A novel anti-PD-1/IL-15 fusion protein JMT108 (SYS6090) with highly selective PD-1⁺ immune cell activation and potent anti-tumor efficacy

Introduction: PD-1 is a key inhibitory receptor highly expressed on exhausted T cells within the tumor microenvironment (TME). PD-1 blockade has shown durable clinical benefit in a subset of cancer patients. However, its limited efficacy and frequent resistance highlight an unmet clinical need for improved approaches to reinvigorate T cell function. IL-15 supports survival, proliferation, and cytotoxicity of CD8⁺ T cells and NK cells, yet systemic delivery has shown limited oncology utility due to rapid clearance and inflammatory toxicity. To address these challenges, we developed JMT108, a PD-1 targeted antibody-cytokine fusion protein containing an attenuated IL 15 mutant and IL15Ralpha sushi domain. This design enables dual immunomodulatory activity: (i) PD-1 checkpoint blockade; and (ii) selective cis-activation of IL-15 signaling in PD-1⁺ immune cells within the TME, enhancing tumor specific immunity while minimizing systemic toxicity. Method: Immune cell proliferation was measured in vitro in human PBMCs (PD-1⁻) and pre-activated T cells (PD-1⁺) using standardized assays. In vivo selectivity for PD-1⁺ versus PD-1⁻ subsets was assessed in cynomolgus monkeys and human hematopoietic stem cell (hHSC) reconstituted mice. Anti-tumor activity was tested in immune-humanized A375 melanoma and Huh-7 hepatocellular carcinoma xenografts. PK/toxicology were characterized in cynomolgus monkeys, and cytokine release potential was evaluated ex vivo in PBMCs. Results: JMT108 showed markedly higher selectivity for PD-1⁺ T cell activation versus N-803, with >10,000 fold lower potency in naïve PBMCs. Notably, it reduced PD-1 expression on activated CD8⁺ T cells, in contrast to the upregulation observed with N-803. In hHSC-mice, JMT108 induced sustained expansion of CD8⁺ effector cells (PD-1⁺) without proliferation of naïve T cells. In cynomolgus monkeys, it exerted a long-lasting (>2 weeks) effect on the expansion of PD-1⁺ immune cells, with PD-1⁻ subsets showing markedly lower proliferation. JMT108 exhibited superior anti-tumor efficacy versus anti-PD-1 antibodies in both A375 and Huh-7 models, accompanied by robust expansion of tumor-infiltrating immune populations. JMT108 demonstrated a favorable PK profile in monkeys and was well tolerated in a 4-week GLP toxicity study, with minimal inflammatory cytokine induction in hPBMC assays. Summary: JMT108, a PD-1-targeted IL-15 fusion protein, selectively activates PD-1⁺ immune cells, downregulates PD-1 on activated/exhausted CD8⁺ T cells, and drives sustained effector cell expansion with limited off-target proliferation. It achieves greater anti-tumor efficacy than anti -PD-1 antibodies, with favorable PK and safety profile,and low cytokine release risk. JMT108 has been in Phase I clinical trial (NCT06877650).