21 results about "Cyclic dinucleotides" patented technology

Disclosed herein are cyclic di-nucleotide compounds and derivatives thereof that may be useful as STING agonists, and a pharmaceutical composition comprising the same. Also disclosed herein is the process for synthesis and to uses of such cyclic di-nucleotide compounds in various diseases including cancer, HIV infection and HBV infection.

To provide a novel stereoselective method for producing a cyclic dinucleotide derivative that can be used for an antibody-immunostimulator conjugate, and a production intermediate thereof, and to provide methods for producing a cyclic dinucleotide-linker and antibody-immunostimulator conjugate using the production method.SOLUTION: The present invention relates to a method that makes it possible to produce, in large amounts and with high yield, a cyclic dinucleotide derivative having a desired steric configuration, by using an optically active phosphitylation agent twice, during coupling and cyclization.SELECTED DRAWING: None

Cyclic dinucleotides (CDRs) are signaling molecules for cancer therapy, acting as second messengers for intracellular events initiated by GPCR activation and stimulating factors for the interferon gene (STING), thus significantly influencing tumor suppression. Simultaneously, when cancer occurs in a subject, angiogenesis and cell growth proceed at very high rates in vivo, creating a hypoxic environment due to incomplete angiogenesis in cancerous tissue. This environment can be highly conducive to the proliferation of anaerobic bacteria such as Salmonella strains or Escherichia coli. Therefore, this invention relates to a DNA construct incorporating a gene encoding an enzyme for synthesizing cancer therapeutic signaling molecules (e.g., CDRs), or to strains transformed with a vector containing the DNA construct. According to the invention, the DNA construct or strains transformed with a vector containing the DNA construct target cancer in a subject and then secrete C-di-AMP or C-di-GMP synthases in the surrounding environment of the cancer, thus enabling highly effective prevention or treatment of cancer while allowing for real-time cancer diagnosis.

The present invention belongs to the technical field of medical nanomaterials, and specifically discloses a HIFU nano-synergist and its preparation and application. The synergist includes nanoparticles loaded with banovanthraquinone and cyclic dinucleotides, and the nanoparticles are spherical nanoparticles with a metal organic framework formed by self-assembly of metal ions and banovanthraquinone cyclic dinucleotides, and the metal ions are preferably manganese ions. The present invention utilizes the response characteristics of metal coordination bonds to acid to effectively release and synergistically treat anticancer drugs banovanthraquinone and cyclic dinucleotides in tumor tissues, thereby enhancing the anti-tumor effect; banovanthraquinone can selectively act on hypoxic cells, while overcoming hypoxia resistance to kill tumor cells without harming normal tissues; manganese ions and cyclic dinucleotides are used in combination to activate the interferon gene stimulator (STING) pathway, enhance the body's innate immunity and adaptive response, thereby reversing the immunosuppression caused by the tumor microenvironment and promoting tumor immunotherapy.

In the present invention, cyclic dinucleotides or their compositions are used as biological response modifiers to enhance the immune response of subjects with deficient immune systems, with a low or absent response to vaccine antigens, or with a deficient immune response to pathogens. The formulations of the present invention are capable of modifying the biological response in such a way as to eliminate the lack of response, resulting in the development of a high-avid immune response that prevents disease caused by infectious agents, particularly viruses with the ability to evade immune surveillance mechanisms and, consequently, suppress the induction of an effective, high-avid adaptive response.The present invention also comprises cyclic dinucleotide formulations, which can be administered alone, in combination with other biological response modifiers, or in vaccine formulations with antigens. The proposed invention further includes a method for preventing or treating acute respiratory infections, preventing disease severity, and blocking transmission by inducing an immune response at the point of entry (nasopharyngeal mucosa), preventing or reducing person-to-person transmission of pathogens / viruses in preventive vaccine formulations, as well as in formulations used for prophylaxis before and after exposure to acute respiratory infections.

It is desired to develop a novel CDN derivative having a STING agonist activity and a therapeutic agent and / or a therapeutic method for a disease associated with a STING agonist activity using the novel CDN derivative. In addition, it is desired to develop a therapeutic agent and / or a therapeutic method for a disease associated with STING agonist activity, which can specifically deliver the novel CDN derivative to a target cell or organ.SOLUTION: The present invention provides novel CDN derivatives having strong STING agonist activity, and antibody CDN derivative conjugates comprising the novel CDN derivatives.SELECTED DRAWING: None

The present disclosure provides a method of producing cyclic dinucleotides (CDNs) on a commercial scale. Also provided are pharmaceutical compositions comprising a purified CDN preparation and use thereof to stimulate the immune system in a subject.

