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WO2024186264A1 - Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine - Google Patents

Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine Download PDF

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WO2024186264A1
WO2024186264A1 PCT/SG2023/050713 SG2023050713W WO2024186264A1 WO 2024186264 A1 WO2024186264 A1 WO 2024186264A1 SG 2023050713 W SG2023050713 W SG 2023050713W WO 2024186264 A1 WO2024186264 A1 WO 2024186264A1
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antibody
mmol
compound
solvate
ester
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Inventor
Bin Zou
Bryan K.S. Yeung
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Axcynsis Therapeutics Pte Ltd
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Axcynsis Therapeutics Pte Ltd
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Priority to CN202380095535.9A priority Critical patent/CN120826407A/zh
Priority to AU2023435820A priority patent/AU2023435820A1/en
Priority to KR1020257029158A priority patent/KR20250155017A/ko
Publication of WO2024186264A1 publication Critical patent/WO2024186264A1/fr
Priority to MX2025010161A priority patent/MX2025010161A/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/68—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/68—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/68—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention disclosed herein relates to novel trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates and a process for the preparation of the antibody-drug conjugates.
  • the invention further relates to pharmaceutical dosage forms comprising the novel trabectedin or lurbinectedin derivatives or the corresponding antibodydrug conjugates.
  • the invention relates to new trabectedin and lurbinectedin derivatives, corresponding antibody-drug conjugates and corresponding pharmaceutical dosage forms for use as medicament or for use in the treatment of specific cancer types.
  • ADCs antibodydrug conjugates
  • ADCs are able to deliver the cytotoxic compounds in a targeted manner and thus often allow for a more efficient cancer therapy.
  • ADCs represent a challenging area of development given the potential complexity of the payload, the chemistry of the linker and the available antibodies and so there remains a need for the development of alternative or improved ADCs. Therefore, careful consideration is required on the selection of the various components.
  • the ADC technology may be considered as being superior to other approaches including improved efficacy over antibody drugs and reduced risk of adverse effects compared to conventional anti-cancer agents, for its ability to target cancer cells with minimum impact to healthy cells, and only release drugs under specific conditions.
  • trabectedin belonging to the family of ecteinascidins, and the structurally related lurbinectedin have recently gained attraction by cancer researchers:
  • Trabectedin and lurbinectedin are DNA alkylating agents and are capable to induce tumor cell apoptosis, re-structuring of the tumor microenvironment and inhibit angiogenesis. They show potent cytotoxicity in many different cancer cell lines across a broad range of cancer types.
  • WO 2011/147828 Al discloses syntheses for derivatives of both, trabectedin and lurbinectedin.
  • WO 2020/084115 Al and WO 2021/214126 Al disclose lurbinectedin derivatives and corresponding ADCs. Summary of the invention
  • the present invention inter alia provides novel compounds derived from trabectedin and lurbinectedin, and corresponding anti-body drug conjugates which are useful in the treatment of cancer.
  • the trabectedin and lurbinectedin derivatives according to the present invention do show improved in vitro potency over that of the parent drugs and they were successfully tested against several tumor cell lines, both as conventional active ingredient and in a target-specific approach using corresponding ADCs.
  • the present invention generally relates to compounds of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof: wherein R 1 is a substituent having a negative inductive effect;
  • the present invention further relates to compounds of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -C 1-4 alkyl.
  • the present invention still further relates to a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl.
  • a substituent having a negative inductive effect refers to hydrogen as the reference, i.e. a substituent (including monoatomic substituents) which negative inductive effect is stronger than that of hydrogen.
  • alkyl refers to an unsubstituted and saturated hydrocarbon group (branched or unbranched). Where indicated, the number of carbons refers to all carbons present in that group, including in sidechains.
  • C 1-4 alkyl is meant to include to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 (n-propyl), -CH(CH 3 ) 2 (iso-propyl), -CH 2 CH 2 CH 2 CH 3 (n-butyl), -CH 2 CH 2 CH(CH 3 ) 2 (iso-butyl), -CH(CH 3 )CH 2 CH 3 (sec -butyl) and -CH(CH 3 )3 (tert-butyl).
  • -CH 3 is a preferred embodiment thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided: wherein R 1 is a substituent having a negative inductive effect;
  • R 3 , R 4 and R 5 are excluded:
  • R 2 is -OCH 3 , R 3 is -OH, R 4 is -H and R 5 is -H.
  • a compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -C 1-4 alkyl; with the proviso that compounds of formula (VII) having the following combination of R 2 , R 3 and R 4 are excluded:
  • R 2 is -H, R 3 is -H and R 4 is -H;
  • R 2 is -OCH 3
  • R 3 is -H
  • R 4 is -H.
  • a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof is provided: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl.
  • the compounds provided according to the present invention may be used as payloads for corresponding antibody-drug conjugates. Therefore, still another aspect of the present invention relates to antibody-drug conjugate of formula (XIX):
  • Ab denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof
  • L denotes a linker
  • D denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein; and wherein
  • D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.
  • Another aspect of the present invention relates to a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to the foregoing aspects for use as a medicament, or, according to still another aspect, for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.
  • Another aspect of the present invention relates to the antibody-drug conjugate defined hereinabove for use as a medicament, or, according to still another aspect, for use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.
  • D is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein;
  • L is a linker as disclosed hereinbelow
  • Still another aspect of the present invention relates to a method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to according to the foregoing as aspects, a therapeutically effective amount of the antibody-drug conjugate according to according to the foregoing as aspects, or the pharmaceutical dosage form according to the foregoing as aspects.
  • the compounds of the present invention are potent payloads when used in antibody-drug conjugates.
  • the compounds were tested as payloads with different chemical linkers in combination with Cirmtuzumab (anti-RORl), Sacituzumab (anti-TROP2) and Trastuzumab (anti-HER 2 ).
  • Additional antibodies tested include Patritumab (anti-HER 3 ), Mirvetuximab (anti-FRoc) and Cetuximab (anti-EGFR).
  • the cytotoxicity of antibody-drug conjugate is superior to the cytotoxic effects attributable to the respective payload and antibody alone.
  • the antibody-drug conjugates of the present invention allow for a targeted therapy of ovarian cancer, breast cancer and stomach cancer.
  • R 2 is -OCH 3
  • R 3 is -OH
  • R 4 is -H
  • R 5 is -H.
  • R 1 in formula (I) is -OH or -C ⁇ N .
  • the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • R 4 is -H, -CH 2 ORR4 or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl, preferably R 4 is -H, -CH 2 OH or -CH 2 NH 2 ; and/or R 5 is -H or -C 1-4 alkyl, preferably R 5 is -H or -CH 3 .
  • formula (I) may be one of the following:
  • R 4 is -H, -CH 2 OR R4 or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl, preferably R 4 is -H; and/or R 5 is -H or -C 1-4 alkyl, preferably R 5 is -H.
  • - R 1 is -OH or -C ⁇ N :
  • R 4 is -H
  • formula (I) is one of the following: ; or
  • the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • - R 2 is -H, -OCH 3 or -OCH 2 CH 2 OH;
  • R 4 is -H
  • formula (I) is one of the following:
  • the present invention relates to a compound of formula (I) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • - R 2 is -H, -OCH 3 or -OCH 2 CH 2 OH;
  • R 4 is -H;
  • R 5 is -H.
  • formula (I) is one of the following:
  • another aspect of the present invention relates to a compound of formula (VII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -C 1-4 alkyl; with the proviso that compounds of formula (VII) having the following combination of
  • R 2 , R 3 and R 4 are excluded:
  • R 2 is -H, R 3 is -H and R 4 is -H; and R 2 is -OCH 3 , R 3 is -H and R 4 is -H.
  • R 1 in formula (VII) is -OH or -C ⁇ N .
  • the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • - R 4 is -H or -CH 3 .
