78 results about "TLR9" patented technology

The invention relates to the technical field of biological medicine, and discloses a nano composite adjuvant as well as a preparation method and application thereof. The composite adjuvant mainly comprises a TLR9 agonist CpG ODN, a nanoscale liposome, a cationic lipid DOTAP and a high-efficiency immunologic stimulant QS-21, several adjuvant components are prepared into the stable and uniform nanoscale liposome by adopting a microfluidic synthesis method, CpG is wrapped inside the nanoscale liposome, QS-21 is adsorbed outside the nanoscale liposome, a stable immunologic stimulation compound is formed, and the immunologic stimulant can be used for immunologic detection of the TLR9 agonist CpG ODN, the cationic lipid DOTAP and the high-efficiency immunologic stimulant QS-21. All the components have a remarkable synergistic effect, and are matched with corresponding antigens to generate strong and lasting cellular immune and humoral immune responses.

AAV vectors are ideally suited for long-term delivery of a combination of broadly neutralizing antibodies to achieve sterilizing immunity to HIV. Unfortunately, host immune responses to the delivered antibody have severely limited the efficacy. The TLR9 pathway has been identified in initiating adaptive immune responses against AAV and delivered bNAbs. To enhance this strategy, we validated Hydroxychloroquine, a known drug inhibitor of the TLR9 pathway, as a pretreatment to AAV delivery to avoid anti-drug antibody responses. TLR9 signaling inhibition was validated using a HEK-Blue hTLR9 reporter cell line and CpG stimulation. Hydroxychloroquine was also validated in a 3-macaque trial where AAV9-3BNC117 and AAV9-10-1074 were administered along with 3 doses of hydroxychloroquine once a week starting 1 week before AAV inoculation. Unlike historical controls, where 3BNC117 and 10-1074 expression is lost within the first 4-5 weeks, 2 macaques maintained 10-1074 expression and 1 macaque maintained 3BNC117 for the duration of the trial. Anti-3BNC117 antibodies were only observed in 2 of the 3 macaques and were significantly delayed. Anti-10-1074 antibody responses were a log lower than typically observed in historic controls. The use of hydroxychloroquine as a pretreatment for AAV inoculation is a promising strategy. The significant decrease in anti-10-1074 antibody levels and the successful delivery of 10-1074 in 2 macaques and 3BNC117 in 1 macaque was very encouraging. Extending the dosage of hydroxychloroquine beyond 3 doses may be sufficient to observe long-term bNAb expression in all animals and further decrease ADA responses. Together, these data suggest that the short-term treatment of hydroxychloroquine at the time of AAV inoculation has a meaningful impact on tolerance induction to our AAV-delivered bNAbs.

Some embodiments of the present disclosure relate to one or more compositions that upregulate the production of one or more sequences of mRNA. The sequences of mRNA may encode for translation of a target biomolecule, thereby causing an increase in bioavailability of the target biomolecule within a subject that is administered the one or more compositions. In some embodiments of the present disclosure, the target biomolecule is a fusion protein with an Fc fragment, such as a toll-like receptor 3-Fc (TLR3-Fc). In some embodiments of the present disclosure, the target biomolecule is toll-like receptor 9-Fc (TLR9-Fc). In some embodiments of the present disclosure, the target biomolecule is deoxyribonuclease I-Fc (DNAse I-Fc). In some embodiments of the present disclosure, the target biomolecule is neural growth factor-Fc (NGF-Fc). In some embodiments of the present disclosure, the target biomolecule is insulin-Fc.