In the present invention, a cyclic dinucleotide or a composition thereof is used as a biological response modulator to improve an immune response in a subject having a low immune system function, a low / no response to a vaccine antigen, or a poor immune response to a pathogen. The formulations of the present invention are able to alter biological responses in a manner that eliminates non-responsiveness, thereby producing a high affinity immune response to prevent diseases caused by infectious agents, in particular viruses, which have the ability to evade the immune surveillance mechanism and thus inhibit the induction of high affinity and efficient adaptive responses. The invention also includes formulations of cyclic dinucleotides that can be administered alone, in combination with other biological response modulators, or in antigen-containing vaccine formulations. The proposed invention also includes methods of preventing or treating acute respiratory infections, preventing disease severity and blocking propagation by inducing an immune response at the entry site (nasopharyngeal mucosa), whether in a prophylactic vaccine formulation or in a formulation for prophylaxis before / after exposure of acute respiratory infections, and pathogen / virus transmission between people can be prevented or reduced.

: The present invention provides a compound of general formula I: (I), wherein R represents hydrogen, a linker structure or anl antibody attached by the linker structure. 5 Compounds of general formula I are useful in treatment or prevention of cancer.

This invention provides a pentavalent oxythiophosphine monomer, its asymmetric catalytic synthesis method, and its application. The structure of the pentavalent oxythiophosphine monomer is shown in Formula 3. The synthesis method involves an asymmetric catalytic coupling reaction between the intermediate compound shown in Formula 1a-3 and the compound shown in Formula 2 under the catalysis of a chiral cinchona bark catalyst, thereby generating the pentavalent oxythiophosphine monomer. Starting from key starting materials, this invention synthesizes two stereopure pentavalent oxythiophosphine monomers with configurations greater than 99% ee values ​​through a coupling reaction under the catalysis of chiral cinchona bark. This invention expands the synthesis method of stereopure oxythiophosphine monomers, and the obtained stereopure oxythiophosphine monomers can be used to synthesize stereopure pentavalent oxythiophosphine nucleoside monomers through coupling reactions. Furthermore, it enables the solid-phase synthesis of chiral PS and PS / PO mixed backbone oligonucleotides and the synthesis of PS cyclic dinucleotides, greatly promoting the research and development of chiral nucleoside drugs.

This invention relates to a composite adjuvant, its preparation method, and its application. The composite adjuvant comprises a first component and a second component. The first component is an aluminum adjuvant that adsorbs a cyclic dinucleotide, and the second component is an aluminum adjuvant that adsorbs monophospholipid A. The mass ratio of the cyclic dinucleotide to the aluminum adjuvant in the first component is 1:(2-20), and the mass ratio of monophospholipid A to the aluminum adjuvant in the second component is also 1:(2-20). When used in combination with various antigens, the composite adjuvant of this invention can effectively enhance the immune response induced by vaccines, with a significantly better enhancement effect than that of a single adjuvant. The composite adjuvant of this invention is low in cost and has good safety, and can be used as a candidate adjuvant for various vaccines, providing new ideas for the development and application of novel vaccine adjuvants.

This invention relates to a cationic emulsion complex adjuvant comprising cyclic dinucleotides, metabolizable oils, cationic lipids, and surfactants. The raw materials for the complex adjuvant components of this invention are readily available, and the preparation process is simple and low-cost. The complex adjuvant formed by the cationic emulsion containing cationic lipids and the cyclic dinucleotides of this invention is stable, biocompatible, has few side effects, and can improve immune efficacy.

Immunogenic formulations by oral route comprising: i) one or more chimeric proteins consisting of an immunologically associated antigen from a pathogenic microorganism of the pig and a molecular adjuvant CD154 from the pig; ii) an adjuvant selected from the cyclic dinucleotide monophosphate family; and iii) an excipient acceptable for oral immunization. A method of inducing an immune response against a pathogen characterized in that an immunogenic formulation comprising: i) one or more chimeric proteins formed from an immunologically related antigen from a swine pathogen fused with a molecular adjuvant CD154 from the swine is administered to the swine by oral route; and ii) an adjuvant selected from the cyclic dinucleotide monophosphate family.

