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WO2022017435A1 - SÉRIE DE BIOMARQUEURS DE SÉQUENCES CONSENSUS DANS UNE SÉQUENCE CDR3 DE CHAÎNE TCR-β ET LEUR APPLICATION - Google Patents

SÉRIE DE BIOMARQUEURS DE SÉQUENCES CONSENSUS DANS UNE SÉQUENCE CDR3 DE CHAÎNE TCR-β ET LEUR APPLICATION Download PDF

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WO2022017435A1
WO2022017435A1 PCT/CN2021/107760 CN2021107760W WO2022017435A1 WO 2022017435 A1 WO2022017435 A1 WO 2022017435A1 CN 2021107760 W CN2021107760 W CN 2021107760W WO 2022017435 A1 WO2022017435 A1 WO 2022017435A1
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pdl1
biomarkers
immune checkpoint
patient
tcr
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王旋
孙继亚
徐伟
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Innovent Biologics Suzhou Co Ltd
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Innovent Biologics Suzhou Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • the invention belongs to the field of biomedicine and relates to the research of clinical biomarkers, in particular to a series of biomarkers of consensus sequences in the CDR3 sequences of TCR-beta chains and applications thereof.
  • Lymphoma is one of the common malignant tumors in my country.
  • Classical Hodgkin's lymphoma (cHL) is a B-cell malignant lymphoma, which occurs mostly in young and middle-aged people. It is characterized by chromosome 9p24.1 mutation and PD. -1 for overexpression.
  • Classical Hodgkin lymphoma (cHL) is a tumor type that responds well to PD-1 antibody therapy.
  • Sintilimab a PD-1 checkpoint inhibitor
  • the safety and efficacy of sintilimab after extended follow-up were evaluated in the Phase II trial of the ORIENT-1 study.
  • the clinical overall response rate (ORR) of PD-1 and PD-L1 antibody drugs in relapsed/resistant (r/r) cHL can be as high as 66%-80% [1-4] .
  • ORR overall response rate
  • T cell receptors are heterodimers responsible for recognizing antigens presented by the major histocompatibility complex (MHC).
  • MHC major histocompatibility complex
  • Most TCRs are composed of two polypeptide chains (namely ⁇ chain and ⁇ chain), and each polypeptide chain contains three highly variable complementarity determining regions (CDRs), namely CDR1, CDR2 and CDR3, respectively.
  • CDRs complementarity determining regions
  • CDR3 is responsible for directly interacting with Binding of polypeptides presented by MHC. Since CDR3 interacts most closely with antigenic peptides, the diversity of CDR3 amino acid sequences provides an indicator of T cell diversity in the T cell repertoire [7-9] .
  • the present application provides a series of biomarkers sharing the CDR3 sequence of the TCR- ⁇ chain and their application in predicting the clinical response of PD-1 antibody to Hodgkin lymphoma.
  • the present inventors have conducted in-depth research and repeated tests to determine the level of TCR-
  • the CDR3 sequence of the beta chain is subjected to high-throughput sequencing, the highly enriched sequence is analyzed, and the relationship between the highly enriched sequence and the patient's T cells for the treatment is studied in combination with clinical observations, thereby completing the present invention. That is, the present invention is as follows:
  • a set of biomarkers is provided, characterized in that, the biomarkers are the consensus amino acid sequence in the CDR3 sequence of T cell receptor (TCR) beta chain;
  • the marker contains RGG in its amino acid sequence.
  • the biomarkers respectively comprise the amino acid sequence shown in any one of SEQ ID NO: 1 to SEQ ID NO: 9; preferably, the biomarkers respectively comprise SEQ ID NO: The amino acid sequence shown in any one of 1-2, SEQ ID NO: 4-6 or SEQ ID NO: 7; more preferably, the biomarkers respectively comprise the amino acid sequences in SEQ ID NO: 2 or SEQ ID NO: 6 amino acid sequence shown.
  • the biomarkers described in the first aspect of the present invention in the preparation of predictive PD1/PDL1 pathway immune checkpoint inhibitors or PD1/PDL1 pathway immune checkpoint inhibitor combination therapeutic agents.
  • kits for evaluating the response effect of a patient with a tumor after administration of a PD1/PDL1 pathway immune checkpoint inhibitor or a PD1/PDL1 pathway immune checkpoint inhibitor combined therapeutic agent comprises the biomarkers described in the first aspect of the present invention.
  • the detection of PD1/PDL1 pathway immune checkpoint inhibitor or PD1/PDL1 pathway immune checkpoint inhibitor combined therapeutic agent in tumors using the kit described in the fourth aspect of the present invention Application in response to effects or adverse reactions.
  • a method for predicting the response effect or adverse reaction after administration of a PD1/PDL1 pathway immune checkpoint inhibitor or a PD1/PDL1 pathway immune checkpoint inhibitor combined therapeutic agent in a tumor patient the method include:
  • PBMC peripheral blood mononuclear cells
  • the PD1/PDL1 pathway immune checkpoint inhibitor described in the second to sixth aspects of the present invention is an anti-PD1 or anti-PDL1 monoclonal antibody, an anti-PD1 or anti-PDL1 bispecific Antibody, anti-PD1 or anti-PDL1 multispecific antibody, ADC drug targeting PD1 or PDL1 or fusion protein targeting PD1 or PDL1; the therapeutic agent is a small molecule drug, antibody, ADC drug, fusion protein or polypeptide.