  • R 4 is -H or -CH 3 , preferably R 4 is -CH 3 .
  • formula (VII) may be one of the following:
  • formula (VII) may for example be one of the following:
  • R 3 is -H or -NHRRS, wherein RR3 is -H or -C 1-4 alkyl, preferably R 3 is -H or -NH 2 .
  • - R 4 is -H or -CH 3 .
  • R 3 is -H or -NH 2 ;
  • - R 4 is -H or -CH 3 .
  • formula (VII) is one of the following:
  • the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • R 2 is -NH 2 ;
  • formula (VII) is the following:
  • the present invention relates to a compound of formula (VII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein - R 1 is -C ⁇ N
  • R 2 is -H, or NH 2 ;
  • R 4 is -H.
  • formula (I) is one of the following:
  • formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof: wherein R 1 is a substituent having a negative inductive effect;
  • R 4 is -H or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl.
  • R 1 in formula (XIII) is -OH or -C ⁇ N .
  • the present invention relates to a compound of formula (XIII) as shown above or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein
  • R 2 is -ORR 2 or -NHRR 2 , wherein RR 2 is -H or -C 1-4 alkyl, preferably R 2 is -OCH 3 or -NH 2 ; and/or
  • - R 4 is -H or -CH 2 NH 2 .
  • R 3 is -H
  • R 4 is -H or -CH 2 NH 2 , preferably R 4 is -CH 2 NH 2 .
  • formula (XIII) may be one of the following:
  • formula (XIII) may for example be the following:
  • R 2 is -OR R2 or -NHR R2 , wherein R R2 is -H or -C 1-4 alkyl, preferably R 2 is -OCH 3 or -NH 2 ; and/or
  • R 4 is -H.
  • R 1 is -OH or -C M:
  • R 2 is -OCH 3 or -NH 2 ;
  • R 3 is -H
  • R 4 is -H.
  • formula (XIII) is one of the following:
  • RR 2 , RR3 and RR4 preferably may independently be -H or -CH 3 .
  • Ab denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof
  • L denotes a linker
  • D denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to the foregoing aspects and embodiments, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to the foregoing aspects and embodiments; and wherein
  • D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.
  • compound D covalently binds to a linker L via nitrogen or oxygen present in the compound.
  • linker L takes the place of a proton (H) present in the respective compound according to the present invention.
  • the anti-body drug conjugate may be described by the following structure according to formula (XIX) wherein the compound binds to the linker L via nitrogen present in R 2 :
  • D may covalently bind to the linker L via any other nitrogen or oxygen atom present in the compound.
  • D covalently binds to L via nitrogen or oxygen present in any of R 2 , R 3 or R 4 , preferably in any of R 2 or R 3 (both for the trabectedin and lurbinectedin derivatives disclosed herein).
  • the antibody-drug conjugate is characterized by a specific so-called drug-to- antibody ratio (also referred to as DAR).
  • the drug-to-antibody ratio is an integer, herein expressed as “z”. Therefore, in one embodiment of the present invention, z is an integer from 1 to 10, preferably 1 to 6, more preferably 2 to 4 and still more preferably 2 or 4.
  • the measurable drug-to-antibody ratio of a given sample (which consists of a large number of anti-body drug conjugate molecules) is usually not an integer but an average number. Therefore, in another embodiment, the antibody-drug conjugate is characterized by a specific average drug-to- antibody ratio which may be less than 1.5, or in a range from at least 1.5 to less than 2.5, or at least 2.5 to less than 3.5.
  • Ab denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof. In a preferred embodiment of the present invention, Ab denotes an antibody.
  • the present invention is not limited to specific antibodies. However, given the structure of the compounds of the present invention and the effect on inhibition towards specific cancer cells lines that is attributable to the structure of the respective compound, certain combinations may be beneficial. In terms of their target, it was found that anti-RORl antibodies, anti-TROP2 antibodies, and anti-HER 2 antibodies may be beneficial. Other useful antibodies include anti-HER 3 antibodies, anti-FRoc antibodies, and anti-EGFR antibodies. Therefore, in another embodiment of the present invention, the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) is selected from anti-HER 2 antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER 3 antibodies, anti-FRoc antibodies, and anti-EGFR antibodies.
  • the antibody, antigenbinding fragment, or an immunologically active portion thereof is selected from the group consisting of anti-HER 2 antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER 3 antibodies and anti-EGFR antibodies, more preferably anti-HER 2 antibodies, anti-TROP2 antibodies and anti-HER 3 antibodies, still more preferably anti-HER 2 antibodies and anti- TR0P2 antibodies, and most preferably anti-HER 2 antibodies.
  • the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) is selected from anti-RORl antibodies or anti-EGFR antibodies, preferably anti-RORl antibodies.
  • Specific antibodies useful for the purpose of the present invention therefore include Cirmtuzumab (as example for an anti-RORl antibody), Sacituzumab (as an example for an anti-TROP2 antibody), and Trastuzumab (as an example for an anti-HER 2 antibody).
  • Other useful antibodies include Patritumab (as example for an anti-HER 3 antibody), Mirvetuximab (as example for an anti-FRoc antibody) and Cetuximab (as example for an anti-EGFR antibody).
  • the antibody, antigenbinding fragment, or an immunologically active portion thereof is selected from the group consisting of Cirmtuzumab, Sacituzumab, Trastuzumab, Patritumab, Mirvetuximab and Cetuximab.
  • the antibody, antigen-binding fragment, or an immunologically active portion thereof is selected from the group consisting of Cirmtuzumab, Sacituzumab, Trastuzumab, Patritumab and Cetuximab, more preferably Sacituzumab, Trastuzumab and Patritumab, still more preferably Sacituzumab and Trastuzumab, and most preferably Trastuzumab.
  • the antibody, antigenbinding fragment, or an immunologically active portion thereof (Ab) is Cirmtuzumab or Cetuximab, preferably Cirmtuzumab.
  • the anti-RORl antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to SEQ ID NO. 3 disclosed in US 2022/0133901 Al, and the sequence of the light chain is essentially identical to SEQ ID NO. 4 disclosed in US 2022/0133901 Al.
  • F a b antigen-binding fragment
  • the anti-TROP2 antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 10418_H, and the sequence of the light chain is essentially identical to Chain ID INN 10418_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 10418 (IMGT release date: 20-Mar-17).
  • IMGT International Immunogenetics Information System
  • the heavy chain of the antigen-binding fragment (F a b) of the anti-TROP2 antibody has the following sequence (SEQ ID NO. 3):
  • the anti-HER 2 antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to the Anti-HER2 Heavy chain, and the sequence of the light chain is essentially identical to the Anti-HER2 Light chain disclosed in the DrugBank under Accession Number DB00072.
  • F a b antigen-binding fragment
  • the heavy chain of the antigen-binding fragment (F a b) of the anti-HER 2 antibody has the following sequence (SEQ ID NO. 5): EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARI YPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGD GFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQ
  • the anti-HER 3 antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 9549_H, and the sequence of the light chain is essentially identical to Chain ID INN 9549_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 9549.
  • F a b antigen-binding fragment comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 9549_H, and the sequence of the light chain is essentially identical to Chain ID INN 9549_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 9549.
  • IMGT International Immunogenetics Information System
  • the heavy chain of the antigen-binding fragment (F a b) of the anti-HER 3 antibody has the following sequence (SEQ ID NO. 7): QVQLQQWGAGLLKP SETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEI NHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTW YFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNH KPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISR TPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPR
  • the anti-FRoc antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to Chain ID INN 10187_H, and the sequence of the light chain is essentially identical to Chain ID INN 10187_L as disclosed in the mAb database of the International Immunogenetics Information System (IMGT) under INN number 10187 (IMGT release date: 26 July 2016).
