77 results about "Transcytosis" patented technology

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Such retro-Michael resistant composition is generally achieved by conformational modification of the albumin, resulting in stereoselective coupling of the linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Such retro-Michael resistant composition is generally achieved by conformational modification of the albumin, resulting in stereoselective coupling of the linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Moreover, these properties also enable transport of the GPCR agonist fusion protein across the blood brain barrier and therefore allow treatment of neural disorders.

A pharmaceutical composition comprises a GPCR agonist fusion protein wherein the GPCR agonist peptide is covalently conjugated to an albumin via a linker in a manner that is resistant to a reverse Michael addition. Advantageously, the compositions presented herein avoid uncoupling of the agonist to the albumin while maintaining the agonist and the albumin in a spatial relationship that allows efficient binding and activation of the GPCR while also enabling gp60-mediated endocytosis transport and FcRn-mediated albumin recirculation. These characteristics enable ultra-low doses of GPCR agonist fusion proteins to produce therapeutic effects while significantly reducing or even completely avoiding side effects that would otherwise be typically associated with unbound agonists. Such reverse Michael resistant compositions are typically achieved by conformationally modifying an albumin, resulting in a stereoselective coupling of a linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Moreover, these properties also enable transport of the GPCR agonist fusion protein across the blood brain barrier and therefore allow treatment of neural disorders.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Such retro-Michael resistant composition is generally achieved by conformational modification of the albumin, resulting in stereoselective coupling of the linker to the albumin.

The invention provides an LPC liposome preparation for brain-targeted delivery of chemotherapeutic drugs as well as a preparation method and application of the LPC liposome preparation. The LPC liposome preparation comprises L-alpha-lysophosphatidylcholine, egg yolk lecithin and cholesterol, and the mass of the L-alpha-lysophosphatidylcholine is 5%-30% of the total mass of the L-alpha-lysophosphatidylcholine, the egg yolk lecithin and the cholesterol. The constructed LPC lipidosome can accelerate endocytosis of the lipidosome in bECs, and the lipidosome is transferred to an endosome recovery way by up-regulating p62, so that the lipidosome is prevented from entering a lysosome degradation way, and the transendocytosis efficiency is remarkably improved.

To provide methods useful for measuring the transcytosis of a molecule in relation to, in particular, in vitro receptor-dependent transcytosis assays for evaluating the clearance rates of therapeutic antibody molecules and Fc-fusion proteins in humans and animals.SOLUTION: A method of determining a pharmacokinetic (PK) parameter of a molecule is provided, the method comprising determining a measure of transcytosis of the molecule or a plurality of the molecules through a cell or a plurality of cells under conditions of physiological pH.SELECTED DRAWING: Figure 1

The disclosure provides the structure of an MFSD2A-SYNC2 complex together with functional data that revealed important molecular aspects of MFSD2A transport cycle, receptor-mediated cell-cell fusion, and pharmacology and resulted in the identification of two novel allosteric modulators of MFSD2A, which are two soluble fragments of SYNC2, namely SYNC2su-co and SYNC2su-co-2, representing first-in-class molecules to inhibit MFSD2A LPCs uptake and increase transcytosis rate.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The present disclosure relates to methods and compositions useful for measuring the transcytosis of a molecule. In particular, the present disclosure relates to in vitro receptor-dependent transcytosis assays for evaluating the clearance rates of therapeutic antibody molecules and Fc-fusion proteins in humans and animals.

Disclosed is a linear or cyclic peptide having an amino acid sequence represented by the formula (1): XN-X5- X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (1), or a pharmaceutically acceptable salt thereof. The peptide, when bound to LRP1, can deliver any drug to brain tissues by transcytosis mediated by LRP1.

The invention relates to an insulin-loaded hybrid nano-vesicle as well as a preparation method and application thereof. The hybrid nano-vesicle is obtained by hybridizing a milk-derived exosome and an insulin-loaded liposome. The milk-derived exosome and the liposome are creatively hybridized and used for co-loading and delivering insulin, the hybridized nano-vesicle can survive in a severe environment of gastrointestinal tracts and protect wrapped insulin, in intestinal tracts, the hybridized nano-vesicle interacts with FcRn on intestinal epithelial cells through surface IgG and triggers transendocytosis, and in addition, the exosome and the liposome can be used for co-loading and delivering insulin. The hybridized nano-vesicles have the advantages that a lysosome degradation pathway is avoided, then the hybridized nano-vesicles are effectively accumulated in the liver through portal veins, insulin is released in the liver to regulate blood sugar, and the hybridized nano-vesicles can be used for preparing insulin oral preparations.

