WO2022012420A1 - Combinaison de nucléotides et son utilisation - Google Patents

Combinaison de nucléotides et son utilisation Download PDF

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WO2022012420A1
WO2022012420A1 PCT/CN2021/105374 CN2021105374W WO2022012420A1 WO 2022012420 A1 WO2022012420 A1 WO 2022012420A1 CN 2021105374 W CN2021105374 W CN 2021105374W WO 2022012420 A1 WO2022012420 A1 WO 2022012420A1
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hla
gene
cancer
carcinoma
genes
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PCT/CN2021/105374
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Chinese (zh)
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冀颜
徐伟
周辉
王树彦
竺东雷
彭波
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信达生物制药(苏州)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • the invention belongs to the field of biological diagnosis, in particular to a combination of nucleotides and uses thereof, and more particularly to a gene biomarker capable of diagnosing the prognostic effect of PD1/PDL1 pathway immune checkpoint inhibitor combined with chemotherapy drugs.
  • Cancer has always been one of the leading causes of death in the world, and has become a major disease that seriously endangers human life and health and restricts social development.
  • Today, the incidence and death toll of cancer are still rising rapidly.
  • Epidemiological data show that in 2018, there were 18.1 million new cancer cases worldwide and 9.6 million cancer deaths.
  • the number of new cancer cases and deaths in my country were about 4.292 million and 2.814 million, respectively, equivalent to an average of 12,000 new cancer cases and 7,500 cancer deaths every day. It can be seen that cancer has become the main cause of death in China, seriously threatening people's health and life, and causing huge public health problems.
  • lung cancer ranks first in the incidence of malignant tumors in my country.
  • the estimated results show that there were about 787,000 new lung cancer cases in my country in 2015, the incidence rate was 57.26/100,000, and the winning rate was 35.96/100,000.
  • the other high-incidence malignant tumors are gastric cancer, colorectal cancer, liver cancer and breast cancer, etc.
  • the top 10 malignant tumors account for about 76.70% of all malignant tumors.
  • non-small cell lung cancer accounts for about 80% to 85% of all lung cancer cases, and about 70% of NSCLC patients have locally advanced or metastatic disease that is not suitable for surgical resection at the time of diagnosis.
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor
  • First-line EGFR inhibitors are recommended for patients with EGFR-mutated advanced NSCLC.
  • the ALK rearrangement rate is about 3%
  • the ALK inhibitor crizotinib is recommended for first-line patients with ALK-rearranged advanced NSCLC.
  • the standard first-line treatment for advanced non-squamous NSCLC in China without EGFR mutation and ALK rearrangement is platinum-containing double-drug chemotherapy, and the survival time after failure of first-line chemotherapy is only 6-9 months. Therefore, the development of new drugs for recurrent or advanced non-squamous NSCLC still needs A long way to go.
  • immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies
  • pembrolizumab was approved for non-small cell lung cancer.
  • nivolumab was also approved for marketing in non-small cell lung cancer; in December 2018, sintilimab was launched for the indication of Hodgkin's lymphoma, and immunological clinical trials for various indications are currently underway, including First-line non-squamous NSCLC.
  • TMB tumor mutational burden
  • MSI microsatellite instability
  • TMB tumor necrosis factor
  • PD-L1, MSI-H, etc. can predict the efficacy.
  • PD-L1 expression is not a good biomarker.
  • TMB the efficacy of immunotherapy can be predicted, different platforms are used for TMB detection in clinical experiments. The detection and analysis accuracy is not enough, and it is not suitable for the prediction of combination therapy, so we need to find a better biomaker to predict the efficacy of combination therapy.
  • the technical problem to be solved by the present invention is to provide some nucleotide combinations and their applications for overcoming the defects in the prior art.
  • the present invention solves the above technical problems through the following technical solutions.
  • nucleotide combination comprising or consisting of the following genes: CD74, CTSZ, ACP5, MS4A6A, CD83, NPC2, GPNMB, C1QB, HLA-DPA1 and HLA-DMB, or mutations in the above genes; and/or
  • the inventors have unexpectedly found that the above-mentioned genes are specifically highly expressed by macrophages in the tumor microenvironment, wherein the "specifically high expression” refers to the expression of the genes in patients who respond to tumor immune combination therapy. Expression was higher than in non-responding patients.
