53 results about "Tlr agonists" patented technology

The invention belongs to the technical field of genetic engineering and biological medicine, and particularly discloses a cascade response type nano-particle with a microenvironment remodeling function and a preparation method and application of the cascade response type nano-particle. The nanoparticle provided by the invention adopts a bionic hybrid membrane engineering strategy: an inner core is formed by loading an exosome inhibitor on a nano material, and the surface is covalently coupled with M2 type macrophage specific targeting peptide; the outer layer coats a macrophage membrane and active oxygen response type liposome composite membrane layer through a co-extrusion technology, and is loaded with a TLR agonist. Animal experiments show that after being injected through caudal vein, the nano-particles are enriched at a tumor site in a targeted manner through homing receptors such as membrane surface integrin alpha4beta1 and the like, and outer membrane cracking is triggered in a high-ROS tumor microenvironment, so that space-time controlled release of a TLR agonist and targeted phagocytosis of an exosome inhibitor by macrophages guided by a targeted peptide are realized. The anti-tumor synergistic effect is achieved through multiple regulation and control mechanisms, and an effective treatment strategy is provided for tumor immunotherapy.

The present invention belongs to the technical field of cancer immunotherapy, and particularly relates to a cholesterol-modified cationic liposome tumor vaccine, a preparation method therefor, and use thereof. In order to solve the problems of poor targeting and strong side effects of TLR agonists in anti-tumor treatment, the present invention provides a cationic liposome prepared from a cholesterol-modified 1V209 molecule, a cationic lipid component, cholesterol, and DSPE-PEG2000, and then the cationic liposome and ovalbumin 5 form the tumor vaccine by electrostatic adsorption. Animal experiments show that the vaccine can induce antigen-specific CD8+ T cells, activate lymphocytes, and generate stronger antigen cross-presentation, more memory T cells, antibodies, and cytokines. Prophylactic inoculation with the vaccine can significantly delay the progression of mouse melanoma and lymphoma and prolong the survival of mice. The combination use of the vaccine and a PD-1 checkpoint inhibitor can further enhance the anti-tumor effect. Therefore, the vaccine is a promising cancer vaccine.

The present application provides methods of treating cancer in a subject involving administering to the subject an SHP-1 inhibitor (e.g., TPI-1 or an analog or derivative thereof) and a pro-inflammatory agent (e.g., a TLR agonist, radiation therapy, or an immune checkpoint inhibitor). In some cases, the methods involve administering an SHP-1 inhibitor when the individual is in an inflammatory response.

The present invention relates to antibody conjugates which are particularly suitable for targeting cells expressing PTK7, in particular tumor cells. An antibody conjugate according to the present invention has structure (1): AB-[(L6) b-{Z-L-D} x] y (1) wherein AB is an antibody capable of targeting a tumor expressing PTK7; l is a joint connecting Z to D; z is a linking group; l6 is-GlcNAc (Fuc) w-(G) j-S-(L7) w '-wherein G is a monosaccharide, j is an integer in the range of 0 to 10, S is a sugar or a sugar derivative, GlcNAc is N-acetylglucosamine, and Fuc is fucose, w is 0 or 1, w' is 0, 1 or 2, and L7 is-N (H) C (O) CH2-,-N (H) C (O) CF2-or-CH2-; d is selected from the group consisting of an anthracycline, a camptothecin, a tubulysin, an endiyne, an amanitine, a duocarmycin, a maytansinoid, an aurestatin, eribulin, a BCL-XL inhibitor, a miscanthus semiaquilaria, a KSP inhibitor, a TLR agonist, an indolo-benzodiazepine dimer or a pyrrolo-benzodiazepine dimer (PBD), and an analog or prodrug thereof; b is 0 or 1; x is 1 or 2; and y is 1, 2, 3 or 4. The invention further relates to a method for preparing said antibody conjugate of structure (1) and to the use of said antibody conjugate of structure (1).

