113 results about "Immune checkpoint molecules" patented technology

The invention provides a tumor detection data analysis method based on a peripheral blood immune marker, and belongs to the technical field of immunodetection.The tumor detection data analysis method comprises the steps that firstly, a peripheral blood sample of a patient is collected, and plasma and cell components are separated; analyzing various immune cell phenotypes by using flow cytometry; determining the concentration of key cell factors; analyzing the molecular expression level of the immune checkpoint; establishing an immune cell subset proportion empirical function; analyzing a cell factor expression mode by using an immune lineage transcriptome analysis model; establishing a tumor immune microenvironment score by combining the immune cell subset proportion and a model output result; the accuracy of the scoring system is verified through clinical follow-up visit and iconography examination; a standardized report template is formulated to provide a tumor early detection basis. Wherein the immune lineage transcriptome analytical model adopts a multi-modal attention fusion network architecture, three different immune data streams can be processed and integrated at the same time, and accurate evaluation of tumor-related immune states is realized.

The present disclosure relates activatable immunocytokines targeted to immune checkpoint molecules such as PD-1, compositions comprising the activatable immunocytokines, and methods of use thereof. The present disclosure also relates activatable IL-2 polypeptides linked to anti-PD-1 polypeptides (e.g., anti-PD-1 antibodies).

The invention discloses a double-target chimeric antigen receptor for co-expression of CD47 and IL-15, a CAR-T cell and application of the CAR-T cell, and belongs to the technical field of genetic engineering, the double-target chimeric antigen receptor comprises a single-chain antibody scFv-EGFRv III, a single-chain antibody scFv-VEGF, CD47 and IL-15; the nucleotide artificial sequence of the single-chain antibody scFv-EGFRv III is as shown in SEQ ID NO. 6; the nucleotide artificial sequence of the single-chain antibody scFv-VEGF is as shown in SEQ ID NO. 9. According to the application disclosed by the invention, by performing sequence optimization on targets EGFRvIII and VEGF, the anti-tumor effect of CAR-T cells in glioblastoma can be improved, and by integrating immune checkpoint molecules CD47 and interleukin-15, the immunosuppression function of a CD47-SIRP alpha signal channel can be locally exerted.

The invention belongs to the technical field of biological medicines, and particularly discloses a nano-engineering T cell membrane coated nano-particle as well as a preparation method and application of the nano-engineering T cell membrane coated nano-particle. Nanoparticles of a specific structure are constructed based on a phospholipid bilayer bionic nanometer platform through a membrane fusion technology, immune clearance caused by phagocytosis of the nanoparticles by macrophages can be avoided through disguise of a T cell membrane, and the blood circulation time is prolonged; the functions of T cells are recovered through specific blocking of immune checkpoint molecules loaded on the immune checkpoint molecules on corresponding immune checkpoint ligands on tumor cells; under ultrasonic radiation, the nano-particles are gradually decomposed and release the sound-sensitive agent to generate a large amount of active oxygen, so that immunogenic death of tumor cells is promoted, more cytotoxic T lymphocytes are recruited to infiltrate into tumor parts, and the recovery of T cell mediated immune response function is facilitated. The synergistic effect of the sound-sensitive agent and the immune checkpoint protein can effectively inhibit tumor growth, induce a long-term immune memory effect and prevent tumor metastasis and recurrence.

Multispecific antibody having a binding site for ICOS and a binding site for a second antigen, e.g., an immune checkpoint molecule such as PD-L1. Use of the multispecific antibody in immuno-oncology, including for treatment of solid tumours.

The invention discloses a construction method of a model for predicting an esophageal squamous cell carcinoma intervention effect. The construction method comprises the following steps: acquiring detection data of a predictive factor in a sample; the predictive factors at least comprise the content or the expression level of a depletion marker of a functional CD8 T cell in a sample and the content or the expression level of a C1QC + macrophage immune checkpoint molecule; and predicting the intervention effect of the esophageal squamous cell carcinoma according to the detection data of the predictive factor. Establishing a space proteomics map of a complex space tissue of a tumor microenvironment (TME) during treatment; key spatial features which are related to specific cell behaviors and influence treatment results are determined and layered; a powerful prediction model of drug response is developed by utilizing a machine learning technology, and the area under curve (AUC) can reach 97%.

Disclosed herein are combination therapies comprising an effective amount of a modulator of the immune checkpoint molecule; and an effective amount of a MDM2 inhibitor.