The invention discloses application of a gene editing virus interfering expression and secretion of enzyme prototype cathepsin D in brain trauma, belongs to the field of gene functions and application, and finds that brain injury is aggravated and nerve dysfunction is aggravated due to the fact that the level of the enzyme prototype cathepsin D in plasma is increased due to the brain trauma through detection. The mechanism is as follows: the enzyme prototype cathepsin D enhances the transendocytosis effect of cerebral vascular endothelial cells after brain trauma, so that plasma inflammatory factors are gathered in damaged brain tissues; meanwhile, the expression of cerebrovascular endothelial cells VCAM-1 is also up-regulated, and neutrophil infiltration in an injured brain region after brain trauma is intensified. Research finds that down-regulation of plasma enzyme prototype cathepsin D can alleviate inflammatory factor concentration and neutrophil density in a brain injury area after trauma, and alleviate neurological function impairment of mice. Aiming at the functions of the plasma prototype cathepsin D, a strategy for reducing the plasma level of the plasma prototype cathepsin D by a gene editing technology for interfering the prototype cathepsin D is provided for treating the cerebral trauma.

The invention belongs to the field of functional nano materials, and particularly relates to pH-responsive nano gel with mechanical property conversion and application of the pH-responsive nano gel. The deformability of the nanogel is measured by using the ratio SD-pH of the diameter Dswoln of the nanogel at a first temperature T1 lower than the critical phase transition temperature of the nanogel to the diameter Dswoln of the nanogel at a second temperature T2 higher than the critical phase transition temperature of the nanogel. The SD-pH1 of the nanogel when the pH1 is 4.5-6 is greater than the SD-pH2 of the nanogel when the pH2 is 6.8-7.4, and the ratio of the SD-pH1 to the SD-pH2 is greater than or equal to 1.6. Compared with a control group, the nanogel disclosed by the invention is proved to have a remarkable pH-responsive mechanical property transformation effect and optimal active transendocytosis efficiency, and has optimal deep penetrating power and anti-tumor effect at a tumor part.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The present invention relates to the field of treatment and prevention of muscle wasting disorders, in particular those involving genetic factors that can be targeted by delivery of therapeutic nucleic acids to muscle cells. With the latter aspect in mind, herein disclosed are pharmaceutical compositions and advantageous components thereof that substantially facilitate effective delivery and release of therapeutic nucleic acids to the correct intracellular compartments of muscle cells, such as the cytosol and / or nucleus, where the therapeutic nucleic acid can reach and act on its genetic target. As disclosed herein, this substantial enhancement of delivery and release is achieved by providing an endosomal escape-promoting saponin in the pharmaceutical composition disclosed herein, comprising a therapeutic nucleic acid and a muscle cell targeting ligand. As demonstrated for the first time herein, this type of saponin surprisingly not only retains its endosomal escape-promoting properties in fully differentiated muscle cells, but also appears to successfully reach and enter muscle cells in vivo via an endothelial transcytosis pathway and subsequent endocytic trapping in the sarcolemma.

This invention discloses nanoparticles based on transcytosis-activating ligands, their preparation method, and applications, particularly in the treatment of fundus diseases. The nanoparticles comprise an enzyme protein core and a polymer shell grown in situ on the protein surface. The polymer shell contains positively charged monomers, transcytosis-activating ligands, and neutral monomers. The nanoparticles can enhance the hydrolytic resistance of enzyme proteins (e.g., antioxidant enzymes), protecting them from degradation during transport and improving delivery stability. Simultaneously, the nanoparticles can also promote the efficient delivery of proteases (especially to the posterior segment of the eye), exhibiting good safety and showing excellent application prospects in the medical field.

This invention discloses an oral frameshift peptide neoantigen vaccine, its preparation method, and its application, relating to the field of biomedical technology. The preparation method includes: 1) synthesizing a sea urchin-like metal-organic framework (MOF) via a hydrothermal method using zinc ions and 3,3''-dihydroxy-2',5'-dimethyl-[1,1':4',1''-terphenyl]-4,4''-dicarboxylic acid; 2) loading the sea urchin-like MOF with a frameshift peptide and a Toll-like receptor 9 agonist via electrostatic interactions and / or van der Waals forces to prepare the oral frameshift peptide neoantigen vaccine. This vaccine not only promotes antigen endocytosis and transcytosis via intestinal microfold cells by activating cyclin 42, but also alleviates immune tolerance mediated by the goblet cell-regulatory T cell immunosuppressive axis and activates specific CD8+. + T cells help prevent the development of Lynch syndrome-related colorectal cancer.

The application belongs to the field of biological pharmacy, and provides application of a compound or a derivative or a salt thereof in prevention and treatment of vertical transmission of viruses, in particular, provides use of a compound or a pharmaceutically acceptable salt thereof in preparation of a medicine, and the medicine is used for at least one of the following: (1) inhibition and / or blocking of transmission of flavivirus from a mother to an embryo and / or a fetus; (2) prevention and / or treatment of flavivirus infection of the embryo and / or the fetus, and diseases caused by the flavivirus infection, wherein the compound comprises a transcytosis pathway inhibitor. The compound or the pharmaceutically acceptable salt thereof cannot significantly reduce the load of the flavivirus in the mother, but can effectively and specifically reduce the amount of the flavivirus infection in the fetus and the pre-embryo, significantly inhibits the vertical transmission of the flavivirus in the fetus or the embryo after the flavivirus infects the mother, and effectively guarantees the safety during pregnancy.

