115 results about "Intracellular domain" patented technology

Recombinant NK cells, and especially recombinant NK-92 cells express a chimeric antigen receptor (CAR) having an intracellular domain of FcεRIγ. Notably, CAR constructs with an intracellular domain of FcεRIγ had a substantially prolonged duration of expression and significantly extended cytotoxicity over time. The CAR may be expressed from RNA and DNA, preferably as a tricistronic construct that further encodes CD16 and a cytokine to confer autocrine growth support. Advantageously, such constructs also enable high levels of transfection and expression of the recombinant proteins and provide a convenient selection marker to facilitate rapid production of recombinant NK / NK-92 cells.

The invention relates to a chimeric T-cell receptor (TCR) comprising a human transmembrane domain, a human intracellular domain and a human intracellular CD3ε domain wherein in at least one of the CD3ε domains, an arginine (R) amino acid residue at position 53 and / or 54 of SEQ ID NO:25, or an arginine (R) amino acid residue at a position that corresponds to said arginine (R) amino acid residue at position 54 of SEQ ID NO:25, is substituted or deleted. The invention further relates to a method of producing a T-cell expressing the chimeric co-stimulatory TCR. The invention further relates to a chimeric T-cell receptor (TCR) comprising a human co-stimulatory domain and a human CD3ε domain. The invention further relates to a method of treating a patient having a tumor or an immune-related disease comprising administering T-cells expressing the chimeric TCR to the patient.

The invention discloses liver-responsive synthetic macrophages and a construction method and tumor immunotherapy application thereof, and belongs to the technical field of biological medicines. The system is an IBMDM cell line of a stable expression alpha SLC17A2-P65 / shSIRP alpha-synM system, and comprises an extracellular domain and an intracellular domain, the extracellular domain is composed of a single-chain antibody scFv for recognizing an antigen SLC17A2 and a transcription factor GAL4-VP16 (GV), and the intracellular domain is composed of a UAS promoter sequence recognized by the GV and P65 / shSIRP alpha. When the antibody responds to the liver, GV is released through the self-cleavage effect of synNotch, and the GV recognizes a UAS promoter sequence after entering a nucleus to activate downstream gene expression. The invention also provides a construction method of the system. The construction method comprises the following three steps: constructing a vector plasmid, packaging lentivirus and constructing a target cell line. The system can be applied to screening anti-liver cancer immunotherapy drugs, and a new research tool is provided for liver cancer treatment.

The invention provides a chimeric antigen receptor for regulating and controlling a signal time sequence and application of the chimeric antigen receptor. The chimeric antigen receptor sequentially comprises a signal peptide, an extracellular domain, a transmembrane domain and an intracellular domain from an N terminal to a C terminal, the extracellular structural domain comprises an antigen recognition region and a hinge region; the intracellular domain comprises a costimulatory signal transduction region and a CD3 [zeta] intracellular region variant; the CD3 [zeta] intracellular region variant comprises three ITAMs, and the arrangement sequence of the ITAMs is ITAM3-ITAM2-ITAM1 from the N end to the C end. Compared with a conventional chimeric antigen receptor containing a wild CD3 zeta intracellular region, the chimeric antigen receptor provided by the invention can significantly enhance the functional activity of immune cells expressing the chimeric antigen receptor, which is specifically embodied in stronger multiplication capacity and durability, and significantly improves the antigen sensitivity and targeted killing efficacy.

The present invention provides for chimeric antigen receptor constructs capable of being expressed in dendritic cells (DCs), and DCs modified to express one or more chimeric antigen receptors (CARs) as well as compositions comprising these modified DCs and methods of stimulating an adaptive immune response in a subject. The intracellular domain of the CAR comprises a toll-interleukin receptor (TIL) intracellular signalling domain and a costimulating domain selected from CD3 signalling domain, CD28 signalling domain and a combined CD28 and CD3 signalling domain.

