5283 - Preclinical pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABN401, a highly selective Met inhibitor, in gastric and non-small-cell lung cancer models

Background

ABN401 is a highly selective best-in-class Met inhibitor that is targeting MET-driven cancers. Met which is also known as a hepatocyte growth factor (HGF) receptor is encoded by the MET gene. MET alterations, including amplification and mutation, and Met overexpression are well known for tumorigenic transformation, tumor growth, angiogenesis, invasion, and metastasis in several cancer types, including gastric and non-small-cell lung cancer (NSCLC). ABN401 shows significant MET signaling inhibition in in vitro and in vivo preclinical studies, especially for cell lines, xenograft, and PDx models which have high MET amplification and/or MET exon 14 deletion.

Methods

In this study, to confirm the pharmacokinetic and pharmocodynamic correlation of ABN401, gastric cancer and NSCLC xenograft models were used. SNU-5, a gastric cancer cell line and EBC-1, a NSCLC cell line both of which has high MET amplification, were used for the xenograft model and dosed at 10 mg/kg and 30 mg/kg of ABN401 by oral administration. Pharmacokinetic parameters were analyzed in both plasma and tumor tissue samples. Pharmacodynamic biomarkers including Met and phospho-Met (T1234/1235) and downstream signaling were analyzed by immunoblotting. In addition, an expression of Met and phospho-Met were analyzed by immunohistochemistry.

Results

The PK results demonstrated that in both gastric and NSCLC xenograft models ABN401 drug was readily distributed to tumor tissues. According to both PD studies, ABN401 showed inhibitory effects of Met and downstream signaling in a time dependent manner for both cancer types. There was also correlated between the PK parameters in plasma and tumor samples and pharmacodynamics studies.

Conclusions

This preclinical PK/PD correlation study of ABN401 provides evidence for human dose predictions and dosing strategy for clinical studies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Abion Inc.

Disclosure

All authors have declared no conflicts of interest.