Regulatory T cell epitopes
Inventors
Martin, William • Rosenberg, Amy S.
Assignees
Food And Drug Administration • Epivax Inc • US Department of Health and Human Services
Publication Number
US-12275956-B2
Publication Date
2025-04-15
Expiration Date
2038-10-05
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Abstract
The present is directed to compositions comprising regulatory T cell epitopes, wherein said epitopes comprise a polypeptide comprising at least a portion of SEQ NOS: 1-14, fragments and/or variants thereof, as well as methods of producing and using the same.
Core Innovation
The invention provides novel therapeutic regulatory T cell epitope compositions, termed "Tregitopes", which comprise polypeptides having sequences comprising, consisting of, or consisting essentially of one or more of SEQ ID NOS: 1-14. These compositions may include isolated, synthetic, or recombinant polypeptides, nucleic acids encoding such polypeptides, chimeric or fusion polypeptides comprising the Tregitopes linked or inserted into heterologous polypeptides, and pharmaceutical compositions containing these elements. The Tregitopes selectively engage and activate naturally occurring regulatory T cells (TRegs), including natural and adaptive TRegs, to suppress unwanted immune responses.
The problem addressed is the limitation of existing broad-based immune cell depleting therapies for inducing immune tolerance in autoimmunity, transplantation, allergy, and immune responses to therapeutic proteins. These therapies weaken the immune system generally, increasing susceptibility to infections and malignancies. There remains a need for less aggressive and more targeted approaches to induce immune tolerance. Additionally, the antigen specificity of natural TRegs in clinically relevant volumes is largely unknown, and there is a need to identify regulatory T cell epitopes present in common autologous proteins, develop compositions containing such epitopes, and methods for their production and use.
The invention harnesses the function of naturally occurring TRegs by providing Tregitope compositions that comprise specific polypeptides derived primarily from coagulation Factor V and Factor VIII sequences. These polypeptides include T cell epitope clusters that bind to multiple HLA alleles and engage T cell receptors. When administered alone or in combination with target antigens (covalently bound, non-covalently bound, or admixed), these compositions stimulate or expand regulatory T cell populations and suppress immune responses through various mechanisms, including cytokine secretion (IL-10, TGF-β) and modulation of antigen presenting cell phenotypes. This approach allows targeted suppression of immune responses, including those directed against therapeutic proteins such as Factor VIII supplements used in Hemophilia A patients.
Claims Coverage
The patent includes one independent composition claim and one independent method claim regarding compositions comprising isolated T-cell epitope polypeptides and methods of inducing regulatory T cells using such compositions.
Composition comprising an isolated T-cell epitope polypeptide linked to a heterologous peptide
A T-cell epitope composition comprising an isolated T-cell epitope polypeptide consisting of the amino acid sequence of SEQ ID NO: 1, wherein the polypeptide is joined directly to, linked directly to, or inserted directly into a heterologous peptide.
Inclusion of additional T-cell epitope polypeptides
The composition may further comprise at least one additional isolated T-cell epitope polypeptide consisting of an amino acid sequence selected from SEQ ID NOS: 2-14.
Location of T-cell epitope polypeptide on heterologous peptide
The T-cell epitope polypeptide can be located at the N-terminus or C-terminus of the heterologous peptide.
Heterologous peptide can be an antibody or antibody fragment
The heterologous peptide can be an antibody or antibody fragment including Fab, F(ab')2, Fv, disulphide linked Fv, scFv, single domain antibody, closed conformation multispecific antibody, disulphide-linked scfv, or diabody.
Method of inducing regulatory T-cells to suppress immune response
A method comprising administration of a therapeutically effective amount of the described T-cell epitope composition to induce regulatory T-cells to suppress an immune response in a subject.
Suppression mediated by natural or adaptive regulatory T cells
The immune suppressive effect of the composition can be mediated by natural regulatory T cells or adaptive regulatory T cells.
Suppression of diverse immune cell responses
The T-cell epitope composition suppresses effector T-cell response, helper T-cell response, B-cell response, and cytokine secretion from effector T-cells.
Combination with antigens and allergens
The method can comprise administration of the composition together with effective amounts of antigens and/or allergens for enhanced suppressive effect.
The claims cover compositions comprising isolated Tregitope polypeptides especially SEQ ID NO: 1 linked to heterologous peptides including antibodies, and methods of using these compositions to induce regulatory T-cells that suppress various immune responses, with or without additional antigens or allergens.
Stated Advantages
Treatment with the Tregitope compositions is highly antigen specific, expanding and stimulating naturally occurring regulatory T cell populations selectively.
The compositions provide a more efficient and less expensive treatment compared to current high dose and prolonged antigen-specific therapies.
The compositions offer a second line of defense treatment when first line treatments such as high dose Factor VIII fail to induce immune tolerance.
Documented Applications
Treatment or prevention of unwanted immune responses in diseases such as autoimmunity (e.g., type 1 diabetes, MS, lupus, rheumatoid arthritis), transplant-related disorders (e.g., graft versus host disease), allergic reactions, immune rejection of biologic medicines including monoclonal antibodies, and immune responses to replacement proteins such as coagulation Factors VIII and toxins like Botulinum toxin.
Induction of immune tolerance to therapeutic proteins, including Factor VIII supplements used to prevent or stop bleeding in Hemophilia A patients.
Treatment or prevention of allergy and asthma by inducing allergen-specific regulatory T cells to suppress overactive immune responses.
Induction of immune tolerance in transplantation to reduce graft rejection and graft versus host disease.
Treatment or prevention of autoimmune disorders by restoring self-tolerance through modulation of regulatory T cells.
Treatment or prevention of type 1 diabetes via modulation of autoimmune responses targeting pancreatic beta cells.
Treatment or prevention of viral infections such as chronic Hepatitis B virus infection by modulating Treg populations.
Treatment or prevention of systemic lupus erythematosus by combination therapy including known regulatory T cell epitopes.
Treatment or prevention of autoimmune thyroiditis and Graves' disease in combination with thyroid-related antigens.
Ex vivo expansion or stimulation of regulatory T cells or antigen presenting cells using Tregitope compositions for cellular therapies.
Use of Tregitope compositions as reagents in in vitro studies of regulatory T cell function.
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