Disclosed is a nucleic acid encoding a chimeric antigen receptor comprising an extracellular domain including an antigen recognition domain consisting of a fully human single variable heavy chain (VH) domain that binds to a first epitope on B-cell maturation antigen (BCMA), a transmembrane domain, and an intracellular domain including a signaling domain.

This invention discloses an engineered CAR-T cell targeting HIF-1α and its application in tumor immunotherapy. The CAR-T cell expresses a chimeric antigen receptor regulated by the hypoxia-responsive element HRE promoter, with its extracellular domain specifically binding to HIF-1α and its intracellular domain employing the 4-1BB+CD3ζ signaling module. Simultaneously, through immune checkpoint knockout and cytokine / chemokine modification, it achieves hypoxia-dependent activation, anti-exhaustion, high infiltration, and strong killing effects. The CAR-T cells of this invention significantly improve the adaptability to the solid tumor microenvironment and therapeutic efficacy, reduce off-target toxicity, and can be used to prepare drugs for treating malignant tumors such as lung cancer, liver cancer, pancreatic cancer, colorectal cancer, and glioblastoma, possessing significant clinical translational value.

Provided are chimeric antigen receptors or functional fragments or variants thereof having a hinge, transmembrane region, and / or intracellular domain of LILRB1. Also provided herein are cells comprising the LILRB1-based receptors, and methods of making and using the same.

The invention belongs to the technical field of tumor immunotherapy, and relates to an anti-Claudin18.2 single-domain antibody, a multifunctional fusion protein, a recombinant natural killer cell (CT-CAR-NK), and preparation and application thereof. Through alpaca immunization and phage display library construction and panning, the single-domain antibody VHH-C18.2-1 specifically combined with Claudin18.2 is obtained, and the amino acid sequence of the single-domain antibody VHH-C18.2-1 is SEQ ID NO: 1. The amino acid sequence of the designed fusion protein is SEQ ID NO: 3, the fusion protein sequentially comprises a VHH-C18.2-1, a flexible Linker, a TGF-beta RII extracellular domain, a CD8alpha hinge region, a CD8alpha transmembrane region, a 4-1BB intracellular domain and a CD3zeta intracellular domain from the N end to the C end, and the fusion protein has the functions of targeting, resisting TGF-beta inhibition and activating signals. The fusion protein gene transfects human peripheral blood CD56 + CD3-NK cells through lentivirus to obtain CT-CAR-NK, in-vitro verification shows that the CT-CAR-NK still keeps efficient killing in an immunosuppression environment, tumor growth can be remarkably inhibited in vivo, the lifetime can be prolonged, and a safe and efficient scheme is provided for Claudin18.2 positive solid tumor treatment.

Provided are a CD19-targeting humanized antibody and chimeric antigen receptor, and the use thereof. The humanized antibody contains CD19 VH and CD19 VL which are selected from one of groups 1) to 8). The CD19-targeting chimeric antigen receptor contains a CD19-targeting extracellular antigen recognition domain, a hinge region, a transmembrane region, and an intracellular domain, wherein the CD19-targeting extracellular antigen recognition domain contains CD19 VH and CD19 VL which are selected from one of groups 1) to 8).

The invention discloses an HSP70-targeting chimeric antigen receptor-macrophage and application thereof in treatment of noise-induced hearing loss, an extracellular domain of the HSP70-targeting chimeric antigen receptor comprises an HSP70 specific binding fragment, an intracellular domain comprises an IL-4 signal channel functional element, a signal switch type CAR structure of the HSP70 is formed, and the macrophage can be used for treating noise-induced hearing loss, so that the HSP70-targeting chimeric antigen receptor-macrophage can be used for treating noise-induced hearing loss. The HSP70-targeted chimeric antigen receptor-macrophage can be used for preparing the HSP70-targeted chimeric antigen receptor-macrophage, is used for mediating polarization of the macrophage to an M2 type and exerting an anti-inflammatory function, is proved to be capable of specifically responding to an inner ear inflammation microenvironment, switching an anti-inflammatory phenotype and protecting hair cells and auditory nerves, can be used for treating noise-induced hearing loss, and can be used for preparing the HSP70-targeted chimeric antigen receptor-macrophage. The limitation that traditional hearing-aid equipment supports treatment on symptoms is broken through, and the hearing-aid device has a remarkable application prospect.

