Enediyne conjugates
Inventors
Verkade, Jorge Merijn Mathieu • HOOGENBOOM, Jorin • VAN BERKEL, Maria Antonia • van Delft, Floris Louis
Assignees
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Publication Number
US-11547763-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The invention relates to compounds of general structure (1): Q-(L1)n-(L2)o-(L3)p-(L4)q-D (1), wherein Q is a click probe; D is a cytotoxin containing an enediyne moiety; L1, L2, L3 and L4 are each individually linkers that together link Q to D; n, o, p and q are each individually 0 or 1, provided that n+o+p+q=1, 2, 3 or 4, wherein D comprises a functional moiety (21): wherein R12═C1-3-alkyl, the wavy line indicates the connection to the remainder of the cytotoxin, and wherein D is conjugated to (L4)q by replacing the amine H atom, and to conjugates obtainable by reacting the compound according to the invention with a protein comprising a click probe F capable of reacting with click probe Q in a click reaction. The invention further relates to a bioconjugate according to general structure (2): Pr-[(L6)-Z-(L1)n-(L2)o-(L3)p-(L4)q-D]xx (2), wherein Z is a connecting group that is formed in a click reaction, L6 is a linker that links Z to Pr and Pr is a (glyco)protein.
Core Innovation
The invention relates to compounds of structure (1) in which a click probe Q is linked to a cytotoxin containing an enediyne moiety D through one or more individually defined linkers L1, L2, L3 and L4. The conjugate is defined by linker-position indicators n, o, p and q, with n+o+p+q constrained to 1, 2, 3 or 4, and by substituent definitions that include R10, R12, R1 and R2.
The remainder of the cytotoxin is specified by R10 being H or SCH3, R12 being ethyl or isopropyl, and R1 being -(L4)q-(L3)p-(L2)o-(L1)n-Q. R2 is defined as —S(C1-C10 alkyl) or —C(R6)2R7, where R6 is H or optionally substituted C1-C6 alkyl and R7 is selected from H, -L5—OR8, or (CH2)sC(O)NR29-L5—OR8, with L5 a polar linker having 1-100 optionally substituted backbone atoms selected from C, N, O and S.
The patent further describes preferred linker architectures including L3 as a self-cleavable PABC spacer, L4 as an aminoalkanoic acid spacer such as Ahx or glycine, and L2 as a peptide spacer such as Val-Cit or Val-Ala. It also describes optional sulfamide-containing options for the polar linker L5 and connecting groups Z formed when click probes Q and F participate in a click reaction, with Z preferably including a triazole moiety.
Claims Coverage
The claim coverage centers on a cytotoxin-click-probe conjugate of structure (1) with an enediyne-containing cytotoxin linked to a click probe through L1-L4, with n, o, p and q each independently 0 or 1 and n+o+p+q equal to 1, 2, 3 or 4. Three inventive features are explicitly identified across the claim summaries, covering the linker chain, the cytotoxin remainder substituent definition, and the hydrophilic disulfide substituent with polar linker L5.
Click-probe linked enediyne cytotoxin conjugate with optional L1-L4 linker chain
A compound of structure (1) in which Q is a click probe and D is a cytotoxin containing an enediyne moiety, where L1, L2, L3 and L4 are individually linkers that together link Q to D, and n, o, p and q are each individually 0 or 1 provided that n+o+p+q=1, 2, 3 or 4.
Cytotoxin remainder substituent definition with R10 and R12
The compound is represented with R10 being H or SCH3, R12 being ethyl or isopropyl, and R1 being -(L4)q-(L3)p-(L2)o-(L1)n-Q, with the wavy lines indicating the connection to the remainder of the cytotoxin.
Hydrophilic disulfide substituent R2 with defined R6/R7 and polar linker L5
R2 is defined as —S(C1-C10 alkyl) or —C(R6)2R7, where each R6 is independently selected from H or optionally substituted C1-C6 alkyl and R7 is selected from H, -L5—OR8, or (CH2)sC(O)NR29-L5—OR8, wherein L5 is a polar linker having 1-100 optionally substituted backbone atoms selected from C, N, O and S, R8 is H or methyl, s is 1, 2 or 3, and R29 is selected from H and -L5—OR8.
The claim coverage is focused on a defined cytotoxin-click-probe conjugate architecture with an enediyne-containing cytotoxin, optional linker segments L1-L4 controlled by n, o, p and q, and a hydrophilic disulfide substituent R2 defined through R6, R7, R8, R29, and the polar linker L5.
Stated Advantages
Reduces aggregation.
Improves aqueous solubility.
Improves click efficiency.
Improves stability.
Improves pharmacokinetics (PK).
Improved solubility.
Improved click conjugation efficiency.
Reduced antibody-drug conjugate aggregation.
Improved pharmacokinetics/tolerability.
Documented Applications
In vitro cytotoxicity of multiple calicheamicin-based ADCs versus controls across HER2-positive and HER2-negative cell lines is described, including HER2-positive BT-474 and JIMT-1 and HER2-negative MDA-MB-231.
Use in antibody-drug conjugate contexts.
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