Compositions including I-domain antigen conjugate compounds and methods for treatment of autoimmune disorders

Patent metadata

Field	Value
Publication number	US-9573983-B2
Application number	US-201313733991-A
Country	US
Kind code	B2
Filing date	Jan 4, 2013
Priority date	Jan 6, 2012
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

The present disclosure provides IDAC compounds capable of presenting two or more signal 1 moieties to a host immune system and methods of using the IDAC compounds to treat or prevent autoimmune disorders in a subject. The present disclosure provides compounds including a modified I-domain peptide having two or more modified lysine residues and two or more signal 1 moieities conjugated to the modified lysine residues of the I-domain peptide and methods of using an making the compounds.

First claim

The invention claimed is:

1. A compound comprising:
a modified I-domain peptide comprising SEQ ID NO: 1 that is capable of binding a D1 domain of ICAM-1, the modified I-domain peptide having two or more modified lysine residues; and
two or more signal 1 moieities conjugated to the modified lysine residues of the I-domain peptide, wherein the two or more signal 1 moieities are the same or different and wherein the two or more signal 1 moieties are chosen from epitopes of proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and a combination thereof, wherein the epitopes of PLP, MBP, and MOG are chosen from peptide sequences selected from the group consisting of: SEQ ID NOs: 2-28, and wherein any signal 1 moiety comprising an epitope of MOG also comprises a poly-ethylene glycol (PEG) spacer.

2. The compound of claim 1 , wherein the signal 1 moieities are conjugated to the modified lysine residues of the I-domain peptide via linkers.

3. The compound of claim 2 , wherein the linker comprises a maleimido group capable of conjugating a cysteine residue of the signal 1 moiety to a lysine residue of the I-domain peptide.

4. The compound of claim 1 , wherein if the peptide sequence of the signal 1 moieties does not include a terminal cysteine residue, the signal 1 moiety is further modified to include a terminal cysteine residue.

5. The compound of claim 1 , wherein at least one signal 1 moiety comprises amino acids 139-151 of PLP having a terminal cysteine (SEQ ID No. 2).

6. The compound of claim 1 , wherein the modified I-domain has about two to 20 modified lysine residues.

7. The compound of claim 3 , wherein the linker comprises one or more spacers to extend the length of the linker.

8. The compound of claim 7 , wherein the spacer is chosen from poly-ethylene glycol (PEG) and poly-Gly.

9. The compound of claim 1 , wherein the modified lysine residues of the I-domain peptide comprise mutation of the lysine residue to a cysteine residue, wherein a thiol group of the cysteine residue is capable of being conjugated to a maleimide residue of a signal 1 moiety.

10. The compound of claim 3 , wherein the maleimido group linker is conjugated to a cysteine residue of the signal 1 moiety and wherein the cysteine residue is chosen from a C-terminal cysteine residue, an N-terminal cysteine residue, or both.

11. A compound comprising:
a modified I-domain peptide comprising SEQ ID NO: 1, wherein two or more lysine residues are modified with a maleimido group, and
two or more signal 1 moieties conjugated to the modified lysine residues of the I-domain peptides, wherein the signal 1 moieties are chosen from epitopes of proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) modified with poly-ethylene glycol (PEG), and combinations thereof, wherein the epitopes of PLP, MBP, and MOG are chosen from peptide sequences selected from the group consisting of: SEQ ID NOs: 2-28, and further comprising a terminal cysteine residue.

12. The compound of claim 11 , wherein at least two signal 1 moieties are different.

13. The compound of claim 1 , wherein the epitopes of PLP, MBP, and MOG are chosen from peptide sequences selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 7, wherein SEQ ID NO: 7 is further modified to comprise a terminal cysteine residue.

Assignees

• Univ Kansas

Inventors

• Siahaan Teruna J
• Manikwar Prakash
• Kiptoo Paul Kipkemboi
• Badawi Ahmed
• Buyuktimkin Barlas
• Stewart John M

Classifications

• C07K14/70553

  Integrin beta2-subunit-containing molecules, e.g. CD11, CD18 · CPC title

• C07K14/4713 Primary

  Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title