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ENHANCED VISUALIZATION OF COLONIC POLYPS USING FLUOROPHORE-CONJUGATED CLAUDIN-1 ANTIBODIES IN THE CPC-APC MOUSE MODEL
Shanglei Liu
*1, Kristin Cox
1, Siamak Amirfakhri
1, Sunidhi Jaiswal
2, Sumbal Talib
2, Mark Primeaux
2, Satish K. Singh
3, Joseph R. Pisegna
3, Aaron Mohs
2, Surinder Batra
2, Robert Hoffman
1, Punita Dhawan
2, Michael Bouvet
11Surgery, UC San Diego Health, San Diego, CA; 2University of Nebraska Medical Center, Omaha, NE; 3Veterans Health Administration Operations, Washington,
Introduction: Early detection and removal of polyps remains the best way to prevent colon cancer. However, polyps may be difficult to identify visually, with miss rates on colonoscopy between 9-27% for precancerous polyps up to 1 cm. Furthermore, hyperplastic polyps (HP) have little to no malignant potential but can be visually indistinguishable from sessile serrated adenomas (SSA). In the present study we used Tumor-Associated Glycoprotein 72 (TAG-72), Mucin 5AC (MUC5AC), and Claudin-1 (CLDN1) antibodies conjugated to near-infrared fluorophores to increase detection of precancerous polyps in adenomatous polyposis coli flox mice with a
Cdx2-Cre transgene (
CPC-APC) that develop dysplastic colon polyps with the goal of translation to human use.
Methods: Polyp formation was confirmed in CPC-APC at 12 weeks of age via mouse colonoscopy using the ColoView System. TAG-72, MUC5AC, and CLDN1 antibodies conjugated to IRDye800 (IR800) were administered intravenously at 100mg. Mice were sacrificed post injection at 48 hours. Ex-vivo colon imaging was performed using the Pearl® Trilogy (LICORbio™) fluorescence imaging systems. Polyp to background ratios (PBR) were calculated from colon background and the antibodies with the highest average PBR underwent further analysis at 48 vs 72 time points as well as different dosages of 50 mg, 100 mg, and 150 mg. Immunohistochemistry of the polyps was performed with standard methods.
Results: 12 mice were used for the experiment with a total of 62 polyps analyzed. The presence of observed polyps on gross examination was confirmed via histology. CLDN1-IR800 had the highest PBR at 7.6 ± 3.9 followed by MUC5AC-IR800 at 4.7 ± 4.1 and TAG72-IR800 at 3.6 ± 0.5. CLDN1-IR800 was then further analyzed at varying dosages and timing which demonstrated a significantly higher signal strength at 150 ug compared to 50 ug (0.07 ± 0.03 vs 0.01 ± 0.006, p<0.05) while having similar PBR between 48 vs 72 hours timepoints (see figure 1). Immunohistochemistry confirmed strong expression of CLDN1 within the polyps. The fluorescence signal could be definitively detected in polyps as small as 1 mm in diameter (see figure 2).
Conclusion:CLDN1-IR800 enhances polyp visualization using fluorescence imaging technology in CPC-APC mice. An average fluorescence signal intensity of 7 times higher than background can be detected in the polyp tissue of CPC-APC mice, making polyps as small as 1 mm visible using CLDN1-IR800. There is good signal quality within the tissue between 48-72 hours post injection making CLDN1-IR800 an ideal candidate for future clinical studies
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