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  • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
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Definitions

• the invention relates to use of topoisomerase I inhibitors linked to a
• the invention entails the exploitation of synthetic lethal interactions in cancer cells, where a defect in a gene necessary for DDR causes a second gene to become essential for cell survival.
• Topoisomerase I inhibitors are well known for treatment of various cancers, as they are inhibitors of the essential ligation step catalyzed by topoisomerase I to remedy single strand DNA damage that occurs due to relief of tension caused by supercoiling in DNA replication. (DNA replication requires topoisomerase I.) Topoisomerase I inhibitors include camptothecin and analogs thereof. Many of these compounds are approved and used in chemotherapy in the treatment of a wide variety of cancers.
• topoisomerase I inhibitor In cancer cells with certain genetic defects the administration of a topoisomerase I inhibitor has been observed to have enhanced efficacy as compared to cancer cells without such defects.
• one topoisomerase inhibitor, SN-38 has been administered as a conjugate with polyethylene glycol in BRCA1 -deficient mice with mammary tumors and not only is the combination of BRCA1 deficiency with the inhibition by SN-38 of topoisomerase effective, but it also overcomes ABCG2 mediated resistance. See, for example, Zander, S.A.L. et al., PLOS One (2012) 7:e45248.
• topoisomerase inhibitors have been administered in combination with additional anticancer agents that are DDR inhibitors and/or cell cycle checkpoint inhibitors. See, for example, Abal, M. et al., Oncol. Gene (2004) 23: 1737-1744, Wainberg, Z.A. et al., Targ Oncol. (2017) 12:775-785; Verschraegen, C.F. et al., Cancer (2013) 5:418-429; and Gray, J. et al., Cancer Biol and Ther. (2012) 13:614-622; Josse, R e.al, Cancer Res (2014) 74:6968-6978; Ma, C.X., et al, Breast Cancer Res Treat (2013) 137:483-492.
• WRN Werner Syndrome helicase
• topoisomerase I inhibitors including SN-38
• SN-38 Coupling of topoisomerase I inhibitors, including SN-38, to macromolecules has been reported by Zhao, H. et al., Bioconjugate Chem. (2008) 19:849-859 and Koizumi, F. et al., Cancer Res. (2006) 66: 10048-10056.
• a particular set of conjugates useful in the invention is disclosed by Santi, D.V. et al., J. Med. Chem. (2014) 57:2303-2314.
• An additional conjugate commonly denoted NKTR-102 which is a PEGylated irinotecan, is also known.
• the present invention provides improved methods of treatment with
• topoisomerase I inhibitors in tumor subjects which methods take advantage of either an inherent defect in DDR of a subject either associated with a germline mutation or other dysfunction in the cancer cells of the subject or combination treatment with additional agents that result in synthetic lethality.
• topoisomerase I is essential for DNA replication, which is essential for cell growth and for replication.
• topoisomerase I such as irinotecan and its active metabolite, SN-38
• DDR DNA damage response
• topoisomerase I inhibitors coupled to a solubilizing agent such as polyethylene glycol (PEG).
• PEG polyethylene glycol
• the protocols of the invention are most importantly performed in human subjects, although the invention is also applicable to other mammalian subjects, including laboratory models for testing disease treatments. The protocols are also useful in livestock and companion animals.
• topoisomerase I inhibitor with a linkage to a macromolecule that decouples through beta elimination
• the pharmacokinetics can be adjusted to provide more effective and tolerable treatments in a subject having a defect in DDR, or in combination with inhibitors of a cell cycle checkpoint pathway and/or with an inhibitor of DDR.
• the conjugates of the invention can also be administered in doses that mitigate the synergistic toxicity of topoisomerase I inhibitors with such additional agents.
• the invention is directed to a method to treat cancer in a subject in need of such treatment, said subject having been identified as having one or more defects in DNA damage response (DDR).
• the method comprises administering to the subject an effective amount of a topoisomerase I inhibitor coupled to a macromolecule through a linker that provides decoupling through a beta elimination mechanism.
• the invention is directed to a method to treat cancer in a subject, which comprises administering to the subject an effective amount of a topoisomerase I inhibitor coupled to a macromolecule through a linker that provides decoupling through a beta elimination mechanism in combination with an effective amount of an additional inhibitor of DDR.
