CN113230397A - Novel immunologic adjuvant, compound and application thereof - Google Patents

Novel immunologic adjuvant, compound and application thereof Download PDF

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CN113230397A
CN113230397A CN202110582373.4A CN202110582373A CN113230397A CN 113230397 A CN113230397 A CN 113230397A CN 202110582373 A CN202110582373 A CN 202110582373A CN 113230397 A CN113230397 A CN 113230397A
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adjuvant
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王竹林
靳广毅
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants

Abstract

The invention provides a novel immunologic adjuvant, a compound and application thereof, wherein the immunologic adjuvant is composed of a general formula I, II or III. The immune adjuvant forms a tight ligand by using the micromolecule TLR7 stimulant with immune enhancement effect and aluminum hydroxide, and can superpose immune cell activation effect on the basis of keeping the characteristics of the aluminum adjuvant.

Description

Novel immunologic adjuvant, compound and application thereof
Technical Field
The invention relates to the field of immunization and vaccine adjuvants, in particular to a novel immunologic adjuvant, a novel compound and application thereof.
Background
Conventional vaccine adjuvants include inorganic aluminum adjuvants including aluminum hydroxide, aluminum sulfate, aluminum potassium sulfate dodecahydrate (alum), aluminum phosphate, etc., vegetable oil adjuvants, Freund's incomplete adjuvants, complete Freund's adjuvants, etc.; the vegetable oil adjuvant comprises peanut oil emulsion adjuvant, mineral oil, vegetable oil, etc.
The vegetable oil adjuvant and the Freund's adjuvant have adverse reactions such as local stimulation and the like. One of the important roles of traditional aluminum adjuvants in vaccines is to physically adsorb antigen, locally retain and stabilize vaccine components to sufficiently attract immune presenting cells for antigen presenting treatment. The aluminum adjuvant has the advantages of good safety, capability of fixing antigen at an immune position and the like, but the aluminum adjuvant has no activation enhancing effect on immune cells.
Disclosure of Invention
The invention aims to solve the technical problems that the inorganic aluminum series adjuvant lacks the activation and enhancement effect on immune cells and the vegetable oil adjuvant and Freund's adjuvant have adverse reactions such as local stimulation and the like, and provides a novel immunologic adjuvant, a novel compound and application thereof.
The technical scheme for solving the technical problems is to provide a novel immunologic adjuvant, wherein the immunologic adjuvant is composed of the following general formula I, II or III:
Figure BDA0003085896420000021
the general formulas I, II and III are all composed of phosphorylated micromolecular TLR7 agonist and aluminum hydroxide, wherein n is a molecular integer and is more than or equal to 1 and less than or equal to 100; l in the general formula I is one of a linear alkyl chain and a linear alkoxy chain.
Preferably, L is a linear alkyl chain between 2 and 20 carbon atoms long.
Preferably, L is a linear alkoxy chain with a number of oxygen atoms between 2 and 20.
Preferably, 45. ltoreq. n.ltoreq.55.
Preferably, the structural formula of the immunoadjuvant is:
Figure BDA0003085896420000031
embodiments of the present invention also provide a compound, the structural formula of which includes:
Figure BDA0003085896420000041
the invention also provides an application of the compound in preparing an immunologic adjuvant, wherein the immunologic adjuvant is used as an anti-tumor immune activator.
The invention also provides application of the compound in preparing immunomodulatory drugs, vaccines, immune cell activators or immunopotentiators.
According to the novel immunologic adjuvant, the compound and the application thereof, a tight ligand is formed by the micromolecule TLR7 excitant with the immunity enhancement effect and aluminum hydroxide, so that the induction capability of a humoral immune antibody can be enhanced on the basis of keeping the characteristics of the aluminum adjuvant, and the activation effect of immune cells is superposed. Particularly, the small phosphate molecule TLR7 agonist with a thiourea structure not only enhances the activation effect of TLR7, but also enhances the binding capacity to aluminum.
Drawings
FIG. 1 is a schematic representation of TLR7 pathway activation for compounds T-I, T-II, T-III and T-IV;
FIG. 2 is a schematic representation of the tumor-inhibiting effect of the 54 peptide vaccine (Vac);
FIG. 3 is a schematic representation of the effect of CTL-targeted killing induced by a representative vaccine;
FIG. 4 shows the results of antibody induction by 4 representative vaccines and a simple aluminum adjuvant vaccine according to the present invention;
FIG. 5 is a graph showing the effect of T-III on thiourea binding of aluminum in the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from conventional biochemical manufacturers unless otherwise specified.
