WO2024047811A1 - Composition pharmaceutique pour le traitement du lymphome - Google Patents

Composition pharmaceutique pour le traitement du lymphome Download PDF

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Publication number
WO2024047811A1
WO2024047811A1 PCT/JP2022/032837 JP2022032837W WO2024047811A1 WO 2024047811 A1 WO2024047811 A1 WO 2024047811A1 JP 2022032837 W JP2022032837 W JP 2022032837W WO 2024047811 A1 WO2024047811 A1 WO 2024047811A1
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Prior art keywords
lymphoma
bcv
ebv
positive
myc
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PCT/JP2022/032837
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English (en)
Japanese (ja)
Inventor
ジェイソン チャン
チュン キット オン
正聡 波佐間
耕治 福島
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シンバイオ製薬株式会社
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Priority to PCT/JP2022/032837 priority Critical patent/WO2024047811A1/fr
Priority to KR1020230114664A priority patent/KR20240031153A/ko
Priority to PCT/JP2023/031556 priority patent/WO2024048657A1/fr
Publication of WO2024047811A1 publication Critical patent/WO2024047811A1/fr

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    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the technical field of the present invention relates to the treatment of lymphoma.
  • Lymphoma is a type of blood cancer and is known to be a disease that occurs when lymphocytes become cancerous.
  • Non-Patent Document 1 describes that non-Hodgkin's lymphoma is the most common hematological malignant tumor in the world, accounting for approximately 3% of cancer diagnoses and deaths.
  • Non-Patent Document 2 states that the incidence of Hodgkin's lymphoma has been on the rise for the past 10 years, particularly among women, young people, and people from Asian countries.
  • Non-Patent Document 3 describes the possibility of treatment targeting CD19.
  • Non-Patent Document 4 describes the possibility of treatment targeting EZH2.
  • BCV brincidofovir
  • a pharmaceutical composition for treating lymphoma comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • This pharmaceutical composition can be used to treat lymphoma.
  • Figure 1 shows the results of investigating the effect of BCV treatment on the proliferation of lymphoma cells.
  • Figure 2 shows the results of examining the effects of BCV or various antiviral drug treatments on the proliferation of EBV-positive NK/T lymphoma cells.
  • Figure 3 shows the results of administering BCV to NSG mice transplanted with lymphoma cells.
  • Figure 4A shows the results of examining the effect of BCV treatment on Myc gene expression in lymphoma cells.
  • FIG. 4B shows the results of examining the effect of BCV treatment on the expression of genes controlled by Myc in lymphoma cells.
  • Figure 5 shows the results of examining the effect of BCV treatment on immunogenic cell death.
  • FIG. 1 shows the results of investigating the effect of BCV treatment on the proliferation of lymphoma cells.
  • Figure 2 shows the results of examining the effects of BCV or various antiviral drug treatments on the proliferation of EBV-positive NK/T lymphoma cells.
  • Figure 3 shows the results of administering BCV to N
  • FIG. 6 shows the results of examining the influence of BCV and various anticancer drug treatments, or BCV treatment and gamma irradiation, on the proliferation of lymphoma cells.
  • FIG. 7 shows the results of examining the effect of BCV treatment on the growth of MYC-amplified lymphoma (EBV positive or negative).
  • a method for treating lymphoma which includes the step of administering BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject.
  • lymphoma can be treated with a novel therapeutic approach.
  • the above lymphoma may be a MYC-positive lymphoma.
  • MYC-positive lymphoma particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • MYC-positive lymphoma a high growth-inhibiting effect can be obtained not only against EBV-positive lymphoma but also against EBV-negative lymphoma.
  • the subject may be, for example, a MYC-positive subject.
  • MYC-positive subject particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • a high growth-inhibiting effect can be obtained not only in subjects suffering from EBV-positive lymphoma but also in subjects suffering from EBV-negative lymphoma.
  • the above treatment method may include, for example, a step of identifying a MYC-positive subject.
  • a step of identifying a MYC-positive subject particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • a high growth-inhibiting effect can be obtained not only in subjects suffering from EBV-positive lymphoma but also in subjects suffering from EBV-negative lymphoma.
