Abstract 3787: Pharmacokinetics and pharmacodynamics of AV-203, a humanized anti-ERBB3 antibody

Abstract

Abstract ERBB3 is widely expressed in human carcinomas, and its over expression is associated with poor prognosis in patients with various carcinomas, (i.e., breast, ovarian, prostate, colorectal, pancreatic, gastric, and head and neck cancers). The presence of ERBB3 correlates with local to distal metastasis in lung, gastric, and colorectal cancers as well as bone invasion in prostate cancer. Activation of ERBB3 is also implicated in the development of resistance to current cancer treatments. Due to its lack of kinase activity, the activation of the ERBB3 receptor is dependent on heterodimerization with active receptor tyrosine kinases (RTKs). The recruitment of ERBB3 into active, heterodimer complexes is mediated by its ligand Neuregulin-1 (NRG-1) or by amplified, over expressed RTKs in a ligand independent manner. Therefore, ERBB3 can crosstalk with most major receptors involved in cancer development and maintenance such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and c-MET. AV-203 is a potent, humanized anti-ERBB3 antibody that inhibits both ligand-dependent and independent activation of ERBB3 both in vitro and in vivo. Pharmacokinetics and pharmacodynamics of AV-203 were characterized in mice using the A549 non-small cell lung cancer xenograft model. AV-203 administered IV in mice exhibits acceptable pharmacokinetics supporting preclinical efficacy studies. AV-203 administered IV in A549 NSCLC xenograft tumor bearing mice had lower serum AUC than naïve mice, demonstrating that the presence of human ErbB3 may alter the PK parameters of AV-203. In evaluating pharmacodynamics in vivo, AV-203 was able to down regulate total ERBB3 and ERBB3 signaling in A549 tumors in a time-dependent manner. Inhibition of ERBB3 signaling correlated with significant dose-dependent tumor growth inhibition in the A549 xenograft model. Dose scheduling studies with the constant AV-203 dose of 2.5 mg/kg revealed that the most efficacious schedule is the more frequent dosing at Q3D. In comparing the total dose of 10 mg/kg per 14 day cycle, at varying dose per injection and frequency, AV-203 resulted in significant tumor growth inhibition at all dose schedules. These data conclude that the efficacy of AV-203 is driven by total drug exposure and that AV-203 is not dependent on Cmax for its antitumor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3787. doi:1538-7445.AM2012-3787