Bifunctional degraders of galactose-deficient immunoglobulins

Patent metadata

Field	Value
Publication number	US-2025228957-A1
Application number	US-202519060384-A
Country	US
Kind code	A1
Filing date	Feb 21, 2025
Priority date	Apr 29, 2023
Publication date	Jul 17, 2025
Grant date	—

Abstract

A composition of matter including a deglycosylated IgA-binding moiety, a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) on the surface of hepatocytes or other degrading cells in a patient or subject, and optionally, a linker moiety connecting deglycosylated IgA-binding moiety and the cellular receptor-binding moiety, wherein the composition of matter is useful for removing galactose-deficient IgA1 in a patient or subject.

First claim

1 . A composition of matter having the chemical formula [AGN101]:

wherein,
is a means for binding galactose-deficient Immunoglobulin A1 (Gd-IgA1);
is a cellular receptor-binding moiety comprising an N-acetyl-D-galactosamine (GalNAc) group; and
L is a linking group,
a is 1, b is 1, 2, or 3, and c is 1 or 2.

2 . The composition of matter of claim 1 , wherein is an antibody or an antigen-binding fragment thereof capable of binding to Gd-IgA1.

3 . The composition of matter of claim 1 , wherein comprises the polypeptide sequences of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.

4 . The composition of matter of claim 1 , wherein the comprises a heavy chain polypeptide sequence of SEQ ID NO: 1 and light chain polypeptide sequence SEQ ID NO: 2.

5 . The composition of matter of claim 1 , wherein the comprises a heavy chain polypeptide sequence of SEQ ID NO: 3 and light chain polypeptide sequence SEQ ID NO: 2.

6 . The composition of matter of claim 1 , wherein comprises a heavy chain polypeptide sequence of SEQ ID NO: 4 and light chain polypeptide sequence SEQ ID NO: 2.

7 . The composition of matter of claim 1 , wherein L comprises one or more —(O)C—[(CH 2 ) n O] m (CH 2 ) n NH—, —[(CH 2 ) n O] m NHC(O)[(CH 2 ) n O] m NH—, and —[(CH 2 ) n O] m {NHC(O)[(CH 2 ) n O] m } p NH—, wherein each m and n are independently 1 to 10.

8 . The composition of matter of claim 1 , wherein the linker comprises one or more —[(CH 2 ) n —O] m —, wherein each m and n are independently 1 to 10.

9 . The composition of matter of claim 1 , wherein L comprises —(CH 2 ) n —O—(CH 2 CH 2 O) n —(CH 2 ) n —, wherein each n is independently 1-10.

10 . The composition of matter of claim 1 , wherein AT comprises an IgG1 heavy chain or an antigen-binding fragment thereof that is connected to L at an amino acid residue selected from K246 and K248 of the IgG1 heavy chain.

11 . The composition of matter of claim 10 , wherein AT is connected to L at the amino acid residue K248 of the IgG1 heavy chain.

12 . The composition of matter of claim 1 , wherein b is 3, and each TBT comprises an N-acetyl-D-galactosamine (GalNAc) group.

13 . The composition of matter of claim 1 , wherein b is 3, and

comprises the chemical formula:

wherein,
Z B is absent, —(CH 2 ) IM —, —C(═O)—(CH 2 ) IM —, or —C(═O)—(CH 2 ) IM —NR M —;
R M is H or C 1 -C 3 alkyl; and
each occurrence of IM is independently 1, 2, or 3.

14 . The composition of matter of claim 1 , wherein b is 2 or 3, and

has the chemical formula [MAT01A], [MAT01B], [MAT01C], or [MAT01D]:

15 . The composition of matter of claim 1 , wherein c is 2.

16 . The composition of matter of claim 1 having the chemical formula shown in FIG. 3 .

Assignees

• Biohaven Therapeutics Ltd

Inventors

• Dubowchik Gene M
• Vaill Ada
• Caldwell Reese M
• Linhares Brian M
• Leahy David K
• Bryson James
• Marcin Lawrence R

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07K2317/90

  characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin · CPC title

• C07K2317/41

  Glycosylation, sialylation, or fucosylation · CPC title

• C07K16/42

  against immunoglobulins · CPC title

• A61K47/6807 Primary

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title