56 results about "Immune checkpoint molecules" patented technology

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 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.

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 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.

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.

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.

According to the invention, a novel immune checkpoint molecule SIDT1 is found. The SIDT1 is a powerful T cell inhibition factor mainly expressed on CD8 < + > T cells. A series of SIDT1 inhibitors are identified in the invention. The SIDT1 inhibitor can enhance the anti-tumor CD8T cell reaction and limit tumor progression, so that a new thought is provided for treatment and prevention of related tumor patients with PD-1 treatment resistance.

The invention relates to an application of a CXCL13 + CD8 + T cell subset in preparation of a product for predicting prognosis of a melanoma patient, and the CXCL13 + CD8 + T cell subset is used as an analysis target to prepare a reagent for analyzing immune cell functions. Wherein the CXCL13 < + > CD8 < + > T cell subset refers to a CD8 < + > T cell subset capable of releasing a CXCL13 signal. Compared with the prior art, the research shows that by analyzing the expression level of effector molecules and immune checkpoint molecules in a tumor microenvironment and the density of a three-level lymph structure, the prognosis of a tumor patient can be more accurately predicted, and the reactivity of tumors to immunotherapy can be predicted; at present, a report for reflecting immune characteristics of melanoma by using the CXCL13 + CD8 + T cell subset as a biomarker is not found. The infiltration level of CXCL13 + CD8 + T cells in tumor tissues is quantitatively evaluated through flow cytometry, and more accurate and sensitive indexes are provided for prognosis evaluation of melanoma and liver cancer patients.

Described herein are bispecific antibodies simultaneously targeting both CHI3L1 and the immune checkpoint molecule PD-1. These antibodies manifest enhanced synergistic cytotoxic effects compared to the effects of individual CHI3L1 and PD-1 antibodies, alone or in combination. Methods of treating a cancer by administering the bispecific antibodies described herein are also provided.

Described herein are compounds that are inhibitors of p21-activated kinases (PAKS). In particular, the compounds described herein are demonstrated to be selective PAK4 inhibitors. The compounds described herein are also demonstrated to reduce the expression of key immune checkpoint molecules, such as PD-1 and CHEK2. Also described herein are pharmaceutical compositions containing such compounds, methods for using such compounds in the treatment of cancers, more specifically, the treatment of pancreatic and lung cancers, and to related uses.

This invention discloses an immune cell with enhanced anti-tumor effect, its preparation method, and its application. Experiments using this invention show that... SERTAD1 CD8 gene overexpression + T cells can enhance their function in anti-tumor immunotherapy. SERTAD1 Gene overexpression can downregulate CD8 + The expression of immune checkpoint molecules on T cells upregulates the expression of mRNAs of tumor-killing cytokines. In the MC38-OVA subcutaneous tumor model, Naïve CD8 cells were extracted from OT-I mice. + T cells were infected with a virus to overexpress SERTAD1, followed by adoptive transfer to mice. The results showed that SERTAD1 overexpression enhanced CD8 expression. + T cells kill MC38-OVA cells, inhibit the growth of MC38-OVA tumor cells, and overexpress SERTAD1 CD8. + The tumor volume and weight in the T-cell adoptive group were significantly smaller than those in the control group.

In combination with conventional therapies (e.g., targeted therapy, chemotherapy, and angiogenesis inhibitors etc.), immunotherapies targeting checkpoint molecules have shown promise in the treatment of solid or liquid tumors. However, apoptotic regulatory T cells (Treg) induced by such therapies often become more suppressive in the tumor microenvironment (TME), through increased generation of adenosine tightly controlled by ectonucleotidases, viz. CD39 and CD73. CD39 / ENTPD1, a novel checkpoint molecule, is highly expressed and activated on the tumor vasculature and infiltrating immune cells, promoting tumor growth. Deletion or blockade of CD39 enhances anti-tumor activity by augmenting anti-tumor immune responses and inhibiting tumor angiogenesis. The present invention is based at least in part on the development of anti-CD39 antibodies which mediate CD39 downregulation on immune cells, such as T-cells with markers of T-cell exhaustion, and the demonstrated utility of these antibodies in blocking tumor growth with minimal side effects in pre-clinical models.

The present invention relates to a binding protein that specifically binds at least two proteins, wherein said binding protein comprises (i) an antibody or antibody fragment specially binding a first protein and (ii) a multimer, wherein each monomer of the multimer specifically binds a second target and wherein the multimer is inserted between the VH domain and the CH1 domain of the antibody or antibody fragment. In some embodiments, the first target is an immune checkpoint molecule, the second target is a TNFRSF member and the multimer is a multimer of a TNFRSF ligand. The present invention also relates to a pharmaceutical composition comprising said binding protein and the use thereof for the treatment of cancer.

