1111 results about "Natural Killer Cell Inhibitory Receptors" patented technology

The present invention is directed to universal T cells and their use in treating diseases and other physiological conditions. More specifically, the present invention is directed to universal T cells and their use in treating treating B-lineage acute lymphoblastic leukemia (B-ALL) in particular and malignancy in general. The universal T cells contain (i) nucleic acid encoding a chimeric antigen receptor (CAR) to redirect their antigen specificity and effector function and (ii) nucleic acids encoding shRNA and/or siRNA molecules to down-regulate cell-surface expression of T cell classical HLA class I and/or II genes to avoid recognition by recipient T cells. The universal T cells may also contain a nucleic acid encoding a non-classical HLA gene, such as an HLA E gene to enforce expression of HLA E genes and/or an HLA G gene to enforce expression of HLA G genes, to avoid recognition by recipient NK cells. The universal T cells may further contain a nucleic acid encoding a selection-suicide gene.

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use. Also included is a method for obtaining an enriched population of NK cells from a mixed population of NK cells and T cells.

The invention is directed to a polypeptide comprising a human IL-2 mutein numbered in accordance with wild-type IL-2 wherein said human IL-2 is substituted at at least one of positions 20, 88 or 126, whereby said mutein preferentially activates T cells over NK cells. D20H and I, N88G, I, and R, in particular have a relative T cell-differential activity much greater than native IL-2, with predicted associated reduced in vivo toxicity. The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

Compounds for targeted immunotherapy, compositions comprising the compounds and use of the compounds in the treatment of diseases such as cancer are disclosed. The compounds having the structure of formula TM-Ln-AM, wherein TM is a targeting moiety, AM is an activating moiety that is capable of activating a human dendritic cell, NK cell, or tumor cell, or a combination thereof, Ln is a linker, and n is an integer selected from 0 and 1.

The present invention concerns CAR, CAR-T and CAR-NK constructs, preferably comprising a scFv antibody fragment against a disease-associated antigen or a hapten. More preferably, the antigen is a TAA, such as Trop-2. The constructs may be administered to a subject with a disease, such as cancer, autoimmune disease, or immune dysfunction disease, to induce an immune response against disease-associated cells. Where the constructs bind to a hapten, the subject is first treated with a hapten-conjugated antibody that binds to a disease associated antigen. Therapy may be supplemented by other treatments, such as debulking procedures (e.g., surgery, chemotherapy, radiation therapy) or coadministration of other agents. More preferably, administration of the construct is preceded by predosing with an unconjugated antibody that binds to the same disease-associated antigen. Most preferably, an antibody against CD74 or HLA-DR is administered to reduce systemic immunotoxicity induced by the constructs.

The present invention relates to the identification of 4Ig-B7-H3 protein as a tumor associated molecule that imparts protection from NK cell-mediated lysis via a 4Ig-B7-H3 receptor on NK cells. The invention provides compounds that interfere with interactions between the 4Ig-B7-H3 protein and its receptor that can be used to potentiate NK cell cytotoxicity. Also provided are compounds that bind 4Ig-B7-H3-expressing cells so as to inhibit or eliminate them. The compounds are particularly useful in the treatment of tumors, inflammatory conditions, infections and transplantation. Also provided are methods for diagnosing disease by detecting a 4Ig-B7-H3 protein.

The invention discloses a method for amplifying NK cells of human beings under the condition of in vitro culture, which is characterized in that a peripheral blood mononuclear cell (PBMC) is taken asthe original culturing material, and the PBMC is cultured together with an engineering cell which is built by adopting the genetic engineering method and is used for stimulating the growth of the NK cell. The built engineering cell which is used for stimulating the growth of the NK cell expresses several cytokines (IL-2, IL-12, IL-15, IL-18, 4-1BB) which can promote the growth of the NK cell on the surface of the K562 cell; after irradiation and inactivation with gamma-rays, the engineering cell is cultured with the PBMC in vitro, as a result, the amplification effect of the stimulation methodin the invention is hundreds of times stronger than that of the currently universal method in which soluble cytokines are added purely to the culture solution; and after cultured for 3 weeks, the non-NK cells in the PBMC are mainly dead and disappeared, the NK cells are proliferated in great quantity, the purity of the NK cells reaches over 96% and the total number of the NK cells is amplified byover 1500 times.

