39 results about "Death Receptors" patented technology

The present disclosure provides genetically modified iPSC-derived γδT cells and their precursors. A double genomic disruption in the suppressor of cytokine signaling 1 (SOCS1) gene and the cytokine-inducible sh2-containing protein (CISH) gene are provided, as is a triple genomic disruption in genes for SOCS1, CISH, and Bcl-2 interacting mediator of cell death (BIM), as is a quadruple genomic disruption in genes for SOCS1, CISH, BIM, and cell surface death receptor (FAS), as is a quintuple genomic disruption in genes for SOCS1, CISH, BIM, β-2-Microglobulin (B2M), and class II transactivator (CITTA), as is a sextuple genomic disruption in genes for SOCS1, CISH, BIM, B2M, CITTA, and FAS. Also provided is genetically modified iPSC-derived γδT cells and their precursors with improved proliferation and tumor killing activity. Also provided are genetically modified iPSC-derived γδT cells and their precursors further comprising CD19 CAR. The present disclosure further provides methods making and using such cells, as well as gene editing systems.

The present disclosure provides genetically modified iPSC-derived γδT cells and their precursors. A double genomic disruption in the suppressor of cytokine signaling 1 (SOCS1) gene and the cytokine-inducible sh2-containing protein (CISH) gene are provided, as is a triple genomic disruption in genes for SOCS1, CISH, and Bcl-2 interacting mediator of cell death (BIM), as is a quadruple genomic disruption in genes for SOCS1, CISH, BIM, and cell surface death receptor (FAS), as is a quintuple genomic disruption in genes for SOCS1, CISH, BIM, β-2-Microglobulin (B2M), and class II transactivator (CIITA), as is a sextuple genomic disruption in genes for SOCS1, CISH, BIM, B2M, CIITA, and FAS. Also provided is genetically modified iPSC-derived γδT cells and their precursors with improved proliferation and tumor killing activity. Also provided are genetically modified iPSC-derived γδT cells and their precursors further comprising CD19 CAR. The present disclosure further provides methods making and using such cells, as well as gene editing systems.

The invention relates to a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist for use in a method of treating a patient suffering from a tumour. The invention further relates to a pharmaceutical composition, comprising a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist and, optionally, an inducer of senescence. The invention further relates to methods of treating a patient having a tumour, and to a calcium homeostasis disruptor in combination with a selective DR5 agonist, for use in a method of selectively killing senescent cells, including senescent cancer cells.

Disclosed herein, in some aspects, are methods of treating autoimmune diseases or conditions using TCR targeting molecules or cells expressing TCR targeting molecules. TCR targeting molecules can comprise a moiety that binds to a TCR variable beta chain (TCRBV) or a TCR variable alpha chain (TCRAV). TCR targeting molecules can further comprise one, two or all of: (ii) an immune cell engager; (iii) a cytokine inhibitor molecule; (iv) a cytotoxic agent; and / or (v) a death receptor signal enhancer. Additionally, disclosed herein, in some aspects, are nucleic acids encoding the same, and methods of producing the aforesaid molecules.

The present invention relates to monospecific or bispecific antibody molecules that specifically bind antigens of Death Receptors, which are members of the tumor necrosis factor (TNF) receptor Superfamily (TNFR-SF) with an intracellular death domain. The invention relates in particular to antibody molecules of the IgG1 isotype having a mutation in the Fc region that enhances clustering of IgG molecules after target binding. The invention further relates to a combination of antibody molecules binding different epitopes on one or more specific Death Receptors. The invention also relates to pharmaceutical compositions containing these molecules and the treatment of cancer using these compositions.

The disclosure provides TNF-like ligand 1a (TL1a)-binding proteins comprising an antigen binding domain of an antibody which binds specifically to TL1a and inhibits interaction of TL1a and Death Receptor 3 (DR3) and which does not inhibit the interaction of TL1a and Decoy Receptor 3 (DcR3). The disclosure also provides uses of the TL1a-binding proteins.

The present invention relates to a multispecific antibody comprising a FAPα-binding region comprising at least a first heavy chain variable region and a first light chain variable region, and a DR4-binding region comprising a second heavy chain variable region and a second light chain variable region. The invention further provides pharmaceutical compositions comprising the antibody, and uses of the antibody in therapeutic and diagnostic procedures, particularly in cancer treatment.

