Modified antibody, antibody-conjugate and process for the preparation thereof
Inventors
van Delft, Floris Louis • Van Geel, Remon • Wijdeven, Maria Antonia
Assignees
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Publication Number
US-12194107-B2
Publication Date
2025-01-14
Expiration Date
Abstract
The present invention relates to an antibody comprising a GlcNAc-S(A)x substituent, wherein S(A)x is a sugar derivative comprising x functional groups A wherein A is independently selected from the group consisting of an azido group, a keto group and an alkynyl group and x is 1, 2, 3 or 4, wherein said GlcNAc-S(A)x substituent is bonded to the antibody via C1 of the N-acetylglucosamine of said GlcNAc-S(A)x substituent, and wherein said N-acetylglucosamine is optionally fucosylated.The invention also relates to an antibody-conjugate, in particular to an antibody-conjugate according to the Formula (20) or (20b), wherein AB is an antibody, S is a sugar or a sugar derivative, D is a molecule of interest, and wherein said N-acetylglucosamine is optionally fucosylated (b is 0 or 1).The invention further relates to a process for the preparation of a modified antibody, to a process for the preparation of an antibody-conjugate, and to said antibody-conjugate for use as a medicament.In addition, the invention relates to a kit of parts comprising an azide-modified antibody and a linker-conjugate, wherein said linker-conjugate comprises a (hetero)cycloalkynyl group and one or more molecules of interest.
Core Innovation
The invention relates to homogeneous antibody-conjugates defined by Formula (20) or (20b), where an antibody bears GlcNAc at an N-glycosylation site and optionally fucose. The conjugate further includes a linker and an active substance that is biologically and/or pharmaceutically active, with structural scope defined by variables and substituent options.
The disclosed constructions center on engineered glycan modification at core GlcNAc, optionally fucosylated, and attachment of linker-conjugates bearing cyclooctyne/alkyne or azide-reactive groups. Mutant galactosyltransferase catalysts are used with defined sugar-nucleotide donors to install azido, keto, and alkynyl functionalities onto the glycan core GlcNAc substrate.
After generating the core-GlcNAc conjugation substrate, conjugation proceeds by click-type cycloaddition concepts, including azide-cyclooctyne (SPAAC) and azide-terminal alkyne (Cu(I) click) chemistry. The resulting conjugates are described as homogeneous with controlled stoichiometry and as providing stability advantages, including resistance or inertness characteristics.
Claims Coverage
The provided independent claim defines an antibody-conjugate by Formula (20) or (20b) with an antibody featuring GlcNAc at an N-glycosylation site and optional fucose, a linker L, and an active substance D coupled through defined substituent options. The claim includes multiple inventive features via parameterized structural definitions and formula-specific integer ranges.
Formula-defined antibody-conjugate with GlcNAc and optional fucose
An antibody-conjugate according to Formula (20) or (20b) comprising an antibody with GlcNAc present at an N-glycosylation site and optional fucose, together with specified carbohydrate-related groups and structural parameters.
Defined linker and active substance
A conjugation framework in which D is an active substance that is biologically and/or pharmaceutically active, coupled via a linker L.
Specific structural options for substituents and linking unit X
R1 is selected from the specified substituent options, and X is selected from C(R1)2, O, S, or NR2 with R2 defined as R1 or L(D), together with q constrained to 0 or 1 under the stated proviso.
Formula-specific integer ranges for a, a′, and a+a′
For Formula (20), a is 4, 5, 6 or 7; for Formula (20b), a is 0-7 and a′ is 0-7 with a+a′ constrained to 4, 5, 6 or 7.
Across the provided independent claim, coverage is directed to antibody-conjugates defined by Formula (20) or (20b) with GlcNAc at an N-glycosylation site and optional fucose, a defined linker L, and an active substance D, with extensive parameterized structural constraints for the substituent framework and formula-specific integer ranges.
Stated Advantages
Site-specificity and stoichiometry homogeneity.
Drug to Antibody Ratio (DAR) near theoretical with low standard deviation.
Favorable reaction kinetics.
Reduced manufacturing waste.
Chemical stability of the resulting conjugates, including triazoles inert to hydrolysis and oximes/hydrazones inert at neutral conditions.
Homogeneous ADCs with predetermined conjugation site and DAR.
Improved conjugation efficiency and near-complete conversion.
Enhanced manufacturability with reduced waste.
Documented Applications
Medical use described for treating cancer, including trastuzumab targeting HER2-positive breast cancer with selective killing of HER2-expressing cells versus HER2-negative cells and associated tumor volume reduction.
Therapeutic use in cancer, including HER2-positive breast cancer, using HER2-targeted ADCs.
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