US20160375147A1 - Maytansinoid derivatives, conjugates thereof, and methods of use - Google Patents

Maytansinoid derivatives, conjugates thereof, and methods of use Download PDF

Info

Publication number
US20160375147A1
US20160375147A1 US15/081,759 US201615081759A US2016375147A1 US 20160375147 A1 US20160375147 A1 US 20160375147A1 US 201615081759 A US201615081759 A US 201615081759A US 2016375147 A1 US2016375147 A1 US 2016375147A1
Authority
US
United States
Prior art keywords
compound
integer
formula
methyl
antibody
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.)
Abandoned
Application number
US15/081,759
Other languages
English (en)
Inventor
Thomas Nittoli
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.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=55650789&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20160375147(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Priority to US15/081,759 priority Critical patent/US20160375147A1/en
Assigned to REGENERON PHARMACEUTICALS, INC. reassignment REGENERON PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NITTOLI, THOMAS
Publication of US20160375147A1 publication Critical patent/US20160375147A1/en
Priority to US16/712,941 priority patent/US20200385402A1/en
Priority to US17/528,144 priority patent/US12297207B2/en
Priority to US19/093,440 priority patent/US20250223299A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A61K47/48384—
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A61K47/48561—
    • 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
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • 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
    • A61K47/6849—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
    • A61K47/6889—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
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/08—Bridged 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
    • C07D498/12—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 three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present disclosure concerns maytansinoid derivatives, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.
  • Proliferative diseases for example cancer
  • Current treatments of proliferative diseases include surgery, radiation, chemotherapy, hormone-based therapy and/or immunotherapy.
  • a number of these treatments, particularly chemotherapy utilize anti-proliferative drugs that limit the spread of the abnormal cells.
  • these drugs are typically indiscriminate in their ability to kill cells, affecting both normal and abnormal cells.
  • ADCs Antibody drug conjugates
  • ADCs are compounds composed of an antibody that is linked, via a chemical linker, to a cytotoxic agent. Such compounds leverage the antibody's binding specificity for its target to deliver a cytotoxic agent to an abnormal cell.
  • A is arylene or heteroarylene
  • L is a linker
  • BA is a binding agent
  • k is an integer from 1 to 30. Also provided herein are stereoisomers of compounds of Formula (I).
  • A is arylene or heteroarylene.
  • A is arylene or heteroarylene and L is a linker.
  • stereoisomers of compounds of Formula PT1 are also provided herein.
  • FIG. 1 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamido-citrulline-valine-caprolyl-6-maleimidyl.
  • FIG. 2 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 3 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 4 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 5 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 6 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-fluoro)benzamido-Cit-Val-Cap-Mal.
  • FIG. 7 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-trifluoromethyl)benzamido-Cit-Val-Cap-Mal.
  • FIG. 8 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-methoxy)benzamido-Cit-Val-Cap-Mal.
  • FIG. 9 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamide.
  • FIG. 10 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-fluoro-4-amino)benzamide
  • FIG. 11 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-trifluoromethyl-4-amino)benzamide.
  • FIG. 12 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-methoxy-4-amino)benzamide.
  • FIG. 13 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-trifluoromethyl-4-amino)benzamide.
  • FIG. 14 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-chloro-4-amino-5-fluoro)benzamide.
  • FIG. 15 depicts a general synthetic sequence for preparing compounds of Formula (II) wherein substituent R is defined herein and below.
  • FIG. 16 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2,5-difluoro-4-amino)benzamide.
  • FIG. 17 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-fluoro-4-amino)benzamide
  • FIG. 18 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-chloro-4-amino)benzamide.
  • FIG. 19 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(5-amino-8-carboxyquinoline)carboxamide.
  • FIG. 20 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-bromo-4-amino)benzamide.
  • FIG. 21 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methoxy-4-amino)benzamide.
  • FIG. 22 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-methyl-4-amino)benzamide.
  • FIG. 23 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methyl-4-amino)benzamide.
  • FIG. 24 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(8-amino-5-carboxyquinoline)carboxamide.
  • FIG. 25 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methoxy-4-amino)benzamido-Cit-Val-Cap-Mal.
  • FIG. 26 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-fluoro-4-amino)benzamido-Cit-Val-Cap-6-amine.
  • FIG. 27 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-methoxy-5-amino)benzamide.
  • FIG. 28 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-4-methoxy)benzamide.
  • FIG. 29 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-5-fluoro)benzamide.
  • FIG. 30 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-fluoro-5-amino)benzamide.
  • FIG. 31 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino)benzamide.
  • FIG. 32 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-4-fluoro)benzamide.
  • FIG. 33 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-4-aminobenzamide-adipic-NHS.
  • FIG. 34 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamide-Cap-Mal.
  • FIG. 35 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-methylsulfonyl-4-amino)benzamide.
  • FIG. 36 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-hydroxy-4-amino)benzamide.
  • FIG. 37 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-amino)benzamide.
  • FIG. 38 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(4-methoxy-2-amino)benzamide.
  • FIG. 39 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-morpholino-4-amino)benzamide.
  • FIG. 40 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-acetamido-4-amino)benzamide.
  • FIG. 41 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-4-aminobenzamide-Cit-Val-cap-diBromomethylacryl.
  • FIG. 42 depicts the deconvoluted mass spectroscopy (MS) spectrum of the antibody drug conjugate, PRLR-Q-63 conjugate from EXAMPLE 43.
  • FIG. 43 depicts the deconvoluted MS spectrum of the Isotype Control-Q-63 conjugate from EXAMPLE 43.
  • FIG. 44 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 45 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 46 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 47 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • alkyl refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkyl. Alkyl includes, but is not limited to, those having 1-20 carbon atoms, i.e., C 1-20 alkyl; 1-12 carbon atoms, i.e., C 1-12 alkyl; 1-8 carbon atoms, i.e., C 1-8 alkyl; 1-6 carbon atoms, i.e., C 1-6 alkyl; and 1-3 carbon atoms, i.e., C 1-3 alkyl.
  • alkyl moieties include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • haloalkyl refers to alkyl, as defined above, wherein the alkyl includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.
  • alkenyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyl is optionally substituted and can be linear, branched, or cyclic. Alkenyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2-20 alkenyl; 2-12 carbon atoms, i.e., C 2-12 alkenyl; 2-8 carbon atoms, i.e., C 2-8 alkenyl; 2-6 carbon atoms, i.e., C 2-6 alkenyl; and 2-4 carbon atoms, i.e., C 2-4 alkenyl. Examples of alkenyl moieties include, but are not limited to vinyl, propenyl, butenyl, and cyclohexenyl.
  • alkynyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be linear, branched, or cyclic.
  • Alkynyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2-20 alkynyl; 2-12 carbon atoms, i.e., C 2-12 alkynyl; 2-8 carbon atoms, i.e., C 2-8 alkynyl; 2-6 carbon atoms, i.e., C 2-6 alkynyl; and 2-4 carbon atoms, i.e., C 2-4 alkynyl.
  • alkynyl moieties include, but are not limited to ethynyl, propynyl, and butynyl.
  • alkoxy refers to a monovalent and saturated hydrocarbon radical moiety wherein the hydrocarbon includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom, e.g., CH 3 CH 2 —O for ethoxy.
  • Alkoxy substituents bond to the compound which they substitute through this oxygen atom of the alkoxy substituent.
  • Alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy.
  • Alkoxy includes, but is not limited to, those having 1-20 carbon atoms, i.e., C 1-20 alkoxy; 1-12 carbon atoms, i.e., C 1-12 alkoxy; 1-8 carbon atoms, i.e., C 1-8 alkoxy; 1-6 carbon atoms, i.e., C 1-6 alkoxy; and 1-3 carbon atoms, i.e., C 1-3 alkoxy.
  • alkoxy moieties include, but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, a pentoxy moiety, a hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.
  • haloalkoxy refers to alkoxy, as defined above, wherein the alkoxy includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.
  • aryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms.
  • Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
  • aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 aryl; 6 to 15 ring carbon atoms, i.e., C 6-15 aryl, and 6 to 10 ring carbon atoms, i.e., C 6-10 aryl.
  • Examples of aryl moieties include, but are limited to phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
  • arylene refers to a divalent moiety of an aromatic compound wherein the ring atoms are only carbon atoms.
  • Arylene is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
  • Examples of aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 arylene; 6 to 15 ring carbon atoms, i.e., C 6-15 arylene, and 6 to 10 ring carbon atoms, i.e., C 6-10 arylene.
  • alkaryl refers to an aryl that is substituted with at least one alkyl. Alkaryl is optionally substituted.
  • heteroalkyl refers to an alkyl in which one or more carbon atoms are replaced by heteroatoms.
  • heteroalkenyl refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms.
  • heteroalkynyl refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms.
  • Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl is optionally substituted.
  • heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, sulfinylalkyl.
  • heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.
  • heteroaryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom.
  • heteroaryl moieties include, but are not limited to those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryl is optionally substituted.
  • heteroarylene refers to an arylene in which one or more ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. Heteroarylene is optionally substituted.
  • heterocycloalkyl refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl is optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.
  • optionally substituted when used to describe a radical moiety, e.g., optionally substituted alkyl, means that such moiety is optionally bonded to one or more substituents.
  • substituents include, but are not limited to halo, cyano, nitro, haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,
  • R A , R B , and R C are, independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B , together with the atoms to which they are bonded, form a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted and wherein one or more ring atoms is optionally replaced with a heteroatom.
  • R A , R B , and R C are not hydrogen atoms.
  • R A is methyl.
  • R A is methylamino, methylsulfonyl, and methylsulfinyl. In some examples, R A is methylamino.
  • R A is methylamino, methylsulfonyl, and methylsulfinyl. In some examples, R A is methylamino.
  • the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted with substituents which are further optionally substituted with additional substituents.
  • the substituent bonded to the group is unsubstituted unless otherwise specified.
  • binding agent refers to any molecule capable of binding with specificity to a given binding partner.
  • linker refers to a divalent moiety that covalently links the binding agent to the maytansinoid derivatives described herein.
  • amide synthesis conditions refers to reaction conditions suitable to effect the formation of an amide, e.g., by the reaction of a carboxylic acid, activated carboxylic acid, or acyl halide with an amine.
  • amide synthesis conditions refers to reaction conditions suitable to effect the formation of an amide bond between a carboxylic acid and an amine.
  • the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with an amine to form an amide.
  • Suitable conditions to effect the formation of an amide include, but are not limited to, those utilizing reagents to effect the reaction between a carboxylic acid an amine, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflu
  • a carboxylic acid is first converted to an activated carboxylic ester before reacting with an amine to form an amide bond.
  • the carboxylic acid is reacted with a reagent.
  • the reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forming a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid onto the protonated reagent.
  • this activated ester is more susceptible subsequently to nucleophilic attack by an amine than the carboxylic acid is before it is converted. This results in amide bond formation.
  • the carboxylic acid is described as activated.
  • Exemplary reagents include DCC and DIC.
  • terapéuticaally effective amount refers to an amount (of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • Certain groups, moieties, substituents, and atoms are depicted with a wiggly line that intersects a bond or bonds to indicate the atom through which the groups, moieties, substituents, atoms are bonded.
  • cyclic group e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl
  • substituents bonded to a cyclic group are meant to indicate, unless specified otherwise, that the cyclic group may be substituted with that substituent at any ring position in the cyclic group or on any ring in the fused ring group, according to techniques set forth herein or which are known in the field to which the instant disclosure pertains.
  • subscript q is an integer from 0 to 4 and in which the positions of substituent R 1 are described generically, includes the following groups in which the positions of substituent R 1 are described specifically:
  • the substituent R 1 may be bonded to any ring position in the cyclic group or on any ring in the fused ring group which is not occupied by one of these substituents other than R 1 .
  • the following non-limiting representative illustrations indicate that the cyclic group can be substituted with the indicated substituent at any ring position or on either ring in the fused ring group:
  • A is arylene or heteroarylene
  • L is a linker
  • BA is a binding agent
  • k is an integer from 1 to 30.
  • A is arylene. In some embodiments, A is heteroarylene. In some embodiments, the arylene or heteroarylene is substituted with one or more electron withdrawing groups and/or one or more electron donating groups.
  • A is a divalent radical of benzene, of pyridine, of naphthalene, or of quinolone, which are optionally substituted.
  • A is a divalent radical of benzene which is optionally substituted with a member selected from the group consisting of amino, amido, alkyl, halo, haloalkyl, alkoxy, and haloalkoxy.
  • A is:
  • A is:
  • A is:
  • R 1 is C 1-6 alkyl or C 1-6 alkoxy. In some of these embodiments, R 1 is methyl, ethyl, methoxy, or ethoxy. In some of these embodiments, R 1 is methoxy.
  • R 1 is, independently, alkyl or halo. In some embodiments, R 1 is, independently, C 1-6 alkyl, C 1-6 haloalkyl, or halo. In some embodiments, R 1 is, independently, halo. In some embodiments, R 1 is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R A is methyl.
  • R 1 is hydroxyl.
  • R 1 is N-methylformamide.
  • R 1 is morpholinyl.
