Bifunctional degraders of galactose-deficient immunoglobulins
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.
1 . A composition of matter having the chemical formula [AGN101]:
wherein,
is a galactose-deficient Immunoglobulin A1 (Gd-IgA1) binding moiety comprising a heavy chain comprising the polypeptide sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, and a light chain comprising the polypeptide sequences of SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14;
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
comprises a heavy chain polypeptide sequence of SEQ ID NO: 1 and light chain polypeptide sequence SEQ ID NO: 2.
3 . The composition of matter of claim 1 , wherein
comprises a heavy chain polypeptide sequence of SEQ ID NO: 3 and light chain polypeptide sequence SEQ ID NO: 2.
4 . 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.
5 . 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.
6 . The composition of matter of claim 1 , wherein L comprises one or more —[(CH 2 ) n —O] m —, wherein each m and n are independently 1 to 10.
7 . 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.
8 . The composition of matter of claim 1 , wherein
comprises an IgG1 heavy chain that is connected to L at an amino acid residue selected from K246 and K248 of the IgG1 heavy chain according to the EU numbering scheme.
9 . The composition of matter of claim 8 , wherein
is connected to L at the amino acid residue K248 of the IgG1 heavy chain.
10 . The composition of matter of claim 1 , wherein b is 3, and each
comprises an N-acetyl-D-galactosamine (GalNAc) group.
11 . 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.
12 . The composition of matter of claim 1 , wherein b is 2 or 3, ar
has the chemical formula [MAT01A], [MAT01B], [MAT01C], or [MAT01D]:
13 . The composition of matter of claim 1 , wherein c is 2.
14 . The composition of matter of claim 1 , wherein a is 1, b is 3, c is 2, each
has the chemical formula [MAT01A]:
and
wherein
comprises an IgG1 heavy chain that is connected to respective L at an amino acid residue selected from K246 and K248 of the IgG1 heavy chain according to the EU numbering scheme.