Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06052—Val-amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61K47/54—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 organic compound
  • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
• • 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
  • A61K47/54—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 organic compound
  • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
• • 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
  • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
  • A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• • 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
  • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/61—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—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
  • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
• • 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
  • A61K47/6855—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 the tumour determinant being from breast cancer 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/52—Constant or Fc region; Isotype
  • C07K2317/522—CH1 domain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/52—Constant or Fc region; Isotype
  • C07K2317/526—CH3 domain

Definitions

• the invention provides linkers for the improvement in the solubility of antibody drug conjugates (ADCs) which comprise one or more hydrophobic drug compounds.
• ADCs antibody drug conjugates
• chemical linker which links the drug moiety to the targeting moiety.
• an ADC uses a hydrophobic drug moiety, however when such drug moieties are used in combination with a relatively hydrophobic linker, solubilty issues can arise which can affect the biocompatibility and pharmaceutical efficacy of the ADC.
• the invention provides linkers for the use in improving the solubility of Linker-Drug conjugates in which such conjugates comprise one or more hydrophobic drug compounds, wherein the linkers comprise one or more hydrophilic groups.
• linkers comprise one or more hydrophilic groups.
• the invention further provides linkers for the use in improving the solubility of antibody drug conjugate (ADC) in which the ADC comprises one or more hydrophobic drug compounds, wherein the linkers comprise one or more hydrophilic groups.
• ADC antibody drug conjugate
• the linkers comprise one or more hydrophilic groups.
• linkers which comprise one or more self immolate groups, wherein the one or more self immolate groups are each substituted with one or more hydrophilic moieties.
• Linker-Drug groups wherein the linker comprises one or more self immolate groups coupled to the Drug, and wherein the one or more self immolate groups are each substituted with one or more hydrophilic moieties.
• antibody drug conjugates comprising one or more Linker-Drug groups, wherein the linker comprises one or more self immolate groups coupled to the Drug, and wherein the one or more self immolate groups are each substituted with one or more hydrophilic moieties.
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Linker-Drug group of Formula (I) is a Linker-Drug group of Formula (II), or pharmaceutically acceptable salt thereof:
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide linker comprising one to four amino acid residues;
• R 2 is a hydrophilic moiety;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• D is an Antibody Drug Conjugate of Formula (III):
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide linker
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C1-C6alkyl or a C3-C8cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Antibody Drug Conjugate of Formula (III) is an Antibody Drug Conjugate of Formula (IV):
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide linker comprising one to four amino acid residues;
• R 2 is a hydrophilic moiety;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Another aspect of the invention are linkers having the structure of Formula (V),
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• L 3 is a spacer moiety
• linker Formula (V) is a linker having the structure of Formula (VI),
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• R 2 is a hydrophilic moiety
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl,
• L 3 is a spacer moiety
• the linkers described herein which comprise a hydrophilic moiety, contribute to the overall hydrophilicity of Antibody-Drug Conjugates (ADCs) and improve aqueous solubility of the ADC.
• the linkers described herein also unexpectedly reduce ADC aggregation and improve pharmacokinetic and pharmacodynamic properties of ADCs.
• the hydrophilic linkers described herein allow for improved aqueous solubility of the Linker-Drug group described herein thereby allowing for improved antibody conjugation to the Linker-Drug group, which improves the purification and overall synthetic yields of ADCs, in particular ADCs which comprise hydrophobic drug moieties.
• FIGURE.1 Line graphs of cellular activity of antibody drug conjugates titrated across selected cell lines A: HT-29 PCAD+; B: FaDu; C: HCC70; D:HT-29; and E: HCC1954.
• FIGURE.2 Line graphs of caspase-3/7 activity of antibody drug conjugates titrated across HCC1954 cell line after A: 24 hours and B: 48 hours.
• FIGURE.3 Efficacy and tolerability of PCAD-ADCs and the huIgG1 isotype-matched control ADCs in the HCC70 human TNBC xenograft model in SCID-beige female mice.
• alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation.