  • the above lymphoma may be an EBV-positive lymphoma.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • this EBV-positive lymphoma a higher growth-inhibiting effect can be obtained than in EBV-negative lymphoma.
  • the subject may be, for example, an EBV-positive subject.
  • EBV-positive subject particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • a higher antiproliferative effect is obtained in EBV-positive subjects than in subjects suffering from EBV-negative lymphoma.
  • the above treatment method may include, for example, a step of identifying an EBV-positive subject.
  • a step of identifying an EBV-positive subject particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • a higher antiproliferative effect is obtained in EBV-positive subjects than in subjects suffering from EBV-negative lymphoma.
  • the above treatment method may include, for example, the step of identifying MYC-positive and EBV-positive subjects.
  • particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • the lymphomas mentioned above may be MYC-positive and EBV-positive lymphomas.
  • particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • the above lymphoma may be, for example, EBV-positive NK/T lymphoma, MYC-positive EBV-positive NK/T lymphoma, MYC-positive DLBCL, MYC-positive double-hit DLBCL, or MYC-positive triple-hit DLBCL.
  • EBV-positive NK/T lymphoma EBV-positive NK/T lymphoma
  • MYC-positive EBV-positive NK/T lymphoma MYC-positive DLBCL
  • MYC-positive double-hit DLBCL MYC-positive double-hit DLBCL
  • MYC-positive triple-hit DLBCL MYC-positive triple-hit
  • the above treatment method may include the step of administering a chemotherapeutic agent to the subject.
  • a chemotherapeutic agent to the subject.
  • particularly excellent therapeutic effects can be obtained by the combination.
  • this combination treatment results in synergistic effects of BCV and chemotherapeutic agents.
  • the synergistic effect includes, for example, an effect that exceeds the effect obtained by adding the lymphoma growth inhibitory effect obtained by BCV monotherapy and the lymphoma growth inhibitory effect obtained by chemotherapeutic agent monotherapy.
  • Particularly good therapeutic effects can be obtained by using antimetabolites or topoisomerase inhibitors in combination with BCV.
  • particularly excellent therapeutic effects can be obtained by using immune checkpoint inhibitors in combination with BCV.
  • Chemotherapeutic agents may be administered to a subject before, simultaneously with, or after administration of BCV. Simultaneously with administration includes the same period, and may be substantially simultaneous with consideration of normal treatment procedures. Simultaneous administration includes the case where BCV and chemotherapeutic agent are administered as a combination drug.
  • the subject is a human or a non-human mammal (e.g., mouse, guinea pig, hamster, rat, mouse, rabbit, pig, sheep, goat, cow, horse, cat, dog, marmoset). , monkeys, or chimpanzees).
  • the patient may also be a patient who has been diagnosed with lymphoma or a patient who is in need of treatment for lymphoma.
  • the above treatment method includes, for example, (i) identifying a MYC-positive or EBV-positive subject as a lymphoma treatment target; (ii) identifying a MYC-positive or EBV-positive lymphoma subject as a lymphoma treatment target; (iii) detecting MYC or EBV in the subject; (iv) detecting the presence or absence of MYC positivity or EBV positivity in the subject; (v) detecting the presence or absence of MYC or EBV positivity in the subject; (v) detecting the presence or absence of MYC or EBV positivity in the subject; (e.g., plasma, serum, or whole blood); (vi) detecting MYC or EBV in the collected specimen; or (vii) treating the subject who provided the specimen in which MYC or EBV was detected.
  • Detection may be performed using gene amount, mRNA amount, protein amount, or gene translocation as an indicator. Detection may be an inspection.
  • the above treatment method includes, for example, identifying a subject with lymphoma as a lymphoma treatment target, identifying a lymphoma marker-positive subject as a lymphoma treatment target, and administering a therapeutically effective amount of BCV or chemotherapeutic agent to the target.
  • the method may include the steps of administering, suppressing the proliferation of lymphoma cells in a subject, reducing lymphoma markers in a subject, or suppressing swelling of lymph nodes in a subject.