Novel human interleukin-2 (IL-2) muteins or variants thereof, and nucleic acid molecules and variants thereof are provided. Methods for producing these muteins as well as methods for stimulating the immune system of an animal are also disclosed. In addition, the invention provides recombinant expression vectors comprising the nucleic acid molecules of this invention and host cells into which expression vectors have been introduced. Pharmaceutical compositions are included comprising a therapeutically effective amount of a human IL-2 mutein of the invention and a pharmaceutically acceptable carrier. The IL-2 muteins have lower toxicity than native IL-2 or Proleukin® IL-2, while maintaining or enhancing NK cell-mediated effects, and can be used in pharmaceutical compositions for use in treatment of cancer, and in stimulating the immune response.

The invention discloses a method for constructing a human peripheral blood immune cell bank. The method comprises the following steps of: collecting human peripheral blood, separating autologous plasma, separating a peripheral blood mononuclear cell, separating a mononuclear cell by the peripheral blood mononuclear cell and freezing, separating a T lymphocyte by the peripheral blood mononuclear cell and freezing, separating a B lymphocyte by the peripheral blood mononuclear cell and freezing, separating an NK cell by the peripheral blood mononuclear cell and freezing, and encoding and puttingin storage. According to the invention, immune cells of health or young people are separated and are respectively independently frozen, and relative numbers are stored and put into storage, so that the stored human immune cells have the characteristics of high activity, high purity and convenience for use, and fetal calf serum can be replaced by the human autologous plasma, so that introduction of a foreign protein can be avoided. Meanwhile, the method, provided by the invention, has the advantages of low cost, low requirements on laboratory conditions, and wide application.

The present invention relates to non-lethal methods of conditioning a recipient for bone marrow transplantation. In particular, it relates to the use of nonlethal doses of total body irradiation, total lymphoid irradiation, cell type-specific or cell marker-specific antibodies, especially antibodies directed to bone marrow stromal cell markers, NK cells, or the CD8 cell marker, cytotoxic drugs, or a combination thereof. The methods of the invention have a wide range of applications, including, but not limited to, the conditioning of an individual for hematopoietic reconstitution by bone marrow transplantation for the treatment of hematologic malignancies, hematologic disorders, autoimmunity, infectious diseases such as acquired immunodeficiency syndrome, and the engraftment of bone marrow cells to induce tolerance for solid organ, tissue and cellular transplantation.

The invention relates to a method for in-vitro amplification of NK cells, and in particular relates to a method for massive in-vitro amplification of NK cells, wherein the method comprises the following steps of: a, inoculating a peripheral blood mononuclear cell in a CD3McAb and CD226McAb pre-coated culture bottle for coculture; b, adding 1L-2 and 1L-18, coculturing for 72hours to stimulate amplification of NK cells; c, transferring the NK cells, K562 cells after lethal treatment and a serum-free medium containing 1L-2 and 1L-18 in a cell culture bag for coculture; and d, collecting the NK cells. According to the method for in-vitro amplification of the NK cells, two antibodies CD3McAb and CD226McAb are simultaneously coated, so the cell factor synthesis and ADCC effect are promoted, and killing toxicity of the NK cells is remarkably improved; the activation and amplification on the NK cells are achieved just by the 1L-2 and 1L-18 cell factors, so the amplification multiple and cell toxicity of the NK cells are guaranteed, and the cost of cell culture is reduced.

Methods and compositions for modulating interleukin-21 (IL-21)/IL-21 receptor (MU-1) activity using agonists or antagonists of IL-21 or IL-21 receptor (“IL-21R” or “MU-1”), are disclosed. IL-21/IL-21R antagonists can be used to induce immune suppression in vivo, e.g., for treating or preventing immune cell-associated pathologies (e.g., pathologies associated with aberrant activity of one or more of mature T cells (mature CD8+, mature CD4+ T cells), mature NK cells, B cells, macrophages and megakaryocytes, including transplant rejection and autoimmune disorders). IL-21/IL-21R agonists can be used by themselves or in combination with an antigen, e.g., as an adjuvant (e.g., a vaccine adjuvant), to up-regulate an immune response in vivo, e.g., for example, for use in treating cancer and infectious disorders.