The present invention relates to imidazo[1,2-a]pyridine and [1,2,4]triazolo[1, 5-a]pyridine derivatives of formula (I) or a salt thereof. The present compounds are inhibitors of TLR9 and useful in treating preventing, or slowing fibrotic diseases, such as e.g. liver fibrosis, renal fibrosis, biliary fibrosis or pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

The present invention relates to the field of biomedical technologies, and discloses a long-acting and stable recombinant RSV vaccine based on glycan modification and phase change materials. The vaccine comprises the following components in parts by mass: RSV F protein modified with dynamic glycans: 1 part; multi-stage phase change materials: 3-5 parts, and the multi-stage phase change materials are composed of polyethylene glycol-stearate and lauric acid-cholesterol complex, wherein the mass ratio of polyethylene glycol-stearate to lauric acid-cholesterol is 2-3:1; TLR9 agonist: 0.05-0.15 part; STING agonist: 0.02-0.08 part; amphiphilic block copolymer PLGA-PEG-PLL: 0.5-1.5 parts. The present invention solves the problems of easy inactivation, poor targeting and insufficient immunogenicity of traditional vaccines, is applicable to the prevention and treatment of viral infectious diseases, and has the application potential for large-scale production.

Compositions and methods for making and using anti-TLR9 agents, for example, monoclonal antibodies, TLR9-binding antibody fragments, and derivatives are described, as are kits, nucleic acids encoding such molecules, diagnostic reagents and kits that include anti-TLR9 agents, and methods of making and using the same.

Some embodiments of the present disclosure relate to one or more compositions that upregulate the production of one or more sequences of mRNA. The sequences of mRNA may encode for translation of a target biomolecule, thereby causing an increase in bioavailability of the target biomolecule within a subject that is administered the one or more compositions. In some embodiments of the present disclosure, the target biomolecule is a fusion protein with an Fc fragment, such as a toll-like receptor 3-Fc (TLR3-Fc). In some embodiments of the present disclosure, the target biomolecule is toll-like receptor 9-Fc (TLR9-Fc). In some embodiments of the present disclosure, the target biomolecule is deoxyribonuclease I-Fc (DNAse I-Fc). In some embodiments of the present disclosure, the target biomolecule is neural growth factor-Fc (NGF-Fc). In some embodiments of the present disclosure, the target biomolecule is insulin-Fc.

Compositions and methods for making and using anti-TLR9 agents, for example, monoclonal antibodies, TLR9-binding antibody fragments, and derivatives are described, as are kits, nucleic acids encoding such molecules, diagnostic reagents and kits that include anti-TLR9 agents, and methods of making and using the same.

The invention relates to the field of biomedical technologies and pharmaceutical preparations, and discloses a TLR9 + HA201 composite adjuvant and a preparation method and application thereof, and the TLR9 + HA201 composite adjuvant freeze-drying preparation comprises the following components: a TLR9 + HA201 composite adjuvant, a TLR9 + HA201 composite adjuvant, a TLR9 + HA201 composite adjuvant freeze-drying agent, a TLR9 + HA201 composite adjuvant freeze-drying agent, a TLR9 D-(+)-trehalose; l-glutamic acid; a citrate buffer solution; the pH value of the aqueous solution to be freeze-dried is 6.5-7.5, the concentration of the D-(+)-trehalose is 8% w / v-12% w / v, the concentration of the L-glutamic acid is 0.8% w / v-1. 5% w / v, and the concentration of the citrate buffer solution is 15-25 mM. Through the synergistic effect of D-(+)-trehalose and L-glutamic acid in a specific citrate buffer system, efficient protection on the biological activity of the TLR9 + HA201 composite adjuvant is achieved, and the freeze-dried preparation shows the immune activation ability basically consistent with that before freeze-drying after being redissolved.

The invention relates to the field of biological medicine, in particular to cationic lipid capable of being used for nucleic acid delivery, application of the cationic lipid in a TLR9 agonist composition, and a preparation method and application of the composition. Compared with a single vaccine, the TLR9 agonist LNP adjuvant compatible vaccine prepared from the cationic lipid has a more remarkable immune enhancement effect, and compared with a commercially available vaccine adjuvant and an adjuvant prepared from phospholipid used in a commercially available LNP product, the TLR9 agonist LNP adjuvant compatible vaccine prepared from the cationic lipid has stronger immune efficacy, longer duration time and better immune effect. The toxicity and distribution control of the toxicity are realized.

