Selective inhibition of T follicular helper cells for treatment of autoimmune disorders
Inventors
PATEL, Preeyam S. • Schneider, Robert J.
Assignees
Publication Number
US-12168003-B2
Publication Date
2024-12-17
Expiration Date
2040-12-02
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Abstract
Disclosed herein is a method of inhibiting T Follicular Helper (TFH) cell-mediated differentiation and/or activation in a subject. This method involves administering to a subject in need of treatment for an autoimmune disorder a eukaryotic translation initiation factor 4E (eIF4E) inhibitor to inhibit TFH cell-mediated differentiation and/or activation in the subject. Also disclosed is a method of inhibiting T Follicular Helper (THF) cell differentiation or TFH cell activity.
Core Innovation
The invention relates to a method for inhibiting T Follicular Helper (TFH) cell-mediated differentiation and/or activation in a subject by administering a eukaryotic translation initiation factor 4E (eIF4E) inhibitor. This approach targets TFH cell-mediated processes that are involved in autoimmune disorders. The method can be applied to a subject in need of treatment for conditions such as multiple sclerosis, rheumatoid arthritis, asthma, allergies, autoimmune encephalitis, lupus nephritis, type I diabetes, and others outlined in the patent.
A major problem addressed by the invention is that TFH cells, while essential for normal immune responses, can accumulate pathologically and are associated with the development and maintenance of autoimmune diseases. Their expansion promotes the formation and perpetuation of germinal centers and ectopic lymphoid follicles, causing enhanced differentiation of B cells into high-affinity antibody-producing plasma cells, which contributes to autoimmunity. Prior to this invention, there were no specific pharmacologic inhibitors of TFH cells available to treat such diseases selectively.
The disclosed method is based on the discovery that TFH cells have an acute requirement for high levels of eIF4E, making them uniquely susceptible to inhibitors that target eIF4E-mediated translation. Administering an eIF4E inhibitor—such as small molecules (including 4EGI-1, 4EIR-Cat, ribavirin and derivatives), interfering RNAs, or antisense oligonucleotides targeting eIF4E—selectively impairs TFH cell differentiation and viability, without affecting other T cell subsets (TH1, TH2, TH17, and Treg cells) or inducing toxicity. This selectivity allows for treatment, prevention, and reversal of autoimmune diseases mediated by TFH cells, as demonstrated by animal model data described in the patent, which show reductions in TFH cells and corresponding autoimmune responses.
Claims Coverage
The patent claims one primary inventive feature covering the method of inhibiting TFH cell-mediated differentiation and/or activation in subjects using a eukaryotic translation initiation factor 4E (eIF4E) inhibitor for treatment of a range of autoimmune disorders.
Method of inhibiting TFH cell-mediated differentiation and/or activation using eIF4E inhibitors
The method comprises administering to a subject in need of treatment for an autoimmune disorder an eukaryotic translation initiation factor 4E (eIF4E) inhibitor to inhibit TFH cell-mediated differentiation and/or activation in the subject. Key aspects include: - The autoimmune disorder can be multiple sclerosis, rheumatoid arthritis, asthma, allergies and food allergies, anaphylactic responses, Jorgen syndrome, autoimmune encephalitis (EAE), lupus nephritis, Type I diabetes, juvenile dermatomyositis, autoimmune myasthenia gravis, autoimmune thyroid disease, atherosclerosis, or graft versus host disease. - The inhibitor may be selected from reversibly binding nucleotide analogues resembling m7GTP and derivatives, covalently binding inhibitors to the eIF4E m7GTP (cap) binding site, inhibitors of eIF4E binding to eIF4G, antisense RNAs, antisense oligonucleotides (ASOs), ribavirin and compounds structurally similar to 7-methyl-GTP, 7-methyl-GMP analogues and derivatives, or 4E binding protein mimetic peptides. - Inhibitors specifically mentioned include: 4EGI-1, 4Ei-1, eFT-4Ei-1, eFT-4Ei-2, eFT-4Ei-3, 4Ei10, 4EIR-Cat, ribavirin, 4EBP mimetic peptides, Bn7GMP, and derivatives. - The eIF4E inhibitor may be a nucleic acid molecule such as an ASO (including LY2275796), siRNA, shRNA, or miRNA. - The method is effective to inhibit TFH cell-mediated differentiation, activation, B-cell differentiation, and activation of TH17 cells, with specificity (i.e., without inducing toxicity or affecting other T cell subsets such as TH1, TH2, TH17, or Treg cells). - The eIF4E inhibitor may be used in mammals, including humans across all age groups.
The inventive feature centers on the selective inhibition of TFH cell-mediated differentiation and/or activation using various eIF4E inhibitors to treat specified autoimmune disorders, with specificity and reduced off-target effects relative to non-selective strategies.
Stated Advantages
The method selectively downregulates TFH cell differentiation and viability without disrupting or inhibiting other T cell types (TH1, TH2, TH17, and regulatory T cells), preserving overall immune function and limiting toxic side effects.
eIF4E inhibition can prevent, ameliorate, or reverse autoimmune disease by targeting TFH cells, allowing both prophylactic and therapeutic application—including reversal of established disease or its progression.
Treatment is effective without inducing toxicity and can achieve reductions in pathogenic cells and clinical symptoms within a short time frame (e.g., three days of treatment).
The approach is more selective and less toxic than BCL6 inhibitors, as it does not directly inhibit BCL6 or disrupt differentiation of other T cell subsets.
Selective inhibition of eIF4E is well tolerated in animal models and does not adversely affect non-TFH CD4+ T cells or general immune responses during infection or vaccination.
Documented Applications
Treatment, prevention, and/or reversal of autoimmune diseases mediated by TFH cells, including multiple sclerosis (MS), rheumatoid arthritis, asthma, systemic lupus erythematosus (SLE), allergies, food allergies, anaphylactic responses, Jorgen syndrome, autoimmune encephalitis (EAE), lupus nephritis, Type 1 diabetes, juvenile dermatomyositis, autoimmune myasthenia gravis, autoimmune thyroid disease, atherosclerosis, and graft versus host disease.
Inhibition of TFH cell-mediated B cell differentiation and germinal center (GC) formation to prevent pathogenic high-affinity antibody production in autoimmune pathogenesis.
Suppression of TFH cell-mediated activation of TH17 cells and formation of ectopic lymphoid follicles in central nervous system autoimmune conditions (e.g., EAE).
Use in the setting of infection or allergic sensitization (e.g., Staphylococcus aureus, Aspergillus fumigatus models) to prevent or modulate TFH cell and GC B cell development.
Applicable across various mammalian subjects, including humans of any age group.
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