Granted Patent B2

US 12,221,460 · App. 18/336,436 · Granted Feb 11, 2025

Inventors: He Xu (North Andover, MA); Hong Myung Lee (Cambridge, MA); Christopher Arendt (Boston, MA)

Assignee: Takeda Pharmaceutical Company Limited

C07H21/00A61K31/7084A61K39/39558A61K47/6849A61K47/6889A61K47/6891A61P35/00

Abstract

Claims (133)

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 8;

Ab is an anti-CCR2 antibody or an anti-CCR2 antigen-binding fragment;

R 2′ is C 1 -C 4 alkyl;

W is selected from:

 wherein

is the point of attachment to the carbonyl group; and

is the point of attachment to Z;

Z is Ala-Val or Val-Ala;

U is

 wherein

p is an integer from 1 to 6;

q is an integer from 1 to 20;

is the point of attachment to Z;

is the point of attachment to Q;

Q is selected from

 wherein

is the point of attachment to U;

is the point of attachment to Ab;

and

D is

 wherein:

R 1 and R 2 are each independently a hydroxy group or a halogen atom;

B 1 is:

 wherein

R 18 is hydrogen or C 1-6 alkyl;

R 19 is a halogen atom; and

is the point of attachment to D; and

B2 is:

 wherein

is the point of attachment to D; and

is the point of attachment to the parent molecular moiety; and

Q 2 and Q 4 are each independently an oxygen atom or a sulfur atom.

2. The method of claim 1 , wherein Q is

3. The method of claim 2 , wherein W is

4. The method of claim 3 , wherein R 2 is —CH 3 .

5. The method of claim 4 , wherein a is an integer from 2 to 6.

6. The method of claim 1 , wherein D is:

wherein is the point of attachment to the parent molecular moiety.

7. The method of claim 1 , wherein the compound is a compound of formula (VI):

wherein a is an integer from 1 to 8.

8. The method of claim 7 , wherein the antibody is monoclonal antibody 1D9 or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of CCR2.

9. The method of claim 7 , wherein the anti-CCR2 antibody or anti-CCR2 antigen-binding fragment comprises a light chain CDR1 comprising amino acids 24-39 of SEQ ID NO: 1; a light chain CDR2 comprising amino acids 55-61 of SEQ ID NO: 1; a light chain CDR3 comprising amino acids 94-102 of SEQ ID NO: 1; a heavy chain CDR1 comprising amino acids 31-35 of SEQ ID NO: 2; a heavy chain CDR2 comprising amino acids 50-68 of SEQ ID NO:2; and a heavy chain CDR3 comprising amino acids 101-106 of SEQ ID NO:2.

10. The method of claim 7 , wherein the anti-CCR2 antibody, or anti-CCR2 antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1.

11. The method of claim 9 , wherein the anti-CCR2 antibody or anti-CCR2 antigen-binding fragment further comprises a heavy chain constant region selected from human immunoglobulins IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 heavy chain constant regions and a light chain constant region selected from the group consisting of human immunoglobulins IgGK and IgGλ light chain constant regions.

12. The method of claim 10 , wherein the anti-CCR2 antibody or anti-CCR2 antigen-binding fragment further comprises a heavy chain constant region selected from human immunoglobulins IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 heavy chain constant regions and a light chain constant region selected from the group consisting of human immunoglobulins IgGκ and IgGλ light chain constant regions.

13. The method of claim 7 , wherein the anti-CCR2 antibody comprises a heavy chain region of SEQ ID NO: 3 and a light chain region of SEQ ID NO: 4.

14. The method of claim 1 , wherein the cancer is selected from colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharynx cancer, larynx cancer, esophageal cancer, stomach cancer, duodenal cancer, small intestinal cancer, breast cancer, ovarian cancer, testis tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, transitional cell cancer of the renal pelvis and ureter, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, malignant bone tumor, bladder cancer, and blood cancer.

15. The method of claim 1 , further comprising administering a checkpoint inhibitor.

16. The method of claim 1 , further comprising administering an antibody that binds Programmed Death Ligand 1 (an anti-PD-L1 antibody).

17. A method for stimulating an immune response in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 8;

Ab is an anti-CCR2 antibody or an anti-CCR2 antigen-binding fragment;

R 2′ is C-C 4 alkyl;

W is selected from:

 wherein

is the point of attachment to the carbonyl group; and

is the point of attachment to Z;

Z is Ala-Val or Val-Ala;

U is

 wherein

p is an integer from 1 to 6;

q is an integer from 1 to 20;

is the point of attachment to Z;

is the point of attachment to Q;

Q is selected from

wherein

is the point of attachment to U;

is the point of attachment to Ab;

and

D is

 wherein:

R 1 and R 2 are each independently a hydroxy group or a halogen atom;

B 1 is:

 wherein

R 18 is hydrogen or C 1-6 alkyl;

R 19 is a halogen atom; and

is the point of attachment to D; and

B 2 is:

 wherein

is the point of attachment to D; and

is the point of attachment to the parent molecular moiety; and

Q 2 and Q 4 are each independently an oxygen atom or a sulfur atom.

18. A method for preparing a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 8;

Ab is an anti-CCR2 antibody or an anti-CCR2 antigen-binding fragment;

R 2′ is C 1 -C 4 alkyl;

W is selected from:

 wherein

is the point of attachment to the carbonyl group; and

is the point of attachment to Z;

Z is Ala-Val or Val-Ala;

U is

 wherein

p is an integer from 1 to 6;

q is an integer from 1 to 20;

is the point of attachment to Z;

is the point of attachment to Q;

Q is selected from

 wherein

is the point of attachment to U;

is the point of attachment to Ab;

and

D is

 wherein:

R 1 and R 2 are each independently a hydroxy group or a halogen atom;

B 1 is:

 wherein

R 18 is hydrogen or C 1-6 alkyl;

R 19 is a halogen atom; and

is the point of attachment to D; and

B 2 is:

 wherein

is the point of attachment to D; and

is the point of attachment to the parent molecular moiety; and

Q 2 and Q 4 are each independently an oxygen atom or a sulfur atom;

the method comprising:

treating an anti-CCR2 antibody or an anti-CCR2 antigen-binding fragment with a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:

U is

 wherein

p is the point of attachment to the carbonyl group; and

q is the point of attachment to Z;

is the point of attachment to Z;

is the point of attachment to Q′; and

Q′ is selected from

 wherein

is the point of attachment to U.

19. The method of claim 18 , wherein the anti-CCR2 antibody or anti-CCR2 antigen-binding fragment comprises one or more interchain disulfide bonds that are reduced prior to treatment with the compound.

20. The method of claim 19 , wherein reducing the one or more interchain disulfide bonds comprises treatment with TCEP.

Assignments (2)

Continuity (6)

References Cited (151)