.The present invention the most only limits the pick up calcium of these citings and combines adjuvant and vaccine thereof and helping understanding.
One. pick up calcium adjuvant and TLR9 part CPG use in conjunction: pick up calcium adjuvant belongs to double-stranded RNA such as PIC adjuvant,
It it is the part of TLR3 receptor.CPG is CPG, is the part of TLR9, is divided into according to nucleotide sequence and length
A, B, C class, A and C class activating B cell (lysosome part) and Plasmacytoid DC, produce IFN-α.B class activates
B cell (inner body is divided) also makes DC ripe.Just there is the effect improving immunity further with pick up calcium adjuvant use in conjunction.
With synthetic proteins MUC as tumor vaccine use in conjunction CPG2395 and PIC, being relatively used alone more can enhancing body effectively
Anti-tumor immune response, to CD4+T cell and CD8+T cell is the most relatively used alone height, to the prevention of pulmonary carcinoma white mice with turn
The minimizing use in conjunction moving stove is also good than being used alone.
In vitro, stimulate splenocyte alone or in combination with CPG2395 and PIC, carry out cytokine secretion profile and cell increases
Grow the detection of ability；CPG2395 and PIC is alone or in combination as the adjuvant immunity mice of MUCI polypeptide antigen in vivo,
By ELISA method detection immune serum in antibody titer, CTL killing experiments detection killer T cell cytotoxicity,
The change of each cell subsets before and after Flow Cytometry analysis immunity；In tumor prevention is tested, tied by tumour inhibiting rate and Lung metastases
The metrics evaluation such as joint number are both as the adjuvant impact on MUCI immune mouse tumor prevention effect.
Result shows that the splenocyte of external use CPG2395, PIC and the two associating and normal mouse is received after being mixed 24 hours
Collection cells and supernatant, detect CPG2395 with PIC to combine compared with being used alone preferably to induce IL-12, TNF-a with
And the generation of IFN-Y.Immunized mice splenocyte is carried out flow cytometry typing, combines group mice CD4+T cell and CD8+
The rising of the most alone group of cell quantity.After CPG2395 with PIC combines as adjuvant and MUCI combined immunization C57BL/6 mice
After inoculation Lewis lung cancer, the preventive effect of pulmonary carcinoma is better than CPG2395 or PolyIC separately as parallel group of adjuvant.And
The quantity of Pulmonary metastasis focuses is the most less.Concrete outcome is to inoculate lotus tumor white mice after different adjuvant is combined with MUCI vaccine respectively
Within latter 33 days, putting to death, peel off tumor body and weigh, solution takes lungs, observes and record quantity and the size of pulmonary's metastasis.Add up and count
Calculate the average weight of each group of tumor.Result shows in matched group that average tumor weighs 6.14g scholar 1.749, and CPG2395 adjuvant group is put down
All tumors are heavily 3.79g scholar 2.789, P=0.282.The average tumor of PI:C adjuvant group is heavily 3.19g scholar 2.199, P=0.141, combines group swollen
Tumor is minimum, and average tumor is heavily only 2.5g scholar 2.479, P=0.016.Show the adjuvant of CPG2395, PIC and MUCI combined immunization
Effect is better than alone group, it is possible to preferably activates the immunne response of body, preferably suppresses tumor to develop.
The part PIC of two .TLR3 receptors and the part R848 use in conjunction of TLR7/8 receptor also combine carcinoembryonic antigen
Promote after CEA526-533 peptide fragment that dendritic cell (DC) is ripe, compare can be obviously enhanced anticancer effect with being used alone PIC:
Toll-like receptor (TLR) 2,3,4,7,8,9 ligand selectivity ground use in conjunction can further inducing dendritic shape thin
Born of the same parents (DC) are ripe, produce the desired positive result of a series of tumour immunity, as raised CCR7, CD40, CD80, CD86
Expression, raise Th1, lower Th2 reaction, the secretion of mediation IFN-Y, IL-12, TNF, IL-6 etc., and necessarily
The negative regulation effect of Treg is blocked in degree.
1, DC packet and concrete operation method:
A. associating TLR group DC (TLR-DC): at the last two days addition 20ug/ml PIC and 1.5ug/ml R848 cultivated.
B. associating TLR and load CEA526-533 peptide fragment group DC (TLR-DC+CEA): in the additions in last two days cultivated
20ug/ml PIC and 1.5ug/ml R848, is subsequently adding the peptide fragment CEA526-533 of 4oug/ml, is placed in cell culture incubator.