• C 1 - C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
• C 1 -C 6 alkyl groups include methyl (a C 1 alkyl), ethyl (a C 2 alkyl), 1-methylethyl (a C 3 alkyl), n-propyl (a C 3 alkyl), isopropyl (a C 3 alkyl), n-butyl (a C 4 alkyl), isobutyl (a C 4 alkyl), sec- butyl (a C 4 alkyl), tert-butyl (a C 4 alkyl), n-pentyl (a C 5 alkyl), isopentyl (a C 5 alkyl), neopentyl (a C 5 alkyl) and hexyl (a C 6 alkyl).
• alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond.
• C 2 -C e alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
• C 2 -C 6 alkenyl groups include ethenyl (a C 2 alkenyl), prop-1-enyl (a C 3 alkenyl), but-1-enyl (a C 4 alkenyl), pent-1-enyl (a C 5 alkenyl), pent-4-enyl (a C 5 alkenyl), penta-1,4-dienyl (a C 5 alkenyl), hexa-1-enyl (a C 6 alkenyl), hexa-2-enyl (a C 6 alkenyl), hexa-3-enyl (a C 6 alkenyl), hexa-1-,4-dienyl (a C 6 alkenyl), hexa-1-,5-dienyl (a C 6 alkenyl) and hexa-2-,4-dienyl (a C 6 alkenyl).
• C 2 -C 3 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to three carbon atoms, which is attached to the rest of the molecule by a single bond.
• Non-limiting examples of "C 2 -C 3 alkenyl” groups include ethenyl (a C 2 alkenyl) and prop-1-enyl (a C 3 alkenyl).
• alkylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation.
• C 1 -C 6 alkylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms.
• C 1 -C 6 alkylene groups include methylene (a C 1 alkylene), ethylene (a C 2 alkylene), 1-methylethylene (a C 3 alkylene), n-propylene (a C 3 alkylene), isopropylene (a C 3 alkylene), n-butylene (a C 4 alkylene), isobutylene (a
• alkenylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at
• C 2 -C 6 alkenylene refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to six carbon atoms.
• C 2 -C 6 alkenylene groups include ethenylene (a C 2 alkenylene), prop-1-enylene (a C 3 alkenylene), but-1-enylene (a C 4 alkenylene), pent-1-enylene (a C 5 alkenylene), pent-4- enylene (a C 5 alkenylene), penta-1,4-dienylene (a C 5 alkenylene), hexa-1-enylene (a
• C 6 alkenylene hexa-2-enylene (a C 6 alkenylene), hexa-3-enylene (a C 6 alkenylene), hexa-1-,4- dienylene (a C 6 alkenylene), hexa-1-,5-dienylene (a C 6 alkenylene) and hexa-2-,4-dienylene (a C 6 alkenylene).
• Non-limiting examples of "C 2 -C 3 alkenylene” groups include ethenylene (a C 2 alkenylene) and prop-1-enylene (a C 3 alkenylene).
• cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system.
• fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantanyl.
• Non-limiting examples monocyclic C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
• polyethylene glycol refers to a linear chain, a branched chain or a star shaped configuration comprised of (OCH 2 CH 2 ) groups.
• polyalkylene glycol refers to a linear chain, a branched chain or a star shaped configuration comprised of (O(CH 2 ) m ) t groups.
• the terms“Drug moiety”,“D”, or“drug”, as used herein, refer to any compound possessing a desired biological activity and a reactive functional group that may be used to incorporate the drug into the linker-drug group of the invention.
• the desired biological activity includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
• the reactive functional group forms a bond to the“A” in compounds of Formula (I) and Formula (II) and conjugates of Formula (III) and Formula (IV).
• the Drug moiey has a nitrogen atom that can form a bond with“A”.
• the Drug moiety has a hydroxyl group that can form a bond with“A”.
• the Drug moiety has a carboxylic acid that can form a bond with“A”. In other embodiments, the Drug moiety has a carbonyl group that can form a bond with“A”. In still other embodiments, the Drug moiety has a sulfhydryl group that can form a bond with“A”.
