Activated cytotoxic compounds for attachment to targeting molecules for the treatment of mammalian disease conditions
Inventors
Bell, Stanley C • Fegley, Glenn • Cosenza, Stephen • Duke, Jodie • Premkumar, Reddy E • Ramana, Reddy M. V.
Assignees
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Publication Number
US-8273787-B2
Publication Date
2012-09-25
Expiration Date
Abstract
Activated cytotoxic compounds are described for attachment to targeting molecules for the treatment of a mammalian disease condition which comprise, an activator, a spacer linker, a linker (e.g., self-immolative), and a cytotoxic drug selected from the group consisting of AMINO-SUBSTITUTED (E)-2,6-DIALKOXYSTYRYL 4-SUBSTITUTED BENZYLSULFONES, AMINO-AND-HYDROXY SUBSTITUTED STYRYLSULFONANILIDES, and SUBSTITUTED PHENOXY- AND PHENYLTHIO-STYRYLSULFONE DERIVATIVES. Activated cytotoxic compound attached to a targeting molecule are described wherein the targeting molecule is selected from the group consisting essentially of an antibody, a receptor, a ligand, a cytokine, a hormone, and a signal transduction molecule. The invention is further directed to a method of treatment of disease conditions.
Core Innovation
The invention describes activated cytotoxic compound structures for attachment to a targeting molecule for the treatment of proliferative disorders. Each activated cytotoxic compound comprises an activator, a spacer linker, a linker, and a cytotoxic drug, and the linker is a self-immolative linker selected from para-Aminobenzyl Alcohol (PABA), 3,3-Dimethyl-4-hydroxybutyric Acid, an Ethylenediamine, γ-Aminobutyric Acid (GABA), 2-Hydroxycinnamic Acid, “Trimethyl Lock”, or an Ethanolamine.
The spacer linker is selected from Glutaryl, Diglycoyl, Succinyl, Homophthalyl, or Amino-PEG-Acid. The patent further identifies activated cytotoxic drugs including (E)-2,4,6-trimethoxystyryl-4-methoxy-3-aminobenzylsulfone (ON 01500), (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenol (ON 013100), and/or (E)-2,4,6-trimethoxystyryl-4-methoxy-3-aminophenylsulfonamide (ON 24160), together with activators selected from N-Hydroxysuccinimidyl, N-Hydroxyphthalimideyl, o-Nitrophenyl, Acyl azide, p-Nitrophenyl, N-Hydroxybenzotriazoleyl, Pentachlorophenyl, Pentafluorophenyl, or 2,4,6-trichlorophenyl.
The described attachment concept extends to a targeting molecule that binds a specific biological target, where the targeting molecule is covalently attached to an activator, a spacer linker, a self-immolative linker, and a cytotoxic drug. Prodrug activation is described in connection with self-immolative cleavage and efficient intracellular payload release, and the activated cytotoxic prodrug concept is directed to treatment of proliferative disorders.
Claims Coverage
The document includes two independent claims. Together, they cover activated cytotoxic compounds defined by an activator, a spacer linker, a self-immolative linker, and a cytotoxic drug, with one independent claim further requiring a targeting molecule that binds a specific biological target.
Activated cytotoxic compound with self-immolative linker architecture and ON cytotoxic drug
An activated cytotoxic compound for attachment to a targeting molecule for the treatment of proliferative disorders comprising an activator, a spacer linker, a linker, and a cytotoxic drug, wherein the linker is para-Aminobenzyl Alcohol (PABA), 3,3-Dimethyl-4-hydroxybutyric Acid, an Ethylenediamine, γ-Aminobutyric Acid (GABA), 2-Hydroxycinnamic Acid, “Trimethyl Lock”, or an Ethanolamine; the spacer linker is Glutaryl, Diglycoyl, Succinyl, Homophthalyl, or Amino-PEG-Acid; the activated cytotoxic drug is ON 01500, ON 013100, and/or ON 24160; and the activator is N-Hydroxysuccinimidyl, N-Hydroxyphthalimideyl, o-Nitrophenyl, Acyl azide, p-Nitrophenyl, N-Hydroxybenzotriazoleyl, Pentachlorophenyl, Pentafluorophenyl, or 2,4,6-trichlorophenyl.
Covalently attached targeting molecule with activator, spacer linker, self-immolative linker, and cytotoxic drug
An activated cytotoxic compound for attachment to a targeting molecule that binds a specific biological target for the treatment of proliferative disorders comprising a targeting molecule covalently attached to an activator, a spacer linker, a self-immolative linker, and a cytotoxic drug, wherein the self-immolative linker is para-Aminobenzyl Alcohol (PABA), 3,3-Dimethyl-4-hydroxybutyric Acid, an Ethylenediamine, γ-Aminobutyric Acid (GABA), 2-Hydroxycinnamic Acid, “Trimethyl Lock”, or an Ethanolamine, and the spacer linker is Glutaryl, Diglycoyl, Succinyl, Homophthalyl, or Amino-PEG-Acid.
The independent claims center on activated cytotoxic compounds built from an activator, a specified spacer linker, a specified self-immolative linker, and specified ON cytotoxic drugs, with one claim further requiring a targeting molecule that binds a specific biological target.
Stated Advantages
Plasma stability.
Efficient intracellular payload release.
Reduced ADC aggregation.
Low immunogenicity.
Maintained binding affinity.
Improved tumor targeting and drug release is described in connection with the activated cytotoxic prodrug concept.
Improved activity/selectivity toward HER2-overexpressing cells.
Documented Applications
Treatment of proliferative disorders using activated cytotoxic compounds attached to targeting molecules, including cancer (as an example proliferative disorder) and ADC/immunoconjugate contexts.
Targeting biological targets using covalent attachment of activated cytotoxic compounds to internalizing monoclonal antibodies such as Trastuzumab directed to HER2.
Targeted treatment of proliferative disorders using targeting molecules for tumor specific surface antigens and binding/internalization into cancer cells [procedural detail omitted for safety].
Examples include targeting malignant cell surface biological targets using antibodies such as Trastuzumab, CD138, and CD38 (multiple myeloma) and HER2.
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