21 results about "Neo antigens" patented technology

The application belongs to the field of biological medicine, and discloses a drug screening method for promoting tumor neoantigen production. The method comprises the following steps: under the condition of immune activation, a to-be-screened compound is applied to a neoantigen generation defect cell model; indexes such as the expression level of the neoantigen or the neoantigen-MHC complex, the immune checkpoint molecule, the survival state or cytotoxicity of tumor cells, the activation or proliferation ability of immune cells, and the like are detected; and the candidate compound is comprehensively evaluated. The method realizes a three-dimensional integrated evaluation system of "neoantigen induction efficiency-tumor cytotoxicity characteristics-T cell immune activity" for the first time, can high-throughput screen a large-scale compound library, specifically recognizes and evaluates the comprehensive effect of the candidate compound, thereby efficiently discovers a lead drug with the activity of promoting tumor neoantigen production, solves the fundamental defect that the existing screening technology cannot target the evaluation of the neoantigen induction capacity, and provides a universal and expandable screening platform for the development of an immunotherapy sensitizer.

The present invention provides an anti-cancer vaccine comprising: (i) at least one peptide comprising the amino acid sequence of a neoantigen encoded by a mutant homologous recombination (HR) DNA repair gene selected from the group: BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C and RAD51D, wherein the mutant gene comprises a reversion mutation; and / or (ii) at least one polynucleotide encoding the at least one peptide of (i). Also provided are engineered T cells that recognise said neoantigen. Related methods and medical uses of the vaccine and / or engineered T cell are provided, including for the treatment of cancers, such as homologous recombination (HR) deficient cancers that acquire PARP inhibitor resistance or platinum resistance by development of reversion mutations in an HR DNA repair gene selected from the group: BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C and RAD51D.

The present disclosure provides compositions and methods for targeting a neoantigen to, for example, treat or prevent cancer. Disclosed embodiments include binding proteins, such as T cell receptors, that bind to a neoantigen:HLA complex. The binding proteins further comprise a construct comprising a fusion protein of a CD95 ectodomain and a CD137 intracellular signaling domain (Fas-41BB), and a CDS co-receptor α or β chain. The disclosed binding proteins are highly sensitive to antigen, and are capable of inducing activation of host T cells at low concentrations of peptide antigen. In certain embodiments, binding proteins of the present disclosure are non-alloreactive against, are substantially non-alloreactive against, and / or have a low risk of alloreactivity against (i) amino acid sequences from the human proteome and / or (ii) against human HLA alleles. Polynucleotides encoding such binding proteins can be introduced into a host cell, such as a T cell, and the cell can be used in immunotherapy for treating various cancers.

This invention belongs to the field of biomedical technology, specifically disclosing the application of a CTL epitope peptide derived from the neoantigen ESR1 or its encoded nucleic acid in the preparation of a drug for treating tumors. Through analysis of the COSMIC database, epitope prediction, and in vitro and in vivo immunomodulatory activity experiments, this invention identified an HLA-A2-restricted CTL epitope peptide derived from the neoantigen ESR1. This mutant epitope peptide originates from a high-frequency mutation of ESR1 and can effectively stimulate and induce the production of neotope-specific cytotoxic T lymphocytes, specifically distinguishing between wild-type and mutant sequences, and killing tumor cells expressing the mutant epitope, exhibiting good anti-tumor effects. The resulting drug for treating tumors may contain the CTL epitope peptide derived from the neoantigen ESR1 or its encoded nucleic acid, or may contain a T-cell receptor, chimeric antigen receptor, or its encoded nucleic acid that specifically recognizes the mutant epitope peptide, demonstrating good therapeutic potential and clinical application prospects.

This invention discloses an oral frameshift peptide neoantigen vaccine, its preparation method, and its application, relating to the field of biomedical technology. The preparation method includes: 1) synthesizing a sea urchin-like metal-organic framework (MOF) via a hydrothermal method using zinc ions and 3,3''-dihydroxy-2',5'-dimethyl-[1,1':4',1''-terphenyl]-4,4''-dicarboxylic acid; 2) loading the sea urchin-like MOF with a frameshift peptide and a Toll-like receptor 9 agonist via electrostatic interactions and / or van der Waals forces to prepare the oral frameshift peptide neoantigen vaccine. This vaccine not only promotes antigen endocytosis and transcytosis via intestinal microfold cells by activating cyclin 42, but also alleviates immune tolerance mediated by the goblet cell-regulatory T cell immunosuppressive axis and activates specific CD8+. + T cells help prevent the development of Lynch syndrome-related colorectal cancer.

