Abstract 4575: Novel monoclonal antibody targeting EMMPRIN for pancreatic cancer therapy

Abstract

Abstract Purpose: To evaluate a novel monoclonal antibody targeting extracelluar matrix metalloproteinase (EMMPRIN) in orthotopic pancreatic-cancer murine models. Methods: In vitro cytotoxic assay of anti-EMMPRIN mAb was conducted with MIA PaCA-2 and PANC-1 human pancreatic-cancer cell lines. Binding assay of Tc-99m labeled anti-EMMPRIN mAb was repeated three times independently for MIA PaCa-2 cells or MIA PaCa-2 cells silenced for EMMPRIN gene expression by siRNA. For the in vivo animal study, MIA PaCa-2 cells were implanted in groups 1-6, while EMMPRIN silenced cells were implanted in group 7. For groups 1-4 (solid tumor model, n=5-7/group), dosing started at 21 days after cell implantation, while dosing started immediately after cell implantation for groups 5-7 (residual tumor model, n=10-12/group); groups 1 and 2 were injected with PBS and anti-EMMPRIN mAB (0.2mg) twice weekly for 3 weeks respectively; ultrasound imaging (USI) was applied at days 21, 28, 35, and 42 to determine tumor volume. Groups 3 and 4 were injected with PBS and anti-EMMPRIN mAb (1mg) twice weekly for 2 weeks, respectively; USI and diffusion-weighted MRI were applied at days 21, 28, and 35. Groups 5 and 6 were injected with PBS and anti-EMMPRIN mAB (0.2mg) twice weekly for 3 weeks respectively; group 7 was injected with PBS during the same time. For groups 5-7, USI was applied at 15 and 21 days post cell injection. Ki-67 and TUNEL staining were conducted on tumor sections from groups 1 and 2 at the study end. Results: In vitro treatment with antibody alone did not demonstrate significant cytotoxic effect in either cell line. The Kd in MIA PaCa-2 cells was 4.31±0.59 (mean ± SE) nM, which was not statistically different from that in EMMPRIN silenced cells. The average number of EMMPRIN per MIA PaCa-2 cell was 582,000±56,000, significantly higher than that per EMMPRIN silenced cells at 220,000±89,000 (p=0.03). Tumor-volume increases of group 1 relative to day 21 were 282±33, 495±107, and 725±166% at days 28, 35, and 42, while those of group 2 were 191±7, 263±27, and 429±39%; groups 1 and 2 were statistically different at day 28 (p=0.03), not at the other days. Group 3 showed an increase in tumor-volume of 317±55 and 505±96% at days 28 and 35 respectively, while those in group 4 were 189±27 and 244±41%; groups 3 and 4 were statistically different at day 35 (p=0.04), but not at day 28. Mean intra-tumoral ADC change of group 4 was not statistically significant from that of group 3. Tumor volumes of groups 5-7 were 66±17, 21±5, and 4±2mm3 at day 15, while those at day 21 were 240±41, 80±15, and 15±4mm3, which represent statistical differences among groups at each day (p<0.05). Proliferating cell density of group 2 was significantly lower than that of group 1 (p=0.01), while apoptotic cell densities were not. Conclusion: Tumor growth was successfully arrested following treatment with anti-EMMPRIN antibody for both solid- and residual-tumor models, consistent with reduced proliferating cell density. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4575. doi:10.1158/1538-7445.AM2011-4575