129 results about "CTLA-4" patented technology

The present invention provides human sequence antibodies against CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

The present disclosure provides combinations of immunotherapeutics and methods for treating medical conditions that are characterized by the lack of an effective immune response, for example as would result following a down-regulation of MHC class I, such as in cancer. The immunotherapeutic compositions of the invention, which can be used to treat the medical conditions, include one or more immunostimulatory antibodies or molecules having specificity for CTLA-4, PD-1, PD-L1, PD-L2, CD40, OX40, CD137, GITR, ILT2, or ILT3, or ligands for these molecules (e.g., an isolated fully-human monoclonal antibody) in association with one or more alloantigens, such as, vector(s) capable of expressing protein(s) or peptide(s) that stimulate T-cell immunity against tissues or cells, formulated in a pharmaceutically acceptable carrier. The proteins or peptides may comprise class I major histocompatibility complex (MHC) antigens, β2-microglobulins, or cytokines. The MHC antigen may be foreign to the subject. The MHC antigen may be HLA-B7.

The invention concerns an isolated monoclonal antibody, which is specific and agonistic for CTLA-4, whereby the antibody does not bind to the C″D loop of CTLA-4.

Methods of inducing T cell proliferation and expansion in vivo for treating conditions wherein antigen-specific T cell immune response are therapeutically desirable such as cancer, infection, inflammation, allergy and autoimmunity and for enhancing the efficacy of vaccines are provided. These methods comprise the administration of at least one CD27 agonist, preferably an agonistic CD27 antibody, alone or in association with another moiety such as immune stimulant or immune modulator such as an anti-CD40, OX-40, 4-IBB, or CTLA-4 antibody or an agent that depletes regulatory cells, or a cytokine. These mono and combination therapies may also optionally include the administration of a desired antigen such as a tumor antigen, an allergen, an autoantigen, or an antigen specific to an infectious agent or pathogen against which a T cell response (often CD8+) is desirably elicited.

Presented herein are therapeutic agents that modulate one or more immune functions and uses of such therapeutic agents in the prevention, treatment and management of diseases. In one aspect, the therapeutic agents modulate one or more signal transduction pathways induced by the binding of B7-H7 to B7-H7CR, or the binding of B7-H2 to either ICOS, CD28, or CTLA-4. In another aspect, the therapeutic agents modulate the binding of B7-H7 to B7-H7CR, or the binding of B7-H2 to either ICOS, CD28, or CTLA-4. The therapeutic agents can be used in the prevention, treatment and / or management of diseases in which it might be useful to modulate one or more immune functions (e.g., cancer, infectious disease, autoimmune disease, and transplantation rejection). In another aspect, presented herein are methods for identifying receptor-ligand interactions.

A method and compound for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection are disclosed. The compound is an antisense oligonucleotide analog compound having a targeting sequence complementary to a preprocessed CTLA-4 mRNA region identified by SEQ ID NO: 22 in SEQ ID NO: 1, spanning the splice junction between intron 1 and exon 2 of the preprocessed mRNA of the subject. The compound is effective, when administered to a subject, to form within host cells, a heteroduplex structure (i) composed of the preprocessed CTLA-4 mRNA and the oligonucleotide compound, (ii) characterized by a Tm of dissociation of at least 45° C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.

The invention discloses a specific-binding PD-1 and / or CTLA-4 dual variable domain immunoglobulin (DVD-Ig) obtained by modifying anti-PD-1 and CTLA-4 antibodies through adopting a molecular biology method. An anti-PD-1 antibody variable domain is intramolecular and an anti-CTLA-4 antibody is extramolecular, the anti-PD-1 antibody variable domain is extramolecular and the anti-CTLA-4 antibody is intramolecular, and two structures respectively keep the combination characteristics of PD-1 and / or CTLA-4 molecules. The anti-CTLA-4 and PD-1 dual variable domain immunoglobulin has potential tumor treatment values.

Provided are methods and antisense oligonucleotide analogs for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection. The oligonucleotide analogs provided herein comprise a targeting sequence complementary to a preprocessed CTLA-4 mRNA region that spans the splice junction between intron 1 and exon 2 of the preprocessed CTLA-4 mRNA. Also provided are methods of use, in which the oligonucleotides are effective, when administered to a subject, to form within host cells, a heteroduplex structure (i) composed of the preprocessed CTLA-4 mRNA and the oligonucleotide compound, (ii) characterized by a Tm of dissociation of at least 45° C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.

