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WO2025151608A1 - Unités de liaison pour conjugués ligand-médicament et leurs procédés de fabrication et d'utilisation - Google Patents

Unités de liaison pour conjugués ligand-médicament et leurs procédés de fabrication et d'utilisation

Info

Publication number
WO2025151608A1
WO2025151608A1 PCT/US2025/010902 US2025010902W WO2025151608A1 WO 2025151608 A1 WO2025151608 A1 WO 2025151608A1 US 2025010902 W US2025010902 W US 2025010902W WO 2025151608 A1 WO2025151608 A1 WO 2025151608A1
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WO
WIPO (PCT)
Prior art keywords
drug
antibody
substituted
unsubstituted
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/010902
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English (en)
Inventor
Yi Zhu
Weili WAN
Tianzi YU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Systimmune Inc
Original Assignee
Systimmune Inc
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Filing date
Publication date
Application filed by Systimmune Inc filed Critical Systimmune Inc
Publication of WO2025151608A1 publication Critical patent/WO2025151608A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/6849—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 receptor, a cell surface antigen or a cell surface determinant
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • ADCs Antibody -Drug Conjugates
  • ADCs are a new type of targeted therapy that combine the advantages of high selectivity of antibodies and high activity of cytotoxic drugs. With their "high efficiency and low toxicity" characteristics, ADCs have become a research hotspot in the field of targeted cancer therapy. In recent years, the rapid development has led to the three generations of ADCs.
  • L 1 and L 2 are the same or different, each independently selected from, without limitation, hydrogen, deuterium, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10 heterocyclic, carboxylic acid, amide, ester, sulfite, sulfonate, phosphoric acid, pyrophosphoric acid, natural or unnatural amino acid residues, polyethylene glycol, or a combination thereof;
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, the combination of one or more of substituted or unsubstituted Ci-Ce alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, polyethylene glycol;
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, substituted or unsubstituted Ci -Ce alkylene;
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, Ci-Ce alkylene;
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, methylene, ethylene;
  • L 5 and L 6 are each independently present or absent, identical or different when present, selected from, without limitation, hydrogen, deuterium, oxygen, sulfur, hydroxyl, carbonyl, amide, ester, tert-butoxycarbonyl (Boc), benzyl oxy carbonyl (Cbz), allyl oxy carbonyl (Alloc), benzyl, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C ealkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, polyethylene glycol in one or more combinations;
  • L 6 is absent, L 5 is present, and 1? is selected from, without limitation, hydrogen, Ci-Ce alkyl;
  • L 6 is absent, L 5 is present, and L 5 is hydrogen;
  • Z is N, O, S or quaternary amines
  • Z is N.
  • W 1 and W 2 are the same or different, each independently selected from, without limitation, a group linked to a carboxyl group, an amino group, a carbonyl group, a sulfhydryl group, an azide group, an alkenyl group, a conjugated dienyl group, an alkynyl group, a tetrazine group, and in one embodiment, from a group linked to a sulfhydryl group, wherein at least one of W 1 or W 2 is selected from a connecting group comprising the structure of a maleimide.
  • M® is selected from H® , Li® , Na® , K® or NH4®. wherein, the position shown by the wavy line at the end of the structure is the attachment site, and the wavy line in the middle of the structure indicates either of the two chiralities, the / ⁇ -absolute or S- absolute configuration;
  • At least one of W 1 or W 2 is selected from a connecting group comprising a maleimide structure; each Lp is selected from the same or different groups including, but not limited to, substituted or unsubstituted Ci-Ce alkyl groups, chlorine, bromine, iodine, OMs, OTs;
  • W 1 and W 2 are the same or different, each independently selected from, without limitation, the following structures, or its racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates thereof:
  • At least one of W 1 or W 2 is selected from a connecting group comprising a maleimide structure.
  • said connector group is derived from, without limitation, the following structures:
  • Lp is selected from the same or different groups, including but not limited to deuterium, chlorine, bromine, iodine, OMs, OTs;
  • said connector group may be derived from, without limitation, the following structures: In one embodiment, said connector group may derived from, without limitation, the following structures:
  • L 1 and L 2 are the same or different, each independently selected from, without limitation, hydrogen, deuterium, substituted or unsubstituted Ci-Ce alkyl, substituted or un substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10- membered heterocyclic, carboxylic acid, amide, ester, sulfite, sulfonate, phosphoric acid, pyrophosphoric acid, natural or unnatural amino acid residues polyethylene glycol, or a combination thereof;
  • D is a drug unit.
  • D may be a drug and/or a drug precursor.
  • the drug unit is linked to L by a covalent bond;
  • said linker-drug compound has a structure such as Formula IV-A or IV-B, in one embodiment, having a structure such as Formula IV-A,
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, substituted or unsubstituted Ci-Ce alkylene;
  • L 8 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, carboxylic acid, amide, ester, sulfinyl, sulfonate, phosphoric acid, pyrophosphoric acid, natural or unnatural amino acid residues, polyethylene glycol, or a combination thereof;
  • L 8 is selected from the carboxyl group
  • L 9 is selected from the group consisting of one or more combinations selected from the group consisting of oxygen, sulfur, carbonyl, amide, ester, substituted or unsubstituted Ci-Ce alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocycloalkyl, or polyethylene glycol;
  • L 10 is not present
  • W 1 and W 2 are as defined above;
  • Z is N, O, S or quaternary amines; In one embodiment, Z is N;
  • D is a drug and said drug is linked to L by a covalent bond
  • D is a drug precursor and said drug precursor is linked to L by a covalent bond.
