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1. WO2022112469 - METHODS FOR DIAGNOSIS AND MONITORING OF TOXIC EPIDERMAL NECROLYSIS

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Publication Number WO/2022/112469
Publication Date 02.06.2022
International Application No. PCT/EP2021/083093
International Filing Date 26.11.2021
IPC
A61P 37/00 2006.1
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
37Drugs for immunological or allergic disorders
C07K 14/47 2006.1
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
46from vertebrates
47from mammals
C12Q 1/6883 2018.1
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING 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
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6883for diseases caused by alterations of genetic material
CPC
A61P 37/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
37Drugs for immunological or allergic disorders
C07K 14/70517
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
705Receptors; Cell surface antigens; Cell surface determinants
70503Immunoglobulin superfamily
70517CD8
C07K 14/7158
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
705Receptors; Cell surface antigens; Cell surface determinants
715for cytokines; for lymphokines; for interferons
7158for chemokines
C12N 9/16
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes; Proenzymes; Compositions thereof
14Hydrolases (3)
16acting on ester bonds (3.1)
C12N 9/2497
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9Enzymes; Proenzymes; Compositions thereof
14Hydrolases (3)
24acting on glycosyl compounds (3.2)
2497hydrolysing N- glycosyl compounds (3.2.2)
C12Q 1/6883
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6883for diseases caused by alterations of genetic material
Applicants
  • INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) [FR]/[FR]
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) [FR]/[FR]
  • ECOLE NORMALE SUPÉRIEURE DE LYON [FR]/[FR]
  • HOSPICES CIVILS DE LYON [FR]/[FR]
  • UNIVERSITÉ CLAUDE BERNARD - LYON 1 [FR]/[FR]
Inventors
  • VOCANSON, Marc
  • VILLANI, Axel
  • NOSBAUM, Audrey
  • ROZIERES, Aurore
Agents
  • INSERM TRANSFERT
Priority Data
20306460.527.11.2020EP
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) METHODS FOR DIAGNOSIS AND MONITORING OF TOXIC EPIDERMAL NECROLYSIS
(FR) PROCÉDÉS DE DIAGNOSTIC ET DE SURVEILLANCE DE LA NÉCROLYSE ÉPIDERMIQUE TOXIQUE
Abstract
(EN) In the present invention, inventors investigate the representation of T cell subsets in Toxic epidermal necrolysis (TEN) a life-threatening cutaneous adverse drug reaction (cADR), characterized by massive epidermal necrosis. To better understand why skin symptoms are so severe in TEN disease, inventors conducted a prospective immunophenotyping study on skin samples and blood from 18 TEN patients, using mass cytometry and next generation TCR sequencing. Deep sequencing of the T cell receptor CDR3 repertoire revealed massive expansion of unique CDR3 clonotypes in blister cells. Over-represented clonotypes were mainly effector memory CD8+CD45RA-CCR7- T cells, and expressed high levels of cytotoxic (Granulysin and Granzymes A & B) and activation (CD38) markers. Thus present invention relates to non-invasive, specific and rapid methods for diagnostic and monitoring Toxic Epidermal Necrolysis. More specifically present invention relates to methods for diagnosis and/or monitoring of Toxic Epidermal Necrolysis through detection of a specific population of T ymphocytes in a subject. The present invention also relates to a method of preventing or treating a Toxic Epidermal Necrolysis in a subject in need thereof.
(FR) Dans la présente invention, les inventeurs ont étudié la représentation de sous-ensembles de lymphocytes T dans la nécrolyse épidermique toxique (NET), une réaction cutanée indésirable à un médicament (cADR) mettant en danger la vie, caractérisée par une nécrose épidermique massive. Pour mieux comprendre pourquoi les symptômes de la peau sont tellement graves dans la maladie NET, les inventeurs ont mené une étude d'immunophénotypage prospective sur des échantillons de peau et du sang provenant de 18 patients atteints de NET, à l'aide d'une cytométrie de masse et d'un séquençage de TCR de nouvelle génération. Le séquençage profond du répertoire CDR3 du récepteur des lymphocytes T a révélé une expansion massive de clonotypes CDR3 uniques dans des cellules alvéolaires. Les clonotypes surreprésentés étaient principalement des lymphocytes T mémoires effecteurs CD8+CD45RA-CCR7-, et exprimaient des niveaux élevés de marqueurs cytotoxiques (Granulysine et Granzymes A & B) et de marqueurs d'activation (CD38). La présente invention se rapporte donc à des procédés non invasifs, spécifiques et rapides de diagnostic et de surveillance de la nécrolyse épidermique toxique. Plus particulièrement, la présente invention se rapporte à des procédés de diagnostic et/ou de surveillance de la nécrolyse épidermique toxique par la détection d'une population spécifique de lymphocytes T chez un sujet. La présente invention se rapporte également à une méthode de prévention ou de traitement d'une nécrolyse épidermique toxique chez un sujet en ayant besoin.
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