靶向 B7-H7 的新型 ADC——NPX125 的临床前疗效与安全性特征

Introduction: B7-H7 is a member of the B7 family, with strong expression in multiple cancer indications in addition to its known role as an immune regulator. B7-H7 upregulation is correlated with poor patient outcomes while its normal tissue expression is limited, making it very attractive for targeting tumors. Here, we report the development of NPX125, a novel B7-H7-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor and a novel linker. NPX125 has potent in vitro activity, stable pharmacokinetic profile, favorable safety profile, and in vivo antitumor responses in nonclinical studies. Methods: The target specificity and species cross-reactivity of NPX125 were assessed by flow cytometry on endogenous B7-H7+ and overexpressing B7-H7 cell lines. Internalization was tracked with Fabfluor-pH reporter conjugated-NPX125 using Incucyte® imaging. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro by luminescence-based cell viability assays and in xenograft mouse models in vivo . The safety profile was evaluated in a dose escalation toxicokinetic study in cynomolgus monkeys. Animals were evaluated for 4 weeks after a single intravenous dose of NPX125. Clinical observations, hematology, chemistry, cytokine, and immunophenotyping samples were collected. At completion, pathology evaluation of selected tissues was performed. NPX125 pharmacokinetics was assessed in rats and monkeys by measurement of both total and drug-conjugated antibodies. Results: NPX125 showed cross reactivity to human and monkey B7-H7 with on-cell binding. Incucyte® imaging analyses in a HER2 positive cell line showed faster internalization compared to Trastuzumab-Dxd. NPX125 demonstrated cytotoxic activity in tumor cell lines (EC50 ~ 0.19 nM to 2.95 nM) with a wide range of B7-H7 expression levels and significant bystander effect on B7-H7 negative cell lines. NPX125 was tested in several in vivo tumor models expressing a wide range of B7-H7 protein levels, demonstrating anti-tumor activity. Furthermore, NPX125 was stable in circulation with minimal free payload release in rats and monkeys (T1/2 = 352 and 135 hr, respectively and ~0.07% of the total injected payload released at Cmax in NHP). NPX125 was well tolerated in monkeys with a NOAEL of at least 10 mg/kg and no NPX125-related changes in clinical signs, body weight, food appetence, hematology, clinical chemistry, urinalysis, immunophenotyping, and organ weights. Increases in IL-1RA and IL-8 concentrations were noted with possible dose proportionality. Possible NPX125-related findings were present in the gastrointestinal tract. Conclusions: NPX125 exerted potent antitumor activity against B7-H7-expressing tumors in in vitro and in vivo models and showed favorable pharmacokinetic and safety profiles in nonclinical species. The data presented here supports clinical development of NPX125 as a promising treatment strategy.