67 results about "Cell killing" patented technology

Provided is use of a new immune checkpoint PIEZO1 pathway in tumor T-cell therapy. A PIEZO1 inhibitor can be used for treating cancers, improving the killing ability of T cells, and improving the therapeutic effect of an immune checkpoint inhibitor.

The invention belongs to the technical field of biological medicine, and discloses an anti-BCMA antibody or an antigen binding fragment thereof as well as a preparation method and application thereof. The amino acid sequences of the heavy chain variable regions CDR1-3 of the anti-BCMA antibody or the antigen binding fragment thereof provided by the invention are respectively shown as SEQ ID NO: 2-4, and the amino acid sequences of the light chain variable regions CDR1-3 are respectively shown as SEQ ID NO: 6-8. The anti-BCMA antibody or the antigen binding fragment thereof has excellent affinity for the BCMA protein, especially an extracellular fragment, can specifically recognize and bind the BCMA protein well, and can be used as a detection antibody of the BCMA protein to realize non-diagnostic purpose detection of the BCMA; meanwhile, the anti-BCMA antibody or the antigen binding fragment thereof can also effectively kill tumor cells overexpressing BCMA, such as pfeffer cells, through complement-dependent cytotoxicity, the cell killing rate is up to 99%, and the anti-BCMA antibody or the antigen binding fragment thereof can be used as an inhibitor of abnormal bone marrow cells overexpressing BCMA protein, is a very potential active ingredient for resisting malignant tumors of a blood system, and has broad application prospects. Good application prospects are realized.

The invention provides an anti-CDH17 antibody or an antigen binding fragment thereof, a CDH17-targeted antibody drug conjugate (ADC) and application thereof. The anti-CDH17 antibody provided by the invention can be specifically combined with CDH17 protein, and has a relatively strong CDH17 expression tumor cell killing effect, so that the anti-CDH17 antibody has high-specificity treatment application potential of CDH17 expression tumor. Furthermore, the anti-CDH17 antibody provided by the invention can be effectively internalized on CDH17 expression tumor cells, ADC formed by coupling the anti-CDH17 antibody with a small-molecule toxic compound keeps high internalization activity and strong binding capacity to target protein CDH17, and shows high killing activity to the CDH17 expression tumor cells.

The invention relates to a mutant PD1 extracellular domain fragment and CAR and NK cells containing the fragment. Specifically, the invention provides a polypeptide which is the mutant PD1 extracellular domain fragment and contains an amino acid sequence as shown in SEQ ID NO: 1 or consists of the amino acid sequence as shown in SEQ ID NO: 1. The CAR provided by the invention contains the polypeptide. The invention also provides an NK cell for expressing the CAR. The tumor cell killing capacity of the NK cell expressing the CAR containing the mutant PD1 extracellular domain is obviously higher than that of the NK cell expressing the CAR containing the wild type PD1 extracellular domain.

A method for treating tumors using a combination of an oncolytic virus vaccine and immune cells. The method specifically includes the following step: treating the tumors by using a combination of the immune cells and the oncolytic virus vaccine; the oncolytic virus vaccine includes a recombinant oncolytic virus expressing a tumor antigen and is used for targeting the tumor cells; the immune cells express a chimeric antigen receptor paired with the tumor antigen, and are used for killing or destroying the tumor cells targeted; the recombinant oncolytic virus includes an M protein, G protein, N protein, P protein and L protein subjected to site-directed mutagenesis. The tumor antigen expressed by the oncolytic virus vaccine can guide the immune cells to reach the target tumor tissue center, achieving a curative effect where 1+1 is greater than 2, with a tumor cell killing rate being up to 100% at most.

Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base editing screens to generate thousands of variants at gene loci annotated with known or potential clinical significance. We discover a broad landscape of putative gain- (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and its regulatory subunit PIK3R1, LCK, SOS, AKT1, and RHOA. Base editing of PIK3CD and PIK3R1 variants in T cells with an engineered T cell receptor specific against a melanoma epitope or in different generations of CD19 chimeric antigen receptor T (CAR-T) cells demonstrates that discovered GOF variants, but not LOF or silent mutation controls, enhanced signaling, cytokine production and lysis of cognate melanoma and leukemia cell models, respectively. Additionally, we show that generations of CD19 CAR-T cells engineered with PIK3CD GOF mutations demonstrate enhanced antigen-specific signaling, cytokine production, and leukemia cell killing, including when benchmarked against other recent strategies.