  • the tumor immune combination can be conventional in the art, such as PD1 immune checkpoint inhibitor combined with chemotherapy.
  • the nucleotide combination comprises or consists of the following genes:
  • nucleotide combination comprises LAP3, IFNGR1, TBXAS1, SPI1, SNX10, LYZ, HCK, ACP5, CTSH, ASAH1, MAN2B1, CD33, RASSF4, MS4A6A, DOK1, PLEK, NPC2, CD80, CCR2, NCKAP1L, ACP2, P2RX4, TLR2, CASP1, IDH1, N4BP2L1, ITGAX, C1orf162, PLA2G7, ATP6V1B2, FERMT3, TMEM86A, MERTK, SLAMF8, FCER1G, ATP6V0D1, SCIMP, TNFSF13, CTSS, MNDA, TMEM144, CYBB, SMCO4, C2, TPP1, P2RY6, CLEC7A, SMPDL3A, C1QB, OLR1, LRRC25, CD163, FUCA1, CSF1R, ADAP2, TMEM106A, ZNF267, FPR3, CARD9,
  • nucleotide combination comprises or consists of the following genes:
  • the second technical solution of the present invention is: the application of the nucleotide combination according to the one of the technical solutions in the preparation of a diagnostic reagent for the prognosis of a patient who has been administered a PD1/PDL1 pathway immune checkpoint inhibitor; Preferably, the patient has been administered a PD1/PDL1 pathway immune checkpoint inhibitor in combination with a chemotherapy drug.
  • the third technical solution of the present invention is: a kit for evaluating the prognostic effect of a patient after administration of PD1/PDL1 pathway immune checkpoint inhibitor or administration of PD1/PDL1 pathway immune checkpoint inhibitor combined with chemotherapy drugs, the reagent
  • the kit contains reagents for detecting the expression level of the combination of nucleotides as described in one of the technical solutions.
  • the expression level can be determined by any convenient method, and many suitable techniques are known in the art.
  • suitable techniques include: real-time quantitative PCR (RT-qPCR), digital PCR, microarray analysis, whole transcriptome shotgun sequencing (RNA-SEQ), direct multiplex gene expression analysis, enzyme-linked immunosorbent assay (ELISA), protein Chips, flow cytometry (eg, Flow-FISH of RNA, also known as FlowRNA), mass spectrometry, Western blots, and northern blots.
  • the reagents may be reagents suitable for determining the expression of the gene in question using any of the techniques described herein, such as RT-qPCR, digital PCR, microarray analysis, whole transcriptome shotgun sequencing, or direct multiplex gene expression analysis.
  • the kit may include primers suitable for determining the expression of the gene in question using, eg, T-qPCR, digital PCR, microarray analysis, whole transcriptome shotgun sequencing or direct multiplex gene expression analysis. The design of suitable primers is routine and within the skill of the artisan. Kits for direct multiplex gene expression analysis may also or alternatively include fluorescent probes for determining the expression of the gene in question.
  • kits may also include RNA extraction kits and/or reagents for reverse transcription of RNA into cDNA.
  • the kit may also include one or more articles of manufacture and/or reagents for carrying out the methods, such as buffers, and/or a device for obtaining the test sample itself, such as a device for obtaining and/or isolating the sample, and Containers for processing samples (these components are usually sterile).
  • one or more articles of manufacture and/or reagents for carrying out the methods such as buffers, and/or a device for obtaining the test sample itself, such as a device for obtaining and/or isolating the sample, and Containers for processing samples (these components are usually sterile).
  • the fourth technical solution of the present invention is: a system for evaluating the prognostic effect of a patient after administration of a PD1/PDL1 pathway immune checkpoint inhibitor or a PD1/PDL1 pathway immune checkpoint inhibitor combined with a chemotherapeutic drug, the system comprising a tool And a computer, the tool is used to determine the expression level of the nucleotide combination as described in one of the technical solutions.
