Neodegrader conjugates

Patent metadata

Field	Value
Publication number	US-2025090681-A1
Application number	US-202218566822-A
Country	US
Kind code	A1
Filing date	Jun 2, 2022
Priority date	Jun 3, 2021
Publication date	Mar 20, 2025
Grant date	—

Abstract

The present disclosure provides neoDegraders and neoDegraders conjugated to binding moieties. Also provided are compositions comprising the conjugates. The compounds and compositions are useful for treating a disease or condition, e.g., cancer, in a subject in need thereof.

First claim

1 - 48 . (canceled)

49 . A conjugate of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
a is 1 to 10;
L is

is the point of attachment to the nitrogen atom;
is the point of attachment to Bm; and
Bm is an antibody comprising a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:9 and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:10.

50 . The conjugate of claim 49 , wherein the conjugate is of formula (I).

51 . The conjugate of claim 49 , wherein the conjugate is the pharmaceutically acceptable salt of formula (I).

52 . The conjugate of claim 49 , or the pharmaceutically acceptable salt thereof, wherein a is 2 to 8.

53 . The conjugate of claim 49 , or the pharmaceutically acceptable salt thereof, wherein a is 3 to 5.

54 . A conjugate of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
a is 1 to 10;
L is

is the point of attachment to the nitrogen atom;
is the point of attachment to Bm; and
Bm is an antibody or antigen binding portion thereof that is capable of specifically binding to CD33.

55 . The conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, wherein a is 2 to 8, and L is

56 . The conjugate of claim 55 , or the pharmaceutically acceptable salt thereof, wherein a is 3 to 5.

57 . The conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, wherein:
L is

and
Bm is an antibody or an antigen binding portion thereof comprising a heavy chain variable region (VH) complementarity determining region (CDR) 1 (VH-CDR1), comprising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, a light chain variable region (VL) CDR1 (VL-CDR1) comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7.

58 . The conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, wherein:
L is

and
Bm is an antibody or an antigen binding portion thereof comprising a VH comprising the amino acid sequence as set forth in SEQ ID NO: 4 and a VL comprising the amino acid sequence as set forth in SEQ ID NO:8.

59 . The conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, wherein Bm is an antibody comprising a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:9 and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:10.

60 . The conjugate of claim 54 , wherein the conjugate is of formula (I).

61 . The conjugate of claim 54 , wherein the conjugate is the pharmaceutically acceptable salt of formula (I).

62 . The conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, wherein L is covalently bound to Bm through a sulfur atom in Bm.

63 . A pharmaceutical composition comprising the conjugate of claim 49 , or the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

64 . A method of treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of the conjugate of claim 49 , or the pharmaceutically acceptable salt thereof.

65 . A method of treating myelodysplastic syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of the conjugate of claim 49 , or the pharmaceutically acceptable salt thereof.

66 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of the conjugate of claim 49 , or the pharmaceutically acceptable salt thereof.

67 . The method of claim 66 , wherein the cancer is breast cancer, gastric cancer, lymphoma, acute myeloid leukemia, multiple myeloma, head and neck cancer, squamous cell carcinoma, or hepatocellular carcinoma.

68 . A compound of formula (II) or a pharmaceutically acceptable salt thereof:

69 . A compound of formula (III) or a pharmaceutically acceptable salt thereof:

70 . A compound selected from the group consisting of:

wherein ND is a neodegrader compound and Bm is an antibody or antigen binding portion thereof,

wherein ND is a neodegrader compound;

 or a pharmaceutically acceptable salt of any one of the foregoing.

71 . An antibody comprising a heavy chain which comprises the amino acid sequence as set forth in SEQ ID NO:9 and a light chain which comprises the amino acid sequence as set forth in SEQ ID NO:10.

72 . A process of preparing the conjugate of claim 54 , or the pharmaceutically acceptable salt thereof, the process comprising reacting an antibody or antigen binding portion thereof with a compound of formula (I-1):

or a pharmaceutically acceptable salt thereof, wherein:
L′ is

 and
is the point of attachment to the nitrogen atom.

73 . A process selected from the group consisting of:
(a) a process for preparing compound 14 comprising reacting compound 12 with compound 13, thereby producing compound 14; wherein
compound 12 is:

compound 13 is:

compound 14 is:

(b) a process for preparing compound 15

Assignees

• Orum Therapeutics Inc
• Bristol Myers Squibb Co

Inventors

• Fishkin Nathan
• Park Peter U
• Bai Chen

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title