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WO2025076525A1 - Biomarqueur et thérapie de précision pour maladie inflammatoire - Google Patents

Biomarqueur et thérapie de précision pour maladie inflammatoire Download PDF

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WO2025076525A1
WO2025076525A1 PCT/US2024/050228 US2024050228W WO2025076525A1 WO 2025076525 A1 WO2025076525 A1 WO 2025076525A1 US 2024050228 W US2024050228 W US 2024050228W WO 2025076525 A1 WO2025076525 A1 WO 2025076525A1
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seq
assay
dna fragment
ntr
aluym1
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Toby A. FUCHS
Gene PETRELLA
Tyler ARTNER
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Neutrolis Inc
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Neutrolis Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/21—Endodeoxyribonucleases producing 5'-phosphomonoesters (3.1.21)
    • C12Y301/21001—Deoxyribonuclease I (3.1.21.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • NTR-016PC/119601-5016 BIOMARKER AND PRECISION THERAPY FOR INFLAMMATORY DISEASE PRIORITY This application claims the benefit of, and priority to, U.S. Provisional Application No. 63/542,824, filed October 6, 2023, the contents of which are hereby incorporated by reference in their entirety.
  • DESCRIPTION OF THE XML FILE SUBMITTED ELECTRONICALLY This application contains a sequence listing. The sequence listing has been submitted electronically via EFS-Web as an XML entitled “NTR-016PC_119601- 5016_Sequence_Listing.xml.” The sequence listing is 524,398 bytes in size, and was created on or about October 6, 2024.
  • FIG.1A shows a schematic representation of the chromatin substrate and nucleosomal units.
  • FIG.1B compares enzymatic activity of D1L3 on chromatin substrate in comparison with DNASE 1.
  • DNASE 1 digests chromatin to generate fragments of random sizes, indicating a lack of preferential location of digestion.
  • the DNA persists even after 1 hour, suggesting the DNASE 1 is inefficient in digesting chromatin.
  • D1L3 digests chromatin to generate a ladder of fragments of distinct sizes that are DB1/ 151380125.4 1 NTR-016PC/119601-5016 consistent with digestion in the linker regions of nucleosomes, leading to production of mononucleosomes and oligonucleosomes, followed by an efficient complete digestion, as indicated by near absence of any DNA after 15 minutes of digestion.
  • FIG. 2A to FIG. 2C demonstrate that D1L3 enzyme can generate circulating nucleosomes in blood.
  • FIG.2A shows a schematic representation of the experiment.
  • FIG. 5B demonstrate that a distinct cytokine profile before administration of NTR-441 predicted the extent of a repeated element amplicon of the hyper- nucleosome length marker (e.g., the AluYm1 amplicon Type B) that is detectable in EDTA- plasma samples derived from COVID-19 patients treated with NTR-441.
  • FIG. 5A is a scatterplot of rho values of Spearman correlation of pre-dose levels of 45 cytokines with the increase of the AluYm1 amplicon Type B in EDTA-plasma samples after infusion of NTR- 441 plotted as a function of probability value (p value).
  • the reverse primer has a nucleotide sequences selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125 and 127.
  • the qPCR is performed using TAQMAN.
  • a real-time polymerase chain reaction monitors the amplification of a targeted DNA molecule during the PCR, i.e. in real- time.
  • Real-time PCR can be used quantitatively, and semi-quantitatively.
  • Two common methods for the detection of PCR products in real-time PCR are: (1) non-specific fluorescent dyes that intercalate with any double-stranded DNA (e.g., SYBR Green (I or II)), and (2) sequence-specific DNA probes that are labelled with a fluorescent reporter which permits detection only after hybridization of the probe with its complementary sequence (e.g. TAQMAN).
  • the assay format is TAQMAN real-time PCR.
  • TAQMAN probes are hydrolysis probes that are designed to increase the specificity of quantitative PCR.
  • the TAQMAN probe principle relies on the 5′ to 3′ exonuclease activity of Taq polymerase to cleave a dual-labeled probe during hybridization to the complementary target sequence, with fluorophore-based detection.
  • the isothermal amplification is Recombinase Polymerase Amplification (RPA), Loop-Mediated Isothermal Amplification (LAMP), or Single Primer Isothermal Amplification (SPIA).
  • the isothermal amplification employs a forward primer having a nucleobase sequence selected from SEQ ID NOs: 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, and 66.