• drug moiety As drugs in the official United States
• Pharmacopeia official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement thereof Exemplary drugs are set forth in the Physician's Desk Reference (PDR) and in the Orange Book maintained by the U.S. Food and Drug Administration (FDA).
• PDR Physician's Desk Reference
• FDA Food and Drug Administration
• the Drug moiety (D) can be a cytotoxic, cytostatic or
• cytotoxic or immunosuppressive drugs include, for example, antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, topoisomerase inhibitors, vinca alkaloids, or the like.
• cytotoxic drugs include, for example, auristatins, camptothecins, duocarmycins, etoposides, maytansines and maytansinoids, taxanes, benzodiazepines or benzodiazepine containing drugs (e.g., pyrrolo[1,4]-benzodiazepines (PBDs), indolinobenzodiazepines, and
• oxazolidinobenzodiazepines oxazolidinobenzodiazepines
• vinca alkaloids oxazolidinobenzodiazepines
• the Drug moiety of the present invention is preferably hydrophobic having a SlogP value of 1.5 or greater, 2.0 or greater, or 2.5 or greater.
• drugs to be used in the present invention will have a SlogP value from (a) about 1.5, about 2, or 2.5 to about 7, (b) about 1.5, about 2, or 2.5 to about 6, (c) about 1.5, about 2 or about 2.5 to about 5, (d) about 1.5, about 2, or 2.5 to about 4, or (e) about 1.5, about 2 or about 2.5 to about 3.
• SlogP Hydrophobicity can be measured using SlogP.
• SlogP is defined as the log of the octanol/water partition coefficient (including implicit hydrogens) and can be calculated using the program MOETM from the Chemical Computing group (SlogP values calculated using Wildman,
• reactive group is a functional group capable of forming a covalent bond with a functional group of an antibody or antibody fragment.
• functional groups include reactive groups of Table 1 provided herein.
• the term“coupling group”, as used herein, refers to a bivalent moiety which links the bridging spacer to the antibody or fragment thereof.
• the coupling group is a bivalent moiety formed by the reaction between a reaction group and a functional group on the antibody or fragment thereof.
• Non limiting examples of such bivalent moieties include the bivalent chemical moieties given in Table 1 and Table 2 provided herein.
• bridging spacer refers to one or more linker components which are covalently attached together to form a bivalent moiety which links the bivalent peptide spacer to the reactive group or links the bivalent peptide space to the coupling group.
• the“bridging spacer” comprises a carboxyl group attached to the N-terminus of the bivalent peptide spacer via an amide bond.
• spacer moiety refers to one or more linker components which are covalently attached together to form a moiety which links the self-immolative spacer to the hydrophilic moiety.
• bivalent peptide spacer refers to bivalent linker comprising one or more amino acid residues covalently attached together to form a moiety which links the bridging spacer to the self immolative spacer.
• the one or more amino acid residues can be an residue of amino acis selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucune (N
• a“bivalent peptide spacer” is a combination of 2 to four amino acid residues where each residue is independently selected from a residue of an amino acid selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu),
• phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine
• linker component refers to the following
• n 1-18
• phenyl including 1,2- 1,3- and 1,4- di-substituted phenyls
• C 5 -C 6 heteroaryl a C 3 -C 8 cycloalkyl (including 1,1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and 1,4-disubstituted cyclohexyl), and a C 4 -C 8 heterocycloalkyl;
• y a residue of an amino acid selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu),methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucune (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethyl pyrrolysine;
• each residue is independently selected from a residue of an amino acid selected from alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu),methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucune (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethyl pyrrolysine, for example Val-Cit;
• the self-immolative spacer comprises one or more protecting (triggering) groups which are susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage
• protecting (triggering) groups which are susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage
• protecting (triggering) groups which are susceptible to acid-induced cleavage, peptidase-induced cleavage
• PG is a protecting (triggering) group
• X a is O, NH or S
• X b is O, NH, NCH 3 or S;
• X c is O or NH
• Y a is CH 2 , CH 2 O or CH 2 NH
• Y b is CH 2 , O or NH
• Y c is a bond, CH 2 , O or NH
• LG is a leaving group such as a Drug moiety (D) of the Linker-Drug group of the invention.