The invention discloses application of a reagent for detecting a predictive factor in preparation of a product for predicting an intervention effect of a patient with esophageal squamous cell carcinoma. The reagent for detecting the predictive factor comprises a reagent for detecting the content or expression level of a depletion marker of functional CD8 T cells in a sample and a reagent for detecting the content or expression level of immune checkpoint molecules of C1QC + macrophages in the sample. According to the method, key spatial features which are related to specific cell behaviors and influence treatment results are determined and layered; a powerful prediction model of drug response is developed by utilizing a machine learning technology, and the area under curve (AUC) can reach 97%.

The invention discloses a regulation mechanism research method of depleted precursor CD8T cells, and relates to the field of immunology and molecular biology. Comprising the following steps: detecting the expression level of the ARHGAP9 gene in a chronic virus infection model; constructing a T cell specific ARHGAP9 gene knockout animal model; the influence of ARHGAP9 deletion on the frequency, phenotype and function of the Tpex cell is analyzed; a single cell transcriptome sequencing technology reveals that ARHGAP9 regulates and controls a downstream signal channel of a Tpex cell. By constructing a chronic virus infection model, detecting the expression dynamic state of the ARHGAP9 gene, knocking out an animal model by utilizing T cell specificity ARHGAP9, and combining flow cytometry, qPCR, single cell transcriptome sequencing and other technologies, the invention discloses the effect of the ARHGAP9 as a novel immune checkpoint molecule, and provides a theoretical basis for developing Tpex cell targeting immunotherapy.

The name of the invention is T cell activation antibodies. The present invention provides antibodies comprising an antigen binding region that binds to CD137. The present invention also provides a bispecific antibody comprising a first antigen binding region that binds to CD137 and a second antigen binding region that binds to an immune checkpoint molecule, an immune stimulatory molecule or a tumor antigen. The invention provides pharmaceutical compositions comprising the antibodies and methods of treating cancer.

Disclosed herein are DNA monoclonal antibodies that target checkpoint molecules. Also disclosed herein are compositions comprising recombinant nucleic acid sequences encoding antibodies or fragments thereof targeting immune checkpoint molecules. The present disclosure also provides methods of using the compositions and methods of production to prevent and / or treat a disease in a subject.

Disclosed herein are DNA monoclonal antibodies that target checkpoint molecules. Also disclosed herein are compositions comprising recombinant nucleic acid sequences encoding antibodies or fragments thereof targeting immune checkpoint molecules. The present disclosure also provides methods of using the compositions and methods of production to prevent and / or treat a disease in a subject.

The invention discloses an application of Siglec-10 / G or a fusion protein containing a Siglec-10 / G protein structure in preparation of a medicine for treating glioma. The application finds that Siglec-10 / G is a new key myeloid immune checkpoint molecule in a glioma immunosuppression microenvironment, and reveals a specific molecular mechanism that Siglec-10 / G and related action signals (such as MUC1, CKB and GOT1) thereof influence glioma generation. The Rebinant Mouse Siglec-10 (C-Fc) provided by the invention can be combined with a ligand on the surface of a tumor cell, so that endogenous Siglec-10 / G signal transduction on MDM is competitively blocked, the anti-tumor immunity of a tumor-bearing mouse is improved, the growth of glioma is inhibited, the survival time of the tumor-bearing mouse is prolonged, and the Rebinant Mouse Siglec-10 (C-Fc) can be used for treating glioma.

The application belongs to the technical field of biological medicine, and particularly relates to the application of HEG1, HEG1 monoclonal antibody and the application in tumor treatment. It is proved that HEG1 is an immune checkpoint molecule with NK cell as an action target on the surface of tumor cells. The application provides the sequence of the HEG1 monoclonal antibody. The HEG1 monoclonal antibody has high specificity and high affinity for the HEG1 protein on the surface of tumor cells, can compete with HEG1 to bind and mediate the recognition and killing of natural killer cells NK cells on tumor cells, and block the immune escape. The application provides a new gene and direction for the treatment of tumors, provides an innovative idea for the development of precise targeted drugs, and has important conversion value and clinical application prospect in the field of tumor treatment.

