How to Enhance the ADCC Potential of NK Cells?

The potential to enhance NK cells’ antibody-dependent cellular cytotoxicity (ADCC) is a promising approach to improve cancer immunotherapy. NK cells can recognize antibodies bound to tumor antigens via Fc receptors, leading to target cell destruction via ADCC. The FcγRIII receptor (CD16) is a key player in this process and is available in two isoforms: CD16a-158-F/F (low affinity) and CD16a-158-V/V (high affinity). High-affinity variants are often engineered into NK cells to enhance ADCC. For example, high-affinity CD16 variants combined with IL-2 expression in NK92 cells increased tumor cell lysis when paired with a monoclonal antibody.

Some in vivo studies, such as those involving CD38 knockout NK cells in combination with daratumumab, have demonstrated enhanced therapeutic efficacy against multiple myeloma. In addition, combining FcR-engineered NK cells with monoclonal antibodies against tumor-associated antigens can further enhance ADCC, as seen with anti-PDL1 treatment of meningioma.

However, CD16 is susceptible to ADAM17-mediated cleavage, which impairs ADCC. To overcome this, non-cleavable CD16 variants have been developed to improve efficacy in preclinical models. In addition, high-affinity CD16 receptors have been co-expressed with CAR receptors in NK cells, resulting in enhanced particle polarization and cytotoxic activity.

Further engineering techniques, such as incorporating CD16 into CAR constructs with signaling domains (CD28, 4-1BB, and CD3ζ), have shown enhanced ADCC against CD20-positive tumors. Complex chimeric receptors, such as the ASIMut receptor that binds multiple FcR domains, also show promise for enhancing target cell lysis.

Overall, NK cell receptor engineering represents a powerful strategy to enhance ADCC, providing more precise and effective NK cell-based cancer therapeutics.

References

[1] Audrey Page et al., Cellular & Molecular Immunology 2024 (https://lnkd.in/euvuFK3R)

[2] Feifei Li and Sheng Liu, Frontier in Immunology 2022 (https://doi.org/10.3389/fimmu.2022.1083462)