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