  • the above treatment methods or subjects may optionally not include, for example: cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), or variola virus (VaV) infection.
  • CMV cytomegalovirus
  • AdV adenovirus
  • BKV BK virus
  • VaV variola virus
  • identifying subjects with CMV, AdV, BKV, or VaV seropositive subjects identifying subjects in need of CMV, AdV, BKV, or VaV infection prevention or treatment; allogeneic transplantation or allogeneic transplantation; (e.g., hematopoietic cell transplantation), identifying subjects in need of immunosuppressants, identifying immunosuppressed subjects, treatment of virus-induced tumors in immunosuppressed subjects. or methods aimed at preventing or treating viral (e.g., CMV, AdV, BKV, or VaV) infection.
  • viral e.g., CMV, AdV, BKV, or VaV
  • composition for treating lymphoma, comprising BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • lymphoma can be treated with a novel therapeutic approach.
  • the above lymphoma may be a MYC-positive lymphoma.
  • MYC-positive lymphoma particularly excellent therapeutic effects are obtained with BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • MYC-positive lymphoma a high growth-inhibiting effect can be obtained not only against EBV-positive lymphoma but also against EBV-negative lymphoma.
  • the above lymphoma may be an EBV-positive lymphoma.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • a higher growth-inhibiting effect can be obtained for EBV-positive lymphoma than for EBV-negative lymphoma.
  • the above lymphoma may be a MYC-positive or EBV-positive lymphoma.
  • BCV its pharmaceutically acceptable salts, or solvates thereof.
  • the above lymphoma may be, for example, EBV-positive NK/T lymphoma, MYC-positive EBV-positive NK/T lymphoma, MYC-positive DLBCL, MYC-positive double-hit DLBCL, or MYC-positive triple-hit DLBCL.
  • EBV-positive NK/T lymphoma EBV-positive NK/T lymphoma
  • MYC-positive EBV-positive NK/T lymphoma MYC-positive DLBCL
  • MYC-positive double-hit DLBCL MYC-positive double-hit DLBCL
  • MYC-positive triple-hit DLBCL MYC-positive triple-hit
  • the above pharmaceutical composition may be used in combination treatment of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a chemotherapeutic agent.
  • a chemotherapeutic agent particularly excellent therapeutic effects can be obtained by the combination.
  • this combination treatment results in synergistic effects of BCV and chemotherapeutic agents.
  • the synergistic effect includes, for example, an effect that exceeds the effect obtained by adding the lymphoma growth inhibitory effect obtained by BCV monotherapy and the lymphoma growth inhibitory effect obtained by chemotherapeutic agent monotherapy.
  • the above pharmaceutical composition includes a pharmaceutical composition containing BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the treatment of lymphoma.
  • a pharmaceutical composition containing BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the treatment of lymphoma.
  • BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a pharmaceutical composition for the treatment of lymphoma.
  • BCV a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in combination treatment with a chemotherapeutic agent.
  • a pharmaceutical composition is provided for the treatment of lymphoma, comprising a salt thereof, or a solvate thereof, or a chemotherapeutic agent. According to this pharmaceutical composition, as described above, particularly excellent therapeutic effects can be obtained when used in combination.
  • the above pharmaceutical composition includes a pharmaceutical composition for use in the treatment method of (1) above.
  • This treatment method includes at least one of the steps (1) above (eg, including steps (i) to (vii)).
  • a companion diagnostic method which includes the step of detecting the presence or absence of MYC positivity in a subject.
  • the method includes a diagnostic method for evaluating the effectiveness of treatment with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof prior to administration.
  • treatment can be administered to a population with high therapeutic effects.
  • subjects include patients suffering from lymphoma.
  • a companion diagnostic method includes the step of detecting the presence or absence of EBV positivity in a subject.
  • the method includes a diagnostic method for evaluating the effectiveness of treatment with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof prior to administration.
  • treatment can be administered to a population with high therapeutic effects.
  • subjects include patients suffering from lymphoma.
