Abstract 4494: Physical and metabolic stability of SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10

Abstract

Abstract Oncology drugs must remain sufficiently stable during storage, following formulation, after introduction into the bloodstream and during their entry into cells to ensure accurate dosing. After uptake by cells, the biologically active form of the drug also needs to remain stable long enough to achieve an optimal anti-tumor response. SH7139, our most advanced small molecule therapeutic for non-Hodgkin's lymphoma, was designed to target and bind to a unique site on HLA-DR10, a cell surface receptor found on B-cell lymphocytes and over-expressed on many B-cell derived malignancies. Previous studies conducted with lymphoma and other cell lines have shown that SH7139 binds selectively and is highly cytotoxic only to tumor cells expressing HLA-DR10. SH7139 has also been shown to be highly effective in treating human Burkitt's lymphoma (Raji) in a mouse xenograft model. All of the studies performed to date suggest SH7139 meets the necessary stability requirements. No degradation of the drug has been observed during storage at -20°C over a period of 30 months. SH7139 is also stable when dissolved in water or saline over a wide range of pH (pH 2 to 9). Instability is only observed at a highly alkaline pH. At pH 12, a slow auto-catalytic cleavage reaction releases a fragment of one of the recognition elements. The amide bonds linking the three recognition elements to the lysine and miniPEG scaffold of SH7139 remain stable in plasma. Hepatocytes metabolize SH7139 at a moderate rate and produce two primary metabolites. The same metabolites are produced by both canine and human hepatocytes, and the smaller product, 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyaniline, is rapidly glucuronidated to facilitate its excretion. Both the physical and metabolic stability of SH7139 are consistent with the drug's observed anti-lymphoma activity. This research was supported by the National Cancer Institute Phase II SBIR award R44CA159843-02 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. Citation Format: Rod Balhorn, Saphon Hok, Monique Cosman Balhorn. Physical and metabolic stability of SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10. [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 4494. doi:10.1158/1538-7445.AM2015-4494