  • SLE Treatment of SLE often involves long-term immunosuppression, which carries the risk of drug toxicity and impacts quality of life. Mild SLE is typically managed with NSAIDS, antimalarials, and/or low-dose corticosteroids, while moderate SLE is managed with higher doses of corticosteroids and immunosuppressive medications. Severe SLE requires potent immunosuppressive agents, chemotherapy and in extreme cases, plasmapheresis or cellular therapy. Exemplary disease modifying immunosuppressive agents for treatment of SLE include azathioprine, mycophenolate mofetil, calcineurin inhibitors and cyclophosphamide, (for Lupus Nephritis (LN)).
  • Biologics for the treatment of SLE include belimumab and anifrolumab.
  • disease exacerbations flares
  • Treatments for SLE often involve the long-term administration of a combination of different drugs over many years.
  • disease exacerbations flares
  • D1L3 and engineered variants provide an opportunity to improve therapy for SLE (and other rheumatic and inflammatory diseases including gout and vasculitis), as a substitute or combination with existing therapies.
  • the DNase therapy is a D1L3 enzyme as described in WO 2024/107701, which is hereby incorporated by reference in its entirety.
  • the D1L3 enzyme comprises an amino acid sequence that has at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 97% sequence identity to amino acids 21 to 282 of SEQ ID NO: 833 (Isoform 1) or amino acids 21 to 252 of SEQ ID NO: 834 (Isoform 2).
  • the D1L3 variant comprises the incorporation of non-native cysteines, which can contribute to dimerization, including incorporation of non-native cysteines at the N- terminus.
  • the disclosure provides a D1L3 dimer, which can be used in therapy according to the disclosure.
  • the D1L3 variant comprises a substitution of cysteine at position 48 (C48) with respect to SEQ ID NO: 833, to further control dimerization positions.
  • the mutation can be selected from C48A, C48G, and C48S.
  • Exemplary D1L3 variants in accordance with this disclosure include SEQ ID NO: 837, SEQ ID NO: 838, SEQ ID NO: 839, SEQ ID NO: 840, SEQ ID NO: 841, SEQ ID NO: 842, or SEQ ID NO: 843.
  • the D1L3 variant comprises a fusion or conjugation to a half- life extending moiety.
  • the polymer is a polyethylene glycol (PEG).
  • the PEG is conjugated to the N-terminus.
  • the PEG polymer connects two D1L3 variant molecules through their N-termini.
  • the PEG is conjugated to the C-terminus.
  • the PEG polymer connects two D1L3 variant molecules through their C-termini.
  • the treatment for the inflammatory or autoimmune disease comprises (or further comprises) administering an immunosuppressive drug.
  • the treatment comprises one or more of corticosteroid, azathiopurine, mycophenolate mofetil, cyclophosphamide, voclosporin, belimumab and anifrolumab.
  • the level of the DNA fragment is determined with EDTA plasma or serum, wherein the elevated level is elevated as compared to a reference value.
  • the method further comprises comparing relative abundance of the DNA fragment in the EDTA plasma with a baseline EDTA plasma obtained before administration of the DNase therapy to confirm therapeutic activity of the DNase therapy.
  • a greater abundance of the DNA fragment in EDTA plasma compared to the baseline EDTA plasma by a factor of at least about 1.5, or at least about 2, or at least about 4, or at least about 6, or at least about 8, or at least about 10, is indicative of targeting of extracellular trap (ET) and/or neutrophil extracellular trap (NET) by the DNase therapy.
  • the sample is serum.
  • kits may include one or more of the following components: (i) at least one reaction chamber for performing a polymerase amplification reaction; and/or (ii) at least one nucleic acid lateral flow assay device; and/or (iii) at least one sample collection device.
  • Any reaction chambers known in the art as applicable for use with amplification reactions (such as, but not limited to, RPA and PCR) may be utilized in accordance with the present disclosure.
  • the reaction chambers may include one or more dried reagents for performing the amplification reactions.
  • the reaction chambers may comprise a dried reagent composition that includes a recombinase, a polymerase, and a single-stranded DNA binding protein.
  • a dried reagent composition that includes a recombinase, a polymerase, and a single-stranded DNA binding protein.
