WO2022066032A1 - Procédé de pronostic de l'efficacité de traitement d'arthrite rhumatoïde avec une préparation d'olokizumab - Google Patents

Procédé de pronostic de l'efficacité de traitement d'arthrite rhumatoïde avec une préparation d'olokizumab Download PDF

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WO2022066032A1
WO2022066032A1 PCT/RU2020/000502 RU2020000502W WO2022066032A1 WO 2022066032 A1 WO2022066032 A1 WO 2022066032A1 RU 2020000502 W RU2020000502 W RU 2020000502W WO 2022066032 A1 WO2022066032 A1 WO 2022066032A1
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polymorphisms
olokizumab
rheumatoid arthritis
rsl
treatment
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Russian (ru)
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Андрей Александрович ЗАМЯТНИН
Дмитрий Сергеевич МИХАЙЛЕНКО
Марина Вячеславовна НЕМЦОВА
Ирина Владимировна БУРЕ
Екатерина Борисовна КУЗНЕЦОВА
Мария Степановна ЛЕМАК
Вадим Владимирович Тарасов
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федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет)
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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
    • 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

Definitions

  • the invention relates to medicine, namely to genetics and rheumatology, and can be used to predict the effectiveness of treatment with olokizumab in patients with rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic systemic inflammatory disease of the connective tissue with progressive joint damage and autoimmune disorders.
  • autoimmune arthritis reaches almost 1% of the world's population, which makes it an urgent problem of modern healthcare [Scherer, H.U.; Haupl, T.; Burmester, G.R. The etiology of rheumatoid arthritis. J. Autoimmun. 2020, 110, 102400].
  • a characteristic feature of rheumatoid arthritis is a pronounced clinical polymorphism, which consists in a wide variability in symptoms and clinical forms.
  • rheumatoid arthritis is considered as a multifactorial disease that develops in the presence of a genetic predisposition and provoking environmental factors [Karami, J.; Aslani, S.; Jamshidi, A.; Garshasbi, M.; Mahmoudi, M. Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 2019, 702, 8-16].
  • HLA-DRB1 alleles which encode unfavorable variants of the SE epitope and are associated with the development of rheumatoid arthritis with a high level of anticitrulline antibodies (ACA-positive rheumatoid arthritis). These alleles account for 18% of the hereditary component of ACA-positive rheumatoid arthritis and only 2.4% of ACA-negative rheumatoid arthritis.
  • HLA-DRB1 SE epitope occurs in 64-70% of patients with rheumatoid arthritis, 55% of their healthy relatives, but only in 35% of individuals on average in the population [Castro-Santos, R.; Diaz-Pena, R. Genetics of rheumatoid arthritis: a new boost is needed in Latin American populations. Rev. Bras. Reumatol. (English Ed. 2016, 56, 171-177.].
  • HLA-DRB1 sequencing showed that in European populations in patients with rheumatoid arthritis, alleles *04:01 and *04:04 predominate in frequency, in East Asia - *04:05. Alleles *04:02 and 04:03 are protective.
  • amino acid substitutions at positions 11 and 13 of DR4 are also associated with rheumatoid arthritis (alleles *04:01/*04:04/*04:05 vs. DR1 *01:01) [Okada, Y.; Kim, K.; Han, W.; Pillai, N.E.; Ong, RT-H.; Saw, W.-Y.; Luo, M.; Jiang, L.; Yin, J.; Bang, S.-Y.; et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum. Mol. Genet. 2014, 23, 6916-6926].
  • Each of the 100 non-HLA genomic loci shown to be associated with rheumatoid arthritis in genomic association studies contains, on average, four potential candidate genes (377 genes in total). Of these, only 19 candidate genes as markers of predisposition demonstrate alleles associated with amino acid substitutions that can affect the functional activity of the protein they encode.
  • PTPN22 and CTLA4 were identified as the main candidate genes in Caucasians, PADI4 in Asians, and the odds ratio in statistical analysis of 1.4 or more was shown for the ILF3, TYK2, IL20RB, TNFAIP3 and some other genes [Korczowska I. Rheumatoid arthritis susceptibility genes : An overview (2014) World J Orthop; 5(4): 544-549].
  • the first line of therapy for rheumatoid arthritis in most cases includes methotrexate.