  • a companion diagnostic method which includes the step of detecting the presence or absence of MYC positivity and EBV positivity in a subject.
  • the method includes a diagnostic method for evaluating the effectiveness of treatment with BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof prior to administration.
  • treatment can be administered to a population with high therapeutic effects.
  • subjects include patients suffering from lymphoma.
  • for a companion diagnostic method to any of the above comprising means for measuring the gene dosage, mRNA content, protein content, or gene translocation of MYC or EBV.
  • a kit or composition is provided.
  • a method is provided. According to this method, treatment can be administered to a population with high therapeutic effects.
  • subjects include patients suffering from lymphoma.
  • BCV brincidofovir
  • BCV includes a compound having a structure represented by the following formula.
  • BCV can also be designated by the IUPAC name [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid.
  • BCV is an abbreviation for brincidofovir, and they have the same meaning.
  • the term BCV may include salts of BCV or solvate forms thereof.
  • lymphoma includes malignant lymphoma.
  • Malignant lymphoma includes, for example, diseases caused by canceration of lymphocytes.
  • Malignant lymphoma includes, for example, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
  • Non-Hodgkin lymphoma includes, for example, B cell lymphoma, T/NK cell lymphoma, or Hodgkin lymphoma.
  • B-cell lymphomas include, for example, follicular lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, or chronic lymphocytic leukemia/small lymphocytic Including lymphoma.
  • T/NK cell lymphomas include peripheral T cell lymphoma, angioimmunoblastic T cell lymphoma, anaplastic large cell lymphoma, adult T cell leukemia lymphoma, extranodal NK/T cell lymphoma/nasal type, and cutaneous lymphoma (eg, mycosis fungoides).
  • Hodgkin's lymphoma includes, for example, classic Hodgkin's lymphoma or nodular lymphocyte-predominant Hodgkin's lymphoma.
  • Classic Hodgkin's lymphoma or nodular lymphocyte-predominant Hodgkin's lymphoma.
  • Nodular lymphocyte-predominant Hodgkin's lymphoma For more information on lymphoma, see, for example, Nirmal, J Oral Maxillofac Pathol. 2020 May-Aug;24(2):195-199, Singh et al., J Family Med Prim Care. 2020 Apr; 9(4): 1834- 1840, or Voltin et al., Cancers (Basel). 2020 Mar 5;12(3):601.
  • the therapeutic effect or onset of lymphoma is diagnosed by examining lymph node swelling using CT, PET, or MRI, histological examination of lymph nodes or masses, or testing for malignant lymphoma tumor markers (e.g., sIL2-R) in the blood. You may. Diagnosis of lymphoma may be performed, for example, by the method described in Nirmal (supra) or Voltin et al (supra). The therapeutic effect on lymphoma may be evaluated, for example, by observing changes in lymphoma cell proliferation over time after drug administration. A state in which cell proliferation is suppressed includes a state in which the proliferation rate of test cells is significantly reduced compared to before drug treatment.
  • the proliferation rate may be measured, for example, using absorbance as an index, or may be determined from image data.
  • the therapeutic effect on lymphoma may be evaluated, for example, by observing a decrease in tumor volume after administration of the drug. At this time, it may be determined that there is a therapeutic effect if the amount of tumor mass is significantly reduced compared to before drug administration or when a negative control was administered.
  • the therapeutic effect on lymphoma may be measured, for example, using the amount of lymphoma marker in the patient or patient-derived sample as an index. At this time, it may be determined that there is a therapeutic effect when the marker amount is significantly reduced compared to before drug administration or when a negative control was administered.
  • the mass amount or marker amount after administration of the drug may be reduced to 0.9, 0.7, 0.5, 0.3, or 0.1 times or less compared to before administration or when administering a negative control.
  • the lymphoma includes MYC-positive, MYC-negative, EBV-positive, or EBV-negative lymphoma.
  • MYC-positive or EBV-positive lymphoma high therapeutic effects can be obtained using BCV, its pharmaceutically acceptable salts, or solvates thereof.
