32 results about "Asialoglycoprotein receptor" patented technology

The present invention provides a novel method of synthesizing branched galactose-terminal glycoproteins. A number of these glycoproteins have binding affinity to the asialoglycoprotein receptor. The present invention also provides novel conjugates having branched galactose-terminal glycoproteins that is complexed to a therapeutically effective agent, such as an isolated protein, polysacharides, lipids and radioactive isotope. These conjugates may be used to deliver the therapeutically effective agent to mammalian cells generally, and to hepatocytes specifically.

A peptide clearing agent is provided for clearance of a conjugate of an enzyme and a binding molecule which binds specifically at a target location from a non-target location in a subject. The peptide clearing agent binds the active site of the enzyme. The peptide also binds to the asialoglycoprotein receptor expressed by hepatic cells to facilitate clearance through the liver. The peptide may be glycosylated to facilitate clearance through the liver by binding to hepatic cells expressing an asialoglyco-protein receptor. Typically, the peptide prevents or inhibits enzyme activity upon binding to the enzyme and is not substantially modified by the enzyme activity. The peptide may be based upon the dipeptide amino-naphthoic acid (ANA)-glutamate (GIu) and may comprise the amino acid sequence serine (Ser)-Alanine (Ala)-amino-naphthoic acid (ANA)-glutamate (GIu). In such cases, the enzyme of interest is typically CPG2.

The invention provides a paramagnetic metal complex and a synthetic method and application thereof. The paramagnetic metal complex is an arabinogalactan-modified 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacethyl paramagnetic metal complex. A magnetic resonance imaging contrast agent prepared from the paramagnetic metal complex has high stability, water solubility and relaxation rate and is targeted to liver and kidney, so that targeted imaging is realized, and the imaging contrast and definition are improved. The paramagnetic metal complex has a good effect on raising the early diagnosis levels of diseases of liver and kidney organs, is about 2 times the relaxation rate of dotarem, has very long targeted radiography imaging time, can be easily prepared into a solution with required concentration for intravenous injection, is suitable for sterilizing and disinfecting with a hot pressing method, can be selectively identified by an asialoglycoprotein receptor on a liver parenchyma surface, and has high selectivity on livers of human beings or other mammals.

The present invention generally relates to antibodies specific for asialoglycoprotein receptor (ASGPR) and their use for selectively delivering effector moieties that influence cellular activity. In addition, the present invention relates to polynucleotides encoding such antibodies, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the antibodies of the invention, and to methods of using them in the treatment of disease.

The invention discloses a RNA aptamer of a targeting hepatocyte and a nucleotide sequence thereof, and relates to the field of hepatic disease diagnosis and treatment. The RNA aptamer provides a novel specific and efficient molecule of a targeting hepatocyte for the field of hepatic disease diagnosis and treatment. In the invention, through using the new combinatorial chemical technology SELEX, and taking hepatic ASGPR (asialoglycoprotein receptor) large subunits as target proteins, an RNA aptamer which can specify the ASGPR is screened from a single-stranded RNA random library. The aptamer can be formed into a special stemloop structure in a random sequence region thereof, combines with big liver ASGP receptor subunit H1 protein with high specific affinity and can combine to liver cells in a targeted mode by high specific affinity. The RNA aptamer provides a new choice for developing a liver disease targeted diagnostic reagent and treatment drug.

The invention relates to a human asialoglycoprotein receptor (ASGPR) monoclonal antibody as well as a preparation method and application thereof. The monoclonal antibody can be used for well recognizing an ASGPR antigen, cannot perform cross reaction with other proteins, and is very high in specificity and sensitivity. The antibody disclosed by the invention can be applied to identification of primary hepatocellular carcinoma and metastatic liver cancer, separation and detection of circulating liver cancer cells, liver imaging and targeted delivery of liver medicines or genes.

