Abstract 5498: Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The tridentate selective high affinity ligand (SHAL) SH7139 is selectively cytotoxic at sub-nanomolar concentrations to lymphoma cells over-expressing HLA-DR10. Recent studies suggest SH7139 is unusual in that multiple mechanisms may contribute to its killing of targeted tumor cells. Electron microscopy data suggest one mechanism involves the triggering of a cell-signaling event that leads to the induction of apoptosis when SH7139 binds to a unique site on HLA-DR10 (the same region/epitope recognized by the Lym-1 antibody). A second mechanism appears to involve the internalization of SH7139 by tumor cells and the subsequent release of it's three individual recognition elements/ligands by metabolic cleavage of the amide bonds that link them to a scaffold (a unique feature of SHALs). Analogous to the process of toxin delivery by antibody-drug conjugates, once these ligands are released inside the cell, they can each inhibit a different key pathway required for tumor cell survival. Additional metabolic conversions of these ligands by the tumor cells to toxic metabolites may also contribute to cell killing through the inhibition of a number of other critical cellular functions. The third proposed mechanism is based on the fact that the target receptor HLA-DR10 participates in the activation of T-cells. The binding of SH7139 to the antigen binding pocket of HLA-DR10 may trigger an immune response that targets the cancer cells with bound drug. All three proposed mechanisms are currently under study. If multiple diverse mechanisms of action contribute to SH7139's cytotoxicity, it will be extremely difficult for lymphoma cells to develop a resistance to the drug. 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: Monique Cosman Balhorn, Saphon Hok, Rod Balhorn. Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139. [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 5498. doi:10.1158/1538-7445.AM2015-5498