Copolymers for suppression of autoimmune diseases, and methods of use
Random three- and four-amino acid copolymers having lengths of 14-, 35- and 50-amino acid residues are provided. Fifty-mers of FEAK were effective inhibitors of MBP 85-99- or proteolipid protein (PLP) 40-60-specific HLA-DR-2-restricted T cell clones. These copolymers efficiently suppressed the mouse disease EAE, which was induced in a susceptible SJL/J (H-2 s ) strain of mice with either whole spinal cord homogenate (WSCH) or with the encephalitogenic epitope PLP 139-151 (SEQ ID NO:4). YFAK 50-mer having a molar ratio of about Y 0.8:F 0.2 inhibited binding of biotinylated MBP 85-99 epitope to HLA-DR-2 molecules more efficiently than either unlabeled MBP 85-99 or Copaxone®. YFAK and FAK copolymers efficiently suppressed EAE induced in SJL/J (H-2 S ) mice with the encephalitogenic epitope PLP 139-151. Copolymers YFAK, VYAK and tryptophan-containing VWAK were efficacious in alleviating severity and duration of symptoms of EAE induced by MBP 85-99 (SEQ ID NO:2), in a humanized mouse model expressing genes for both an HLA-DR-2 linked to multiple sclerosis (MS) in humans and for a T cell receptor from an MS patient.
1. A method for treating multiple sclerosis (MS) in a subject, comprising administering to the subject a linear random copolymer comprising amino acids alanine (A), lysine (K), phenylalanine (F), and tyrosine (Y).
2. A method for reducing frequency of recurrent episodes of multiple sclerosis in a subject, the method comprising administering to the subject a linear random copolymer comprising amino acids alanine (A), lysine (K), phenylalanine (F), and tyrosine (Y).
3. A method for reducing severity of at least one symptom of multiple sclerosis in a subject, the method comprising administering to the subject a linear random copolymer comprising amino acid alanine (A), lysine (K), phenylanine (F), and tyrosine (Y).
4. A method according to claim 3 , wherein the symptom of multiple sclerosis is selected from demyelination, formation of patches of hardened tissue in brain or spinal cord, and encephalomyelitis.
5. A method according to claim 1 , further comprising administering the linear random copolymer in two or more doses.
6. A method according to claim 1 , further comprising administering the linear random copolymer subcutaneously.
7. A method according to claim 1 , wherein the subject is a human.
8. A method according to claim 1 , further comprising administering a dose of at least about 2 mg per subject per day, at least about 5 mg per subject per day, at least about 10 mg per subject per day, or at least about 20 mg per subject per day.
9. A method according to claim 1 , further comprising administering a dose in the range of about 50 to about 400 micrograms of the copolymer per kilogram of the subject per day.
10. A method according to claim 1 , wherein the linear random copolymer comprises at least about 25 amino acid residues.
11. A method according to claim 1 , wherein the linear random copolymer comprises at least about 35 amino acid residues.
12. A method according to claim 1 , wherein the linear random copolymer comprises at least about 50 amino acid residues.
13. A method according to claim 1 , wherein the linear random copolymer comprises at least about 70 amino acid residues.
14. A method according to claim 1 , further comprising co-administering an additional therapeutic agent.