• the invention is directed to a method to treat cancer in a subject, which comprises administering an effective amount of a topoisomerase I inhibitor coupled to a macromolecule through a linker that provides decoupling through a beta elimination mechanism in combination with an effective amount of a cell cycle checkpoint pathway inhibitor.
• the method may also include a procedure to diagnose the subject for the presence of the defect; and in embodiments where more than one agent (including the invention conjugates) is administered, the coadministration of more than one agent may be simultaneous or in sequence in either order of the agents.
• the difference in time of administration of coadministered agents may be as long as days.
• the agents may also optionally be administered in the same composition.
• topoisomerase I inhibitor coupled to a macromolecule through a linker that provides decoupling through a beta elimination mechanism in combination with either an additional DDR inhibitor or a checkpoint pathway inhibitor or both.
• a combination of the topoisomerase I inhibitor conjugate of the invention with either or both an additional DDR inhibitor and a cell cycle checkpoint inhibitor is included within the scope of the invention.
• use of more than one DDR inhibitor and/or more than one cell cycle checkpoint inhibitor in combination with the topoisomerase I inhibitor conjugate is included in the scope of the invention.
• Figure 1 shows a schematic outline of the invention approach wherein single treatment with topoisomerase I inhibitor may be offset by various repair or cell cycle checkpoints as in panel A.
• the subject has an inherent DDR defect, e.g., a mutation in the BRCA gene as in panel B
• the effect of topoisomerase I inhibition is strengthened, and this is further strengthened by an inhibitor of DNA damage repair such as a PARP inhibitor as in panel C (PARP is poly ADP ribose polymerase).
• Figure 2 shows the state of the art with regard to sensitivity to topoisomerase I inhibitors of various DDR defects, both with respect to germline in non-germline DDR associated with various genes.
• Figures 3A- 3C show the synergistic effect of an SN-38 conjugate of the invention with an inhibitor of PARP on tumor growth and on event free survival.
• Figures 4A-4C show the impact of BRCA 1 or BRCA 2 deficiency on effectiveness of the SN-38 conjugate in treating tumors in mice.
• the invention takes advantage of synergistic attacks on the DNA damage response that might be mounted in cancer cells to affect their successful replication.
• the topoisomerase I inhibitor conjugates that cause DNA damage may be combined with either inhibitors of DDR or other inhibitors that interfere with DNA damage repair or replication.
• the DDR is an extremely complex process involving various mechanisms of fixing DNA to correct errors that occur either through mutation or through errors in the replication process itself. Part of this response is also a control mechanism involving cell cycle checkpoints that ensures that DNA is properly repaired or replicated before the cell divides or alternatively to effect apoptosis so that error-ridden DNA is not transmitted to daughter cells.
• the present invention employs a combination of a particular DDR inhibitor— a topoisomerase I inhibitor with other obstacles to successful replication including other inhibitors of DDR and inhibitors of cell cycle checkpoint pathways including instances wherein the cancer cells themselves are defective in their ability to respond to DNA damage.
• the invention utilizes a conjugate of a topoisomerase I inhibitor coupled to a macromolecule through a linker that provides decoupling through a beta elimination mechanism.
• Suitable topoisomerase I inhibitors are typically camptothecin and analogs, including irinotecan, otherwise known as CPT-l 1, and its active metabolite, SN-38, as well as topotecan, 9-amino-camptothecin, and water soluble analogs, such as GI 147211 and GI 149893.
• the macromolecule is a linear or branched or multi-armed, polyethylene glycol.
• PEG is linear or branched and, when q is 2-8, multi-armed, polyethylene glycol
• R 1 is CN or S0 2 NR 2 2 , wherein each R 2 is independently alkyl, aryl, heteroaryl, alkylalkenyl, alkylaryl, or alkylheteroaryl, or two R 2 taken together can form a ring;
• the conjugate may be of the formula:
• n 200-250.
• the conjugate may be PLX038, which is of the above formula where m is 1 and n is approximately 225.
• the conjugates useful in the invention are generally provided in standard pharmaceutical formulations in combination with one or more pharmaceutically acceptable excipients, in some cases wherein the pH is between 4.0 and 6.0. Standard formulations can be found, for example, in Remington Pharmaceutical Sciences, Latest Edition, Mack Publishing Company, Easton, Pennsylvania.
• the invention is based on the favorable properties of a conjugate that has suitable pharmacokinetics for combination with either endogenous DDR defects or with
• coadministered compounds that are cell cycle checkpoint inhibitors or DDR inhibitors.