  • the above-mentioned anti-PD1 or anti-PDL1 monoclonal antibodies are nivolumab, pembrolizumab, cimilimab, toripalizumab, camrelizumab, tira Libizumab, sintilimab; atezolizumab, avelumab, durvalumab, adebrelimab, pacmilimab, envafolimab; preferably, the anti-PD1 monoclonal antibody is Sindi limumab.
  • the tumor described in the first to sixth aspects of the present invention is Hodgkin's lymphoma; preferably, the tumor is classic Hodgkin's lymphoma.
  • “Adverse reactions” refers to the occurrence of harmful reactions that are not related to the purpose of treatment during the process of preventing, diagnosing or treating diseases by applying drugs according to normal usage and dosage. Examples include immune-related adverse reactions (irAEs) or other concomitant side effects that occur during treatment.
  • irAEs immune-related adverse reactions
  • Immuno checkpoint inhibitors some drugs developed for corresponding immune checkpoints, whose main function is to block the interaction between tumor cells expressing immune checkpoints and immune cells, thereby blocking the inhibition of immune cells by tumor cells effect.
  • the present invention finds for the first time that after a patient with classic Hodgkin lymphoma (cHL) is treated with sintilimab, the change in the abundance of the CDR3 sequence of the TCR- ⁇ chain of the patient is related to the efficacy and clinical efficacy of the drug. There is a good correlation between side effects.
  • cHL Hodgkin lymphoma
  • a in Figure 1 shows the experimental steps of Example 1 and the relationship between the efficacy of each patient and the time of administration after administration, wherein CR means complete remission; PR means partial remission; PD means disease progression; irAE means immune related adverse reactions;
  • FIG. 1 shows the sequence number of the total TCR- ⁇ chain CDR3 detected by each patient, the sequence number of the TCR- ⁇ chain CDR3 sequence obtained by sequencing and the analysis of the consensus sequence among different patients;
  • C in Figure 1 shows the enrichment abundance of the CDR3 sequences (i.e. dominant sequences) of the highest 3 TCR- ⁇ chains in each patient as a percentage of the top 100 sequence abundances, respectively;
  • D in Figure 1 shows an analysis of the abundance of the CDR3 sequences of the top three TCR-beta chains in each patient (i.e., the dominant sequence) over time, and the presence or absence of "RGG" in the dominant sequence and efficacy
  • CR means complete remission
  • PR means partial remission
  • irAE means immune-related adverse reactions
  • Figure 2 shows the presence in each patient of the CDR3 sequences of up to three TCR-beta chains (ie, predominant sequences) in each patient.
  • test materials, test reagents and instruments used in the examples of the present invention are all commercially available.
  • Sintilimab ie, Q3W
  • Test patients 4 patients of ORIENT-1 (NCT03114683), numbered p01, p02, p03 and p04, respectively.
  • the "ORIENT-1" is a multi-center, single-arm, phase II clinical study conducted in China for patients with relapsed or refractory classical Hodgkin lymphoma who have undergone at least second-line systemic chemotherapy. To evaluate the safety and efficacy of sintilimab.
  • TCR ⁇ chain is first amplified by multiplex PCR, and the multiplex PCR contains two stages of PCR1 stage and PCR2 stage, and the primer combination used has been described in the patent (CN105087789A) .
  • the PCR1 stage uses a primer pool pair for the V and J regions of each TCR- ⁇ to amplify CDR3, and the PCR2 stage uses a unified primer pool.
  • the specific method of PCR1 stage template DNA (600ng, 1 ⁇ l) was added to 25 ⁇ l of QIAGEN Multiplex PCR master mix, 5 ⁇ l of Q solution, 1 ⁇ l of forward primer set library and 1 ⁇ l of reverse primer set library, and then amplified.
  • the reaction system was formed by using the Multiplex PCR Kit (QIAGEN, Germany). The following PCR program was then performed: 15 min at 95°C followed by 10 cycles of amplification (94°C, 30s denaturation; 60°C, 90s annealing and 72°C, 30s extension). After the final extension at 72°C for 5 min, the system was cooled to 4°C.
  • the product of PCR 1 stage was purified with magnetic beads (Agencourt No. A63882, Beckman, Beverly, MA, USA). All PCR1-stage products were used as templates for PCR2, and PCR2-stage amplification was performed.
  • PCR2 stage The products of PCR2 stage were gel electrophoresed to recover fragments between 200-350bp, purified by QIAquick Gel Purification Kit (QIAGEN), and Illumina HiSeq3000 was used for paired-end sequencing with a read length of 151bp.
  • the sequencing analysis algorithm was based on the software R (version 3.5.1).
  • Patient p01 PR occurred 6 weeks after the initiation of sintilimab treatment, achieved CR after 24 weeks, and then developed irAE - diabetic ketosis at 48 weeks. A total of 217,043 sequences were sequenced against the CDR3 of patient p01. Three dominant sequences were identified: p01-1, p01-2 and p01-3, and the enrichment abundance of these three dominant sequences accounted for 17.1%, 17.0% and 12.0% of the abundance of the top 100 sequences, respectively. Among them, the dominant sequence p01-1: CASSGTSGSTDTQYF (SEQ ID NO: 1) was significantly enriched at the 36th week, and decreased to the basal level at the 48th week.
