Abstract 1697: NW024-1, a novel ALPP/ALPPL2-targeting antibody drug conjugate with a topoisomerase 1 inhibitor payload, demonstrates potent antitumor efficacy

Abstract Background: Placental alkaline phosphatases, ALPP and ALPPL2, are highly homologous (97%) membrane-bound proteins involved in fetal development. They are highly expressed in a variety of tumor cells including ovarian (70%), endometrial (41%), lung (NSCLC, 25%) and gastric (25%), but have limited expression levels in normal tissues, making them ideal targets for the development of antibody-drug conjugates (ADCs). Here, an ALPP/ALPPL2-targeting ADC NW024-1 was developed, consisting of a humanized IgG1 anti-ALPP/ALPPL2 antibody conjugated via a hydrophilic linker to a topoisomerase 1 inhibitor payload (TOP1i), designed to selectively deliver the cytotoxic agent to ALPP/ALPPL2-expressing cells. NW024-1 was tested in vitro and in vivo to evaluate its therapeutic potential. Methods: A library of ALPP/ALPPL2-binding clones was screened for cell binding, internalization and affinity. The humanized antibody was conjugated to the TOP1i payload with DAR8 using a cleavable linker. The in vivo efficacy of NW024-1 was evaluated in a mouse xenograft model of gastric cancer (NCI-N87), administered with a single dose of 3 mg/kg and 10 mg/kg to evaluate anti-tumor activity. Results: The antibody showed strong binding to human ALPP/ALPPL2 (EC50 = 1.32 nM) low expressing cells, but no binding to human ALPI /ALPL high expressing cells. In vitro, it displayed robust internalization into ALPP/ALPPL2 positive cells and low nanomolar affinity to ALPP (KD = 1.32 nM) and ALPPL2 (KD = 0.85 nM). NW024-1 showed ALPP/ALPPL2-dependent cell killing. In vivo, NW024-1 achieved near-complete tumor regression (TGI > 95%) at 3 and 10 mg/kg for single dose, and was well tolerated in mice as indicated by body weight. Conclusions: NW024-1 is a novel ADC exhibiting a favorable profile and potent antitumor efficacy. These findings highlight its promising therapeutic potential for ALPP-expressing tumors and support its further advancement into clinical investigation. Citation Format: Juanjuan Li, Wenting Luo, Li Liu, Yiran Wu, Gang Liu, Changcheng Li, Yaolan Dai, Jiabao Liu, Zhijian Li, Lixia Wang, Dan Wang, Dan Mi, Jiaoyi Zhong, Bin Liu, Desi Pan, Zhigang Guo. NW024-1, a novel ALPP/ALPPL2-targeting antibody drug conjugate with a topoisomerase 1 inhibitor payload, demonstrates potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1697.