The invention provides an immune checkpoint joint detection method based on a multi-microsphere flow-type immunofluorescence method, and belongs to the technical field of multi-microsphere flow-type immunofluorescence method detection.The immune checkpoint joint detection method comprises the steps that seven fluorescent microspheres are coupled with PD-L2, TIM-3, TNFRSF7, PD-1, PD-L1, LAG-3 and CTLA-4 to capture antibodies to form a multi-detection system; the method comprises the following steps: incubating a plasma sample and an antibody microsphere mixed solution to form a first immune complex, adding a biotin-labeled detection antibody and phycoerythrin-labeled streptavidin to construct a fluorescence-labeled sandwich immune complex, detecting by using a flow cytometry to obtain fluorescence intensity data, and converting the fluorescence intensity data into a concentration value; and the optimal immune checkpoint combination is screened by applying a multi-dimensional Carnot diagram optimization algorithm, and a combination modulation factor is calculated to determine the disease risk level, so that the technical problem that the accuracy of disease risk assessment is insufficient due to the fact that multi-index collaborative analysis cannot be realized in immune checkpoint molecular detection is solved.

Provided herein are multivalent particles and multivalent particle compositions that express immune checkpoint molecules.

The invention discloses a biomarker for predicting drug resistance of pancreatic cancer to a KRAS inhibitor and application of the biomarker, and relates to the technical field of biological medicines. The invention reveals that the immune checkpoint molecule VTCN1 mediates the drug resistance of the KRAS inhibitor by activating the TNF-NF-kappa B pathway for the first time, breaks through the limitation that the existing drug resistance mechanism only focuses on gene mutation or bypass activation, and provides a brand new target for drug resistance intervention; tumor stem cell characteristics and TNF pathway activation are synchronously inhibited, and the defect that an existing single-pathway inhibitor is insufficient in curative effect is overcome. Meanwhile, the VTCN1 inhibitor and the KRAS inhibitor are combined for use, the drug resistance of the pancreatic cancer to the KRAS inhibitor can be effectively reversed, so that the treatment effect of the KRAS inhibitor is further improved, the drug resistance of cancer cells to the KRAS inhibitor is reduced, and an application prospect is provided for precise treatment of the pancreatic cancer.

Provided are an engineered cell with enhanced tumor killing ability and use thereof. The engineered cell is site-specifically integrated with a polynucleotide encoding and expressing a secretory protein. The secretory protein comprises: (1) a first secretory protein and a second secretory protein, the first secretory protein being an inhibitor of immune checkpoint molecule PD1, and the second secretory protein being different from the first secretory protein; or (2) a double-antibody, multi-antibody, or fusion protein comprising a domain that specifically binds to the immune checkpoint molecule PD1. The engineered cell is prepared in a non-viral manner. The engineered cell efficiently kills tumor cells at a tumor site, has higher safety, and has stronger tumor killing ability.

The present disclosure provides antibodies, including antibody fusions, that specifically bind to human PD-L1 protein (huPD-L1) and are capable of reducing, inhibiting, and / or completely blocking the immunoregulatory effects mediated by PD-L1, such as binding to the immune checkpoint molecule PD-1 in the tumor microenvironment. In addition, the antibodies include fusions with the cytokine inhibitory factor IL10 that are capable of supplementing and / or activating the cytotoxic effects of CD8+ T cells in the tumor microenvironment. The present disclosure also provides methods of using the antibodies (and compositions thereof) to treat diseases and conditions that are responsive to reducing, inhibiting, and / or blocking the immunoregulatory functions or activities mediated by the binding of PD1 to PD-L1.

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for or comprising administering to an individual in need thereof an inhibitor of an inhibitory immune checkpoint molecule and / or a stimulatory immune checkpoint molecule and a formulation, wherein the formulation comprises at least two different species or genera of non-pathogenic, live bacteria, and each of the non-pathogenic, live bacteria comprise non-pathogenic colony forming live bacteria, a plurality of non-pathogenic germinable bacterial spores, or a combination thereof, and optionally the non-pathogenic bacteria or non-pathogenic bacteria arising from germination of the germinable spores can individually or together metabolize urolithin A from ellagic acid, or can individually or together synthesize urolithin A.