The invention relates to the technical field of biology, in particular to an anti-LIV-1 antibody or an antigen binding fragment thereof, an antibody drug conjugate and application thereof. Specifically, the LIV-1 antibody obtained by the invention has higher affinity and good endocytosis rate; the antibody drug conjugate containing the antibody has a remarkable cell killing effect and has a very strong tumor growth inhibition effect. The invention also relates to application of the antibody or the antigen binding fragment thereof and the antibody drug conjugate in preparation of drugs for treating cancers, and the antibody or the antigen binding fragment thereof and the antibody drug conjugate play an important role in treatment of human tumors.

Provided are the construction, preparation and use of a functionally enhanced universal CAR-DNT cell. Specifically, provided is a chimeric antigen receptor construct. A CAR function-enhancing element and IL-10 are sequentially fused to the C-terminus of a tumor antigen-targeting CAR via a self-cleaving peptide, and the CAR construct is introduced into a DNT cell, thereby obtaining a functionally enhanced universal CAR-DNT cell, namely, an IL10-CD19-CAR-mbIL15-DNT cell. The cell specifically targets CD19, and has a stronger and more sustained cell killing activity and better safety, thus providing a new therapy for CD19-mediated diseases.

The invention provides a CAR-NK cell for knocking out KIR2DL5 targeting HER2 as well as a preparation method and application of the CAR-NK cell, and belongs to the technical field of genetic engineering.The CAR-NK cell is obtained by adopting a chimeric antigen receptor with HER2 as a target spot to infect an NK cell and then knocking out a KIR2DL5 gene; the chimeric antigen receptor taking the HER2 as the target spot comprises an HER2 single-chain antibody; the nucleic acid artificial sequence of the HER2 single-chain antibody is as shown in SEQ ID NO. 2. According to the application disclosed by the invention, the interaction of KIR2DL5-PVR is blocked by knocking out NK cell immune checkpoints, so that tumor immune escape is avoided, and the activity of killing tumor cells by CAR-NK cells is remarkably enhanced; according to the invention, by optimizing the nucleic acid artificial sequence of HER2, the secretion ability of CAR-NK cell factors, the tumor killing efficiency and the in-vivo inhibition effect on tumors can be improved.

The application discloses application of DUSP4 in preparation of a marker for predicting the curative effect of immunotherapy of hepatocellular carcinoma and a sensitizing drug, and belongs to the technical field of biological medicine.The application finds that high expression of dual specificity phosphatase 4 (DUSP4) is significantly related to high response rate and long survival period of an immunological checkpoint blocking therapy for a hepatocellular carcinoma patient.DUSP4 promotes CD8+ T cell and NK cell infiltration and remodels an immune microenvironment by inhibiting a TGF-beta signal path, down-regulating an immunosuppressive factor and up-regulating an antigen presenting molecule and a chemotactic factor.The application provides a kit and a method for detecting the expression level of DUSP4 to predict an immunotherapy response, and a combined drug composition comprising a DUSP4 activator or a TGF-beta inhibitor and an immunological checkpoint inhibitor.Experiments prove that up-regulation of the expression of DUSP4 can significantly enhance T cell killing function, and produces a synergistic anti-tumor effect with an anti-PD-1 antibody.The application provides a new strategy for precise stratified treatment and overcoming immunological drug resistance of hepatocellular carcinoma.

The invention relates to an antibody drug conjugate for treating tumors, and belongs to the technical field of biological medicines. The invention provides an antibody drug conjugate for treating tumors. The structural general formula of the antibody drug conjugate is Ab-[L1-L2-L3-L4-D] p, wherein Ab is a monoclonal antibody targeting a tumor cell surface antigen, D is a bioactive molecule having an inhibition effect on tumor cells, p is drug loading capacity, and L1-L2-L3-L4 are linkers connecting the monoclonal antibody and the bioactive molecule. The antibody drug conjugate has good druggability. Meanwhile, the antibody drug conjugate has an obvious in-vitro cell killing effect on NCI-H82 cells, SHP-77 cells and DMS-53 cells, and the antibody drug conjugate can obviously reduce the volume of tumors in NCI-H82 tumor-bearing mice and SHP-77 tumor-bearing mice and has a great application prospect in tumor treatment.

