Synergistic anti-tumor effect with combination of a novel small molecule Smac mimetic compound (SM-164) and agonist TRAIL-R monoclonal Abs (Mapatumumab & Lexatumumab).

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4871 Background: Agonism of the TRAIL receptor (TRAIL-R) pathway by monoclonal antibodies (mAbs) is a promising biologic therapy currently under clinical development for the treatment of cancer. As part of our small molecule development program synergy was demonstrated when small molecule Smac mimetic compounds were combined with the TRAIL ligand in both TRAIL-sensitive and TRAIL-resistant cell lines. In the current study we investigated the effect of combined treatment of the dimeric Smac mimetic compound SM-164 and TRAIL-R agonist mAbs, Mapatumumab and Lexatumumab against several human cancer cell lines. Methods: Cell growth inhibition was measured using WST-based assays and Cell Titer Glo. The CalcuSyn program was used to assess drug interaction by calculating the Combination Index (CI) value. Xenograft models were used to determine the in vivo anti-tumor activity of SM-164 and Mapatumumab or Lexatumumab. Summary: We tested cell growth inhibition of SM-164 and either Mapatumumab or Lexatumumab in prostate, breast, lung, esophageal and colon cancer cell lines. Strong synergy was observed with combinations of SM-164 and both TRAIL-R mAbs at ineffective doses for both single agents in PC-3 (CI<0.004), MDA-231 (CI<0.005) and HCT-116 (CI<0.02) cancer cells. Significant changes in IC50 were observed in those cell lines treated with the combinations consisting of either TRAIL-R mAb and SM-164. These results demonstrate that the combination of SM-164 and TRAIL-R mAbs has synergistic cytotoxic effects across a range of human tumor cell lines. In vivo efficacy was evaluated in MDA-231 and HCT-116 xenografts. Complete tumor regression (eight out of eight tumors) was observed only in the combination of SM-164 (5 mg/kg, QD x 5/wk, 2 wks), with Lexatumumab (2.5 mg/kg, 2x/wk, 2 wks), with a T/C value of 0% in the MDA-231 xenograft. Lower anti-tumor activity was observed with single-agent, with T/C values of 79% for SM-164, and 36% for Lexatumumab. The combination of Mapatumumab and SM-164 had been evaluated in two xenograft models. In MDA-231 xenograft model, the combination of Mapatumumab (2.5 mg/kg) and SM-164 (5 mg/kg) resulted in a T/C of 36%, compared to 88% and 79% for both single agent groups. In HCT-116 xenograft model combination of Mapatumumab (10 mg/kg) and SM-164 (5 mg/kg) induced significant tumor growth inhibition when compared to either of the single-agent treatment groups. Our results show that combination treatment of SM-164 and Lexatumumab causes immediate and sustained tumor regression in vivo in mice carrying MDA-231 xenografts . Minimal changes in body weight with the combination regimen. Conclusion: Targeting the apoptosis pathways with small molecule Smac mimetics in combination with agonist TRAIL-R mAbs provides a novel therapy that holds great potential in overcoming TRAIL resistance in a broad range of human malignancies.