  • said linking moiety L has the structure shown in Formula V below,
  • Ai, A2, and A3 each absent or present, independently; when Ai is present, Ai is a modifying unit, in one embodiment, from a branchable unit and/or a hydrophilic unit; when A2 is present, A2 is a breakable or a non-breakable unit; when A3 is present, A3 is an elimination unit and/or a chelation unit; the position shown by the wavy line is the connection site.
  • A2 may be present or absent.
  • said A2 when A2 is present, said A2 is selected from, without limitation, a breakable or unbreakable unit.
  • the unbreakable unit is selected from, without limitation, a substituted or unsubstituted Ci-Ce alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, an aryl, a heteroaryl, a C3-C10 cycloalkyl, a 3-10-membered heterocyclic, an amide, an ester, polyethylene glycol, or a combination thereof.
  • said enzymatically sensitive connection unit is selected from, without limitation, a histone protease breakable connection unit, a phosphodiesterase and/or pyrophosphate esterase breakable connection unit, a P-glucuronidase breakable connection unit, a 0-galactosidase breakable connection unit, a sulfate esterase breakable connection unit or a combination thereof.
  • said drug is selected from, without limitation, cytotoxic drugs.
  • said drug is obtained by chelating a drug precursor with a metal ion, such as a radioisotope.
  • said drug precursor is selected from, without limitation,
  • said drug precursor is obtained by chelating the drug with a metal ion, such as a radioisotope.
  • said cytotoxic agent is selected from, without limitation, a DNA damaging agent, a DNA topoisomerase inhibitor, a microtubule and/or microtubule protein inhibitor, an RNA polymerase inhibitor, or a combination thereof.
  • said DNA damaging agents include, but are not limited to, derivatives of calicheamicin, anthramycin, ecteinascidins toxin, adriamycin, mitomycin, duocarmycin, or a combination thereof.
  • said DNA topoisomerase inhibitors include, but are not limited to, derivatives of camptothecin, podophyllotoxin, etoposide, or a combination thereof.
  • said microtubule and/or microtubule protein inhibitors include, but are not limited to, derivatives of maytansine, auristatin, eribulin, tubulysin, or a combination thereof.
  • said drug is selected from, without limitation, the following structures:
  • X- is independently selected from Cl-, Br- I’, MeSO 3 -, CF3COO In one embodiment, X- is CF 3 COO’ ;
  • D is selected from the following structures:
  • each X' is independently selected from Cl', Br, F, MeSCh', CFaCOO'. in one embodiment, X' is CFaCOO' .
  • said drug precursor includes, but is not limited to, the following structure:
  • said radioisotope is selected from, without limitation, 18 F, 67 Ga, 68 Ga, 99m Tc, 123 I, 125 I, 131 I, 90 Y, 177 Lu, 47 Sc, 64 Cu, 67 Cu, 32 P, 186 Re, 188 Re, 89 Sr, 153 Sm, 198 Au, 166 Ho, 165 Dy, 169 Er, 149 Tb, 161 Tb, 211 At, 212 Bi, 213 Bi, 212 Pb, 223 Ra, 225 Ac, or a combination thereof.
  • said radioisotope is selected from, without limitation, 68 Ga, " m Tc, 131 I, 90 Y, 177 Lu, 64 Cu, 211 At, 213 Bi, 212 Pb, 225 Ac, or a combination thereof
  • L 8 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, carboxylic acid, amide, ester, sulfinyl, sulfonate, phosphoric acid, pyrophosphoric acid, natural or unnatural amino acid residues, polyethylene glycol, or a combination thereof;
  • L 7 is selected from the group consisting of one or more combinations of a substituted or unsubstituted Ci-Ce alkylene group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted Ci-Ct, alkynyl group, an aryl group, a heteroaryl group, a C3-C10 cycloalkyl group, a 3-10-membered heterocycloalkyl group, a carbonyl group, an amide group, an ester group, a sulfinyl group, a sulfonate group, a phosphoric acid group, a pyrophosphoric acid group, a natural or unnatural amino acid residue, or a polyethylene glycol;
  • W 3 and W 4 are the same or different, each independently and non-limitingly selected from a connecting group.
  • at least one of W 3 and W 4 is selected from a group comprising a succinimide structure; in one embodiment, the succinimide structure is a closed-ring form, an open-ring form or any combination thereof; in one embodiment, the succinimide structure is in an open-ring form or any combination of closed-ring form and open-ring form; in one embodiment, the succinimide structure is in a ring-opening form;
  • L 1 , L 2 , L 8 , L 7 and/or W 3 , W 4 are covalently linked to the circle.
  • the circles are selected from scaffolds containing basic groups;
  • D is a drug unit.
  • D may be a drug and/or a drug precursor.