The invention provides a double-target chimeric antigen receptor, a CAR-T cell and application of the double-target chimeric antigen receptor and the CAR-T cell, and belongs to the technical field of hybrid peptides. The double-target chimeric antigen receptor comprises EGFRvIII scFv and GRP78 scFv; the nucleotide sequence of the EGFRvIII scFv is as shown in SEQ ID NO. 2; and the nucleotide sequence of the GRP78 scFv is as shown in SEQ ID NO. 4. According to the invention, by targeting two antigen targets of EGFRvIII and GRP78, the targeting specificity is enhanced, and the ability of CAR-T cells to kill glioblastoma is enhanced. Compared with a single-target CAR-T cell (EGFRvIII-CAR-T cell or GRP78-CAR-T cell), the T cell modified by the double-target chimeric antigen receptor provided by the invention has better cell factor secretion capability and better killing effect on tumor cells.

A multi-specific antigen-binding protein targeting BCMA, CD19 and CD3. Specifically, provided is a tri-specific T cell adapter formed by linking an anti-BCMA scFv, an anti-CD19 scFv and an anti-CD3 Fab. The multi-specific T cell adapter is capable of simultaneously targeting BCMA, CD19 and CD3 with high binding affinity, thereby linking target cells and T cells, and promoting the killing effect of T cells. The present invention has the prospect of being applied in the anti-tumor field.

The invention provides an anti-CDH17 antibody or an antigen binding fragment of the anti-CDH17 antibody. The anti-CDH17 antibody can be a double-epitope antibody obtained by construction. The anti-CDH17 antibody provided by the invention can be specifically combined with CDH17 protein, has a relatively strong CDH17 expression tumor cell killing effect, can be effectively internalized on CDH17 expression tumor cells, and can be prepared into ADC (Analog to Digital Converter) which is effectively internalized on CDH17 expression tumor cells and has high killing activity; particularly, compared with an antibody combined with a CDH17 single epitope, the double-epitope antibody disclosed by the invention has more accurate and multi-dimensional antigen recognition capability and higher targeting property.

The invention relates to application of a proteasome inhibitor in preparation of a medicine for treating tumors resistant to a tyrosine kinase inhibitor, and in the application, a plurality of strains of liver cancer cells with drug resistance to lenvatinib or regorafenib are constructed by utilizing a plurality of human liver cancer cell lines with different genetic backgrounds; a high-throughput CRISPR (clustered regularly interspaced short palindromic repeats) gene knockout screening technology and a patent medicine gene CRISPR library are utilized, and gene targets of which the gene knockout or inactivation can better kill drug-resistant cells are specifically identified from thousands of patent medicine genes. Wherein the function inactivation of a plurality of genes in the proteasome family shows more obvious cell killing activity in a plurality of drug-resistant cell models compared with non-drug-resistant cells. The invention discovers and verifies that the proteasome inhibitor has a specific killing effect on tyrosine kinase inhibitor drug-resistant liver cancer for the first time.

An anti-tumor pharmaceutical composition based on immune checkpoint blocking and a use thereof. The anti-tumor pharmaceutical composition comprises: paroxetine hydrochloride and a T cell enhancer, the T cell enhancer being at least one of vitamin E and thymosin. By means of a series of in vivo and in vitro experiments, it was found for the first time that cannabidiol and paroxetine hydrochloride can effectively reduce the expression of PD-L1 on a tumor cell membrane, thereby blocking the PD-1 / PD-L1 signaling pathway and enhancing the effect of T cells in killing tumor cells. T cell enhancer added on this basis can further increase the number and activity of T cells and significantly enhance the killing ability of T cells after relief from immunosuppression, greatly improving the anti-tumor effect of a drug. The components cannabidiol, paroxetine hydrochloride, and vitamin E+thymosin of the pharmaceutical composition can have a synergistic effect to improve the anti-tumor effect.