  • the dominant sequence p01-2 CASSQVSRGGTAEQYF (SEQ ID NO: 2) consistently increased from week 0 and continued to increase, reaching a peak enrichment at week 48.
  • Patient p02 achieved PR at 6 weeks after starting sintilimab treatment, achieved CR at 15 weeks, and then developed fibroids at 24 weeks.
  • the fibroid immune response is not clinically defined as an irAE.
  • a total of 88,583 sequences were sequenced against the CDR3 of patient p02.
  • Three dominant sequences were identified: p02-1, p02-2 and p02-3, and the enrichment abundance of these three dominant sequences accounted for 11.5%, 9.9% and 9.4% of the abundance of the top 100 sequences, respectively.
  • Patient p03 achieved tumor remission after sintilimab treatment, developed irAE pneumonitis at week 6 and had to discontinue treatment.
  • a total of 133,368 sequences were obtained by CDR3 sequencing.
  • Three dominant sequences were identified: p03-1, p03-2 and p03-3, and the enrichment abundance of these three dominant sequences accounted for 72.8%, 3.9% and 3.7% of the abundance of the top 100 sequences, respectively.
  • the dominant sequence p03-1 CASSIAGGSYEQYF (SEQ ID NO: 7) accounted for 65% of the entire TCR pool at baseline.
  • p03-2 CASRGGSYEQYF (SEQ ID NO: 8) and p03-3: CASSNRGGNEQFF (SEQ ID NO: 9) reached peak enrichment at week 6. Despite irAEs, p03 achieved PR from week 14 to week 36 after discontinuation.
  • Patient p04 No tumor remission during sintilimab treatment. Hepatic dysfunction of the irAE occurred at week 36 and treatment had to be discontinued. A total of 99,290 sequences were sequenced for CDR3. Three dominant sequences p04-1, p04-2 and p04-3 were identified, and the enrichment abundance of these three dominant sequences accounted for 16.7%, 4.3% and 2.9% of the abundance of the top 100 sequences, respectively.
  • the dominant sequence p04-1 CASSHNRGNEEKLFF (SEQ ID NO: 10) was significantly enriched at week 36
  • the dominant sequence p04-2 CASSPSAGRFGEQYF (SEQ ID NO: 11)
  • p04-3 CASSYKLTGVANYGYTF (SEQ ID NO: 12) No significant enrichment occurred at 36 weeks.
  • 5 of the 6 dominant sequences i.e., p01-1, p01-2, p02-1, p02-2, and p02-3 in p01 and p02 of the 2 patients with CR response were composed of 4 Patients shared, except that the above-mentioned 5 dominant sequences were not defined as dominant sequences in p03 and p04 (see the left half of Figure 2 for details).
  • the CDR3 sequences of the dominant TCR-beta chain were not identical in treatment-responsive patients, at least one RGG-containing CDR3 sequence was present in these patients. Since the CDR3 sequences contribute significantly to TCR binding to antigen, the presence of a common RGG indicates binding to the same antigen.
  • the GLIPH clustering algorithm [10] was used (this algorithm can identify the same specificity based on sequence similarity. Clustering TCR sequences to better analyze the large number of TCR sequences that have been identified, the algorithm can also predict the HLA restriction of these TCR clusters based on the subject's genotype, thereby helping to explore new antigens) Analysis of these sequences in Amino acid similarity. It was found that sequences containing "RGG" appeared most frequently among the 12 dominant sequences in 4 patients (p ⁇ 0.0001, see Figure 2 for details). More importantly, this RGG sequence was only present in responders (ie present in patients p01, p02 and p03) and was absent in non-responding patient p04.
  • the common TCR- ⁇ chain-CDR3 sequence may recognize tumor antigens associated with cHL. Some of these common sequences are more reactive and can expand rapidly after PD-1 blockade therapy. Once TCRs with these "highly occurring and co-existing" dominant sequences (9 sequences p01-1 to p03-3 as shown in Figure 2) predominate in a given T cell pool, their expansion may would lead to a better antitumor response after immunotherapy. In addition, baseline TCR abundance and expansion of dominant sequences were also associated with the incidence of clinical irAEs or other concomitant side effects.
  • patient p01 the occurrence of diabetic ketosis irAEs coincided with the occurrence of the highest abundance of the predominant sequences p01-2 and p01-3
  • patient p02 the occurrence of fibroid complications coincided with the predominant sequence p02-1 , the highest abundance of p02-2 and p02-3 occurred at the same time
  • patient p03 the dominant sequence p03-1 was extremely abundant, which may be related to the occurrence of pneumonia soon after PD-1 treatment.
  • patient p04 the occurrence of liver dysfunction irAE coincided with the occurrence of the highest abundance of the predominant sequence p04-1.
  • Patient p01, patient p02, and patient p03 were patients with clinical response to treatment, and all of their three dominant TCR- ⁇ chain CDR3 sequences had one or two RGG-containing sequences, and all of them were in RGG-containing sequences. irAEs or other immune responses occur when the highest abundance of enrichment is reached. However, in the CDR3 sequence of the dominant TCR- ⁇ chain in p04 of the only patient with progressive disease (corresponding patient with no response), no RGG sequence was found.

