Abstract B078: NPX125, a novel ADC targeting B7-H7, shows potent activity in solid tumors

Abstract Introduction: B7-H7 is a member of the B7 family, known for its role as an immune regulator. B7-H7 is upregulated across many tumors with restricted and limited expression in normal tissues, and its upregulation is correlated with poor patient outcomes. Since these features make B7-H7 a very attractive tumor targeting molecule, NextPoint has developed B7-H7-directed antibody drug conjugate (ADC). ADCs were produced using antibodies previously raised against distinct B7-H7 epitopes with cross-reactivity to both human and cynomolgus macaque proteins. These drug molecules were tested for in vitro and in vivo activity and developability, enabling the lead selection of NPX125 as the development candidate. Methods: B7-H7 protein expression was assessed in hundreds of tumors across multiple indications, selected normal tissues, and tumor cell lines by immunohistochemistry (IHC). Binding efficacy was measured by flow cytometry on endogenous and overexpressing B7-H7 positive cell lines. Internalization was tracked with Fabfluor-pH reporter using Incucyte® imaging. In vitro cytotoxicity was evaluated by luminescence-based cell viability assays with CellTiter-Glo® to detect ATP in the media. Pharmacokinetic features were assessed in rats by measurement of both the IgG1 and the full form of the ADC, IgG1 conjugated to its payload. In vivo activity was tested against B7-H7–expressing xenograft tumors in immunodeficient mice. Results: Tumor cells from colorectal, non-small cell lung, pancreatic, renal and gastric cancer displayed the highest protein levels of B7-H7, with normal B7-H7 expression restricted to substructures of the intestine and lung. NPX125 ADC had similar on-cell binding capacities as parental antibodies. Incucyte® imaging analyses in HER2 positive cell line SKBR3 showed faster internalization compared to Trastuzumab-Dxd. NPX125 demonstrated cytotoxic activity in tumor cell lines with a wide range of B7-H7 expression levels and significant bystander effect on B7-H7 negative cell lines. Pharmacokinetics in rats showed a terminal half-life of >7 days and good payload stability. NPX125 was tested in several in vivo tumor models expressing a wide range of B7-H7 protein levels, demonstrating anti-tumor activity with minimal body weight changes. A single dose of NPX125 in vivo resulted in a 20-day tumor growth delay, while a lower single dose was significantly reducing tumor growth. Conclusions: Collectively, these preclinical studies establish B7-H7 as an attractive ADC target and demonstrate significant anti-tumor activity of a B7-H7 targeting ADC, NPX125, across different levels of B7-H7 expression on tumor cells. The data presented here supports clinical development of NPX125 as a promising treatment strategy. Citation Format: Emilien Loeuillard, Bijan Etemad-Gilbertson, Susannah L. Hewitt, Yasmin Hashambhoy-Ramsay, Katalin Kis-Toth, Jamie Strand, Riale Gilligan, Silvia Ferrati, Tatiana Novobrantseva, Matthew Rausch. NPX125, a novel ADC targeting B7-H7, shows potent activity in solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B078.