• a linker component can be a chemical moiety which is readily formed by reaction between two reactive groups.
• Non-limiting examples of such chemical moieties are given in Table 1.
• R 32 in Table 1 is H, C 1-4 alkyl, phenyl, pyrimidine or pyridine;
• R 35 in Table 1 is H, C 1- 6 alkyl, phenyl or C 1-4 alkyl substituted with 1 to 3–OH groups;
• R 37 in Table 1 is independently selected from H, phenyl and pyridine;
• q in Table 1 is 0, 1, 2 or 3;
• R 8 or R 13 in Table 1 is H or methyl;
• R 9 or R 14 in Table 1 is H, -CH 3 or phenyl; and
• R in Table 1 is H or a suitable substituent, e.g.,
• a wavy line ( ) indicates the point of attachment of the partial structure to the rest of the molecule.
• the term“self-immolative spacer”, as used herein, refers a moiety comprising one or more triggering groups (TG) which are activated by acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase induced cleavage, phosphodiesterase induced cleavage, phosphatase induced cleavage, protease induced cleavage, lipase induced cleavage or disulfide bond cleavage, and after activation the protecting group is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of a leaving group.
• Such cascade of reactions can be, but not limited to, 1,4-, 1,6- or 1,8- elimination reactions.
• Non-limiting examples of such self-immolative spacer include:
• TG is a triggering group
• X a is O, NH or S
• X b is O, NH, NCH 3 or S;
• X c is O or NH
• Y a is CH 2 , CH 2 O or CH 2 NH
• Y b is CH 2 , O or NH
• Y c is a bond, CH 2 , O or NH
• LG is a leaving group such as a Drug moiety (D) of the Linker-Drug group of the invention.
• Lp is an enzymatically cleavable bivalent peptide spacer and A, D, L 3 and R 2 are as defined herein.
• the self-immolative spacer is moiety having the structure
• Lp is an enzymatically cleavable bivalent peptide spacer and D, L 3 and R 2 are as defined herein.
• the self-immolative spacer is moiety having the structure , where Lp is an enzymatically cleavable bivalent peptide spacer and D, L3 and R 2 are as defined herein.
• D is a quaternized tertiary amine- containing Drug moiety, wherein the ammonium cation optionally exists as a zwitterionic form or has a monovalent anionic counterion.
• hydrophilic moiety refers to moiety that is has hydrophilic properties which increases the aqueous solubility of the Drug moiety (D) when the Drug moiety (D) is attached to the linker group of the invention.
• hydrophilic groups include, but are not limited to, polyethylene glycols, polyalkylene glycols, sugars, oligosaccharides, polypeptides a C 2 -C 6 alkyl substituted with 1 to 3 groups and
• R a is H or C 1-4 alkyl optionally substiltuted with either OH or C 1-4 alkoxyl, and each of m and n is an integer between 2 and 25 (e.g., between 3 and 25).
• the hydrophilic moiety comprises .
• antibody refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen. Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources.
• a naturally occurring“antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region
• VH light chain variable region
• FR framework regions
• variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
• the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.
• An antibody can be a monoclonal antibody, human antibody, humanized antibody, camelised antibody, or chimeric antibody.
• the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
• antibody fragment or“antigen-binding fragment” or“functional fragment” refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hinderance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen.
• antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody.
• An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005).
• Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3) (see U.S. Patent No.: 6,703,199, which describes fibronectin polypeptide minibodies).
• scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
• a synthetic linker e.g., a short flexible polypeptide linker
• an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.
• CDR complementarity determining region
• HCDR1, HCDR2, and HCDR3 three CDRs in each heavy chain variable region
• LCDR1, LCDR2, and LCDR3 three CDRs in each light chain variable region
• the precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by
• the CDRs correspond to the amino acid residues that are defined as part of the Kabat CDR, together with the amino acid residues that are defined as part of the Chothia CDR.
• the CDRs defined according to the“Chothia” number scheme are also sometimes referred to as“hypervariable loops.”