  • MYC-positive lymphomas, BCV, its pharmaceutically acceptable salts, or their solvates have high therapeutic effects on lymphomas that are EBV-positive, negative, or both. is obtained.
  • positive includes positive gene expression. Positive may include increased gene expression compared to a healthy person or a person previously confirmed to be negative.
  • detection of MYC or EBV positive/negative in the subject or the subject's lymphoma can be carried out by, for example, collecting the subject's lymphoma cells, plasma, or whole blood, and detecting MYC or EBV in the sample. This can be done by measuring gene expression. Gene expression can be measured, for example, by RT-PCR, DNA chip, or immunostaining. At this time, the sample collected from the subject is compared with the sample collected from a healthy person or a person previously confirmed to be negative, and the gene expression of MYC or EBV is significantly increased in the sample collected from the subject.
  • MYC or EBV positive detection of MYC or EBV positive/negative status of the subject or the subject's lymphoma can be carried out, for example, by collecting the subject's lymph nodes and immunostaining them for MYC or EBV. At this time, the specimen collected from the subject is compared with the specimen collected from a healthy person or a person previously confirmed to be negative, and the staining intensity of MYC or EBV is significantly increased in the specimen collected from the subject. MYC or EBV positive.
  • the above gene expression or staining intensity is increased by, for example, 1.5, 2, 3, 4, 5, 10, 20, or 50 times, or within a range of any two of these values, relative to the comparison target. Including being present.
  • detection of MYC positivity/negativeness in the subject or target lymphoma can be performed, for example, by detecting MYC translocation by fluorescence in situ hybridization (FISH) (for example, Salam et al., J Cancer 2020 ; 11(1):190-198 or Epperla et al., Cancer. 2017 Nov 15;123(22):4411-4418).
  • FISH fluorescence in situ hybridization
  • EBV positivity/negative of the subject or the subject's lymphoma for example, quantify EBV DNA in plasma or whole blood using a commercially available DNA quantification kit (e.g., Accugene m-EBV (Abbott Japan LLC)).
  • IgM antibodies against EBV capsid antigens in serum can be detected using a commercially available antibody detection kit (for example, BioPlex EBV IgM kit (Bio-Rad Laboratories, Inc.)).
  • the lymphoma includes, for example, double hit or triple hit lymphoma.
  • Double-hit lymphomas include, for example, lymphomas with MYC and BCL2 gene rearrangements.
  • Triple hit lymphomas include, for example, lymphomas with MYC, BCL2, and BCL6 gene rearrangements.
  • Detection of double-hit or triple-hit lymphoma can be performed, for example, by detecting translocations by FISH (see, eg, Salam et al (supra) or Epperla et al (supra)).
  • Lymphoma includes, for example, high grade lymphoma.
  • MYC contains a protein known as a transcription control factor.
  • MYC, Myc, and c-Myc have the same meaning herein.
  • the primary accession number of MYC listed in UniProt is, for example, P01106.
  • EBV stands for Epstein-Barr virus. EBV is known as a virus with double-stranded DNA (for example, Rivailler et al., J Virol. 2002 Dec; 76(23): 12055-12068 or Correia et al., J Virol. 2018 Nov 15; 92 (22): see e01132-18).
  • the chemotherapeutic agent is not particularly limited and includes, for example, an anticancer agent.
  • Anticancer agents include, for example, microtubule inhibitors, DNA synthesis inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, cytotoxic substances, immune checkpoint inhibitors, or other anticancer agents.
  • Microtubule inhibitors include, for example, vinca alkaloids or taxanes. Vinca alkaloids include, for example, vincristine, vinblastine, vindesine, vinorelbine, or eribulin.
  • Taxane drugs include, for example, paclitaxel or docetaxel.
  • DNA synthesis inhibitors include, for example, antimetabolites, topoisomerase inhibitors, platinum drugs, antitumor antibiotics, or alkylating agents.
  • Antimetabolites include, for example, pemetrexed, 5-fluorouracil, S-1, gemcitabine, or capecitabine.
  • Topoisomerase inhibitors include, for example, irinotecan, topotecan, etoposide, or zobuzoxacin.