  • the computer is programmed to determine the prognostic effect based on the patient's gene expression data.
  • the fifth technical solution of the present invention is: a method for predicting the response of a patient diagnosed with cancer after administration of a PD1/PDL1 pathway immune checkpoint inhibitor or a PD1/PDL1 pathway immune checkpoint inhibitor combined with a chemotherapeutic drug, comprising the following steps :
  • the nucleotide combination as described in one of the technical solutions is provided, and based on the expression of each gene in the combination, the patients are divided into a gene high expression group and a gene low expression group, and the PFS conditions of the two groups of patients are compared. Statistically different, high or low expression of the combined gene was considered to be associated with a corresponding therapeutic effect.
  • the PD1/PDL1 pathway immune checkpoint inhibitor is preferably PD1 antigen binding protein or PDL1 antigen binding protein; wherein the PD1 antigen binding protein or PDL1 antigen binding protein is preferably a monoclonal antibody or a bispecific antibody, Multispecific antibodies; for example, nivolumab, pembrolizumab, silimumab, toripalizumab, camrelizumab, tislelizumab, sintilimab; atezolizumab, avelumab, durvalumab, adebrelimab, pacmilimab, envafolimab;
  • the PD1/PDL1 pathway immune checkpoint inhibitor is sintilimab.
  • the chemotherapeutic drugs preferably include pemetrexed, gemcitabine or paclitaxel, and platinum; wherein, the platinum is preferably cisplatin and/or carboplatin.
  • the patient preferably has a cancer selected from the group consisting of adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma and adenocarcinoma, cholangiocarcinoma, colorectal carcinoma, lymphoma, diffuse large B-cell lymphoma , esophageal cancer, glioma, head and neck squamous cell carcinoma, mixed renal carcinoma, acute myeloid leukemia, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic cancer , pheochromocytoma and paraganglioma, prostate adenocarcinoma, sarcoma, skin melanoma, gastric cancer, gastric and esophageal cancer, testicular cancer, thyroid cancer, thymoma, endometrial
  • the sixth technical solution of the present invention is: the application of the nucleotide combination according to one of the technical solutions in screening PD1/PDL1 pathway immune checkpoint inhibitory drugs.
  • the reagents and raw materials used in the present invention are all commercially available.
  • nucleotide combination of the present invention can carry out effective disease prediction or prognosis diagnosis, especially in the treatment of PD1/PDL1 pathway immune checkpoint inhibitor combined with chemotherapeutic drugs.
  • Figure 1 shows the PFS curves of sample patients with RNA sequences in treatment and control groups and all patients in treatment and control groups.
  • Figure 2A and Figure 2B are the PFS curves of myloid_gene_set in the treatment group and the control group.
  • Figures 3A and 3B are PFS curves of TAM_gene_set in the treatment group and the control group.
  • Figure 4A and Figure 4B are the PFS curves of myloid_gene_set_filtered in the treatment group and the control group.
  • Figures 5A and 5B are PFS curves of TAM_gene_set_filtered in the treatment group and the control group.
  • the present invention is a combination of sintilimab combined with chemotherapy drugs pemetrexed and platinum or placebo combined with chemotherapy drugs pemetrexed and platinum in Chinese subjects with advanced or recurrent non-squamous non-small cell lung cancer.
  • placebo combined with pemetrexed, cisplatin or carboplatin was used as a parallel control, and the patients received sintilimab or placebo combined with pemetrexed, cisplatin or carboplatin for 4 cycles, and then received sintilimab or placebo combined with pemetrexed, cisplatin or carboplatin.
  • Limumab or placebo monotherapy plus pemetrexed maintenance therapy, and the maximum duration of sintilimab treatment was 24 months.
  • Biological pathway enrichment analysis method set the total number of genes N, there are two groups of genes (query group, that is, favorably predictive gene set; reference group, that is, a biological pathway), and the genes are divided into four groups: A group (a genes, both in query group and reference group), B group (b genes, in query group, not in reference group), C group (c genes, not in query group, in reference group) and D group (d genes, not in the query group, not in the reference group).