• VH heavy chain variable domain
• HCDR1 e.g., insertion(s) after position 35
• HCDR2 HCDR2
• HCDR3 CDR amino acid residues in the light chain variable domain
• VL CDR amino acid residues in the light chain variable domain
• LCDR1 e.g., insertion(s) after position 27
• 50-56 LCDR2
• LCDR3 CDR amino acid residues in the light chain variable domain
• the CDR amino acids in the VH are numbered 26-32 (HCDR1) (e.g., insertion(s) after position 31), 52-56 (HCDR2), and 95-102 (HCDR3)
• the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion(s) after position 30), 50-52 (LCDR2), and 91-96 (LCDR3).
• the CDRs comprise or consist of, e.g., amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.
• the CDR amino acid residues in the VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to“Kabat”).
• CDR1 the CDR amino acid residues in the VH
• CDR2 53-102
• CDR3 the CDR amino acid residues in the VL
• CDR3 are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to“Kabat”).
• the CDR regions of an antibody can be determined using the program IMGT/DomainGap Align.
• epitope includes any protein determinant capable of specific binding to an immunoglobulin or otherwise interacting with a molecule.
• Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
• An epitope may be“linear” or “conformational.” Conformational and linear epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
• phrases“monoclonal antibody” or“monoclonal antibody composition” as used herein refers to polypeptides, including antibodies, bispecific antibodies, etc., that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition.
• monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
• human antibody includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik, et al. (2000. J Mol Biol 296, 57-86).
• immunoglobulin variable domains e.g., CDRs
• CDRs immunoglobulin variable domains
• the structures and locations of immunoglobulin variable domains may be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and
• ImMunoGenTics (IMGT) numbering (see, e.g., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services (1991), eds. Kabat et al.; Al Lazikani et al., (1997) J. Mol. Bio.273:927948); Kabat et al., (1991) Sequences of Proteins of
• the human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or
• human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
• recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences.
• recombinant means such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombin
• Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that,
• an Fc region refers to a polypeptide comprising the CH3, CH2 and at least a portion of the hinge region of a constant domain of an antibody.
• an Fc region may include a CH4 domain, present in some antibody classes.
• An Fc region may comprise the entire hinge region of a constant domain of an antibody.
• the invention comprises an Fc region and a CH1 region of an antibody.
• the invention comprises an Fc region CH3 region of an antibody.
• the invention comprises an Fc region, a CH1 region and a Ckappa/lambda region from the constant domain of an antibody.
• a binding molecule of the invention comprises a constant region, e.g., a heavy chain constant region.
• a constant region is modified compared to a wild-type constant region.
• the polypeptides of the invention disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1, CH2 or CH3) and/or to the light chain constant region domain (CL).
• Example modifications include additions, deletions or substitutions of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc.
• binding specificity refers to the ability of an individual antibody combining site to react with one antigenic determinant and not with a different antigenic determinant.
• the combining site of the antibody is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. Binding affinity of an antibody is the strength of the reaction between a single antigenic determinant and a single combining site on the antibody. It is the sum of the attractive and repulsive forces operating between the antigenic determinant and the combining site of the antibody.
• affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody“arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
• conservative sequence modifications refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site- directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine,
• acidic side chains e.g., aspartic acid, glutamic acid
• uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
• nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
• beta- branched side chains e.g., threonine, valine, isoleucine
• aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine.
• one or more amino acid residues within an antibody can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested using the functional assays described herein.
• homologous or“identity” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules.
• two nucleic acid molecules such as, two DNA molecules or two RNA molecules
• two polypeptide molecules or between two polypeptide molecules.
• a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position.
• the homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous.
• Percentage of“sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
• the percentage can be calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity.
• the output is the percent identity of the subject sequence with respect to the query sequence.
• the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
• the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
• the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol.48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
• the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package
• a particularly preferred set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
• the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
• nucleic acid and protein sequences described herein can be used as a“query sequence” to perform a search against public databases to, for example, identify other family members or related sequences.
• Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10.
• Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25:3389-3402.
