Next-Generation Anti-PD-L1/IL-15 Immunocytokine Elicits Superior Antitumor Immunity in Cold Tumors with Minimal Toxicity

• DOI: 10.2139/ssrn.4569726
• Publication Date: 2023-09-13T19:55:17Z
• Authors: Wenqiang Shi; Nan Liu; Zexin Liu; Yuqi Yang; Qiongya Zeng; Yang Wang; Luyao Song; Junsheng Chen; Mingyuan Wu; Lin Zhou; Fengping Zhu; Likun Gong; Jianwei Zhu; Long Jiang; Huili Lu

Immunocytokines have demonstrated promising efficacy in preclinical studies, but their clinical applications are still limited by dose-related toxicities. To address the safety challenges of immunocytokines, here we propose a next-generation immunocytokine concept involving design tumor-conditional anti-PD-L1/IL-15 prodrug (LH05), which innovatively masks IL-15 with steric hindrance its flanking moieties. The successfully attenuated “cytokine sink” effect circulation and significantly reduced systemic toxicities associated wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within tumor microenvironment (TME), LH05 released active superagonist exhibited potent antitumor effects both syngeneic mouse models xenograft models. Mechanistically, depends on innate adaptive immunity, particularly NK cell functions. Further investigations revealed that increases infiltration CD8+ T cells stimulating expression chemokines CXCL9 CXCL10, promotes cytotoxicity these cells, thus skews TME towards Th1-type fires up “cold” tumors. Our findings provide compelling proof-of-concept for development contributes to current knowledge strategies immunotherapy patients tumors or resistance immune checkpoint inhibitors.