Take out after 3-4 hour, wash away unnecessary unconjugated skin section, i.e. obtain associating TLR the DC of load CEA.
C. load CEA526-533 peptide fragment group DC (conventional DC+CEA) of cellar culture: add the peptide fragment of 4oug/ml
CEA526-533, is placed in cell culture incubator, takes out, wash away unnecessary unconjugated skin section, i.e. obtain load after 3-4 hour
The DC of CEA526-533.
D. cellar culture DC group.
2, result:
(1). the IL-12 secretory volume of associating TLR group DC is significantly higher than conventional group, respectively 948.67 scholar 104.36pg and 215.24
Scholar 19.3spg, P ＜ 0.01.
(2). with combining the effector lymphocyte obtained after TLR group DC co-cultures, MC38-CEA colon-cancer cell is answered cell in more efficient:
During target cell (E: T) ratio, there is certain lethal effect, be significantly better than conventional group (P ＜ 0.05).
(3). for MC38 cell with combine TLR group and effector lymphocyte that conventional group DC co-cultures is all without obvious lethal effect,
Two groups of no significant differences (P ＞ 0.05).
(4), in the mouse tumor model that .MC38-CEA colon-cancer cell is set up, associating TLR activates and the DC of load CEA peptide fragment
The mouse tumor average external volume of vaccine group is significantly less than remaining each group (P ＜ 0.01), and survival period is substantially better than remaining each group
(P ＜ 0.01).
(5) in the mouse tumor model that MC38 colon-cancer cell is set up, each group tumor average volume no significant difference (P ＞ 0.05), and each group
Mouse storaging current no significant difference (P ＞ 0.05).
3, conclusion
(1). the DC vaccine more conventional DC vaccine of associating TLR group can secrete more IL 1.
(2). the Peptide-specific CTL s vaccine-induced for DC of associating TLR group can produce anti-mouse MC38-CEA intestinal cancer effectively
The specific immune response of cell.
(3) the DC vaccine of .16.3.21 associating TLR group and load CEA has significant Suppressive effect also to colon cancer tumor-bearing mice
The life cycle of mice can be extended.
Three. double-stranded RNA adjuvant use in conjunction transfecting formulations effect:
1, growth of tumour cell is significantly inhibited: double-stranded RNA adjuvant extracellular directly acts on lung cancer cell types, thin to pulmonary carcinoma
Born of the same parents' suppression ratio is less than 30%, adds transfection reagent PEI, under suitable blend proportion, measures OD value by MTT 570nm,
Show that the intracellular effect of double-stranded RNA adjuvant substantially suppresses the growth P ＜ 0.05 of A549.
2, Increase Apoptosis of Lung Cancer Cells is remarkably promoted: use Annexin V/FITC-PI double dyeing method display double-stranded RNA adjuvant and transfection
Reagent PEI, under suitable blend proportion, acts on 24 hours A549 cells and obvious apoptosis occurs, relatively matched group (PBS group),
Individually double-stranded RNA group, independent transfection reagent PEI group all there were significant differences P ＜ 0.05.
3, raise cell receptor TLR3, RIG-1, MDA-5 and the expression of IFN-β: double-stranded RNA be TLR3, RIG-1,
The part of MDA-5.Under suitable blend proportion, A549 cell 3,6 is acted on transfection reagent PEI with double-stranded RNA adjuvant
Using fluorescence quantitative PCR detection TLR3, RIG-1, MDA-5 and IFN-β mrna expression level after hour, result shows
Show that double-stranded RNA adjuvant and transfection reagent PEI group substantially raise TLR3, RIG-1, MDA-5 and the table of IFN-β mRNA
Reach, 6 little constantly, all have aobvious with other matched groups (PBS group), independent double-stranded RNA group, independent transfection reagent PEI group
Write difference P ＜ 0.01.
The foregoing is only the related embodiment of the present invention, these examples not thereby limit the scope of the claims of the present invention, simply profit
With the present invention illustrate and specify that pick up calcium associating adjuvant and containing pick up calcium associating Adjuvanted vaccines more simple pick up calcium adjuvant and
More prominent promotion immune effect is had containing pick up calcium Adjuvanted vaccines.Every present invention of utilization illustrates pick up calcium associating adjuvant
Data or equivalence flow process that formula, calibration scope and pick up calcium associating Adjuvanted vaccines formula, calibration scope are made convert, or directly
Or indirectly it is used in other relevant technical fields, the most in like manner it is included in the scope of patent protection of the present invention.