The invention relates to a polyethylene glycol-lactobionic acid modified aminated hectorite nano particle as well as a preparation method and application thereof. The preparation method of the polyethylene glycol-lactobionic acid modified aminated hectorite nano particle comprises the following steps: firstly, carrying out reaction on lactobionic acid with polyethylene glycol, wherein one end of the polyethylene glycol is an amino group, and the other end of the polyethylene glycol is a carboxyl, so that pegylated lactobionic acid is obtained; secondly, modifying hectorite with (3-aminopropyl) dimethyl ethoxy silane, so that a certain amount of amino groups are formed on the surface of the hectorite; thirdly, modifying nano clay hectorite with the pegylated lactobionic acid, so that a lactobionic acid modified functional hectorite nano composite material is obtained; the lactobionic acid modified functional hectorite nano composite material can be used for preparing a nano medicine carrying system with a lactobionic acid targeting function. The polyethylene glycol-lactobionic acid modified aminated hectorite nano particle has the advantages that stability and biological compatibility of a nano particle are improved, and a specific targeting effect on liver cancer cells highly expressed by an asialoglycoprotein receptor is realized, so that a synthesized nano medicine carrying composite material can be applied to targeted delivery of an anti-cancer drug. The preparation method of the polyethylene glycol-lactobionic acid modified aminated hectorite nano particle is simple, mild in reaction conditions and easy to operate and has an industrialization implementation prospect.

Methods and kits for detecting hepatocellular carcinoma recurrence or metastasis, and of measuring markers of hepatocellular carcinoma, including markers of hepatocellular carcinoma recurrence or metastasis, in a blood sample obtained from a subject by (a) isolating circulating tumor cells (CTCs) by contacting a blood sample obtained from the subject with a set of capture antibodies, wherein the capture antibodies specifically bind asialoglycoprotein receptor (ASGPR), Glypican-3, and epithelial cell adhesion molecule (EpCAM); (b) contacting the isolated CTCs with an antibody that specifically binds vimentin; and (c) measuring the number of vimentin-positive CTC.

The invention relates to a double targeting hepatic tumor drug as well as a synthetic method and application thereof. The double targeting hepatic tumor drug has a terminal structure (galactose or N-acetyl galactose) capable of specifically binding to asialoglycoprotein receptor at the surface of a hepatocyte, and therefore the double targeting hepatic tumor drug is capable of binding to the asialoglycoprotein receptor so as to be brought into the interior of a hepatic tumor cell by means of the endocytosis of the hepatic tumor cell. On the other hand, experiments prove that the enzyme hydrolysis of the overexpressed cathepsin B in hepatic tumor cell lysosome is performed on the double targeting hepatic tumor drug to release Adriamycin, that is, active ingredients are released while the level of cathepsin B can be reduced, so as to slow down tumor progression. In summary, the double targeting hepatic tumor drug prepared by the invention uses asialoglycoprotein receptor and cathepsin Bas double target spots for having an effect, has obvious therapeutic effect, and meanwhile significantly reduces the toxic and side effects on other normal tissues and cells.

The invention discloses a positron imaging agent <18>F-FPGalNAc as well as a preparation method and an application thereof. The structural formula of the positron imaging agent is show in the description. The positron imaging agent <18>F-FPGalNAc contains an N-acetylgalactosamine group, binding affinity of the N-acetylgalactosamine group and an ASGPR (asialoglycoprotein receptor) is far higher than that of a galactose group and the ASGPR, and the positron imaging agent <18>F-FPGalNAc can specifically target tumors such as HepG2, A549, MDA-MB-231, MCF-7, HCT116 and the like with high ASGPR expression and has a good imaging effect.

The present invention provides an engineered regulatory T cell (Treg) comprising a chimeric antigen receptor (CAR) wherein the CAR comprises an antigen recognition domain that specifically binds to an asialoglycoprotein receptor (ASGR). The present invention also provides a method of promoting liver tissue repair and / or regeneration in a subject comprising the step of administering to the subject an engineered Treg comprising a CAR or a pharmaceutical composition comprising the engineered Treg wherein the CAR comprises a liver-specific antigen recognition domain.

The application belongs to the technical field of genetic engineering, and discloses application of a genetic engineering editing site and obtained asialoglycoprotein receptor 1 (ASGR1) mutant gene topreparation of a mammal liver injury sensitive model. By performing gene editing on a suitable editing site in an ASGR1 gene sequence, an animal model steady to passage and liable to induce into liver injuries is obtained, and a steady breeding population is established. The invention establishes a method for obtaining a genetic engineering non-human mammal model population steady to passage andliable to induce into liver injuries, and meets all experiment needs.