The present invention provides thymic T regulatory cells (ThyTreg cells) that encode or alternatively express a chimeric antigen receptor (CAR) comprising an extracellular domain, a hinge region, a transmembrane domain, and an intracellular domain, wherein the intracellular domain comprises a cytoplasmic costimulatory domain having a sequence having at least 85% identity with SEQ ID NO: 1, and a cytoplasmic stimulatory domain. The present invention also provides compositions and uses in immunotherapy.

The application discloses a bispecific chimeric antigen receptor targeting HER2 and HLA-G and application thereof, and belongs to the tumor immunotherapy field.The chimeric antigen receptor comprises an extracellular domain, a hinge domain, a transmembrane domain and at least one intracellular domain, and the extracellular domain comprises an anti-HER2 single-chain antibody and an anti-HLA-G single-chain antibody.The bispecific chimeric antigen receptor of the application can effectively improve the killing signal of immune cells, and can effectively avoid the inhibition of the immunosuppressive signal on the function of immune cells, thereby delaying the recurrence of tumors, and has very important clinical application value.

Modified natural killer (NK) cells or T cells expressing hematopoietic growth factor receptors are provided. In some aspects, the modified NK cells or T cells express thrombopoietin receptors, erythropoietin receptors, or chimeric peptides comprising an extracellular domain, a transmembrane domain, and an intracellular domain including an intracellular signaling domain of an interleukin receptor. Methods for treating cancer subjects are also provided, comprising administering modified NK cells or T cells to the subject in combination with a thrombopoietin receptor agonist or an erythropoietin receptor agonist, and in some instances, in combination with interleukin-2, particularly reduced or low doses of IL-2.

The invention relates to a chimeric antigen receptor based on a functional fragment of an MAVS protein, in particular to a chimeric antigen receptor (CAR) construct positioned on a cell membrane, and an intracellular structural domain of the CAR construct contains the functional fragment derived from the MAVS protein. The MAVS protein is a truncated body with deletion or mutation of a mitochondrial positioning region of the MAVS protein. The engineered immune cell for expressing the CAR construct disclosed by the invention has specific targeting property and a remarkable anti-tumor effect.

The present application relates to the technical fields of biological medicine and cellular immunotherapy, and particularly relates to a signal conversion receptor targeting IL-10, an engineered macrophage and application thereof. The signal conversion receptor is composed of an extracellular domain and a transmembrane domain and an intracellular domain derived from TLR9, and the extracellular domain sequentially comprises a signal peptide, a HA tag and a specific binding domain of an IL-10 receptor alpha subunit from N-terminal to C-terminal. The present application further prepares an engineered macrophage SR CAR-M capable of specifically recognizing IL-10 and converting it into a TLR9 activation signal, which can induce macrophages to polarize to M1 type and has excellent phagocytosis and killing capacity for bladder cancer, breast cancer, lung cancer and melanoma cells, and can be used for preparing related tumor treatment drugs, overcoming the common problems of existing cell therapy, such as easy exhaustion, difficult infiltration and easy inhibition in solid tumors, and having significant clinical transformation potential.

Described is a polypeptide including the intracellular domain of CX3CL1 (CX3CL1-ICD), including an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and pharmaceutical compositions including the above-described polypeptide and a pharmaceutically acceptable excipient. Also included are nucleic acids expressing the polypeptides and expression cassettes and vectors comprising the nucleic acids. The polypeptides can be used in methods of treating a subject exhibiting a symptom of a neurodegenerative disease and / or diagnosed with a neurodegenerative disease and methods of treating a subject exhibiting a symptom of diabetes and / or diagnosed with diabetes comprising administering to the subject the pharmaceutical composition described herein.