  • it may be advisable to use pharmacogenetic tests to select an individual dosage and reduce the likelihood of toxic effects [Smolen, JS; Landewe, R.B.M.; Bijlsma, JWJ; Burmester, G. R.; Dougados, M.; Kerschbaumer, A.; McInnes, I. B.; Sepriano, A.; van Vollenhoven, RF; de Wit, M.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis.
  • DMARD drugs can be prescribed as second and third lines of therapy: inhibitors of tumor necrosis factor, interleukin 6, CD-20 B-lymphocytes, as well as costimulatory factors.
  • the feasibility of using DMARDs alone or in combination is determined based on the severity of symptoms of the disease after 3 and 6 months from the start of use according to clinical rating scales [Singh, JA; Saag, KG; Bridges, S.L.; Akl, E.A.; Bannuru, R.
  • sensitivity to tocilizumab may differ, for example, due to the replacement of asparagine by alanine in codon 358 of the IL6R gene, which shifts the balance and increases the relative concentration of the soluble form of the receptor by 35% [Maldonado-Montoro, M.; Canadas-Garre, M.; Gonzalez-Utrilla, A.; Angel Calleja-Hemandez, M. Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis. Pharmacogenomics J. 2018, 18, 167-172.].
  • loci polymorphisms
  • Olokizumab is a monoclonal antibody that blocks the assembly of the IL6/IL6R ligand-receptor complex [Serio I, Tovoli F. Rheumatoid arthritis: new monoclonal antibodies. Drugs Today (Bare). 2018 Mar;54(3):219-230.].
  • SNPs polymorphisms
  • 41 SNPs were characterized as a marker system associated with erosive joint damage.
  • Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium. sci rep. 2019 Oct 15;9(1): 14812. doi: 10.1038/s41598-019-51255-0.].
  • the disadvantage of this method is the presence in the system of only hormone genes and their receptors without taking into account other candidate genes, limited predictive value (low odds ratio) and applicability only to patients with seropositive rheumatoid arthritis.
  • Genotyping is carried out using the PCR method and subsequent extension of internal primers with the detection of reaction products on a capillary sequencer in fragment analysis mode
  • the disadvantage of this method is a limited set of polymorphisms, the absence of association markers for other types of DMARD drugs successfully used to treat rheumatoid arthritis, in particular, olokizumab.
  • genotyping of alleles of the DRB1 locus is carried out by the method of multiprimer allele-specific real-time PCR (RU No. FSR 2008/03891 of 09/27/2017).
  • a study using this set of reagents consists of the stages of DNA extraction (sample preparation) and real-time PCR amplification. DNA probes are introduced into the reaction mixture for amplification, each of which carries a fluorescent label and a fluorescence quencher.
  • the kit of reagents includes reaction mixtures for typing 13 groups of DRB1 alleles: *01, *03, *04, *07, *08, *09, *10, *11, *12, *13, *14, *15, *16.
  • the amount of DNA analyzed should be at least 1 ng, the time of amplification takes from 2.5 hours. As a result, it is possible to identify alleles, in particular *04, associated with rheumatoid arthritis and other autoimmune diseases.
  • the disadvantage of this method is the analysis of only the DRB1 locus, which does not allow to determine unfavorable alleles that are not related to HLA, but nevertheless associated with the development, clinical course and response to therapy of rheumatoid arthritis.
  • Closest to the proposed invention is a method for predicting the effectiveness of treatment of rheumatoid arthritis with monoclonal antibodies to TNF-alpha based on the allelic polymorphism of the TNF gene promoter (patent RU 2 485 511 C2). The method is based on the genotyping of the polymorphism at position -857 of the TNFA gene. If the T allele in a homo- or heterozygous state is detected in a patient, a high probability of the effectiveness of therapy with infliximab is predicted, in contrast to patients with the C/C genotype.
  • the disadvantage of the prototype is the absence in the test system of other significant polymorphisms and candidate genes for rheumatoid arthritis, in addition, the method is not intended to predict the effectiveness of other targeted drugs, in particular olokizumab.
  • the technical problem to be solved by the invention is to determine the predictors of the development of an effective clinical response to treatment with olokizumab in patients with rheumatoid arthritis, which would allow individualization of therapy.
  • the technical result of the proposed invention is the possibility of predicting the effectiveness of the drug olokizumab in the treatment of rheumatoid arthritis based on the results of molecular genetic analysis.