  • R 1 is, independently, alkyl, alkoxy, or halo. In some embodiments, R 1 is, independently, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or halo. In some embodiments, R 1 is, independently, halo. In some embodiments, R 1 is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
  • A is:
  • A is:
  • A is:
  • A is:
  • n 0, 1 or 2.
  • A is:
  • n 0, 1 or 2.
  • A is:
  • n is 0 or 1; and R 1 is alkoxy, halo, or haloalkyl.
  • A is:
  • n is 0 or 1; and R 1 is alkoxy, halo, or haloalkyl. In some examples, R 1 is alkoxy.
  • A is:
  • n is 0 or 1; and R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl.
  • A is:
  • n is 0 or 1; and R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl. In some examples, R 1 is C 1-6 alkoxy.
  • A is:
  • n 0 or 1
  • R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl
  • L is
  • b is an integer from 2 to 8.
  • A is:
  • n 0 or 1
  • R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl
  • L is
  • b is an integer from 2 to 8.
  • A is:
  • n 0, 1, 2, 3, or 4.
  • A is:
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, halo, or C 1-6 haloalkyl
  • n 0, 1 or 2.
  • A is:
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, or C 1-6 haloalkyl. In certain of these embodiments, R 1 is methoxy or methyl. In some specific embodiments, R 1 is methoxy.
  • A is:
  • A is:
  • R 1 is halo or trifluoromethyl
  • n 0, 1 or 2.
  • A is:
  • A is:
  • X is a hydrogen atom, halo, or trifluoromethyl.
  • A is:
  • X is a hydrogen atom, halo, or trifluoromethyl
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • R 1 is sulfonyl. In some embodiments, R 1 is N-methylformamide. In some embodiments, R 1 is hydroxyl. In some embodiments, R 1 is morpholinyl.
  • A is:
  • R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, halo, haloalkyl, or haloalkoxy;
  • R 1 is the bond to the carbonyl.
  • R 1 is alkyl or alkoxy.
  • R 1 is propylamino, difluoro-methoxy, phenyl, 2-fluorophenyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • X is F, Cl, Br, CN, methoxy, dimethylamino or cyclopropyl
  • A is:
  • X is F, Cl, Br, CN, methoxy, dimethylamino, 1-methyl-ethyl-thio or cyclopropyl;
  • A is:
  • each R 1 is independently, at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy;
  • R 1 is the bond to the carbonyl.
  • R 1 is hydrogen, fluoro, trifluoromethyl, or methoxy.
  • R 1 is fluoro, chloro, bromo, or iodo.
  • A is:
  • A is:
  • each R 1 is independently, at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy,
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • n 0, 1 2, or 3.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl;
  • n 0, 1 2, 3 or 4.
  • A is:
  • A is:
  • A is:
  • X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl.
  • X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methoxy, ethoxy, or trifluoromethyl.
  • A is:
  • X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl.
  • X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methoxy, ethoxy, trifluoromethyl or methoxy;
  • linker portion of the conjugates described herein is a divalent moiety that covalently links the binding agent to the maytansinoid derivatives described herein.
  • Suitable linkers include those that release the maytansinoid portion in the presence of an enzyme or at a particular pH range or value.
  • the linker comprises an enzyme-cleavable moiety.
  • Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages.
  • the linker comprises a cathepsin-cleavable linker.
  • the linker comprises a non-cleavable moiety. In some embodiments, the non-cleavable linker is
  • the non-cleavable linker is
  • Suitable linkers also include, but are not limited to, those that are chemically bonded to two cysteine residues of a single binding agent, e.g., antibody. Such linkers can serve to mimic the antibody's disulfide bonds that are disrupted as a result of the conjugation process.
  • the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L -, or D - ⁇ -amino acids.
  • the linker comprises alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, or derivative thereof.
  • the linker comprises valine and citrulline.
  • the linker is:
  • SP is a spacer
  • AA 1 is an amino acid
  • AA 2 is an amino acid.
  • the spacer is a divalent moiety that connects the AA 1 -AA 2 moiety to the binding agent (BA).
  • Suitable spacers include, but are not limited to, those comprising alkylene or polyethylene glycol.
  • the ends of the spacers, i.e., the portion of the spacer directly bonded to the binding agent or AA 1 can be moieties derived from reactive moieties that are used for purposes of coupling the naked antibody or AA 1 to the spacer during the chemical synthesis of the conjugate.
  • suitable spacers include, but are not limited to, a primary amine-terminated alkylene or a primary amine-terminated polyethylene glycol.
  • the primary amine-terminating end of the spacer can be directly bonded to a deglycosylated antibody or aglycosylated antibody in the presence of transglutaminase.
  • the spacer comprises an alkylene. In some embodiments, the spacer comprises a C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer comprises a primary amine-terminated alkylene. In some embodiments, the spacer comprises a NH 2 —C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • bonds to cysteines of a binding agent are bonds to cysteines of a binding agent
  • b is an integer from 2 to 8.
  • the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • g is an integer from 2 to 20. In some embodiments, g is 2-8. In some embodiments, g is 2, 4, 6, or 8.
  • the spacer is
  • n is an integer from 4 to 10. In some embodiments, n is 4, 5, 6, 7, 8, 9, or 10.
  • the spacer is:
  • the spacer is
  • n is an integer from 4 to 10. In some embodiments, n is 4, 5, 6, 7, 8, 9, or 10.
  • the spacer is
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • X is N or O
  • R N and R M are each, independently, hydrogen or alkyl
  • b is an integer from 1 to 8.
  • AA 1 -AA 2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.
  • AA 1 -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA 1 -AA 2 is: valine-citrulline.
  • the linker is:
  • SP is a spacer
  • R AA1 is an amino acid side chain
  • R AA2 is an amino acid side chain.
  • amino acid side chain refers the monovalent non-hydrogen substituent bonded to the ⁇ -carbon of an ⁇ -amino acid, including natural and non-natural amino acids.
  • exemplary amino acid side chains include, but are not limited to, the ⁇ -carbon substituent of alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline.
  • the linker is:
  • SP is a spacer
  • the linker is:
  • b is an integer from 2 to 8.
  • the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • b is an integer from 2 to 8.
  • the linker is:
  • b is an integer from 2 to 8.
  • the linker is:
  • g is an integer from 2 to 20. In some embodiments, g is 2 to 8. In some embodiments, g is 2, 4, 6, or 8.
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • Suitable binding agents include, but are not limited to, antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, or any other cell binding or peptide binding molecules or substances.
  • the binding agent is an antibody.
  • the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment (Fab, Fab′, and F(ab)2, minibody, diabody, tribody, and the like), or bispecific antibody.
  • Antibodies herein can be humanized using methods described in U.S. Pat. No. 6,596,541 and US Publication No. 2012/0096572, each incorporated by reference in their entirety.
  • the binding agent binds to an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
  • an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
  • antigens include, but are not limited to, molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alpha1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor vmc, factor IX, tissue factor (TF), and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and -beta; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophag
  • antigens also include, but are not limited to, BCMA, SLAMF7, B7H4, GPNMB, UPK3A, and LGR5.
  • the antigens include prolactin receptor (PRLR) or prostate-specific membrane antigen (PSMA).
  • PRLR prolactin receptor
  • PSMA prostate-specific membrane antigen
