Bis-octahydrophenanthrene carboxamides and protein conjugates thereof
Inventors
Han, Amy • Murphy, Andrew J. • Olson, William
Assignees
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Publication Number
US-12338199-B2
Publication Date
2025-06-24
Expiration Date
Abstract
Provided herein are compounds, compositions and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.
Core Innovation
The invention provides compounds of Formula A, or pharmaceutically acceptable salts, stereoisomeric forms, regioisomers, and solvates thereof, in which a linker moiety L is defined as a linker or X—Y—Z. X is —NH— or —O—, Y includes an enzymatically cleavable moiety, a self-immolative group, an acid-labile moiety comprising an alkoxamine, ketoxamine, carbonate, or phosphonate, PEG, and/or a sugar moiety comprising a glucuronide, and may further include an enhancement group comprising a cyclodextrin and/or an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid.
Z is a binding agent linker (BL) covalently bound to BA, where BA is an antibody or an antigen binding fragment thereof. The compounds define an average number of units of a payload conjugated to BA as k, ranging from about one to about eight, and further specify structural variables Q1, Q2, W, R, R6, and R7.
The disclosed embodiments also include BA linked via one or more N295 residues, or via one or more N295 and N297Q residues, and BA having binding specificity for Her2 or PRLR. The framework is presented as a Formula A antibody or antigen binding fragment payload conjugate with defined linker cleavage or lability motifs together with enhancement groups and specified BA attachment context.
Claims Coverage
The consolidated claim coverage centers on a Formula A compound with a defined X—Y—Z linker architecture and a covalently bound binding agent linker to an antibody or antigen binding fragment BA. Across the items, the independent claim set includes six inventive feature groupings built around linker chemistry, payload conjugation stoichiometry k, and defined substituent options, with dependent refinements narrowing k and BA linkage specificity.
Formula a compound with covalently bound binding agent linker and antibody or antigen binding fragment
A compound of Formula A, or a pharmaceutically acceptable salt, stereoisomeric form, regioisomer, or solvate, wherein L is a linker or X—Y—Z, X is —NH— or —O—, and Z is a binding agent linker (BL) covalently bound to BA, where BA is an antibody or antigen binding fragment thereof.
Linker y with cleavable, self-immolative, acid-labile, peg, glucuronide, and enhancement groups
Y is an enzymatically cleavable moiety, a self-immolative group, an acid-labile moiety comprising an alkoxamine, ketoxamine, carbonate, or phosphonate, PEG, and/or a sugar moiety comprising a glucuronide, and the moiety may further include an enhancement group comprising a cyclodextrin and/or an alkyl, heteroalkyl, alkylenyl, or heteroalkylenyl sulfonic acid.
Average payload conjugation stoichiometry k
k ranges from about one to about eight as an average number of units of a payload conjugated to BA, with narrower embodiments reciting about one to about four or approximately two.
Defined substituent architecture for q1, q2, w, r, r6, and r7
Q1 and Q2 are independently —CH2—, C(O)—, —C(H)(OH)—, or —C(OH)2—; W is —CH2—, —N(H)—, or —O—; R is independently hydrogen, —OH, C1-6 alkyl, or —OP(O)(OR6)(OH); each R6 is independently hydrogen, an amino acid residue, a peptide, or alkyl; and each R7 is independently halo, C1-6 alkyl, C1-6 alkoxy, —CN, O-glucose, O-amino acid residue, or O-PEGn, where n is an integer from zero to three.
BA linkage via N295 or N295 and N297Q residues
BA is an antibody or an antigen binding fragment linked via one or more N295 residues, and in additional embodiments via one or more N295 and N297Q residues.
BA binding specificity for Her2 or PRLR
BA is an antibody or an antigen binding fragment thereof having binding specificity for Her2 or PRLR.
The claims are directed to Formula A antibody or antigen binding fragment conjugates that combine a specified linker architecture, a covalently attached binding agent linker, defined payload conjugation stoichiometry k, and constrained substituent sets. Dependent coverage further refines k and specifies BA linkage through N295 and N295/N297Q residues, as well as binding specificity for Her2 or PRLR.
Stated Advantages
Reduced atherosclerotic lesion area.
Reduced macrophage content in vivo.
Full activation of LXR signaling with antibody-LXR conjugates.
Superior or variable EC50 versus free payloads (for the evaluated systems).
No significant changes reported in serum lipids, hepatic triglyceride/cholesterol, or de novo lipogenesis changes in the in vivo assessment.
Improved therapeutic window versus systemic small-molecule LXR modulators.
Documented Applications
Use in antibody-drug conjugates to enable target-specific LXR modulation and improved therapeutic outcomes in atherosclerosis models.
Delivery of LXR agonist payloads via antibody-drug conjugates and evaluation of LXR binding and activation using THP1/LXR-Luc and TR-FRET coactivator assay formats.
Induction assessment of ABCA1/ABCG1 gene expression in differentiated macrophages and evaluation of cholesterol efflux using a BODIPY-cholesterol assay.
In vivo assessment of an anti-MSR1 antibody-LXR conjugate in Msr1hu/hu ApoE−/− mice, including evaluation of atherosclerotic lesion area and macrophage content.
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