The invention discloses a tissue-targeted protein targeted-degradation compound and application thereof, relates to the field of pharmacy, and particularly relates to a compound or pharmaceutically acceptable salt, stereoisomer, solvate or polymorphic substance thereof. The compound is a protein targeted-degradation chimera with tissue targeting ability. A structure of the compound comprises three parts: A-BD-CON, wherein the part A is a protein targeted-degradation chimera (PROTAC), one end of the structure of the part A is a target protein binding ligand, and the other end of the structure of the part A is a ubiquitin ligase ligand; and the part CON is a ligand of an asialoglycoprotein receptor (ASGPR) and has a function of targeting a specific tissue of the PROTAC. On the basis of the protein targeted-degradation chimera (PROTAC) which is very difficult in medicine preparation, the functions of liver tissue enriching and cell targeting are further realized, and the solubility, the cell permeability and the drug effect in specific target tissues of the PROTAC are improved, so that the medicine preparation property of the PROTAC is improved on the whole.

An ELISA method for detecting human soluble asialoglycoprotein receptor (sASGPR). The method is based on a specific ligand of ASGPR and the specific recognition of ASGPR. Galactosylated serum albumin (GSA) is selected as the specific ligand of ASGPR, and the GSA is prepared from human serum albumin and has the advantages of being low in cost, easy to prepare, easy to preserve and the like. The detection limit of the method is applicable to detection of sASGPR in a human serum sample, there is no need to use special and large instruments and equipment, and the method can be carried out in an ordinary laboratory, has the advantages of being high in specificity, good in stability, easy and convenient to operate, low in cost and the like, and provides certain reference value for clinical liver function assessment.

The present invention discloses a novel liver targeting drug carrier which comprises: a targeting antenna and an adaptor; the targeting antenna is a four antennas capable of being specifically recognized by an asialoglycoprotein receptor on the surfaces of liver cells, and the tail ends of the four antennas are sugar units; and the adaptor is used for connecting drugs and the targeting antennas, and is a polypeptide chain which can be degraded by specific proteolytic enzyme in liver cells. According to the invention, the four-antenna sugar unit, especially N-acetyl-D-galactosamine, is used asa liver specific targeting reagent; and polypeptides capable of being degraded by specific proteolytic enzymes enriched in the liver are combined as adapters, so that the novel carrier can specifically target the liver and enter cells, and is selectively degraded in the liver cells to release drugs. The carrier can be combined with various medicines for treating liver diseases and selectively delivering the medicines to the liver, so that bioavailability of the medicines is improved, the side effect on other tissues is reduced, and the carrier is a novel efficient specific liver targeting medicine carrier.

The invention belongs to the technical field of biological medicines, and particularly relates to a lactobionic acid-novel indocyanine green conjugate as well as a preparation method and application thereof. Firstly, new indocyanine green and three different diamines are used as raw materials to synthesize aminated new indocyanine green through nucleophilic substitution reaction, and then the aminated new indocyanine green and lactobionic acid are condensed to obtain three lactobionic acid-new indocyanine green conjugates. The conjugate provided by the invention can be used for liver cancer targeted delivery of the new indocyanine green, and the obtained conjugate can be specifically recognized by an asialoglycoprotein receptor highly expressed on the surface of a liver cancer cell, and is taken by the liver cancer cell through a receptor-mediated pathway, so that the liver cancer cell intake of the new indocyanine green is remarkably improved; the obtained conjugate has an in-vitro photodynamic effect superior to or equivalent to that of free new indocyanine green, has a liver cancer cell photodynamic killing effect superior to that of the free new indocyanine green, and has application prospects in liver cancer photodynamic therapy and liver cancer diagnosis.

The present invention provides a human asialoglycoprotein receptor determination reagent, which comprises the following components: a first reagent, which comprises a buffer solution, an anti-interference agent A, a dispersant and a coagulation accelerator; and the second reagent comprises a polyclonal antibody connected with an insoluble carrier and a monoclonal antibody of an anti-sH2a specific structural domain EGHRG pentapeptide. A buffer solution, an anti-interference agent A, a dispersing agent and a coagulant are combined for use, and are matched with a polyclonal antibody connected with an insoluble carrier and a monoclonal antibody of anti-sH2a specific structural domain EGHRG pentapeptide, so that the rapid detection of the human asialoglycoprotein receptor in a sample is realized, and meanwhile, the precision of a determination result is ensured.