  • Binding agents also include, but are not limited to, ankyrin repeat proteins, interferons, lymphokines such as IL-2 or IL-3, hormones like insulin and glucocorticoids, growth factors such as EGF, transferrin and fibronectin type III.
  • the binding agents interact with or bind to tumor antigens, including antigens specific for a type of tumor or antigens that are shared, overexpressed or modified on a particular type of tumor.
  • tumor antigens include, but are not limited to: alpha-actinin-4 with lung cancer, ARTC1 with melanoma, BCR-ABL fusion protein with chronic myeloid leukemia, B-RAF, CLPP or Cdc27 with melanoma, CASP-8 with squamous cell carcinoma, and hsp70-2 with renal cell carcinoma as well as the following shared tumor-specific antigens, for example: BAGE-1, GAGE, GnTV, KK-LC-1, MAGE-A2, NA88-A, TRP2-INT2.
  • the binding agent is an antibody. In some embodiments, the binding agent is a monoclonal antibody. In some embodiments, the binding agent is a polyclonal antibody. In some embodiments, the antibody is an anti-PSMA, anti-MUC16, or anti-EGFRvIII, or anti-STEAP-2 antibody.
  • the linkers can be bonded to the binding agent, e.g., antibody or antigen-binding molecule, through an attachment at a particular amino acid within the antibody or antigen-binding molecule.
  • exemplary amino acid attachments that can be used in the context of this aspect of the disclosure include, e.g., lysine (see, e.g., U.S. Pat. No. 5,208,020; US 2010/0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005/089808; U.S. Pat. No.
  • cysteine see, e.g., US 2007/0258987; WO 2013/055993; WO 2013/055990; WO 2013/053873; WO 2013/053872; WO 2011/130598; US 2013/0101546; and U.S. Pat. No. 7,750,116
  • selenocysteine see, e.g., WO 2008/122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105:12451-12456
  • formyl glycine see, e.g., Carrico et al., Nat. Chem.
  • Linkers can be conjugated via glutamine via transglutaminase-based chemo-enzymatic conjugation (see, e.g., Dennler et al., Bioconjugate Chem. 2014, 25, 569-578).
  • Linkers can also be conjugated to an antigen-binding protein via attachment to carbohydrates (see, e.g., US 2008/0305497, WO 2014/065661, and Ryan et al., Food & Agriculture Immunol., 2001, 13:127-130) and disulfide linkers (see, e.g., WO 2013/085925, WO 2010/010324, WO 2011/018611, WO 2014/197854, and Shaunak et al., Nat. Chem. Biol., 2006, 2:312-313).
  • the binding agent is an antibody, and the antibody is bonded to the linker through a lysine residue. In some embodiments, the antibody is bonded to the linker through a cysteine residue.
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n is an integer from 0 to 4.
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 5;
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n is an integer from 0 to 4.
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 5;
  • SP is a spacer
  • R AA1 is an amino acid side chain
  • R AA2 is an amino acid side chain.
  • A is:
  • SP is a spacer
  • R AA1 is an amino acid side chain
  • R AA2 is an amino acid side chain.
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n is an integer from 0 to 4.
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 5;
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n is an integer from 0 to 4.
  • n is an integer from 0 to 3;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 5;
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n, m, p, and q are 0, 1, or 2;
  • b is an integer from 2 to 8.
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • BA is an antibody
  • A is:
  • R 1 is, independently at each occurrence, is halo
  • n 0, 1, or 2;
  • A is:
  • A is:
  • R AA2 is an amino acid side chain.
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • R 1 independently at each occurrence, is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, aralkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro,
  • q is an integer from 0 to 5;
  • A is:
  • the compound of Formula I is:
  • A is arylene or heteroarylene
  • L 1 and L 2 are linkers
  • BA is a binding agent
  • k is an integer from 0 to 30
  • t is an integer from 0 to 8.
  • L 1 is a linker which binds to the BA through a lysine residue.
  • the subscript, k represents the number of linkers, L 1 , bonded to the BA through lysine residues on the BA.
  • L 2 is a linker which binds to the BA through a cysteine residue.
  • the subscript, t represents the number of linkers, L 2 , bonded to the BA through cysteine residues on the BA.
  • t when the linker, L 2 , is a monodentate linker, t is an integer from 0 to 8. In some embodiments, when the linker, L 2 , is a bidentate linker, t is an integer from 0 to 4. In some of these examples, the sum of k+t is equal to 1-8.
  • the compound of Formula I is:
  • L 1 and L 2 are linkers
  • BA is a binding agent.
  • L 1 is a linker which binds to the BA through a lysine residue.
  • L 2 is a linker which binds to the BA through a cysteine residue.
  • the compound of Formula I is:
  • L 1 and L 2 are linkers
  • BA is a binding agent.
  • L 1 is a linker which binds to the BA through a lysine residue.
  • L 2 is a linker which binds to the BA through a cysteine residue.
  • A is:
  • the linker is:
  • SP is a spacer
  • AA 1 is an amino acid
  • AA 2 is an amino acid.
  • the spacer is a divalent moiety that connects the AA 1 -AA 2 moiety to the binding agent (BA).
  • Suitable spacers include, but are not limited to, those comprising alkylene or polyethylene glycol.
  • the ends of the spacers, i.e., the portion of the spacer directly bonded to the binding agent or AA 1 can be moieties derived from reactive moieties that are used for purposes of coupling the antibody or AA 1 to the spacer during the chemical synthesis of the conjugate.
  • the spacer comprises an alkylene. In some embodiments, the spacer comprises a C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • the spacer is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • bonds to cysteines of a binding agent are bonds to cysteines of a binding agent
  • b is an integer from 2 to 8.
  • the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • g is an integer from 2 to 20. In some embodiments, g is 2-8. In some embodiments, g is 2, 4, 6, or 8.
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • X is N or O
  • R N and R M are each, independently, hydrogen or alkyl
  • b is an integer from 1 to 8.
  • AA 1 -AA 2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.
  • AA 1 -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA 1 -AA 2 is: valine-citrulline.
  • the compound of Formula I is:
  • R N and R M are each, independently, hydrogen or aryl
  • b is an integer from 1 to 8
  • A is aryl or heteroaryl
  • t is an integer from 1-8.
  • the compound of Formula I is:
  • the compound of Formula I is:
  • k is an integer from 1 to 30. In some embodiment, k is an integer from 1 to 8. In some embodiment, k is an integer from 1 to 6. In some embodiments, k is an integer from 1 to 4. In some embodiments, k is an integer from 1 to 3. In some embodiments, the drug-antibody ratio (DAR) of the conjugate is from 1.0 to 3.0.
  • DAR drug-antibody ratio
  • A is arylene or heteroarylene.
  • these compounds represent the payload portion of the conjugates described herein and are released, e.g., by enzyme proteolysis, following internalization of the conjugate into a cell.
  • the methods provided herein include methods of treating a proliferative disease, e.g., cancer, comprising administering to a patient a therapeutically effective amount of a conjugate, e.g., antibody-drug conjugate that releases a compound of Formula (II) following internalization of said conjugate into a cell in said patient.
  • these compounds represent the metabolic product of the conjugates described herein, e.g., enzyme proteolysis product. In some embodiments, these compounds represent the catabolic product of the conjugates described herein. In some embodiments, these compounds represent the cellular product of the conjugates described herein.
  • A is a divalent radical of benzene, of pyridine, of naphthalene, or of quinolone, which are optionally substituted.
  • A is arylene
  • A is:
  • the compound of Formula (II) is a compound of the Formula (IIA):
  • R 1 and n are as defined herein.
  • the compound of Formula (II) is a compound of the Formula (IIB):
  • R 1 and q are as defined herein.
  • the compound of Formula (II) is a compound of the Formula (IIB2):