  • the drug unit D is linked to L by a covalent bond;
  • D is a drug and said drug is linked to L by a covalent bond; In one embodiment, D is a drug precursor and said drug precursor is linked to L by a covalent bond.
  • said ligand-drug conjugate or its racemate, enantiomer, diastereoisomer, ring-opening form, pharmaceutically acceptable salt or solvate thereof is characterized in that said ligand-drug conjugate has a structure as shown below in Formula VII-A or VII-B, in one embodiment, having a structure as shown in Formula VII-A; wherein,
  • L 1 and L 2 are the same or different, each independently selected from, without limitation, carboxyl,
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, Ci-Ce alkylene;
  • L 3 and L 4 are the same or different, each independently selected from, without limitation, methylene, ethylene;
  • L 5 and L 6 are each independently present or absent, and when present are identical or different, and are selected from, without limitation, hydrogen, deuterium, oxygen, sulfur, hydroxyl, carbonyl, amide, ester, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), benzyl, substituted or unsubstituted Ci-Ce alkylidene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, polyethlene glycol, or a combination thereof;
  • L 6 is absent, L 5 is present, and L 5 is selected from, without limitation, hydrogen, substituted or unsubstituted Ci-Ce alkyl;
  • L 7 is selected from the group consisting of one or more combinations of a substituted or unsubstituted Ci-Ce alkylene group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, an aryl group, a heteroaryl group, a C3-C10 cycloalkyl group, a 3-10-membered heterocycloalkyl group, a carbonyl group, an amide group, an ester group, a sulfinyl group, a sulfonate group, a phosphoric acid group, a pyrophosphoric acid group, a natural or unnatural amino acid residue, or a polyethylene glycol;
  • L 7 is carbonyl
  • L 8 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted Ci-Ce alkyl, substituted or un substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocyclic, carboxylic acid, amide, ester, sulfinyl, sulfonate, phosphoric acid, pyrophosphoric acid, natural or unnatural amino acid residues, polyethylene glycol, or a combination thereof;
  • L 8 is selected from the carboxyl group
  • L 9 is selected from the group consisting of one or more combinations selected from the group consisting of oxygen, sulfur, carbonyl, amide, ester, substituted or unsubstituted Ci-Ce alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, 3-10-membered heterocycloalkyl, or polyethylene glycol;
  • STEAP1 antibody anti-SLAMF7/CSl antibody, anti-NaPi2B/SLC34A2 antibody, anti-GPNMB antibody, anti-HER3(ErbB3) antibody, anti-HLA-G antibody, anti- MUC1/CD227 antibody, anti-EGFR/HER3 antibody, anti-AXL antibody, anti-GPC3 antibody, anti-CD166 antibody, anti-B7- H3(CD276) antibody, anti-PTK7/CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-N0TCH3 antibody, anti-Nectin 4 antibody, anti-TROP-2 antibody, anti-NKG2D antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-CD71 antibody anti-EphA2 antibody, anti-LYPD3 antibody, anti-TF antibody, anti-FGFR2 antibody, anti-FGFR3 antibody,
  • Ai, Az, and A3 each are present or absent, independently; when Ai is present, Ai is selected from a modifying unit, in one embodiment, from a branchable unit and/or a hydrophilic unit; when A2 is present, A2 is selected from a breakable unit or a non-breakable unit; when A3 is present, A3 is selected from an elimination unit and/or a chelation unit; the position shown by the wavy line is the connection site.
  • said A2 when A2 is present, said A2 is selected from, without limitation, a breakable or unbreakable unit, wherein the unbreakable unit is non-limitingly selected from a substituted or unsubstituted Ci-Ce alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, an aryl, a heteroaryl group, a C3-C10 cycloalkyl group, a 3-10-membered heterocycloalkyl group, an amide, an ester group, or a polyethlene glycol, or a combination thereof.
  • the unbreakable unit is non-limitingly selected from a substituted or unsubstituted Ci-Ce alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, an ary
  • said drug is selected from, without limitation, a cytotoxic drug, a radioisotope, a detection and/or diagnostic reagent, an enzyme inhibitor, a protein degrading agent, an immunomodulator, a peptide, or a nucleotide.
  • said drug is a cytotoxic drug.
  • said drug is obtained by chelation of a drug precursor with a metal ion, such as a radioisotope.
  • said DNA topoisomerase inhibitors include, but are not limited to, camptothecin derivatives, podophyllotoxin derivatives, etoposide derivatives, or a combination thereof.
  • said RNA polymerase inhibitors include, but are not limited to, amanitin peptide derivatives, or a combination thereof.
  • said drug is obtained by chelation of a drug precursor with a metal ion, such as a radioisotope.
  • said drug precursor includes, but is not limited to, the following structure,
  • nl, n2, n3 and n4 are independently selected from integers or decimals of 0-10, and nl, n2, n3 and n4 are not 0 at the same time; in one embodiment, at least one of n2, n3 and n4 is not 0; In one embodiment, nl, n2 and n3 are 0, and n4 is not 0; and the sum of nl+n2+n3+n4 is an integer or decimal from 1 to 10, for example, 1-1.5, 1.5- 2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5-9, 9-9.5 or 9.5-10, in one embodiment, an integer or decimal selected from 2-8, and in one embodiment an integer or decimal selected from 3-6
  • Tg is selected from ligands, in one embodiment, from antibodies.
