An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

Area of Science:

• Synthetic biology
• Biotechnology
• Immunotherapy

Background:

• Applied engineering principles in synthetic biology offer potential for medical revolution.
• However, redesigned organisms have not yet significantly impacted practical drug development.

Purpose of the Study:

• To engineer a semi-synthetic organism for generating modified human cytokine IL-2 variants.
• To identify IL-2 variants with improved pharmacological properties and distinct receptor specificities.

Main Methods:

• Utilized an engineered microbe with a six-letter semi-synthetic DNA code for site-specific amino acid substitutions in IL-2.
• Generated IL-2 variants, modified them with PEG polymers via click chemistry, and screened for desired properties.
• Characterized THOR-707's IL-2 receptor engagement and evaluated its in vivo efficacy in mouse models.

Main Results:

• Identified THOR-707, an IL-2 variant selectively engaging the IL-2 receptor beta/gamma complex.
• THOR-707 induced large-scale activation of CD8+ T cells and NK cells in mice without Treg expansion.
• In tumor-bearing mice, THOR-707 enhanced drug accumulation, stimulated immune cells, and reduced tumor growth.

Conclusions:

• THOR-707 exhibits significant immune modulatory and anti-tumor properties.
• This study represents a fundamental advance in applying synthetic biology to medicine.
• Engineered semi-synthetic organisms can serve as cellular factories for discovering and producing novel biologics.