Peptides that block presentation of antigenic islet peptides by HLA-DQ8 and methods for treating type-1 diabetes
Inventors
TOMER, Yaron • OSMAN, Roman • Lombardi, Angela
Assignees
Montefiore Medical Center • Albert Einstein College of Medicine • Icahn School of Medicine at Mount Sinai
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Publication Number
US-12552854-B2
Publication Date
2026-02-17
Expiration Date
Abstract
The disclosure provides polypeptides that specifically bind to HLA-DQ8 for treating Type 1 Diabetes (TID) and methods using same for reducing autoimmune destruction of pancreatic islet beta cells. In particular, the present disclosure relates to peptides containing at least one D-amino acid that are capable of blocking the presentation of antigenic islet peptides (e.g., lnsB:9-23) by HLA-DQ8, and to their uses, especially as it relates to the prevention and/or treatment of TID.
Core Innovation
The disclosure provides peptide-based D-amino-acid polypeptides defined by specific amino acid sequence frameworks and specific sequences, including SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 12, in which each amino acid is a D-amino acid. The sequences permit position-specific residue options and optional NH2 and COOH D-amino-acid extensions, and are designed to function as HLA-DQ8-binding polypeptides, including a retro-inverso D-peptide (RI-EXT) that binds HLA-DQ8.
The disclosure further provides polypeptide-HLA-DQ8 complexes that include HLA-DQ8, including an HLA-DQ8 alpha chain and HLA-DQ8 beta chain, and that can be formed on antigen presenting cells. Within these complexes, HLA-DQ8 binding is associated with blocking presentation of the autoimmune islet antigen InsB:9-23 to CD4+ T-cells and with inhibition of T-cell activation through reduced engagement with the T-cell receptor.
The disclosure is grounded in a stated immunological rationale focused on the involvement of HLA-DQ8-InsB:9-23 in type 1 diabetes, with the polypeptides described as preventing or treating type 1 diabetes. It also reports reduced T-cell activation ex vivo and in a humanized DQ8 mouse in vivo, reduced islet peptide recall responses using PBMCs from recent-onset DQ8+ type 1 diabetes patients, and rationale for expansion to other autoimmune diseases driven by MHC class II.
Claims Coverage
The independent claims cover D-amino-acid polypeptides defined by specific sequence constraints or by SEQ ID NO: 4 or SEQ ID NO: 12, together with polypeptide/HLA-DQ8 complex formats presented by antigen presenting cells. The inventive coverage centers on D-amino-acid sequence definitions, HLA-DQ8 binding, and decreased ability to induce T-cell activation in the context of InsB:9-23, with four inventive features identified.
D-amino-acid polypeptide sequence with defined position substitutions
A polypeptide comprising the amino acid sequence of SEQ ID NO: 1 with X1 being V, L, F, or Y and X2 being L, A, S, C, or G; or the amino acid sequence of SEQ ID NO: 2 with X1 being V, L, F, or Y, X2 being L, A, S, C, or G, X3 being L or G, X4 being H or G, wherein each amino acid of the amino acid sequence is a D-amino acid.
D-amino-acid polypeptide sequence defined by SEQ ID NO: 4 or SEQ ID NO: 12
A polypeptide comprising an amino acid sequence of SEQ ID NO: 4 or an amino acid sequence of SEQ ID NO: 12, wherein each amino acid of the amino acid sequence is a D-amino acid.
HLA-DQ8-specific polypeptide within an HLA-DQ8 complex
A complex comprising a polypeptide and an HLA-DQ8, optionally specified as human HLA-DQ8, including a polypeptide that binds HLA-DQ8.
APC presentation with decreased ability to induce T-cell activation versus an HLA-DQ8/InsB:9-23 reference complex
An APC complex that expresses an MHC class II molecule and has a decreased ability to induce T-cell activation relative to a second APC comprising HLA-DQ8 bound to InsB:9-23, wherein the decreased ability is specified as a percentage reduction.
Overall, the claims cover D-amino-acid polypeptides defined by specific SEQ ID-constrained sequences and specific sequences, optionally refined to specifically bind HLA-DQ8, and complexes in which the polypeptide is presented via an APC expressing MHC class II. The APC-related claims require decreased ability to induce T-cell activation versus a second APC complexed with HLA-DQ8 bound to InsB:9-23.
Stated Advantages
Blocks presentation of the autoimmune islet antigen InsB:9-23 to CD4+ T-cells.
Inhibits T-cell activation ex vivo and in a humanized DQ8 mouse in vivo.
Reduces islet peptide recall responses using PBMCs from recent-onset T1D patients.
Prevents or treats type 1 diabetes.
Supports selective, personalized therapy in DQ8-positive individuals.
Claims minimal generalized immunosuppression.
Provides rationale for expansion to other autoimmune diseases driven by MHC class II.
Documented Applications
Prevention or treatment of type 1 diabetes using D-amino-acid polypeptides that bind HLA-DQ8 and block InsB:9-23 presentation to CD4+ T-cells.
Use of polypeptide-HLA-DQ8 complexes formed on antigen presenting cells to inhibit CD4+ T-cell activation in the context of InsB:9-23.
In vitro and ex vivo contexts described through binding inhibition assays and measurements of IL-2, IFN-gamma, and proliferation in mixed lymphocyte reactions and PBMCs.
In vivo evidence described using humanized DQ8 mouse.
T1D treatment or therapy context for DQ8-positive individuals based on reduced T-cell activation and recall responses.
Ex vivo testing of RI-EXT/RI-CT for blocking other diabetogenic peptides in SJL-DQ8 mice with cytokine readouts.
Investigation of reduced T-cell activation and reduced islet peptide recall responses using PBMCs from recent-onset T1D patients.
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