The present application relates to the technical fields of biological medicine and cellular immunotherapy, and particularly relates to a signal conversion receptor targeting IL-10, an engineered macrophage and application thereof. The signal conversion receptor is composed of an extracellular domain and a transmembrane domain and an intracellular domain derived from TLR9, and the extracellular domain sequentially comprises a signal peptide, a HA tag and a specific binding domain of an IL-10 receptor alpha subunit from N-terminal to C-terminal. The present application further prepares an engineered macrophage SR CAR-M capable of specifically recognizing IL-10 and converting it into a TLR9 activation signal, which can induce macrophages to polarize to M1 type and has excellent phagocytosis and killing capacity for bladder cancer, breast cancer, lung cancer and melanoma cells, and can be used for preparing related tumor treatment drugs, overcoming the common problems of existing cell therapy, such as easy exhaustion, difficult infiltration and easy inhibition in solid tumors, and having significant clinical transformation potential.

This invention belongs to the field of antitumor drug delivery technology, and discloses a dual-drug sequential delivery system, a composite hydrogel, its preparation method, and its applications. This invention achieves sequential release by encapsulating a cobalt (Co)-polyphenol coordination nanozyme (CoNZ) in a hydrogel and integrating it with microfibrils loaded with chloroquine (CQ). This invention provides a promising new approach to improving the treatment of CRPC by initially inducing ROS-mediated oxidative damage, subsequently inhibiting autophagy and blocking the TLR9 / NF-κB signaling pathway, synergistically disrupting the survival mechanisms of tumor cells.

The invention relates to application of rosa rugosa in preparation of a medicine for treating IBD (infectious bursal disease). According to the invention, firstly, it is found that the branchlet rose has a repairing effect on damage caused by IBD; researches find that the aqueous extract of rugosa branchlet can play a role by repairing intestinal barriers and inhibiting TLR4, TLR9 and proinflammatory cytokines, so that the aqueous extract of rugosa branchlet is beneficial to treatment of IBD. The invention provides an application prospect of the rosa rugosa in preparation of the medicine for treating IBD.

The invention discloses a foot-and-mouth disease inactivated vaccine immunologic adjuvant composition. The foot-and-mouth disease inactivated vaccine immunologic adjuvant composition comprises a TLR4 agonist, a TLR9 agonist, an anionic surfactant and a cationic high-molecular polymer. The weight ratio of the TLR4 agonist to the TLR9 agonist to the cationic high-molecular polymer to the anionic surfactant is (50 to 150): (50 to 150): (800 to 1100): (1 to 5). The foot-and-mouth disease inactivated vaccine immunologic adjuvant composition provided by the invention not only can provide protective activity for foot-and-mouth disease antigens, but also has the advantages of fast antibody production and high antibody production level after animal immunization, so that animals can obtain good immune protection.

A compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is disclosed. The compound inhibits a toll-like receptor (TLR) signaling pathway. A composition containing the compound and uses thereof are disclosed. The novel compound blocks the TNF-α secretion by inhibiting the expression and activation of NF-κB- and MAPK-related proinflammatory genes, and thus can be utilized as a therapeutic agent for many autoimmune diseases, such as systemic lupus erythematosus, psoriasis and psoriatic arthritis, associated with a hyperactivity of a nucleic acid:

The present disclosure provides a method for treating cancer, which includes, inter alia, a) an intratumoral cell lysis step mediated by cryolysis, and b) an intratumoral administration step of a combination of immunotherapeutic agents including: 1) i) a TLR9 agonist CpG oligodeoxynucleotide, ii) an agonistic anti-CD40 monoclonal antibody, iii) an agonistic anti-OX40 monoclonal antibody, and iv) an anti-CTLA4 monoclonal antibody, or 2) i) a TLR9 agonist CpG oligodeoxynucleotide, ii) an agonistic anti-CD40 monoclonal antibody, iii) an anti-PD1 monoclonal antibody, and iv) an anti-CTLA4 monoclonal antibody.