The invention relates to a method for preparing ultra-small superparamagnetic ferriferrous oxide nanometer particles modified by lactobionic acid. The method includes the steps that after ferric iron salt reacts with natrium sulfurosum, hyperbranched polyethyleneimine and ammonium hydroxide are added, and FI is added after the reaction, and Fe<3>O<4> / PEI.NH<2>-FI is obtained; LA is activated through EDS and NHS and added to a solution of COOH-PEG-NH<2>, and COOH-PEG-LA is obtained after a reaction; the COOH-PEG-LA is activated through EDC and NHS and added to the Fe<3>O<4> / PEI.NH<2>-FI, the mixture conducts a reaction and acetylated, and the ultra-small superparamagnetic ferriferrous oxide nanometer particles are obtained. The method is simple, mild in reaction condition and easy to operate; the prepared nanometer particles are small in particle size and quite high in relaxation rate, have good colloidal stability, biocompatibility and the target ability of high-expression tumor cells of a specific asialoglycoprotein receptor and have potential application value in the field of in-vivo tumor target MR imaging diagnosis.

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and / or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy.Methods of treating disease states and / or conditions in which circulating proteins are associated with the disease state and / or condition are also described herein.

The invention relates to the application of an asialoglycoprotein receptor fragment sH2a as a marker in the preparation of products for diagnosing active liver diseases. The present invention finds through research that by measuring the content of the asialoglycoprotein receptor fragment sH2a in biological samples, it can be well differentially diagnosed with active liver disease, thereby being applied to the early diagnosis and differential diagnosis of active liver disease, and Provide a strong basis for disease treatment. Active liver disease can be efficiently distinguished from inactive liver disease and other types of liver disease (drug-induced hepatitis, fatty liver, etc.) by detecting sH2a. sH2a has the value as a diagnostic marker for active liver disease and has a high diagnostic value . The discovery of this marker provides a new experimental theoretical basis and a new direction for further research on the mechanism of active liver disease and the treatment of active liver disease, and enriches the diagnostic and detection methods of active liver disease.

The invention provides a paramagnetic metal complex and a synthetic method and application thereof. The paramagnetic metal complex is an arabinogalactan-modified 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacethyl paramagnetic metal complex. A magnetic resonance imaging contrast agent prepared from the paramagnetic metal complex has high stability, water solubility and relaxation rate and is targeted to liver and kidney, so that targeted imaging is realized, and the imaging contrast and definition are improved. The paramagnetic metal complex has a good effect on raising the early diagnosis levels of diseases of liver and kidney organs, is about 2 times the relaxation rate of dotarem, has very long targeted radiography imaging time, can be easily prepared into a solution with required concentration for intravenous injection, is suitable for sterilizing and disinfecting with a hot pressing method, can be selectively identified by an asialoglycoprotein receptor on a liver parenchyma surface, and has high selectivity on livers of human beings or other mammals.

The invention provides a 99mTc marked multivalence sugar fan-shaped dendrimer complex with the formula being 99mTc(R-HYNIC)(Tricine)m(L)n and further provides application of the complex, a multivalence sugar fan-shaped dendrimer ligand for preparing the complex and a preparation method thereof. The multivalence sugar fan-shaped dendrimer ligand can form the 99mTc marked complex with a co-ligand, a selectable coligand and radioactive pertechnetate, the complex is high in radiation chemical purity, good in stability and biological performance, high in specific activity, high in liver uptake value and target-to-non-target ratio, capable of being used as a hepatic cell asialoglycoprotein receptor SPECT photographic developer, easy and convenient to prepare and low in cost and has the large-scale and wide-application value.

The invention discloses a liver cancer circulating tumor cell phenotype analysis method. The method comprises the following steps of: 1) constructing a micro-fluidic chip comprising two processing units, wherein each processing unit comprises a micro-array consisting of a plurality of micro-columns with triangular cross sections, two sample inlets positioned on one side of an inlet of the triangular micro-array and two sample outlets positioned on one side of an outlet of the triangular micro-array; the two processing units correspondingly modify epithelial cell adhesion molecule EpCAM antibody and asialoglycoprotein receptor ASGPR antibody 2) samples enter from the inlets of the two processing units correspondingly and flow out from the outlets; and 3) identifying epithelial phenotype andnon-epithelial phenotype of the circulating tumor cells captured by the two processing units through an immunostaining method. According to the method, the capture efficiency, purity and detection rate of the liver cancer circulating tumor cells can be improved, and phenotype analysis can be carried out on the liver cancer circulating tumor cells.

The present invention provides a composition and method for treating an allergic disease. The composition comprises a ligand for asialoglycoprotein receptor 1 (Asgr1). The allergic disease may be atopic dermatitis, allergic rhinitis, urticaria, allergic asthma, allergic conjunctivitis, allergic gastrointestinal inflammation, or anaphylactic shock. The allergic disease may be caused by house dust mites. The present invention also provides a method for determining if a test compound activates human Asgr1.