The present invention relates to compositions and methods for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR α chain, TCR β chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS and further comprising a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Also included are methods and pharmaceutical compositions comprising the modified T cell for adoptive therapy and treating a condition, such as an autoimmune disease.

Nanosecond pulsed electric field (nsPEF) treatments of a tumor are used to cause the tumor to express calreticulin and stimulate an immune response against the tumor and other tumors in a subject. An immune response biomarker can be measured, and further nsPEF treatments can be performed if needed to stimulate or further stimulate the immune response. Cancers that have metastasized may be treated. The treatment can be combined with CD47-blocking antibodies, doxorubicin, CTLA-4-blocking antibodies, and / or PD-1-blocking antibodies. Electrical characteristics of nsPEF treatments can be based on the size, type, and / or strength of tumors and / or a quantity of tumors in the subject.

Methods and compositions for treating inflammatory bowel disease, gastrointestinal inflammation and maintaining normal gut health are described. These methods of the invention involve the administration of abscisic acid in amounts sufficient to alter the expression or activity of PPAR gamma in a cell. Also described are methods for suppressing the expression of cellular adhesion molecules in the gut and methods for increasing CTLA-4 expression on CD4+ T cells through administration of abscisic acid.

Agonists to ICOS in combination with a blocking agent to a T cell inhibitory receptor (e.g., CTLA-4, PD-I, etc.) are demonstrated herein to be useful for the treatment of tumors.

Mutations to the tumor suppressor protein p53 have been observed in 40-60% of all human cancers. These mutations are often associated with high nuclear and cytoplasmic concentrations of p53. Since many tumors exhibit highly elevated p53 levels, the protein is an attractive target for cancer immunotherapy. Unfortunately, p53 is an autoantigen that is likely to be tolerated as a self-protein by the immune system. The present invention is based on the discovery that this self-tolerance can be overcome by administration of recombinant modified vaccinia Ankara (MVA) containing a nucleic acid that encodes p53 (rMVAp53). The invention discloses a method of generating a p53-specific CTL-response to tumor cells expressing mutated p53 by administering a composition comprising rMVAp53. Administration of rMVAp53 decreases tumor development, tumor growth, and mortality in a variety of malignant cell types. These effects are enhanced by administration of CTLA-4 blocker and / or CpG oligodeoxynucleotide immunomodulators.

Mutations to the tumor suppressor protein p53 have been observed in 40-60% of all human cancers. These mutations are often associated with high nuclear and cytoplasmic concentrations of p53. Since many tumors exhibit highly elevated p53 levels, the protein is an attractive target for cancer immunotherapy. Unfortunately, p53 is an autoantigen that is likely to be tolerated as a self-protein by the immune system. The present invention is based on the discovery that this self-tolerance can be overcome by administration of recombinant modified vaccinia Ankara (MVA) containing a nucleic acid that encodes p53 (rMVAp53). The invention discloses a method of generating a p53-specific CTL-response to tumor cells expressing mutated p53 by administering a composition comprising rMVAp53. Administration of rMVAp53 decreases tumor development, tumor growth, and mortality in a variety of malignant cell types. These effects are enhanced by administration of CTLA-4 blocker and / or CpG oligodeoxynucleotide immunomodulators.

A method and compound for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection are disclosed. The compound is an antisense oligonucleotide analog compound having a targeting sequence complementary to a preprocessed CTLA-4 mRNA region identified by SEQ ID NO: 1, spanning the splice junction between intron 1 and exon 2 of the preprocessed mRNA of the subject. The compound is effective, when administered to a subject, to form within host cells, a heteroduplex structure (i) composed of the preprocessed CTLA-4 mRNA and the oligonucleotide compound, (ii) characterized by a Tm of dissociation of at least 45° C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.

The invention discloses a monoclonal antibody and application thereof. The monoclonal antibody consists of light chains and heavy chains, wherein amino acid residue sequences of the variable area of the heavy chains are showed in a sequence 1 in the sequence table, and amino acid residue sequences of the variable area of the light chains are showed in a sequence 2 in the sequence table. The invention combines and constructs anti-CTLA-4 antibodies and anti-4-1BB antibodies to form antihuman 4-1BB and CTLA-4 monoclonal antibodies. Experimental result shows that the monoclonal antibody has an antibody structure and can be respectively combined with human 4-1BB and CTLA-4.