• the default parameters of the respective programs e.g., XBLAST and NBLAST
• XBLAST and NBLAST can be used. See www.ncbi.nlm.nih.gov.
• composition refers to a mixture of a compound of the invention with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• pharmaceutically acceptable chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• an optical isomer or“a stereoisomer”, as used herein, refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
• the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
• a 1:1 mixture of a pair of enantiomers is a "racemic” mixture.
• the term is used to designate a racemic mixture where appropriate.
• “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-lngold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical
• compositions is contemplated.
• pharmaceutically acceptable salt refers to a salt which does not abrogate the biological activity and properties of the compounds of the invention, and does not cause significant irritation to a subject to which it is administered.
• subject encompasses mammals and non-mammals.
• mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
• non-mammals include, but are not limited to, birds, fish and the like. Frequently the subject is a human.
• a subject in need of such treatment refers to a subject which would benefit biologically, medically or in quality of life from such treatment.
• the terms“treat,”“treating,” or“treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat,”“treating,” or“treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat,”“treating,” or“treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
• the term“prevent”,“preventing” or“prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder
• therapeutically effective amount or“therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., reduction or
• a therapeutically effective amount does not induce or cause undesirable side effects.
• a therapeutically effective amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient’s condition.
• a therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved.
• a “prophylactically effective dose” or a“prophylactically effect amount”, of the molecules of the invention can prevent the onset of disease symptoms, including symptoms associated with cancer.
• A“therapeutically effective dose” or a“therapeutically effective amount” of the molecules of the invention can result in a decrease in severity of disease symptoms, including symptoms associated with cancer.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• lsotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.
• the Linker-Drug group of the invention is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C1-C6alkyl or a C3-C8cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 1 The compound of Formula (I), or pharmaceutically acceptable salt
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 2 The compound of Formula (I), or pharmaceutically acceptable salt
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• the group is selected from:
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 3 The compound of Formula (I), having the structure of Formula (II):
• R 1 is a reactive group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues;
• R 2 is a hydrophilic moiety;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 4 The compound of Formula (I) or of any one of Embodiments 1 to 3, or pharmaceutically acceptable salt thereof, wherein:
• R 1 is -ONH 2 , -NH 2 ,
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• each R 3 is independently selected from H and C 1 -C 6 alkyl
• R 4 is 2-pyridyl or 4-pyridyl
• each R 5 is independently selected from H, C 1 -C 6 alkyl, F, Cl, and–OH;
• each R 6 is independently selected from H, C 1 -C 6 alkyl, F, Cl, -NH 2 , -OCH 3 , - OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and–OH;
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 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 and 30;
• Lp is a bivalent peptide spacer comprising an amino acid residue selected from
• glycine valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ; or
• X is ***-CH 2 -triazolyl-C 1-4 alkylene-OC(O)NHS(O) 2 NH-*
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 5 The compound of Formula (I) or of any one of Embodiments 1 to 4, or pharmaceutically acceptable salt thereof, wherein:
• R 1 is , -ONH 2 , or
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit),
• L 3 is a spacer moiety having the structure
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 6 The compound of Formula (I) or of any one of Embodiments 1 to 5, or pharmaceutically acceptable salt thereof, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 7 The compound of Formula (I) or of any one of Embodiments 1 to 6, or pharmaceutically acceptable salt thereof, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure ,
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 8 The compound of Formula (I) or of any one of Embodiments 1 to 7, or pharmaceutically acceptable salt thereof, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L3 is a spacer moiety having the structure ,
• X is ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety.
• Embodiment 9 The compound of Formula (I) or of any one of Embodiments 1 to 8, or pharmaceutically acceptable salt thereof, wherein R 1 is a reactive group selected from Table 1 or Table 2.
• Embodiment 10 The compound of Formula (I) or of any one of Embodiments 1 to 9, or pharmaceutically acceptable salt thereof, wherein:
• R 1 is -ONH 2 , -NH 2 ,
• Embodiment 11 The compound of Formula (I) or of any one of Embodiments 1 to 9, or pharmaceutically acceptable salt thereof, wherein:
• Embodiment 12 The compound of Formula (I) or of any one of Embodiments 1 to 9, or pharmaceutically acceptable salt thereof, wherein:
• R 1 is , ONH 2 , , , , , ,
• Embodiment 13 The compound of Formula (I) or of any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:
• R 1 is , -ONH 2 , , , or .