An adjuvant composition is disclosed by the present disclosure. The adjuvant composition comprises: a saponin conjugate represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a TLR agonist, wherein the formula (I) is shown as follows:

Comprising a multivalent fusion protein and an exosome delivery carrier, and the content of the multivalent fusion protein is 70-90 [mu] g; wherein the multivalent fusion protein is a fusion protein formed by connecting a gB glycoprotein, a gC glycoprotein, a gD glycoprotein and a high-immunogenicity part of an important antigen segment selected from gE and gI; the exosome delivery carrier is a small vesicle extracted and purified from mesenchymal stem cells or HEK 293-F cells, the surface of the exosome delivery carrier is modified with a CD40L single-chain antibody, and the exosome delivery carrier is used for loading multivalent fusion protein; the porcine pseudorabies virus vaccine further comprises adjuvants, and the adjuvants comprise a TLR agonist, CpG oligonucleotide, synthetic liposome and a traditional aluminum salt adjuvant. The porcine pseudorabies virus vaccine also comprises a mucous membrane adsorbent, a penetration enhancer, a stabilizer and a preservative. The invention aims to construct a multivalent fusion protein complex containing a plurality of important antigen segments by using an advanced bioengineering technology, and provides a wider protection effect by combining an efficient exosome delivery platform and a method for enhancing immune response.

The present application provides a method of treating cancer in an individual, the method comprising administering to the individual a tyrosine kinase inhibitor and an inflammatory agent (such as a TLR agonist, a STING activator, radiation therapy, or an immune checkpoint inhibitor). In some cases, the method involves administering the tyrosine kinase inhibitor when the individual is under inflammatory conditions. In one aspect, the present application provides a method of treating cancer in an individual, the method comprising administering to the individual a) a tyrosine kinase inhibitor and b) an inflammatory agent, optionally comprising intermittently administering the tyrosine kinase inhibitor to the individual.

The present invention pertains to the provision of a vaccine comprising a first component (K) and a second component (V), wherein the first component (K) comprises a complex in which a cell penetrating peptide, an antigenic domain and a TLR agonist are functionally linked and the second component (V) comprises an oncolytic recombinant vesicular stomatitis virus expressing an antigenic domain. The invention further pertains to the use of the inventive vaccine in the treatment of cancer. The invention also provides a recombinant vesicular stomatitis virus expressing an antigenic domain and its use in cancer vaccines.

The invention provides immunoconjugates of Formula I comprising an antibody linked by conjugation to one or more toll-like receptor (TLR), amino-azepine derivatives. The invention also provides TLR agonist amino-azepine derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the immunoconjugates through a linker or linking moiety. The invention further provides methods of treating cancer with the immunoconjugates.

The invention provides immunoconjugates of Formula I comprising an antibody linked by conjugation to one or more toll-like receptor (TLR), amino-azepine derivatives. The invention also provides TLR agonist amino-azepine derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the immunoconjugates through a linker or linking moiety. The invention further provides methods of treating cancer with the immunoconjugates.

A Toll-like receptor (TLR) is an indispensable component of an innate immune system and plays a key role in identifying and coping with microbial pathogens. TLR7, TLR8, and TLR9 are located in the endosome-lysosome compartment within the cell and then exclusively used to detect nucleic acids of a microorganism after the microorganism is swallowed and reaches the endosome compartment. The biological importance of the TLR agonists lies in that they can be used as powerful tools for studying innate immune responses, developing vaccines and potential therapeutic applications. In addition, TLR agonists have been explored for use as immunotherapy, while these TLR antagonists can be used as new pathogenic nodes in the context of different autoimmune diseases. Therefore, the agonists and antagonists of the endosomal TLR have therapeutic significance in different clinical backgrounds. The previous study on 8-oxo adenines shows that the C-6-site-NH2 group is extremely important for the recognition of agonistic active sites and the subsequent induction of interferon (IFN). The present invention explores the ability of a hydrogen-substituted 8-oxopurine derivative that does not contain an essential C-6 amine group. The C-6 amino group in the 8-oxopurine derivative is substituted by hydrogen (H), providing an exciting opinion for regulating the endosome TLRs (Toll-Like Receptors). The ability of 8-oxopurine derivatives to modulate the endosomal TLR has been reported, which derivatives are related / interrelated to various substitutions at N-7, N-9 and C-2, all derivatives containing hydrogen at C-6. Structure 1

An adjuvant composition comprises: a saponin conjugate represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a TLR agonist, wherein the formula (I) is shown as follows.

Stable aqueous formulations of adjuvant comprising a TLR7 / 8 agonist or a TLR4 agonist with a helper lipid that are adsorbed to alum are provided. Compositions and methods of using the formulations for stimulating an immune response are also provided.