  • Non-limiting examples of reaction chambers that may be utilized in accordance with DB1/ 151380125.4 15 NTR-016PC/119601-5016 the present disclosure include those disclosed in U.S. 10,036,057 and 10,538,760, the contents of which are hereby expressly incorporated herein by reference in their entirety. Any nucleic acid lateral flow assay devices known in the art for detection of amplification products may be utilized in accordance with the present disclosure.
  • Example 3 Developing a Biomarker for Accumulation of Neutrophil Extracellular Traps (NETs) or Extracellular Chromatin
  • NETs Neutrophil Extracellular Traps
  • Extracellular Chromatin Experiments were performed to identify a nucleosome-based biomarker that is enriched in conditions that feature accumulation of NETs or extracellular chromatin.
  • the Dfam database was used to assemble a library of human genomic repeat elements (FIG. 3A).
  • Targeted elements included transposable elements, including Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs).
  • LINEs Long Interspersed Nuclear Elements
  • SINEs Short Interspersed Nuclear Elements
  • Illustrative target consensus sequences are SEQ ID NOs: 1-6.
  • a library of interchangeable forward and reverse primers was designed and combined in a matrix format, producing a screening library of potential diagnostic assays, which differed by targeting variable positions and/or variable amplicon length.
  • Illustrative primers are SEQ ID NOs: 7-127. As shown in Example 2, the necrotic cells or their chromatin and NETs remain in tissue. Therefore, they are not easily detected in plasma or serum.
  • FIG.3B shows two types of illustrative amplification products.
  • Type A is smaller than 150 base pairs and resistant to DNASE1L3 fragmentation, i.e., it is an end product of D1L3 activity.
  • Type B is larger than 150 base pairs and sensitive to D1L3 fragmentation, i.e., it is a substrate and/or intermediate degradation product.
  • Example 5 Cytokine Profile Before the Administration of NTR-441 Predicts Target Engagement of NTR-441 in COVID-19 Subjects A panel of 45 cytokine were measured in plasma samples of COVID-19 patients that were collected immediately before infusion of NTR-441. Pre-dose cytokine levels were correlated with the extent of target engagement and processing, defined as the increase of the AluYm1 amplicon 1 after infusion of NTR-441.
  • FIG.5A is a scatterplot of rho values of Spearman correlation of pre-dose levels of 45 cytokines with the increase of the AluYm1 amplicon 1 in EDTA-plasma samples after infusion of NTR-441 plotted as a function of probability value (p value).
  • Example 6 Cytokine Profile After the Administration of NTR-441 Predicted with Target Engagement of NTR-441 A panel of 45 cytokines was measured in plasma samples of COVID-19 patients that were collected immediately before, and a various time point after the infusion of NTR-441. Changes in the cytokine profile were analyzed in two groups of patients. The first group comprised the COVID-19 patients with the highest levels of the AluYm1 amplicon 1 after NTR-441 infusion. The second group included all 8 other COVID-19 patients, including the 3 patients that received placebo. As shown in FIG.
  • Example 7 Level of NETs Biomarker in Serum Predicts the Presence of Neutrophil Extracellular Traps (NETs) in Diseases Associated with NETs Serum is generated by allowing the blood to clot, optionally by exposing blood to an activated surface (e.g., silica). Clotting causes the activation of clotting factors, platelets, and neutrophils, leading to generation of NETs. Thus, unlike plasma, serum is enriched with undigested DNA-fragments from NETs that are generated during blood clotting. Serum samples from patients suffering from diseases associated with NETs were studied for the amount of the AluYm1 amplicon Type B.
  • Example 9 Further Development of Assay for the NETs Biomarker
  • the disease specificity for the AluYm1 amplicon is determined, as well as its stability during active disease, and the threshold for the AluYm1 amplicon for a positive precision biomarker test in patients with active SLE.
  • healthy (non-SLE subjects can be used instead of inactive patients).
  • ANOVA or a linear mixed-effects model tailored for assessing data with multiple measurements will be taken from the same subjects across different time points.
  • the statistical analysis will enable determination of significant differences in the biomarker’s means over time, offering insights into its trends and overall stability.
  • These studies can provide a binary classifier (positive/negative) and enable enrollment criteria of SLE patients during an interventional trial with DNASE1L3 therapy, and can provide a pharmacodynamic endpoint. Characterization of the AluYm1 amplicon stability will determine a clinical development strategy for a precision therapy for SLE.
  • AluYm1 amplicon mobile qPCR assay shows good linearity over a wide concentration range with assay efficiencies in the range of 80-90%.
