Tridentate connexon and use thereof
Disclosed are a type of tridentate linkers and use thereof. The tridentate linkers can be used to prepare an antibody drug conjugates as represented by formula I, L-(T-A-D) n I wherein, L is an antibody, antibody fragment or protein; T is a tridentate linker part; A is a cleavable linker group or a noncleavable linker part; D is a drug part; n is an integer of 0-8. The structure of the tridentate linker part is as represented by formula II, wherein, W is substituted aryl, heteroaryl, linear alkyl, cycloalkyl, heterocycloalkyl, or any combination thereof.
1. The antibody drug conjugate wherein the antibody drug conjugate is as represented by formula VI, or VIII:
wherein
C is a cleavable linker;
E is a self-immolative linker;
F is an optional self-immolative linker;
G is a non-cleavable linker;
L is an antibody,
f is an integer of 0-5, g is an integer of 0-5, n′ is an integer of 1-8; Z is O, S, NR 2 , C(═O)O, C(═O)NR 3 , C(═S)O, C(═S)NR 4 , C(═S)S, NR 5 C(═O)NR 6 , NR 7 C(═S)NR 8 , OC(═O)NR 9 ; m is 0 or 1; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from H, linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl; R 1 is linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, poly(ethylene glycol) chain, or any combination thereof; n is an integer of 0-8; X is —NR 10 —, —O—, —S—, —C(═O)—, —C(═S)—, —NR 11 C(═O)—, —NR 12 C(═S)—, —OC(═O)—, —OC(═S)—; R 10 , R 11 , and R 12 is independently selected from H, linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl; R 13 and R 14 , is independently selected from linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or any combination thereof; R 15 and R 16 is independently selected from linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, or any combination thereof; Q is N or CR 17 ; R 17 is independently selected from H, linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, x, y is an integer of 0-8, and x+y≥1; and
D is a drug part.
2. The antibody drug conjugate of claim 1 , wherein the antibody targets cell surface receptors or tumor-related antigens.
3. The antibody drug conjugate of claim 1 , wherein the drug is cytotoxic drug, anti-autoimmune disease drug, or anti-inflammation drug.
4. The antibody drug conjugate of claim 1 , wherein the average D:L ratio is about 4.