• Embodiment 14 The compound of Formula (I) or of any one of Embodiments 1 to 9, or a
• Embodiment 15 The compound of Formula (I) or of any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is -ONH 2 .
• Embodiment 16 The compound of Formula (I) or of any one of Embodiments 1 to 9, or a
• Embodiment 17 The compound of Formula (I) or of any one of Embodiments 1 to 9, or pharmaceutically acceptable salt thereof, wherein:
• Embodiment 18 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 19 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 20 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 21 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 22 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 23 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 24 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 25 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 26 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 27 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 28 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 29 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 30 The compound of Formula (I) or of any one of Embodiments 1 to 8, having the structure:
• Embodiment 31 The compound of Formula (I) or of any one of Embodiments 1 to 8, or pharmaceutically acceptable salt thereof, having the structure of a compound in any of Tables 4A-4C included herein.
• Embodiment 32 A linker of the Linker-Drug group of Formula (I) having the structure of Formula (V),
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• L 3 is a spacer moiety
• Embodiment 33 The linker of Embodiment 32, wherein:
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• L 3 is a spacer moiety
• Embodiment 34 The linker of Embodiment 32 or 33, wherein:
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• the group is selected from:
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• Embodiment 35 The linker of any one of Embodiments 32 to 34, wherein:
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• each R 3 is independently selected from H and C 1 -C 6 alkyl
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer comprising an amino acid residue selected from glycine, valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine;
• L 3 is a spacer moiety having the structure ,
• X is a bond, triazolyl or ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;or
• X is ***-CH 2 -triazolyl-C 1-4 alkylene-OC(O)NHS(O) 2 NH-*
• Embodiment 36 The linker of any one of Embodiments 32 to 35, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from ( ),
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• Embodiment 37 The linker of any one of Embodiments 32 to 36, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 - C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• Embodiment 38 The linker of any one of Embodiments 32 to 37, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G;
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• Embodiment 39 The linker of any one of Embodiments 32 to 38, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups;
• Embodiment 40 The linker of Formual (V) having the structure having the structure of Formula (VI),
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• R 2 is a hydrophilic moiety
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl,
• L 3 is a spacer moiety
• Embodiment 41 The linker of Embodiments 40, wherein:
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• R 2 is a hydrophilic moiety
• A is a bond, -
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl,
• L 3 is a spacer moiety
• Embodiment 42 The linker of Embodiment 40 or 41, wherein:
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups, or a polysarcosine;
• each R 3 is independently selected from H and C 1 -C 6 alkyl
• Lp is a bivalent peptide spacer comprising an amino acid residue selected from glycine, valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine;
• X is a bond, triazolyl or ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ; or
• X is ***-CH 2 -triazolyl-C 1-4 alkylene-OC(O)NHS(O) 2 NH-*
• each n independently is 1, 2, or 3
• the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• Embodiment 43 The linker of any one of Embodiments 40 to 42, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl.
• Embodiment 44 The linker of any one of Embodiments 40 to 43, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group;
• L 3 is a spacer moiety having the structure ,
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups or a polysarcosine;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl.
• Embodiment 45 The linker of any one of Embodiments 40 to 44, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group;
• L 3 is a spacer moiety having the structure ,
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3
• Embodiment 46 The linker of any one of Embodiments 40 to 45, wherein:
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group;
• L 3 is a spacer moiety having the structure ,
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups, or a polysarcosine;
• Embodiment 47 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 48 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 49. The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 50 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 51 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 52 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 53 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 54 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 55 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 56 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 57 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 58 The linker of any one of Embodiments 32 to 46, having the structure:
• Embodiment 59 The linker of any one of Embodiments 32 to 46, having the structure:
• the present invention provides Antibody Drug Conjugates, also reffered to herein as immunoconjugates, which comprise linkers which comprise one or more hydrophilic moieties.