Claims (6)
1. one kind using (pick up calcium adjuvant) containing the poly I: C of kanamycin and calcium ion be core combine other immunopotentiating agents work in coordination with enhancing human body immunity excitor substance------pick up calcium associating adjuvant as the application in preparing immunological adjuvant.
2. according to a kind of vaccine containing pick up calcium associating adjuvant described in right 1.It is characterized in that described adjuvant is to combine adjuvant containing pick up calcium, described vaccine infects (virus and the antibacterial of intracellular infection, parasite etc.) vaccine and various anti-tumor vaccine in including various anti-cell.
3. containing pick up calcium associating adjuvant in the application prepared in the preventative and therapeutic vaccine of mammal or people, including vivo immunization, mucosa-immune, local immunity.
4. according to described in right 1 with the immunologic stimulant stimulated in vitro immunity stem cell containing pick up calcium associating adjuvant, as DC-CIK cell, NK cell, TCL/TCR-T/CAR-T cell make amplification, maturation and or load tumor or infectant antigen feed back internal to reach to strengthen the immune effect of infection in antitumor, anti-cell.It is characterized in that described immunologic stimulant contains skin ammonia calcium associating adjuvant.
5. combine the adjuvant application as non-specific promotion immunity of organisms itself, including being prepared as aqueous injection and the application of various unguentum according to described in right 1 with pick up calcium.It is characterized in that described immunostimulant or immunopotentiating agent contain skin ammonia calcium associating adjuvant.
6., according to claim 1 to 5, no matter pick up calcium associating adjuvant or the vaccine containing pick up calcium associating adjuvant with direct killing to immunity of organism or strengthen non-specific or specific immunity and reach anti-tumor intracellular infection purpose and be the scope of the invention by any approach (respiratory tract, intestinal, muscle, subcutaneous, external etc.) or with any immune dosage form (aqueous injection, lyophilized formulations, Emulsion, unguentum, inhalant, capsule, enema etc.).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109663126A (en) * | 2019-03-01 | 2019-04-23 | 龙阔（苏州）生物工程有限公司 | A kind of vaccine adjuvant and its application and porcine reproductive and respiratory syndrome vaccine |
| CN110168093A (en) * | 2017-09-12 | 2019-08-23 | 广州中科蓝华生物科技有限公司 | It is a kind of transfect cytozoon kit and its application |
| US11617717B2 (en) | 2017-06-19 | 2023-04-04 | Haixiang Lin | Anti-infection and anti-tumor mucosal immune preparation |
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| CN1095951A (en) * | 1993-05-31 | 1994-12-07 | 林海祥 | Poly I: C compound immunologic adjuvant and contain the vaccine of this adjuvant |
| CN101166559A (en) * | 2006-01-13 | 2008-04-23 | 申益皮卡生物技术有限公司 | Immunogenic substances comprising a polyinosinic acid - polycytidilic acid based adjuvant |
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- 2016-04-27 CN CN201610264597.XA patent/CN106075432A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095951A (en) * | 1993-05-31 | 1994-12-07 | 林海祥 | Poly I: C compound immunologic adjuvant and contain the vaccine of this adjuvant |
| CN101166559A (en) * | 2006-01-13 | 2008-04-23 | 申益皮卡生物技术有限公司 | Immunogenic substances comprising a polyinosinic acid - polycytidilic acid based adjuvant |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11617717B2 (en) | 2017-06-19 | 2023-04-04 | Haixiang Lin | Anti-infection and anti-tumor mucosal immune preparation |
| CN110168093A (en) * | 2017-09-12 | 2019-08-23 | 广州中科蓝华生物科技有限公司 | It is a kind of transfect cytozoon kit and its application |
| CN110168093B (en) * | 2017-09-12 | 2023-08-15 | 中科蓝华(广州)生物医药技术有限公司 | Kit for transfecting intracellular parasites and application thereof |
| CN109663126A (en) * | 2019-03-01 | 2019-04-23 | 龙阔（苏州）生物工程有限公司 | A kind of vaccine adjuvant and its application and porcine reproductive and respiratory syndrome vaccine |
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