  • the ring-opening form of said ligand-drug conjugate is selected from, without limitation, the following structures:
  • n is an integer or decimal number selected from 1-10; for example, n may be an integer or decimal number between 1-1.5, 1.5-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5-9, 9-9.5 or 9.5-10); in one embodiment, n may be an integer or decimal number from 2-8; in one embodiment, n may be an integer or decimal number from 3-6;
  • Tg is selected from ligands, in one embodiment, from antibodies.
  • the dotted line represents the bond connected with the succinimide ring-opening structure at any site that can be connected and does not exceed the conventional valence state of each atom.
  • the dotted line connected to No. l S atom means that it is connected to succinimide ring-opening structure at No.1 C atom or No.2 C atom
  • the dotted line connected to No.2 S atom means that it is connected to succinimide ring-opening structure at No.3 C atom or No.4 C atom.
  • said pharmaceutically acceptable salt comprises a salt of sodium, potassium, calcium, or magnesium derived from an acidic functional group in the ligand-drug conjugate or linker-drug compound.
  • the pharmaceutically acceptable salt may be a salt derived from a basic functional group in the ligand-drug conjugate or linker-drug compound including, for example, an acetate, trifluoroacetate, citrate, oxalate, tartrate, malate, nitrate, chloride, bromide, iodide, sulfate, bisulfate, phosphate, lactate, oleate, ascorbate salicylate, formate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.
  • the application provides methods of preparing a ligand-drug conjugate or its racemate, enantiomer, diastereoisomer, ring-opening form, pharmaceutically acceptable salt or solvate thereof.
  • the method includes the step of reacting a reduced Tg with a linker-drug compound or its racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvates in a coupling reaction under suitable conditions to provide the desired conjugate.
  • said method may further comprise the step of purifying the conjugate.
  • the application provides pharmaceutical compositions comprising a linkerdrug compound, its racemate thereof, enantiomer, diastereoisomer, pharmaceutically acceptable salt or solvate, or a ligand-drug conjugate or its racemate thereof, enantiomer, diastereoisomer, ring-opening form, pharmaceutically acceptable salt or solvate.
  • the pharmaceutical composition may optionally further comprise a pharmaceutically acceptable carrier.
  • Figure 1 schematically shows the mechanism of the preferred double linker structure
  • FIG 3 shows the in vitro efficacy of TROP2- ADC-24 in human cancer cell lines of A431 (3A), BxPC3 (3B), Fadu (3C), SW620 (3D), and A431+SW620 (3E);
  • connector refers to a chemical structural fragment or bond that is connected to a ligand at one end and to the drug at the other end by other connecting units, or directly to the drug at the other end.
  • non-limiting means that the event or circumstance subsequently described may or may not occur, and the description includes occasions when the event or circumstance does or does not occur.
  • linking site means a chemical bond or unit of attachment to a ligand, wherein the linking site is selected, without limitation, from a carboxyl, amino, carbonyl, mercapto, azido, alkenyl, conjugated dienyl, alkynyl, tetrazinyl linkage, and in one embodiment from a linkage to a sulfhydryl group.
  • linker units can be categorized into two types: unbreakable linker units and breakable linker units.
  • unbreakable linker units In the case of ligand-drug conjugates containing an unbreakable linker, the mechanism of drug release is as follows: upon binding of the conjugate to the antigen, an active molecule consisting of the small molecule drug, the linker unit, and the amino acid residues of the antibody is released. The resulting change in the structure of the drug molecule does not diminish its cytotoxicity, but because the active molecule is electrically charged (amino acid residues), it cannot penetrate neighboring cells.
  • protein degraders refers to structures that degrade target proteins through mediating the recognition of the target protein by ubiquitination ligases.
  • PROTACs proteins that degrade target proteins via the ubiquitin-proteasome pathway
  • molecular gels which also bind ubiquitination ligases, thereby recognizing and degrading entirely new substrates.
  • peptide refers to a fragment of a compound between an amino acid and a protein, consisting of two or more amino acid molecules connected to each other by a peptide bond, and is a structural and functional fragment of a protein, and non-restricted examples include hormones, enzymes, and so on.
  • enzyme inhibitor refers to a substance that inhibits the activity of a specific enzyme in an organism that is associated with a disease to achieve a therapeutic effect.
  • nucleotide refers to a class of compounds consisting of three substances, namely, purine or pyrimidine bases, ribose or deoxyribose, and phosphate, which have a variety of important biological functions.
  • drug load or “drug-antibody ratio (DAR)” refers to the average amount of cytotoxic drug loaded on each ligand or antibody, which can also be expressed as the ratio of drug to antibody amount and can be an integer or a decimal.
  • the amount of drug loaded may range from an average of 1-10 ligations per antibody, for example, it may be any integer selected from between 1-10 including endpoints 1 and 10, or any decimal number between 1- 10.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3- m ethylbutyl, n-hexyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1 -dimethylbutyl 1,2- dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3 -methylhexyl, 4- methyl
  • the alkyl group may be substituted or nonsubstituted, and when substituted, the substituent group may be substituted at any available point of attachment, said substituent group in one embodiment, being one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane thio, heterocycloalkylthio, or oxo.
