NK group 2 member A (NKG2A), also known as killer lectin like receptor c1 (KLRC1) and CD159a, is a ~38 kDa type II transmembrane protein belonging to the C-type lectin superfamily and plays a role in suppression of cytotoxic CD8+ T cell activity and functions as an immune checkpoint (1,2). NKG2A belongs to a group of natural killer (NK) cell inhibitor receptors (IRs) which includes killer immunoglobulin receptors (KIRs), lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), programmed death ligand-1 (PD-1), and T cell immunoglobulin mucin-3 (TIM-3) (1,3). NKG2A is synthesized as a protein of 233 amino acids (aa) with a theoretical molecular weight of 26.3 kDa and is expressed on CD56hi NK cells, NKT cells, and some CD8+ alphabeta T cells (2,4). Together with CD94, NKG2A forms a heterodimer and acts as a receptor for the MHC Class I molecular human leukocyte antigen (HLA)-E (1-3). The NKG2A/CD94 receptor interaction with the HLA-E ligand results in phosphorylation of NKG2A's immunoreceptor tyrosine-based inhibition motifs (ITIMs), causing suppression of activating signals from immunoreceptor tyrosine-based activation motif (ITAM)- containing T cell receptors (TCR) or other activating receptors like NKG2D, via the intracellular phosphatase SHP1 (2,3,5). Overall, cancer cells utilize the NKG2A-HLA-E interaction and signaling to evade immune surveillance by NK cells and T cells (1-3,5-6).

Similar to cytotoxic T lymphocyte associated protein 4 (CTLA-4) and PD-1, NKG2A has become a prominent target for immune checkpoint blockade and cancer immunotherapy (1-3,5-6). Monalizumab is a novel IgG4 monoclonal antibody developed for blocking NKG2A's interaction with HLA-E and has shown promising results in clinical trials (1-3,5-6). In addition to being used as a single agent, it is being studied as a possible combination therapy with other blocking antibodies such as anti-PD-L1 and anti-epidermal growth factor receptor (EGFR) (2,5,6).

References

1. Alfarra, H., Weir, J., Grieve, S., & Reiman, T. (2020). Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy. Frontiers in immunology, 11, 575609. https://doi.org/10.3389/fimmu.2020.575609

2. Creelan, B. C., & Antonia, S. J. (2019). The NKG2A immune checkpoint - a new direction in cancer immunotherapy. Nature reviews. Clinical oncology, 16(5), 277-278. https://doi.org/10.1038/s41571-019-0182-8

3. Zaghi, E., Calvi, M., Marcenaro, E., Mavilio, D., & Di Vito, C. (2019). Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy. Journal of leukocyte biology, 105(6), 1243-1251. https://doi.org/10.1002/JLB.MR0718-300R

4. Uniprot (P26715)

5. Borst, L., van der Burg, S. H., & van Hall, T. (2020). The NKG2A-HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(21), 5549-5556. https://doi.org/10.1158/1078-0432.CCR-19-2095

6. Andre, P., Denis, C., Soulas, C., Bourbon-Caillet, C., Lopez, J., Arnoux, T., Blery, M., Bonnafous, C., Gauthier, L., Morel, A., Rossi, B., Remark, R., Breso, V., Bonnet, E., Habif, G., Guia, S., Lalanne, A. I., Hoffmann, C., Lantz, O., Fayette, J., ... Vivier, E. (2018). Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell, 175(7), 1731-1743.e13. https://doi.org/10.1016/j.cell.2018.10.014

Long Name

Natural Killer G2A

Alternate Names

CD159a, Klrc1, NKG2

Gene Symbol

KLRC1

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Product Specific Notices for NKG2A/CD159a/KLRC1 Antibody (monalizumab) [Alexa Fluor® 532]

Alexa Fluor (R) products are provided under an intellectual property license from Life Technologies Corporation. The purchase of this product conveys to the buyer the non-transferable right to use the purchased product and components of the product only in research conducted by the buyer (whether the buyer is an academic or for-profit entity). The sale of this product is expressly conditioned on the buyer not using the product or its components, or any materials made using the product or its components, in any activity to generate revenue, which may include, but is not limited to use of the product or its components: (i) in manufacturing; (ii) to provide a service, information, or data in return for payment; (iii) for therapeutic, diagnostic or prophylactic purposes; or (iv) for resale, regardless of whether they are resold for use in research. For information on purchasing a license to this product for purposes other than as described above, contact Life Technologies Corporation, 5791 Van Allen Way, Carlsbad, CA 92008 USA or outlicensing@lifetech.com. This conjugate is made on demand. Actual recovery may vary from the stated volume of this product. The volume will be greater than or equal to the unit size stated on the datasheet.

This product is for research use only and is not approved for use in humans or in clinical diagnosis. Primary Antibodies are guaranteed for 1 year from date of receipt.

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NKG2A/CD159a/KLRC1 Antibody (monalizumab) [Alexa Fluor® 532]

Novus Biologicals, part of Bio-Techne | Catalog # NBP3-28102AF532

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Background: NKG2A/CD159a