This invention discloses a method for screening and validating personalized neoantigens for liver cancer and its application. DNA and RNA are extracted from tumor and adjacent normal tissue samples from patients and subjected to high-throughput sequencing. Mutant peptides are screened, and the patient's HLA typing is determined. The binding affinity of the mutant peptides to HLA alleles is then evaluated, and antigen presentation ability is predicted. Candidate neoantigen peptides are comprehensively screened. The candidate neoantigens undergo coding sequence sequencing, cloning, PCR amplification, in vitro transcription, capping and tailing modifications, and encapsulation to prepare an mRNA-LNP vaccine. The obtained mRNA-LNP vaccine is then transfected into 293T cells in vitro to verify antigen expression efficiency, completing the functional quality control of the mRNA-LNP vaccine. This invention provides a highly efficient, closed-loop system for screening personalized neoantigens for liver cancer and validating vaccines, an integrated approach that directly guides mRNA vaccine construction and in vivo immunogenicity evaluation from multi-omics data screening.

Provided herein are T cell receptors (TCRs) or antigen-binding fragments thereof, such as those that recognize or bind NPM1c neoantigens. In particular, the present disclosure relates to TCRs that bind or recognize specific NPM1c peptides in the context of major histocompatibility complex (MHC) molecules. The present disclosure also relates to nucleic acids encoding such TCRs, engineered cells comprising such TCRs, methods of isolating such TCRs, and uses thereof, e.g., in cell therapy.

Provided herein are methods for making a tumor infiltrating lymphocytes (TILs) product enriched with neoantigen-reactive T cells (NARTs), comprising: generating a plurality of TIL populations by fractioning a tumor sample; selecting one or more TIL populations enriched with NARTs by profiling the plurality of TIL populations using multiplex digital PCR (dPCR); and preferentially expanding the NARTs by co-culturing the one or more TIL populations enriched with NARTs with tumor cells from the tumor sample in a first cell culture medium to generate the TIL product enriched with NARTs. Further provided is a method for assessing tumor reactivity of a population of T cells, comprising measurement of the expression level of a panel of target genes of the population of T cells.

The application belongs to the technical field of immunobiology, and particularly relates to a hepatocellular carcinoma antigen peptide and application thereof. The hepatocellular carcinoma antigen peptide provided by the application is a group of shared neoantigens derived from splicing abnormalities, long fragment insertion and deletion or gene fusion mutations, and has the advantages of good safety, high sharing, strong immunogenicity and high tumor specificity. The number of spots produced by the hepatocellular carcinoma antigen peptide has a statistical difference through immunological enzyme-linked immunospot assay, which indicates that the hepatocellular carcinoma antigen peptide has strong immunogenicity. The hepatocellular carcinoma antigen peptide can specifically activate the killing efficiency of induced expanded T cells on tumor cells to be greater than or equal to 30% through tumor cell killing experiment verification, and has a significant tumor killing effect. The hepatocellular carcinoma antigen peptide has great market value when used for preparing a vaccine for preventing and / or treating hepatocellular carcinoma.

The present disclosure provides a modified bispecific molecule that targets (a) a tumor-specific mutant peptide or mutation-associated neoantigen (MANA) presented by human leukocyte antigens (HLA) on the surface of target cancer cells; and (b) a surface protein (e.g., CD3) expressed on effector immune cells (e.g., T cells), as well as a method of using the molecule in cell therapy to diagnose, prevent, and / or treat human diseases including cancer. The bispecific molecule is modified to additionally include domain orientation modifications, linker modifications, and functional moieties including, e.g., Fc fragments, serum albumin, and / or polyethylene glycol (PEG) groups, which can improve efficacy, therapeutic index, half-life, and ease of manufacture while maintaining functionality and specificity in the treatment of diseases such as cancer.