• the Antibody Drug Conjugates of the invention have the structure of Formula (III),:
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C1-C6alkyl or a C3-C8cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Antibody Drug Conjugates of the invention are provided in the following listing of enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.
• Embodiment 60 The immunoconjugate of Formula (III) wherein:
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• G-L 2 -A is a self-immolative spacer
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 61 The immunoconjugate of Formula (III) or Embodiment 60, wherein:
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues
• the group is selected from: , wherein the * of indicates the point of attachment to an N or a O of the Drug moiety, the *** of ndicates the point of attachment to Lp;
• R 2 is a hydrophilic moiety
• L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 62 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 61 having the structure of Formula (IV),
• Ab is an antibody or fragment thereof
• R 100 is a coupling group
• L 1 is a bridging spacer
• Lp is a bivalent peptide spacer comprising one to four amino acid residues;
• R 2 is a hydrophilic moiety;
• A is a bond, -
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L3 is a spacer moiety
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 63 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 62, wherein:
• Ab is an antibody or fragment thereof
• R 100 indicates the point of attachment to Ab
• each R 3 is independently selected from H and C 1 -C 6 alkyl
• R 4 is 2-pyridyl or 4-pyridyl
• each R 5 is independently selected from H, C 1 -C 6 alkyl, F, Cl, and–OH;
• each R 6 is independently selected from H, C 1 -C 6 alkyl, F, Cl, -NH 2 , -OCH 3 , - OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and–OH;
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer comprising an amino acid residue selected from valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ; or
• X is ***-CH 2 -triazolyl-C 1-4 alkylene-OC(O)NHS(O) 2 NH-*
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 64 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 63, wherein:
• Ab is an antibody or fragment thereof
• R 100 is , , , , ,
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from ( )
• L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups, and a polysarcosine;
• each R a is independently selected from H, C 1 -C 6 alkyl or a C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 65 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 64, wherein:
• Ab is an antibody or fragment thereof
• R 100 is where the *** of R 100 indicates the point of attachment to Ab;
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide or C 2 -C 6 alkyl substituted with 1 to 3 groups, and a polysarcosine;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 66 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 65, wherein:
• Ab is an antibody or fragment thereof
• R 100 is where the *** of R 100 indicates the point of attachment to Ab;
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L3 is a spacer moiety having the structure
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R 2 ;
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups, and a polysarcosine;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 67 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 66, wherein:
• Ab is an antibody or fragment thereof
• R 100 is where the *** of R 100 indicates the point of attachment to Ab;
• each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
• each t is independently selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30;
• Lp is a bivalent peptide spacer selected from (ValCit), where the * of Lp indicates the attachment point to L 1 and the ** of Lp indicates the attachment point to the–NH- group of G; L 3 is a spacer moiety having the structure
• each R b is independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl and wherein the ** of W indicates the point of attachment to X;
• X is ***-CH 2 -triazolyl-*, wherein the *** of X indicates the point of
• R 2 is a hydrophilic moiety selected from polyethylene glycol, polyalkylene glycol, a sugar, an oligosaccharide, a polypeptide, C 2 -C 6 alkyl substituted with 1 to 3 groups, and a polysarcosine;
• D is a Drug moiety comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the Drug moiety,
• y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
• Embodiment 68 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 62, wherein R 100 is a coupling group.
• Embodiment 69 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 63, wherein
• Embodiment 71 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 63, wherein
• R 100 is O , , , , ,
• Embodiment 72 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 63, wherein
• Embodiment 73 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 74 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 75 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 76 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 77 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 78 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 79 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 80 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 81 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 82 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 83 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 84 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiment 85 The immunoconjugate of Formula (III) or any one of Embodiments 60 to 72 having the structure:
• Embodiments 60 to 61 wherein:
• G is , where the * of G indicates the point of attachment to L 2 , and the ** of G indicates the point of attachment to L 3 and the *** of G indicates the point of attachment to Lp.
• Embodiment 87 The compound of Formula (I) or any one of Embodiments 1 to 2, or

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