  • IMGT International Immunogenetics Information System
  • the heavy chain of the antigen-binding fragment (F a b) of the anti-FRoc antibody has the following sequence (SEQ ID NO. 9):
  • DIVLTQSPLSLAVSLGQPAI ISCKASQSVSFAGTSLMHWYHQKPGQQPRLL IYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTF GGGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC .
  • the anti-EGFR antibody has an antigen-binding fragment (F a b) comprising a heavy chain and a light chain, wherein preferably the sequence of the heavy chain is essentially identical to the Anti-EGFR Heavy chain, and the sequence of the light chain is essentially identical to the Anti-EGFR Light chain disclosed in the DrugBank under Accession Number DB00002.
  • F a b antigen-binding fragment
  • the heavy chain of the antigen-binding fragment (Fab) of the anti-EGFR antibody has the following sequence (SEQ ID NO. 11):
  • substantially identical may refer to sequences having a defined percentage of sequential units (e.g., amino acid residues) which are the same when compared and aligned for maximum correspondence over a comparison window, preferably over the entire sequence. Therefore, in a further embodiment it is to be understood that substantially identical sequences are at least 80% identical, preferably at least 90%, more preferably at least 95%, still more preferably at least 98%, and most preferably at least 99%. In an alternative embodiment, the sequences are identical over the entire sequence (100% sequence identity).
  • Percent (%) sequence identity with respect to a reference protein sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known to the skilled person. As used herein, the percent sequence identity refers to the identity determined by BLAST using the so-called blastp algorithm (protein-protein BLAST).
  • D in formula (XIX) is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein.
  • D is a compound according to formula (I), (VII) or (XIII) disclosed herein or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof.
  • Useful combinations of antibodies, an antigen-binding fragments or immunologically active portions thereof (Ab) with compounds, pharmaceutically acceptable salts, esters, solvates, tautomers or stereoisomers thereof for use as payloads (D) according to formula (XIX) include any combination of the individual embodiments disclosed hereinabove pertaining to Ab and D, respectively.
  • D is one of the following: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.
  • D is one of the following: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.
  • D is a compound according to formula (I), wherein R 1 is -C ⁇ N , R 2 is selected from -H, -OCR R2 and -CH 2 CH 2 OR R2 with R R2 being -H or -C 1-4 alkyl, R 3 is -ORR3 or -NHRR3 with RR3 being -H or -C 1-4 alkyl, R 4 is -H or -C 1-4 alkyl, and R 5 is -H or -C 1-4 alkyl, preferably R 1 is -C ⁇ N , R 2 is selected from -H, -OCH 3 and -CH 2 CH 2 OH, R 3 is -OH or -NH 2 , R 4 is -H, and R 5 is -H; or according to formula (VII), wherein R 1 is -OH or -C ⁇ N , R 2 is -NHR R2 with R R2 being -H or -C 1-4
  • D is one of the following: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.
  • D is one of the following, a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof:
  • R 2 is -H or -CH 2 CH 2 OR R2 with R R2 being -H or -C 1-4 alkyl
  • D is one of the following: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer of any of the foregoing.
  • linker L present in formula (XIX) describing the antibodydrug conjugate of the present invention is believed to be not particularly critical, but it may be defined as follows: wherein
  • T and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;
  • H is a hydrophilic unit, wherein h is 0 or 1 ;
  • Y is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.
  • the anti-body drug conjugate may be described by the following structure according to formula (XIX) wherein the compound binds to the linker L via nitrogen present in R 2 :
  • the conjugating group Y of the linker L covalently binds to a sulfur atom present in Ab, which means a sulfur atom present in the antibody, an antigen-binding fragment or an immunologically active portion thereof. Therefore, the antibody-drug conjugate represented by formula (XIX) may have the following structure:
  • T and U are spacer units which may be independently selected from spacer units having from 1 to 24 chain carbons.
  • the indices t and u are independently 0 or 1 which means that both units may be absent or, alternatively, both units may be present.
  • the linker contains at least one of T and U i.e., t + u > 1.
  • Chain carbons are those carbons present in a chain that links T or U to the respective adjacent unit or compound D, including carbons of a ring forming part of that chain. Where present, carbons of substituents or side chains are not included.
  • spacer units that are useful in connection with chemical linkers, including in antibody-drug conjugates.
  • Useful spacer units include branched or unbranched polyalkylene chains as well as polyethylene glycol spacer units having up to 24 chain carbons.
  • the spacer units may also exhibit more complex structures and may include functional groups such as carbonyls.
  • the spacer unit useful for the purpose of the present invention may include cyclic structures such as aromatic and nonaromatic hydrocarbons or heterocycles (including sugars).
  • spacer unit U is one of the following: ; or
  • n is preferably an integer from 5 to 10, more preferably 6 to 8, and most preferably 7.
  • spacer unit T is one of the following: wherein n is preferably an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5 wherein m is preferably 1, and n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6.
  • the linker L may contain a hydrophilic unit H.
  • the skilled person is generally familiar with chemical structures that are capable of introducing hydrophilicity and thereby increasing the tendency of a given compound or, as relevant here, an antibody drug conjugate to be solvated in an aqueous environment.
  • the hydrophilic unit H will be rich in oxygen.
  • the hydrophilic unit H is therefore derived from a PEGylated amino acid, and preferably H is one of the following: wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7
  • the hydrophilic unit H may be the following: wherein n is preferably an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or
  • the conjugating group Y present in the antibody-drug conjugate may be derived from any group that, in its unreacted form, is capable of binding to an antibody, an antigenbinding fragment or an immunologically active portion thereof (Ab). Since it is preferred that the conjugating group Y covalently binds to a sulfur atom of the antibody, an antigen-binding fragment or an immunologically active portion thereof, Y is preferably derived from double bond-containing functional groups. To that extent, particularly suitable functional groups are oc,P-unsaturated carbonyls. Therefore, in one embodiment, Y is a conjugating group derived from maleimide, maleamic acid ester, or allenamide, preferably the conjugating group Y is derived from maleimide. In a more specific and more preferred embodiment, Y is such that L is one of the following: wherein, if present, Re is -H or -C 1-4 alkyl, preferably -H or -CH 3 .
  • the linker L may optionally contain one more amino acid units A so that L may comprise a structural motif that can be represented as (A)o-i2 because a in (A) a is an integer from 0 to 12.
  • a is an integer from 1 to 10, more preferably from 1 to 5, still more preferably 1 to 4, and most preferably 2 or 4.
  • H and h, and A and a, and U and u are such that L is one of the following:
  • L is such that
  • Formula (XIX) is one of the following:
  • Still another aspect of the present invention relates to the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein for use as a medicament, with a more specific aspect relating to the use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.
  • cancer types include ovarian cancer and breast cancer.
  • a particularly preferred embodiment relates to the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein for use in the treatment of papillary serous adenocarcinoma of the ovary or breast adenocarcinoma.
  • the compounds of the present invention exhibit improved efficacy. This finding makes these compounds potent active ingredients for the conventional chemotherapy of ovarian cancer, breast cancer and stomach cancer, especially ovarian cancer and breast cancer.
  • Still another aspect of the present invention relates to the antibody-drug conjugate disclosed herein for use as a medicament, with a more specific aspect relating to the use in the treatment of cancer, preferably ovarian cancer, stomach cancer or breast cancer.
  • cancer types include ovarian cancer and breast cancer.
  • cancer types include stomach cancer and breast cancer.
  • a particularly preferred aspect relates to the antibody-drug conjugate disclosed herein for use in the treatment of gastric carcinoma or breast adenocarcinoma.