  • R', R" and R'" each independently refer to hydrogen, unsubstituted Ci-8 alkyl, unsubstituted Ce-Ci 2 aryl (or Ce-Cio aryl), Ce-Ci 2 aryl (or Ce-Cio aryl) substituted by 1-3 halogens, unsubstituted Ci-8 alkyl, Ci-8 alkoxy or Ci-8 thioalkoxy, or unsubstituted Ce-Ci 2 aryl (or Ce-Cio aryl)-Ci-4 alkyl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may form a 3-, 4-, 5-, 6-, or 7-metacyclic ring together with that nitrogen atom.
  • -NR'R" includes 1-pyrrolidinyl and 4- morpholinyl.
  • substituted alkylidene means that the hydrogen in said alkylidene is replaced by a substituent group which, unless otherwise indicated, may be a variety of groups selected from, without limitation, the following examples: -halogen, -OR', -NR"R", -SR', -SiR'R"R"R'", S(O) 2 NR'R", -NR'S(0)2R", -CN and -NO2, the number of substituents is from 0 to (2m'+l), where m' is the total number of carbon atoms in the group, r', R" and R'" each independently refer to hydrogen, unsubstituted Cns alkyl, unsubstituted C6-C12 aryl (or Ce-Cio aryl), C6-C12 aryl (or Ce-Cio aryl) substituted by 1-3 halogens, unsubstituted C1-8 alkyl, C1-8 alkoxy or
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises from 3 to 20 carbon atoms (i.e. "C3-C20 cycloalkyl"), in one embodiment, from 3 to 12 carbon atoms (i.e. "C3-C12 cycloalkyl”), in one embodiment, comprising 3 to 10 carbon atoms (i.e., "C3-C10 cycloalkyl”), in a further embodiment, comprising 3 to 8 carbon atoms (i.e., "C3-C8 cycloalkyl").
  • Non-limiting examples of said heteroaryl groups are, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, phenyl -pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, benzofuranyl, benzothiopheny, benzo- 1,3 -di oxolane (benzodiazem), isodihydroindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1 -phenyl- 1,2, 3 -triazolyl, 2,3-dihydroindolyl, 2,3 -dihydro
  • R', R" and R'" each independently refer to hydrogen, unsubstituted C1-8 alkyl, unsubstituted Ce-Ci 2 aryl (or Ce-Cio aryl), Ce-Ci 2 aryl (or Ce-Cio aryl) substituted by 1-3 halogens, unsubstituted Ci- 8 alkyl, C1-8 alkoxy or C1-8 thioalkoxy, or unsubstituted Ce-Ci 2 aryl (or Ce-Cio aryl)-C 1-4 alkyl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may form a 3-, 4-, 5-, 6-, or 7- metacyclic ring with that nitrogen atom.
  • -NR'R" includes 1-pyrrolidinyl and 4- morpholinyl.
  • alkoxy refers to-O-(alkyl) and-O-(cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above.
  • Ci-Ce alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are in one embodiment, one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.
  • any group which is not further specified or limited in front of or behind the group means that the group is an unsubstituted group.
  • Ci-Ce alkyl has the same meaning as "unsubstituted Ci- Ce alkyl”. The remaining similar groups are explained and understood with reference to the foregoing.
  • the number of repetitions of the repeating unit -O-CH2-CH2- is 1-30, which means that the number of repetitions of the repeating unit is selected from any integer point value within the range including the two endpoints of 1 and 30, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, or the number of repetitions of the repeating unit is selected from any smaller range value within the range including the two endpoints of 1 and 30, such as 1 -2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20, 20-21, 21-22, 22-23, 23-24, 24-25, 25- 26, 26-27, 27-28, 28-29, 29-30, 1-5, 5-10, 10-15, 15-20, 20-25 or 25-30, etc.
  • the remaining similar groups are explained and understood with reference to the foregoing.
  • hydroxyl refers to the -OH group.
  • amide group means -C(O)N(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl is as defined above.
  • Carboxyl means -C(O)OH or its ionic form.
  • pyrophosphate group means -P(O)2 OP(O)2 OH or its ionic form.
  • solvent compound refers to a linker, linker-drug or ligand-drug conjugate forming a pharmaceutically usable solvent compound with one or more solvent molecules
  • solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate.
  • ligand or "targeting moiety” is a targeting agent such as a macromolecular compound, that can recognize and specifically binds to a target moiety such as an antigen or receptor associated with a target cell.
  • the target moiety or target is usually on the cell surface.
  • the role of the ligand is to present the drug to the target cell population bound to the ligand, and these ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells.
  • the ligand is represented by Tg, and the ligand can form a connecting bond with the connecting unit through a heteroatom on the ligand, such as an antibody or an antigen-binding fragment thereof, wherein the antibody may be a chimeric antibody, a humanized antibody, a fully human antibody or a mouse antibody, in one embodiment, a monoclonal antibody.
  • the role of the ligand unit is to deliver the drug unit to a specific target cell population with which the ligand unit interacts.
  • Ligands include, but are not limited to, proteins, polypeptides and peptides, and non-proteins such as sugars. Suitable ligand units include, for example, antibodies, such as full-length (complete) antibodies and antigen-binding fragments thereof.
