Abstract 5671: MB201, a CD8+ T cell-selective anti-PD-L1 x IL-2 variant fusion protein, exhibits a potent anti-tumor efficacy without peripheral toxicity

Abstract

Abstract Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, is the first approved cancer immunotherapy. However, the clinical application of IL-2 is limited by systemic activation of unexpected immune cells, leading to severe toxicities including vascular leakage syndrome (VLS). These adverse effects were mainly caused by the activation of Treg and endothelial cells bearing IL-2 receptor (IL-2R) αβγ. Recently, studies have mainly focused on the optimization of IL-2Rs binding affinity to selectively invigorate CD8+ T cells in tumors, but the toxicity risk has yet to be solved. To overcome these limitations, we developed MB201, a novel anti-PD-L1 x IL-2v fusion protein, which selectively activates CD8+ T cells by attenuating binding affinity to IL-2Rβγ with no binding to IL-2Rα. MB201 showed a strong binding affinity to PD-L1 (KD value is 0.5 nM) and a weak binding affinity to IL-2Rβγ and IL-2Rαβγ (KD value is 23.8 nM and 30.6 nM, respectively), indicating the preferential targeting PD-L1+ tumor cells. MB201 exhibited a preferential activation of CD8+ T cells than Treg cells, which showed remarkably reduced activation compared to rhIL-2 (more than 100-fold based on EC50). Consistently with the result of T cell activation, MB201 only increased the expansion of CD8+ T cells rather than Treg cells in CD3-stimulated PBMC. Indeed, MB201 induced negligible expansion of immune cells and lower pro-inflammatory cytokine release compared to the rhIL-2 in CD3-unstimulated PBMC, indicating the reduced peripheral toxicity risk. When administered to MC38 syngeneic mice, MB201 showed superior anti-tumor efficacy without both body weight reduction and lung weight gain compared to the avelumab monotherapy or combination therapy with rhIL-2. These preclinical observations support that MB201 has characteristics of a superb safety profile and excellent anti-tumor efficacy, and it may offer an advantageous therapeutic strategy for the treatment of cancer. Citation Format: Bom Park, Hyojoo Bang, Youngjun Jung, Sunjung Cho, Mi Seong Kim, Seok Chan Kang, Sungyoub Jung, Youngjin Park. MB201, a CD8+ T cell-selective anti-PD-L1 x IL-2 variant fusion protein, exhibits a potent anti-tumor efficacy without peripheral toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5671.