The present invention relates to a human CD20 protein of which one or more intracellular domains are modified sufficient to reduce or eliminate intracellular signaling when attached to or bound to a cell membrane, such as T cells, natural killer cells, B cells, myeloid cells, pluripotent stem cells, and hematopoietic stem cells. The invention also relates to a nucleic acid encoding the modified human CD20 protein described herein, and the use of the modified human CD20 protein as a safety switch in chimeric antigen receptor T cell therapy or as a selection marker in gene therapy.

The present invention relates to an intracellular domain of AXL or a fragment derived therefrom, and a use for regulating autophagy using same, wherein the intracellular domain of AXL or the fragment derived therefrom can regulate a selective autophagy pathway in response to an intracellular amyloid beta signal.

The invention provides a chimeric antigen receptor targeting CD19 and / or CD20 and application thereof, the chimeric antigen receptor comprises: an extracellular domain capable of binding to CD20 and / or CD19; the extracellular domain is connected with the amino acid sequence, the transmembrane domain is connected with the extracellular domain, the intracellular domain is connected with the transmembrane domain, and the intracellular domain is selected from all amino acid sequences or partial amino acid sequences of at least one of the following proteins: 2B4, DAP10 and CD3zeta. The chimeric antigen receptor disclosed by the invention has double-target recognition capability and can be simultaneously combined with CD19 and CD20, so that the chimeric antigen receptor can cover a full differentiation stage of pathogenic B cells in autoimmune diseases and block a production path of an autoantibody from a source of a pathological mechanism; meanwhile, based on the inherent regulation and control capability of NK cells on lesion T cells, pathogenic T cells are removed, and the removal effect of B cells is cooperated, so that bidirectional blocking treatment on autoimmune pathology is realized.

This invention provides a humanized antibody targeting CD19, a chimeric antigen receptor, and their uses. The humanized antibody comprises CD19VH and CD19VL, selected from groups 1) to 8). The chimeric antigen receptor targeting CD19 of this invention comprises an extracellular antigen recognition domain, a hinge region, a transmembrane region, and an intracellular domain targeting CD19. The extracellular antigen recognition domain targeting CD19 comprises CD19VH and CD19VL, selected from groups 1) to 8).

The present application relates to signal conversion receptors, and specifically provides a signal conversion receptor comprising an extracellular region, a transmembrane region and an intracellular region, wherein the intracellular region comprises a CD25 intracellular domain, and optionally further comprises an intracellular domain of a costimulatory signaling molecule. An immune effector cell expressing the signal conversion receptor has a higher positive rate, activation level and target cell killing ability compared with a control cell.

The invention relates to a modified myeloid cell comprising a cytokine chimeric receptor (CCR), wherein said CCR comprises an extracellular domain comprising an extracellular domain of a cytokine receptor which binds soluble molecules present in the tumor microenvironment (TME); a transmembrane domain; and an intracellular signaling domain comprising CD40 cytotail, CD3zeta intracellular domain and / or STING or one of its fragments. The invention also relates to a modified cell comprising a CCR and a transgene coding for a cytokine. The invention also relates to therapeutic uses thereof and to methods and pharmaceutical compositions for the treatment of cancer.

Provided herein are chimeric antigen receptors, comprising an extracellular domain capable of binding to an antigen, an Fc region, a flexible linker, a transmembrane domain, and may further comprise at least one intracellular domain that is designed to increase the anti-tumor activities of granulocytes, macrophages, and dendritic cells by increasing their phagocytosis and / or proinflammatory cytokines secretion and / or antigen presentation. Provided herein are vectors and nucleic acid molecules encoding any of the chimeric antigen receptors described herein. Provided herein are methods to genetically engineer granulocyte-macrophage progenitors (GMPs) to express the chimeric antigen receptors described herein. The CAR-Fc-GMPs may be induced to differentiate into macrophages or granulocytes. Provided herein are macrophages and granulocytes that express a CAR-Fc prepared by any of the methods described herein. Provided herein is an immunotherapy method for treating a subject having cancer with GMPs or macrophages or granulocytes that express the chimeric antigen receptors described herein.

