Bifunctional degraders for the treatment of Graves' disease
AssigneeBiohaven Therapeutics Ltd.
InventorsAnna Bunin, Seong Lee, Kathren Croce, Miranda L. Simes, Edward Deramon, Mariano Oppikofer
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Abstract
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.
Claims5
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):
Dependencies are inferred from the claim text.