  • a group a genes, both in query group and reference group
  • B group b genes, in query group, not in reference group
  • C group c genes, not in query group, in reference group
  • D group d genes, not in the query group, not in the reference group
  • Example 1 Multicenter, multicenter, first-line treatment of sintilimab combined with pemetrexed and platinum-based chemotherapy or placebo combined with pemetrexed and platinum-based chemotherapy in subjects with advanced or recurrent non-squamous NSCLC Randomized, double-blind phase III study
  • Carboplatin AUC5 (calculated using Calvert formula), the dose of carboplatin should not exceed 750mg.
  • AUC area under the curve, area under the plasma concentration-time curve
  • the estimated CrCl used in the Calvert formula must not exceed 125ml/min
  • FFPE Paraffin-Embedded, paraffin-embedded
  • FFPE RNA sequence samples of 182 patients were analyzed, as shown in Figure 1. Although only a subset of patients, FFPE RNA sequences were specifically representative from the perspective of progression free survival (PFS, progression-free survival). In the treatment group or the control group, there was no statistical difference in the PFS curves of either the patients with RNA-seq or the whole sample. This shows that the 182 samples used for analysis can represent the clinical characteristics of all samples with statistical significance.
  • FFPE RNA sequences of 182 cases in Example 1 Based on the FFPE RNA sequences of 182 cases in Example 1, it was found that four groups of genes that are specifically highly expressed on macrophages in the tumor immune microenvironment can be used as biomarkers for tumor patient selection, such as for PD1/PDL1 pathway immunity Prediction of response or companion diagnosis of checkpoint inhibitors in combination with chemotherapeutic agents in subjects with advanced or recurrent non-squamous NSCLC.
  • the surv_cutpoint function in the survminer a software package in the statistical software R, is used to select a cutoff value for each gene, and the samples with a value greater than this cutoff value are selected.
  • the set is called the high group (the better curative effect group), and the sample set below this cutoff value is called the low group (the poor curative effect group).
  • the hazard ratio ⁇ 1&p-value ⁇ 0.05 the gene is called a favorably predictive gene.
  • the gene is called unfavorably predictive gene, and the obtained favorably predictive gene is analyzed by biological pathway enrichment analysis method to find the favorably predictive gene that is significantly enriched in the macrophage pathway.
  • the two groups of top nucleotide combinations are obtained, namely myloid_gene_set and TAM_gene_set, and the specific gene sets are shown in Table 2. The relationship between myloid_gene_set, TAM_gene_set and PFS was then evaluated, see Figures 2 and 3.
  • the first step is to evaluate the relationship between gene and PFS for all genes in myloid_gene_set and TAM_gene_set according to the method in 1), and find the favorably predictive gene;
  • the myloid_gene_set and TAM_gene_set are respectively based on the overall expression(OE) score (see https://github.com/livnatje/ImmuneResistance for the method) and the PFS data of the patients in the comb group, using a software package survminer in the statistical software R
  • the surv_cutpoint in select a cutoff for both myloid_gene_set and TAM_gene_set respectively.
  • the sample set greater than this cutoff is called the high group (better curative effect group), and the sample set lower than this cutoff is called the low group (poor curative effect group).
  • the genes with significantly high expression in the high group were retained by the gene expression differential analysis method.
  • the third step is to take the intersection of the genes obtained in the first step and the second step, namely myloid_gene_set_filtered and TAM_gene_set_filtered.
  • the specific gene collection is shown in Table 2. Then evaluate the relationship between myloid_gene_set_filtered and TAM_gene_set_filtered and PFS, see Figure 4 and Figure 5.
  • 2gene_set run the equation in step 1 in comb (treatment group) and chem (control group) in four gene_sets, myloid_gene_set, TAM_gene_set, myloid_gene_set_filtered and TAM_gene_set_filtered, respectively.
  • the comb group includes the high group and the low group
  • the chem group includes the high group and the low group.
  • the low group is set as the reference, and the statistical results indicate the statistical relationship between the high/low group and the patient's PFS.