  • a preferred embodiment of the present invention relates to the antibody-drug conjugate disclosed herein for use as a medicament, wherein the antibody is an anti-RORl antibody, preferably Cirmtuzumab, and/or wherein the invention relates to the antibody-drug conjugate for use in the treatment of ROR1 -positive ovarian cancer; the antibody is an anti-TROP2 antibody, preferably Sacituzumab, and/or wherein the invention relates to the antibody-drug conjugate for use in the treatment of TROP2-positive stomach cancer; the antibody is an anti-HER 2 antibody, preferably Trastuzumab, and/or wherein the invention relates to the antibody-drug conjugate for use in the treatment of HER 2 - positive breast cancer; the antibody is an anti-HER 3 antibody, preferably Patritumab, and/or wherein the invention relates to the antibody-drug conjugate for use in the treatment of HER 3 -positive stomach cancer; the antibody is an anti-FRoc antibody, preferably Mirve
  • the antibodies may have the respective structure disclosed hereinabove. According to the present invention, anti-RORl antibodies may be more preferred, in particular Cirmtuzumab.
  • D is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to formula (I), (VII) or (XIII) disclosed herein, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to formula (I), (VII) or (XIII) disclosed herein;
  • L is a linker as disclosed hereinabove
  • D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.
  • the linker-payload building block of the present invention may thus be represented as follows:
  • Y* denotes the unreacted form of a conjugating group Y that is capable of reacting with Ab, for example with a thiol group present in an antibody.
  • Y* may be a functional group with a carbon-carbon double bond, such as maleimide, maleamic acid ester, or allene amide.
  • the process according to the present invention comprises a step of covalently attaching D to L via nitrogen or oxygen present in any of R 2 , R 3 or R 4 , preferably in any of R 2 or R 3 .
  • the antibody, an antigen-binding fragment or an immunologically active portion thereof is preferably reacted with a reducing agent first in order to reduce one or more of the disulfide groups contained therein, depending on the amount of reducing agent used and the desired drug-to-antibody ratio.
  • a reducing agent Tris(2-carboxyethyl)phosphine (TCEP) may be preferred as a reducing agent.
  • linker-payload building block Only after the reduction, the appropriate amount of linker-payload building block is reacted with the (partially) reduced antibody, antigen-binding fragment or immunologically active portion thereof to provide the antibody-drug conjugate of the present invention having the desired drug-to-antibody ratio according to formula (XIX).
  • Antibodies generally useful for the process of the present invention include anti- HER 2 antibodies, anti-RORl antibodies, anti-TROP2 antibodies, anti-HER 3 antibodies, anti- FRoc antibodies, and anti-EGFR antibodies. Particularly useful antibodies are those explained above as being preferred. These antibodies may further have the structure disclosed hereinabove.
  • the antibody, antigen-binding fragment, or an immunologically active portion thereof (Ab) may be an anti-HER 2 antibody, such as Trastuzumab.
  • the present invention further relates to corresponding pharmaceutical dosage forms comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer disclosed herein, or a therapeutically effective amount of the antibody-drug conjugate disclosed herein.
  • Also disclosed herein is a method of treating cancer, wherein the method comprises administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer as disclosed herein, a therapeutically effective amount of the antibody-drug conjugate disclosed herein, or the pharmaceutical dosage form disclosed above.
  • Preferred cancer types include ovarian cancer, stomach cancer or breast cancer, wherein ovarian cancer and breast cancer may be preferred in terms of efficacy.
  • R 3 , R 4 and R 5 are excluded:
  • R 2 is -OCH 3
  • R 3 is -OH
  • R 4 is -H
  • R 5 is -H.
  • R 2 is -H, -ORR 2 , -OCH 2 CH 2 OR R2 , -OCH 2 C(CH 3 ) 2 ORR 2 ,
  • R 4 is -H, -CH 2 ORR4 or -CH 2 NHRR4, wherein RR4 is -H or -C 1-4 alkyl, preferably R 4 is -H, -CH 2 OH or -CH 2 NH 2 ; and/or R 5 is -H or -C 1-4 alkyl, preferably R 5 is -H or -CH 3 .
  • R 4 is -H, -CH 2 OH or -CH 2 NH 2 , preferably R 4 is -CH 2 NH 2 ; and R 5 is -H or -CH 3 , preferably R 5 is -CH 3 .
  • R 4 is -H or -C 1-4 alkyl; with the proviso that compounds of formula (VII) having the following combination of R 2 , R 3 and R 4 are excluded:
  • R 2 is -H, R 3 is -H and R 4 is -H;
  • R 2 is -OCH 3 , R 3 is -H and R 4 is -H.
  • - R 4 is -H or -CH 3 .
  • R 4 is -H or -CH 3 , preferably R 4 is -CH 3 .
  • a compound of formula (XIII) or a pharmaceutically acceptable salt, ester, solvate, wherein R 1 is a substituent having a negative inductive effect; - R 2 is -H or -X(CH 2 ) P C( 0)o-i(CH 2 )q(C(R R2 )2)o-i(X)o-iR R2 with q and p being independently integers from 0 to 10, wherein X is O or NH, and R R2 is independently -H or -C 1-4 alkyl;
  • R 4 is -H or -CH 2 NHRR 4 , wherein RR 4 is -H or -C 1-4 alkyl.
  • R 2 is -OR R2 or -NHR R2 , wherein R R2 is -H or -C 1-4 alkyl, preferably R 2 is -OCH 3 or -NH 2 ; and/or
  • - R 4 is -H or -CH 2 NH 2 .
  • R 2 is -OCH 3 or -NH 2 , preferably R 2 is -NH 2 ;
  • R 3 is -H
  • R 4 is -H or -CH 2 NH 2 , preferably R 4 is -CH 2 NH 2 .
  • Ab denotes an antibody, an antigen-binding fragment, or an immunologically active portion thereof
  • L denotes a linker
  • D denotes a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of embodiments 1 to 18, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of embodiments 1 to 18; and wherein
  • D covalently binds to L via nitrogen or oxygen present in D, and L covalently binds to Ab; and z is an integer from 1 to 20.
  • an anti-RORl antibody preferably Cirmtuzumab
  • an anti-TROP2 antibody preferably Sacituzumab
  • an anti-HER 2 antibody preferably Trastuzumab.
  • T and U are independently spacer units, each having from 1 to 24 chain carbons, wherein t and u are independently 0 or 1, preferably t + u > 1; each A is independently an amino acid unit, wherein a is an integer from 0 to 12;
  • H is a hydrophilic unit, wherein h is 0 or 1 ;
  • Y is a conjugating group that covalently binds to Ab; wherein preferably the conjugating group Y covalently binds to a sulfur atom present in Ab.
  • R 6 is -H or -C 1-4 alkyl, preferably -H or -CH 3 .
  • U is one of the following: wherein preferably n is an integer from 5 to 10, more preferably 6 to 8, and most preferably 7
  • T is one of the following: wherein preferably n is an integer from 1 to 8, more preferably 1 to 6, and most preferably 2 or 5
  • n is an integer from 2 to 8, more preferably 4 to 7, and most preferably 5 or 6
  • H is derived from a PEGylated amino acid, preferably H is one of the following: wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7 ; or wherein more preferably n is an integer from 5 to 10, still more preferably 6 to 8, and most preferably 7.
  • D is a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof selected from the group consisting of trabectedin, lurbinectedin and the compounds according to any of embodiments 1 to 18, preferably a compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof according to any of embodiments 1 to 18;
  • L is a linker according to any of embodiments 19, or 23 to 28;
  • the antibody is an anti-RORl antibody, preferably Cirmtuzumab; an anti-TROP2 antibody, preferably Sacituzumab; or an anti-HER 2 antibody, preferably Trastuzumab.
  • a pharmaceutical dosage form comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 18, or a therapeutically effective amount of the antibody-drug conjugate according to any of embodiments 19 to 28.
  • a method of treating cancer comprising administering to a subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer according to any of embodiments 1 to 18, a therapeutically effective amount of the antibody-drug conjugate according to any of embodiments 19 to 28, or the pharmaceutical dosage form according to embodiment 36.