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US15/081,759 2015-03-27 2016-03-25 Maytansinoid derivatives, conjugates thereof, and methods of use Abandoned US20160375147A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/081,759 US20160375147A1 (en) 2015-03-27 2016-03-25 Maytansinoid derivatives, conjugates thereof, and methods of use
US16/712,941 US20200385402A1 (en) 2015-03-27 2019-12-12 Maytansinoid Derivatives, Conjugates Thereof, and Methods of Use
US17/528,144 US12297207B2 (en) 2015-03-27 2021-11-16 Maytansinoid derivatives, conjugates thereof, and methods of use
US19/093,440 US20250223299A1 (en) 2015-03-27 2025-03-28 Maytansinoid derivatives, conjugates thereof, and methods of use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562139044P 2015-03-27 2015-03-27
US201562252239P 2015-11-06 2015-11-06
US15/081,759 US20160375147A1 (en) 2015-03-27 2016-03-25 Maytansinoid derivatives, conjugates thereof, and methods of use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/712,941 Continuation US20200385402A1 (en) 2015-03-27 2019-12-12 Maytansinoid Derivatives, Conjugates Thereof, and Methods of Use

Publications (1)

Publication Number Publication Date
US20160375147A1 true US20160375147A1 (en) 2016-12-29

Family

ID=55650789

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/081,759 Abandoned US20160375147A1 (en) 2015-03-27 2016-03-25 Maytansinoid derivatives, conjugates thereof, and methods of use
US16/712,941 Abandoned US20200385402A1 (en) 2015-03-27 2019-12-12 Maytansinoid Derivatives, Conjugates Thereof, and Methods of Use
US17/528,144 Active US12297207B2 (en) 2015-03-27 2021-11-16 Maytansinoid derivatives, conjugates thereof, and methods of use
US19/093,440 Pending US20250223299A1 (en) 2015-03-27 2025-03-28 Maytansinoid derivatives, conjugates thereof, and methods of use

Family Applications After (3)

Application Number Title Priority Date Filing Date
US16/712,941 Abandoned US20200385402A1 (en) 2015-03-27 2019-12-12 Maytansinoid Derivatives, Conjugates Thereof, and Methods of Use
US17/528,144 Active US12297207B2 (en) 2015-03-27 2021-11-16 Maytansinoid derivatives, conjugates thereof, and methods of use
US19/093,440 Pending US20250223299A1 (en) 2015-03-27 2025-03-28 Maytansinoid derivatives, conjugates thereof, and methods of use

Country Status (17)

Country Link
US (4) US20160375147A1 (enrdf_load_stackoverflow)
EP (1) EP3273998B1 (enrdf_load_stackoverflow)
JP (2) JP6948950B2 (enrdf_load_stackoverflow)
KR (2) KR102708103B1 (enrdf_load_stackoverflow)
CN (2) CN107995912A (enrdf_load_stackoverflow)
AU (1) AU2016243527B2 (enrdf_load_stackoverflow)
BR (1) BR112017020149A8 (enrdf_load_stackoverflow)
CA (1) CA2978340C (enrdf_load_stackoverflow)
CL (1) CL2017002422A1 (enrdf_load_stackoverflow)
CO (1) CO2017010890A2 (enrdf_load_stackoverflow)
EA (1) EA034950B1 (enrdf_load_stackoverflow)
IL (1) IL254267B (enrdf_load_stackoverflow)
MX (2) MX386328B (enrdf_load_stackoverflow)
PH (1) PH12017501780A1 (enrdf_load_stackoverflow)
SG (1) SG11201707148PA (enrdf_load_stackoverflow)
WO (1) WO2016160615A1 (enrdf_load_stackoverflow)
ZA (1) ZA201706040B (enrdf_load_stackoverflow)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018093866A1 (en) 2016-11-16 2018-05-24 Regeneron Pharmaceuticals, Inc. Anti-met antibodies, bispecific antigen binding molecules that bind met, and methods of use thereof
WO2018213077A1 (en) 2017-05-18 2018-11-22 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
WO2019094395A2 (en) 2017-11-07 2019-05-16 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
WO2019212965A1 (en) 2018-04-30 2019-11-07 Regeneron Pharmaceuticals, Inc. Antibodies, and bispecific antigen-binding molecules that bind her2 and/or aplp2, conjugates, and uses thereof
WO2019222663A1 (en) 2018-05-17 2019-11-21 Regeneron Pharmaceuticals, Inc. Anti-cd63 antibodies, conjugates, and uses thereof
WO2020172475A1 (en) 2019-02-21 2020-08-27 Regeneron Pharmaceuticals, Inc. Methods of treating ocular cancer using anti-met antibodies and bispecific antigen binding molecules that bind met
WO2021055895A1 (en) 2019-09-19 2021-03-25 Regeneron Pharmaceuticals, Inc. Anti-ptcra antibody-drug conjugates and uses thereof
WO2021097220A1 (en) 2019-11-15 2021-05-20 Seagen Inc. Methods of treating her2 positive breast cancer with tucatinib in combination with an anti-her2 antibody-drug conjugate
WO2021174113A1 (en) 2020-02-28 2021-09-02 Regeneron Pharmaceuticals, Inc. Bispecific antigen binding molecules that bind her2, and methods of use thereof
US11129903B2 (en) 2015-07-06 2021-09-28 Regeneron Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
WO2021211984A1 (en) 2020-04-16 2021-10-21 Regeneron Pharmaceuticals, Inc. Diels-alder conjugation methods
WO2022087243A1 (en) 2020-10-22 2022-04-28 Regeneron Pharmaceuticals, Inc. Anti-fgfr2 antibodies and methods of use thereof
WO2022103724A1 (en) 2020-11-10 2022-05-19 Regeneron Pharmaceuticals, Inc. Selenium antibody conjugates
US11345715B2 (en) 2013-03-15 2022-05-31 Regeneron Pharmaceuticals, Inc. Biologically active molecules, conjugates thereof, and therapeutic uses
US11352446B2 (en) 2016-04-28 2022-06-07 Regeneron Pharmaceuticals, Inc. Methods of making multispecific antigen-binding molecules
US11446389B2 (en) 2016-01-25 2022-09-20 Regeneron Pharmaceuticals, Inc. Maytansinoid derivatives, conjugates thereof, and methods of use
US11596635B2 (en) 2013-08-26 2023-03-07 Regeneron Pharmaceuticals, Inc. Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
US11896682B2 (en) 2019-09-16 2024-02-13 Regeneron Pharmaceuticals, Inc. Radiolabeled MET binding proteins for immuno-PET imaging and methods of use thereof
US12215138B2 (en) 2017-06-07 2025-02-04 Regeneron Pharmaceuticals, Inc. Compositions and methods for internalizing enzymes
US12297207B2 (en) 2015-03-27 2025-05-13 Regeneron Pharmaceuticals, Inc. Maytansinoid derivatives, conjugates thereof, and methods of use

