Treatment of retinal disorders with recombinant T cell receptor ligand (RTL)
Methods are provided for the treatment of a retinal disorder or optic neuritis in a subject. In some embodiments, the methods include administering a therapeutically effective amount of an MHC molecule including covalently linked first, second, and third domains; wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain; or wherein the first domain is an MHC class I α1 domain and the second domain is an MHC class I α2 domain, wherein the amino terminus of the α2 domain is covalently linked to the carboxy terminus of the α1 domain; and wherein the third domain is covalently linked to the first domain and comprises a retinal antigen or an antigen of the central or peripheral nervous system.
1. A method for treating a disorder selected from a retinal disorder and optic neuritis in a subject, comprising:
selecting a subject with a retinal disorder or optic neuritis, wherein the subject does not have uveitis or multiple sclerosis; and
administering to the subject a therapeutically effective amount of a major histocompatibility complex MHC molecule comprising covalently linked first, second, and third domains, wherein the first domain is an MHC class II β1 domain and the second domain is an MHC Class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain, wherein the MHC molecule does not comprise an MHC class II α2 domain or an MHC Class II β2 domain;
wherein the third domain is covalently linked to the first domain, and wherein the third domain comprises an antigenic determinant from a retinal antigen or a myelin protein,
thereby treating the retinal disorder or optic neuritis.
2. The method of claim 1 , wherein the disorder comprises a retinal disorder comprising retinitis pigmentosa, age-related macular degeneration, Stargardt-like macular degeneration, maculopathy, autoimmune retinopathy, diabetic retinopathy, vascular retinopathy, glaucoma, or retinal detachment.
3. The method of claim 1 , wherein the disorder comprises a retinal disorder and the retinal antigen is interphotoreceptor retinoid binding protein (IRBP), arrestin, recoverin, rhodopsin, phosducin, or transducins, wherein the antigenic determinant is 5 to 30 amino acids in length and binds the MHC molecule.
4. The method of claim 3 , wherein the antigenic determinant comprises IRBP 1177-1191 or arrestin 291-310.
5. The method of claim 4 , wherein the antigenic determinant comprises or consists of the amino acid sequence set forth as SEQ ID NO: 2 or SEQ ID NO: 3.
6. The method of claim 1 , wherein the disorder comprises optic neuritis and the antigenic determinant is from a myelin protein, wherein the antigenic determinant is 8 to 30 amino acids in length and binds the MHC molecule.
7. The method of claim 6 , wherein the myelin protein is myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), or proteolipid protein (PLP).
8. The method of claim 7 , wherein the antigenic determinant comprises or consists of MOG 35-55, MOG 1-25, MOG 94-116, MOG 145-160, MOG 194-208, MBP 85-99, MBP 145-164, PLP 139-151, or PLP 95-116.
9. The method of claim 8 , wherein the antigenic determinant comprises or consists of the amino acid sequence set forth as one of SEQ ID NOs: 9-17 and 20.
10. The method of claim 1 , wherein the covalent linkage between the first domain and the second domain comprises a polypeptide linker sequence.
11. The method of claim 1 , wherein the covalent linkage between the first domain and the third domain comprises a polypeptide linker sequence or a disulfide bond.
12. The method of claim 1 , wherein the MHC molecule comprises a human MHC molecule.
13. The method of claim 1 , wherein the first domain is an MHC class II β1 domain and the second domain is an MHC class II α1 domain, wherein the amino terminus of the α1 domain is covalently linked to the carboxy terminus of the β1 domain and wherein the MHC molecule does not comprise an MHC class II α2 domain or an MHC Class II β2 domain.
14. The method of claim 13 , wherein the MHC molecule comprises an HLA-DR, HLA-DP, or HLA-DQ MHC molecule.
15. The method of claim 14 , wherein the MHC molecule is modified by substitution of one or more hydrophobic amino acids within a β-sheet platform of the MHC molecule, such that the MHC molecule exhibits reduced aggregation in solution compared to aggregation exhibited by an unmodified MHC molecule with a wild-type β-sheet platform.
16. The method of claim 15 , wherein the MHC Class II component comprises the α1 and β1 domains of an HLA-DR protein, and wherein the one or more hydrophobic amino acids are selected from V6, I8, A10, F12, L14, and a combination of two or more thereof of the MHC class II α1 domain, and wherein the one or more hydrophobic amino acids are substituted with a non-hydrophobic amino acid.
17. The method of claim 16 , wherein all of V6, I8, A10, F12, and L14 are substituted with a non-hydrophobic amino acid.
18. The method of claim 15 , wherein the non-hydrophobic amino acid is a polar or a charged amino acid.
19. The method of claim 18 , wherein the non-hydrophobic amino acid is serine or aspartic acid.
20. The method of claim 1 , further comprising measuring visual function, retinal function, or retinal structure of the subject.
21. The method of claim 1 , further comprising administering to the subject a second therapy for the retinal disorder or optic neuritis that is not an MHC molecule.