  • FCS fetal calf serum
  • PAB 4-aminobenzyl alcohol
  • PABC p-aminobenzyl carbamate
  • UV ultraviolet
  • MDA-MB-231, NCI-N87, and OV-90 were obtained from American Type Culture Collection (Manassas, USA).
  • MDA-MB-231 cells were cultured in DMEM, supplemented with 10% heat inactivated fetal bovine serum, 100 U/mL penicillin, 100 pg/mL streptomycin, 2 mM glutamine and 1 mM sodium pyruvate.
  • NCI-N87 cells were cultured in RPMI-1640 supplemented with 10% heat inactivated fetal bovine serum, 100 U/mL penicillin and 100 g/mL streptomycin.
  • OV-90 cells were cultured in MCDB 105 medium/medium 199 (1:1) supplemented with 10% heat inactivated fetal bovine serum. All cell lines were maintained at 37 °C with humidified atmosphere of 5% CO2.
  • Lyophilized compounds were dissolved in 100% sterile cell culture grade DMSO, aliquoted and stored under -20 °C.
  • the cells were seeded in 96-well white flat-bottom tissue culture plates at 1 x 10 3 to 2 x 10 3 per 100 pL growth media per well in triplicates and allowed to attach and recover for 24 h.
  • Test compounds were serial-diluted in DMSO to create 9-point titration curves, and subsequently added to the seeded cultures with a final DMSO concentration at 0.02% per well. After another 120 h of incubation at 37°C with 5% CO2, cell viability assay was performed using CellTitre-Glo 2.0 (Promega). Equal volumes of CellTitre-Glo 2.0 to media in the wells were added and mixed for 10 minutes to lyse the cells.
  • Luminescence was measured on a ThermoFisher Varioskan Lux plate reader. [00135] Luminescence values of each test-compound of different concentrations were normalized to the luminescence value of the DMSO-control (0.02%) treated cells and plotted against concentration of test compounds. Sigmoidal curves and CC50 values were generated in GraphPad Prism version 9.4.1, using non-linear regression, variable slope-four parameters curve fit for inhibitor versus response, with R squared values above 0.95. All assays were performed in triplicates and as two independent experiments.
  • Sac Sacituzumab
  • Tra Trastuzumab
  • Cir Cirmtuzumab
  • Pat Patritumab
  • Cet Cetuximab
  • LP linker-payload building block
  • LK linker
  • PL payload
  • Step 1 Synthesis of benzyl (4-hydroxyphenethyl)carbamate.
  • Step 3 Synthesis of benzyl (4-methoxy-3-nitrophenethyl)carbamate.
  • Step 4 Synthesis of 5 -(2-aminoethyl)-2-methoxyaniline hydrochloride (Intermediate A).
  • Step 1 Synthesis of 4-(2-(benzyloxy)ethoxy)-3 -hydroxybenzaldehyde.
  • Step 2 Synthesis of 3-hydroxy-4-(2-hydroxyethoxy) benzaldehyde.
  • Step 4 Synthesis of2-(2-hydroxyethoxy)-5-(2-nitroethyl) phenol.
  • Step 5 Synthesis of 5-(2-aminoethyl)-2-(2-hydroxyethoxy) phenol (Intermediate B).
  • Step 1 Synthesis of5-nitro-lH-indole-3-carbaldehyde.
  • Step 2 Synthesis of (E)-5-nitro-3-(2-nitrovinyl)-lH-indole.
  • Step 3 Synthesis of 3-(2-aminoethyl)-lH-indol-5-amine (Intermediate C).
  • Step 1 Synthesis of benzyl (4-hydroxyphenethyl)carbamate.
  • Step 2 Synthesis of benzyl (4-hydroxy-3-nitrophenethyl) carbamate.
  • Step 3 Synthesis of benzyl (4-(2-(benzyloxy)ethoxy)-3-nitrophenethyl)carbamate.
  • Step 4 Synthesis of 2-(2-amino-4-(2-aminoethyl)phenoxy)ethan-l-ol hydrochloride (Intermediate D).
  • Step 1 Synthesis of benzyl 2-(4-formyl-2-hydroxyphenoxy) acetate.
  • Step 2 Synthesis of benzyl (E)-2-(2-hydroxy-4-(2-nitrovinyl) phenoxy) acetate.
  • Step 3 Synthesis of2-(4-(2-aminoethyl)-2-hydroxyphenoxy) acetic acid (Intermediate E).
  • Step 1 Synthesis of6-nitro-lH-indole-3-carbaldehyde.
  • Step 2 Synthesis of (E)-6-nitro-3-(2-nitrovinyl)-lH-indole.
  • Step 3 Synthesis of 3-(2-aminoethyl)-lH-indol-6-amine (Intermediate F).
  • (£’)-6-nitro-3-(2-nitro vinyl)- IH-indole (750 g, 3.216 mmol, 1.0 eq.) in 20 mL 1,4-dioxane was added 2.5 M LiAlt (1.0 eq.) with dropwise at 0 °C.
  • the reaction was warmed to 70 °C.
  • the reaction was quenched with 16 mL of water, 16 mL 15% aqueous NaOH, 48 mL water, and small amount of MgSCM at 0 °C sequentially.
  • Step 1 Synthesis of(E)-5-nitro-3-(2-nitrovinyl)-lH-indole.
  • Step 2 Synthesis of 5-nitro-3-(l-nitropropan-2-yl)-lH-indole.
  • Step 3 Synthesis of 3-(l-aminopropan-2-yl)-lH-indol-5-amine (Intermediate G).
  • Step 1 Synthesis of 3-(5-methoxy-lH-indol-3-yl)propan-l-ol.
  • Step 2 Synthesis of3-(5-methoxy-lH-indol-3-yl)propyl methane sulfonate.
  • Step 3 Synthesis of 3-(3-azidopropyl)-5-methoxy-lH-indole.
  • Step 4 Synthesis of 3-(5-methoxy-lH-indol-3-yl)propan-l -amine (Intermediate I).
  • Step 1 Synthesis of 2, 2-dimethyl-5-((5-nitro-lH-indol-3-yl)methyl)-l,3-dioxane-4, 6-dione.
  • Step 2 Synthesis of ethyl 3-(5-nitro-lH-indol-3-yl)propanoate.
  • Step 3 Synthesis of 3-(5-nitro-lH-indol-3-yl)propan-l-ol.
  • Step 4 Synthesis of 3-(5-nitro-lH-indol-3-yl)propyl methanesulfonate.
  • Step 6 Synthesis of 3-(3-azidopropyl)-5-nitro-lH-indole.
  • Step 7 Synthesis of 3-(3-aminopropyl)-lH-indol-5-amine (Intermediate I).
  • step 1 in general procedure A a mixture of M24 (30 mg, 0.048 mmol, 1.0 eq.), Intermediate A (65.2 mg, 0.322 mmol, 10 eq.), and NaOAc (29 mg, 0.354 mmol, 11 eq.) in anhydrous EtOH was stirred at 25 °C overnight. After the reaction was completed, the solvent was removed under reduced pressure to give a solid. To the solid was added ethyl acetate and filtered. The filtrate was purified by flash column chromatography (ethyl acetate: n-heptane (1:1)) to afford PL-4 as a light-yellow solid (19 mg, 76.7%).
  • step 2 in general procedure A to a solution of PL-4 (19 mg, 0.0246 mmol, 1.0 eq.) in acetonitrile and water (3/2, v/v, 1 mL) was added silver nitrate (60 mg, 0.353 mmol, 14 eq.). The suspension was stirred at 25 °C for 24 hrs. Then the reaction mixture was quenched by adding to a mixture of ethyl acetate/5% ammonium hydroxide. The combined organic layers were dried over sodium sulfate and concentrated.