Delivery of a payload across a cytoplasmic membrane includes providing a population of cells, contacting the population of cells with a volume of an aqueous solution. The aqueous solution includes an effective load and an alcohol at a concentration greater than 5%. The volume of the aqueous solution may be a function of the exposed surface area of the cell population, or a function of the number of cells in the cell population. Related compositions, instruments, systems, techniques, and articles are also described herein.

The invention lies in the field of treatment and prophylaxis of muscle wasting disorders, in particular the ones involving a genetic factor that can be targeted by a delivery of a therapeutic nucleic acid into the muscle cells. In line with the latter aspect, disclosed herein are pharmaceutical compositions and advantageous components thereof that substantially enhance the effective delivery and release of a therapeutic nucleic acid into the correct internal compartment of the muscle cell, such as the cytosol and / or the nucleus, in which compartment it can reach and act upon its genetic target. As disclosed herein, this substantially enhanced delivery and release is achieved by a provision of an endosomal-escape-enhancing saponin in the disclosed herein pharmaceutical compositions comprising therapeutic nucleic acids and muscle cell-targeting ligands. As for the first time demonstrated herein, these saponin types surprisingly not only appear to retain their endosomal-escape-enhancing properties in fully differentiated muscle cells, but also successfully reach and enter muscle cells in vivo through endothelial transcytosis route followed by endocytic capture at the sarcolemma.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Moreover, these properties also enable transport of the GPCR agonist fusion protein across the blood brain barrier and therefore allow treatment of neural disorders.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The invention relates to a single domain antibody that binds Heparin-binding EGF-like growth factor (HB-EGF) for use in preventing, treating and / or diagnosing e.g. a brain disease, wherein the single domain antibody is in combination with a therapeutic compound and / or a diagnostic / imaging compound. The single domain antibody may in particular be a Variable domain of a Heavy chain only (VHH) antibody of camelid origin or an engineered single-domain antibody (sdAb) of other mammalian and be capable of transporting cargo such as peptides or other molecules into the brain across the blood-brain barrier (BBB) by receptor-mediated transcytosis (RMT). The brain disease may for example be Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, brain tumor, or Hunter syndrome.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.

The present invention relates to the fields of molecular medicine and targeted delivery of therapeutic or diagnostic agents to cells outside the vascular system and into the parenchymal tissue of organs within the body. More specifically, the present invention relates to improved TfR-binding moieties capable of crossing the blood brain barrier (BBB) and capable of carrying and releasing cargo specifically targeted to the parenchymal tissue of the brain. The present invention relates to a transcytosis selection method to obtain VNARs against mammalian blood brain barrier (BBB) receptors using phage display libraries as well as against receptors found in other directional cell barrier systems like the gastrointestinal tract and other organs. The VNARs may be used alone or as components in compositions or as conjugates that target the particular receptor transport systems for delivery of therapeutics or diagnostics to the brain (in the case of BBB receptors) or other tissues.

The present disclosure is directed to nanobody-siRNA conjugates and methods of producing and using same. The nanobody-siRNA conjugates include a nanobody that may direct the conjugate to a target cell. The nanobody-siRNA conjugates are delivered into the target cell via receptor-mediated transcytosis, where the siRNA is delivered to the cell cytoplasm after it exits the endosome. To treat diseases and conditions, such as cancers and autoimmune diseases, the siRNA can be efficiently passed through the BBB to modulate an immune response. The small size of nanobodies allows more efficient targeted delivery than typical antibody systems, while conjugation strategies involving click chemistry permit the multiplexed loading of siRNA to nanobodies for increased therapeutic effects.

The present invention relates to a method of enhancing transendocytosis comprising modulating the expression of vesicle-associated membrane protein 3 (VAMP3) and syntaxin 4 (syntaxin 4, STX-4). Compositions for increasing VAMP3 and / or STX-4 expression in HBMEC, and compositions comprising a target molecule in a form suitable for transendocytosis across the blood brain barrier.

Antibodies can treat neurodegenerative disorders (NDs) caused by misfolded proteins. Still, the blood-brain-barrier (BBB) resists their entry, a barrier that can be reduced by scFv instead of whole antibody and conjugating it with transferrin protein to induce transcytosis. While the scFv binds variable heavy and light chains with a non-cleavable linker, a cleavable linker between the scFv and transferrin protein can reduce exocytosis, enhancing the activity of the scFv.