Granted Patent B2

US 12,485,299 · App. 18/366,028 · Granted Dec 2, 2025

Inventors: Paul H. Song (Suzhou, CN); Gang Qin (Suzhou, CN); Chong Liu (Suzhou, CN)

Assignee: GENEQUANTUM HEALTHCARE (SUZHOU) CO., LTD.

A61K47/6851A61K47/6803A61K47/6849A61P35/00

Abstract

Claims (80)

1 . An antibody-drug conjugate of formula (II):

wherein:

n is an integer of 3 to 10;

Y and W are each independently absent or selected from PABC, a spacer comprising 1-10 amino acids, and a combination thereof;

a and b are each independently 0 or 1;

Lk is a combination of L 1 -L 2 -L 3 ;

L 1 and L 3 are each independently selected from: —CH 2 —, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—, and combination of a C 1-4 alkylene with one of the following groups: —CH 2 —, —NH—, —C(O)—, —NHC(O)—, or —C(O)NH—;

L 2 is absent or is a C 7-34 alkylene, and wherein one or more (—CH 2 —) structures in the alkylene is optionally replaced by —O—;

x is selected from hydrogen, OH, NH 2 , an amino acid fragment comprising 1-10 amino acids, and a nucleotide fragment comprising 1-10 nucleotides;

Lm2 is

or a mixture thereof;

B2 is selected from the following group or their combination: —(CH 2 ) k C(O)—, —(CH 2 ) k C(O)-Val-Cit-PABC-, —(CH 2 ) k C(O)-Val-Cit-PABC-(NH—CR 1 R 2 —C(O)) d —, —(CH 2 ) k1 C(O)—NH—(C 2 H 4 —O) j —(CH 2 ) k2 C(O)-Lys-, —(CH 2 ) k C(O)—(NH—CR 1 R 2 —C(O)) d —NH—(C 2 H 4 —O) j —, and —(CH 2 ) k C(O)—(NH—CR 1 R 2 —C(O)) d ;

R 1 and R 2 are each independently selected from: hydrogen, —OH, —NH 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —NH—C 1-6 alkyl, —C 1-6 alkyl-NH 2 , —N(C 1-6 alkyl)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C(O)—C 1-6 alkyl, —NHC(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)NH—C 1-6 alkyl, —C(O)N(C 1-6 alkyl)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, —NHS(═O) 2 —C 1-6 alkyl, —S(═O) 2 O—C 1-6 alkyl, —S(═O) 2 NH—C 1-6 alkyl, and —S(═O) 2 N (C 1-6 alkyl)—C 1-6 alkyl;

each k, k1, and k2 are independently an integer of 0 to 10;

d is an integer of 1 to 10;

j is an integer of 1 to 10;

PL is a payload which is an immune agonist,

wherein the immune agonist has the structure of formula i:

wherein:

each R 9 is independently selected from hydrogen, halogen, C 1-7 alkyl-OC(O)—C 1-7 alkyl, C 1-7 alkyl-OC(O)—C 2-7 alkenyl, and 5-7 membered heterocycle;

R 10 and R 11 are each independently selected from hydrogen and C 1-7 alkyl;

R 12 is selected from C 1-7 alkyl and C 1-7 alkoxy-C 1-7 alkyl;

R 13 is selected from C 1-7 alkyl, which is optionally substituted by a substituent selected from —OH and —NH 2 ; and

u is 1, 2, 3 or 4;

or

wherein the immune agonist has the structure of formula ii:

wherein:

L 4 is selected from —CH 2 —, —NH—, —O—, and —C(O)—;

R 14 is selected from C 1-7 alkyl, C 1-7 alkoxy, and C 1-7 alkyl-OC(O)—C 1-7 alkyl;

R 15 and R 16 are each independently selected from hydrogen and C 1-7 alkyl;

R 17 is selected from —NH 2 , —OH, C 1-7 alkyl, C 1-7 alkoxy, and —NH—C 1-7 alkyl; and

