Abstract: The invention relates to a novel linker for use in bioconjugates such as antibody-drug-conjugates. The linker according to the invention is represented by formula: wherein: BM is a branching moiety; E is a capping group; SG is a sulfamide group; b, c, d, e, g, i, k, l are independently 0 or 1; f is an integer in the range of 1 to 10; Sp1, Sp2, Sp3, Sp4, Sp5 and Sp6 are a spacer moieties; Z1 and Z2 are connecting groups. The linker according to the invention is useful in the preparation of linker-conjugates and bioconjugates, and can be used for (a) improving conjugation efficiency in the preparation of the bioconjugate, (b) reducing aggregation during the preparation of the bioconjugate and/or of the bioconjugate, (c) increasing stability of the bioconjugate, and/or (d) increasing therapeutic index of the bioconjugate.

Abstract: The present invention is based on the surprising finding that the linker employed in a bioconjugate, such as an anti-body-drug conjugate, is not therapeutically inert but has an effect on the therapeutic index of the bioconjugate. The present invention thus concerns a method for increasing the therapeutic index of a bioconjugate and the bioconjugates for use in treatment, in particular cancer. The bioconjugates according to the invention have a sulfamide linker comprising a group according to formula (1).

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.

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.

Abstract: The present invention concerns a method for the preparation of an alkyne-linker-payload construct of structure Q-L-C(O)—NR3-D (1), comprising reacting (i) an alkyne compound of structure Q-L-C(O)-X (2), wherein Q is an alkyne moiety selected from the group consisting of terminal alkyne and (hetero)cycloalkyne; L is a linker, and X is a leaving group selected from halogen, SR1, O-succinimidyl, O-(hetero)aryl(R2)1-5, wherein R1 is selected from C1-C6 alkyl and (hetero)aryl; and R2 is C1-C6 alkyl, halogen or NO2; with (ii) a molecule of structure D-NHR3 (3), wherein D is a payload, and R3 is selected from hydrogen, optionally substituted C1-C24 alkyl, optionally substituted aryl. The activated ester derivatives (2) are highly stable and provide for smooth and high-yielding attachment to a cytotoxic payload. The invention further concerns a method for preparing bioconjugates and alkyne compound of structure Q-L-C(O)-X (2).

Abstract: The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index.

Abstract: The present invention concerns novel and improved antibody-conjugates for targeting CD30. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index.

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.

Abstract: The current invention concerns methods for the synthesis of 6-azido-6-deoxy-2-N-acetyl-monosaccharide-nucleoside diphosphate, in particular 6-azido-6-deoxy-2-N-acetyl-D-galactosamine-nucleoside diphosphate or 6-azido-6-deoxy-2-N-acetyl-D-glucosamine-nucleoside diphosphate. The synthesis method according to the invention is characterized by being highly efficient and high yielding. Also part of the present invention are key intermediates of this process.

Abstract: The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found N that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index.

Abstract: The current invention concerns compounds, such as antibody-conjugates, with an enhanced selectivity of payload release inside a tumour or in the tumour microenvironment versus payload release in circulation or in healthy cells. The enhanced selectivity is achieved by incorporation of a cleavable linker that requires two consecutive mechanisms for release of the payload. The compounds according to the invention have structure (1): or a salt thereof, wherein AB is an antibody or a reactive moiety capable of reacting with a functional group on an antibody, L1 and L2 are linkers, moiety I contains an activating group and an aromatic ring, X is O or N and D is the payload. The invention further concerns application of these compounds in for example a method of targeting a cell and a method for enhancing the bystander effect of an amino-containing payload. The invention also concerns the payloads that may be released from the compounds according to the invention.

Abstract: The present invention concerns antibody-conjugate having general structure (2): AB-[(L6)-{Z-(L1)n-(L2)o-(L3)p-(L4)q-D}xx]yy?? (2) wherein AB is an antibody capable of targeting Trop-2-expressing tumours and D is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, maytansinoids, enediynes such as calicheamicins, duocarmycins, tubulysins, amatoxins, bleomycins, dolastatins and auristatins, pyrrolobenzodiazepine dimers, indolinobenzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. These antibody-conjugates exhibit an improved therapeutic index. The invention further concerns a process for preparing the antibody-conjugate according to the invention, a method for targeting Trop-2-expressing cells, medical uses of the antibody-conjugates according to the invention.

Abstract: The invention relates to a novel linker for use in bioconjugates such as antibody-drug-conjugates. The linker according to the invention is represented by formula: wherein: BM is a branching moiety; E is a capping group; SG is a sulfamide group; b, c, d, e, g, i, k, l are independently 0 or 1; f is an integer in the range of 1 to 10; Sp1, Sp2, Sp3, Sp4, Sp5 and Sp6 are a spacer moieties; Z1 and Z2 are connecting groups. The linker according to the invention is useful in the preparation of linker-conjugates and bioconjugates, and can be used for (a) improving conjugation efficiency in the preparation of the bioconjugate, (b) reducing aggregation during the preparation of the bioconjugate and/or of the bioconjugate, (c) increasing stability of the bioconjugate, and/or (d) increasing therapeutic index of the bioconjugate.

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.

Abstract: The invention relates to a novel linker for use in bioconjugates such as antibody-drug-conjugates. The linker according to the invention is represented by formula: (I) wherein: —BM is a branching moiety; —E is a capping group; —SG is a sulfamide group; —b, c, d, e, g, i, k, l are independently 0 or 1; —f is an integer in the range of 1 to 10; —Sp1, Sp2, Sp3, Sp4, Sp5 and Sp6 are a spacer moieties; —Z1 and Z2 are connecting groups. The linker according to the invention is useful in the preparation of linker-conjugates and bioconjugates, and can be used for (a) improving conjugation efficiency in the preparation of the bioconjugate, (b) reducing aggregation during the preparation of the bioconjugate and/or of the bioconjugate, (c) increasing stability of the bioconjugate, and/or (d) increasing therapeutic index of the bioconjugate.

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.

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.

Abstract: The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found N that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index.

Abstract: The present invention concerns novel and improved antibody-conjugates for targeting CD30. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index.

Abstract: The present invention is based on the surprising finding that the linker employed in a bioconjugate, such as an anti-body-drug conjugate, is not therapeutically inert but has an effect on the therapeutic index of the bioconjugate. The present invention thus concerns a method for increasing the therapeutic index of a bioconjugate and the bioconjugates for use in treatment, in particular cancer. The bioconjugates according to the invention have a sulfamide linker comprising a group according to formula (1).