  • the ligand unit is a non-antibody targeting agent, it can be a peptide or polypeptide, or a non-protein molecule. Examples of such targeting agents include interferons, lymphokines, hormones, growth factors and colony stimulating factors, vitamins, nutrient transport molecules, or any other cell binding molecules or substances.
  • the linker is covalently attached to the sulfur atom of the ligand.
  • the sulfur atom is the sulfur atom of a cysteine residue, which forms an interchain disulfide bond of the antibody.
  • the sulfur atom is a sulfur atom of a cysteine residue that has been introduced into the ligand unit, which forms an interchain disulfide bond of the antibody.
  • the sulfur atom is a sulfur atom of a cysteine residue that has been introduced into the ligand unit (e.g., by site-directed mutagenesis or chemical reaction).
  • antibody or “antibody unit” includes any part of the antibody structure within the scope to which it belongs. This unit can bind, reactively associate, or complex a receptor, antigen or other receptor unit possessed by the targeted cell population.
  • the antibody can be any protein or protein-like molecule that can bind, complex or react with a part of the cell population to be treated or biomodified.
  • the antibodies constituting the antibody-drug conjugates retain their antigen binding ability in their original wild state. Therefore, the antibody components can bind specifically to the antigen.
  • the antigens involved include, for example, tumor-associated antigens (TAA), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules related to tissue growth and differentiation (such as known or predicted functional), lymphokines, cytokines, molecules involved in cell cycle regulation, molecules involved in angiogenesis, and molecules related to angiogenesis (such as known or predicted functional).
  • TAA tumor-associated antigens
  • cell survival regulators cell survival regulators
  • cell proliferation regulators molecules related to tissue growth and differentiation
  • lymphokines such as known or predicted functional
  • cytokines molecules involved in cell cycle regulation
  • molecules involved in angiogenesis and molecules related to angiogenesis (such as known or predicted functional)
  • Tumor-related factors can be cluster differentiation factors (such as CD proteins).
  • Antibodies used in antibody-drug conjugates include, but are not limited to, antibodies against cell surface receptors and tumor-associated antigens (TAAs).
  • TAAs tumor-associated antigens
  • Such tumor-associated antigens are well known in the industry and can be prepared by antibody preparation methods and information well known in the industry.
  • TAAs tumor-associated antigens
  • To develop effective cellular level targets that can be used for cancer diagnosis and treatment researchers strive to find transmembrane or other tumor-associated polypeptides. These targets can be specifically expressed on the surface of one or more cancer cells, and rarely or not expressed on the surface of one or more non-cancerous cells.
  • tumor-associated polypeptides are more overexpressed on the surface of cancer cells relative to the surface of non-cancerous cells. Confirming such tumor-associated factors can greatly improve the specific targeting characteristics of antibodybased cancer treatment.
  • antigen-related information well known in the industry is marked as follows, including name, other names, and gene bank accession number.
  • Nucleic acid and amino acid sequences corresponding to tumor-associated antigens can be found in public databases, such as Genbank.
  • the antibody targets the corresponding tumor- associated antigen, including all amino acid sequence variants and isotypes, and has at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% homology with the sequence confirmed in the reference, or has biological properties and characteristics that are completely consistent with the tumor-associated antigen sequence in the cited reference.
  • the antibodies described herein are, without limitation, mono-, di- or multi-specific antibodies, or the following antibodies: anti-EGFRvIII antibody, anti -DLL-3 antibody, anti- PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti- TDGF1 antibody, anti-ETBR antibody, anti-MSLN antibody, anti-TIM-1 antibody, anti- LRRC15 antibody, Anti-LIV-1 antibody, anti-CanAg/AFP antibody, anti-Claudinl8.2 antibody, anti-Mesothelin antibody, anti-HER2(ErbB2) antibody, anti-EGFR antibody, anti-c-MET antibody, anti-SLITRK6 antibody, anti-KIT/CD117 antibody, anti-STEAPl antibody, anti- SLAMF7/CS1 antibody, anti-NaPi2B/SLC34A2 antibody, anti-GPNMB antibody, anti- HER3(ErbB3) antibody, anti-MUCl/CD227 antibody, anti-AXL antibody,
  • Antibodies of the application include, but are not limited to, murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, in one embodiment, humanized antibodies and fully human antibodies.
  • the cytotoxic drug is coupled to the thiol-SH of the opened cysteine interchain and/or the thiol-SH of the site-directed mutated cysteine residue through a linking unit, an optional modification unit and a linker unit.
  • the number of drug molecules that can be coupled to the antibody in the coupling reaction may be less than or equal to the theoretical maximum value.
  • the disclosure also includes various deuterated forms of drugs, linkers, linker units-drugs containing linkers, and ligand-drug conjugates containing linkers.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can synthesize deuterated forms of drugs, linkers, linker units-drugs containing linkers, and ligand-drug conjugates containing linkers with reference to relevant literature.
  • deuterated starting materials can be used to prepare deuterated forms of drugs, linkers, linker-drugs containing linkers, and ligand-drug conjugates containing linkers, or they can be synthesized using conventional techniques using deuterated reagents, nonlimiting examples of which include deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, etc.