The invention discloses rhodococcus ruber and application of same as an immunologic adjuvant in preparing vaccine. The rhodococcus ruber is also called rhodococcus ruber RDC-01, and the preservation number is CGMCC (China General Microbiological Culture Collection Center) NO. 16640. The rhodococcus ruber disclosed by the invention has the function of increasing and regulating the body immunity andis capable of nonspecifically enhancing the activity of TB (Tuberculosis) lymphocyte, macrophagocyte and NK cells and inducing multiple cell factors such as interferon, and the rhodococcus ruber canbe used as the immunologic adjuvant after being inactivated so as to be added in an oil-adjuvant inactive vaccine, so that generation of an animal antibody induced by the vaccine can be obviously promoted; compared with single use of the oil-adjuvant inactive vaccine, a high-titre antibody can be generated, the use is safe, long-term and short-term toxic and side effects are not generated, and anapplication prospect in the field of preparation of vaccines for animals is good.

The invention discloses antibacterial and antitumor application of exosomes secreted by NK cells (aNK) activated by transmembrane IL-21 and multiple miRNAs contained in the exosomes, and provides a new method for bacterial infection and antitumor treatment. The method has the advantages that 1, the method is different from antibiotic treatment, and exosome antibiosis has lower side effects; 2, effects of antibacterial treatment can be enhanced through joint use; 3, the exosomes can be stored at low temperature, the miRNAs can be artificially synthesized, costs are low and large-scale production can be achieved; 4, the exosomes and the multiple miRNAs have inhibitory effects on a variety of bacteria, and have wider antibacterial spectra; 5, the miRNAs act on a variety of shared signal pathways of tumor cells, can inhibit a variety of tumors, and have a wide range of antitumor application.

The invention discloses an expansion method of various lymphocyte subpopulations and application of the expansion method to preparation of an adoptive immunotherapy medicine for cancers. The expansion method comprises the following steps: S1, adding IFN gamma and zoledronic acid into a culture medium of PBMC collected in the blood of a tumor patient, and re-adding an OKT3 antibody and recombinant human interleukin-2 after culture to stimulate PBMC so as to finish preliminary expansion; S2, after finish of preliminary expansion, mixing immune lymphocytes with feeder layer cells, and after adding zoledronic acid, an OKT3 antibody and recombinant human interleukin-2, continually performing expansion. By adoption of the expansion method, after twice expansion, the sum of the immune cells can be 10,000 to 80,000 times by expansion, the expanded immune cells include alpha beta T cells, gamma delta T cells, NKT cells and NK cells, and tumor cells can be directly killed, or a cellular immunotherapy drug is prepared to kill the tumor cells.

The invention provides culture platforms, cell media, and methods of differentiating pluriptent cells into hematopoietic cells. The invention further provides pluripotent stem cell-derived hematopoietic cells generated using the culture platforms and methods disclosed herein, which enable feed-free, monolayer culturing and in the absence of ER formation. Specifically, pluripotent stem cell-derived hematopoietic cell of this invention include, and not limited to, iHSC, definitive hemogenic endothelium, hematopoietic multipotent progenitors, T cell progenitors, NK cell progenitors, T cells, and NK cells.

The invention relates to a culture medium efficiently amplifying autologous NK cells and a culture method. The culture medium internally contains interleukin 2(IL-2), interleukin 15(IL-15), interleukin 7(IL-7), interleukin 12(IL-12), tumor necrosis factor alpha (TNFalpha) and CD3-antibody, can efficiently amplify and activate NK cells so as to obtain a large quantity of highly active immune cells with majority of NK cells to be transferred back to human bodies, and has remarkable curative effect in anti-tumor, anti-virus infection and immune adjustment related diseases. The culture medium efficiently amplifying autologous NK cells comprises the culture medium for cultivating cells and added factors added into the culture medium for cultivating cells, is used for cultivating and amplifying a large quantity of autologous activated NK cells, and is characterized in that the added factor comprises interleukin 2(IL-2), interleukin 15(IL-15), interleukin 7(IL-7), interleukin 12(IL-12), tumor necrosis factor alpha (TNF alpha) and CD3-antibody.