A novel antibody-drug conjugate targeting alkaline phosphatases ALPP and ALPPL2 in solid tumors

Alkaline phosphatase placental (ALPP) and ALP-like 2 (ALPPL2) are highly expressed in a wide set of solid tumors, including ovarian, endometrial, gastric and non-small cell lung cancers. Their expression is highly restricted in normal tissues. ALPP/ALPPL2 are attractive targets for antibody-drug conjugate (ADC) and CAR-T therapies. HP-004 is a novel ADC targeting both ALPP and ALPPL2, with high selectivity and enhanced internalization efficiency. HP-004 specifically binds ALPP/ALPPL2 but not the related isozymes ALPI or ALPL, minimizing potential on-target off-tumor liability. In cellular internalization assays using ALPP/ALPPL2 high- and low-expressing tumor cells, HP-004 demonstrated higher uptake and an improved capacity to deliver cytotoxic payload intracellularly across a range of target expression levels. HP-004 is site-specifically conjugated with monomethyl auristatin E (MMAE) with an average DAR about 4. In vitro, HP-004 induced potent target-dependent cytotoxicity in ALPP/ALPPL2-overexpressing tumor cell lines, with an IC₅₀ of approximately 248 pM. In the ALPP/ALPPL2-positive NCI-H1651 xenograft lung cancer model, HP-004 administration achieved near-complete tumor regression at 3 mg/kg (Q2W X4), with complete tumor regression in 6 of 8 mice, demonstrating a robust antitumor activity. HP-004 is further being evaluated in cell line- and patient-derived xenograft models with different expression levels of ALPP and ALPPL2. In parallel, bispecific ADC formats incorporating HP-004 are being explored to further enhance therapeutic index and extend activity to heterogeneous or low-antigen tumors. Collectively, our data support HP-004 as a highly selective ADC candidate with superior internalization, strong preclinical efficacy, and promising potential for translation in solid tumors expressing ALPP/ALPPL2.