The novel immunological adjuvant AlumT provided by the embodiment of the invention comprises a compound shown in the following general formula I:
Figure BDA0003085896420000051
wherein L represents a connecting chain. The general formula I consists of a phosphorylated small molecule TLR7 agonist and aluminum hydroxide, wherein the molecular number of the aluminum hydroxide, namely n, is an integer between 1 and 100, and preferably an integer between 45 and 55.
L represents one of a linear alkyl chain or a linear alkoxy chain. In one embodiment of the invention, L is preferably a linear alkyl chain between 2 and 20 carbon atoms long. L may also be a linear alkoxy chain with a number of oxygen atoms between 2 and 20 (PEG chain).
In one embodiment of the invention, a representative of the novel immunological adjuvant, AlumT, consists of the following AlumT-I:
Figure BDA0003085896420000061
in another embodiment of the invention, a representative of the novel immunological adjuvant, AlumT, consists of the following AlumT-II:
Figure BDA0003085896420000062
in another embodiment of the invention, a representative of the novel immunological adjuvant, AlumT, consists of the following AlumT-III:
Figure BDA0003085896420000063
in another embodiment of the invention, a representative of the novel immunological adjuvant, AlumT, consists of the following AlumT-IV:
Figure BDA0003085896420000071
the TLR7 agonist compounds T-I, T-II, T-III and T-IV in AlumT-I, AlumT-II, AlumT-III and AlumT-IV can be synthesized by the following methods:
T-I Synthesis
Figure BDA0003085896420000072
Firstly 100mg of K-1, 76mg of K-2, 5mg of L-sodium ascorbate and 5mg of CuSO4Dissolve in 100. mu.L water + 400. mu.L DMSO, react at room temperature for 5h, and monitor the reaction by LC-MS. After the reaction was completed, purification was performed by HPLC to obtain 50mg of T-I white solid, the yield was 29.7%. ESI-MS: M/z 715.36[ M + H ]]+。
Synthesis of T-II
Figure BDA0003085896420000081
The synthesis method of T-II has the same steps as the synthesis of T-I, namely 100mg of K-1, 76mg of K-3, 5mg of L-sodium ascorbate and 5mg of CuSO are firstly synthesized4Dissolve in 100. mu.L water + 400. mu.L DMSO, react at room temperature for 5h, and monitor the reaction by LC-MS. After the reaction is finished, purifying by HPLC to obtain a pure product of T-II, ESI-MS, M/z is 708.5[ M + H ]]+。
Synthesis of T-III:
Figure BDA0003085896420000082
the synthesis method comprises the following steps: SZU-102(386mg) and 2-aminoethyl phosphate (125mg) were mixed in 20 times the weight of DMSO, and DIPEA equivalent to the reaction mass was added; the mixture was stirred at room temperature overnight. Freeze drying the reactant, purifying the residue with HPLC to obtain pure T-III product, ESI-MS, M/z 512.12[ M + H%]+。
Synthesis of T-IV:
Figure BDA0003085896420000091
the synthesis method of the compound T-IV is the same as the method process of T-III to obtain a pure product of T-IV, ESI-MS, M/z is 647.22[ M + H ]]+。
TLR7 activation of compounds T-I, T-II, T-III and T-IV the assay was performed by the following method (HEK-Blue)TMDetection)：
Taking HEK-Blue in logarithmic growth phaseTMhTLR7 cells (purchased from InvivoGen), growth medium (Gibco, C11995500BT, Invivo Gen, ant-nr) was discarded, appropriate amounts of 37 ℃ PBS (Hyclone, SH30256.01) were gently rinsed 2 times and PBS was discarded. Adding 2-5mL of PBS (phosphate buffer solution) at 37 ℃, incubating for 1-2 min, scraping cells by using a cell scraper, and then gently blowing and beating the cells to disperse the cells into single cell suspension. Counting the cells and calculating the cell concentration using a hemocytometer using HEK-BlueTMDecpetion solution (from Invivo Gen) adjusted the cell suspension to 2.5X 104Cell plating was performed on 96 well cell culture plates per 180. mu.L well. HEK-Blue was stimulated as designed with concentrations of T-I, T-II, T-III and T-IV (0.1. mu.M, 1. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 40. mu.M)TMhTLR7 cells, Imiquimod were positive controls (1. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 40. mu.M, 80. mu.M). 3 multiple wells were set for each concentration. Incubating for 6-16 h at 37 ℃ under the condition of 5% carbon dioxide. After the incubation, the absorbance was read at 650nm using a full-wavelength microplate reader (BioTek-Epoch). As shown in fig. 1, the relative induction OD values are relative induction OD values at different concentration values (experimental group mean OD value-negative control group mean OD value)/negative control group mean OD value.
As can be seen from FIG. 1, T-I, T-II, T-III and T-IV significantly activate the TLR7 receptor pathway, and belong to TLR7 agonists.
Example 1 AlumT-I preparation:
