70 results about "Ligand binding domain" patented technology

The disclosure relates to immune cells for treatment of blood cancer comprising an activator receptor comprising an extracellular ligand binding domain specific to an activator antigen expressed by blood cancer cells and an inhibitor receptor comprising an extracellular ligand binding domain specific to an inhibitor antigen expressed by non-cancerous blood cells.

This document relates to materials and methods for modulating ligand gated ion channel (LGIC) activity. For example, modified LGICs including at least one LGIC subunit having a modified ligand binding domain (LBD) and / or a modified ion pore domain (IPD) are provided. Also provided are exogenous LGIC ligands that can bind to and activate the modified LGIC, as well as methods of modulating ion transport across the membrane of a cell of a mammal, methods of modulating the excitability of a cell in a mammal, and methods of treating a mammal having a channelopathy.

This document relates to materials and methods for modulating ligand gated ion channel (LGIC) activity. For example, modified LGICs including at least one LGIC subunit having a modified ligand binding domain (LBD) and / or a modified ion pore domain (IPD) are provided. Also provided are exogenous LGIC ligands that can bind to and activate the modified LGIC, as well as methods of modulating ion transport across the membrane of a cell of a mammal, methods of modulating the excitability of a cell in a mammal, and methods of treating a mammal having a channelopathy.

The present invention inter alia relates to a T-cell expressing a chimeric CD 95 receptor comprising a polypeptide, wherein said polypeptide comprises at least one CD 95-derived polypeptide region having at least 60% sequence identity with a polypeptide domain, a polypeptide region or a polypeptide motif of a human CD 95 wildtype receptor, wherein said human CD 95 polypeptide region comprises a CD 95 extracellular ligand binding domain; further wherein said polypeptide comprises at least one non-CD 95-derived co- stimulatory cytoplasmic polypeptide domain, region or motif of a tumor necrosis factor receptor superfamily protein comprising CD40, CD40L, CD27, HVEM, GITR, CD30, OX40, and / or LTBR, an immunoglobulin superfamily (IgSF) protein, a Toll-like-receptor, and / or an IL6-receptor family protein; wherein the T-cell further expresses an engineered T-cell receptor. The present invention also relates to a vector comprising nucleic acids encoding for the CD 95 receptor and the engineered T-cell receptor, as well as to a kit for preparing the T-cells of the present invention, and a pharmaceutical composition comprising the T-cells. The invention also relates to a method for preparing a T-cell for immunotherapy, and to a method for treating a patient having a disease comprising administering the pharmaceutical composition.

The invention relates to an IL5RA cell surface marker. A cell tag comprising an extracellular region, a transmembrane region, and optionally an intracellular region is provided. The extracellular region comprises an IL5 receptor alpha (IL5Ra) sequence linked to a transmembrane domain, and the recombinant polypeptide cannot function in signal transduction. The cell tag can be operably linked to a transgene. Expression of the cell tag allows for the identification, detection, selection, and ablation of cells expressing the transgene and the cell tag. In some embodiments, the genetically modified host cell comprises a transgene comprising a polynucleotide encoding a chimeric antigen receptor comprising a ligand binding domain and a polynucleotide encoding a cell tag. Pharmaceutical formulations produced by the methods and methods of using the pharmaceutical formulations are also described.

Fusion polypeptides are provided and comprise at least two ligand binding domains and a fragment crystallizable (Fc) region of immunoglobulin G (IgG). The ligand binding domains include an amino acid sequence selected from the group consisting of SEQ ID NOS: 1-25 and / or one of the at least two ligand binding domains binds modulates B cell activity while the other modulates T cell activity. Isolated nucleic acids, vectors, and isolated cells encoding or including the fusion peptides are further provided. Pharmaceutical compositions include the fusion peptides and a pharmaceutically-acceptable vehicle, carrier, or excipient. Methods of treating Sjögren's Syndrome and / or Systemic Lupus Erythematosus are also provided and comprise administering to a subject in need thereof the fusion polypeptide including the two ligand binding domains and the Fc region of IgG.

