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US 11,951,175 B2Granted
Bioconjugates containing sulfamide linkers for use in treatment
AssigneeSynaffix B.V.
InventorsJorge Merijn Mathieu Verkade, Maria Antonia Wijdeven, Petrus Josephus Jacobus Maria Van De Sande, Remon Van Geel, Floris Louis Van Delft, Sander Sebastiaan Van Berkel
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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).
Claims21
A method for increasing the therapeutic index of a bioconjugate, comprising preparing the bioconjugate of formula (A):
- B-Z3-L-(D)z (A),
- wherein:
- B is an antibody;
- L is a linker linking Z3 and D,
- Z3 is a connecting group obtained by reacting a reactive group Q′ on a linker-conjugate having a formula Q1-L-D with a functional group F1 on the antibody (B), wherein Z3 is connected to B through a glycan on the antibody;
- z is 1, 2, 3 or 4;
- D is a target molecule;
- and
- each occurrence of “—” is independently a bond or a spacer moiety, by reacting the reactive group Q1 on the target molecule (D) with the functional group F1 on the antibody (B), such that L is formula (8a) or (8b) or a salt thereof:
- wherein:
- a is 0 or 1;
- and
- R1 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3 wherein R3 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, or R1 is an additional target molecule D, wherein the target molecule is optionally connected to N via a spacer moiety;
- b is 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;
- wherein at least one of b, e and i is not 0 and at least one of g, d and c is not 0;
- D is a target molecule;
- Q1 is a reactive group capable of reacting with a functional group F1 present on the antibody;
- Sp1 is a spacer moiety;
- Sp2 is a spacer moiety;
- Sp3 is a spacer moiety;
- Sp4 is a spacer moiety;
- Z1 is a connecting group that connects Q1 or Sp3 to Sp2, O or C(O) or N(R1);
- Z2 is a connecting group that connects D or Sp4 to Sp1, N(R1), O or C(O);
- R1 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3 wherein R3 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups;
- or R1 is D, -[(Sp1)b(Z2)e(Sp4)iD] or -[(Sp2)c(Z1)d(Sp3)gQ1], wherein D, Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above;
- and
- the linker is connected to target molecule D via (Sp4)i.
30 more elements
A method of treatment, comprising administering to a subject a bioconjugate represented by formula (A):
- B-Z3-L-(D)z (A),
- wherein:
- B is an antibody;
- L is a linker linking Z3 and D,
- Z3 is a connecting group obtained by reacting a reactive group Q1 on a linker-conjugate having a formula Q1-L-D with a functional group F1 on the antibody (B), wherein Z3 is connected to B through a glycan on the antibody;
- z is 1, 2, 3 or 4;
- D is a target molecule;
- and
- each occurrence of “—” is independently a bond or a spacer moiety, by reacting the reactive group Q1 on the target molecule (D) with the functional group F1 on a the antibody (B), such that L is represented by formula (8a) or (8b) or a salt thereof:
- wherein:
- a is 0 or 1;
- and
- R1 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S or NR3 wherein R3 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, or R1 is an additional target molecule D, wherein the target molecule is optionally connected to N via a spacer moiety;
- b is 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;
- wherein at least one of b, e and i is not 0 and at least one of g, d and c is not 0;
- D is a target molecule;
- Q1 is a reactive group capable of reacting with a functional group F1 present on the antibody;
- Sp1 is a spacer moiety;
- Sp2 is a spacer moiety;
- Sp3 is a spacer moiety;
- Sp4 is a spacer moiety;
- Z1 is a connecting group that connects Q1 or Sp3 to Sp2, O or C(O) or N(R1);
- Z2 is a connecting group that connects D or Sp4 to Sp1, N(R1), O or C(O);
- R1 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3 wherein R3 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups;
- or R1 is D, -[(Sp1)b(Z2)e(Sp4)i D] or -[(Sp2)c(Z1)d(Sp3)gQ1], wherein D, Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above;
- and
- the linker is connected to target molecule D via (Sp4)i.
30 more elements
Dependencies are inferred from the claim text.