The application discloses an anti-B7H3 full human monoclonal antibody and a derivative product and application thereof, wherein the derivative product comprises a chimeric antigen receptor targeting B7H3, and the chimeric antigen receptor comprises an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory signal domain and an intracellular signal transduction domain, wherein the antigen binding domain is the anti-B7H3 full human monoclonal antibody, and the antibody has an ADCC effect; the chimeric antigen receptor provided by the application has specific targeting effect on B7H3 positive tumor cells, and T cells expressing the chimeric antigen receptor have significant killing effect, and thus have important significance in the tumor treatment field.

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.

Provided are a chemokine CXCL12 fusion protein and a use thereof. The chemokine CXCL12 fusion protein comprises the chemokine CXCL12 and an antibody against a tumor-associated antigen. The chemokine CXCL12 and the antibody against the tumor-associated antigen are directly fused or fused by means of a linker. On the one hand, the provided chemokine CXCL12 fusion protein can promote T cell infiltration and improve targeting. On the other hand, T cell killing signals are highly dependent on target cells, and T cells generate immune signals to kill the target cells only upon coming into contact with the target cells under the mediation of the fusion protein, thereby reducing toxic side effects.

An anti-tumor pharmaceutical composition based on immune checkpoint blocking and a use thereof. The anti-tumor pharmaceutical composition comprises: paroxetine hydrochloride and a T cell enhancer, the T cell enhancer being at least one of vitamin E and thymosin. By means of a series of in vivo and in vitro experiments, it was found for the first time that cannabidiol and paroxetine hydrochloride can effectively reduce the expression of PD-L1 on a tumor cell membrane, thereby blocking the PD-1 / PD-L1 signaling pathway and enhancing the effect of T cells in killing tumor cells. T cell enhancer added on this basis can further increase the number and activity of T cells and significantly enhance the killing ability of T cells after relief from immunosuppression, greatly improving the anti-tumor effect of a drug. The components cannabidiol, paroxetine hydrochloride, and vitamin E+thymosin of the pharmaceutical composition can have a synergistic effect to improve the anti-tumor effect.

The invention provides construction, preparation and application of a universal CAR-DNT (chimeric antigen receptor-DNT) cell with enhanced functions. Specifically, the invention provides a chimeric antigen receptor construct, a CAR function enhancing element and IL-10 are sequentially fused at the C tail end of a CAR of a targeted tumor antigen through a self-cleavage peptide, and the CAR construct is introduced into a DNT cell, so that a function-enhanced universal CAR-DNT cell, namely, an IL10-CD19-CAR-mbIL15-DNT cell, is obtained. The IL10-CD19-CAR-mbIL15-DNT cell disclosed by the invention is specifically targeted to CD19, and has stronger and more lasting cell killing activity and better safety, so that a new therapy is provided for diseases mediated by the CD19.

The application discloses a kind of for NK cell synergistic composition and its in-vitro culture method, it is related to cell culture technical field.The composition for the activation of NK cell includes buffer, and only the following final concentration of cytokine combination is contained in buffer: 100-500U / ml IL-2, 20-50ng / ml IL-7, 5-20ng / ml IL-12, 5-20ng / ml IL-15, 10-50ng / ml IL-18 and 10-30ng / ml IL-21.The composition for the activation of NK cell provided by the application is added to culture medium, the expansion fold and purity of peripheral blood autologous NK cell can be improved, and the killing activity of NK cell is enhanced.It is favorable to improve the curative effect of cell immunotherapy to patient.

The invention discloses application of ME1 in enhancing the anti-tumor function of CAR-T cells, and relates to a preparation method of a chimeric antigen receptor plasmid structure of overexpressed malic enzyme 1 for enhancing the killing activity of the CAR-T cells, in particular to the malic enzyme 1 serving as a gene for enhancing the functions of the CAR-T cells. When the compound is combined with a CAR-T cell treatment product for application, the anti-tumor effect can be remarkably improved.