  • the specified technical result is achieved by implementing a method according to which genotyping of 27 polymorphisms in 18 genes is carried out: rsl 143623, rsl 143634 and rsl6944 ILlBp, rs3784864 (AVSSG), rsl0987742 (FPGS), rs2228145 ⁇ IL6R , rs767455 and rsl28000).
  • rsl7602729 AMPD1 rs874881, rs2240336, rsl748032, rs2240335, rsl 1203367 and rs2301888
  • PADI4 rs5744174 (TLR5)
  • rs2032582 ABS1
  • rsl 974226 (1L17A
  • rs6920220 TNFAIP3
  • rs3213422 DHODH
  • rs419598 IL1RN
  • rs3218253 IL2RB
  • rs360722 and rs360718 IL18
  • rs7574865 STAT4
  • rs7 IL2RA distribute polymorphisms into three groups, the first of which includes polymorphisms rsl 143623 (IL1B), rsl6944 (IL1B), rs3784864 (ABCC1), rslO987742 (FPGS), rs2228145
  • rsl 143634 (IL1B), rsl7602729 (AMPD1), rs360718 (IL18), rsl974226 (IL17A), rs7574865 (STAT4), rs760426 (AIRE), rs2104286 (IL2RA), rs874881 (PADI4), rs2240335 (PADI4), rsl 1203367 (PADI4) associated with hepatotoxicity.
  • Genotypes are determined for each of the indicated polymorphisms of the studied genes and the occurrence of associated alleles in the homozygous and heterozygous states is assessed in accordance with the scoring scale, assigning scores in accordance with Table 1.
  • the sums of KI, K2 and KZ scores are calculated for each of the three groups of polymorphisms, accordingly, both with the obtained values of K1>6 or K2>7 and with the value of KZ ⁇ 5, a high efficiency of treatment with olokizumab is predicted.
  • the method can be used to evaluate the effectiveness of drug treatment in Caucasian individuals, in particular, Russian patients.
  • genomic DNA is isolated in an amount of at least 10 ng / ⁇ l using one of the sets that have a registration certificate, for example, DNA-sorb-B (Federal Scientific Research Institute of Epidemiology of Rospotrebnadzor ), Proba-Ficoll (DNA technology).
  • concentration of the received DNA preparation is measured on a fluorimeter, for example, Qubit 2.0/3.0 using a reagent kit designed for low concentrations of double-stranded DNA, for example, Qubit dsDNA HS Assay.
  • the chips are prepared and loaded at the Ion ChefTM Instrument automatic station, high-throughput sequencing of the obtained amplification library is carried out on the Ion S5TM System semiconductor sequencer (ThermoFisherScientific).
  • the feature of the proposed method lies in the fact that non-HLA genes (polymorphisms) are genotyped, which are grouped depending on a specific prognostic clinical criterion.
  • the first group includes the polymorphisms rsl 143623 and rsl6944 (ILIB), rs3784864 (ABCC), rsl0987742 (FPGS), rs2228145 (IL6R), rs767455 (TNFRSF1A), rsl7602729 (AMPD1), rs2240336 (PADI4), rs5744174 (TLR2AB2), ) and rsl 974226 (IL17A), which showed an association with an early response to olokizumab at week 12 of the drug.
  • IB polymorphisms rsl 143623 and rsl6944
  • ABCC rs3784864
  • FPGS rsl0987742
  • IL6R rs2228145
  • rs767455 TNFRSF1A
  • AMPD1A rsl7602729
  • AMPD1A rs2240336
  • the second group consists of polymorphisms associated with a late response to olokizumab at week 24 of treatment with this drug: rsl974226 (IL17A), rs5744174 (TLR5), rsl6944 and rsl 143634 (ILIB), rs3784864 (ABSH), rs6920220 (TNFAIP3), rs2032582 (ABCB1), rs3213422 (DHODH), rs419598 (IL1RN), rs3218253 (IL2RB), rs360722 (IL18), rsl 748032 and rs2301888 (PADI4), rsl 800692 (TNFRSF1A).
  • rsl974226 IL17A
  • TLR5 rs5744174
  • rsl6944 and rsl 143634 rs3784864
  • ABSH rs6920220
  • TNFAIP3
  • the third group of polymorphisms is designed to assess the risk of side effects (safety) of olokizumab and includes loci associated with hepatotoxicity: rsl 143634 (IL1B), rsl7602729 (AMPD1), rs360718 (IL18), rsl974226 (IL17A), rs7574865 (STAT4), rs760426 (AIRE ), rs2104286 (IL2RA), as well as rs874881, rs2240335 and rsl 1203367 (PADI4).
  • rsl 143634 IL1B
  • AMPD1 rsl7602729
  • IL18 rs360718
  • rsl974226 IL17A
  • STAT4 rs7574865
  • rs760426 AIRE
  • rs2104286 IL2RA
  • PADI4 rs874881, rs22403
  • the polymorphisms included in the groups for evaluating prognostic criteria were selected based on a preliminary study of 125 DNA samples obtained from olokizumab-treated patients with rheumatoid arthritis after progression on the background of methotrexate treatment (these subgroups partially overlap).