  • Platinum preparations include, for example, cisplatin, oxaliplatin, nedaplatin, or carboplatin.
  • Antitumor antibiotics include, for example, anthracyclines (e.g., doxorubicin, liposomal doxorubicin, daunorubicin, epirubicin, idarubicin, aclarubicin, amrubicin, mitoxatron, or pirarubicin), mitomycin C, actinomycin D, bleomycin, bepromycin, or dinostatin stimer.
  • Alkylating agents include, for example, bendamustine, cyclophosphamide, dacarbacine, or ifosfamide.
  • Growth factor inhibitors include, for example, inhibitors of EGF, VEGF, FGF, or IGF.
  • Growth factor inhibitors include, for example, bevacizumab, cetuximab, panitumumab.
  • Tyrosine kinase inhibitors include, for example, gefitinib or erlotinib.
  • Cytotoxic agents include, for example, saporin, emtansine, deruxtecan, or vedotin.
  • Immune checkpoint inhibitors include, for example, drugs that release suppression of T cell activation by immune checkpoint molecules by binding to immune checkpoint molecules or their ligands and inhibiting transmission of immunosuppressive signals.
  • Immune checkpoint inhibitors include, for example, anti-CTLA-4 antibodies (eg, ipilimumab), anti-PD-1 antibodies (eg, nivolumab or pembrolizumab), or anti-PD-L1 antibodies (eg, atezolizumab or avelumab).
  • Other anticancer agents include, for example, L-asparaginase.
  • Forms of chemotherapeutic agents include, for example, low molecular weight compounds or high molecular weight compounds.
  • Chemotherapeutic agents include salts of any one or more of the compounds listed herein, including the salts listed below.
  • the salt is not particularly limited, and includes, for example, an inorganic salt or an organic salt (for example, "Bharat et al., Drug Discov Today. 2021 Feb;26(2):384-398 .” or “Berge et al., J Pharm Sci. 1977 Jan;66(1):1-19.”).
  • Salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • metal salts examples include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, barium salts, etc.), aluminum salts, and the like.
  • Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. including.
  • Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, mesylic acid, tosylic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, Contains salts with benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • Salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and the like.
  • Salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Salts include pharmaceutically acceptable salts.
  • solvates include forms of compounds formed by solute and solvent (see, for example, Healy et a., Adv Drug Deliv Rev. 2017 Aug 1;117:25-46. ). Solvates are not particularly limited, and include, but are not limited to, hydrates (e.g., monohydrates, dihydrates, trihydrates, etc.) or organic solvates (e.g., alcohols (methanol, ethanol, propanol, etc.).
  • the solvent includes a solvent capable of substantially maintaining the physiological activity of the solute after forming the solvate.
  • Solvates include pharmaceutically acceptable solvates.
  • the treatment includes exerting a symptom-improving effect, suppressing effect, recurrence-inhibiting effect, or preventive effect on the patient's disease or one or more symptoms associated with the disease.
  • Treatments also include, for example, treatments that suppress the proliferation of lymphoma cells in the patient, reduce lymphoma markers, suppress lymph node swelling, and suppress lymph node recurrence.
  • the pharmaceutical compositions in (1) to (4) above may be prepared by mixing the active ingredient and one or more pharmaceutically acceptable carriers, for example, and by any method known in the technical field of pharmaceutical sciences. good.
  • the form of use of the pharmaceutical composition is not limited as long as it is used for treatment, and the composition may contain the active ingredient alone or may be a mixture of the active ingredient and any other ingredient.
  • the shape of the carrier is not particularly limited, and may be, for example, solid or liquid (eg, buffer).
  • the content of the carrier may be, for example, a pharmaceutically effective amount.
  • An effective amount may be, for example, an amount sufficient for pharmaceutical stability or delivery of the active ingredient.
  • buffers are effective in stabilizing the active ingredient in the vial.
  • Pharmaceutical compositions may also include stabilizers (eg, mannitol), buffers (eg, arginine), or pH-adjusting agents (NaCl).