The invention discloses a Toll-like receptor (TLR) agonist / organic photosensitizer protein nano-composite as well as a preparation method and application of the Toll-like receptor (TLR) agonist / organic photosensitizer protein nano-composite. In order to overcome the defects of short blood half-life period, low bioavailability and the like of the existing TLR agonist, the protein nano-composite is obtained by forming a compound in a protein cavity by using the TLR agonist and an organic photosensitizer, and has tumor and lymph node dual-targeting characteristics. The protein nano-composite is simple in preparation method, mild in condition, free of an organic solvent, uniform in particle size and has a pH-responsive drug release behavior, and the protein nano-composite is prepared by a one-step method with water as a solvent. Based on an active targeting mechanism mediated by an albumin binding receptor and an active uptake mechanism of antigen presenting cells to albumin, the nano-composite has tumor and lymph node dual-targeting characteristics, has immunotherapy and light therapy effects under irradiation of near-infrared light, and has a good application prospect from two aspects of short-term quick action and long-term body immunity improvement. Tumor growth is effectively restrained, and tumors are expected to be radically treated.

The present application relates to a kind of preparation method and application of HPV recombinant protein therapeutic vaccine, belong to biological medicine technical field, the preparation method of the HPV recombinant protein therapeutic vaccine described includes: a plurality of complex lipid nanoparticles prepared by lipid are simultaneously wrapped and delivered HPV16HPV E6E7 recombinant protein antigen and nucleic acid TLR agonist adjuvant molecule.This application is beneficial to the recombinant protein therapeutic vaccine prepared to induce strong T cell immune response to HPV16E6E7 antigen, kill the cervical cancer cell infected by HPV.In addition, unlike the lipid nanoparticle (LNP) of mRNA vaccine delivery, there is no cation or ionizable lipid in the formula, significantly higher than mRNA vaccine in safety, with greater advantage than mRNA therapeutic vaccine, and low toxicity and side effects, vaccine effect is stable.

Abstract Disclosed herein are Trastuzunab-linked TLR-agonist derivative analogs that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The Trastuzunab-linked TLR-agonist derivative analogs can include a wide range of possible functionalities, but typically have at least one oxime, carbonyl, dicarbonyl, and / or hydroxylamine group. Also disclosed herein are non-natural amino acid Trastuzumab-linked TLR-agonist derivative analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such Trastuzumab-linked TLR-agonist derivative analogs. Typically, the modified Trastuzunab- linked TLR-agonist derivative analogs include at least one oxime, carbonyl, dicarbonyl, and / or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid Trastuzumab-linked TLR-agonist derivative analogs and modified non-natural amino acid Trastuzumab-linked TLR-agonist derivative analogs, including therapeutic, diagnostic, and other biotechnology use. Abstract 20 26 20 50 50 29 J un 2 02 6 A b s t r a c t 2 0 2 6 2 0 5 0 5 0 2 9 J u n 2 0 2 6

The invention discloses a partridge extraction isolate and application thereof. According to the present invention, the chemical components of the partridge are researched, such that eight compounds are separated, and the eight compounds are respectively identified as 2-(1H-indol-3-yl) ethyl-tricosanoate (2-(1H-indol-3-yl) ethyl-tricosate) (1), lariciresinol (2), pinoresin (3), syringesin (4), dioscin (5), coniferyl aldehyde (6), syringaldehyde (7) and sinapinalde (8); the compounds are separated from partridge for the first time, the compound (1) is a new compound, the immunomodulatory effect of the compound (1) on mouse splenic lymphocytes is measured, and the result shows that the compound (1) can remarkably induce secretion of TNF-alpha and IL-6, and shows that the compound has immune activation potential equivalent to that of a classical TLR agonist.

The present application provides conjugates of a SHP-1 inhibitor, such as TPI-1 or an analog or a derivative thereof, conjugated to a pro-inflammatory agent, such as a TLR agonist or an immune checkpoint inhibitor. The present application also provides methods of treating cancer in an individual that involves administering such SHP- 1 inhibitor-pro- inflammatory agent conjugates to the individual. The SHP-1 inhibitor can be conjugated to the pro-inflammatory agent directly or through a linker.

