Abstract 3914: ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers

Abstract

Therapies targeting HER2 have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Unfortunately, many patients recur following HER2-targeted treatments and new therapies are needed. Multiple antibody-drug conjugate (ADC) technologies are being explored in this setting, some of which utilize the anti-HER2 antibody trastuzumab. Here we present the preclinical characterization of a new anti-HER2 biparatopic ADC, ZW49, which is generated from the conjugation of a novel N-acyl sulfonamide auristatin payload to the inter-chain disulfide bond cysteines of the bispecific anti-HER2 IgG1 antibody ZW25, via a protease cleavable linker. A series of in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. In cellular binding assays, it was confirmed that the payload conjugation to ZW25 did not affect the antibody's binding to HER2-expressing cells. ZW49 displayed potent in vitro cytotoxicity in multiple cancer cell lines expressing HER2 and was efficacious in multiple patient-derived xenograft (PDX) models. In mice bearing the HBCx-13b HER2 3+ PDX, two doses of ZW49 administered two weeks apart generated tumor regressions. Furthermore, preliminary results from PDX models with lower levels of HER2 expression treated with ZW49 also generated regressions. In nonhuman primates ZW49 administered intravenously every two weeks for three doses was well tolerated. Based on these findings, we are proceeding with further development of ZW49 as a therapeutic candidate in HER2-expressing cancers. Citation Format: Kevin J. Hamblett, Phil W. Hammond, Stuart D. Barnscher, Vincent K. Fung, Rupert H. Davies, Grant R. Wickman, Andrea Hernandez, Tong Ding, Adam S. Galey, Geoffrey C. Winters, Jamie R. Rich, John S. Babcook. ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3914.

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

“…2A) [29], which can lead to antigen degradation and downregulation of disease-related signaling, such as in the cases of epidermal growth factor receptor (EGFR), HER2, and MET kinase [7,16,20,34]. Such internalization may be useful for delivering antibody-drug conjugates into cells, and a few BpAb-drug conjugates against HER2 are currently undergoing clinical trials [8,11]. In addition, some biparatopic proteins can lock the structure of an antigen, resulting in structure-dependent effects such as agonism or antagonism (Fig.…”

“…Biparatopic antibodies (BpAbs) have been known for almost 30 years [5], but it was not until recently that technological advances [6] allowed the development of biparatopic antibodies with sufficient quality for development into drugs. Currently, two BpAbs against human epidermal growth factor receptor 2 (HER2) are undergoing clinical trial, with one being developed as an antibody-drug conjugate [8,9] and the other being developed as both a naked antibody and an antibody-drug conjugate [10,11]. In addition, one biparatopic DARPin against HER2 is also undergoing clinical trial [12].…”

Novel HER2–targeted therapies for HER2–positive metastatic breast cancer

“…In vivo antitumor activity in patient-derived xenograft models has been demonstrated in cell lines with high and low HER2 levels. 46 A phase 1 dose-finding study with ZW49 is currently ongoing (A Dose Finding Study of ZQ49 in Patients With HER2-Positive Cancers; ClinicalTrials.gov identifier NCT03821233).…”

The “Utility” of Highly Toxic Marine-Sourced Compounds

“…It is currently in a Phase I study under NCT03821233—“ A Dose Finding Study of ZW49 in Patients with HER2-Positive Cancers ”—with patients being actively recruited. The actual structure of the “warhead” has not been formally divulged, but a search of the literature yielded two abstracts presented in 2018 [40,41], which when coupled to information contained in a patent application (WO 2015/095953A1) yielded the basic structure shown (Figure 4; 19 ), a variation on MMAE. The website of Zymeworks implies that there are other potential warheads also under development.…”