Trimaleimide linkers and uses thereof
A type of trimaleimide linkers and uses thereof are disclosed. The trimaleimide linkers can be applied for preparation of antibody-drug conjugate as shown by formula I: L-(T-A-D) n I wherein, L is an antibody, antibody fragment or protein; T is a trimaleimide linker; A is a cleavable linker group or a noncleavable linker; D is a drug; n is an integer ranging from 1 to 8.
1. An antibody-drug conjugate of formula (I):
L-(T-A-D) n (I)
wherein L is an antibody, antibody fragment, or protein; T is a trimaleimide linker; A is other linker part; D is a drug moiety; n is an integer ranging from 1 to 8;
the trimaleimide linker of formula (II):
wherein
Z is selected from O, S, NR 2 , NR 3 C(═O), C(═O)NR 4 , C(═O)O, OC(═O), C(═S)O, OC(═S), C(═S)NR 5 , NR 6 C(═S), C(═S)S, SC(═S), NR 7 C(═O)NR 8 , NR 9 C(═S)NR 10 , OC(═O)NR 11 or NR 12 C(═O)O;
R 1 is selected from alkylene, alkenlene, alkynlene, arylene, —(CH 2 CH 2 O) t —, —(OCH 2 CH 2 ) w —, or any combination thereof, wherein t and w are independently selected from integers ranging from 1 to 18;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H, alkyl, aryl, heterocyclyl, aryl, or heteroaryl;
r is selected from 0 or 1;
s is an integer ranging from 0 to 8;
X is selected from NR 13 , O, S, C(═O), C(═S), C(═O)NR 14 , NR 15 C(═O), NR 16 C(═S), C(═S) NR 17 , OC(═O), C(═O)O, OC(═S), or C(═S)O; wherein R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl or heteroarylalkyl;
o, p and q are integers independently selected from 0 to 8, wherein when one of them is set to zero, the others cannot be zero.
2. The antibody-drug conjugate of claim 1 , wherein A is a cleavable linker group or a noncleavable linker.
3. The antibody-drug conjugate of claim 2 , wherein A is represented by formula (III) or (IV):
C-E e -F f (III)
G g (IV)
wherein C is a cleavable linker, E is a self-immolative linker; F is an optional self-immolative linker; e and f are independently selected from integers ranging from 0 to 5; G is a noncleavable linker; g is an integer ranging from 0 to 5.
4. The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate is represented by formula (V) or (VI):
wherein
L is an antibody, antibody fragment, or protein;
Z is selected from O, S, NR 2 , NR 3 C(═O), C(═O)NR 4 , C(═O)O, OC(═O), C(═S)O, OC(═S), C(═S)NR 5 , NR 6 C(═S), C(═S)S, SC(═S), NR 7 C(═O)NR 8 , NR 9 C(═S)NR 10 , OC(═O)NR 11 , or NR 12 C(═O)O;
R 1 is selected from alkylene, alkenlene, alkynlene, arylene, —(CH 2 CH 2 O) t —, —(OCH 2 CH 2 ) w —, or any combination thereof, wherein t and w are independently selected from integers ranging from 1 to 18;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H, alkyl, aryl, heterocyclyl, aryl, or heteroaryl;
r is selected from 0 or 1;
s is an integer ranging from 0 to 8;
X is selected from NR 13 , O, S, C(═O), C(═S), C(═O)NR 14 , NR 15 C(═O), NR 16 C(═S), C(═S)NR 17 , OC(═O), C(═O)O, OC(═S), or C(═S)O; wherein R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl;
o, p and q are integers independently selected from 0 to 8, wherein when one of them is set to zero, the others cannot be zero.
5. The antibody-drug conjugate of claim 1 , wherein the antibody targets cell surface receptors or tumor-related antigens.
6. The antibody-drug conjugate of claim 1 , wherein the drug is cytotoxic drug, anti-autoimmune disease drug, or anti-inflammation drug.
7. The antibody-drug conjugate of claim 1 , wherein the trimaleimide linker is formed by reacting one of the following formulae with another linker part-drug moiety, followed by conjugation with an antibody, antibody fragment, protein, protein fragment or polypeptide:
Compound
No.
1
2
3
4
5
6
7
8
9
10
8. Use of a trimaleimide linker of formula (VII) for the manufacturing of an antibody-drug conjugate:
wherein Z is selected from O, S, NR 2 , NR 3 C(═O), C(═O)NR 4 , C(═O)O, OC(═O), C(═S)O, OC(═S), C(═S)NR 5 , NR 6 C(═S), C(═S)S, SC(═S), NR 7 C(═O)NR 8 , NR 9 C(═S)NR 10 , OC(═O)NR 11 , or NR 12 C(═O)O;
R 1 is selected from alkylene, alkenlene, alkynlene, arylene, —(CH 2 CH 2 O) t —, —(OCH 2 CH 2 ) w —, or any combination thereof, wherein t and w are independently selected from integers ranging from 1 to 18;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl;
r is selected from 0 or 1;
s is an integer ranging from 0 to 8;
Q is selected from NHR 13 , OH, SH, COOH, C(═S)OH, NR 14 COOH, NR 15 C(═S)OH, NCO, or NCS, wherein R 13 , R 14 , and R 15 are independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl;
o, p and q are integers independently selected from 0 to 8, wherein when one of them is set to zero, the other two cannot be zero,
wherein the use of a trimaleimide linker of formula (VII) comprises the step of adding a pharmaceutically effective amount of the trimaleimide linker of formula (VII) to react with an antibody, antibody fragment, protein, protein fragment or polypeptide to form the antibody-drug conjugate.
9. The use of the claim 8 , wherein the trimaleimide linker has one of the following formulae
Compound
No.
1
2
3
4
5
6
7
8
9
10