Preclinical development of a novel antibody conjugate for intraoperative detection of pancreatic cancer

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PROJECT SUMMARY Pancreatic cancer goes undiagnosed for a number of reasons including, anatomical location, vague and non- localizing symptoms, and a lack of adequately sensitive and specific biomarkers of disease. Combined with lack of blood biomarkers, early detection of pancreatic cancer remains a significant challenge. Unfortunately, this limits therapeutic strategies that are most efficacious. Consequently, approximately 20% of patients with pancreatic cancer are eligible for curative surgery. Of those patients, approximately 75% will have recurrent disease within the next 5 years, even those patients thought to have had negative margins. Despite the abysmal statistics for patients with pancreatic cancer, there are now several pancreatic cancer imaging probes in preclinical and clinical development to try to improve disease removal. Moreover, the increased use of neoadjugant or induction thereapy has resulted in additional patients that become eligible for surgery, if they restage at a lower stage. The opportunity to develop molecularly-targeted probes to pancreatic cancer to improve surgery and the increased numbers of patients that may benefit from surgery are key motivating factors for this project. Mucin-16 (MUC16) is an attractive marker for pancreatic cancer since it is highly overexpressed in malignancies, but not inflamed or healthy pancreas. Recently, we evaluated a murine antiMUC16 antibody, termed AR9.6, with cross-reactivity to human MUC16. In these preclinical studies, we demonstrated durable pancreatic cancer enhancement to at least 6 days postinjectin using IRDy800-labelled AR9.6 compared to an isotype control. Using a pancreatic cancer xenograft, AR9.6-IRDye800 was able to effectively enhance orthotopic and metastatic disease. Metastasis detection is an added benefit because it would prevent patients from unecessary surgery. Murine antibodies, however, are not suitable for clinical translation. Consequently, a humanized form of AR9.6 has now been developed by our collaborative team. An Initial investigation of IRDye800 conjugated to humanized AR9.6 suggests strong binding to MUC16 and in vivo targeting. Therefore, the goal of this project is to perform the preclinical development of NIRF-labelled, humanized AR9.6 to detect PDAC for improved R0 resection and to detect peritoneal metastasis. This goal will be addressed by three specific aims: To (1) develop and evaluate humanized AR9.6-NIRF for targeting of MUC16; (2) ascertain the preclinical contrast-enhancement and safety profile of humanized AR9.6-NIRF conjugates; and (3) demonstrate surgical efficacy of IRDye800-AR9.6 in preclinical models of pancreatic cancer. We hypothesize that the aberrant MUC16 overexpression in pancreatic cancer will allow specific targeting pancreatic cancer with fluorescently labelled huAR9.6. Completion of this research project will result in a fluorescence-guided surgery contrast agent that will be able to (1) improve the rate of R0 pancreatic cancer resections and (2) be able to identify peritoneal metastasis, which will prevent unnecessary surgery and allow optimized treatment strategy.