This application provides a method for treating cancer in an individual, the method comprising administering a myeloid cell activator or myeloid cell activation therapy (such as a TLR agonist or STING agonist) and a TNFα inhibitor to the individual. In some cases, the method further comprises administering an SHP-1 inhibitor and / or a tyrosine kinase inhibitor to the individual, and optionally further comprising administering a lymphocyte activator, such as a cytokine (such as IL-2) and / or an immune checkpoint inhibitor (such as anti-PD-1).

Compositions containing a nucleic acid nanostructure having a desired geometric shape and immunostimulatory agent(s) bound to its surface are provided. The nanostructures can be, for example, in the form of a 6-helix bundle, or icosahedron, or a pentagonal bipyramid. The nanostructure design allows for control of the relative position and / or stoichiometry of the immunostimulatory agent(s) bound to its surface. The immunostimulatory agent(s) displayed on the nanostructure surface are arranged with the preferred number, spacing, and 3D organization to elicit a robust immune response. The displayed antigen can be a TLR agonist, such as a TLR9 agonist. The immunostimulatory compositions may thus be useful as immunogens, vaccines, adjuvants, and the like. Methods of inducing immune responses, and for targeted induction of TLR activation are also provided.

The present application provides conjugates of a SHP-1 inhibitor, such as TPI-1 or an analog or a derivative thereof, conjugated to a pro-inflammatory agent, such as a TLR agonist or an immune checkpoint inhibitor. The present application also provides methods of treating cancer in an individual that involves administering such SHP- 1 inhibitor-pro- inflammatory agent conjugates to the individual. The SHP-1 inhibitor can be conjugated to the pro-inflammatory agent directly or through a linker.

The application relates to the field of biological medicines, and discloses a tumor vaccine containing a polysaccharide adjuvant and application thereof. The tumor vaccine formula comprises, in terms of mass fractions, 100 parts of WT1-CM-betaG NPs, 10 parts of astragalus polysaccharide, 5 parts of quillaja saponin and 1 part of a TLR agonist. The WT1-CM-betaG NPs comprise, in terms of mass fractions, 10 parts of a WT1 polypeptide combination, 50 parts of carboxymethylated beta-glucan nanoparticles CM-betaG NPs, 10 parts of EDC and 6 parts of NHS. The WT1 polypeptide is covalently connected to the carboxymethylated beta-glucan nanoparticles through chemical coupling, and then cooperates with the adjuvant, has a synergistic effect on improving the ability of stimulating DC maturation (high expression of CD80 / CD86 / MHC-II) and improving the secretion of key Th1 type cytokine IL-12p70, can improve the antitumor effect, and has a wide application in treating WT1 positive tumors.

The invention relates to the field of biological medicine, and discloses a tumor vaccine containing a polysaccharide adjuvant and application of the tumor vaccine, and the tumor vaccine is prepared from, by mass, 100 parts of WT1-CM-beta G NPs, 10 parts of astragalus polysaccharide, 5 parts of saponin and 1 part of TLR agonist. The WT1-CM-beta G NPs is prepared from the following components in parts by mass: 10 parts of a WT1 polypeptide combination, 50 parts of carboxymethylated beta-glucan nano CM-beta G NPs, 10 parts of EDC (Ethylene Dichloride) and 6 parts of NHS (N-Hydroxysuccinimide). The WT1 polypeptide is covalently linked to the carboxymethylated beta-glucan nanoparticles through chemical coupling, then the WT1 polypeptide and the carboxymethylated beta-glucan nanoparticles cooperate with the adjuvant, the WT1 polypeptide and the carboxymethylated beta-glucan nanoparticles have a synergistic effect on improving the capability of stimulating DC maturation (highly expressing CD80 / CD86 / MHC-II) and improving the secretion of key Th1 type cell factors IL-12p70, can improve the anti-tumor effect, and have wide application in treating WT1 positive tumors.