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Abstract

L'invention concerne une série de biomarqueurs de séquences consensus dans une séquence CDR3 d'une chaîne TCR-β et une application de ceux-ci. L'invention concerne un ensemble de biomarqueurs, caractérisé par le fait que les biomarqueurs sont des séquences consensus dans la séquence CDR3 d'une chaîne β du récepteur des lymphocytes T (TCR). De préférence, la séquence d'acides aminés des biomarqueurs comprend RGG. Les biomarqueurs décrits peuvent être utilisés pour prédire l'effet de la réponse clinique des inhibiteurs de points de contrôle immunitaire de la voie PD1/PDL1 sur des tumeurs, notamment le lymphome de Hodgkin. Un séquençage à haut débit et une analyse statistique sont effectués sur la séquence CDR3 de la chaîne TCR-β de patients atteints d'un lymphome de Hodgkin qui reçoivent des inhibiteurs de point de contrôle immunitaire de la voie PD1/PDL1, et une séquence dominante est déterminée. A l'aide de l'analyse d'enrichissement de la séquence dominante, il est utile de surveiller et de prédire la réponse et l'irAE du patient après immunothérapie des points de contrôle.
PCT/CN2021/107760 2020-07-22 2021-07-22 SÉRIE DE BIOMARQUEURS DE SÉQUENCES CONSENSUS DANS UNE SÉQUENCE CDR3 DE CHAÎNE TCR-β ET LEUR APPLICATION Ceased WO2022017435A1 (fr)

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Cited By (1)

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WO2024097878A1 (fr) * 2022-11-03 2024-05-10 The Board Of Regents Of The University Of Texas System Utilisation d'une fraction tolérante de lymphocytes t en tant que prédicteur d'événements indésirables liés à l'immunité

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024097878A1 (fr) * 2022-11-03 2024-05-10 The Board Of Regents Of The University Of Texas System Utilisation d'une fraction tolérante de lymphocytes t en tant que prédicteur d'événements indésirables liés à l'immunité

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