44 results about "Immune checkpoint molecules" patented technology

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 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.

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.

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.

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.

The invention discloses an immune cell counting detection method, and belongs to the technical field of immune cell detection. According to the invention, the problem of one-sidedness of the existing detection method is solved, the immune assessment is divided into three levels, and the first level structure detects the proportion and absolute count of the basal lymphocyte subpopulation; the secondary structure deeply analyzes functional subtypes of T cells, including Th1 / Th2 / Th17, initial / memory / activated T cells and regulatory T cells; the tertiary structure is used for evaluating cytokine expression and immune checkpoint molecules; performing multi-parameter detection on the same biological sample through optimized multicolor flow cytometry, and generating a comprehensive immune assessment report; therefore, the whole state and potential problems of the immune system can be intuitively reflected, popularization and application in a clinical examination laboratory are facilitated, comprehensive and deep immune information from the number of cells to the functional state is clinically provided, and the method has important value for diagnosis, treatment monitoring and prognosis evaluation of clinical immune related diseases.

This invention provides a PRSS33-based MDS treatment and immune sensitization activator and its application, revealing the function of PRSS33 as a key tumor suppressor target in myelodysplastic syndromes (MDS). By providing pharmaceutical compositions containing PRSS33 protein, its encoded nucleic acid, or reagents that upregulate its expression, or cell vaccines prepared from MDS cells overexpressing PRSS33, the immune checkpoint molecule CD47 is downregulated to enhance macrophage phagocytosis, thereby effectively inhibiting MDS cell growth in vitro and in vivo. Furthermore, the PRSS33 activator or cell vaccine, when used in combination with immune checkpoint inhibitors, can significantly improve the tumor immune microenvironment and enhance immunotherapy sensitivity. This invention provides novel strategies and products for the diagnosis, prognostic assessment, and targeted-immunotherapy combination therapy of MDS.

A method for generating immuno-free and stress-resistant donor cells comprising editing PRDM1 and FOXP3 genes in T-cells and B-cells with CRISPR-Cas9 and modulating immune responses to reduce inflammation and prevent autoimmunity. Particularly, the present invention discloses a method for treating Type 1 Diabetes, comprising genetically modifying pancreatic beta cells with CRISPR-Cas9, and altering HLA expression, and upregulating immune checkpoint molecules such as PD-L1 to obtain immune-tolerant and stress-resistant pancreatic beta cells.

The invention provides a method for editing and enhancing the anti-tumor function of tumor infiltrating lymphocytes based on a CRISPR-Cas9 system, and belongs to the field of biological medicine. Through multi-target collaborative editing, the obtained tumor infiltrating lymphocyte shows remarkably enhanced survival, proliferation and killing capabilities in a tumor microenvironment, and functional inhibition mediated by immune checkpoint molecule up-regulation and immunosuppressive factors can be effectively overcome, so that the clearance potential of the tumor infiltrating lymphocyte to solid tumors is greatly improved; the technology not only provides a novel immune cell product which is stronger in function and more durable for clinic, but also lays a solid process foundation for developing a next-generation individualized and universal tumor immunotherapy scheme, and has an important transformational medical value and a wide application prospect.

Provided are methods for treating cancers using a compound of Formula I, e.g., 2- (difluoromethoxy)-N-[[5-(2-methoxyphenyl)-1lH-1,2,4-triazol-3-yl]methyl]benzamide, or a pharmaceutically acceptable salt thereof, and at least one immune checkpoint modulator of an immune checkpoint molecule.

The invention belongs to the field of medicinal chemistry, and relates to a ketone compound as well as a preparation method, a pharmaceutical composition and application thereof. The compound is directly combined with an important immune checkpoint molecule PD-L1, inhibits expressions of PD-L1, PD-L2, FGL1 and the like in a direct and indirect manner, realizes an immune suppression checkpoint blocking effect, has anti-tumor and immune regulation effects, and has a structure as follows: R1-R8 are hydrogen, alkyl containing one to five carbons, hydroxyl, aldehyde, carboxyl, acyl and ester (-COOR, R1, R2, R3, R4, R5, R6, R7, R8 and R8 are hydrogen, alkyl containing one to five carbons, hydroxyl, aldehyde, carboxyl, acyl and ester (-COOR); wherein R is alkyl of one to five carbons) and halogen; x is oxygen, sulfur or amine. Wherein the effect of the 8-hydroxy-3-methoxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid is the most remarkable, and the application of the 8-hydroxy-3-methoxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid in the

Multispecific antibodies for use in cancer immunotherapy and methods of treating cancer are provided.SOLUTION: Multispecific antibodies are provided that have binding sites for ICOS and for second antigens, e.g., immune checkpoint molecules such as PD - L1. Also provided is a method of treating cancer in a human patient comprising administering to the patient (i) a multispecific antibody that binds to ICOS and PD-L1 and (ii) an anti-CTLA-4 or anti-PD-1 antibody.SELECTED DRAWING: Figure 1

The present application provides multispecific antibody-like proteins that can comprise one or more binding domains, including a first binding domain (D1), a second binding domain (D2), a third binding domain (D3), a fourth binding domain (D4), a fifth binding domain (D5), or a sixth binding domain (D6). The multispecific antibody-like proteins disclosed herein may be monospecific, bispecific, trispecific, tetraspecific, pentaspecific, or hexaspecific. Binding domains, such as D1, D2, D3, D4, D5, and D6, may each independently have a specific binding affinity for T cell activation receptors, immune cell receptors, immune checkpoint molecules, costimulatory factors, leukocyte receptors, tumor antigens, tumor associated antigens (TAAs), histocyte receptors, cancer cell receptors, or combinations thereof.