The invention relates to a method for culturing an autologous peripheral blood lymphocyte. The method comprises the following steps: (1) separating a mononuclear cell from peripheral blood, resuspending in an X-VIVO15 serum-free culture medium to obtain cell concentration of 1*10<6> / mL, and culturing for 3 days; (2) supplementing the X-VIVO15 serum-free culture medium to 100 mL, adding IL-21*10<3> U / mL, and culturing for 1 day; (3) supplementing the X-VIVO15 serum-free culture medium to 200-240 mL, adding IL-21*10<3> U / mL, and culturing for 3 days; (4) supplementing the X-VIVO15 serum-free culture medium to 1000 mL, adding IL-21*10<3> U / mL, CTLA-4mAb100n g / mL and PD-1mAb100n g / mL; and (5) culturing for 5-7 days to prepare the autologous peripheral blood lymphocyte. The method disclosed by the invention can be used for improving the activation efficiency and amplification efficiency of an effector cell group by adding multiple monoclonal antibodies and cell factors to the X-VIVO15 serum-free culture medium, and can be used for effectively reducing the content of T regulatory cells by covering CTLA-4 and PD-1 molecules of the surfaces of all CIK cells by loading CTLA-4 and PD-1 antibodies in vitro especially, thus further enhancing the killing effect of the CIK cells on tumors.

Bacterial strains are provided having at least one of a reduced size, a sialic acid coat, inducibly altered surface antigens, and expression of PD-L1 or CTLA-4 agonists and / or tryptophanase. The bacteria may have improved serum half-life, increased penetration into tumors, increased tumor targeting and increased antitumor activity. The bacteria are useful for delivery of therapeutic agents that treat of neoplastic diseases including solid tumors and lymphomas.

Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and / or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1 / PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and / or nanoparticle formulations.

Stimulation of T cells to respond to self antigens is achieved through a blockade of CTLA-4 signaling. CTLA-4 blocking agents are combined with antigen preparations, either alone or with additional immune response stimulating agents, in costimulation strategies to break immune tolerance and stimulate an enhanced T-cell response against self antigens. This enhanced response is useful for the treatment of non-immunogenic and poorly-immunogenic tumors, as well as other medical conditions requiring selective tissue ablation.

The invention discloses a nanometer antibody Nb16 for anti-CTLA-4 and a preparation method and application of the nanometer antibody Nb16. The provided nanometer antibody comprises a determinant complementary region and a frame region. The determinant complementary region of the nanometer antibody includes CDR1, CDR2 and CDR3, wherein the amino acid sequence of CDR1 is the 26-35 amino acid of SEQ ID No.1 in a sequence list, the amino acid sequence of CDR2 is 51<st>-59 amino acid of SEQ ID No.1 in a sequence list, and the amino acid sequence of CDR3 is 97-106 amino acid of SEQ ID No.1 in a sequence list. The nanometer antibody Nb16 can combine with T cells and CTLA-4, and can be used for researching and developing a CTLA-4 molecular detection agent, preparing a tumor inhibitor or a tumor cell inhibitor, and preparing a medicine for inhibiting activity of CTLA-4 and prompting T cell proliferation.

In order to provide necessary information for the production of complete human monoclonal antibodies capable of human CD152 (CTLA-4) binding, the primary structures of heavy and light chains have been elucidated. The novel amino acid sequence of identified heavy and light chains are derived from VH3 and Vλ germline genes, respectively. Antibodies comprising such novel structures cause specific binding to soluble recombinant human CD152 as well as to activated human peripheral T cells, where the expression of CD152 has been elevated.

The invention provides polynucleotides and polypeptides encoded therefrom having advantageous properties, including an ability of the polypeptides to preferentially bind a CD28 or CTLA-4 receptor at a level greater or less than the ability of human B7-1 to bind CD28 or CTLA-4, or to induce or inhibit altered level of T cell proliferation response greater compared to that generated by human B7-1. The polypeptides and polynucleotides of the invention are useful in therapeutic and prophylactic treatment methods, gene therapy applications, and vaccines.