51 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.

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).

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.

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:

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.

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.

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.

Disclosed is a compound of formula (I): JPEG2023538608000184.jpg3235 or a salt or prodrug thereof, wherein X, Y, Q1, Q2, R1, and R5 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.

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.

A multi-target DC vaccine based on tumor antigen epitope peptides and its application belong to the field of tumor immunotherapy technology. The vaccine comprises an hr-8 conjugate peptide, an immune adjuvant, a carrier, and an immune memory enhancer. The hr-8 conjugate peptide is a conjugate product formed by chemically linking an hr-8 targeting peptide with at least two different tumor antigen CTL epitope peptides. The immune adjuvant is a combined adjuvant system of the TLR9 agonist CpG ODN and the TLR3 agonist poly(I:C). The carrier is PLGA nanoparticles, and the immune memory enhancer is IL-7 and / or IL-15. This invention utilizes the specific binding of the hr-8 peptide to the DEC-205 receptor on the surface of dendritic cells to achieve efficient synergistic delivery and cross-presentation of multi-target antigens. The combined adjuvant and memory factor significantly enhance CTL activation and promote long-term immune memory formation, giving the multi-target DC vaccine advantages such as strong targeting, broad antigen coverage, and prolonged relapse-free survival.

The invention provides a method for preparing a DCs vaccine, and relates to the technical field of vaccine preparation. The method for preparing the DCs vaccine comprises the following steps: mixing antigens with granulocytes and monocyte colony forming factors (GM-CSF), or performing fusion recombinant expression at a gene level to form a fusion protein, combining the fusion protein with a TLR9 antagonist CpG, activating DCs in in-vitro cell culture, and using the DCs as the vaccine for preventing and treating related diseases, including tumors, infectious diseases, autoimmune diseases and the like.

The present invention belongs to the technical field of cancer immunotherapy and specifically relates to a combination-therapy drug and composition of a cholesterolylated TLR7 liposome and a TLR9 agonist and use thereof. Toll-like receptor agonists have poor targeting capability and significant side effects in anti-tumor treatment, and, as monotherapy in anti-tumor treatment, have limited efficacy. To address the described issues, the present invention provides the cholesterolylated TLR7 liposome, which is prepared from the cholesterol-modified 1V209 molecule 1V209-Cho, a lipid component, and cholesterol, and uses the liposome in combination with the TLR9 agonist to treat tumors. Animal results show that the combination of the liposome and the TLR9 agonist, when administered as nasal drops or by means of intramuscular injection, can significantly inhibit pulmonary metastasis of cervical cancer cells and melanoma cells, indicating that using the cholesterolylated liposome 1V209-Cho-Lip in combination with the TLR9 agonist to treat tumors is a strategy with great potential.

This invention belongs to the field of biomedicine and provides the application of LAPF in the preparation of antiviral drugs. This invention enhances lysosomal acidification in dendritic cells or macrophages by administering LAPF protein, nucleic acid molecules encoding LAPF, or their functional enhancers, thereby promoting TLR9 transport to lysosomes and activating the type I interferon pathway. Experimental results demonstrate that administering LAPF protein, nucleic acid molecules encoding LAPF, or their functional enhancers can significantly reduce the viral load of DNA viruses such as HSV-1, increase the survival rate of infected mice, and enhance IFN-α / β production, exhibiting a good antiviral immune-enhancing effect.

The invention provides a polymer composite adjuvant for an animal vaccine and a preparation method thereof, and the polymer composite adjuvant for the animal vaccine comprises acrylate hydrogel, nano oil emulsion and an immunopotentiator, the acrylate hydrogel is prepared by the following steps: generating a polyacrylate precipitate from an acrylic hydrophilic monomer and an acrylic hydrophobic monomer in a solvent by adopting a precipitation polymerization method, and immersing the precipitate in ultrapure water, the hydrophilic monomer is one of acrylic acid and methacrylic acid, and the hydrophobic monomer is acrylate with the carbon chain length of 10-22; the immunopotentiator is a TLR3 (toll-like receptor 3) or TLR9 (toll-like The polymer composite adjuvant disclosed by the invention has good biocompatibility, low mineral oil content and small side effects, not only can play an antigen slow release role, but also can improve the cellular immune response of an organism, has the average particle size of 40-60 nm, and is good in dispersity, and a prepared vaccine is low in viscosity and easy to inject; and the preparation process is simple, the stability is high, and the biological safety is good.

Formula (I): TIFF2025538180000077.tif32153 (wherein L, R1, R2, R3 and R4 are defined herein) or a salt thereof. Also disclosed are methods of using the compounds as inhibitors of TLR9, and pharmaceutical compositions containing the compounds. These compounds are useful for treating, preventing, or slowing the progression of fibrosis.

A Toll-like receptor agonist is a class C CpG-ODN capable of effectively activating TLR9, wherein its nucleotide sequence includes one of the nucleotide sequences shown in SEQ ID NOs: 1-4, either modified or unmodified. The Toll-like receptor agonist has a significant inhibitory effect on tumor growth. The provided lipid-encapsulated Toll-like receptor agonist can inhibit tumor growth, prevent tumor recurrence, and improve the efficiency of immune activation, either alone or in combination with other therapeutic agents, exhibiting improved performance compared to free Toll-like receptor agonists.

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 a method for treating uveal melanoma liver metastasis in a human subject. The method comprises administering to the subject a therapeutically effective combination of one or more checkpoint inhibitors and a toll-like receptor 9 (TLR9) agonist having the following structure: 5 '-TCG AAC GTT CGA ACG TTC GAA CGT TCG AAT-3' (SEQ ID NO: 1). The one or more checkpoint inhibitors are systemically administered to the subject and the TLR9 agonist is locally administered to the liver of the subject by means of hepatic arterial infusion at a dose sufficient to provide a therapeutically effective concentration in the liver when combined with the checkpoint inhibitor.