LPD002, a novel anti-PD-1/IL-2 fusion protein, demonstrates potent antitumor activity in preclinical studies

Background: The advancement of immunotherapy has significantly improved the survival outcomes for patients with malignant tumors. IL-2 therapy has demonstrated potential in activating tumor-infiltrating antigen-specific T cells and inducing durable anti-tumor responses. However, it often triggers severe systemic toxicities. To improve the therapeutic index, a variety of engineered IL-2 analogs have been developed. Methods: To overcome the challenges of PD-1 blockade and IL-2 therapies, we engineered a novel fusion protein, LPD002, which combines a humanized anti-PD-1 antibody and an engineered IL-2 mutein. The anti-PD-1 antibody portion delivers the IL-2 mutein payload to PD-1 + tumor-infiltrating T cells while blocking the immune-inhibitory signals of the PD-1 pathway. The IL-2 mutein component of LPD002 has been engineered to retain its binding activity to the IL-2 receptor alpha (IL-2Ralpha) subunit and attenuated affinity for the IL-2 receptor beta and gamma (IL-2Rbetagamma) complex, which is designed to maintain peripheral tolerance and activate tumor-infiltrating T cells, thereby mitigating the systemic toxicity associated with IL-2 therapy. We systematically assessed the functional properties of LPD002 through PD-1 blockade and IL-2 signaling assays. The anti-tumor efficacy of LPD002 was investigated using PD-1 humanized mouse models. Meanwhile, we also evaluated its PK performance in cynomolgus monkeys. Results: In IL-2 reporter assays, LPD002 induced enhanced pSTAT5 signaling in PD-1-expressing reporter cells compared with PD-1-null cells. LPD002 also activated pSTAT5 signaling and promoted the proliferation of both activated CD4 + and CD8 + T cells in human PBMCs. Moreover, in both PD-1-sensitive and PD-1-resistant CDX models, LPD002 demonstrated superior anti-tumor efficacy and was well-tolerated. In cynomolgus monkeys, LPD002 displayed a favorable pharmacokinetic profile. Conclusion: LPD002 represents a novel immunotherapeutic strategy that integrates PD-1 blockade with tumor-focused IL-2 activation, eliciting potent anti-tumor activity while reducing systemic toxicity. These preclinical findings demonstrate that LPD002 is a promising therapeutic candidate for solid tumors and warrants further clinical investigation.