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2925563T3 (es) 2016-09-23 2022-10-18 Regeneron Pharma Anticuerpos anti-MUC16 (Mucina 16)
CA3037732A1 (en) 2016-09-23 2018-03-29 Regeneron Pharmaceuticals, Inc. Anti-steap2 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind steap2 and cd3, and uses thereof
WO2018102304A1 (en) 2016-11-29 2018-06-07 Regeneron Pharmaceuticals, Inc. Methods of treating prlr positive breast cancer
CN111712263B (zh) * 2017-11-30 2024-12-17 拉德克斯公司 基于美登木素生物碱的药物递送系统
WO2020057543A1 (zh) * 2018-09-21 2020-03-26 中国人民解放军军事科学院军事医学研究院 基于芳硝基的连接子、含连接子的抗体偶联药物及连接子的用途
CN113292574B (zh) * 2020-02-21 2022-05-03 四川大学 一类手性多环的托品烷化合物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4260608A (en) * 1978-11-14 1981-04-07 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and methods of use thereof
US20130029900A1 (en) * 2011-06-21 2013-01-31 Immunogen, Inc. Novel maytansinoid derivatives with peptide linker and conjugates thereof

Family Cites Families (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
JPS55164686A (en) 1979-06-11 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
CA2026147C (en) 1989-10-25 2006-02-07 Ravi J. Chari Cytotoxic agents comprising maytansinoids and their therapeutic use
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US7087411B2 (en) 1999-06-08 2006-08-08 Regeneron Pharmaceuticals, Inc. Fusion protein capable of binding VEGF
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US20070258987A1 (en) 2000-11-28 2007-11-08 Seattle Genetics, Inc. Recombinant Anti-Cd30 Antibodies and Uses Thereof
EP1258255A1 (en) 2001-05-18 2002-11-20 Boehringer Ingelheim International GmbH Conjugates of an antibody to CD44 and a maytansinoid
US20090068178A1 (en) 2002-05-08 2009-03-12 Genentech, Inc. Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin
US20110250133A1 (en) 2003-01-13 2011-10-13 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
US7276497B2 (en) 2003-05-20 2007-10-02 Immunogen Inc. Cytotoxic agents comprising new maytansinoids
CN104059147A (zh) 2003-06-27 2014-09-24 艾默根佛蒙特有限公司 针对表皮生长因子受体的缺失突变体的抗体及其使用
GB0316294D0 (en) 2003-07-11 2003-08-13 Polytherics Ltd Conjugated biological molecules and their preparation
TW200539855A (en) 2004-03-15 2005-12-16 Wyeth Corp Calicheamicin conjugates
EP1753463A2 (en) 2004-06-01 2007-02-21 Genentech, Inc. Antibody drug conjugates and methods
CA2587589A1 (en) 2004-11-29 2006-06-22 Seattle Genetics, Inc. Engineered antibodies and immunoconjugates
UA94388C2 (ru) 2004-12-09 2011-05-10 Центокор, Инк. Антиинтегриновый иммуноконьюгат и способы лечения с его помощью
BRPI0612529A2 (pt) 2005-06-20 2010-11-23 Psma Dev Company Llc conjugados de anticorpo-medicamento de psma
WO2007001851A2 (en) 2005-06-20 2007-01-04 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
AU2006280146B2 (en) 2005-08-09 2012-06-28 Immunogen, Inc. Method of acylating maytansinol with chiral amino acids
EP1977252B1 (en) 2005-12-22 2012-12-05 Baxter International Inc. Improved monocyte activation test better able to detect non-endotoxin pyrogenic contaminants in medical products
US7750116B1 (en) 2006-02-18 2010-07-06 Seattle Genetics, Inc. Antibody drug conjugate metabolites
WO2008052187A2 (en) 2006-10-27 2008-05-02 Genentech. Inc. Antibodies and immunoconjugates and uses therefor
RU2448979C2 (ru) 2006-12-14 2012-04-27 Ридженерон Фармасьютикалз, Инк. Антитела человека к дельта-подобному лиганду-4 человека
WO2008122039A2 (en) 2007-04-02 2008-10-09 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Selenocysteine mediated hybrid antibody molecules
CN101687037B (zh) 2007-05-08 2013-07-10 健泰科生物技术公司 半胱氨酸改造的抗muc16抗体和抗体药物偶联物
EP2167963B1 (en) 2007-05-23 2019-04-17 Ventana Medical Systems, Inc. Polymeric carriers for immunohistochemistry and in situ hybridization
PL3269366T3 (pl) 2008-03-18 2020-07-27 Genentech, Inc. Kombinacje koniugatu przeciwciało anty-HER2-lek i lapatinibu, i sposoby zastosowania
UA108598C2 (xx) 2008-04-30 2015-05-25 Високоефективні кон'югати та гідрофільні зшиваючі агенти (лінкери)
EP2374481B1 (en) 2008-07-21 2015-11-04 Polytherics Limited Novel reagents and method for conjugating biological molecules
EP2403538B1 (en) 2009-03-04 2017-10-04 Polytherics Limited Conjugated proteins and peptides
WO2010126551A1 (en) 2009-04-30 2010-11-04 Immunogen, Inc. Potent conjugates and hydrophilic linkers
JO3182B1 (ar) 2009-07-29 2018-03-08 Regeneron Pharma مضادات حيوية بشرية عالية الالفة مع تولد الاوعية البشرية - 2
AU2010283632B2 (en) 2009-08-10 2016-08-25 Ucl Business Plc Reversible covalent linkage of functional molecules
TW201116297A (en) 2009-10-02 2011-05-16 Sanofi Aventis Antibodies that specifically bind to the EphA2 receptor
UY32913A (es) 2009-10-02 2011-04-29 Sanofi Aventis Nuevos maitansinoides y el uso de dichos maitansinoides para preparar conjugados con un anticuero
US8501692B2 (en) 2009-12-14 2013-08-06 The Regents Of The University Of Michigan Compositions and methods for altering cocaine esterase activity
CN102933236B (zh) 2010-04-15 2014-10-08 斯皮罗根有限公司 吡咯并苯二氮卓类及其结合物
US20130244905A1 (en) 2010-07-06 2013-09-19 Ed Grabczyk Reporter for RNA Polymerase II Termination
LT2601298T (lt) 2010-08-02 2017-03-10 Regeneron Pharmaceuticals, Inc. Pelė, kuri gamina rišančius baltymus, apimančius vl domenus
MX339739B (es) 2010-09-01 2016-06-07 Bayer Ip Gmbh N-(tetrazol-5-il)-y n-(triazol-5-il)arilcarboxamidas y su uso como herbicidas.
BR112013010569A2 (pt) 2010-10-29 2017-07-04 Immunogen Inc moléculas de ligação de egfr não antagonísticas e imunoconjugados das mesma
CN106349254A (zh) 2010-11-03 2017-01-25 伊缪诺金公司 包含新型安丝菌素衍生物的细胞毒性剂
CN108524510A (zh) 2011-05-16 2018-09-14 皇家飞利浦有限公司 生物正交药物活化
ES2898854T3 (es) 2011-05-27 2022-03-09 Ambrx Inc Composiciones que contienen, métodos que implican, y usos de derivados de dolastatina enlazados con aminoácidos no naturales
US8815226B2 (en) 2011-06-10 2014-08-26 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
CN104011018B (zh) 2011-10-14 2016-12-14 麦迪穆有限责任公司 可用于制备吡咯并苯并二氮杂卓的合成方法和中间体
EA028457B1 (ru) 2011-10-14 2017-11-30 Медимьюн Лимитед Пирролобензодиазепины
JP6399930B2 (ja) 2011-10-14 2018-10-03 シアトル ジェネティクス，インコーポレーテッド ピロロベンゾジアゼピンおよび標的コンジュゲート
JP6393617B2 (ja) 2011-10-14 2018-09-19 シアトル ジェネティクス，インコーポレーテッド ピロロベンゾジアゼピンおよび標的コンジュゲート
WO2013068874A1 (en) 2011-11-11 2013-05-16 Pfizer Inc. Antibody-drug conjugates
JP2015500287A (ja) 2011-12-05 2015-01-05 アイジェニカ・バイオセラピューティクス・インコーポレイテッドＩｇｅｎｉｃａ Ｂｉｏｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 抗体−薬物のコンジュゲート、ならびに関連する化合物、組成物および方法
GB201210770D0 (en) 2012-06-18 2012-08-01 Polytherics Ltd Novel conjugation reagents
MX2014015682A (es) 2012-06-19 2015-07-23 Polytherics Ltd Proceso novedoso para preparacion de conjugados de anticuerpo y conjugados de anticuerpo novedosos.
DK2911699T3 (en) 2012-10-23 2018-02-12 Synaffix Bv Modified antibody, antibody conjugate and method of preparation thereof
NO2789793T3 (enrdf_load_stackoverflow) 2012-10-24 2018-01-27
US10131682B2 (en) * 2012-11-24 2018-11-20 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules
TW201425336A (zh) 2012-12-07 2014-07-01 Amgen Inc Ｂｃｍａ抗原結合蛋白質
CN103333179B (zh) 2012-12-21 2017-06-16 百奥泰生物科技(广州)有限公司 类美登素衍生物及其制备方法和用途
