Optimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Current cancer immunotherapies often lack specificity for tumor cells or tumor-residing regulatory T-cells (Tregs).
• Tumor necrosis factor receptor 2 (TNFR2) is overexpressed on tumor cells and Tregs but not on T effectors (Teffs), making it a promising target for specific immunotherapy.
• TNFR2 expression is widespread across diverse human cancer types.

Purpose of the Study:

• To develop and optimize a novel, human-directed TNFR2 antibody antagonist for targeted cancer immunotherapy.
• To evaluate the tumor microenvironment (TME) specificity and functional efficacy of engineered TNFR2 antagonists.

Main Methods:

• Designed and tested a novel human TNFR2 antibody antagonist.
• Utilized cell-based TME assays to assess antagonist function, including tumor cell and Treg killing, and Teff sparing.
• Engineered chimeric human versions, optimized isotype (IgG2), and introduced hinge stabilization mutations to enhance antagonist performance.

Main Results:

• The TNFR2 antagonist demonstrated TME specificity by selectively eliminating TNFR2-expressing tumor cells and Tregs while allowing Teff proliferation.
• Engineered TNFR2 antagonists with human IgG2 isotype and hinge stabilization exhibited improved function compared to earlier versions.
• Optimal antagonists feature hinge stabilization and wide antibody arm separation for binding newly synthesized TNFR2 on tumor cells.

Conclusions:

• Optimized TNFR2 antibody antagonists, particularly human IgG2 isotypes with hinge stabilization, offer highly TME-specific immunotherapy.
• These antagonists function by forming a nonsignaling cell surface dimer upon binding TNFR2, leading to selective tumor cell and Treg elimination.
• This approach presents a promising strategy for developing targeted cancer immunotherapies with reduced off-target effects.