TNFR2 Antagonist Polypeptides for T-Reg Suppression in Immunotherapy
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Solution Overview
Problem
The development of T lymphocyte-based cancer immunotherapy is hindered by regulatory T cells (T-reg cells) that suppress the activity of tumor-reactive T lymphocytes, undermining the immune response against cancer cells.
Innovation Solution
Development of antagonistic tumor necrosis factor receptor superfamily polypeptides, such as TNFR2-binding polypeptides, which inhibit the proliferation and activity of T-reg cells and promote the expansion of cytotoxic CD8+ T cells, using IgG2 isotype antibodies and antigen-binding fragments with specific binding characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T lymphocytes are used for cancer immunotherapy, then tumor-reactive T cells can eradicate tumor material, but regulatory T cells suppress the activity of tumor-reactive T lymphocytes
Solution Approach 1:
The patent extracts and removes the harmful suppression function by targeting regulatory T cells specifically through TNFR2 antagonism. The antibody selectively binds to TNFR2 expressed on regulatory T cells, extracting their suppressive capability from the immune system while preserving tumor-reactive T cell activity.
Solution Approach 2:
The patent converts the harmful suppressive function of regulatory T cells into a beneficial target. By identifying TNFR2 as a marker on regulatory T cells, the invention transforms their harmful suppression into a specific target for therapeutic intervention, allowing selective neutralization of their suppressive activity.
2Reliability
If chemical modulators are developed to inhibit T-reg cell activity, then the scope and efficacy of adoptive cancer immunotherapy can be improved, but the complexity of pharmacological investigations increases
Solution Approach 1:
The patent introduces a specific antibody as an intermediary agent that mediates the inhibition of regulatory T cell activity. This antibody serves as a well-defined pharmacological tool with characterized binding properties, simplifying the pharmacological investigation compared to developing small molecule modulators.
Solution Approach 2:
The patent utilizes the IgG2 isotype with specific hinge region characteristics (lack of cysteine residues at positions 232 and 233) to achieve optimal antagonistic activity. This parameter change in antibody structure enables superior TNFR2 antagonism while maintaining manufacturability and clinical utility.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These polypeptides effectively inhibit T-reg cell proliferation and activity, promoting the expansion of cytotoxic CD8+ T cells, thereby enhancing the immune response against cancer cells and improving the efficacy of cancer immunotherapy.
Implementation Method 1
antagonistic tumor necrosis factor receptor superfamily polypeptides, such as single-chain polypeptides and antibodies, that specifically bind to TNFR2
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.