Nanobody-Engineered Natural Killer Cell Conjugates for Solid Tumor Adoptive Immunotherapy.

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Natural killer (NK) cell immunotherapy is a promising cancer treatment.
• NK cells often lack specific tumor-targeting ligands, limiting their effectiveness.
• Solid tumors frequently overexpress the human epidermal growth factor receptor (EGFR).

Purpose of the Study:

• To develop a glycoengineering strategy to enhance NK cell-based immunotherapy for solid tumors.
• To equip NK cells with nanobodies targeting EGFR for improved tumor specificity.

Main Methods:

• Sortase A-mediated ligation coupled nanobody 7D12 to DBCO-PEG4-GGG-NH2.
• Bioorthogonal click chemistry attached DBCO-7D12 to azide-bearing NK92MI cells.
• Evaluated 7D12-NK92MI cell specificity, affinity, and efficacy against EGFR-positive and negative tumor cells in vitro and in vivo.

Main Results:

• Engineered 7D12-NK92MI cells demonstrated high specificity and affinity for EGFR-overexpressing tumor cells.
• These modified NK cells increased cytokine secretion and effectively killed EGFR-positive tumors.
• The 7D12-NK92MI cells showed broad anticancer spectrum, extensive tumor penetration, and excellent therapeutic efficacy and safety in mouse models.

Conclusions:

• Glycoengineering NK cells with nanobodies provides a non-genetic strategy for targeted cancer immunotherapy.
• This approach enhances NK cell-mediated killing of solid tumors overexpressing EGFR.
• The developed 7D12-NK92MI cells represent a potential novel therapeutic for targeted cancer immunotherapy.