18F-FDG PET/CT imaging of pancreatic tumor xenografts to evaluate a novel anti-EMMPRIN mAb

Objectives To evaluate a novel mAb targeting human EMMPRIN with/without gemcitabine in an orthotopic pancreatic-tumor murine model via 18F-FDG PET/CT imaging.

Methods ATPLite assay was employed to measure killing efficacy of anti-EMMPRIN mAb in MIA PaCa-2 cells. Binding assay of Tc-99m-anti-EMMPRIN mAb was performed for MIA PaCa-2 cells (n=3). Six groups of SCID mice bearing orthotopic MIA PaCa-2 tumor xenografts were also used. Tc-99m-anti-EMMPRIN mAb or isotype control mAb were i.v. injected into groups 1 and 2 (n=5/group) respectively, and SPECT/CT imaging and biodistribution analysis followed at 4 hours and 24 hours post-injection respectively. Groups 3-6 (n=6/group) were i.p. injected with PBS, gemcitabine (120mg/kg BW), anti-EMMPRIN mAb (0.2mg), or a combination respectively, twice weekly for 2 weeks. 18F-FDG PET/CT imaging was performed weekly for 3 weeks, and intratumoral SUV and tumor-volume changes were quantified. Ki67 staining was performed on tumors of groups 3-6.

Results ATPLite assay indicated a modest cytotoxic effect of the novel mAb. Binding affinity (Kd) was 4.31±0.59 nM, while EMMPRIN number per cell was 582,000±56,000. SPECT imaging and biodistribution analysis confirmed specific uptake of Tc-99m-anti-EMMPRIN mAb in tumor (27.6±3.2 and 5.8±1.7 %ID/g for groups 1 and 2 respectively). Tumor SUV changes of groups 3-6 at 7 days after therapy initiation were 35±13, -19±19, 25±26, and -26±13% respectively, and 134±56, 60±32, 43±30, and -25±16% at day 14, while tumor-volume changes of groups 3-6 were 111±24, 72±26, 83±27, and 3±8% at day 7 and 399±48, 275±57, 204±34, and 35±8% at day 14 respectively. SUV change of group 6 was significantly lower than control, while tumor-volume changes of groups 5 and 6 were significantly lower than control. A significant decrease in cell proliferation was validated by combination therapy relative to control.

Conclusions The significantly reduced tumor SUV and proliferating cell density support the clinical usefulness of anti-EMMPRIN mAb for pancreatic cancer therapy