Compound having a structure represented by one or more of the formulas I-a1 and I-c1: or a pharmaceutically acceptable salt, solvate, hydrate, crystal form, tautomer or diastereomer thereof, wherein: A is a tumor-directed unit with a molecular weight of 3000 Da or less and is a PSMA-binding unit; B is a spacer; C is a splittable or non-splittable left; D is a self-destructing spacer; c and d can each be 0 or an integer of 1 or more; preferably 0, 1, 2 or 3; wherein each occurrence of B, C and D may be in any order; and wherein each of E-a1 and E-c1 is a TLR7 agonist unit which is a structure of the formula E-a1 or E-c1 respectively. This includes: where Z a1 C3-Alkynyl is; U 1 -W 1Selected from: and R is selected from H, C 1-3 -Alkyl, C 1-3 -Haloalkyl and C 1-3 -Heteroalkyl; and R 1 selected from C 1-8 -Alkyl, C 2-8 -Cycloalkyl, (C 3-6 -Cycloalkyl) C 1-3 -alkyl, C 1-7 -Heteroalkyl, C 2-7 -Cycloheteroalkyl, -C (=O) NH (C 1-3 -alkyl), -C 1-3 -Alkyl (C=O) OME, -C(=O)NH (C 2-8 -Cycloalkyl), (C 2-7 -Cycloheteroaryl) C 1-3 -alkyl and (C 6-10 -Aryl) C 1-3 -alkyl; each optionally substituted with one or more substituents, preferably selected from OH, CH3, OMe, CN, -C(=O)Me, F2CH, SO2Me and halogen.

The invention discloses a tumor holoantigen nano vaccine as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The nano vaccine comprises a composite liposome, a nucleic acid TLR agonist adjuvant, a tumor cell membrane antigen and a tumor cell soluble antigen. The membrane antigen is embedded into the lipid bilayer, and the soluble antigen and the adjuvant are wrapped in the inner cavity of the lipid to form the nanoparticles with accurate structures. The preparation method comprises the following steps: splitting a tumor cell separation membrane antigen and a soluble antigen; mixing the membrane antigen and lipid to form a lipid phase, and mixing the soluble antigen and an adjuvant to form a water phase; finally, the two phases are self-assembled into the nano vaccine through a micro-fluidic chip. The two antigens are synergistically combined at the nanoscale, the problems that a single antigen is weak in immunogenicity and incomplete in coverage are solved, the synergic anti-tumor effect far better than that of a single antigen vaccine is shown in an animal model, the preparation process is universal and controllable, and an efficient platform is provided for individualized tumor immunotherapy.

Aspects of the present disclosure relate to functionalized polymers and methods of use thereof. Certain aspects are directed to polymers comprising adjuvants for use in stimulating an immune response. In some cases, provided are polymers comprising inflammasome activators, in some cases also comprising a TLR agonist, which may be formulated in a pharmaceutical composition. Also disclosed are methods for improving vaccine efficacy and immunotherapy efficacy. Certain aspects relate to compositions and methods for stimulation of CD4+ and / or CD8+ T cell responses in a subject.

The present invention concerns antibody-conjugates which are especially suitable for the targeting of PTK7-expressing cells, in particular tumour cells. The antibody-conjugates according to the invention have structure (1):AB-[(L6)b-{Z-L-D}x]y  1Herein, AB is an antibody capable of targeting PTK7-expressing tumours; L is a linker that links Z to D; Z is a connecting group; L6 is -GlcNAc(Fuc)w-(G)j-S-(L7)w′-, wherein G is a monosaccharide, j is an integer in the range of 0-10, S is a sugar or a sugar derivative, GlcNAc is N-acetylglucosamine and Fuc is fucose, w is 0 or 1, w′ is 0, 1 or 2 and L7 is —N(H)C(O)CH2—, —N(H)C(O)CF2— or —CH2—; D is selected from the group consisting of anthracyclines, camptothecins, tubulysins, enediynes, amanitins, duocarmycins, maytansinoids, auristatins, eribulins, BCL-XL inhibitors, hemiasterlins, KSP inhibitors, TLR agonists, indolinobenzodiazepine dimers or pyrrolobenzodiazepine dimers (PBDs), and analogues or prodrugs thereof; b is 0 or 1; x is 1 or 2; and y is 1, 2, 3 or 4. The invention further concerns a method for preparing the antibody-conjugates of structure (1) and application of the antibody-conjugates of structure (1).

The invention provides immunoconjugates of Formula I comprising an anti-Claudin 18.2 antibody linked by conjugation to one or more toll-like receptor (TLR), amino-azepine derivatives. The invention also provides TLR agonist amino-azepine derivative intermediate compositions comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the immunoconjugates through a linker or linking moiety. The invention further provides methods of treating cancer with the immunoconjugates.