  • 1 point is assigned to the homozygous associated genotype, and 0 points for other genotypes. If the classifier is the occurrence of an allele, then in the presence of an associated allele, 1 point is assigned, in the absence - 0 points.
  • Table 1 shows the composition of the groups of tested polymorphisms associated with the clinical characteristics of genotypes and their conditional scores for calculating the prediction of the effectiveness of olokizumab.
  • genotyping allows the selection of patients with progression of rheumatoid arthritis after methotrexate treatment and a high probability of effective use of olokizumab relative to the average population level.
  • Diagnostic sensitivity was defined as the proportion of patients belonging to the group of presumably high efficacy of olokizumab based on the results of the proposed method and showing an improvement in the condition according to the DAS28 and/or ACR20/50 scales in the absence of signs of hepatotoxicity, to the total number of patients with a decrease in the intensity of rheumatoid arthritis according to the DAS28 and /or ACR20/50 in the absence of signs of hepatotoxicity by the 24th week of olokizumab use. Diagnostic sensitivity was 87%.
  • Diagnostic specificity was defined as the proportion of samples belonging to the group of presumably population-average efficacy of olokizumab and/or an increased risk of hepatotoxicity based on the results of the proposed method and which did not show improvement on the DAS28 scales (ACR20/50) and/or signs of hepatotoxicity, to the total number of patients with no a significant decrease in the intensity of rheumatoid arthritis according to the DAS28 (and / or ACR20 / 50) scales, as well as an increase in the level of liver enzymes and signs of hepatotoxicity by the 24th week of olokizumab use. Diagnostic specificity was 72%.
  • the present invention is illustrated by specific examples of implementation, demonstrating the possibility of achieving the desired technical result.
  • Example 1 Patient K., aged 54, diagnosed with seropositive rheumatoid arthritis M.05.08, progression during treatment with methotrexate.
  • genotypes were determined for each of the indicated polymorphisms of the studied genes and an assessment was made of the occurrence of associated alleles in the homozygous and heterozygous states in accordance with the scoring scale presented in Table 1.
  • Example 2 Patient N., aged 59, diagnosed with seropositive rheumatoid arthritis M.05.08, progression during treatment with methotrexate.
  • genotypes were determined for each of the indicated polymorphisms of the studied genes and an assessment was made of the occurrence of associated alleles in the homozygous and heterozygous states in accordance with the scoring scale presented in Table 1.
  • Example 3 Patient R., aged 35, diagnosed with seropositive rheumatoid arthritis M.05.08, progression during treatment with methotrexate.
  • Table 4 associated with early and late response to treatment with olokizumab, respectively, did not exceed the threshold value, and the sum of scores for the group of polymorphisms associated with hepatotoxicity was equal to the threshold value, and therefore the efficacy of olokizumab therapy was predicted, not exceeding the average population characteristics.
  • the use of the proposed method makes it possible to predict the clinical response to treatment with olokizumab.
  • This method can be used for personalized selection of therapy for patients with rheumatoid arthritis, in particular, in the Russian population.

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Abstract

L'invention se rapporte au domaine de la médecine, notamment à la génétique et à la rhumatologie, et peut être utilisée afin de pronostiquer l'efficacité de traitement d'une préparation d'olokizumab chez des patients souffrant d'arthrite rhumatoïde. Ce procédé comprend le génotypage de 27 polymorphismes dans 18 gènes, la répartition des polymorphismes en trois groupes, la définition des génotypes de chacun des polymorphismes et l'estimation d'occurrence des allèles associés dans des combinaisons homozygotes et hétérozygotes conformément à une échelle de points. En fonction de la comparaison de la somme des points de chacun des groupes de polymorphismes à des valeurs seuils, on tire une conclusion sur l'efficacité de la thérapie par olokizumab.
PCT/RU2020/000502 2020-09-28 2020-09-29 Procédé de pronostic de l'efficacité de traitement d'arthrite rhumatoïde avec une préparation d'olokizumab WO2022066032A1 (fr)

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