Antibody-dependent cellular cytotoxicity of anti-programmed death-ligand 1 antibodies for T cells attenuate their antitumor efficacy in a murine tumor model

We evaluated the significant determinants of the therapeutic efficacy of anti-programmed death-ligand 1 (aPD-L1) monoclonal antibodies (aPD-L1 mAbs) by comparing the differences in antibody-dependent cellular cytotoxicity (ADCC) activity of aPD-L1 mAbs of different isotypes (clones 10F.9G2 and MIH6). In MM48 tumor-bearing mice, MIH6 without ADCC activity inhibited tumor growth by more than 90 %, whereas 10F.9G2 with ADCC activity showed slight antitumor effect. The dissociation constant of PD-L1 on MM48 cell surface was approximately 100-fold lower for MIH6 than for 10F.9G2. However, antibody uptake by cells was comparable for both aPD-L1 mAbs. The half-life and amount of intact form of aPD-L1 mAbs in tumors were 2.6- and 1.6-fold higher in MIH6 cells than in 10F.9G2 cells, respectively. Therefore, differences in the pharmacokinetics of PD-L1 mAbs along with different ADCC activities are insufficient to explain their different antitumor effects. Only 10F.9G2 reduced the number of CD8⁺ T cells in MM48 tumor-bearing mice. These results suggest that the difference in efficacy of aPD-L1 mAbs could be because aPD-L1 mAbs recognize PD-L1 on T cells, and the number of CD8⁺ T cells exerting antitumor effect is depleted by 10F.9G2 through ADCC activity. In conclusion, the effect of differences in the pharmacokinetics of aPD-L1 mAbs on the antitumor effect in MM48 tumor-bearing mice was considered negligible. Additionally, the difference in ADCC activity of aPD-L1 mAbs caused a decrease in CD8⁺ T cells, and this off-target effect was considered a factor affecting their antitumor effects.