Sulfamide linker, conjugates thereof, and methods of preparation
Inventors
Verkade, Jorge Merijn Mathieu • Wijdeven, Maria Antonia • VAN DE SANDE, Petrus Josephus Jacobus Maria • Van Berkel, Sander Sebastiaan • van Delft, Floris Louis
Assignees
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Publication Number
US-11850286-B2
Publication Date
2023-12-26
Expiration Date
Abstract
The present invention relates to a compound comprising an alpha-end and an omega-end, the compound comprising on the alpha-end a reactive group Q1 capable of reacting with a functional group F1 present on a biomolecule and on the omega-end a target molecule, the compound further comprising a group according to formula (1) or a salt thereof:Said compound may also be referred to as a linker-conjugate. The invention also relates to a process for the preparation of a bioconjugate, the process comprising the step of reacting a reactive group Q1 of a linker-conjugate according to the invention with a functional group F1 of a biomolecule. The invention further relates to a bioconjugate obtainable by the process according to the invention.
Core Innovation
The invention relates to a bioconjugate comprising a biomolecule B and a target molecule D, where B and D are covalently linked via a group according to formula (1). The group according to formula (1) is covalently linked to an alpha-end on one side and an omega-end on the other side, with the alpha-end comprising the biomolecule B and the omega-end comprising the target molecule D. The definition includes an index a of 0 or 1 and a substituent R1 selected from hydrogen and specified alkyl, cycloalkyl, (hetero)aryl, alkyl(hetero)aryl, and (hetero)arylalkyl groups, optionally substituted and optionally interrupted by O, S and NR3, and in one alternative R1 is a target molecule D optionally connected to N via a spacer moiety.
The described linker-conjugate and bioconjugate scaffolds define sulfamide-based linker constructs in which a sulfamide group is positioned between the alpha- and omega-ends, with related formula variants indicated. The reactive group Q1 is linked to a biomolecule via a complementary functional group F1, and the target molecule D is linked via connecting groups Z1, Z2, and Z3 and spacers Sp1 to Sp4, using a linker-construct concept of Q1-Sp-Q2 or (Q1)y-Sp-(Q2)z.
Bioconjugation is described using cycloaddition, including Diels-Alder and preferably alkyne-azide 1,3-dipolar cycloaddition, yielding a 1,2,3-triazole linkage. The sulfamide-containing linkers are described as improving bioconjugation efficiency and speed, and as reducing aggregation while increasing solubility or polarity; improved water solubility enables conjugation to hydrophobic targets with a water solubility threshold of ≤0.1% w/w. The invention also includes salts of the bioconjugate.
Claims Coverage
The independent claim defines a bioconjugate framework in which a biomolecule is covalently linked to a target molecule through a group according to formula (1), with defined alpha-end and omega-end placement, an index a of 0 or 1, and a defined substituent R1. The claim coverage also includes specific biomolecule and target molecule classes and salts of the bioconjugate. In total, the provided claim content centers on four inventive features.
Bioconjugate with alpha-end biomolecule and omega-end target molecule via formula (1) group
A bioconjugate comprising a biomolecule B and a target molecule D, with a group according to formula (1) covalently linked to an alpha-end comprising the biomolecule B and an omega-end comprising the target molecule D.
Biomolecule selection and target molecule selection for the bioconjugate
The biomolecule B is selected from proteins, polypeptides, peptides, glycans, nucleic acids, oligonucleotides, polysaccharides, oligosaccharides and enzymes; and the target molecule D is selected from colchicine, vinca alkaloids, anthracyclines, camptothecins, taxanes, calicheamycins, tubulysins, an inhibitory peptide, amanitin, deBouganin, duocarmycins, maytansines, auristatins and pyrrolobenzodiazepines.
Defined structural parameters a and R1 and optional N connection through spacer
a is 0 or 1; and R1 is selected from hydrogen and defined C1-C24 alkyl, C3-C24 cycloalkyl, C2-C24 (hetero)aryl, C3-C24 alkyl(hetero)aryl and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by heteroatoms O, S and NR3, with R3 hydrogen or C1-C4 alkyl, or R1 is a target molecule D optionally connected to N via a spacer moiety.
Salt of the bioconjugate
The bioconjugate includes a salt of the bioconjugate.
The claim coverage centers on a bioconjugate architecture in which a biomolecule is covalently linked at the alpha-end and a target molecule is covalently linked at the omega-end through a group according to formula (1), with explicit selections for biomolecule B, target molecule D, and R1. The claim set also explicitly includes salts of the bioconjugate.
Stated Advantages
Improved water solubility enables conjugation to hydrophobic targets with a stated water solubility threshold of ≤0.1% w/w.
Improved solubility for hydrophobic target molecules.
Reduced aggregation for hydrophobic target molecules.
Improves conjugation efficiency and speed.
Increases solubility/polarity.
Documented Applications
Conjugation enabling the binding of a biomolecule to hydrophobic targets.
Bioconjugation using sulfamide-based linker-conjugates with an alpha-end reactive group Q1 for reaction with a biomolecule functional group F1 and an omega-end target molecule D.
Use of cycloaddition-based conjugation strategies, including Diels-Alder and 1,3-dipolar cycloaddition, in forming the bioconjugates.
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