Synaffix B.v.

Synahix B.v.

Jorge Merijn Mathieu Verkade

Floris Louis Van Delft

Maria Antonia Wijdeven

Sander Sebastiaan Van Berkel

Petrus Josephus Jacobus Maria Van De Sande

Ryan Heesbeen

Remon Van Geel

Jorin Hoogenboom

Inge Catharina Josephina Hurkmans

Brian Maria Gerardus Janssen

Maria Antonia Van Berkel

Remon Gvan Eel

The present invention concerns antibody-conjugate having general structure (2):AB-[(L)-{Z—(L)—(L)—(L)—(L)-D}]   (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.

Antibody-conjugates for targeting of tumours expressing Trop-2

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.

Synthesis of 6-azido-6-deoxy-2-n-acetyl-hexosamine-nucleoside diphosphate

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: 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.

Sulfamide linkers for use in bioconjugates

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).

Bioconjugates containing sulfamide linkers for use in treatment

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 Qcapable of reacting with a functional group Fpresent 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 Qof a linker-conjugate according to the invention with a functional group Fof a biomolecule. The invention further relates to a bioconjugate obtainable by the process according to the invention.

Sulfamide linker, conjugates thereof, and methods of preparation

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. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F)-P in the presence of a catalyst, wherein S(F)is a sugar derivative comprising x functional groups Fcapable of reacting with a functional group Q, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F)moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Qcapable of reacting with functional group Fand a target molecule D connected to Qvia a linker Lto obtain the antibody-conjugate wherein linker L comprises S&#x2014;Z-Land wherein Zis a connecting group resulting from the reaction between Qand F. The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting CD30-expressing cells.

Antibody-conjugates with improved therapeutic index for targeting CD30 tumours and method for improving therapeutic index of antibody-conjugates

The invention relates to compounds of general structure (1): Q-(L)-(L)-(L)-(L)-D (1), wherein Q is a click probe; D is a cytotoxin containing an enediyne moiety; L, L, Land Lare 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 R&#x2550;C-alkyl, the wavy line indicates the connection to the remainder of the cytotoxin, and wherein D is conjugated to (L)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-[(L)-Z-(L)-(L)-(L)-(L)-D](2), wherein Z is a connecting group that is formed in a click reaction, Lis a linker that links Z to Pr and Pr is a (glyco)protein.

Enediyne conjugates

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. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F)-P in the presence of a catalyst, wherein S(F)is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F)moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Qcapable of reacting with functional group Fand a target molecule D connected to Qvia a linker Lto obtain the antibody-conjugate wherein linker L comprises S&#x2014;Z-Land wherein Zis a connecting group resulting from the reaction between Qand F. The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting HER2-expressing cells.

Antibody-conjugates with improved therapeutic index for targeting HER2 tumours and method for improving therapeutic index of antibody-conjugates

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: &#x2014;BM is a branching moiety; &#x2014;E is a capping group; &#x2014;SG is a sulfamide group; &#x2014;b, c, d, e, g, i, k, l are independently 0 or 1; &#x2014;f is an integer in the range of 1 to 10; &#x2014;Sp, Sp, Sp, Sp, Spand Spare a spacer moieties; &#x2014;Zand Zare 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. 

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 Qcapable of reacting with a functional group Fpresent 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 Qof a linker-conjugate according to the invention with a functional group Fof a biomolecule. The invention further relates to a bioconjugate obtainable by the process according to the invention.

The invention relates to a glycoprotein comprising an optionally fucosylated glycan according to formula (105) or (106), wherein Su(A)x is a modified sugar moiety comprising one or more functional groups A. Functional group A is independently selected from the group consisting of a thiol group, a halogen, a sulfonyloxy group, a halogenated acetamido group, a mercaptoacetamido group and a sulfonated hydroxyacetamido group. The invention also relates to a glycoprotein-conjugate wherein a glycoprotein according to the invention is conjugated to a molecule of interest. Said molecule of interest may for example be an active substance. The invention further relates to a process for the preparation of a modified glycoprotein, and to a method for the preparation of a glycoprotein-conjugate. The invention particularly relates to modified antibodies, antibody-conjugates, antibody-drug conjugates and methods for the preparation thereof. 

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Eindhoven, Netherlands

Jorge Merijn Mathieu Verkade