The present application relates to a death receptor 5 (DR5) domain variant. The present application further relates to a fusion protein containing the DR5 domain variant, which has one or more of the following properties: (1) the ability to bind to TRAIL, (2) blocking apoptosis induced by the TRAIL / DR5 pathway, (3) reducing the size of myocardial infarction in cardiac ischemia and / or ischemia-reperfusion, and (4) having a protective effect against cerebral infarction. The present application further provides a method for producing the fusion protein and uses thereof.

An immune related adverse event marker and a kit. The immune related adverse event marker comprises CD183. The immune related adverse event marker can effectively predict immune related adverse events caused by programmed death receptor 1 antibody / programmed death-ligand antibody therapy, thereby facilitating intervention and treatment of immune related adverse events.

The present application relates to a kind of nanobody of programmed death receptor 1 and its preparation method and application.The nanobody includes heavy chain variable region, the amino acid sequence of CDR1 of the heavy chain variable region includes the sequence shown in SEQ ID NO.1, the amino acid sequence of CDR2 includes the sequence shown in SEQ ID NO.2, the amino acid sequence of CDR3 includes the sequence shown in SEQ ID NO.3.The present application utilizes PD-1 protein immunization alpaca, constructs antibody display library, screens the antibody binding PD-1 protein, obtains the nanobody of programmed death receptor 1 with high specificity and affinity, and has the ability to block the combination of PD-1 and PD-L1, enhances the function of immune cell.

The invention discloses a CAR-NK cell of a targeted death receptor 5 as well as a preparation method and application of the CAR-NK cell. The preparation method comprises the following steps: constructing a virus for expressing CAR of targeted DR5; sorting NK cells by adopting a negative selection method; the method comprises the following steps: adopting an NK cell amplification reagent purchased from Yicosai, adding 1-10% of Super Grow purchased from Daraceae into an NK culture medium, and culturing NK cells; and after culturing for 5-9 days, adding a virus for expressing the CAR of the targeted DR5 and a virus transduction enhancer, culturing at 37 DEG C in 5% CO2, and after the cell density is increased to 1-3 * 10 < 6 > cells / mL, carrying out passage to obtain the target DR5. According to the amplification process, the culture medium which is definite in component, free of serum and free of animal source components is adopted, feeder cells and pure cell factors are not used for stimulating and culturing the NK cells from human peripheral blood, large-scale and long-term amplification of the high-purity CAR-NK cells can be achieved, and the amplification process can be used for allogeneic retransfusion.

The present invention relates to a multispecific antibody comprising at least a FAPα binding region comprising a first heavy chain variable region and a first light chain variable region; and a DR4 binding region comprising a second heavy chain variable region and a second light chain variable region. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

Provided are methods for treating cancers in subjects in need thereof. In some embodiments, the methods include administering to a subject in need thereof a first composition that includes an effective amount of a binding agent that selectively binds to a tetrapeptide motif of a human CRD3 of a DR5 polypeptide and a second composition that includes an effective amount of a DR5 agonist. Also provided are methods for activating DR5 biological activities in cells, tissues, and organs, optionally cells, tissues, and organs present in subject; and compositions for use in the presently disclosed methods, including but not limited to compositions that include an effective amount of a binding agent that selectively binds to the tetrapeptide motif RKCR (SEQ ID NO: 101) of a human CRD3 of DR5 and an effective amount of a DR5 agonist and antibodies that bind to a death receptor 5 (DR5) polypeptide, including but not limited to bispecific antibodies.

In some embodiments, methods for treating autoimmune diseases or conditions using TCR-targeting molecules or cells expressing TCR-targeting molecules are disclosed herein. TCR-targeting molecules may include a moiety that binds to a variable TCR beta chain (TCRBV) or a variable TCR alpha chain (TCRAV). TCR-targeting molecules may further include one, two, or all of the following: (ii) immune cell engagers, (iii) cytokine inhibitors, (iv) cytotoxic agents, and / or (v) death receptor signal enhancers. Furthermore, in some embodiments herein, encoding nucleic acids and methods for producing the aforementioned molecules are disclosed herein.