CN103254213B (zh) 2012-12-21 2015-02-25 百奥泰生物科技(广州)有限公司 类美登素酯的制备方法及用于所述方法的组合物
MY183572A (en) * 2013-03-15 2021-02-26 Regeneron Pharma Biologically active molecules, conjugates thereof, and therapeutic uses
CN103254311B (zh) 2013-05-09 2015-05-13 齐鲁制药有限公司 一种制备抗体-美登素类生物碱药物偶联物的方法
WO2014194030A2 (en) 2013-05-31 2014-12-04 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
WO2014197866A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Modified antibodies and related compounds, compositions, and methods of use
WO2014197871A2 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Antibody-drug conjugates, compositions and methods of use
ES2891755T3 (es) 2013-06-06 2022-01-31 Pf Medicament Anticuerpos anti-C10orf54 y utilizaciones de los mismos
WO2014197854A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Novel linkers for antibody-drug conjugates and related compounds, compositions, and methods of use
US9545451B2 (en) 2013-08-21 2017-01-17 Regeneron Pharmaceuticals, Inc. Anti-PRLR antibodies and methods for killing PRLR-expressing cells
TWI641620B (zh) 2013-08-21 2018-11-21 再生元醫藥公司 抗－ｐｒｌｒ抗體及其用途
EP3038624B1 (en) * 2013-08-26 2024-09-25 Regeneron Pharmaceuticals, Inc. Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
US20160354105A1 (en) 2013-11-26 2016-12-08 Segway Orthopaedics, Inc. Surgical Blade with Viewing Aperture
CA2927806C (en) 2013-11-27 2023-01-10 Redwood Bioscience, Inc. Hydrazinyl-pyrrolo compounds and methods for producing a conjugate
WO2015081857A1 (en) 2013-12-02 2015-06-11 Hong Kong Baptist University Anticancer maytansinoids with two fused macrocyclic rings
CA2950155C (en) 2014-06-02 2021-11-23 Regeneron Pharmaceuticals, Inc. Biologically active molecule conjugates, reagents and methods of manufacture, and therapeutic uses
BR112017020149A8 (pt) 2015-03-27 2023-05-02 Regeneron Pharma Derivados de maitansinoide, conjugados dos mesmos e métodos de uso
NZ744373A (en) 2016-01-25 2025-03-28 Regeneron Pharma Maytansinoid derivatives, conjugates thereof, and methods of use
CA3037732A1 (en) 2016-09-23 2018-03-29 Regeneron Pharmaceuticals, Inc. Anti-steap2 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind steap2 and cd3, and uses thereof
US11814428B2 (en) 2019-09-19 2023-11-14 Regeneron Pharmaceuticals, Inc. Anti-PTCRA antibody-drug conjugates and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4260608A (en) * 1978-11-14 1981-04-07 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and methods of use thereof
US20130029900A1 (en) * 2011-06-21 2013-01-31 Immunogen, Inc. Novel maytansinoid derivatives with peptide linker and conjugates thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Doronina, Svetlana O. et al, "Development of potent monoclonal antibody aurostatin conjugates for cancer therapy." Nat. Biotech. (2003) 21(7) p778-785 *
Dubowchik, Gene M. et al, "Cathepsin b-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen specific in vitro anticancer activity." Bioconjugate Chem. (2002) 13 p855-869 *
Wolf, Philipp, "Anti-psma antibody-drug conjugates and immunotoxins." Chapter 15 of Antibody-drug conjugates and immunotoxins (2012) Gail Phillips (ed) ISBN 978-1-4614-5456-4 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11345715B2 (en) 2013-03-15 2022-05-31 Regeneron Pharmaceuticals, Inc. Biologically active molecules, conjugates thereof, and therapeutic uses
US12378258B2 (en) 2013-03-15 2025-08-05 Regeneron Pharmaceuticals, Inc. Biologically active molecules, conjugates thereof, and therapeutic uses
US11596635B2 (en) 2013-08-26 2023-03-07 Regeneron Pharmaceuticals, Inc. Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses
US12297207B2 (en) 2015-03-27 2025-05-13 Regeneron Pharmaceuticals, Inc. Maytansinoid derivatives, conjugates thereof, and methods of use
US11129903B2 (en) 2015-07-06 2021-09-28 Regeneron Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
US12297257B2 (en) 2015-07-06 2025-05-13 Regeneron Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
US11191844B2 (en) 2015-07-06 2021-12-07 Regeneran Pharmaceuticals, Inc. Multispecific antigen-binding molecules and uses thereof
US11446389B2 (en) 2016-01-25 2022-09-20 Regeneron Pharmaceuticals, Inc. Maytansinoid derivatives, conjugates thereof, and methods of use
US11352446B2 (en) 2016-04-28 2022-06-07 Regeneron Pharmaceuticals, Inc. Methods of making multispecific antigen-binding molecules
US11142578B2 (en) 2016-11-16 2021-10-12 Regeneron Pharmaceuticals, Inc. Anti-MET antibodies, bispecific antigen binding molecules that bind MET, and methods of use thereof
WO2018093866A1 (en) 2016-11-16 2018-05-24 Regeneron Pharmaceuticals, Inc. Anti-met antibodies, bispecific antigen binding molecules that bind met, and methods of use thereof
WO2018213077A1 (en) 2017-05-18 2018-11-22 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12215138B2 (en) 2017-06-07 2025-02-04 Regeneron Pharmaceuticals, Inc. Compositions and methods for internalizing enzymes
WO2019094395A2 (en) 2017-11-07 2019-05-16 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US12037411B2 (en) 2018-04-30 2024-07-16 Regeneron Pharmaceuticals, Inc. Antibodies, and bispecific antigen-binding molecules that bind HER2 and/or APLP2, conjugates, and uses thereof
WO2019212965A1 (en) 2018-04-30 2019-11-07 Regeneron Pharmaceuticals, Inc. Antibodies, and bispecific antigen-binding molecules that bind her2 and/or aplp2, conjugates, and uses thereof
US12252544B2 (en) 2018-05-17 2025-03-18 Regeneron Pharmaceuticals, Inc. Anti-CD63 antibodies, conjugates, and uses thereof
WO2019222663A1 (en) 2018-05-17 2019-11-21 Regeneron Pharmaceuticals, Inc. Anti-cd63 antibodies, conjugates, and uses thereof
WO2020172475A1 (en) 2019-02-21 2020-08-27 Regeneron Pharmaceuticals, Inc. Methods of treating ocular cancer using anti-met antibodies and bispecific antigen binding molecules that bind met
US11896682B2 (en) 2019-09-16 2024-02-13 Regeneron Pharmaceuticals, Inc. Radiolabeled MET binding proteins for immuno-PET imaging and methods of use thereof
WO2021055895A1 (en) 2019-09-19 2021-03-25 Regeneron Pharmaceuticals, Inc. Anti-ptcra antibody-drug conjugates and uses thereof
US11814428B2 (en) 2019-09-19 2023-11-14 Regeneron Pharmaceuticals, Inc. Anti-PTCRA antibody-drug conjugates and uses thereof
WO2021097220A1 (en) 2019-11-15 2021-05-20 Seagen Inc. Methods of treating her2 positive breast cancer with tucatinib in combination with an anti-her2 antibody-drug conjugate
US11958910B2 (en) 2020-02-28 2024-04-16 Regeneron Pharmaceuticals, Inc. Bispecific antigen binding molecules that bind HER2, and methods of use thereof
WO2021174113A1 (en) 2020-02-28 2021-09-02 Regeneron Pharmaceuticals, Inc. Bispecific antigen binding molecules that bind her2, and methods of use thereof
WO2021211984A1 (en) 2020-04-16 2021-10-21 Regeneron Pharmaceuticals, Inc. Diels-alder conjugation methods
US11866502B2 (en) 2020-10-22 2024-01-09 Regeneron Pharmaceuticals, Inc. Anti-FGFR2 antibodies and methods of use thereof
WO2022087243A1 (en) 2020-10-22 2022-04-28 Regeneron Pharmaceuticals, Inc. Anti-fgfr2 antibodies and methods of use thereof
WO2022103724A1 (en) 2020-11-10 2022-05-19 Regeneron Pharmaceuticals, Inc. Selenium antibody conjugates

