37 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.

The present invention relates to the field of medicines, and discloses a cyclic dinucleotide prodrug molecule and a preparation method and application thereof. The cyclic dinucleotide prodrug molecule has a structure as shown in Formula I, Formula II or Formula III, can autonomously cross the cell membrane, release the cyclic dinucleotide, and has high cell activity.

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

The invention generally relates to an improved processes for the preparation of a cyclic dinucleotide which is useful as a STING agonist.

The invention discloses a cyclic dinucleotide analogue containing a triazole structural unit as well as a preparation method and application of the cyclic dinucleotide analogue. The cyclic dinucleotide analogue containing the triazole structural unit is obtained by taking a macrocyclic ribose phosphate skeleton containing a diazido group as a substrate and expanding the macrocyclic ribose phosphate skeleton and an aromatic alkynyl compound through a click chemistry method, has relatively good biofilm formation inhibition activity, has a potential application prospect, and can be widely applied to biofilm biofilm formation inhibition. According to the invention, a cyclic dinucleotide analogue library is enriched, and biological research of cyclic dinucleotide and development of immunotherapy are promoted.

Cyclic dinucleotides, which are a type of signaling substance for cancer treatment, are secondary messengers of intracellular events initiated by GPCR activation and act as a stimulator of interferon genes (STING), and thus can have a significant effect on tumor suppression. Meanwhile, when cancer occurs in a subject, angiogenesis and cell growth proceed at a very high rate in the body, and thus an oxygen-deficient environment is created due to incomplete angiogenesis in cancer tissues, which may be very suitable for the proliferation of anaerobic bacteria such as Salmonella sp. strains or E. coli. Therefore, the present invention relates to a DNA construct into which is introduced a gene for an enzyme that synthesizes a signaling substance for cancer treatment, e.g., a cyclic dinucleotide, or to a strain transformed with a vector comprising the DNA construct. The DNA construct or the strain transformed with a vector comprising the DNA construct, according to the present invention, targets cancer in a subject and then secretes C-di-AMP or C-di-GMP synthase in the surrounding environment of the cancer, and thus can very effectively prevent or treat cancer and, at the same time, can diagnose cancer in real time.

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.

Lipid binding protein based complexes for carrying cyclic dinucleotides (CDNs) and uses thereof, pharmaceutical compositions comprising the complexes, and methods of making the complexes.

The invention discloses a cyclic dinucleotide compound as well as a conjugate and application thereof, and particularly discloses an antibody-immunostimulatory conjugate as shown in a formula II or pharmaceutically acceptable salt thereof. The antibody-immunostimulation conjugate provided by the invention has good tumor specificity and has an obvious inhibition effect on tumors. # imgabs0 #

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.

Disclosed in the present invention are a cyclic dinucleotide compound, a conjugate thereof, and use thereof, and particularly disclosed is an antibody-immunostimulant conjugate represented by formula II or a pharmaceutically acceptable salt thereof. The antibody-immunostimulant conjugate provided by the present invention has good tumor specificity and exhibits a significant inhibition effect on tumors.

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.

It is desired to develop an antibody-drug conjugate that can be administered systemically and specifically deliver a STING agonist to target cells and organs (e.g., tumor sites), as well as a therapeutic agent and / or treatment method for diseases related to the STING agonist activity, such as diseases that can be treated based on immune activation (e.g., cancer). The present invention provides a novel antibody-CDN derivative conjugate that can be administered systemically and exhibits an anti-tumor effect in tumors expressing an antigen.

Disclosed herein are new cyclic dinucleotide compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulation of immune response to disease, and induce Stimulator of Interferon Genes (STING) dependent type I interferon production and co-regulated genes in a human or animal subject are also provided for the treatment diseases such as cancer, particularly metastatic solid tumors and lymphomas, inflammation, allergic and autoimmune disease, infectious disease, and for use as anti-viral agents and vaccine adjuvants.

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.

To provide an improved processes for the preparation of a cyclic dinucleotide which is useful as a STING agonist.SOLUTION: As illustrated in the following formula, compound A is used to introduce a phosphate group into a nucleoside protected with an appropriate protecting group to yield compound 3, which is then reacted with the 5'-hydroxyl group of another nucleoside, and a phosphate group is introduced again into the 3'-amino group of the 3'-amino ribose portion. Subsequently, a cyclization reaction is induced between the 5'-hydroxyl group and the phosphate group, followed by deprotection to create the cyclic dinucleotide. This invention offers advantages in terms of its shorter synthesis process and reduced use of toxic reagents.SELECTED DRAWING: None

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.

To develop an antibody-drug conjugate capable of being systemically administered and delivering a STING agonist specifically to a target cell or organ (for example, a tumor lesion), and a therapeutic agent and / or therapeutic method using the antibody-drug conjugate for diseases related to STING agonist activity, for example, diseases (for example, cancers) to which immunostimulation therapy can be applied.SOLUTION: The present invention provides a novel antibody-CDN derivative conjugate which can be systemically administered and exhibits an antitumor effect against an antigen-expressing tumor.SELECTED DRAWING: Figure 1

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 present invention relates to a pharmaceutical combination comprising i) cyclic dinucleotides packaged into a virus-like particle (VLP) and ii) an anti-CTLA-4 antibody or a fragment thereof binding a CTLA-4 antigen, and to uses thereof, in particular for the treatment of cancer or of a STING-mediated disease or disorder.