Multifunctional molecules that include i) an antigen binding domain that binds to a T cell receptor beta chain constant domain 1 or T cell receptor beta chain constant domain 2; and one, two or all of: (ii) an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); (iii) a cytokine molecule or cytokine inhibitor molecule; (iv) a death receptor signal enhancer; and / or (v) a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

The invention relates to a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist for use in a method of treating a patient suffering from a tumor. The invention further relates to a pharmaceutical composition, comprising a calcium homeostasis disruptor in combination with a selective Death Receptor 5 (DR5) agonist and, optionally, an inducer of senescence. The invention further relates to methods of treating a patient having a tumor, and to a calcium homeostasis disruptor in combination with a selective DR5 agonist, for use in a method of selectively killing senescent cells, including senescent cancer cells.

The invention provides an immune-related adverse reaction marker and a kit. The immune-related adverse reaction marker and the kit can effectively predict immune-related adverse reaction caused by programmed death receptor 1 antibody / programmed death ligand antibody treatment. The immune-related adverse reaction marker comprises CCL20, CXCL11, CXCL10 or CXCL9, and the immune-related adverse reaction marker comprises CCL20, CXCL11, CXCL10 or CXCL9. The immune-related adverse reaction marker and the kit provided by the technical scheme of the invention can effectively predict immune-related adverse reactions, so that the immune-related adverse reactions can be conveniently intervened and treated.

The invention provides an application of neochamaejasmine B in preparation of an insecticide for inducing insect nerve cell apoptosis, and belongs to the technical field of botanical pesticides. The neochamaejasmine B induces nerve cell apoptosis of pests such as cotton bollworm and the like by activating a caspase-10 dependent death receptor pathway, and the expression is chromatin coagulation, DNA damage and mitochondrial membrane potential reduction. The IC50 value is 56.08 mu M and is equivalent to that of fipronil, but the environmental safety is remarkably improved. The invention provides a new thought for developing efficient and low-toxicity botanical insecticides.

The invention relates to the technical field of biological pharmaceutical materials, in particular to application of poly-4, 6-dialkyne sebacic acid-chitosan gel, a composite medicine and a preparation method of the composite medicine. According to the application, the poly-4, 6-dialkyne sebacic acid-chitosan gel is used for bearing the programmed death receptor 1 antibody. According to the application, triple mechanisms of physical coating, electrostatic stabilization and intelligent release of the poly-4, 6-dialkyne sebacic acid-chitosan gel are adopted, so that the bottleneck problems of poor stability, high off-target toxicity and the like in the delivery process of the PD-1 antibody are solved, and an innovative carrier system is provided for tumor immunotherapy.

The present application provides an immune-related adverse event marker and a kit, which can effectively predict immune-related adverse events caused by the treatment of a programmed death receptor 1 antibody / programmed death ligand antibody. The immune-related adverse event marker includes: CCL20, CXCL11, CXCL10 or CXCL9. The immune-related adverse event marker and kit provided by the technical solution of embodiments of the present application can effectively predict immune-related adverse events, thereby facilitating therapeutic intervention for immune-related adverse events.

The present application relates to a death receptor 5 (DR5) domain variant. The invention also relates to a fusion protein containing the DR5 structural domain variant. The fusion protein has one or more of the following properties: (1) the fusion protein can be combined with TRAIL; (2) blocking cell apoptosis induced by a TRAIL / DR5 pathway; (3) reducing the area of myocardial infarction in cardiac ischemia and / or ischemia-reperfusion; and (4) the pharmaceutical composition has a protective effect on cerebral infarction. The invention also provides a preparation method and application of the fusion protein.

The invention provides a multifunctional molecule combined with T cells and application of the multifunctional molecule to treatment of autoimmune diseases. A multifunctional molecule comprising i) an antigen binding domain that binds to a TCR variable beta chain (TCRBV) antigen; and one, two or all of (ii) an immune cell adaptor (e.g., selected from an NK cell adaptor, a T cell adaptor, a B cell adaptor, a dendritic cell adaptor or a macrophage adaptor); (iii) a cytokine molecule or a cytokine inhibitor molecule; and / or (iv) a death receptor signal enhancer. In addition, nucleic acids encoding the multifunctional molecules, methods of producing the molecules, and methods of treating autoimmune diseases using the molecules are also disclosed.

