LPD002, a novel anti-PD-1/IL-2 fusion protein, demonstrates potent antitumor activity in preclinical studies
Presenter: Zhijian Cai, MS Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Xiaoli Zhang 1 , Zhijian Cai 1 , Shoujia Liu 2 , Wenci Gong 1 1 Lepu Biopharma Co., Ltd., Shanghai, China, 2 Shanghai Miracogen Inc., Shanghai, China
Abstract
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-2Rα) subunit and attenuated affinity for the IL-2 receptor beta and gamma (IL-2Rβγ) 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.
Disclosure
X. Zhang, Lepu Biopharma Co., Ltd. Employment. Z. Cai, Lepu Biopharma Co., Ltd. Employment. S. Liu, Shanghai Miracogen Inc. Employment. W. Gong, Lepu Biopharma Co., Ltd. Employment.
Cited in
Control: 1292 · Presentation Id: 9644 · Meeting 21436