Background LASN500 is a potent antibody to IL-18 binding protein (IL-18BP) that can both liberate active IL-18 that is complexed with IL-18BP and prevent IL-18BP from blocking free IL-18. In cancer, IL-18 acts as a pluripotent cytokine that signals primarily by inducing interferon gamma (IFNγ) production, resulting in anti-tumor immunity. However, IL-18 also induces IL-18BP production, which acts as an immune checkpoint protein to shut down IL-18 activity.¹ Interestingly, anti-PD-1 treatment in patients has also been reported to induce IL-18BP expression, possibly acting as an inhibitory signal induced by anti-PD-1 therapy.²

To explore the role of IL-18BP in anti-PD-1 resistant disease, we created a highly potent surrogate anti-mouse IL-18BP antibody, mIL-18BP mAb. mIL-18BP mAb can liberate mIL-18 from its complex with mIL-18BP, similar to LASN500’s ability to liberate hIL-18 from hIL-18BP.

Methods mIL-18BP mAb was used as a LASN500 mouse surrogate to assess activity in two anti-PD-1 sensitive and two anti-PD-1 resistant syngeneic mouse tumor models. Treatments included single agent mIL-18BP mAb, anti-PD-1, or the combination of both antibodies. Tumor growth was assessed, and the tumors were analyzed for gene and protein expression.

Results In the anti-PD-1 sensitive models, stimulation with anti-PD-1 alone led to elevation of CD3 and IFNγ levels as expected. Interestingly, mIL-18BP mAb was also able to significantly improve anti-PD-1 efficacy in some models.

In contrast, in the anti-PD-1 resistant models, anti-PD-1 alone was not able to induce an increase in T cells. Significant mIL-18BP mAb single agent efficacy however was observed. Importantly, the combination of mIL-18BP mAb with anti-PD-1 was able to induce significant upregulation of T cells correlating with an increase in efficacy for the combination. Analysis of protein levels demonstrated that IFNγ levels were similarly low with single agent anti-PD-1 treatment, but combination mIL-18BP mAb and anti-PD-1 was able to upregulate IFNγ.

Conclusions mIL-18BP mAb inhibits formation of IL-18/IL-18BP complex and is efficacious in anti-PD-1 resistant mouse models. Additionally, the combination of anti-PD-1 with mIL-18BP mAb led to increased anti-tumor activity compared to either single agent alone in multiple models. Analysis of tumor lysates confirmed increases in T cell and cytokine levels that correlated with efficacy. These data suggest that LASN500, a potent antibody to human IL-18BP, has the potential to enhance immune response in both anti-PD-1 sensitive and resistant patient disease by expanding T-cell populations in the tumor microenvironment.

References

1. Fabbi M, et al. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97:665–75.

2. Zhou T, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020;583:609–614.