Abstract 1533: ZW220, a novel NaPi2b-targeting antibody drug conjugate bearing a topoisomerase 1 inhibitor payload

Background: NaPi2b is a multi-pass transmembrane sodium-dependent phosphate transport protein encoded by the gene SLC34A2. NaPi2b is involved in normal phosphate homeostasis and its expression is found in the lung, liver, and small intestine. NaPi2b is highly expressed in ovarian carcinomas, lung adenocarcinomas, and colorectal carcinomas. ZW220 is an antibody-drug conjugate (ADC) targeting human NaPi2b, wherein a humanized IgG1 antibody is conjugated to novel camptothecin-based topoisomerase I inhibitor, ZD06519. The drug linker in ZW220 is comprised of a maleimide anchor and a glycyl glycyl phenylalanyl glycine (GGFG)-aminomethyl (AM) cleavable sequence. Materials and Methods: A series of in vitro and in vivo studies were conducted to interrogate the mechanism of action and the therapeutic potential of ZW220. The binding, internalization, potency, and bystander effect of ZW220 were evaluated in vitro using endogenous NaPi2b-expressing ovarian and lung cancer cell lines. In vivo, the anti-tumor activity of ZW220 was evaluated in a panel of cell line derived xenograft (CDX) models and ovarian patient derived xenograft (PDX) models featuring a range of NaPi2b expression. The pharmacokinetic (PK) profile of ZW220 was determined in Tg32 mice, a transgenic mouse expressing human neonatal Fc receptor (hFcRn). Results: ZW220 antibody exhibited cross-reactivity to human and cynomolgus monkey NaPi2b, nanomolar binding affinity and rapid internalization in NaPi2b-expressing cell lines in vitro. ZW220 elicited target-specific, sub-nanomolar cytotoxicity in two-dimensional monolayer and three-dimensional tumor spheroid models and demonstrated bystander-mediated cell killing in cancer cell co-culture assays. The treatment of a panel of ovarian PDXs with a single dose of 6 mg/kg of ZW220 resulted in robust tumor growth inhibition. ZW220 demonstrated a favourable PK profile in Tg32 mice, with comparable half-life to its parental unconjugated antibody. These results support the potential of ZW220 as a novel therapeutic agent which may help address unmet medical need in patients with NaPi2b-expressing tumors. Citation Format: Andrea Hernandez Rojas, Jodi Wong, Dunja Urosev, Sam Lawn, Kaylee Wu, Saki Konomura, Manuel Lasalle, Diego A. Alonzo, Luying Yang, Mark Petersen, Lemlem T. Degefie, Araba P. Sagoe-Wagner, Sohyeong Kang, Chi Wing Cheng, Raffaele Colombo, Daya Siddappa, Stuart D. Barnscher, Jamie R. Rich. ZW220, a novel NaPi2b-targeting antibody drug conjugate bearing