  • the dosage, administration interval, administration method, and administration route are not particularly limited, and can be appropriately selected depending on the patient's age, weight, symptoms, target organ, etc.
  • the pharmaceutical composition also preferably contains a therapeutically effective amount of the active ingredient, or an effective amount that exerts the desired effect.
  • a therapeutically effective amount includes the amount necessary for clinically observed improvement in symptoms in the patient.
  • pharmaceutically acceptable includes conditions suitable for use commensurate with a reasonable benefit/risk ratio within the scope of sound medical judgment.
  • Components other than BCV in the pharmaceutical composition are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected depending on the purpose.
  • the route of administration of BCV, its pharmaceutically acceptable salt, or solvate thereof, or its pharmaceutical composition to the subject is determined by using an effective route for treatment.
  • the dosage form it is preferable to use one that is effective for treatment, and may be, for example, a solid preparation (e.g., tablet), a liquid preparation (e.g., oral suspension), or an injection (e.g., intravenous injection). .
  • the dosage, administration interval, and administration method of BCV, its pharmaceutically acceptable salt, or solvate thereof, or its pharmaceutical composition to the subject should be determined based on the patient's age and It can be selected as appropriate depending on body weight, symptoms, target organs, etc.
  • the dosage may be, for example, 0.01 to 200 mg/kg body weight per dose.
  • the administration interval may be, for example, once or twice every 1 to 28 days or every 1 to 4 weeks. More specifically, it includes intravenous injections of 20 to 80 mg/day. It may also include 20-80 mg/day intravenously twice a week.
  • the dosage of BCV may include 10-40 mg or 10-20 mg/day intravenously. It may also include intravenous injections of 10-40 mg twice a week or 10-20 mg/day.
  • the range of 10 to 80 mg shown here may be, for example, 10, 20, 30, 40, 50, 60, 70, or 80 mg, or within any two of these ranges.
  • "significantly” means, for example, a statistically significant difference evaluated using Student's t-test (one-sided or two-tailed), and p ⁇ 0.05 or p ⁇ 0.01. Good too. Alternatively, the state may be such that a substantial difference has occurred.
  • Example 2 The experimental procedure was the same as in Example 1, and the drugs used were BCV, acyclovir, ganciclovir, adefovir, foscarnet, and penciclovir.
  • BCV showed a significantly superior cytostatic effect on EBV-positive NK/T lymphoma cells.
  • Example 4 Whole transcript sequencing of NK-S1 and KAI-3 cell lines treated with BCV was performed.
  • Gene set enrichment analysis (GSEA) was performed using the Molecular Signatures Database (MSigDB) Hallmark gene set. A gene set was considered to be significantly enriched if the False Discovery Rate (FDR) q value of the normalized enrichment score (NES) was less than 0.05.
  • Quantitative PCR was performed using Maxima SYBR Green/ROX qPCR Master Mix (Thermo Scientific, USA). The ⁇ Ct of gene mRNA expression was the difference from the internal control GAPDH Ct value, and ⁇ Ct was calculated by subtracting the ⁇ Ct value of the treated group from the ⁇ Ct value of the untreated control group. Expression ratios were calculated using the formula 2 - ⁇ Ct .
  • NK-S1 and KAI-3 cell lines were treated with BCV (0.1ug/ml or 1ug/ml) or DMSO alone for 72 hours.
  • BCV 0.1ug/ml or 1ug/ml
  • DMSO DMSO alone
  • calreticulin staining cells were incubated with calreticulin antibody (1:100, 30 min at room temperature) (#ab92516, Abcam), washed and resuspended in PBS before analysis on a cell analyzer.
  • BD LSR Fortessa BD Biosciences, San Jose, CA, USA
  • data were analyzed using FlowJo version 10.8.0 (BD Biosciences, San Jose, CA, USA).
  • Extracellular levels of HMGB1 upon BCV treatment were measured using the Lumit HMGB1 immunoassay (Promega, Madison, WI, USA).
  • NK-S1 cell lines were treated with selected doses of etoposide, gemcitabine, or gamma irradiation with or without BCV (0.1 ⁇ g/ml).