  • pharmaceutical composition refers to a mixture containing one or more antibody-drug conjugates or their stereoisomers, pharmaceutically acceptable salts or solvates, or linker drugs or their stereoisomers, pharmaceutically acceptable salts or solvates, and other chemical components, as well as other components such as physiologically or pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to promote administration to an organism, facilitate the absorption of active ingredients, and thus exert biological activity.
  • the preparation of conventional pharmaceutical compositions can be found in various pharmacopies including for example the Chinese Pharmacopoeia or USP.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be preventive, in terms of completely or partially preventing, modulatin, of alleviating a disease or its symptoms; and/or therapeutic, in terms of partially or completely stabilizing or curing a disease and/or side effects due to a disease.
  • subject includes a human or non-human animal.
  • exemplary human subjects include humans (referred to as patients, for example) or normal individuals suffering from a disease (e.g., a disease described herein).
  • non-human animal includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • Serine benzyl ester hydrochloride (43.16 mmol, 40 g) was weighed and dissolved in DCM (200 mL). The system was cooled to 0 °C, and TEA (90.46 mmol, 12.6 mL) was added dropwise. After the addition was completed, the mixture was stirred for 20 min. At the same temperature, a solution of o-nitrobenzenesulfonyl chloride (45.32 mmol, 10.04 g) in DCM (30 mL) was added dropwise to the system. After the reaction was completed by TLC monitoring, saturated NaHCCh aqueous solution (100 mL) was added to the reaction system to quench the reaction.
  • R-isoserine 113.2 mmol, 12.0 g was weighed and dissolved in THF (500 mL). The system was cooled to 0°C, and an aqueous solution (250 mL) of Na2COs (138.7 mmol, 15.0 g) was added, followed by a THF solution (200 mL) of Fmoc-Cl (138.7 mmol, 36.6 g). The reaction was allowed to rise to room temperature for 6 h, and the reaction was complete as determined by TLC. The product was concentrated to remove most of the THF, and EA (200 mL x 3 times) was added for extraction.
  • the mixed solution was extracted with ethyl acetate (100 mL*3 times), dried over anhydrous sodium sulfate, and concentrated and used directly in the next reaction.
  • the above crude compound and 100 mL of DMF were added to a 250 mL round-bottom flask, followed by DBU (21 mmol, 3.2 mL).
  • the reaction was stirred at room temperature for about 0.5 h. After TLC detection, the reaction was completed, and the mixture was concentrated under reduced pressure by a water pump.
  • Step 1 Compound Ila
  • Step 3 Compound 16c
  • Compound 16b 400.8 mg, 0.31 mmol
  • DCM (10 mL) were added to a 25 mL singlenecked bottle, and di(p-nitrobenzene) carbonate (102.3 mg, 0.32 mmol) and DIPEA (33 uL, 0.32 mmol) were added in sequence at room temperature.
  • the mixture was reacted for 2 h after the addition was completed. After the reaction was completed under TLC monitoring, the insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure and used directly in the next step without purification.
  • Example 20 Referring to the synthetic route of Example 19, 15.8 mg of white solid compound LD-17 was prepared; LC-MS [M/2+H]+: m/z 704.5.
  • Step 1 Compound 29a Ml (50 mg, 0.136 mmol) and 15 mL THF were added to a 25 mL round-bottom flask and stirred in an ice-water bath for 15 min. Toluenesulfonic acid monohydrate (2.6 mg, 0.0136 mmol) was added and stirred for 10 min. Auristatin E (88.2 mg, 0.12 mmol) was added and stirred in an ice-water bath after the addition was complete. The starting material disappeared after TLC detection for about 1 h. The reaction was quenched with saturated sodium bicarbonate. The mixed solution was extracted with ethyl acetate (50 mL * 3 times), dried over anhydrous sodium sulfate, and concentrated for the next step.
  • Tri-tert-butyl l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (8.62 g, 16.7 mmol) and 100 mL of anhydrous THF were added to a 250 mL round-bottom flask, and compound 40a (6.81 g, 16.8 mmol) and potassium carbonate (2.37 g, 16.8 mmol) were added in sequence at room temperature. After maintaining the reaction at room temperature for 2.5 h. TLC monitoring showed that the starting material disappeared.
  • OPM-293 ProFeed was added at 5% (v/v) on the first day after transfection, and OPM-293 ProFeed was added again at 5% (v/v) on the third day after transfection. The supernatant was collected by centrifugation on the sixth day after transfection.
  • the cell expression supernatant was collected and passed through a Protein A affinity chromatography column (UniMab 50, Suzhou Nanovita Technology Co., Ltd.), eluted with 0.05 M sodium acetate (pH 3.6), and the captured antibody was adjusted to pH 7.0 with 1 M Tris-HCl (pH 8.8).
  • the amino acid sequences of the heavy chain (HC, SEQ ID NO: 17) and the light chain (LC, SEQ ID NO: 18), HC variable region (VH, SEQ ID NO: 13), and LC variable region (VL, SEQ ID NO: 14) of the anti-TROP2 antibody are listed in Sequence Listing.