The invention relates to bispecific antigen binding proteins (ABP), such as bispecific antibodies, that bind with a first antigen binding site to both leukocyte immunoglobulin-like receptor subfamily B1 (LILRB1) and LILRB2 while not binding to, or binding with significantly less affinity to, leukocyte immunoglobulin-like receptor subfamily A (LILRA). The bispecific ABP of the invention bind with a second antigen binding site to immune checkpoint (molecules) such as PD-1 or PD-L1. The bispecific ABP of the invention can also inhibit the interaction between LILRB1 and / or LILRB2 and a natural ligand of ULRB receptors (e.g. interacting proteins, such as HLA-G) on immune cells and the inhibition of such interaction can reduce immune cell suppression and thereby support anti-infection and anti-tumour immune responses in a subject suffering from such diseases. Bispecific molecules combining LILRB1 / 2 antagonism with inhibition of immune checkpoints, such as the inhibition of the PD-1 / PD-L1 axis, is specifically useful in the treatment of proliferative disorders. Also provided are methods of reducing the immune suppression of cells involved with a cell-mediated immune response, and / or methods for treating infective- and / or proliferative diseases, using an LILRB1 and / or LILRB2 antigen binding protein such as an antibody binding to both LILRB1 and / or LILRB2, as well as certain related aspects including detection, diagnostic and screening methods.

Provided are antibodies capable of binding an antigen in an adenine nucleotide-dependent manner. Examples of adenine nucleotides include ATP, ADP and AMP, which are frequently present in tumor microenvironment at much higher concentrations in normal tissues. Such antibodies, if designed to target a tumor associated antigen or immune checkpoint molecule, can target tumor tissues more specifically than conventionally antibodies and thus have improved therapeutic index.

Provided herein are compositions comprising a functionalized pancreatic extracellular matrix (CP-PAN-ECM) comprising at least one immune checkpoint molecule. Also provided herein are methods of making these compositions and using these compositions for the treatment of diabetes.

The present disclosure pertains to the field of biomedicine, and specifically relates to a method for treating, suppressing, reducing the severity of, lowering the risk of, or inhibiting the metastasis of cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of an IAP inhibitor, a therapeutically effective amount of a modulator of an immune checkpoint molecule, and optionally a therapeutically effective amount of a tubulin inhibitor. The present disclosure further relates to a pharmaceutical composition or kit comprising an IAP inhibitor, a modulator of an immune checkpoint molecule, and optionally a tubulin inhibitor.

The present application relates to a kind of based on chemotactic factor CXCL12 mutant modification double specific fusion protein and its application as immune checkpoint molecule targeted degradation platform in tumor immunotherapy, belong to biological medicine field.The specific problem of the present application is how to effectively enhance the effect of tumor immunotherapy, especially solve the problem of immune escape phenomenon in tumor microenvironment in traditional immunotherapy.To this end, the present application proposes a new KineTAC targeted degradation platform, specifically designs a new chemotactic factor CXCL12 and target protein binding polypeptide (such as anti-PD-1 / PD-L1 monoclonal antibody, anti-LAG-3 monoclonal antibody, etc.) Fusion expression protein molecule, enhance its binding affinity with receptor CXCR4 and CXCR7, and avoid stimulating tumor cell growth proliferation.The fusion protein can target and degrade the immunosuppressive molecules on the surface of tumor cells and immune cells, thereby enhancing the immune response of immune cells and improving the anti-tumor effect.

According to the immune checkpoint molecule and the pharmaceutical application thereof, a kit for detecting ILDR2 comprises an antibody specifically combined with ILDR2 protein or a primer pair for detecting ILDR2 mRNA, and the kit is used for detecting the expression level of ILDR2 in a liver cancer tissue sample in vitro. The invention discloses application of detection of B7 family protein ILDR2 expression quantity in liver cancer diagnosis and treatment. It is found for the first time that ILDR2 is highly expressed in liver cancer, and the highly expressed ILDR2 is poorly related to prognosis of patients. Liver cancer cells express ILDR2 to inhibit the anti-tumor function of CD4 + T cells, promote formation of regulatory T cells and inhibit polarization of the CD4 + T cells to Th1. The ILDR2 is knocked down, so that liver cancer cell proliferation can be obviously inhibited. Detection of ILDR2 expression can better guide treatment of liver cancer patients with high ILDR2 expression, and targeted ILDR2 can screen candidate immune checkpoint drugs for treating liver cancer.

Disclosed herein are DNA monoclonal antibodies that target checkpoint molecules. Also disclosed herein are compositions comprising recombinant nucleic acid sequences encoding antibodies or fragments thereof targeting immune checkpoint molecules. The present disclosure also provides methods of using the compositions and methods of production to prevent and / or treat a disease in a subject.

The present invention discloses a dual-target chimeric antigen receptor, CAR-T cells and applications thereof that co-express CD47 and IL-15, belonging to the field of genetic engineering technology. The dual-target chimeric antigen receptor includes a single-chain antibody scFv-EGFRvⅢ, a single-chain antibody scFv-VEGF, CD47, and IL-15; the artificial nucleotide sequence of the single-chain antibody scFv-EGFRvⅢ is shown in SEQ ID NO.6; the artificial nucleotide sequence of the single-chain antibody scFv-VEGF is shown in SEQ ID NO.9. The present invention can enhance the anti-tumor effect of CAR-T cells in glioblastoma by sequence optimization of the targets EGFRvⅢ and VEGF, and can locally exert the immunosuppressive function of the CD47-SIRPα signaling pathway by integrating the immune checkpoint molecules CD47 and interleukin-15.

