TREGITOPE CONSTRUCTS USEFUL IN THE PREVENTION AND TREATMENT OF TYPE 1 DIABETES
The present disclosure generally relates to novel Tregitope-blood component conjugates and modified polypeptides comprising Tregitopes, with said modified peptides being capable of reacting with blood components to form such Tregitope-blood component conjugates. In aspects, the Tregitope-blood component conjugates include a blood component which acts as a carrier protein (e.g., albumin), and further include a modified polypeptide comprising one or more regulatory T cell epitopes (termed “Tregitopes”), the polypeptide having been modified by attaching a reactive moiety to the polypeptide that is capable of forming a bond (e.g., a covalent linkage) with a reactive functionality on the blood component. The present disclosure also relates to methods of using said Tregitope-blood component conjugates and modified polypeptides comprising Tregitopes in the treatment and prevent of autoimmune disorders, such as type 1 diabetes.
1 . A Tregitope-blood component conjugate comprising: a modified polypeptide, said modified polypeptide having a reactive moiety attached thereto and said modified polypeptide comprising one or more regulatory T cell epitopes or
wherein said modified polypeptide is further linked to a blood component.
2 - 3 . (canceled)
4 . The Tregitope-blood component conjugate of claim 1 , wherein said one or more regulatory T cell epitopes comprises of one or more amino acid sequences selected from the group consisting of SEQ ID NOS: 1-55, and/or fragments and variants thereof, and optionally 1 to 12 additional amino acids distributed in any ratio on the N terminus and/or C-terminus of the polypeptide of SEQ ID NOS. 1-55.
5 . The Tregitope-blood component conjugate of claim 1 , wherein said one or more regulatory T cell epitopes comprises SEQ ID NO: 1.
6 . The Tregitope-blood component conjugate of claim 1 , wherein said one or more regulatory T cell epitopes comprises SEQ ID NO: 28.
7 . The Tregitope-blood component conjugate of claim 1 , wherein said blood component is albumin.
8 . The Tregitope-blood component conjugate of claim 1 , wherein said blood component is human serum albumin.
9 . The Tregitope-blood component conjugate of claim 1 , wherein said modified polypeptide further comprises a T1Dgen peptide.
10 . The Tregitope-blood component conjugate of claim 9 , wherein the T1Dgen peptide comprise one or more amino sequences selected from the group consisting of SEQ ID NOS: 56-63.
11 . The Tregitope-blood component conjugate of claim 1 , wherein the reactive moiety is attached to the amino terminal amino acid of the modified polypeptide.
12 . The Tregitope-blood component conjugate of claim 1 , wherein the reactive moiety is attached to the carboxy terminal amino acid of the modified polypeptide.
13 . The Tregitope-blood component conjugate of claim 1 , wherein the reactive moiety is attached to an amino acid positioned between the amino terminal amino acid and the carboxy terminal amino acid of the modified polypeptide.
14 . The Tregitope-blood component conjugate of claim 1 , wherein the reactive moiety is a succinimidyl or maleimido group.
15 . The Tregitope-blood component conjugate of claim 1 , wherein the reactive moiety is a 3-maleimidoproprionic acid moiety.
16 . The Tregitope-blood component conjugate of claim 1 , wherein a conjugation between the blood component and the modified polypeptide is a maleimide linkage.
17 - 29 . (canceled)
30 . A method for suppressing an autoimmune response characteristic of T1D in a subject in need thereof, the method comprising administering to the subject a Tregitope-blood component conjugate of claim 1 .
31 . (canceled)
32 . The method according to claim 30 , wherein the administration shifts one or more antigen presenting cells, dendritic cells, or T cells to a regulatory phenotype.
33 . (canceled)
34 . The method according to claim 30 , wherein the regulatory phenotype is characterized by a decrease in CD11c and HLA-DR expression in the dendritic cells or other antigen presenting cells.
35 . (canceled)
36 . The method according to claim 30 , wherein the administration of the one or more regulatory T-cell epitopes activates CD4 + /CD25 + /FoxP3 + regulatory T-cells.
37 . The method according to claim 30 , wherein the administration suppresses an immune response selected from the group consisting of an innate immune response, an adaptive immune response, an effector T cell response, a memory T cell response, a helper T cell response, a B cell response, a ηκT cell response, or any combination thereof.
41 . A pharmaceutical composition comprising a Tregitope-blood component conjugate according to claim 1 and a carrier, excipient, and/or adjuvant.
42 . (canceled)