Abstract 2475: MB5029: A novel anti-PD-1 x IL-2v with improved safety profile and enhanced anti-tumor efficacy by selectively targeting activated T cells

Abstract Interleukin-2 (IL-2) offers therapeutic potential for cancer treatment, however, its clinical application is limited due to systemic adverse effects, such as vascular leakage syndrome (VLS). Notably, the high affinity of IL-2 for the IL-2 receptor α (IL-2Rα) activates immune-suppressive Treg cells and endothelial cells, leading to undesired outcomes. To address this challenge, a number of clinical studies are under development including non-α IL-2 variant (IL-2v) drugs and further the anti-PD-1 x IL-2v for targeted delivery of its IL-2v to PD-1 enriched T cells. Nevertheless, concerns about peripheral toxicity have not yet been solved. Thus, here we present MB5029, a novel anti-PD-1 x IL-2v bispecific fusion protein with modulated IL-2R binding affinity to mitigate the peripheral toxicity maintaining the anti-tumor efficacy. MB5029 has unique characteristics with no binding affinity to IL-2Rα and reduced binding affinity to IL-2Rγ, which is widely and highly expressed in various immune cells. MB5029 exhibited strong STAT5 phosphorylation activity under activated conditions but weak activity in the resting conditions, while the anti-PD-1 x IL-2v (non-α) showed strong STAT5 phosphorylation in both resting and activated conditions. In addition, MB5029 strongly induced the expansion of CD8+ T cells in the activated conditions but less expansion of CD8+ T cells in the resting conditions, in contrast to anti-PD-1 x IL-2v (non-α). The murine surrogate of MB5029 showed remarkable anti-tumor efficacy without body weight loss at the dose range of 1 to 10 mg/kg, whereas anti-muPD-1 x IL-2v (non-α) showed significant body weight loss in several tumor-bearing mice models. Moreover, MB5029 showed 100% complete regression (6/6) at the dose of 5 mg/kg or higher in the MC38 tumor model. The mice with complete response showed no signs of relapse upon tumor re-challenge until day 56, indicating a durable memory response. MB5029 exhibited a comparatively superior safety profile in normal mice. While anti-muPD-1 x IL-2v (non-α) led to significant body weight loss at the dose of 5 mg/kg in normal mice, the murine surrogate of MB5029 was shown to be well-tolerated up to a dose of 30 mg/kg without body weight loss. MB5029 exhibited dose-proportional PK properties and induced expansion of CD8+ T cells in a dose-dependent manner in cynomolgus monkeys. MB5029 is shown to be well-tolerated up to 9 mg/kg without severe clinical signs and no significant increase in eosinophil and cytokines in the blood. Overall, MB5029 represents a promising potential as an immunotherapeutic approach, as it has demonstrated both strong efficacy and good tolerability, along with improved safety margins. Citation Format: Bom Park, Hyojoo Bang, So Woon Kim, Suna Kim, Sunjung Cho, Suyoon Kim, Minwoo Kim, Youngjin Park, Jun-Eui Park. MB5029: A novel anti-PD-1 x IL-2v with improved safety profile and enhanced anti-tumor efficacy by selectively targeting activated T cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2475.