  • the amino acid sequences of complementarity determining regions (CDRs) were underlined in SEQ ID NO: 13, 14 and listed as SEQ ID NO: 1-6 for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDRL2, and CDRL3, respectively.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • Example 47 The ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • Example 49 The ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • Example 61 The ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ARC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • the ARC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • Example 81 wherein TROP2 is an antibody targeting TROP2.
  • the ADC of this example was prepared according to the universal preparation method of ligand-drug conjugate in Example 44.
  • Control ADC-1 was prepared according to the method of W02015098099A1 (incorporated herein by reference in its entirety). wherein TROP2 is an antibody targeting TROP2.
  • Compound 6b was condensed with the MC linker to prepare the Linker-Drug of the control ADC, ADC-3 (see Example 82 for the method of preparation).
  • Example 85 Control ADC-4 Compound 29a was condensed with MC-Gly-Gly-Phe linker to prepare Linker-Drug of the control ADC, ADC-4 (see Example 83 for the method of preparation).
  • the antibody-drug conjugates were analyzed by mass spectrometry to determine the hydrolysis of the antibody-drug conjugate linker.
  • the succinimide linker in the antibody-drug conjugate of this application exists in the form of partial ring opening or even complete ring opening.
  • Example 88 Monomer rate of ADCs by SEC-HPLC Column: Biocore SEC-300 5 um, 4.6* 300 mm;
  • Each ADC sample was aseptically diluted to a final drug concentration of 0.6 mg/mL and incubated in a 37°C water bath for 0, 3, and 7 days, respectively.
  • the sample and control ADCs were purified and extracted, and their DAR values were determined.
  • TROP2-ADC-06 and TROP2-ADC-24 showed no significant decrease in DAR value after incubation in plasma for 7 days (Table 6).
  • the antibody-drug conjugates disclosed herein have excellent stability in plasma.
  • Example 90 In vitro pharmacodynamics of ADCs
  • Assay medium RPMI-1640 medium + 10% FBS + 100 U/mL Penicillin/Streptomycin; Basal medium: Genpex Bio; FBS: ExCell Bio;
  • CTG high sensitivity chemiluminescence detection technology was used to quantify adenosine triphosphate (ATP) in living cells for calculating the cell survival rate.
  • ATP adenosine triphosphate
  • mice a subcutaneous xenograft model of human epidermal carcinoma cells A431 was established in BALB/c-nu mice.
  • the A431cell suspension (1.3> ⁇ 10 6 cells in 0.1 mL) were injected subcutaneously into the right scapula of 6 ⁇ 7-week-old BALB/c-nu mice.
  • the mice were randomly divided into 13 groups, namely, a lysate control group (Vehicle) and 12 dosing groups, and each group requires 6 mice.

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Abstract

La demande concerne, entre autres, des unités de liaison cycliques à pont auto-stabilisantes et leur application dans des conjugués anticorps-médicament, des composés lieur-médicament préparés par incorporation desdits lieurs, et des conjugués ligand-médicament ayant une qualité stable et une excellente homogénéité. La demande divulgue également des procédés de préparation des lieurs, des composés lieur-médicament et des conjugués ligand-médicament, ainsi que l'application des composés lieur-médicament et des conjugués ligand-médicament dans le traitement de tumeurs, d'infections et de maladies immunitaires.
PCT/US2025/010902 2024-01-10 2025-01-09 Unités de liaison pour conjugués ligand-médicament et leurs procédés de fabrication et d'utilisation Pending WO2025151608A1 (fr)

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Citations (4)

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US20060074008A1 (en) * 2002-07-31 2006-04-06 Senter Peter D Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
WO2018185526A1 (fr) * 2017-04-06 2018-10-11 Hangzhou Dac Biotech Co., Ltd Conjugaison d'un médicament cytotoxique avec une bis-liaison
US20190345186A1 (en) * 2017-01-24 2019-11-14 Pfizer Inc. Calicheamicin deratives and antibody drug conjugates thereof
US20190388555A1 (en) * 2016-11-25 2019-12-26 Mabwell (shanghai) Bioscience Co., Ltd. Di-substituted maleic amide linker for antibody-drug conjugating and preparation method and use thereof

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US20060074008A1 (en) * 2002-07-31 2006-04-06 Senter Peter D Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
US20190388555A1 (en) * 2016-11-25 2019-12-26 Mabwell (shanghai) Bioscience Co., Ltd. Di-substituted maleic amide linker for antibody-drug conjugating and preparation method and use thereof
US20190345186A1 (en) * 2017-01-24 2019-11-14 Pfizer Inc. Calicheamicin deratives and antibody drug conjugates thereof
WO2018185526A1 (fr) * 2017-04-06 2018-10-11 Hangzhou Dac Biotech Co., Ltd Conjugaison d'un médicament cytotoxique avec une bis-liaison

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VOLLMAR BREANNA S., FRANTZ CHRIS, SCHUTTEN MELISSA M., ZHONG FIONA, DEL ROSARIO GEOFFREY, GO MARY ANN T., YU SHANG-FAN, LEIPOLD DO: "Calicheamicin Antibody–Drug Conjugates with Improved Properties", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 20, no. 6, 1 June 2021 (2021-06-01), US , pages 1112 - 1120, XP093337314, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-20-0035 *

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