Formula (I): [0003] Disclosed is a compound of formula TIFF2025538181000083.tif26153, or a salt thereof, wherein R1, R2, R3, and R4 are as defined herein. Also disclosed are methods of using the compound as an inhibitor of TLR9, and pharmaceutical compositions containing the compound. These compounds are useful for treating, preventing, or slowing the progression of fibrosis.

The present invention relates to imidazo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine derivatives of Formula (I): or a salt or prodrug thereof. These compounds are TLR9 inhibitors useful for the treatment, prevention or slowing of a fibrotic disease, such as liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

The present invention relates to 1H-pyrrolo[3,2-c]pyridine and 1H-pyrrolo[2,3-c]pyridine derivatives of formula (I) or a salt thereof. The present compounds are inhibitors of TLR9 and useful in treating preventing, or slowing fibrotic diseases, such as e.g. liver fibrosis, renal fibrosis, biliary fibrosis or pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

The present application relates to triterpene glycoside saponin-derived adjuvants, TLR4 agonists and antagonists, TLR9 agonists and antagonists, and combinations thereof, as well as pharmaceutical compositions comprising the foregoing and methods of making and of using the foregoing in the treatment of certain diseases.

The present invention relates to immunostimulatory oligonucleotides. Compositions and methods for stimulating toll-like receptor 9 (TLR9) are provided. More particularly, disclosed herein are immunostimulatory oligonucleotides, methods of enhancing immunostimulatory properties of oligonucleotides, and methods of eliciting an immune response.

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 invention relates to a CpGODN molecule and an application thereof. According to the CpG adjuvant, by optimizing a core CpG motif (such as 5 '-GACGTT-3') and a flanking sequence thereof, the activation efficiency of a Toll-like receptor 9 (TLR9) is remarkably improved. In order to further enhance the stability and the targeting property of the CpG adjuvant, the CpG oligonucleotide is subjected to phosphorothioate modification, and the CpG adjuvant shows excellent immune activation ability in both in-vitro and in-vivo experiments, can significantly enhance the immunogenicity of vaccines, overcomes the species effect, has a good stimulation effect on both mouse and human lymphocytes, and can be used for preparing the immunopotentiator. The compound has a remarkable synergistic effect with an aluminum adjuvant, realizes relatively balanced cell humoral immune response, and has a wide application prospect in the field of vaccine development.

Aspects of the invention relate to immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of a disorder, such as cancer. The IS-SNA may be administered together with a checkpoint inhibitor.

Compositions and pharmaceutical compositions are provided herein which can comprise oligonucleotides, such as synthetic CpG oligonucleotides, related to immune responses, and / or other ingredient(s). Compositions and pharmaceutical compositions described herein include those that result in a TLR9 activation. Also described are methods, among other things, for accelerating wound healing, for cell expansion, and improved methods of activated cell expansion by compositions and pharmaceutical compositions herein.

Some embodiments of the present disclosure relate to one or more compositions that upregulate the production of one or more sequences of mRNA. The sequences of mRNA may encode for translation of a target biomolecule, thereby causing an increase in bioavailability of the target biomolecule within a subject that is administered the one or more compositions. In some embodiments of the present disclosure, the target biomolecule is a fusion protein with an Fc fragment, such as a toll-like receptor 3-Fc (TLR3-Fc). In some embodiments of the present disclosure, the target biomolecule is toll-like receptor 9-Fc (TLR9-Fc). In some embodiments of the present disclosure, the target biomolecule is deoxyribonuclease I-Fc (DNAse I-Fc). In some embodiments of the present disclosure, the target biomolecule is neural growth factor-Fc (NGF-Fc). In some embodiments of the present disclosure, the target biomolecule is insulin-Fc.

Disclosed are compounds of formula (I) and (II): JPEG2023539136000114.jpg32103, or a salt thereof, wherein X, Y, Q1, Q2, G, R1, and R3 are defined herein. Also disclosed are methods of using such compounds as inhibitors of TLR9 and pharmaceutical compositions containing such compounds. These compounds are useful for treating, preventing, or slowing fibrotic diseases.