Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers
Authors: Hamblett KJ , Barnscher SD , Davies RH , Hammond PW , Hernandez A , Wickman GR , Fung VK , Ding T , Garnett G , Galey AS , Zwierzchowski P , Clavette BC , Winters GC , Rich JR , Rowse GJ , Babcook JS , Hausman D 
Published: May 2019

Abstract
Background: HER2-targeted therapies have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Despite this, there remains a need for new treatments that are well tolerated and effective not only for cancers with high HER2 expression levels but also those with lower levels of expression. ZW49 is an antibody drug conjugate (ADC) that combines a novel auristatin payload (potent anti-cancer agent) with the unique mechanisms of action of the anti-HER2 biparatopic antibody, ZW25, which binds to the same domains as trastuzumab and pertuzumab. In preclinical studies in cancer cell lines with low to high levels of HER2 expression, ZW25 is associated with increased binding and internalization compared to trastuzumab, while the novel N-acyl sulfonamide auristatin payload has demonstrated increased in vivo tolerability compared to other microtubule inhibitors. ZW49 therefore has the potential to address unmet medical need across a range of HER2-expressing cancers.
Methods: Multiple in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. Internalization and cell growth inhibition of ZW49 were evaluated in HER2-expressing cell lines. Anti-tumor activity was assessed in patient-derived xenograft (PDX) tumor models of HER2 low and high expressing breast cancers. Tolerability was assessed in a 6-week repeat-dose non-GLP toxicology study in non-human primates (NHP) with intravenous administration of ZW49 at either 9 mg/kg or 12 mg/kg once every two weeks.
Results: In vitro, ZW49 was more rapidly internalized into HER2-expressing cells compared to a monospecific trastuzumab-ADC. ZW49 also displayed potent in vitro cell growth inhibition in several breast cancer cell lines with a range of HER2 expression. This activity was confirmed in multiple in vivo PDX models, including a HER2 IHC 3+ HBCx-13b xenograft where two doses of ZW49 at 3 mg/kg or higher generated tumor regressions, and a HER2 IHC 1+ ST-910 xenograft where a single dose of ZW49 at 6 mg/kg or higher generated regressions. In both models, regressions occurred at exposures that were well tolerated in NHP. In a repeat dose pilot non-GLP study the highest dose tested (12 mg/kg) was considered to be the no observed adverse effect level (NOAEL) and a GLP repeat-dose toxicology study was ongoing at the time of abstract submission.
Conclusions: ZW49 is a novel biparatopic HER2-targeted ADC that demonstrated anti-tumor activity in low and high HER2-expressing breast cancer cell lines and PDX models. Notably, tumor regressions were observed at exposure levels that were well tolerated in NHP. These results support the potential of ZW49 as a novel therapeutic agent that may help address unmet medical need in patients with high and low HER2-expressing cancers.
Citation Format: Hamblett KJ, Barnscher SD, Davies RH, Hammond PW, Hernandez A, Wickman GR, Fung VK, Ding T, Garnett G, Galey AS, Zwierzchowski P, Clavette BC, Winters GC, Rich JR, Rowse GJ, Babcook JS, Hausman D. ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-13.