  • step 1 in general procedure A a mixture of M24 (100 mg, 0.16 mmol, 1.0 eq.), 5-(2-aminoethyl)-2-(2-hydroxyethoxy)phenol (160 mg, 0.8 mmol, 5 eq.), HO Ac (96.1 mg, 1.6 mmol, 10 eq.), and NaOAc (25.6 mg, 0.32 mmol, 2 eq.) in anhydrous EtOH (10 mL) was stirred for 2 hrs at room temperature. The solvent was removed under reduced pressure and purified by flash column chromatography on neutral aluminum oxide (dichloromethane: methanol (50: 1)) to afford PL-2 as a light-yellow solid (68.0 mg, 52.8%).
  • step 2 in general procedure A to a solution of PL-2 (19 mg, 0.0246 mmol, 1.0 eq.) in acetonitrile and water (3/2, v/v, 1 mL) was added silver nitrate (60 mg, 0.353 mmol, 14 eq.). The suspension was stirred at 25 °C for 24 hrs, and then treated with a mixture of 5% ammonium hydroxide in ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-HPLC to afford PL-6 as a yellow solid (6 mg, 31.9% yield).
  • step 1 in general procedure A a mixture of M24 (30 mg, 0.048 mmol, 1.0 eq.), Intermediate D (112.6 mg, 0.48 mmol, 10 eq.), and NaOAc (38.6 mg, 0.48 mmol, 10 eq.) in anhydrous EtOH was stirred at 25 °C overnight. The solvent was removed under reduced pressure to give a solid. The ethyl acetate was added, and the mixture was filtered. The filtrate was purified by flash column chromatography on silica gel (dichloromethane: methanol (50: 1)) to afford PL-7 as a white solid (15 mg, 39%).
  • step 1 in general procedure A a mixture of M24 (10 mg, 0.016 mmol, 1.0 eq), 3-(2-aminoethyl)aniline (138 mg, 0.08 mmol, 5.0 eq), NaOAc (12.8 mg, 0.016 mmol, 10.0 eq) in anhydrous EtOH (10 mL) was stirred at r.t overnight. The solvent was removed under reduced pressure and the residue was purified by Prep-TLC (dichloromethane: methanol (10:1)) to afford PL-12 (6.1 mg, 51.2%) as a light-yellow solid. LC-MS (ESI) m/z: 740.4 [M+H] + .
  • PL-9 (6 mg, 0.0073 mmol, 1.0 eq.), AgNCh (12.4 mg, 0.0073 mmol, 10.0 eq.) was suspended into acetonitrile: H2O (3:2, v/v). The solution was stirred at r.t. for 24 hr in the absence of light. The suspension was quenched with a mixture of saturated brine and saturated sodium bicarbonate, and filtered. The resulting solution was purified by preparative HPLC to obtain PL-22 (0.97 mg, 16.3% yield) as white solid. LC-MS (ESI) m/z: 819 [M+H] + .
  • step 2 in general procedure B to a solution of PL-5 (65 mg, 0.0833 mmol, 1.0 eq.) in acetonitrile and water (3/2, v/v, 1 mL) was added silver nitrate (212 mg, 1.248 mmol, 15eq.). The suspension was stirred at 25 °C for 24 hrs, and then treated with a mixture of saturated sodium bicarbonate and brine. The precipitated solid was filtered out and the filtrate was extract with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-HPLC to afford PL-3 as a yellow solid (2.6 mg, 4%).
  • Mc-Gly-Gly-Phe-Gly (CAS# 2413428-36-9, also referred to as Mc-GGFG) was purchased from a commercial supplier and used without further purification.
  • reaction mixture was purified by Cis chromatography (ACN/H2O from 10% ⁇ 100%) and lyophilized to provide Fmoc-Gly-Gly-Gly- Gly- Val-Cit-PAB-OH (1.4 g, 80% yield) as a white powder.
  • Fmoc-Gly-Gly-Gly-Gly-Gly-Gly-Val-Cit-PAB-OH 200 mg, 0.24 mmol, 1.0 eq. was dissolved into 5 mL Et2N/DMSO (1:1) and stirred for Ali. After the reaction was completed, the solution was concentrated and purified by Cis column chromatography (ACN/H2O from 10% ⁇ 100%) and lyophilized to provide Gly-Gly-Gly-Gly-Gly-Val-Cit-PAB-OH (139 mg, 95% yield) as a white powder.
  • LP-10 [00257] To a solution of PL-4 (20 mg, 0.026 mmol, 1.0 eq.) and LK-9 (16.2 mg, 0.026 mmol, 1.0 eq.) in 5 mL anhydrous DMF were added HOBt (71.36 mg, 0.52 mmol, 20.0 eq.) and EDCI (101.2 mg, 0.52 mmol, 20.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to provide LP-10 as a white solid (4.6 mg, 12.9% yield). LC-MS (ESI) m/z: 1368.8 [M+H] + .
  • LP-22 [00271] To a solution of PL-16 (5 mg, 0.0063 mmol, 1.0 eq.) and LK-1 (18.15 mg, 0.0189 mmol, 3.0 eq.) in 1 mL anhydrous DMF : pyridine (4: 1) was added HOAt (0.9 mg, 0.252 mmol, 1.0 eq.) and DIPEA (13.15 mg, 0.1 mmol, 16.0 eq.). After the addition, the mixture was stirred at r.t. overnight. The reaction mixture was purified by Prep-HPLC to obtain LP-22 (5 mg, 49.1% yield) as a white solid. LC-MS (ESI) m/z: 809.8 [1/2M+1] + .
  • LP-35 was prepared following the procedure for LP-34.
  • Unconjugated residual linker payloads in the reaction solution were removed by treating with 300 mg/mL dextran coated charcoal (Sigma). A 10% dextran coated charcoal suspension by volume was added into the reaction solution. After vortexing, the mixture was shaken for 2 hrs at 4 °C, then the supernatant was taken for detection of residual linker payload content, if percentage of free linker payload is above 1%, the above process should be repeated for several times until the free linker payload reaches the standard (3 times of treatment can meet the requirement). When the treatment was complete, the mixture was centrifugated and the supernatant was collected by using a syringe and a hydrophilic membrane filter to filter out the activated carbon. The buffer of the desired ADC was replaced with a suitable storage buffer through 4 times of ultrafiltration and stored at -80 °C.
  • HPLC instrument Waters e2695 High performance Liquid chromategraphy system. Column: BioResolve® RP mAb Polyphenyl (4.6x100 mm, 2.7 pm) (Waters).
  • Mobile phase mobile phase A (MPA): 0.1% TFA-H2O;
  • Mobile phase B MPB: 0.1% TFA-ACN; the following elution procedure (35%-45%) was followed, in which the volume of mobile phase A was 90%-90% and that of mobile phase B was 10%-10% in 0-3 min.
  • the volume of mobile phase A was 90%-65% and that of mobile phase B was 10%-35 % in 3-5 min.
  • the volume of mobile phase A is 5%-0% and that of mobile phase B is 95%-100% in 5-20 min. From 24 to 26 min, the volume of mobile phase A was 0-100%, and the volume of mobile phase B was 100%- 0%.
  • the volume of mobile phase A was 100%-100% and that of mobile phase B was 0%-0% in 26-30 min.
  • Detection conditions The flow rate of mobile phase was set at 1 mL/min, the detection wavelength was set at 280 nm, and the column temperature was 65 °C.
  • DAR value calculation formula: DAR (L0 peak area ratio x 0 + LI peak area ratio x 1 + HO peak area ratio x o + Hl peak area ratio x 1 + H2 peak area ratio x 2 + H3 peak area ratio x 3) / 100 x 2.
  • HPLC instrument Waters e2695 High Performance Liquid Chromatography system. Column: MabPacTM HIC -Butyl 5 pm 4.6 x 100 mm (Thermo).
  • Mobile phase mobile phase A (MPA): 1.5 M (NH4)2SC>4 + 50 mM potassium phosphate (pH 7.0);
  • the volume of mobile phase A and B was 95%-5% and 5%-95% respectively during 2-22 min.
