36 results about "Tlr agonists" patented technology

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).

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 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

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.

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 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 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.

The present application provides methods of treating a cancer in an individual that involves administering to the individual a tyrosine kinase inhibitor and a pro-inflammatory agent (such as a TLR agonist, a STING activator, a radiation therapy, or an immune checkpoint inhibitor). In some cases, the methods involve administering a tyrosine kinase inhibitor when the individual is under an inflammation reaction.

The present application provides methods of treating cancer in a subject comprising administering to the subject a tyrosine kinase inhibitor and a pro-inflammatory agent, such as a TLR agonist, a STING activator, radiotherapy, or an immune checkpoint inhibitor. In some cases, the methods include administering a tyrosine kinase inhibitor when the individual is in an inflammatory response.

Disclosed herein are TLR-agonists and antibody-drug conjugates thereof. TLR agonist-antibody-drug conjugates of the disclosure comprise an antibody or an antibody fragment that can bind to HER2, and contain at least one non-natural amino acid. The TLR-agonist may be conjugated to a non-natural amino acid of the antibody via an oxime linkage. Further disclosed are methods for making and using such non-natural amino acid-containing TLR-agonists-antibody-drug conjugates, including therapeutic, diagnostic, and other biotechnology uses.

The invention discloses a method for producing high-titer antiserum based on combinatorial immunity, and belongs to the technical field of biological medicine. According to the invention, the TLR agonist and the cell factor are added as immunologic adjuvants, and the TLR agonist activates innate immunity and provides a good immune microenvironment for mRNA-induced antigen-specific immune reaction; the cytokines regulate functions of immune cells and promote recognition and response of the immune cells to mRNA expression antigens. The TLR agonist and the cell factor have a synergistic effect, so that the functions of immune cells can be effectively regulated, proliferation and differentiation of T cells can be promoted, Th1 type immune response can be enhanced, and the immune function of cells can be improved; meanwhile, B cells are promoted to generate high-titer antiserum, and the humoral immune function is enhanced. Compared with pure mRNA immunization, the combined immunization method disclosed by the invention can be used for obtaining antiserum with remarkably improved titer.

The present invention provides various compositions and methods useful for the treatment of cancer, such as cancers that are resistant to immune checkpoint blockade and / or are resistant to treatment with PD-1, PD-L1 or CTLA-4 inhibitors. In some embodiments the present invention provides compositions comprising one or more CD40 agonists (e.g. CD40 agonist antibodies), TLR agonists, and / or IL10 receptor inhibitors or IL10 inhibitors, and / or various combinations thereof, optionally together with one or more immune checkpoint inhibitors, and the use of such compositions in treatment of tumors.

The invention belongs to the field of biological medicines and materials, and particularly relates to a polypeptide coupled imidazole quinoline compound as well as a synthesis method and application thereof. According to the compound, polypeptide and a TLR agonist R848 are accurately coupled at active sites of the compound. The single molecule not only has tumor killing activity, but also has low non-specific toxicity; and after further coordination with metal iridium, the anti-tumor activity can be enhanced. Besides, the compound can respond to the level of glutathione in a tumor microenvironment, controllable release of the immunologic adjuvant R848 is achieved, and therefore the anti-tumor effect is achieved through the synergistic mechanism of chemical treatment and immunoregulation. The compound can effectively integrate chemical killing and immunotherapy, kill tumor cells through multiple ways and multiple mechanisms and remodel a tumor immune microenvironment. The compound is further delivered by adopting a nano preparation, so that the accumulation efficiency of the compound in tumor tissues can be improved, microenvironment responsive release is realized, and high-efficiency and low-toxicity tumor treatment is expected to be realized.

Disclosed are pharmaceutical compositions formulated from immunomodulators formed from glycogen nanoparticles, such as monodisperse phytoglycogen nanoparticles, complexed with a pattern recognition receptor agonist, such as a TLR agonist which can be poly I:C. Also disclosed are methods of treating solid tumor cancers using the described immunomodulators, and uses of the immunomodulators to treat solid tumor cancers and to manufacture medicaments to treat solid tumor cancers.

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):Herein, 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).

Disclosed is a compound represented by the following structural formula (I): or a pharmaceutically acceptable salt thereof. The variables of structural formula (I) are described herein. The compound of the inventon can be attached to chelating groups for radionuclide binding and are therefore suitable for radioimaging and / or radiotherapy applications, for example the disclosed compounds can be radiolabeled with a positron emitter such as 18P, 68Ga or MCu, and used for positron emission tomography (PET). Alternatively, the compounds can be radiolabeled with an alpha particle emitter such as 225 Ac, a beta particle emitter such as 67Cu or 177Lu, or an Auger electron emitter (e.g. niIn, 67Ga, "mTc, 195mPt, 125I and 1231). The compounds can also be attached to a cytotoxic agent for targeted delivery of the cytotoxic agent to tumors, for example conjugated to gemcitabine or doxycycline, or a venom. Likewise, the compounds can be conjugated to compounds having physiological effects, such as TLR agonists to stimulate the immune response of a recipient.

The invention discloses a compound represented by the following structural formula (I). Or a pharmaceutically acceptable salt thereof. The variables of Structural Formula (I) are described herein. The compounds of the invention can be attached to chelating groups for radionuclide binding, and thus are suitable for radioimaging and / or radiotherapy applications, for example, the disclosed compounds can be radiolabeled with positron emitters such as 18F, 68Ga or 64Cu, and used for positron emission tomography (PET). Alternatively, the compounds can be radiolabeled with an alpha particle emitter such as 225 Ac, a beta particle emitter such as 67 Cu or 177 Lu or Auger electron emitters (e.g., 111 In, 67 Ga, 99 mTc, 195 mPt, 125 I, and 123 I). The compounds may also be attached to a cytotoxic agent for targeted delivery of the cytotoxic agent to a tumor, such as conjugated to gemcitabine or doxycycline or venom. Likewise, the compound may be conjugated to a compound having a physiological action, such as a TLR agonist, to stimulate the immune response of the receptor.

Toll-like receptors (TLRs) are integral components of the innate immune system, serving as key players in the recognition and response to microbial pathogens. TLR7, TLR8 and TLR9 are located inside the cell within the endosomal-lysosomal compartments, subsequently specialized for detecting microbial nucleic acids after microbes get phagocytosed and reach the endosomal compartments. The biological importance of TLR agonists lies in their ability to serve as powerful tools for studying innate immune responses, developing vaccines, and potential therapeutic applications. Additionally, TLR agonists have been explored as immunotherapies, whereas antagonists of these TLRs could serve as novel pathogenic node in different autoimmune disease contexts. Thus, both agonists and antagonists of these endosomal TLRs have therapeutic significance in different clinical context. The previous studies in 8-oxoadenine class depicted that the C-6 position -NH2 group is extremely important for recognition of the agonistic active site and subsequent interferon (IFN) induction. The present invention explores ability of 8-oxopurine derivatives, which does not contain the essential C-6 amine group and was replaced with hydrogen. The replacement of C-6 amino with a hydrogen (H) in 8-oxopurine derivatives provided exciting insight into these endosomal TLR modulation. The ability to modulate the endosomal TLRs by 8- oxopurine derivatives in correlation / interrelation with various substitution at N-7, N-9 and C-2 with all the derivatives containing hydrogen at C-6 were reported.