Provided are recombinant cytokine receptors that comprise an IL-2 intracellular domain and an extracellular domain that binds to a cytokine other than IL-2. Also provided herein are Treg cell comprising recombinant cytokine receptors and methods of use.

A recombinant fusion protein is disclosed. The fusion protein comprises (a) a CD55 peptide sequence, (b) a linker sequence located at the C-terminus of the CD55 sequence, (c) a transmembrane domain located at the C-terminus of the linker sequence, and (d) an intracellular domain located at the C-terminus of the transmembrane domain. The fusion protein does not contain a GPI anchor. The fusion protein can be expressed with an N-terminal secretory signal peptide that is cleaved to produce a mature protein on the surface of a cell line or enveloped virus. An oncolytic virus expressing the fusion protein is resistant to complement inactivation and can be used to treat cancer.

The application belongs to the technical field of biology and relates to an RSV pre-F mutant, a preparation method and application thereof. Compared with a wild-type F0 polypeptide, the RSV pre-F mutant satisfies the following conditions: (1) does not contain a furin enzyme cutting site fragment, a P27 polypeptide, a transmembrane domain and an intracellular domain; (2) has mutations S180C, S186C, A170C, V179C, A241C, Q279C, D486C and A490C; and (3) the C terminal of an F1 polypeptide is not connected or connected with an aggregation motif. The mutant and a trimeric conformation thereof are both highly stable, can self-assemble into a trimer without a heterologous trimeric domain, can induce high levels of binding antibodies and neutralizing antibodies after immunization, avoid high levels of non-neutralizing active binding antibodies produced when immunization is performed on the heterologous trimeric domain, and thus improve the quality of antibodies.

Provided herein are particles or compositions comprising one or more nucleic acid molecules encoding a chimeric antigen receptor (CAR) and / or a polypeptide comprising i) a ligand binding extracellular domain (ECD), ii) an immune cell activating intracellular domain (ICD); and iii) transmembrane domains linking the ECD and the ICD, polypeptides comprising these domains and nucleic acid molecules encoding these polypeptides. Also provided herein are compositions comprising these nucleic acid molecules and methods of using these compositions. Also provided herein are viral particles comprising these nucleic acid molecules.

In aspects, a chimeric cytokine receptor (CCR) is provided that comprises (i) a single chain variable fragment (scFv) which specifically binds to an antigen, one or more extracellular interleukin receptor domains, an interleukin receptor transmembrane domain, and an interleukin receptor intracellular domain; and (ii) a single chain variable fragment (scFv) which specifically binds to an antigen, one or more extracellular interleukin receptor common gamma chain (γc) domains, a γc transmembrane domain, and a γc intracellular domain.

The invention relates to the technical field of biology, and discloses a construction method and application of a BCMA full-length receptor in a nano phospholipid plate. The construction method of the BCMA full-length receptor comprises the following steps: reacting a BCMA extracellular domain, a BCMA transmembrane region and an intracellular domain containing site-specific mutagenesis, CaCl2 and sortase A, after the reaction is finished, purifying by using a nickel affinity column, collecting an imidazole elution component, and enriching to obtain the BCMA full-length receptor in the nano phospholipid plate. According to the construction method, the extracellular domain of the BCMA and the BCMA transmembrane region and the intracellular domain in the nano phospholipid plate are connected through Sortase A enzyme, the BCMA full-length receptor is obtained in an in-vitro near-physiological environment, the method is simple, protein is easy to obtain, and the defect that the transmembrane region is poor in solubility is overcome; meanwhile, the structure-function of the BCMA can be studied in vitro by marking the functional structure domain of the BCMA at a fixed point.