• the conjugates when administered to subjects provide a continuous low dose exposure to the topoisomerase I inhibitor wherein the concentration of the free inhibitor can be maintained between 15 and 5 nM between once or twice weekly administrations or over a protocol of administration, for example, of once every two weeks. In any case, the conjugates provide consistent low dose exposure to the active drug.
• Cell cycle checkpoints include Gl-S, S, and G2/M. Any of these can be targeted in combination with the topoisomerase I inhibitor conjugate, and/or in combination with additional agents that target components needed for successful checkpoint transition. This may be also against a background of an endogenous defect in cell cycle checkpoint control.
• Suitable cell cycle checkpoint targets include checkpoint kinase 1 or 2 (CHK1 or CHK2), ataxia telangiectasia mutated (ATM) kinase, ataxia telangiectasia and Rad3 related (ATR) kinase, Weel kinase and p53.
• CHK1 or CHK2 checkpoint kinase 1 or 2
• ATM ataxia telangiectasia mutated
• ATR Rad3 related
• Suitable DDR inhibitors include those that target homologous recombination (HR), e.g. poly(ADP-ribose) polymerase (PARP) inhibitors and/or other DDR pathways, including an HEJ, HR, alt-NHEJ/MMEJ, SSA, ICL, SSB, BER, TLS, NER and MMR.
• HR homologous recombination
• PARP poly(ADP-ribose) polymerase
• MX-1 xenografts The MX-l cell line was obtained from Charles River Labs (Frederick, Maryland). 1 Cells were cultured in RPMI-1640, 10% FBS and 1% 2 mM L-glutamine at 37°C in 95% air/5% C0 2 atmosphere.
• NCr nude mice Female NCr nude mice (N CrTac:NCr -Foxnl nu ; ⁇ 6-7 weeks old) from Taconic Bioscience (Cambridge City, Indiana) were housed at the EiCSF Preclinical Therapeutics Core vivarium (San Francisco, California). All animal studies were carried out in accordance with EiCSF Institutional Animal Care and Else Committee. Tumor xenografts were established by subcutaneous injection with MX-l tumor cells (2xl0 6 cells in 100 m ⁇ of serum free medium mixed 1 : 1 with Matrigel) into the right flank of female NCr nude mice. When tumor xenografts reached 1000-1500 mm 3 in donor mice, they were resected, cut into MX-l tumor cells (2xl0 6 cells in 100 m ⁇ of serum free medium mixed 1 : 1 with Matrigel) into the right flank of female NCr nude mice. When tumor xenografts reached 1000-1500 mm 3 in donor mice, they were res
• MX-l cells are BRCA 1 deficient and CAPAN-l cells are supplied as either BRCA 2 deficient (-/-) or not deficient (+/+).
• the general protocol of Example 1 was followed with mice bearing tumors of these cell lines.
• dosages were single i.p. injections of 137 pg/kg of irinotecan or 4, 40 or 120 pg/kg of PLX038A.
• dosages were single i.p. injections of 137 pg/kg irinotecan
• Figures 4A-4C show the results of these dosages on tumor volumes, which were measured twice weekly.
• FIG. 4B A comparison of Figures 4B and 4C shows the effect of BRCA 2 deficiency on the effectiveness of treatment with irinotecan or PLX038A - only the very highest dose of PLX038A was comparably effective for both deficient and non-deficient cells. The effectiveness of all other dosage levels was enhanced in the BRCA 2 deficient cells.

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  • 2019-01-11 CA CA3087628A patent/CA3087628A1/en active Pending
  • 2019-01-11 RU RU2020126774A patent/RU2020126774A/ru unknown
  • 2019-01-11 MX MX2020007306A patent/MX2020007306A/es unknown
  • 2019-01-11 CN CN201980008227.1A patent/CN111587115A/zh active Pending
  • 2019-01-11 MX MX2020007442A patent/MX2020007442A/es unknown
  • 2019-01-11 JP JP2020538819A patent/JP2021510701A/ja active Pending
• 2020
  • 2020-07-13 MX MX2023005786A patent/MX2023005786A/es unknown
• 2023
  • 2023-03-07 US US18/118,650 patent/US20230321286A1/en not_active Abandoned
  • 2023-07-11 US US18/220,742 patent/US20240082436A1/en not_active Abandoned
  • 2023-10-31 JP JP2023186470A patent/JP7703001B2/ja active Active

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