The present invention inter alia relates to a chimeric transmembrane receptor comprising a polypeptide, wherein the polypeptide comprises at least one T cell immunoreceptor with Ig and ITIM domains (TIGIT) polypeptide region comprising a TIGIT extracellular ligand binding domain; further wherein the polypeptide comprises at least one non-TIGIT polypeptide region, wherein the at least one non-TIGIT polypeptide region comprises a transmembrane polypeptide region of CD2, CD40, HVEM, or CD30, and wherein the at least one non-TIGIT polypeptide region comprises at least one costimulatory cytoplasmic polypeptide domain, region or motif of CD2, CD40, HVEM, or CD30, or wherein the transmembrane domain is from TIGIT and further wherein the at least one non-TIGIT polypeptide region comprises at least one costimulatory cytoplasmic polypeptide domain, region or motif of CD2 or CD28. The invention also relates to corresponding nucleic acids, vectors and T-cells comprising or expressing the chimeric receptors, to a pharmaceutical composition comprising the T-cells, and to methods for preparing a T-cell for immunotherapy and for treating a disease, respectively, wherein the chimeric transmembrane receptor is used.

This document relates to materials and methods for controlling ligand gated ion channel (LGIC) activity. For example, modified LGICs including at least one LGIC subunit having a modified ligand binding domain (LBD) and / or a modified ion pore domain (IPD) are provided. Also provided are exogenous LGIC ligands that can bind to and activate the modified LGIC, as well as methods of modulating ion transport across the membrane of a cell of a mammal, methods of modulating the excitability of a cell in a mammal, and methods of treating a mammal having a channelopathy.

Disclosed are systems, components of systems, and methods for sensing extracellular ligands and / or modulating expression of an endogenous or exogenous gene in a cell. In some embodiments, the disclosed systems and methods comprise or utilize first and second exogenous extracellular sensors and / or nucleic acid sequences encoding the first and second exogenous extracellular sensors, wherein the first exogenous extracellular sensor comprises: a) a ligand binding domain; b) a transmembrane domain; c) a protease cleavage site; and d) a functional domain comprising an RNA-binding subdomain fused to a transcription regulatory subdomain; and the second exogenous extracellular sensor comprises: e) a ligand binding domain, f) a transmembrane domain, and g) a protease domain that cleaves the protease cleavage site of the first exogenous extracellular receptor.

A reversibly gated effector polypeptide e.g. a chimeric antigen receptor (protease-activating CD45-gate CAR) comprising an extracellular CD45 recruiting domain, a protease-cleavable linker, and a polypeptide comprising an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain. Nucleic acids including vectors and expression vectors that encode the protease-activating CD45-gate CAR and cells including immune cells such as T cells that comprise and express the nucleic acids. Methods of treatment of various conditions including various forms of cancer comprising administering the cells including CAR T cell therapy. In some embodiments, the CD45 gate at least partially inhibits activation of the protease-activating CD45-gate CAR when the protease-activating CD45-gate CAR binds antigen. The inhibition is at least partially diminished, relieved and / or eliminated when the protease-activating CD45-gate CAR is exposed to a protease that can cleave the linker.

Methods and compositions are provided for reversibly localizing proteins to the exterior part of the cell surface. Essentially, the protein must comprise, in addition to a transmembrane domain, also a hormone receptor like the estrogen receptor alpha or the progesterone receptor. Compositions provided herein can include nucleic acids that encode polypeptides of interest and the ligand binding domain (LBD) of a nuclear hormone receptor. Medical applications are provided, including controlling the toxicity of CAR T cells.

In some aspects, the invention teaches pharmaceutical compositions that include a TGF-β ligand trap, and methods of using a TGF-β ligand trap to treat, prevent, or reduce the progression rate of pulmonary hypertension (PH). The invention also provides methods of using a TGF-β ligand trap to treat, prevent, or reduce the progression rate of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, right ventricular hypertrophy, diseases associated with excessive TGF-β signaling, diseases associated with excessive GDF15 signaling, and diseases associated with excessive PAI-1 signaling. The invention further provides methods of using a TGF-β ligand trap to reduce right ventricular systolic pressure in a subject.

Disclosed herein are methods of treating prostate cancer in a subject in need thereof, wherein the prostate cancer in the subject expresses one or more androgen receptor splice variants lacking the ligand-binding domain, including AR-V7.

The present invention provides a method of slowing the progression of ER + breast cancer in a patient comprising administering to the patient an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof and an effective amount of a CDK4 / 6 inhibitor (CDK4 / 6i) wherein breast cancer: (i) is estrogen receptor positive (ER +); (ii) having at least one function-acquired missense mutation within the ligand binding domain (LBD) of the estrogen receptor 1 (ESR1) gene; and (iii) have progressed and / or have oncogenic mutations in genes other than ESR1 during previous treatment with a CDK4 / 6 inhibitor.