The present application provides an immune related adverse event marker and a test kit, which can effectively predict immune related adverse events caused by programmed cell death receptor 1 antibody / programmed cell death ligand antibody treatment. The immune related adverse event marker comprises CD196. The immune related adverse event marker and the test kit provided by the technical solution of the embodiments of the present application can effectively predict immune related adverse events, thereby facilitating interventional treatment for immune related adverse events.

The present disclosure provides modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising chimeric antigen receptors (CARs) specific for Death receptor-5 (DR5), and compositions and methods related thereto.

The present invention relates to a multispecific antibody comprising at least a FAPα binding region comprising a first heavy chain variable region and a first light chain variable region; and a DR4 binding region comprising a second heavy chain variable region and a second light chain variable region. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

A bispecific antibody that includes a first antigen binding site that is specific for a death receptor 5 (DR5) polypeptide and a second antigen binding site that is specific for a folate receptor alpha-1 (FOLR1) polypeptide, wherein the bispecific antibody includes: (i) a heavy chain amino acid sequence that includes SEQ ID NO:1 and a light chain amino acid sequence that includes SEQ ID NO:2; (ii) a heavy chain amino acid sequence that includes SEQ ID NO:11 and a light chain amino acid sequence that includes SEQ ID NO:2; (iii) a heavy chain amino acid sequence that includes SEQ ID NO:5 and a light chain amino acid sequence that includes SEQ ID NO: 6; or (iv) an scFv fragment that includes a knob-into-hole structure comprising SEQ ID NOs: 3 and 4.

Disclosed herein, in some aspects, are methods of treating autoimmune diseases or conditions using TCR targeting molecules or cells expressing TCR targeting molecules. TCR targeting molecules can comprise a moiety that binds to a TCR variable beta chain (TCRBV) or a TCR variable alpha chain (TCRAV). TCR targeting molecules can further comprise one, two or all of: (ii) an immune cell engager; (iii) a cytokine inhibitor molecule; (iv) a cytotoxic agent; and / or (v) a death receptor signal enhancer. Additionally, disclosed herein, in some aspects, are nucleic acids encoding the same, and methods of producing the aforesaid molecules.

Multifunctional molecules that include i) an antigen binding domain that binds to a T cell receptor beta chain constant domain 1 or T cell receptor beta chain constant domain 2; and one, two or all of: (ii) an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); (iii) a cytokine molecule or cytokine inhibitor molecule; (iv) a death receptor signal enhancer; and / or (v) a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

The invention relates to the field of biological medicine, and discloses a cell apoptosis inducer based on death receptor signaling pathway activation and a preparation method thereof. The inducer takes polypeptide molecules as an active component, activates a Caspase cascade reaction to induce apoptosis through specific binding with a death receptor, and has low toxicity to non-recipient cells. The core technology comprises the following steps: 1, polypeptide optimization design: through 1-5 amino acid substitution, chemical modification or fusion protein strategy, stability and targeting are improved; 2, preparing the polypeptide by a solid-phase synthesis or gene recombination technology, and combining purification identification processes such as HPLC (High Performance Liquid Chromatography) and mass spectrum; and 3, the preparation adopts a nano delivery system or sustained release microspheres, so that the in-vivo delivery efficiency and half-life period are enhanced. The problems of poor polypeptide stability, low delivery efficiency and insufficient safety in the prior art are solved, the polypeptide has the advantages that the tumor affinity is improved by 10 times, the half-life period is prolonged to 72 hours, the off-target toxicity is remarkably reduced, and the polypeptide is suitable for the fields of tumor treatment and the like.

In some aspects, disclosed herein are methods of treating an autoimmune disease or condition using a TCR targeting molecule or a cell expressing a TCR targeting molecule. The TCR targeting molecule may comprise a moiety that binds to a TCR variable beta chain (TCRBV) or a TCR variable alpha chain (TCRAV). The TCR targeting molecule may further comprise one, two, or all of: (ii) an immune cell zygote; (iii) a cytokine inhibitor molecule; (iv) a cytotoxic agent; and / or (v) a death receptor signal enhancer. Additionally, in some aspects, disclosed herein are nucleic acids encoding the TCR targeting molecules and methods of producing the foregoing molecules.