Non-linear self-immolative linkers and conjugates thereof
Inventors
Elgersma, Ronald Christiaan • Huijbregts, Tijl • Coumans, Rudy Gerardus Elisabeth
Assignees
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Publication Number
US-11419944-B2
Publication Date
2022-08-23
Expiration Date
Abstract
The present invention relates to linker-drug compounds (LDs) and antibody-drug conjugates (ADCs) comprising a non-linear self-immolative linker, which is cleavable or transformable under appropriate conditions and which reduces the hydrophobicity of the antibody-drug conjugate.
Core Innovation
The invention relates to a linker-drug compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The compound includes V1 as a conditionally-cleavable or conditionally-transformable moiety that is cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process, and Z as a cytotoxic drug comprising a phenolic hydroxyl group through which Z is attached to the linker.
The formula (I) framework specifies structural indices n and m, where n is 0, 1, 2, or 3 and m is 0 or 1. The disclosed embodiments include non-linear self-immolative or exo-linker architectures, duocarmycin derivatives or CBI dimer derivatives, and peptide-based V1 moieties including di-, tri-, or tetra-peptide constructs such as valylalanine, valyllysine, valylcitrulline, phenylalanyllysine, or alanylphenylalanyllysine, optionally capped with an amine blocking group or a water-soluble group.
The invention further extends to antibody-drug conjugates in which the linker-drug is site-specifically conjugated to an antibody or antigen-binding fragment via engineered cysteines defined by Kabat and Eu numbering. The provided content describes these ADC architectures as reducing hydrophobicity and aggregation, reducing susceptibility to cathepsin B cleavage, and improving in vivo efficacy in xenograft comparisons versus linear comparator ADCs.
Claims Coverage
Independent claim coverage centers on a linker-drug compound of formula (I) and ADC embodiments. The combined inventive features include a conditionally-cleavable or conditionally-transformable V1, a cytotoxic drug Z attached through a phenolic hydroxyl group, defined structural indices n and m, peptide-defined V1 options, and site-specific engineered-cysteine conjugation with an average DAR constraint.
Conditionally-cleavable or conditionally-transformable moiety V1
V1 is a conditionally-cleavable or conditionally-transformable moiety that is cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process.
Phenolic hydroxyl attachment of cytotoxic drug Z
Z is a cytotoxic drug comprising a phenolic hydroxyl group through which Z is attached to the linker.
Linker structural parameters n and m
The compound of formula (I) has n equal to 0, 1, 2, or 3, and m equal to 0 or 1.
Peptide-based conditionally cleavable or transformable V1
V1 contains a di-, tri-, or tetra-peptide bonded to the linker through its C-terminal side, optionally capped at the N-terminal side with an amine blocking group or a water-soluble group, including valylalanine, valyllysine, valylcitrulline, phenylalanyllysine, or alanylphenylalanyllysine.
Site-specific antibody conjugation via engineered cysteine
The antibody-drug conjugate is site-specifically conjugated to an antibody or antigen-binding fragment via an engineered cysteine at specified heavy- and light-chain positions defined by Kabat and Eu numbering.
ADC average DAR constraint
The antibody-drug conjugate is defined with an average DAR y from 1 to 6, with n in the range 0 to 3, and is an ADC compound of formula (III) including an antibody or antigen-binding fragment thereof.
Overall, the claims cover linker-drug compounds of formula (I) with a conditionally-cleavable or conditionally-transformable V1 and a phenolic-hydroxyl-attached cytotoxic drug Z, with n and m restricted to the stated ranges. Dependent coverage further narrows V1 and Z to specific peptide and payload options and extends the subject matter to ADCs with engineered-cysteine site-specific conjugation and an average DAR range.
Stated Advantages
Improved in vivo efficacy.
Reduced susceptibility to cathepsin B cleavage versus linear comparator ADCs.
Reduced hydrophobicity and aggregation.
Improved physicochemical/PK properties.
Hydrophobicity analysis is described by analytical HIC with a relative hydrophobicity metric.
Cellular binding and selectivity are described for PSMA/5T4-positive versus PSMA/5T4-negative cell lines.
In vitro cytotoxicity is described via IC50 values comparing non-linear linker-drugs to a linear comparator linker-drug.
Site-specific Fab/Fc conjugation effects are noted.
Xenograft efficacy notes are included using an LNCaP-C4.2 model.
Documented Applications
Use in antibody-drug conjugates (ADCs).
ADC targeting of PSMA.
ADC targeting of 5T4 antigen.
Use in solid tumors and hematological malignancies.
Use in tumor xenograft model context for efficacy comparisons.
Antibody-drug conjugates.
PSMA/5T4-positive and PSMA/5T4-negative cell line binding and selectivity analysis.
In vitro cytotoxicity evaluation.
Xenograft efficacy evaluation using an LNCaP-C4.2 model.
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