This invention provides materials and methods for regulating ligand-gated ion channel (LGIC) activity. [Solution] A modified LGIC is provided, comprising at least one LGIC subunit having a modified ligand-binding domain (LBD) and / or a modified ion-pore domain (IPD). Also provided are an exogenous LGIC ligand capable of binding to and activating the modified LGIC, as well as a method for regulating ion transport across the membrane of mammalian cells, a method for regulating cellular excitability in mammals, and a method for treating mammals with channel disorders.

The invention provides a natural protein immobilization method. The method comprises the following steps: step 1, reacting a reactant with target natural-state protein; step 2, preparation of a reactant modification interface; and step 3, fully mixing the natural-state protein 5-HTT with the obtained reactant modification interface, stirring at room temperature for 6 hours, and washing with PBS for 3 times to complete high-activity immobilization of the natural-state 5-HTT. Through the proximity effect of ligand-functional protein affinity interaction, a nucleophilic amino acid residue at a specific site of the native protein and a ligand electrophilic group are induced to be subjected to a covalent reaction, the ligand is released through synchronous self-cleavage, and a ligand binding domain is exposed, so that high-activity one-step capture of the native protein is realized; the technical problems of low immobilization efficiency, serious protein activity loss and low specificity of low-abundance natural state functional protein in a complex system are successfully solved.

The disclosure provides methods for treating estrogen receptor positive (ER+) cancer in a patient who has progressed on an aromatase inhibitor. Of particular interest are ER+ cancers that do not harbor a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. The provided methods involve the administration of an effective amount of lasofoxifene, a pharmaceutically acceptable salt, prodrug or functional derivative thereof.

The invention relates to the technical field of computational toxicology, and discloses a method for calculating combination of perfluorinated and polyfluorinated alkyl compounds and PPARalpha based on a pharmacophore model, which comprises the following steps: acquiring a PFAS initial data set, acquiring a PPARalpha ligand binding domain crystal structure, and optimizing the structure; selecting representative PFAS to carry out molecular docking, and carrying out simulated annealing optimization to obtain an optimal binding posture; then generating a pharmacophore model; the models are screened; performing rigid fitting screening by using a pharmacophore model; carrying out molecular dynamics simulation on the representative hit object, and verifying the stability; protein is extracted by culturing cells in vitro, a thermal displacement experiment is carried out, and the thermal stability effect of PFAS on PPARalpha is verified. According to the method, comprehensive virtual screening of PFAS-PPAR alpha interaction based on pharmacophores is provided, a calculation framework based on protein and compound structures is established, and the method is suitable for environmental pollutant screening and safer chemical design.

The present invention relates to a chimeric antigen receptor comprising a ligand binding domain, a transmembrane domain, a costimulatory domain and an intracellular signaling domain wherein the costimulatory domain comprises a mutated CD27 intracellular region. The invention also relates to engineered immune cells comprising such chimeric antigen receptors and their use in the treatment of diseases, such as cancer, autoimmune diseases, infections.

The disclosure provides methods for treating estrogen receptor positive (ER+) cancer in a patient who has progressed on an aromatase inhibitor. Of particular interest are ER+ cancers that do not harbor a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. The provided methods involve the administration of an effective amount of lasofoxifene, a pharmaceutically acceptable salt, prodrug or functional derivative thereof.

The invention relates to the technical field of genetic engineering and pesticide detection, in particular to a recombinant plasmid, a genetically engineered bacterium and a method for detecting neonicotinoid pesticides in an environment. According to the invention, a genetic engineering bacterium is constructed by cloning a ligand binding domain ECD part of a nicotine acetylcholine receptor alpha7 subunit into an expression vector and further expressing recombinant plasmids by using escherichia coli. According to the invention, the genetically engineered bacterium is used as a single fluorescent protein bioreceptor for detecting neonicotinoid pesticides in an environment, and the detection method does not need expensive instruments and professional detection personnel, and does not need tedious pretreatment and long-time culture incubation or analysis; according to the method, the environmental neonicotinoid pesticide can be subjected to targeted in-situ rapid identification and quantitative detection, so that the detection time is shortened, the development of an environmental neonicotinoid pesticide analysis and detection method is promoted, and the method is of great significance to subsequent environmental neonicotinoid pesticide control strategy development and water environment ecological protection.