To provide methods and compositions for sensitization of tumor cells to immune therapy.SOLUTION: Provided herein are methods and compositions related to the treatment or prevention of cancer (e.g., by targeting a tumor in a subject having cancer) by administering to the subject an agent that inhibits autophagy. In certain aspects, provided herein are methods of composition related to methods of sensitizing a cancer cell to tumor necrosis factor alpha (TNF-α)- mediated killing by contacting the cancer cell or administering an agent that inhibits autophagy. Provided herein are methods and compositions for increasing the sensitivity of cancer cells to T cell killing (e.g., tumor necrosis factor-α (TNF -α)- mediated killing) by inhibiting autophagy and / or the NF-κB pathway.SELECTED DRAWING: None

The invention relates to an anti-delta-like ligand 3 monoclonal antibody and application thereof, and belongs to the technical field of biology. The invention provides a monoclonal antibody for resisting a delta-like ligand 3 (DLL3), and research shows that the monoclonal antibody has high affinity and high specificity to the delta-like ligand 3, and the monoclonal antibody has high endocytosis efficiency in cells with high expression of the delta-like ligand 3; meanwhile, research shows that an antibody-coupled drug obtained by coupling the monoclonal antibody and an anti-tumor drug through a joint has relatively strong target cell killing activity, and the antibody-coupled drug obtained by coupling the monoclonal antibody and the anti-tumor drug through the joint has relatively good in-vivo anti-tumor activity, which can be seen that the antibody-coupled drug has relatively good anti-tumor activity. The monoclonal antibody can effectively target neuroendocrine tumors, and has great application prospects in preparation of neuroendocrine tumor treatment drugs.

Provided is a dual-target BCMA / CD19 chimeric antigen receptor construct. Membrane-bound interleukin-15 is fused, via a self-cleaving peptide, at the C-terminus of a bispecific CAR targeting BCMA and CD19, and the CAR construct is introduced into a DNT cell, such that a universal dual-target BCMA / CD19-CAR-DNT cell having enhanced function is obtained. The cell simultaneously targets BCMA and CD19, and has cell-killing activity, thereby providing a new treatment for BCMA- and / or CD19-mediated diseases.

This invention relates to the fields of biology, medicine, and clinical medicine, and specifically to the application of a novel immune checkpoint pathway, PIEZO1, in tumor T-cell therapy. Specifically, the invention provides the use of PIEZO1 inhibitors in treating cancer, enhancing T-cell killing capacity, and improving the therapeutic efficacy of immune checkpoint inhibitors. The novel immune checkpoint PIEZO1 and its downstream pathways described in this application have pioneered innovative strategies for tumor immunotherapy.

This invention belongs to the field of biomedical technology, specifically relating to an anti-tumor nanomaterial, its preparation method, and its application. The anti-tumor nanomaterial is formed by in-situ growth of calcium peroxide on the surface of black phosphorus nanosheets to create hierarchical black phosphorus-calcium peroxide nanosheets, followed by coating the surface of these composite nanosheets with hyaluronic acid. After entering tumor cells, the anti-tumor nanomaterial releases calcium ions and hydrogen peroxide, triggering an abnormal increase in calcium ions and oxidative stress within the cells, thereby causing mitochondrial dysfunction and inducing tumor cell death. Simultaneously, the released calcium ions combine with phosphate ions produced by the degradation of black phosphorus, forming calcium phosphate mineralization deposits within the tumor tissue, inducing tumor biocalcification. Changes in calcium signaling and the oxidative stress process can also promote the infiltration and activation of immune cells, thereby regulating the tumor immune microenvironment and achieving a synergistic effect of cell killing, biocalcification induction, and immune regulation within tumor tissue.

The invention discloses a humanized antibody targeting human CD33 and application thereof, and belongs to the field of biological medicine. The invention provides a monoclonal antibody targeting human CD33, and also provides a composition containing the monoclonal antibody, a multispecific antibody, a chimeric antigen receptor and an antibody conjugate. The monoclonal antibody targeting human CD33 has the characteristics of high affinity and strong killing effect on target cells, and is beneficial to prediction, diagnosis and treatment monitoring of related diseases such as myelogenous leukemia.