Background Interleukin-2 (IL-2) is a pleiotropic cytokine that plays pivotal roles in the immune response. It induces the proliferation of T cells and NK cells and demonstrates therapeutic anti-tumor activity. CD80 expressed on antigen-presenting cells provides co-stimulatory signals for T cell activation and immune responses via CD28 binding. Conversely, CD80 acts as a checkpoint molecule when bound to CTLA-4. Despite the active and progressive efforts put into the development of immune checkpoint inhibitors for cancer therapy, notable unmet medical needs continue to persist. To address these challenges and provide a safe and effective immune-boosting agent, we generated a novel CD80-IgG4-IL2v3 bispecific fusion protein which allows tumor-targeted delivery of IL-2 and robust proliferation of anti-tumor effector cells.
Methods The evaluation of anti-tumor efficacy and tumor-infiltrating lymphocytes (TIL) was conducted using the EMT6 syngeneic tumor model. Analysis of peripheral lymphocyte alterations was carried out in nonhuman primates (NHP). Intra-tissue concentration analysis of GI-102 was performed utilizing the LL/2 syngeneic tumor model.
Results The N-terminal CD80 domain of GI-102 is designed to target and block CTLA-4, while the C-terminal IL-2v3 domain has no binding affinity to IL-2Rα, while maintaining the affinity towards IL-2Rβγ. In the EMT6 syngeneic mouse model, GI-102-treated group showed significantly reduced tumor volume and percent of tumor growth rate compared with other groups. The analysis of the TIL revealed that GI-102 induced a robust expansion of both CD8+ T and NK cells in tumor microenvironment (TME), relative to vehicle control and Proleukin®. However, in comparison to Proleukin®, injection of GI-102 did not lead to an expansion of Tregs population in TME compared. A similar pattern was observed in peripheral lymphocytes of NHP that were administered GI-102 and Proleukin®. Human PBMC treated with GI-102 were analyzed for cytokine release, and no increase in inflammatory cytokines associated with cytokine release syndrome was observed with GI-102. Following the injecting GI-102 into mice bearing LL/2 tumors, elevated levels of GI-102 were detected from serum, tumor and lymphoid organs, suggesting the CD80-guided distribution of the molecule towards area reach in lymphocytes.
Conclusions GI-102 is a novel anti-cancer agent that activates immune cells and modulates tumor-infiltrating lymphocytes. This potent IL-2-based bispecific fusion protein has great potential to deliver effective therapeutic outcomes for a various types of cancer. It exhibits low toxicity and does not activate Treg, further enhancing its therapeutic value as the next-generation IL-2.
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