Antagonistic TNFR2 Polypeptides for T-Reg Suppression
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Solution Overview
Problem
Current cancer immunotherapy approaches are hindered by the suppressive activity of regulatory T cells (T-reg cells), which inhibit the effectiveness of tumor-reactive T lymphocytes.
Innovation Solution
Development of antagonistic tumor necrosis factor receptor superfamily polypeptides, such as single-chain polypeptides, antibodies, and antigen-binding fragments, that specifically bind to human TNFR2, thereby inhibiting the proliferation and activity of T-reg cells and promoting the expansion of T effector cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If regulatory T cells are present to maintain peripheral tolerance, then self-cell protection is improved, but tumor-reactive T cell activity is suppressed
Solution Approach 1:
The patent extracts and isolates the TNFR2 receptor from T-reg cells as a specific target. By developing antagonistic polypeptides that specifically bind to TNFR2, the invention selectively removes or blocks the suppressive function of T-reg cells without affecting other immune cells, thereby extracting the harmful element while preserving the beneficial regulatory function
Solution Approach 2:
The invention changes the binding parameter of the antagonistic polypeptides to specifically target TNFR2 with high affinity. By optimizing the polypeptide structure to achieve specific binding to TNFR2 epitopes, the patent alters the interaction parameters between immune cells and cytokines, thereby modulating T-reg cell activity while preserving other immune functions
2Productivity
If adoptive immunotherapy is used to enhance cancer cell cytotoxicity, then tumor eradication is improved, but T-reg cell suppression undermines effectiveness
Solution Approach 1:
The patent applies preliminary anti-action by administering antagonistic TNFR2 polypeptides before or concurrent with adoptive immunotherapy. This pre-blocks the suppressive mechanism that T-reg cells would otherwise activate, preventing them from undermining the effectiveness of tumor-reactive T cells before they can exert their cytotoxic effect
Solution Approach 2:
The antagonistic polypeptides serve as intermediary molecules that mediate between the adoptive immunotherapy and the T-reg cells. By binding to TNFR2 on T-reg cells, these intermediaries block the suppressive signaling pathway, allowing the adoptive immunotherapy to function effectively without being suppressed
Data Source
AI summary
Described are antagonistic TNFR2 polypeptides, such as antibodies and antigen-binding fragments thereof, and the use of these polypeptides to inhibit the proliferation of regulatory T cells (T-regs) and/or myeloid-derived suppressor cells (MDSCs), to expand T effector cell populations or function, and to reduce the proliferation of, or directly kill, tumor cells, such as tumor cells that express TNFR2 antigen. The polypeptides, such as antibodies and antigen-binding fragments thereof, are TNFR2 antagonists, such as dominant TNFR2 antagonists. The polypeptides can be used to suppress the T-reg- or MDSC-mediated deactivation of tumor reactive T lymphocytes, expand populations of tumor-reactive cytotoxic T cells, and/or to directly kill TNFR2+ tumor cells. The antagonistic TNFR2 polypeptides described herein can be used to treat a wide variety of cancers and infectious diseases.