  • Cell viability was quantified using the Promega CellTiter-Glo® 2.0 Cell Viability Assay (Promega, Madison, WI, USA) according to the manufacturer's protocol.
  • CI Combination Index
  • Example 7 Various B-cell lymphoma cell lines were treated with BCV at various concentrations for 96 hours. Cell viability was quantified using the Promega CellTiter-Glo® 2.0 Cell Viability Assay (Promega, Madison, WI, USA) according to the manufacturer's protocol. Public databases were consulted for the presence or absence of EBV and molecular information. Raji, Daudi, and VAL shown in FIG. 7 are EBV-positive B-cell lymphoma cell lines, and BJAB and DB are EBV-negative B-cell lymphoma cell lines. Both are MYC-amplified B lymphomas (MYC-positive B lymphomas). VAL is triple-hit lymphoma and DB is double-hit lymphoma.
  • BCV shows a clear cell proliferation inhibitory effect on B lymphomas in which MYC is amplified, and has the same effect on EBV-negative B lymphomas (DB, BJAB) as it does on EBV-positive B lymphomas (Raji, Daudi, VAL). It showed a high growth inhibitory effect.

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Abstract

L'invention concerne une méthode de traitement du lymphome.　Composition pour le traitement du lymphome, la composition contenant du BCV, un sel de qualité pharmaceutique de celui-ci, ou un solvate du BCV ou le sel de celui-ci. Le lymphome peut être un lymphome MYC positif. Le lymphome peut être un lymphome EBV positif. La composition pharmaceutique peut être utilisée conjointement avec un agent chimiothérapeutique.
PCT/JP2022/032837 2022-08-31 2022-08-31 Composition pharmaceutique pour le traitement du lymphome WO2024047811A1 (fr)

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PCT/JP2022/032837 WO2024047811A1 (fr) 2022-08-31 2022-08-31 Composition pharmaceutique pour le traitement du lymphome
KR1020230114664A KR20240031153A (ko) 2022-08-31 2023-08-30 림프종의 치료용 약학 조성물
PCT/JP2023/031556 WO2024048657A1 (fr) 2022-08-31 2023-08-30 Composition pharmaceutique pour le traitement du lymphome

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013501056A (ja) * 2009-08-03 2013-01-10 キメリクス，インコーポレイテッド ウイルス感染およびウイルス誘発腫瘍を治療する組成物および方法

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JP2013501056A (ja) * 2009-08-03 2013-01-10 キメリクス，インコーポレイテッド ウイルス感染およびウイルス誘発腫瘍を治療する組成物および方法

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Title
ABDULKARIM B, ET AL: "Antiviral agent Cidofovir decreases Epstein-Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies.", ONCOGENE, NATURE PUBLISHING GROUP UK, LONDON, vol. 22, no. 15, 17 April 2003 (2003-04-17), London , pages 2260 - 2271, XP002311595, ISSN: 0950-9232, DOI: 10.1038/sj.onc.1206402 *
LUPPI M; TROVATO R; BAROZZI P; VALLISA D; ROSSI G; RE A; RAVAZZINI L; POTENZA L; RIVA G; MORSELLI M; LONGO G; CAVANNA L; RONCAGLIA: "Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir", BLOOD CANCER JOURNAL, NATURE PUBLISHING GROUP UK, LONDON, vol. 19, no. 3, 20 January 2005 (2005-01-20), London, pages 473 - 476, XP037781058, ISSN: 0887-6924, DOI: 10.1038/sj.leu.2403646 *
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TIPPIN TIMOTHY K., MORRISON MARION E., BRUNDAGE THOMAS M., MOMMÉJA-MARIN HERVÉ: "Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies", THERAPEUTIC DRUG MONITORING., LIPPINCOTT WILLIAMS AND WILKINS., NEW YORK, NY, US, vol. 38, no. 6, 1 December 2016 (2016-12-01), NEW YORK, NY, US , pages 777 - 786, XP093143712, ISSN: 0163-4356, DOI: 10.1097/FTD.0000000000000353 *

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