The application is a divisional application of the Chinese invention patent application with application number 202410914209.2, application date of 2024.07.09 and invention name of "Molecular switch for controlling the transformation of colorectal cancer cell genome from MSS to MSI, inhibitor and application thereof". The application discloses the application of verteporfin or VT103 in reducing the level of MMR protein, and belongs to the technical field of medicine. The application finds that verteporfin and VT103 can transform the microsatellite stable state of colorectal cancer cell genome into a microsatellite unstable state, induce the tumor cells with microsatellite instability to exhibit reduced expression of mismatch repair proteins, increased mutation load and increased neoantigen load, can increase the mutation frequency of tumor cells, stimulate the generation of tumor neoantigen peptides, realize the transformation from "cold" tumor cells that cannot respond to immunotherapy to "hot" tumor cells, and provide a theoretical basis for the development of drugs for microsatellite stable digestive tract tumors and the treatment strategy of microsatellite stable tumors by targeting YAP / TAZ-TEAD combined with immunotherapy.

The purpose of the present invention is to provide a means for selecting subject-derived neoantigens. The above problem is solved by providing a method for selecting a subject-derived neoantigen, said method comprising: a step of acquiring sequence data of a normal cell and a cancer cell derived from a subject, a step of identifying a gene having a genetic mutation specific to the cancer cell, and a step of identifying a peptide based on a wild-type gene corresponding to the gene having the genetic mutation specific to the cancer cell from a major histocompatibility complex (MHC)-presented peptide database, wherein the genetic mutation is a missense mutation, and the peptide based on the wild-type gene corresponding to the gene having the genetic mutation has a wild-type amino acid corresponding to the position of an amino acid mutation due to the genetic mutation.

Disclosed is a method for processing peptide sequences exceeding a unit length through a process of folding when predicting neoantigens using peptide sequences and HLA class I and / or HLA class II allele sequences. According to the method, peptide sequences contained in cancer tissue can determine neoantigens in the cancer tissue, regardless of the diversity in length of the peptide sequences. Accordingly, it is possible to overcome the imbalance and lack of information in training data on length and more accurately predict a binding force to determine the neoantigens in the cancer tissue.

The application discloses a gp96 tumor neoantigen prediction method and application thereof, and relates to the technical field of tumor neoantigen prediction. The method comprises the following steps: S1, isolation and purification of gp96-tumor polypeptide complexes; S2, dissociation and purification of polypeptides; S3, mass spectrometric identification and sequence analysis of mutant peptides; S4, MHC affinity prediction; and S5, immunogenicity verification. The application takes gp96 as a natural biological concentrator, the captured polypeptides include products in a natural antigen processing path of tumor cells, and antigen peptide segments with potential immunological significance are enriched. In combination with MHC affinity prediction and immunogenicity function verification, the true positive rate of neoantigen screening is significantly improved. In a verification experiment on colon cancer samples, among 7 candidate neoantigens obtained through prediction, 4 can significantly activate autologous T cells of a patient to secrete IFN-gamma, and show a high immunogenicity verification positive rate.

This application discloses a method, system, device, and storage medium for predicting the immunogenicity of neoantigens. The method includes: acquiring tumor mutation data and synthesizing candidate peptides; constructing a training set with HLA typing and immune tags; extracting and fusing multi-omics feature vectors covering dimensions such as binding affinity, complex stability, presentation probability, expression level, mutation frequency, and clonal abundance; training the model using random balanced forest and XGBoost ensemble learning to obtain an immunogenicity prediction model; outputting immunogenicity probability scores for the peptides to be predicted and prioritizing them accordingly to generate a neoantigen list. This application significantly improves the accuracy and screening efficiency of neoantigen immunogenicity prediction by fusing multi-omics features and integrating the immunogenicity prediction model.