R 18 is selected from —CH 2 -aryl, and —CH 2 -heteroaryl, wherein the aryl and the heteroaryl are each independently optionally substituted by a substituent selected from —C(O)OH

and

or

wherein the immune agonist has the structure of formula iii:

wherein:

R 19 is selected from —OH, —NH 2 , C 1-7 alkyl, C 1-7 alkoxy, and —NH—C 1-7 alkyl; and

R 20 is selected from —CH 2 -aryl, wherein the aryl is optionally substituted by two substituents selected from —OH, C 1-7 alkoxy and —C 1-7 alkyl-piperidinyl;

or

wherein the immune agonist has the structure of formula iv:

wherein:

L 5 is selected from —CH 2 —, —NH—, —C(O)—, —NHC(O)—, and —C(O)NH—;

R 21 is selected from

wherein B is a heteroaryl ring;

R 22 is selected from hydrogen and C 1-7 alkyl;

R 23 and R 24 are each independently selected from hydrogen and C 1-7 alkyl;

L 6 is selected from —CH 2 — and —C(O)—;

R 25 is selected from —N(C 1-7 alkyl)(C 1-7 alkyl);

R 26 , R 27 , and R 28 are each independently selected from hydrogen and C 1-7 alkyl; and

v is 1, 2 or 3;

z is an integer of 1 to 20; and

A is a targeting molecule which is an antibody or an antigen binding fragment.

2 . The antibody-drug conjugate of claim 1 , wherein Lk is L 1 -L 2 -L 3 , L 1 is —NH—, L 3 is —C(O)—, L 2 is —(C 2 H 4 —O) i —C 2 H 4 —, and i is an integer of 2 to 10.

3 . The antibody-drug conjugate of claim 2 , wherein i is 4.

4 . The antibody-drug conjugate of claim 1 , wherein each k, k1, and k2 are independently 0, 1, or 2.

5 . The antibody-drug conjugate of claim 1 , wherein each k, k1, and k2 are independently 1 or 2.

6 . The antibody-drug conjugate of claim 1 , wherein Y and W are independently selected from leucine (Leu), glutamine (Gln), PABC, Phe-Lys-PABC, Val-Cit-PABC, and Val-Lys-PABC.

7 . The antibody-drug conjugate of claim 1 , wherein a and b are 0.

8 . The antibody-drug conjugate of claim 1 , wherein R 1 and R 2 are both methyl.

9 . The antibody-drug conjugate of claim 1 , wherein x is NH 2 .

10 . The antibody-drug conjugate of claim 1 , wherein j is 1, 3, or 4.

11 . The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate is selected from the following:

12 . The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate is selected from the following:

13 . The antibody-drug conjugate of claim 1 , wherein the immune agonist is selected from imidazoquinolines.

14 . The antibody-drug conjugate of claim 1 , wherein the antibody is an anti-human HER2 antibody.

15 . The antibody-drug conjugate of claim 14 , wherein the anti-human HER2 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 1 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 2; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 3 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 4; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 5 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 6; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 7 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 8; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 9 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 11 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 12; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 13 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 14; or

comprises a light chain having the amino acid sequence of SEQ ID NO: 15 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 16.

16 . The antibody-drug conjugate of claim 1 , wherein the antibody is an anti-human TROP2 antibody.

17 . The antibody-drug conjugate of claim 16 , wherein the anti-human TROP2 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 17 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 18; or comprises a light chain having the amino acid sequence of SEQ ID NO: 19 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 20.

18 . The antibody-drug conjugate of claim 1 , wherein the antibody is an anti-human CLDN18.2 antibody.

19 . The antibody-drug conjugate of claim 18 , wherein the anti-human CLDN18.2 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 21 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 22; or comprises a light chain having the amino acid sequence of SEQ ID NO: 23 and comprises a heavy chain having the amino acid sequence of SEQ ID NO: 24.

20 . The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate has a drug to antibody ratio (DAR) of an integer or non-integer of 1 to 20.

21 . The antibody-drug conjugate of claim 1 , wherein the immune agonist

is selected from the following:

Assignments (1)

Priority Claims (1)

Continuity (2)

References Cited (65)