一种搭载人源唾液酸酶的抗B7-H3抗体,可增强先天性和适应性抗肿瘤免疫应答

Tumor hypersialylation, overexpression of sialoglycans on cancer cell surfaces, plays a critical role in cancer progression by suppressing both innate and adaptive anti-tumor immunity. Previously, we demonstrated that an untargeted engineered human sialidase enzyme exhibited single agent and T cell-dependent antitumor activity in preclinical tumor models, a favorable safety profile in non-human primates (NHPs) and cancer patients, and proof-of-mechanism of immune modulation and antitumor signals in cancer patients in a clinical trial (NCT05259696). These findings enabled the development of a platform technology in which the engineered human sialidase is fused to tumor-associated antigen (TAA)-targeting antibodies to achieve deeper and longer tumor desialylation, enhancing both antibody-mediated effector cell cytotoxicity (innate immunity) and T-cell-mediated tumor killing (adaptive immunity). Here we report that fusion of the engineered human sialidase to anti-B7-H3 nanobody, designated E-688 (also called HLX316) significantly improves tumor desialylation depth, durability, and efficacy in vitro and in vivo , while maintaining a favorable safety profile. In assays using hypersialylated, B7-H3-expressing cancer cell lines, E-688 demonstrated markedly increased potency and pharmacodynamic (PD) effects compared with the untargeted sialidase, showing > 1,000-fold improvement in desialylation . In vivo , E-688 also exhibited increased durability of desialylation compared with the untargeted sialidase, extending the PD effect in disease models. Furthermore, desialylation of tumor cell surfaces with E-688 was shown to potentiate antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), enhancing antibody-mediated effector cell-killing of tumor cells. Single-agent in vivo efficacy was observed in multiple mouse tumor models. In an A375 humanized mouse model, E-688 was superior to the B7-H3 antibody, untargeted sialidase, and anti-PD-1 antibody. E-688 was also well tolerated with no toxicity findings in a Good Laboratory Practice (GLP) one-month repeat-dose toxicity study in NHPs, with the NOAEL (no observed adverse effect level) determined to be 150 mg/kg. In summary, E-688 represents a first-in-class cancer therapy, a human-sialidase-armed anti-tumor antibody, that desialylates immunosuppressive tumor-surface sialoglycans to enhance innate and adaptive antitumor immunity. By enabling deeper and more sustained tumor desialylation, E-688 enhances antibody-mediated NK- and macrophage- killing of tumor cells and adaptive antitumor immune responses, while maintaining a favorable tolerability profile. Its clinical development is supported by strong in vitro, in vivo , and GLP toxicology data. Additional targets are currently in development to support a platform-based approach.