The present invention provides a composite molecule, a nucleic acid, a vector, a host cell, and a pharmaceutical composition, and uses of the composite molecule, the nucleic acid, the vector, the host cell, and the pharmaceutical composition in preparation of drugs for treating cancers. The composite molecule comprises an anti-tumor antibody domain, a linker, and pro-IL-15; the anti-tumor antibody domain is linked to the pro-IL-15 by means of the linker; the anti-tumor antibody domain is a complete antibody against an immune checkpoint molecule, a tumor antigen molecule or an immune activation molecule, or a nano antibody or an antigen binding fragment thereof; the linker is a polypeptide linker or a non-peptide linker; the pro-IL-15 is a fusion protein comprising IL-15, an IL-15Rα sushi domain, and a linker peptide, and optionally comprising an IL-15Rβ extracellular domain; and the IL-15Rβ extracellular domain, the IL-15, and the IL-15Rα sushi domain are linked by means of the linker peptide.

The present invention relates to a mutant protein of a single-chain variable fragment having improved stability and, more specifically, to a mutant protein of a single-chain variable fragment having excellent binding affinity to immune checkpoint molecules and superior in vivo stability, in which a heavy-chain variable region including CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3 and a light-chain variable region including CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6 are linked by a stability-enhancing linker of SEQ ID NO: 7.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by unleashing exhausted CD8+ T-cell thereby restoring anti-tumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Here, the inventors show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T-cells, interacts and enhances PD-1 activity. In mice, CD8+ T-cell specific deletion of Nrp1 improves spontaneous and anti PD1 antibody anti-tumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T-cells predicts poor outcome of patients treated with anti-PD1 (e.g. pembrolizumab). Finally, the combination of anti-NRP1 and anti-PD1 antibodies is synergistic in human, specifically in CD8+ T-cells anti-tumor response. Thus the therapeutic inhibition of NRP1 alone or combined with an immune checkpoint inhibitor (e.g. anti-PD1 antibody) could efficiently repress tumor growth in human cancer. The present invention also relates to multispecific antibodies comprising at least one binding site that specifically binds to an immune checkpoint molecule (e.g. PD-1), and at least one binding site that specifically binds to NRP-1. The present invention also relates to a population of cells engineered to express a chimeric antigen receptor (CAR) and wherein the expression of NRP-1 in said cells is repressed.

This invention belongs to the field of biomedicine and tumor immunotherapy technology, specifically relating to a monoclonal antibody targeting the immune checkpoint molecule CD276 (B7-H3) and its applications. The applicant conducted immunization and screening work around the human CD276 antigen, selecting two representative monoclonal antibody clones, 2B2-1 and 5G4-2, from multiple candidate antibodies. The nucleotide and amino acid sequences of their heavy and light chain variable regions were determined, and their performance in flow cytometry, T-cell killing assays, immunohistochemistry, ELISA, and Biacore affinity assays was systematically evaluated. Experimental results show that the above antibodies can specifically recognize and bind to CD276, efficiently distinguish between CD276-high and low-expressing cells, and enhance the killing activity of T cells against CD276-high expressing tumor cells in an in vitro co-culture system. This provides an excellent antibody backbone for the subsequent construction of diagnostic kits, ADC drugs, or bispecific antibodies.

The present disclosure provides a method for the treatment of neoplastic disease in a mammalian subject the method comprising the administration of an IL-10 agent in combination with the administration of at least one modulator of at least one immune checkpoint pathway. The present disclosure further provides a method for the treatment of neoplastic disease wherein the neoplasm has a low or intermediate tumor mutation burden, low or intermediate level of expression of the immune checkpoint molecule, or metastatic neoplastic disease.

Antibodies that include an antigen binding region that binds to CD137 are provided herein. Also provided herein are bispecific antibodies that include a first antigen binding region that binds to CD137 and a second antigen binding region that binds to an immune checkpoint molecule, an immune stimulatory molecule, or a tumor antigen. Pharmaceutical compositions that include the antibodies and methods of treating cancer are provided.

The present invention relates to single therapy comprising an effective amount of a MDM2 inhibitor, as well as combination therapies comprising an effective amount of a modulator of the immune checkpoint molecule; and an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula or a pharmaceutically acceptable salt thereof.