  • the volume of mobile phase A was 5%-0% and that of mobile phase B was 95%-100% during 22-24 min. From 24 to 26 min, the volume of mobile phase A was 0-100%, and the volume of mobile phase B was 100%-0%.
  • the volume of mobile phase A was 100%-100% and that of mobile phase B was 0%-0% in 26-30 min.
  • Detection conditions The flow rate of mobile phase was set at 1 mL/min, the detection wavelength was set at 280 nm, and the column temperature was set at 30 °C.
  • HPLC instrument 1260 Agilent High Performance Liquid Chromatography system. Column: Waters Xbridge® BEH200 SEC (7.8 x 300 mm, 3.5 pm). Mobile phase: 50 mM PB + 200 mM Arg (pH 6.80) +10% IPA, elution according to the following procedure, 0- 30 min mobile phase A volume of 100%-100%.
  • Detection conditions The flow rate of mobile phase was set at 0.5 mL/min, the detection wavelength was 280 nm and 254 nm, and the column temperature was 26 °C.
  • HPLC instrument Waters e2695 High Performance Liquid Chromatography system. Column: XBridge® C18 3.5pm 4.6 * 150 mm (Waters).
  • Mobile phase mobile phase A (MPA): 0.1% TFA-H2O;
  • Detection conditions The flow rate of mobile phase was set at 0.5 mL/min, the detection wavelength was set at 254 nm, and the column temperature was set at 30 °C.
  • Reagent I Preparation: A solution of 10 g sodium chloride in 30 mL anhydrous methanol and 50 mL acetonitrile was stirred at room temperature for more than one hour, and then let stand for one hour. The supernatant was filtered by 0.22 pm organic membrane and stored at room temperature for three months.
  • Reagent II Preparation A mixture of 100 mL reagent I, 15 mL DMSO and 85 mL ADC storage buffer was well mixed and stored at room temperature (valid for 2 months).
  • Sample for testing 85 pg of ADC was mixed with 3 pL DMSO for 5 min, then to this was added 60 pL of reagent I. The mixture was mixed well for 5-10 min and centrifuged at 2000 rpm for 2 min. Finally, 20 pL supernatant was injected into HPLC, eluted by the above elution procedure, and the chromatogram was recorded.
  • Free linker payload (mol/mol%) molar concentration of residual linker payload/molar concentration of antibody X100.
  • HPLC instrument 1260 Agilent High Performance Liquid Chromatography system. Column: Waters Xbridge® BEH200 SEC (7.8 * 300 mm, 3.5 pm). Mobile phase: 50 mM PB + 200 mM Arg (pH 6.80) +10% IPA, the following elution procedure was followed, 0- 30 min mobile phase A volume of 100%-100%;
  • Detection conditions Flow rate of mobile phase was set at 0.5 mL/min, detection wavelength was set at 280 nm, and column temperature was set at 26 °C.
  • Experimental procedure 20 pg ADC sample (the volume depends on the concentration of the sample) was injected into the HPLC, eluted by the above elution procedure, and the chromatogram was recorded.
  • Sacituzumab (3.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-1 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-1 (CADC (mg/mL): 2.58, volume (ml): 0.743, yield: 64.0%).
  • CADC volume/mL
  • SEC-DAR 0.46
  • SEC purity 82.69%
  • free linker payload mol/mol%): 0.42%.
  • Sacituzumab (3.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-2 (CADC (mg/mL): 1.74, volume (mL): 0.938, yield: 54.3%).
  • CADC volume/mL
  • SEC-DAR 1.40, SEC purity: 89.68% and free linker payload (mol/mol%): 1.25%.
  • Sacitu- vonab (3.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-3 (CADC (mg/mL): 1.78, volume (mL): 0.815, yield: 48.3%).
  • CADC volume/mL
  • SEC-DAR 0.68, SEC purity: 74.94% and free linker payload (mol/mol%): -0.07%.
  • Sacitu- vonab (3.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-4 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-4 (CADC (mg/mL): 2.39, volume (mL): 0.676, yield: 53.6%).
  • CADC volume/mL
  • SEC-DAR 0.69
  • SEC purity 80.76%
  • free linker payload mol/mol%): -0.95%.
  • Trastuzumab (3.0 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-1 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-5 (CADC (mg/mL): 2.94, volume (mL): 0.861, yield: 84.3%).
  • CADC volume/mL
  • SEC-DAR 1.58, SEC purity: 83.30% and free linker payload (mol/mol%): 0.37%.
  • Trastuzumab (3.0 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-6 (CADC (mg/mL): 2.69, volume (mL): 0.849, yield: 76.3%).
  • CADC mg/mL
  • SEC-DAR 2.38, SEC purity: 92.51% and free linker payload (mol/mol%): 0.91%.
  • Trastuzumab (3.0 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-7 (CADC (mg/mL): 3.19, volume (mL): 0.715, yield: 76.0%).
  • CADC volume/mL
  • SEC-DAR 0.76
  • SEC purity 83.43%
  • free linker payload mol/mol%): -0.04%.
  • Trastuzumab (5 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 2.6 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-3 (10 mg/mL, 7.5 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-8 (CADC (mg/mL): 1.857, volume (mL): 0.300, yield: 19.4%).
  • RP-DAR 3.82, SEC purity: 84.9% and free linker payload (mol/mol%): 0.52%.
  • Trastuzumab (3.0 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-4 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-9 (CADC (mg/mL): 2.53, volume (mL): 0.985, yield: 83.0%).
  • CADC CADC (mg/mL): 2.53, volume (mL): 0.985, yield: 83.0%).
  • SEC-DAR 1.51, SEC purity: 81.55% and free linker payload (mol/mol%): -1.11%.
  • Cirmtuzumab (3.0 mg, 4.21 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-2 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-10 The mixture was purified by treating with dextran coated charcoal once and filtered through hydrophilic membrane filter, followed by five times of ultrafiltration to afford ADC-10 (CADC (mg/mL): 2.89, V (mL): 0.766, yield: 74.0%).
  • CADC CADC (mg/mL): 2.89, V (mL): 0.766, yield: 74.0%).
  • SEC-DAR 2.50
  • RP- DAR 1.77
  • SEC purity 95.73%
  • free linker payload mol/mol%): 0.68%.
  • Cirmtuzumab 1.0 mg, 4.21 mg/mL, 1.0 eq.
  • 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 3.2 eq.) aqueous solution.
  • the reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC- 11 (CADC (mg/mL): 2.80, V (mL): 0.114, yield: 32.0%).
  • CADC mg/mL
  • V mL
  • yield 32.0%.
  • SEC-DAR 1.78, SEC purity: 85.39% and free linker payload (mol/mol%): 0.28%.
  • Cirmtuzumab 1.0 mg, 4.21 mg/mL, 1.0 eq.
  • 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 2.4 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Cirmtuzumab (3.0 mg, 4.21 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 3.0 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Cirmtuzumab 1.0 mg, 4.21 mg/mL, 1.0 eq.
  • 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.0 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Cirmtuzumab 1.0 mg, 4.21 mg/mL, 1.0 eq.
  • 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution.
  • the reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-9 (10 mg/mL, 4 eq.) in DMSO at 20 °C for 0.5 hour.
  • ADC-15 (CADC (mg/mL): 3.56, V (mL): 0.126, yield: 45.0%).
  • CADC mg/mL
  • V mL
  • yield 45.0%.
  • SEC-DAR 1.53, SEC purity: 81.16% and free linker payload (mol/mol%): 0.63%.
  • Patritumab 1.0 mg, 3.77 mg/mL, 1.0 eq.
  • 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution.
  • the reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs.
  • ADC-16 The mixture was purified by treating with dextran coated charcoal, twice and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-16 (CADC (mg/mL): 5.12, V (mL): 0.070, yield: 35.8%).
