Unlocking the Potential of Human CD8 T-cells: The Impact of NB005.1 Anti-KLRG1 mAb

The introduction highlights that immune checkpoint blockers (ICBs) have significantly improved cancer treatment outcomes, but not all patients respond well, prompting the search for alternative strategies. The focus is on the Killer cell Lectin-like Receptor G1 (KLRG1), which is found on certain immune cells and has an inhibitory role. KLRG1 is present on highly differentiated T-cells with potent cytotoxic abilities, and a significant portion of these cells are found within the tumor microenvironment (TME). The hypothesis is that inhibiting KLRG1 could boost the effectiveness of these T-cells in the TME, either on its own or in conjunction with ICBs.

The methodology involves creating monoclonal antibodies (mAbs) that target the extracellular domain of human KLRG1. These mAbs were produced using mouse immunization and hybridoma techniques. The antibodies were tested for their binding potency and ability to block the KLRG1 ligand, as well as their capacity to enhance the effector functions of CD8 T-cells. Functional assays were conducted, including measuring the production of IFNγ or TNFα by KLRG1-positive CD8+ T-cells in various co-culture conditions. A human IgG1-LALA antibody was used as a control, and the potential synergy with PD-1 was also assessed.

The results show that one of the antibodies, NB005.1, exhibited high binding affinity for human KLRG1 on CD8 T-cells and Jurkat cells. Blocking KLRG1 with NB005.1 activated CD8 T-cells and increased IFNγ production, validating the inhibitory role of KLRG1. The same effect was observed when the antibody was used with human peripheral blood mononuclear cells (hPBMCs) stimulated under certain conditions.

In conclusion, NB005.1, a fully humanized monoclonal antibody, binds to KLRG1 with high affinity and effectively blocks its interaction with its ligand. This leads to an enhancement of T-cell effector functions, as evidenced by increased IFNγ production. These findings support the potential of NB005.1 for further preclinical evaluation as a standalone treatment or in combination with existing ICBs.