  • the hazard ratio of the high/low group in the treatment group (comb) is ⁇ 1 and p-value ⁇ 0.05, indicating that In the comb group, the patients in the high group (better curative effect group) had a longer progression-free survival than the patients in the low group (poor curative effect group); while in the control group (chem), the hazard ratio of the high/low group was ⁇ 1, but the p- value>0.05, indicating that in the control group (chem), there was no difference in PFS between the high and low groups.
  • the input contains only myloid_gene_set, TAM_gene_set, myloid_gene_set_filtered, or TAM_gene_set_filtered gene expression data in samples in different tumors (https://portal.gdc.cancer.gov/), to predict these The probability of belonging to the high group in the tumor sample.
  • the high group represents patients with tumor microenvironment subtypes that may have a better prognosis for combination therapy (anti-PD1 antibody combined with chemotherapy drugs). Take all tumors of TCGA (The Cancer Genome Atlas, Tumor Genome Atlas) as an example.
  • ACC Adrenocortical carcinoma, adrenal cortical carcinoma
  • BLCA Breast Urothelial Carcinoma, bladder urothelial carcinoma
  • BRCA Breast invasive carcinoma, breast invasive carcinoma
  • CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma, cervical squamous cell carcinoma
  • CHOL Cervocarcinoma, cholangiocarcinoma
  • COADREAD Cold adenocarcinoma/Rectum adenocarcinoma Esophageal carcinoma, colorectal cancer
  • DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma, diffuse large
  • Table 3 Proportion of samples predicted to be likely to respond to anti-PD1 antibodies and chemotherapeutics in TCGA multiple tumor types by myloid_gene_set, TAM_gene_set, myloid_gene_set_filtered, and TAM_gene_set_filtered
  • these four gene sets can not only play a predictive role in PD1/PDL1 pathway immune checkpoint inhibitors combined with chemotherapy drugs, especially in the combination of sintilimab combined with pemetrexed, platinum (cisplatin or carboplatin) in the It plays an obvious predictive role in the treatment of patients with advanced or recurrent non-squamous NSCLC, and can also play a role in predicting efficacy in the above-mentioned indications.

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Abstract

Combinaison de nucléotides et son utilisation. La combinaison de nucléotides comprend les gènes suivants : CD74, CTSZ, ACP5, MS4A6A, CD83, NPC2, GPNMB, C1QB, HLA-DPA1, et HLA-DMB, ou des mutations desdits gènes ; et/ou un gène tel que LAP3, IFNGR1, TBXAS1, SPI1, SNX10 ou des mutations desdits gènes. Les gènes sont des gènes exprimés spécifiquement par un macrophage dans un microenvironnement tumoral. L'utilisation de la combinaison de nucléotides permet une prédiction efficace de la maladie ou un diagnostic pronostique, et fournit notamment un bon effet prédictif dans le traitement combiné avec un inhibiteur de point de contrôle immunitaire de la voie PD1/PDL1 et un médicament de chimiothérapie.
PCT/CN2021/105374 2020-07-17 2021-07-09 Combinaison de nucléotides et son utilisation WO2022012420A1 (fr)

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CN117079710A (zh) * 2023-08-18 2023-11-17 上海爱谱蒂康生物科技有限公司 生物标志物及其在预测和/或诊断utuc肌肉浸润中的应用
CN117079710B (zh) * 2023-08-18 2024-05-31 上海爱谱蒂康生物科技有限公司 生物标志物及其在预测和/或诊断utuc肌肉浸润中的应用

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Publication number Priority date Publication date Assignee Title
CN116904590A (zh) * 2023-02-21 2023-10-20 芜湖胤星医学检验实验室有限公司 一种基于数字pcr平台的食管癌基因检测引物、探针及试剂盒
CN117079710A (zh) * 2023-08-18 2023-11-17 上海爱谱蒂康生物科技有限公司 生物标志物及其在预测和/或诊断utuc肌肉浸润中的应用
CN117079710B (zh) * 2023-08-18 2024-05-31 上海爱谱蒂康生物科技有限公司 生物标志物及其在预测和/或诊断utuc肌肉浸润中的应用

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