10mg (14. mu. mol) of T-I was added to 2.5mL of purified deionized water, and 14. mu.L of a solution containing 0.56mg NaOH was added to form a clear solution. Then, 2mL of Alhydrogel (Invivogen, containing 9.0-11.0mg/mL of aluminum), 1mL of histidine buffer (100mM, pH6.5) and 4.5mL of deionized water were added. The resulting mixture was slowly stirred at room temperature for 1 hour to obtain AlumT-I adjuvant (about 10 mL). Standing at room temperature at 20-25 deg.C for storage. Wherein the mass ratio of T-I to aluminum is 1:2, and the molar ratio is 1: 53.
The preparation of AlumT-II, AlumT-III and AlumT-IV is the same as that of AlumT-I.
Example 2 preparation of 54 peptide vaccine (Vac) Using peptide 54 peptide of FZD7 protein as antigen
Frizzled7(FZD7) is an antigenic marker of tumor stem cells [ "Frizzled 7as an emitting target for cancer therapy". Cell signal.2012apr; 24 (846-51. doi:10.1016/j.cellsig.2011.12.009. "Frizzled-7 as a potential thermal target in a polar cancer cell". Neopalasia.2008Jul; 697-705, selecting the main 54 peptide as antigen to prepare therapeutic vaccine;
APVCTVLDQAIPPCRSLCERARQGCEALMNKFGFQWPERLRCENFPVHGAGEIC (54 peptide) 10mg is added into 10mL of AlumT-I adjuvant, and the mixture is gently shaken at room temperature to obtain 54 peptide vaccine (Vac 1).
Example 3 immune anti-tumor experiments with the 54 peptide vaccine (Vac1 vaccine, i.e. 54 peptide + AlumT-I) as a therapeutic vaccine
Selecting a BALB/c mouse which is homologous with CT26.WT cells and is 4-6 weeks old, and injecting the BALB/c mouse into the back of the mouse subcutaneously by 2.0 multiplied by 105When the diameter of a tumor reaches 4-5 mm, the tumor-bearing mice are randomly divided into a PBS group, an Alum group (Alhydrogel), an Alum +54 peptide, a T-I +54 peptide and a Vac1 group (vaccine group, AlumT-I +54 peptide), wherein each group comprises 10 mice. Both the group injections and the vaccine injections were started, and the Alum group contained Al (1mg/Alhydrogel 100. mu.L), the Alum +54 peptide group (containing Al 1mg/Alhydrogel 100. mu.L plus 54 peptide 100. mu.g), the T-I +54 peptide (containing T-I100. mu.g plus 54 peptide 100. mu.g plus PBS 100. mu.L), and the Vac1 group (vaccine group, AlumT-I100. mu.L plus 54 peptide 100. mu.g). The injection volume of each group is 100 μ L, and the vaccine is injected on the 8 th, 12 th, 15 th, 19 th and 22 th days after the tumor implantation, 5 times in total, and subcutaneous injection is performed around the tumor. Tumor size volumes were measured periodically for each group of mice. Counting the growth size of each group of tumors on day 36 to calculate the tumor inhibition rate; spleen lymphocytes from each group of mice were extracted for use. The specific effect is shown in fig. 2, and the results shown in fig. 2 indicate that the inhibition rate reaches 90% on day 25, i.e., the Vac1 vaccine has and is significantThe antitumor effect of (1).
EXAMPLE 4 tumor cell killing assay (CTL) of effector cells in vitro
On day 25, 3 mean tumor-bearing mice were treated from each group, splenic lymphoid effector cells (using lymphocyte separation medium (Dakewe, Beijing China) and CT26 cells were co-cultured at 50:1 for 4 hours. the killing of effector cells against target cells (CT26) was detected by the LDH method using a non-radioactive cytotoxicity detection kit (Promega, Madison, USA) according to the kit product instructions, and the results are shown in FIG. 3. As can be seen in FIG. 3, the Vac1 vaccine group had significantly improved targeted killing effects.
Example 5 antibody assay experiment of AlumT-I- -AlumT-IV as an adjuvant for prophylactic vaccines
Group 4 vaccines (Vac2, Vac3, Vac4) prepared with AlumT-II, AlumT-III, AlumT-IV and 54 peptide, prepared according to the method for preparing AlumT-I +54(Vac1) peptide vaccine, were prepared using a simple aluminum adjuvant [ Alhydrogel,54 peptide: Al (OH)3＝1:2(w/w)]And a blank control. 6X10 BALB/c mice of 4-6 weeks old are selected, 5 vaccines are divided into five groups, and then the five groups of vaccines are injected into the hind leg muscle, and the five groups of vaccines are injected into the hind leg muscle for three times on the 1 st day, the 7 th day and the 21 st day, and each injection is 100 mu L. Serum was isolated from the 35 th day and the anti-54 peptide antibody titer was measured by ELISA, and the results are shown in FIG. 4, which shows that each group of vaccines induced high titer antibodies compared to the aluminum adjuvant alone.
Although small molecule TLR7 agonists can act as vaccine adjuvants themselves, their non-specific mobility profile in vivo diminishes the local specificity required as a vaccine. The AlumT adjuvant not only maintains the advantages of an aluminum adjuvant, but also overcomes the defect that TLR7 is used as the adjuvant, enhances the induction capability of humoral immune antibodies on the basis of maintaining the characteristics of the aluminum adjuvant, and superposes the activation effect on immune cells. In particular to a small-molecule phosphate TLR7 agonist with a thiourea structure, which not only enhances the activation effect of TLR7, but also enhances the binding capacity to aluminum (figure 5).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (8)