Also Published As

Publication number Publication date
IL254267A (en) 2018-06-28
MX2021008101A (es) 2021-08-05
KR20240142591A (ko) 2024-09-30
MX2017012380A (es) 2018-04-11
CO2017010890A2 (es) 2020-04-13
NZ735426A (en) 2024-09-27
JP2018516851A (ja) 2018-06-28
CA2978340C (en) 2024-05-28
EP3273998B1 (en) 2019-09-04
EA034950B1 (ru) 2020-04-09
PH12017501780A1 (en) 2018-04-30
CN115645543A (zh) 2023-01-31
EP3273998A1 (en) 2018-01-31
CA2978340A1 (en) 2016-10-06
EA201700464A1 (ru) 2018-11-30
AU2016243527A1 (en) 2017-09-21
MX386328B (es) 2025-03-18
KR20170131587A (ko) 2017-11-29
KR102708103B1 (ko) 2024-09-20
AU2016243527B2 (en) 2021-04-29
US20200385402A1 (en) 2020-12-10
ZA201706040B (en) 2020-05-27
BR112017020149A8 (pt) 2023-05-02
BR112017020149A2 (pt) 2018-09-11
CN107995912A (zh) 2018-05-04
US20250223299A1 (en) 2025-07-10
SG11201707148PA (en) 2017-10-30
US20220259225A1 (en) 2022-08-18
IL254267B (en) 2021-03-25
WO2016160615A1 (en) 2016-10-06
JP6948950B2 (ja) 2021-10-13
CL2017002422A1 (es) 2018-03-16
JP2021113191A (ja) 2021-08-05
US12297207B2 (en) 2025-05-13

Similar Documents

Publication Publication Date Title
US12297207B2 (en) Maytansinoid derivatives, conjugates thereof, and methods of use
US11446389B2 (en) Maytansinoid derivatives, conjugates thereof, and methods of use
CA3099920A1 (en) Splicing modulator antibody-drug conjugates and methods of use
JP2023116497A (ja) シクロデキストリンタンパク質薬物コンジュゲート
HK1242628A1 (en) Maytansinoid derivatives, conjugates thereof, and methods of use
HK1242628B (en) Maytansinoid derivatives, conjugates thereof, and methods of use
HK1257219B (en) Maytansinoid derivatives, conjugates thereof, and methods of use

Legal Events

Date Code Title Description
AS Assignment

Owner name: REGENERON PHARMACEUTICALS, INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NITTOLI, THOMAS;REEL/FRAME:038870/0339

Effective date: 20160506

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCV Information on status: appeal procedure

Free format text: NOTICE OF APPEAL FILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION