Methods and compositions for immunomodulation
Inventors
Briscoe, David M. • Klagsbrun, Michael • BRUNEAU, Sarah • KOCHUPURAKKAL, Nora • NAKAYAMA, Hironao
Assignees
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Publication Number
US-12397037-B2
Publication Date
2025-08-26
Expiration Date
Abstract
The methods and uses described herein relate to the modulation of the immune system by modulation of Sema3F levels and/or activity, e.g. suppressing allograft rejection or inflammation by administering a Sema3F agonist or increasing an immune response by administering a Sema3F inhibitor.
Core Innovation
The patent describes SEMA3F as a secreted inhibitor that interacts with NRP2 and Plexin A1 to reduce PI3K activity and suppress PI-3K/Akt/mTOR signaling. The suppression includes effects on mTORC2 assembly and downstream Akt/mTOR phosphorylation, and the patent frames mTORC2 as the primary intermediate.
The downstream effects described include reduced VEGF transcription/secretion, inactivation of RhoA, and cytoskeletal stress-fiber collapse. These effects are associated with reduced tumor cell and endothelial cell activation and suppression of angiogenesis.
In vivo, the patent describes xenograft experiments in which SEMA3F overexpression or systemic adenoviral delivery reduces tumor growth and induces collapsed, non-patent CD31+ vessels with reduced pAkt/pmTOR/pS6K. The discussion also mentions dependence on NRP2 and Plexin A1 components and a potential mechanistic involvement of PTEN with caveats for PTEN-deficient tumor lines.
The disclosed method also includes reducing Akt/mTOR signaling in a subject by administering a Sema3F polypeptide, with Sema3F acting through binding NRP-2, with involvement of Plexin A1, to affect downstream signaling associated with immune responses. The document reports suppression of immune activation markers, reduced cytokines, and reduced graft rejection, and it also describes Sema3F/NPR-2/Plexin A1 inhibitors to enhance immune responses and further inhibit signaling pathways.
Claims Coverage
The independent claim covers reducing Akt/mTOR signaling in a subject using a Semaphorin Family III Member F (Sema3F) polypeptide with high sequence identity. The dependent claims further narrow the method by specifying polypeptide identity and administration form, targeting local inflammation, and selecting subject populations such as autoimmune disease, with some dependent claims further specifying additional anti-inflammatory agent classes.
Reducing Akt/mTOR signaling by administering a Sema3F polypeptide
Administering to a subject in need thereof a Semaphorin Family III Member F (Sema3F) polypeptide comprising a sequence having at least 95% identity to the sequence of SEQ ID NO: 1 or SEQ ID NO: 5.
Local administration to inflammation for reducing Akt/mTOR signaling
Administering the Sema3F polypeptide locally to a site of inflammation.
Administration by selected injection routes
Administering the Sema3F polypeptide intramuscularly, subcutaneously, or intradermally.
Treatment of autoimmune disease by reducing Akt/mTOR signaling
Performing the method with a subject who has an autoimmune disease.
Autoimmune disease selected from specified conditions
Performing the method for an autoimmune disease selected from Type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, or autoimmune thyroiditis.
Co-administration with an additional anti-inflammatory agent from specified drug classes
Further comprising selecting an additional anti-inflammatory agent selected from a steroid, a calcineurin inhibitor, a mTOR inhibitor, an analogue thereof, or an anti-proliferative agent.
Across the independent and dependent claims, the core coverage is reducing Akt/mTOR signaling through administering a high-identity SEMA3F polypeptide, with further claim scope directed to local inflammation delivery, specific autoimmune subject populations, and optional co-therapy with additional anti-inflammatory agent classes.
Stated Advantages
Suppress immune responses, including reduced T-cell activation markers and cytokines, and reduced graft rejection.
Enhance immune responses when using Sema3F/NRP-2/Plexin A1 inhibitors.
Reduces Akt/mTOR signaling.
Suppresses PI-3K/Akt/mTOR signaling, including mTORC2 assembly and Akt/mTOR phosphorylation.
Reduces VEGF transcription/secretion.
Inactivates RhoA and causes cytoskeletal stress-fiber collapse.
Reduces tumor cell and endothelial cell activation and suppresses angiogenesis.
Reduces tumor growth in xenograft models.
Induces collapsed, non-patent CD31+ vessels with reduced pAkt/pmTOR/pS6K.
Documented Applications
Reducing Akt/mTOR signaling for immune suppression in settings including allograft rejection, autoimmune diseases, and local inflammatory conditions such as rash and allergic reaction.
Treatment or use in autoimmune diseases including Type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, and autoimmune thyroiditis.
Application to enhance immune responses using Sema3F/NRP-2/Plexin A1 inhibitors.
Reducing tumor growth and suppressing angiogenesis in xenograft experiments, including induced collapsed, non-patent CD31+ vessels with reduced pAkt/pmTOR/pS6K.
Local administration to a site of inflammation as part of reducing Akt/mTOR signaling.
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