Sulfamide linkers for use in bioconjugates

Patent metadata

Field	Value
Publication number	US-11957763-B2
Application number	US-202017135703-A
Country	US
Kind code	B2
Filing date	Dec 28, 2020
Priority date	Feb 8, 2016
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

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; Sp 1 , Sp 2 , Sp 3 , Sp 4 , Sp 5 and Sp 6 are a spacer moieties; Z 1 and Z 2 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.

First claim

The invention claimed is:

1. A compound comprising a target molecule D covalently connected to a reactive group Q′ via a linker represented by the following formula:

wherein:
BM is a branching moiety;
E is a capping group;
SG is a sulfamide group according to formula (1);
b is independently 0 or 1;
c is 0 or 1;
d is 0 or 1;
e is 0 or 1;
f is an integer in the range of 1 to 10;
g is 0 or 1;
i is 0 or 1;
k is 0 or 1;
1 is 0 or 1;
Sp 1 is a spacer moiety;
Sp 2 is a spacer moiety;
Sp 3 is a spacer moiety;
Sp 4 is a spacer moiety;
Sp 5 is a spacer moiety;
Sp 6 is a spacer moiety;
Z 1 is a connecting group;
Z 2 is a connecting group,

wherein one of the bonds labelled with * is connected to reactive group Q 1 and one of the bonds labelled with * is connected to target molecule D, and wherein the sulfamide group SG is represented by formula (1):

wherein
a is 0 or 1; and
R 1 is selected from the group consisting of hydrogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero) aryl groups, C 3 -C 24 alkyl (hetero) aryl groups and C 3 -C 24 (hetero) arylalkyl groups, wherein the C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero) aryl groups, C 3 -C 24 alkyl (hetero) aryl groups and C 3 -C 24 (hetero) arylalkyl groups are optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR 3 wherein R 3 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl groups, or R 1 is a further target molecule D, wherein the target molecule is optionally connected to N via a spacer moiety, and

wherein one of the bonds labelled with * is connected to the branching moiety, optionally via spacer Sp 5 , and the other bond labelled with * to a capping group E, optionally via spacer Sp 6 , and
wherein the target molecule D is selected from the group consisting of active substances, reporter molecules, polymers, solid surfaces, hydrogels, nanoparticles, microparticles and biomolecules; and the reactive group Q 1 is selected from the group consisting of, optionally substituted, N-maleimidyl groups, halogenated N-alkylamido groups, sulfonyloxy N-alkylamido groups, ester groups, carbonate groups, sulfonyl halide groups, thiol groups or derivatives thereof, alkenyl groups, alkynyl groups, (hetero)cycloalkynyl groups, bicyclo[6.1.0]non-4-yn-9-yl groups, cycloalkenyl groups, tetrazinyl groups, azido groups, phosphine groups, nitrile oxide groups, nitrone groups, nitrile imine groups, diazo groups, ketone groups, (O-alkyl) hydroxylamino groups, hydrazine groups, halogenated N-maleimidyl groups, 1,1-bis(sulfonylmethyl)methyl-carbonyl groups or elimination derivatives thereof, carbonyl halide groups, allenamide groups, 1,2-quinone groups, and triazine groups.

2. The compound according to claim 1 , wherein the capping moiety E is selected from hydrogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero) aryl groups, C 3 -C 24 alkyl (hetero) aryl groups, C 3 -C 24 (hetero) arylalkyl groups, wherein the C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero) aryl groups, C 3 — C 24 alkyl (hetero) aryl groups and C 3 -C 24 (hetero) arylalkyl groups are optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR 3 wherein R 3 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl groups, or E is a further target moiety D.

3. The compound according to claim 2 , wherein capping moiety E is selected from a polyethylene glycol group represented by —(CH 2 CH 2 O) 5 CH 3 , wherein s is an integer in the range of 1-10, a C 1 -C 24 alkyl group, C 2 -C 24 (hetero) aryl group or a C 3 -C 24 alkyl(hetero)aryl group.

4. The compound according to claim 3 , wherein capping moiety E is a polyethylene glycol group represented by —(CH 2 CH 2 O) 5 CH 3 , wherein s is an integer in the range of 2-4, or a benzyl group.

5. The compound according to claim 1 , wherein branching moiety BM is selected from a carbon atom, a nitrogen atom, a phosphorus atom, an aromatic ring, a (hetero)cycle or a polycyclic moiety.

6. The compound according to claim 1 , wherein Sp 5 , Spa, Sp 3 and Sp 4 , if present, are independently selected from the group consisting of linear or branched C 1 -C 20 alkylene groups, the alkylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and NR 3 , wherein R 3 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl groups.

7. The compound according to claim 1 , wherein Q 1 is according to formula (9a), (9q), (9n), (9o) or (9p):

wherein U is 0 or NR 9 , and R 9 is hydrogen, a linear or branched C 1 -C 12 alkyl group or a C 4 -C 12 (hetero)aryl group.

8. The compound according to claim 1 , wherein target molecule D is a substance that is biologically and/or pharmaceutically active.

9. A compound comprising a target molecule D covalently connected to a biomolecule B via a linker represented by the following formula:

wherein:
BM is a branching moiety;
E is a capping group;
SG is a sulfamide group according to formula (1);
b is independently 0 or 1;
c is 0 or 1;
d is 0 or 1;
e is 0 or 1;
f is an integer in the range of 1 to 10;
g is 0 or 1;
i is 0 or 1;
k is 0 or 1;
1 is 0 or 1;
Sp 1 is a spacer moiety;
Sp 2 is a spacer moiety;
Sp 3 is a spacer moiety;
Sp 4 is a spacer moiety;
Sp 5 is a spacer moiety;
Sp 6 is a spacer moiety;
Z 1 is a connecting group;
Z 2 is a connecting group,

wherein one of the bonds labelled with * is connected to biomolecule B and one of the bonds labelled with * is connected to target molecule D, and wherein the sulfamide group SG is represented by formula (1):

wherein
a is 0 or 1; and
is selected from the group consisting of hydrogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups, wherein the C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups are optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR 3 wherein R 3 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl groups, or R 1 is a further target molecule D, wherein the target molecule is optionally connected to N via a spacer moiety,
and wherein one of the bonds labelled with * is connected to the branching moiety, optionally via spacer Spy, and the other bond labelled with * to a capping group E, optionally via spacer Sp 6 ,
and wherein the biomolecule B is selected from the group consisting of proteins, polypeptides, peptides, glycans, lipids, nucleic acids, oligonucleotides, polysaccharides, oligosaccharides, enzymes, hormones, amino acids and monosaccharides and the target molecule D is selected from the group consisting of active substances, reporter molecules, polymers, solid s

Assignees

• Synaffix Bv

Inventors

• Van Berkel Sander Sebastiaan
• Heesbeen Ryan
• Verkade Jorge Merijn Mathieu
• Wijdeven Maria Antonia
• Van Delft Floris Louis

Classifications

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• C07K14/00

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title