Abstract 2597: BGB-3111 is a novel and highly selective Bruton's tyrosine kinase (BTK) inhibitor
Authors: Li Na , Sun Zhijian , Liu Ye , Guo Mingming , Zhang Yilu , Zhou Dongping , Zhang Bo , Su Dan , Zhang Shuo , Han Jing , Gao Yajuan , Guo Yunhang , Wang Zhiwei , Wei Min , Luo Lusong , Wang Lai 
Published: August 2015

Abstract
BTK, an essential component of the BCR pathway, has emerged as novel target in the treatment of B-cell malignancies. Although Ibrutinib, the first-in-class irreversible inhibitor of BTK, showed promising clinical activity, recent study revealed that ibrutinib could antagonize rituximab induced antigen-dependent cell-mediated cytotoxicity (ADCC) by inhibiting ITK kinase activity (Kohrt et. al., 2013), suggesting the potential limitations in its clinical application. BGB-3111 is a novel, highly selective, second generation BTK inhibitor, currently under clinical investigation in hematological cancers. Its biochemical, cellular and in vivo activities were reported in this study.
In both biochemical and cellular assays, BGB-3111 demonstrated nanomolar BTK inhibition activity. In several MCL and DLBCL cell lines, BGB-3111 inhibited BCR aggregation-triggered BTK autophosphorylation, blocked downstream PLC-γ2 signaling, and potently inhibited cell proliferation. In comparison with ibrutinib, BGB-3111 showed much more restricted off-target activities against a panel of kinases, including ITK. While ibrutinib significantly inhibited rituximab-induced NK cell IFN-γ secretion and in vitro cytotoxicity on mantle cell lymphoma cells, BGB-3111 was at least 10-fold weaker than ibrutinib in inhibiting rituximab induced ADCC, consistent with its weak ITK inhibition activity.
In mouse BTK occupancy assays, treatment with BGB-3111 resulted in a dose-dependent BTK occupancy and showed about 3-fold more potency than ibrutinib in target organs, including PBMC and spleen. BGB-3111 induced dose-dependent anti-tumor effects against REC-1 MCL xenografts engrafted either subcutaneously or systemically via tail vein injection in mice. In the subcutaneous xenografts, BGB-3111 at 2.5 mg/kg BID showed similar activity as ibrutinib at 50 mg/kg QD, its clinical relevant dose. In the systemic model, the median survival of BGB-3111 25 mg/kg BID group was significantly longer than those of both ibrutinib 50 mg/kg QD and BID groups. In an ABC-subtype DLBCL (TMD-8) subcutaneous xenograft model, BGB-3111 also demonstrated better anti-tumor activity than ibrutinib. Preliminary 14-day toxicity study in rats showed that BGB-3111 was very well tolerated and maximal tolerate dose (MTD) was not reached when it was dosed up to 250mg/kg/day.
In conclusion, BGB-3111 is a highly selective and potent BTK inhibitor. It does not affect rituximab-induced ADCC and demonstrated better efficacy than ibrutinib in xenograft models, supporting further clinical investigation of this compound both as single agent and in combination with anti-CD20 antibodies in hematological cancers.
Citation Format: Na Li, Zhijian Sun, Ye Liu, Mingming Guo, Yilu Zhang, Dongping Zhou, Bo Zhang, Dan Su, Shuo Zhang, Jing Han, Yajuan Gao, Yunhang Guo, Zhiwei Wang, Min Wei, Lusong Luo, Lai Wang. BGB-3111 is a novel and highly selective Bruton's tyrosine kinase (BTK) inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2597. doi:10.1158/1538-7445.AM2015-2597