EphA2 targeting agents developed herein are potent peptide-mimetics with high affinity (Kds 8-20 nanomolar) for the ligand binding domain, called targefrin. Monomeric versions of targefrin act as antagonists while dimeric versions (targefrin-dimer) of the agent cause receptor internalization and degradation via a lysosomal pathway. Hence, targefrin-dimer agents are effective in reducing pro-oncogenic EphA2 levels in cancer cells when used as single agents or in combination with standards of care. Targefrin-dimers can also sensitive cancer cells that developed resistance to EGER or BRAE inhibitors, and potentially other anti-cancer agents. In addition, the dimeric agents can be conjugated with chemotherapy such as paclitaxel to deliver selectively cytotoxic agent to EphA2 expressing cancer cells. Monomeric agents can be linked to chemotherapy via a stable cleavable linker, accumulate the cytotoxic at the tumor, that then would enter the tumor. Novel composition and examples of these applications are reported.

Provided herein are mutants of the estrogen receptor alpha ligand binding domain (ER-LBD), and inducible cell death systems comprising mutants of the estrogen receptor alpha ligand binding domain (ER-LBD). Also provided are methods for using the same, e.g., to induce cell death in cells.

The present disclosure discloses a chimeric antigen receptor targeting TF and uses thereof, the chimeric antigen receptor targeting TF comprising: (a) an extracellular ligand binding domain having binding affinity to TF, (b) a transmembrane domain, and (c) an intracellular signaling domain; the intracellular signaling domain comprises a costimulatory signaling domain derived from 4-1BB and a primary intracellular signaling domain derived from CD3 zeta.

The EphA2 targeting agents developed herein are potent peptidomimetics having a high affinity (Kd 8-20 nanomole) to the ligand binding domain referred to as tagfolin. Monomeric versions of tagfolin act as antagonists, while dimeric versions of said agents (tagfolin dimers) result in internalization and degradation of receptors via lysosomal pathways. Thus, when used as a single agent or in combination with a standard care, the tagfolin dimer agent is effective in reducing cancerogenic EphA2 levels in cancer cells. Tagfolin dimers may also sensitize cancer cells that are resistant to EGFR or BRAF inhibitors and potentially other anti-cancer agents. Furthermore, the dimeric agent can be conjugated to a chemotherapeutic agent, such as paclitaxel, to selectively deliver a cytotoxic agent to the EphA2-expressing cancer cells. The monomeric agent can be linked to the chemotherapeutic agent via a stable cleavable linker, causing the cytotoxic to accumulate at the tumor, which then enters the tumor. Novel compositions and examples of these applications are reported.

The disclosure relates to immune cells for treatment of blood cancer comprising an activator receptor comprising an extracellular ligand binding domain specific to an activator antigen expressed by blood cancer cells and an inhibitor receptor comprising an extracellular ligand binding domain specific to an inhibitor antigen expressed by non-cancerous blood cells.

Protein complexes targeting CD47, PD-L1, and / or TIGIT are provided, as well as methods for using the same. In one embodiment, the protein complex comprises a CD47-binding domain having all or part of the SIRPα extracellular domain, a PD-L1-binding domain having all or part of the PD-1 extracellular domain, and a TIGIT ligand-binding domain having all or part of the TIGIT extracellular domain.

Herein is reported a class of chiral compounds with paradoxical effects on the androgen receptor (AR). The (R)-enantiomers behave like classical anti-androgens while the (S)-enantiomers activate AR signaling. In castration-resistant prostate cancer, the change during the course of therapy to growth in the presence of AR targeted therapeutics, a harbinger of progression to lethal disease, is commonly attributed to acquired mutations of the AR-ligand binding domain. This is the first report of an antagonist-agonist duality solely due to structural enantiomerism, without any modification to the AR binding site.

A reversibly gated effector polypeptide e.g. a chimeric antigen receptor (protease-activating CD45-gate CAR) comprising an extracellular CD45 recruiting domain, a protease-cleavable linker, and a polypeptide comprising an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain. Nucleic acids including vectors and expression vectors that encode the protease-activating CD45-gate CAR and cells including immune cells such as T cells that comprise and express the nucleic acids. Methods of treatment of various conditions including various forms of cancer comprising administering the cells including CAR T cell therapy. In some embodiments, the CD45 gate at least partially inhibits activation of the protease-activating CD45-gate CAR when the protease-activating CD45-gate CAR binds antigen. The inhibition is at least partially diminished, relieved and / or eliminated when the protease-activating CD45-gate CAR is exposed to a protease that can cleave the linker.

The present disclosure provides synthetic receptor systems for engineering mammalian cell-based devices to sense soluble, physiological cues.