TY - JOUR
T1 - Development of a MUC16-targeted near-infrared fluorescent antibody conjugate for intraoperative imaging of pancreatic cancer
AU - Olson, Madeline T.
AU - Wojtynek, Nicholas E.
AU - Talmon, Geoffrey A.
AU - Caffrey, Thomas C.
AU - Radhakrishnan, Prakash
AU - Ly, Quan P.
AU - Hollingsworth, Michael A.
AU - Mohs, Aaron M.
N1 - Funding Information:
The authors thank Dr. Denis Svechkarev for his assistance with optical probe development, Dr. Madi Madiyalakan (OncoQuest, Inc.) for his assistance with antibody acquisition, A.J. Crawford for her assistance with orthotopic surgical techniques, Paul Grandgenett and the Rapid Autopsy Program for providing patient samples, and Constance McKee (Manzanita Pharmaceuticals, Inc.) for providing the Fluobeam imaging system. This work was supported by NIH grants, U01CA210240 (to M.A. Hollingsworth), P30CA036727 (Fred and Pamela Buffett Cancer Center at UNMC), CA208108 (to P. Radhakrishnan), P50CA127297 (SPORE in Pancreatic Cancer), 5R50CA211462 (NCI Research Specialist), T32CA009476 (to M.T. Olson), and the Nebraska Research Initiative (to A.M. Mohs).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Surgical resection is currently the only potentially curative option for patients with pancreatic cancer. However, the 5-year survival rate after resection is only 25%, due in part to high rates of R1 resections, in which cells are left behind at the surgical margin, resulting in disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to reduce incomplete resections and improve intraoperative assessment of cancer. Mucin-16 (MUC16), a protein biomarker highly overexpressed in pancreatic cancer, is a potential target for FGS. In this study, we developed a fluorescent MUC16-targeted antibody probe, AR9.6-IRDye800, for image-guided resection of pancreatic cancer. We demonstrated the efficacy of this probe to bind human pancreatic cancer cell lines in vitro and in vivo. In an orthotopic xenograft model, AR9.6-IRDye800 exhibited superior fluorescence enhancement of tumors and lower signal in critical background organs in comparison to a nonspecific IgG control. The results of this study suggest that AR9.6-IRDye800 has potential for success as a probe for FGS in pancreatic cancer patients, and MUC16 is a feasible target for intraoperative imaging.
AB - Surgical resection is currently the only potentially curative option for patients with pancreatic cancer. However, the 5-year survival rate after resection is only 25%, due in part to high rates of R1 resections, in which cells are left behind at the surgical margin, resulting in disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to reduce incomplete resections and improve intraoperative assessment of cancer. Mucin-16 (MUC16), a protein biomarker highly overexpressed in pancreatic cancer, is a potential target for FGS. In this study, we developed a fluorescent MUC16-targeted antibody probe, AR9.6-IRDye800, for image-guided resection of pancreatic cancer. We demonstrated the efficacy of this probe to bind human pancreatic cancer cell lines in vitro and in vivo. In an orthotopic xenograft model, AR9.6-IRDye800 exhibited superior fluorescence enhancement of tumors and lower signal in critical background organs in comparison to a nonspecific IgG control. The results of this study suggest that AR9.6-IRDye800 has potential for success as a probe for FGS in pancreatic cancer patients, and MUC16 is a feasible target for intraoperative imaging.
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U2 - 10.1158/1535-7163.MCT-20-0033
DO - 10.1158/1535-7163.MCT-20-0033
M3 - Article
C2 - 32404409
AN - SCOPUS:85089165775
SN - 1535-7163
VL - 19
SP - 1670
EP - 1681
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 8
ER -