Benzazepine compounds, conjugates, and uses thereof
Inventors
COBURN, Craig Alan • Baum, Peter Robert • Smith, Sean Wesley
Assignees
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Publication Number
US-10428045-B2
Publication Date
2019-10-01
Expiration Date
Abstract
Benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. The disclosed benzazepine compounds are useful, among other things, in the treating of cancer and modulating TLR8. Additionally, benzazepine compounds incorporated into a conjugate with an antibody construct are described herein.
Core Innovation
The disclosed subject matter relates to antibody-linked conjugates represented by a formula in which Antibody is an antibody construct, L3 is a linker moiety, and D is a compound represented by Formula (IIB), or a pharmaceutically acceptable salt thereof. The conjugate framework defines L10 and L2 selections, with L10 bound to R5, and constrains substituent variables including R1, R2, R4, R5, R10, R20-R23, and R24-R25 through specified optionally substituted carbocycle and heterocycle classes.
The disclosed linker architecture includes cleavable and noncleavable embodiments, including L3 being cleavable by a lysosomal enzyme, peptide-associated linker structures with L4 as the C-terminal of a peptide and L5 selected from a bond, alkylene, or heteroalkylene, and RX* motifs including a bond and a succinimide or hydrolyzed succinimide moiety attached to a residue of an antibody construct. The linker moiety enables release of benzazepine D via enzymatic cleavage, including proteases and lysosomal beta-glucuronidase.
The document further presents benzazepine-based compound families and small-molecule payloads, including Formula (IA), Formula (IB), Formula (IIIA), Formula (IIIB), Formula (IVA), and Formula (IVB), with extensive variable definitions for substituents and linker-related groups. It also describes immune-stimulatory linked payload preparation and related benzo[b]azepine dicarboxamide compounds.
Claims Coverage
The consolidated claim coverage centers on one independent antibody-linker-compound conjugate claim, with additional dependent refinements that specify cleavable linker behavior, peptide and succinimide-related linker architectures, specific peptide sequences, and therapeutic use contexts. In total, the combined claim features emphasize the antibody construct, the defined linker moieties, the Formula (IIB) compound D, and the constrained substituent scopes for the payload scaffold.
Antibody-linker-compound conjugate with Formula (IIB) payload
A conjugate represented by a formula wherein Antibody is an antibody construct, L3 is a linker moiety, and D is a compound represented by the structure of Formula (IIB), or a pharmaceutically acceptable salt thereof.
Defined linker selections for L10 and L2
L10 is selected from —C(O)— and —C(O)N(R10)—*, where * represents where L10 is bound to R5—; and L2 is selected from —C(O)— and —C(O)N(R10)—.
Constrained substituent scope for the compound D scaffold
R1 and R2 are independently selected from hydrogen and C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, optionally substituted as listed; R4 is selected from OR10, —N(R10)2, —C(O)N(R10)2, —C(O)R10, —C(O)OR10, —S(O)R10, and —S(O)2R10; R5 is selected from unsaturated C4-8 carbocycle, bicyclic carbocycle, and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle; and R10, R20-R23, and R24-R25 are defined by the listed substituent sets, including the option that R24 and R25 taken together form an optionally substituted saturated C3-7 carbocycle.
L3 cleavable by a lysosomal enzyme
A conjugate in which L3 is cleavable by a lysosomal enzyme.
Peptide-associated linker architecture with succinimide motif
A conjugate in which L3 is represented by a formula where L4 is defined as the C-terminal of a peptide, L5 is selected from a bond, alkylene, and heteroalkylene, and RX* includes a bond and a succinimide or hydrolyzed succinimide moiety attached at a point to a residue of an antibody construct.
Peptide of L3 includes Val-Cit or Val-Ala
A conjugate characterized in that the peptide of L3 includes Val-Cit or Val-Ala.
Breast cancer treatment using HER2, TROP2, or Liv-1 binding antibody construct
A method of treating breast cancer by administering an effective amount of a pharmaceutical composition, where an antibody construct specifically binds to human HER2, TROP2, or Liv-1.
The consolidated claim coverage is directed to antibody-linker-drug conjugates in which an antibody construct is linked through defined linker moieties to a Formula (IIB) compound D, with extensive variable constraints on the payload scaffold. The dependent claim features further narrow the disclosure to lysosomal-enzyme-cleavable and peptide/succinimide-based linker architectures, specific peptide sequences, and a breast cancer treatment context with HER2, TROP2, or Liv-1 targeting.
Stated Advantages
Reduces bystander effects.
Reduces nonspecific toxicities.
Improves circulation stability.
Prevents maleimide reverse reaction.
Obtains more homogeneous DAR4 conjugates.
Increases stability.
Avoidance of aggregation while enabling linkage from antibody constructs to hydrophobic benzazepines.
Self-immolative enzymatic release of benzazepine D after cleavage, including 1,6-elimination.
Lysosome-associated enzymatic cleavage enabling liberation of D.
Linker-dependent bystander cell killing via metabolic diffusion.
Reduction or enhancement of aggregation of conjugates.
The conjugates and compositions are described as enabling tumor cell killing and cancer treatment.
Documented Applications
Treating breast cancer by administering a pharmaceutical composition in which an antibody construct specifically binds to human HER2, TROP2, or Liv-1.
Disease treatment, including cancer treatment.
Immune-stimulatory activity is evaluated using TLR7/TLR8 reporter assays, including HEK-Blue hTLR7 and HEK-Blue hTLR8.
Immune-stimulatory induction is evaluated in PBMC/monocytes/macrophages by measuring TNFα induction.
Targeting tumor antigens, including use in an immune stimulation/TLR8 agonist context.
Therapeutic targeting of tumor antigens with antibodies including anti-CD40 antibody, anti-HER2 antibody, and anti-TROP2 antibody.
Antibody conjugates to a TLR8 agonist, including benzazepine-based TLR8 agonists, with concepts favoring TLR8 selectivity over TLR7.
Cancer treatment, including tumor cell killing.
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