A cyclic dinucleotide metal compound, and a preparation and application thereof are provided. The cyclic dinucleotide metal compound is [M(cyclic dinucleotide)] or [M'2(cyclic dinucleotide)], where M is Mg2+, Zn2+, Mn2+ or Fe2+, and M' is Li+. The cyclic dinucleotide is 2'3'-cGAMP, c-di-AMP, c-di-GMP, c-di-IMP, c-GMP-IMP or a derivative thereof.

This invention relates to the fields of chemical synthesis of nucleosides and oligonucleotides and innate immunity. The invention discloses a cyclic dinucleotide 2′,3′-cG 4′‑Me AMP, its preparation method, and its application in the preparation of innate immune activators, wherein the cyclic dinucleotide 2′,3′-cG 4′‑Me The chemical structure of AMP is shown below. Compared with the natural cyclic dinucleotide 2′,3′-cGAMP, 2′,3′-cGAMP has different chemical structures. 4′‑Me AMP exhibits higher serum stability and significantly enhances innate immune activation in human cells carrying the inactivated STING-R232H mutant, demonstrating its potential therapeutic value in diseases related to STING dysfunction.

In an enzymatic synthesis of 3′,3′-cGAMP, other types of cyclic dinucleotides, c-di-GMP and c-di-AMP, are produced as by-products. One problem to be solved in order to establish a practical method for enzymatic synthesis of 3′,3′-cGAMP is suppression of production of these other types of cyclic dinucleotides during the synthesis. As a result of intensive studies, the inventors of the present invention found a variation of 3′,3′-cGAMP synthase by which the production of c-di-GMP and c-di-AMP is suppressed, and established a 3′,3′-cGAMP enzymatic synthesis system using this variation of the enzyme to complete the present invention. This enzyme brings about significantly reduced production of c-di-GMP and c-di-AMP, compared to the wild-type 3′,3′-cGAMP synthase. Accordingly, a production method using this enzyme makes it possible to reduce the production of other types of cyclic dinucleotides in comparison to conventional enzymatic synthesis methods, and efficiently synthesize 3′,3′-cGAMP.

The present invention relates in a first aspect to a modified, like an acetylated polypeptide representing a modified polypeptide of Traspain or homologs thereof. In addition, the present invention relates to a method for preparing the same and its use in preventive or therapeutic vaccination. Further, a composition is provided comprising the modified, e.g. acetylated polypeptide according to the present invention in combination with an adjuvant, in particular, a cyclic dinucleotide adjuvant. Further, an active agent is present in said composition, in particular benznidazole or Nifurtimox. In addition, a composition is provided comprising the modified, e.g. acetylated polypeptide according to the present invention combined with an adjuvant and an active agent which is particularly useful in prophylactic and therapeutic vaccination. The modified polypeptide according to the present invention and the respective composition, in particular, the combination of the polypeptide, adjuvant and active agent demonstrated superior properties suitable for use in the field of prevention and immunotherapy of e.g. Chagas disease.

The application belongs to the field of biological medicine engineering, and relates to a preparation method of a cyclic dinucleotide, comprising the following steps: synthesizing the cyclic dinucleotide in a reaction system containing a dinucleotide cyclase and nucleoside triphosphates, centrifuging a reaction product, and obtaining supernatant; and purifying the cyclic dinucleotide from the supernatant by using a macroporous adsorption resin, wherein gradient elution is performed by using a 5-100 mM triethylamine-acetic acid solution as phase A and a mixed solution containing 70-80% phase A and 20-30% methanol as phase B. The macroporous adsorption resin is used to separate and purify the cyclic dinucleotide, the operation is relatively simple, the separation and purification time can be significantly shortened, the separation and purification speed is improved, and the obtained product has high purity.

This invention relates to multifunctional cyclic dinucleotide compounds of formula (X) and their derivatives, which can be used as prodrugs for inducing apoptosis or antiviral activity, and can also modulate immune pathways to generate therapeutically beneficial immune responses. This disclosure further relates to pharmaceutical compositions and combinations comprising the cyclic dinucleotide compounds of this invention, methods for synthesizing them, and their medical uses.

Compositions containing lipid nanoparticles and nucleic acid therapeutic agents are disclosed. For example, calcium phosphate nanoparticles having a lipid coating are provided, wherein the calcium phosphate nanoparticles include a cyclic dinucleotide and the lipid coating includes phosphatidylserine. The compositions can be formulated for administration to the lungs of a subject via inhalation, or for administration via injection. Methods for the treatment of lung cancer and other cancers are also described. Targeted delivery of therapeutic agents such as cyclic dinucleotides to antigen presenting immune cells via the disclosed methods can elicit beneficial antitumor immunity.