Antibody-conjugates with improved therapeutic index for targeting HER2 tumours and method for improving therapeutic index of antibody-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 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x 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 Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises S—Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 . 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.
1. A method for targeting HER2-expressing cells, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is obtainable by:
(i) contacting a glycoprotein comprising 1 or 2 core N-acetylglucosamine moieties with a compound of the formula S(F 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F 1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x moiety to the core-GlcNAc moiety, to obtain a modified antibody according to Formula (24):
wherein S(F 1 ) x and x are as defined above; AB represents an antibody; GlcNAc is N-acetylglucosamine; Fuc is fucose; b is 0 or 1; and y is 1 or 2; and
(ii) reacting the modified antibody with a linker-conjugate comprising a functional group Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises S—Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 ,
wherein the antibody AB is trastuzumab, S(F 1 ) x is connected to the core-GlcNAc linked to amino acid N300, S(F 1 ) x is 6-azido-6-deoxy-N-acetylgalactosamine, Q 1 is according to formula (9q), L 2 is —CH 2 —O—C(O)—NH—S(O) 2 —NH—(CH 2 —CH 2 —O) 2 —C(O)-Val-Cit-PABC- and target molecule D is Ahx-May, wherein Ahx-May is:
and
wherein formula (9q) is
2. The method according to claim 1 , wherein the targeting HER2-expressing cells includes one or more of treating, imaging, diagnosing, preventing the proliferation of, containing and reducing HER2-expressing cells, in particular HER2-expressing tumours.
3. The method according to claim 1 , wherein the subject suffers from a disorder selected from breast cancer, bladder cancer, pancreatic cancer, gastric cancer.
4. The method according to claim 1 , wherein the antibody-conjugate exhibits increased therapeutic index.
5. The method according to claim 4 , wherein the increased therapeutic index is selected from:
(a) increasing the therapeutic efficacy of the antibody-conjugate; and/or
(b) increasing the tolerability of the antibody-conjugate.
6. A method for targeting HER2-expressing cells, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is represented by Formula (41):
wherein:
R 33 and R 34 are hydrogen;
nn=1
Y=O
L 2 (D) r =—O—C(O)—NH—S(O) 2 —NH—(CH 2 —CH 2 —O) 2 —C(O)-Val-Cit-PABC-Ahx-May, wherein Ahx-May is:
pp is 0
y is 1 or 2;
Fuc is fucose;
GlcNAc is N-acetylglucosamine, which is linked to amino acid N300;
S is 6-deoxy-N-acetylgalactosaminyl; and
antibody AB is trastuzumab.
7. The method according to claim 6 , wherein the targeting HER2-expressing cells includes one or more of treating, imaging, diagnosing, preventing the proliferation of, containing and reducing HER2-expressing cells, in particular HER2-expressing tumours.
8. The method according to claim 6 , wherein the subject suffers from a disorder selected from breast cancer, bladder cancer, pancreatic cancer, gastric cancer.
9. The method according to claim 6 , wherein the antibody-conjugate exhibits increased therapeutic index.
10. The method according to claim 9 , wherein the increased therapeutic index is selected from:
(a) increasing the therapeutic efficacy of the antibody-conjugate; and/or
(b) increasing the tolerability of the antibody-conjugate.