  • CADC mg/mL
  • V mL
  • yield 35.8%
  • HIC-DAR 1.32
  • SEC purity 91.74%
  • free linker payload mol/mol%): 0.37%.
  • Sacituzumab (1.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Sacituzumab (1.0 mg, 11.26 mg/mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-14 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs.
  • ADC-20 The mixture was purified by treating with dextran coated charcoal twice and filtered through a hydrophilic membrane filter, followed by three times ultrafiltration to afford ADC-20 (CADC (mg/mL): 3.70, V (mL): 0.092, yield: 34%).
  • CADC mg/mL
  • V mL
  • yield 34%).
  • HIC-DAR 1.45
  • SEC-DAR 1.90
  • SEC purity 97.61%
  • free linker payload mol/mol%): not detected.
  • Sacituzumab (0.7 mg, 3.09 mg/mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-5 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-21 (CADC (mg/mL): 3.07, V (mL): 0.14, yield: 61.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.58, SEC purity: 94.6%.
  • Sacituzumab (0.45 mg, 3.09 mg/mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-6 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-22 (CADC (mg/mL): 2.80, V (mL): 0.11, yield: 68.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 1.11, SEC purity: 100%.
  • Sacituzumab (0.45 mg, 3.09 mg/mL, 1.0 eq.) in PBS pH 7.4 was partially reduced by adding TCEP (1 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-8 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs. The mixture was purified by three times ultrafiltration to afford ADC-23 (CADC (mg/mL): 2.07, V (mL): 0.14, yield: 64.4%). The following characteristic values were obtained according to common characterization protocols for ADCs. HIC-DAR: 0.78, SEC purity: 93.2%.
  • Mirvetuximab (1.0 mg, 6.70 mg/mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Mirvetuximab (1.0 mg, 6.70 mg/mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Cetuximab 1.0 mg, 6.47 mg/mL, 1.0 eq.
  • 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Cetuximab 1.0 mg, 6.47 mg/mL, 1.0 eq.
  • 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution.
  • the reduction was conducted at 20 °C for
  • Cetuximab 1.0 mg, 6.47 mg/mL, 1.0 eq.
  • 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.5 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for
  • ADC-29 (CADC (mg/mL): 12.21, V (mL): 0.05, yield: 61.05%).
  • HIC-DAR 1.04, SEC purity: 85.13% and free linker payload (mol/mol%): ⁇ 1%.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-6 (10 mg/mL, 4 eq.) in DMSO at 20 °C for 0.5 hrs.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-34 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs.
  • ADC- 31 (CADC (mg/mL): 10.59, V (mL): 0.05, yield: 51.18%).
  • CADC mg/mL
  • V mL
  • HIC-DAR 0.71
  • SEC purity 98.99%
  • free linker payload mol/mol%): ⁇ 1%.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-7 (10 mg/mL, 4.0 eq.) in DMSO at 22 °C for 1.0 h.
  • ADC-32 (CADC (mg/mL): 6.32, V (mL): 0.12, yield: 75.8%).
  • CADC mg/mL
  • V mL
  • yield 75.8%.
  • HIC-DAR 2.0, SEC purity: 99.95% and free linker payload (mol/mol%): not detected.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 8.0 was partially reduced by adding TCEP (2 mg/mL, 1.8 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-8 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs.
  • ADC-33 (CADC (mg/mL): 13.00, V (mL): 0.045, yield: 58.50%).
  • CADC mg/mL
  • V mL
  • yield 58.50%.
  • HIC-DAR 1.01
  • SEC purity 84.42%
  • free linker payload mol/mol%): ⁇ 1%.
  • Trastuzumab (1.0 mg, 38.7 mg/mL, 1.0 eq.) in 50 mM PBS pH 6.0 was partially reduced by adding TCEP (2 mg/mL, 2.0 eq.) aqueous solution. The reduction was conducted at 20 °C for 1.5 hrs, and then conjugated with LP-9 (10 mg/mL, 4.0 eq.) in DMSO at 20 °C for 0.5 hrs.
  • ADC-34 (CADC (mg/mL): 3.92, V (mL): 0.097, yield: 38%).
  • CADC mg/mL
  • V mL
  • yield 38%).
  • HIC-DAR 1.52
  • SEC-DAR 1.69
  • SEC purity 97.17%
  • free linker payload mol/mol%): not detected.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-12 (10 mg/mL, 4.0 eq.) in DMSO at 22 °C for 1 hr.
  • ADC-35 (CADC (mg/mL): 3.15, V (mL): 0.16, yield: 50.4 %).
  • CADC CADC (mg/mL): 3.15, V (mL): 0.16, yield: 50.4 %).
  • HIC-DAR 2.4, SEC purity: 94.72% and free linker payload (mol/mol%): 0.71 %.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-11 (10 mg/mL, 4.0 eq.) in DMSO at 22 °C for 1.0 hr.
  • ADC-36 (CADC (mg/mL): 6.24, V (mL): 0.12, yield: 74.9 %).
  • CADC mg/mL
  • V mL
  • yield 74.9 %.
  • HIC-DAR 1.9, SEC purity: 99.92% and free linker payload (mol/mol%): not detected.
  • Trastuzumab (1.0 mg, 38.9 mg/mL, 1.0 eq.) in 50 mM PBS pH 7.4 was partially reduced by adding TCEP (10 mM, 1.8 eq.) aqueous solution. The reduction was conducted at 22 °C for 2.0 hrs, and then conjugated with LP-30 (10 mg/mL, 4.0 eq.) in DMSO at 22 °C for 1 h.

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Abstract

La présente invention concerne de nouveaux dérivés de trabectédine et de lurbinectédine, des conjugués anticorps-médicament correspondants, et un procédé de préparation des conjugués anticorps-médicament. L'invention concerne en outre des formes posologiques pharmaceutiques comprenant les nouveaux dérivés de trabectédine ou de lurbinectédine ou les conjugués anticorps-médicament correspondants. En outre, l'invention concerne de nouveaux dérivés de trabectédine et de lurbinectédine, des conjugués anticorps-médicament correspondants, et des formes posologiques pharmaceutiques correspondantes destinées à être utilisées en tant que médicament ou destinées à être utilisées dans le traitement de types de cancers spécifiques.
PCT/SG2023/050713 2023-03-07 2023-10-24 Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine Pending WO2024186264A1 (fr)

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CN202380095535.9A CN120826407A (zh) 2023-03-07 2023-10-24 包含曲贝替定和芦比替定衍生物的抗体药物偶联物
AU2023435820A AU2023435820A1 (en) 2023-03-07 2023-10-24 Antibody-drug conjugates comprising trabectedin and lurbinectedin derivatives
KR1020257029158A KR20250155017A (ko) 2023-03-07 2023-10-24 트라벡테딘 및 루르비넥테딘 유도체를 포함하는 항체-약물 접합체
MX2025010161A MX2025010161A (es) 2023-03-07 2025-08-27 Conjugados de anticuerpo-farmaco que comprenden derivados de trabectedina y lurbinectedina

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SGPCT/SG2023/050138 2023-03-07
PCT/SG2023/050138 WO2024186263A1 (fr) 2023-03-07 2023-03-07 Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine

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PCT/SG2023/050713 Pending WO2024186264A1 (fr) 2023-03-07 2023-10-24 Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine

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WO (2) WO2024186263A1 (fr)

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CN119591621A (zh) * 2023-09-11 2025-03-11 泰诚思(上海)生物医药有限公司 新型海鞘素衍生物、其制备方法及用途、抗体药物偶联物及其应用

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MX2025010161A (es) 2025-10-01
AU2023435820A1 (en) 2025-08-07
KR20250155017A (ko) 2025-10-29
CN120826407A (zh) 2025-10-21

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