1. A novel immunoadjuvant, characterized in that it consists of formula I, II, or III:
Figure FDA0003085896410000011
the general formulas I, II and III are all composed of phosphorylated micromolecular TLR7 agonist and aluminum hydroxide, wherein n is an integer and is more than or equal to 1 and less than or equal to 100; l in the general formula I is one of a linear alkyl chain and a linear alkoxy chain.
2. The novel immunoadjuvant of claim 1, wherein L is a linear alkyl chain between 2 and 20 carbon atoms long.
3. The novel immunoadjuvant of claim 1, wherein L is a linear alkoxy chain having an oxygen number of 2 to 20.
4. The novel immunoadjuvant of claim 1, wherein 45. ltoreq. n.ltoreq.55.
5. The novel immunoadjuvant of claim 1, wherein the formula of the immunoadjuvant is:
Figure FDA0003085896410000021
Figure FDA0003085896410000031
6. a compound having a structural formula comprising:
Figure FDA0003085896410000032
Figure FDA0003085896410000041
7. use of a compound according to claim 6 for the preparation of an immunoadjuvant for use as an anti-tumour immunoactivator.
8. Use of a compound of claim 6 for the preparation of an immunomodulatory drug, vaccine, antibody, immune cell activator or immunopotentiator.
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CN111643661A (en) * 2020-06-08 2020-09-11 王竹林 Novel immunologic adjuvant, compound and application thereof
CN112957463A (en) * 2021-02-22 2021-06-15 深圳市康居正医药科技有限公司 Immune activation type antibody and application thereof

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