M. A. Turner1, S. Amirfakhri1, H. Nishino1, N. Neel1, R. M. Hoffman1, 2, P. J. Yazaki3, M. Bouvet1 1University Of California – San Diego, Surgery, San Diego, CA, USA 2AntiCancer, Inc., San Diego, CA, USA 3City Of Hope National Medical Center, Beckman Research Institute, Duarte, CA, USA
Introduction:
Colorectal liver metastasis (CRLM) will develop in 60% of patients with colorectal cancer. For patients where a metastasectomy is indicated, the cure rate after CRLM resection is only 20%. Therefore new methods to improve R0 resection rates are critical. Fluorophore conjugated anti-carcinoembryonic antigen (CEA) antibodies have been shown to selectively label colorectal liver metastases but with limited tumor-to-liver ratio (TLR). The present study reports the use of a humanized anti-CEA antibody conjugated to a PEGylated near infrared (NIR) dye which can target liver metastasis in an orthotopic mouse model with high TLR.
Methods:
The humanized anti-CEA hT84.66-M5A monoclonal antibody was conjugated in the hinge to a long chain PEG molecule with a lysine sidearm containing the near infrared IR800 dye to synthesize a conjugate termed M5A-IR800 Sidewinder. The human colon cancer LS174T cell line was surgically orthotopically implanted (SOI) in the liver and cecum of nude mice using previously grown subcutaneous tumors. Dosing and timing of imaging of orthotopic models was determined based on subcutaneous model imaging. In-vivo imaging was performed with the Pearl Trilogy Imager (LICOR, Lincoln, NE) with excitement at 800 nm.
Results:
M5A-IR800 Sidewinder brightly and selectively imaged LS174T tumors in all 3 models. The subcutaneous model had the highest tumor to background ratio (TBR) at 72 hours after receiving 75 µg of M5A-IR800 Sidewinder. The cecal orthotopic models had an average TBR of 10.1 after 72 hours. The liver orthotopic model had an average TLR of 7.5 at 72 hours.
Conclusion:
The anti-CEA M5A-IR800 Sidewinder brightly and selectively targeted LS174T colon cancer in the liver providing clear distinction between tumor and normal tissue. This is an improvement over the non-PEGylated M5A-IR800 previously reported which successfully targeted LS174T colon cancer in a cecal orthotopic murine model but had high background signal in the liver. M5A-IR800 Sidewinder is a promising candidate for clinical use in fluorescence-guided surgery to detect CRLM and improve R0 resection.