  • silico analysis of the AluYm1 amplicon predicts GC content, melting temperature, and primer-dimer propensity that is favorable for qPCR.
  • the specificity of the AluYm1 amplicon-mediated amplification was assessed via agarose gel electrophoresis observing a single band of the expected size, about 200 bp. Additional parameters affecting assay efficiency will be optimized, such as primer concentrations, different commercial sources of components for the qPCR reaction, reaction conditions (annealing temperature, extension time, cycling parameters), DNA extraction methods, purification steps, and storage conditions.
  • capture of the biomarker can follow isothermal amplification.
  • the direct capture of nucleic acids of interest from blood followed by lateral flow elucidation has been demonstrated for microRNAs.
  • direct capture can be accomplished using specialized peptide nucleic acids (PNA) which have an uncharged backbone of N-(2- aminoethyl)-glycine units linked by peptide bonds. This chemical property of PNAs promotes strand invasion of double-stranded nucleic acids via complementary sequence base pairing with a binding affinity far greater than standard DNA or RNA duplexes.
  • PNA peptide nucleic acids
  • the LFT can employ ultra-bright gold nanoshell reporters (nanoComposix) to increase sensitivity and visualize the biomarker at the test line without instrumentation (FIG. 9B).
  • Sequences from the AluYm1 amplicon will be used to design two PNA probes: (1) A 6-carboxyfluorescein (6FAM)-labelled PNA capture probe (using the AluYm1 amplicon forward primer sequence) to functionalize anti-FAM-coated gold nanoshells and bind to target sequence and (2) a biotin-labelled PNA sensing probe (using the AluYm1 amplicon reverse primer sequence) to concentrate the gold nanoshell complex on the test line.
  • 6FAM 6-carboxyfluorescein
  • Synthetic double stranded DNA having the full consensus sequence used for the AluYm1 amplicon primer design has been produced to use as a standard to test this PNA-based LFT. Initial experiments will be conducted with this standard in physiological buffers with and without macromolecular crowding agents known to enhance lateral flow assays. Purified DB1/ 151380125.4 28 NTR-016PC/119601-5016 genomic DNA will be used as a standard and determine the limit of visual detection (LOD) of the biomarker. If the sensitivity of the PNA-based direct approach is not sufficient or ideal to visualize the AluYm1 amplicon in human samples, an amplification step for the AluYm1 amplicon can be incorporated. Amplification can employ conventional PCR or isothermal amplification.

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Abstract

La présente invention procure un biomarqueur pour l'accumulation de pièges extracellulaires de neutrophiles (NET) ou de chromatine extracellulaire. La présente invention procure également des procédés de traitement des maladies inflammatoires, y compris des procédés pour déterminer la réponse au traitement, des procédés de sélection des patients pour le traitement et la détermination de la dose thérapeutique.
PCT/US2024/050228 2023-10-06 2024-10-07 Biomarqueur et thérapie de précision pour maladie inflammatoire Pending WO2025076525A1 (fr)

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US63/542,824 2023-10-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160115547A1 (en) * 2005-05-27 2016-04-28 John Wayne Cancer Institute Use of free circulating dna for diagnosis, prognosis, and treatment of cancer
US20210277372A1 (en) * 2017-08-18 2021-09-09 Neutrolis, Inc. Engineered dnase enzymes and use in therapy
US20220162575A1 (en) * 2018-10-08 2022-05-26 Neutrolis, Inc. Engineering of dnase enzymes for manufacturing and therapy
US20220333182A1 (en) * 2016-08-17 2022-10-20 The Regents Of The University Of California REAGENTS FOR DETECTING ALU ELEMENTS IN CELL-FREE DNA (cfDNA)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160115547A1 (en) * 2005-05-27 2016-04-28 John Wayne Cancer Institute Use of free circulating dna for diagnosis, prognosis, and treatment of cancer
US20220333182A1 (en) * 2016-08-17 2022-10-20 The Regents Of The University Of California REAGENTS FOR DETECTING ALU ELEMENTS IN CELL-FREE DNA (cfDNA)
US20210277372A1 (en) * 2017-08-18 2021-09-09 Neutrolis, Inc. Engineered dnase enzymes and use in therapy
US20220162575A1 (en) * 2018-10-08 2022-05-26 Neutrolis, Inc. Engineering of dnase enzymes for manufacturing and therapy

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