The application provides a manganese dioxide nanovaccine for dendritic cell targeted delivery of tumor neoantigens and a preparation method and application thereof, and belongs to the technical field of biological medicines. Hollow mesoporous MnO2 nanoparticles are prepared; the MnO2 nanoparticles and 10K-Adpgk aqueous solution are mixed, stirred, and centrifuged to obtain MA nanoparticles; DLin-MC3-DMA, DSPC, DSPE-PEG-Dcpep, cholesterol and chloroform are mixed, first ultrasonic water bath is carried out, rotary evaporation is carried out, MA sterile enzyme-free water is added, second ultrasonic water bath is carried out, and then extrusion and filtration are carried out to obtain MA@DC-NLP, namely the manganese dioxide nanovaccine for dendritic cell targeted delivery of tumor neoantigens. The obtained nanovaccine can accurately and efficiently co-deliver tumor antigens and immune adjuvants to the immune system, activate a strong and long-lasting anti-tumor immune response, and provide a controllable scheme for tumor immunotherapy.

This invention relates to a jet microneedle delivery device capable of achieving controllable initial diffusion and precise targeted drug delivery, compositions for local tumor injection, drug-device combination products, and their use in the preparation of drugs for local tumor injection. The jet microneedle delivery device uses a conventional needle-free jet injection power source, combined with one or more microneedles to achieve diffusion and precise delivery. The composition includes a boron compound drug component, an immune adjuvant, and a drug carrier. Through a specially designed jet microneedle delivery device, boron compound radiotherapy drugs can be delivered locally to the tumor, avoiding the problems of traditional intravenous administration where drugs struggle to reach the tumor interior and surface, and where systemic toxicity or overdose radioactivity limits the maximum drug dose and therapeutic effect. The high-concentration local delivery of the composition not only improves the local therapeutic effect on the tumor but also effectively generates tumor-specific antibodies through neoantigens produced during treatment, assisted by the immune adjuvant.

This invention relates to γδT cell culture technology, specifically a method and application for activating γδT cells using circulating tumor cells (CTCs) or their derivatives. The method includes obtaining donor-derived γδT cells; obtaining CTCs or their derivatives from cancer patients; and co-culturing the γδT cells with the CTCs or their derivatives in an in vitro co-culture system, thereby activating the γδT cells under the stimulation of the CTCs or their derivatives to obtain CTC-γδT cells. This invention utilizes patient-derived circulating tumor cells as the activation stimulus for γδT cells, enabling the resulting γδT cells to recognize tumor-associated antigens and personalized neoantigens, overcoming tumor heterogeneity and antigen escape problems.

The disclosure relates to methods of treating cancer in a subject administering nucleic acid molecules comprising a nucleic acid sequence encoding a plurality of neoantigens. Vaccines, compositions comprising coding regions encoding neoantigens organized in a pattern of nucleic acid sequences are also disclosed as well as methods of immunizing a subject using the same.

The present disclosure provides modified bispecific molecules that target (a) tumor-specific mutant peptides or mutant-associated neoantigens (MANAs) presented by human leukocyte antigens (HLAs) on the surface of target cancer cells; and (b) surface proteins (e.g., CD3) expressed on effector immune cells (e.g., T cells), and methods of using the same for cell therapy to diagnose, prevent, and / or treat human diseases, including cancer. The bispecific molecules are modified to additionally comprise domain orientation modifications, linker modifications, and functional moieties, including, for example, Fc fragments, serum albumin, and / or polyethylene glycol (PEG) groups, that can improve their potency, therapeutic index, half-life, and manufacturability, while maintaining functionality and specificity in the treatment of diseases, such as cancer.

A method for identifying T-cells that are antigen-specific for at least one neoantigen that is likely to be presented on surfaces of tumor cells of a subject. Peptide sequences of tumor neoantigens are obtained by sequencing the tumor cells of the subject. The peptide sequences are input into a machine-learned presentation model to generate presentation likelihoods for the tumor neoantigens, each presentation likelihood representing the likelihood that a neoantigen is presented by an MHC allele on the surfaces of the tumor cells of the subject. A subset of the neoantigens is selected based on the presentation likelihoods. T-cells that are antigen-specific for at least one of the neoantigens in the subset are identified. These T-cells can be expanded for use in T-cell therapy. TCRs of these identified T-cells can also be sequenced and cloned into new T-cells for use in T-cell therapy.