Bifunctional degraders for the treatment of Graves' disease
A composition of matter including an anti-TSH receptor autoantibody-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 the anti-TSH receptor autoantibody-binding moiety and the cellular receptor-binding moiety, wherein the composition of matter is useful for removing anti-TSH receptor autoantibody from a patient or subject, such as a Graves' disease patient.
1 . A composition of matter having Formula (I):
wherein,
each {circle around (A)} is a moiety having SEQ ID NO: 7 or a TSHR antigen protein thereof, wherein the TSHR antigen protein amino acid sequence has 95% sequence identity with SEQ ID NO: 7, wherein the amino acid sequence of the TSHR antigen protein has the same numbering as SEQ ID NO: 7 according to the EU numbering scheme, wherein the differences in amino acid sequence between the sequence of SEQ ID NO: 7 and sequence of the TSHR antigen protein are due only to conservative amino acid substitutions, and wherein the TSHR antigen protein is capable of binding to anti-TSH receptor autoantibody;
each
is a linking moiety connecting {circle around (A)} and
each
is a peptide moiety having SEQ ID NO: 8, wherein the moieties
are linked together via two disulfide bridges
as shown in Formula (II), wherein one disulfide bridge links cysteine residues located in position 11 of SEQ ID NO: 8 of each moiety
and wherein the other disulfide bridge links cysteine residues located in position 14 of SEQ ID NO: 8 of each moiety
each
is a linker moiety connecting
and {circle around (E)} wherein each
is connected to
via a side chain amino group of a lysine residue of
to form
and
each {circle around (E)} is an asialoglycoprotein receptor (“ASGPR”) binding moiety comprising an N-acetyl-D-galactosamine (“GalNAc”) group having Formula (II):
2 . The composition of matter of claim 1 , wherein
each chemical bond or a peptide connecting moiety comprising an amino acid selected from the group consisting of G, E, L, P, Q, S, and T.
3 . The composition of matter of claim 1 , wherein each
comprises a moiety selected from the group consisting of:
wherein,
X 2 are independently CH 2 , O, S, NR 4 , C(O), S(O), S(O) 2 , S(O) 2 O, OS(O) 2 , or OS(O) 2 O;
X 3 are independently O, S, NR 4 , wherein R 4 is H or a C 1 -C 3 alkyl; and
k and n are independently 1 to 25.
4 . The composition of matter of claim 1 , wherein each {circle around (E)} comprises a moiety selected from the group consisting of:
wherein,
X 2 are independently CH 2 , O, S, NR 4 , C(O), S(O), S(O) 2 , S(O) 2 O, OS(O) 2 , or OS(O) 2 O;
X 3 are independently O, S, NR 4 , wherein R 4 is H or a C 1 -C 3 alkyl; and
k and n are independently 1 to 25.
5 . The composition of matter of claim 1 , wherein each
comprises a group having Formula (IV) or Formula (V):