Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer Journal Article

Authors: Houghton, J. L.; Zeglis, B. M.; Abdel-Atti, D.; Aggeler, R.; Sawada, R.; Agnew, B. J.; Scholz, W. W.; Lewis, J. S.
Article Title: Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer
Abstract: Molecular imaging agents for preoperative positron emission tomography (PET) and near-infrared fluorescent (NIRF)-guided delineation of surgical margins could greatly enhance the diagnosis, staging, and resection of pancreatic cancer. PET and NIRF optical imaging offer complementary clinical applications, enabling the noninvasive whole-body imaging to localize disease and identification of tumor margins during surgery, respectively. We report the development of PET, NIRF, and dual-modal (PET/NIRF) imaging agents, using 5B1, a fully human monoclonal antibody that targets CA19.9, a well-established pancreatic cancer biomarker. Desferrioxamine (DFO) and/or a NIRF dye (FL) were conjugated to the heavy-chain glycans of 5B1, using a robust and reproducible site-specific (ss) labeling methodology to generate three constructs (ssDFO-5B1, ssFL-5B1, and ssdual-5B1) in which the immunoreactivity was not affected by the conjugation of either label. Each construct was evaluated in a s.c. xenograft model, using CA19.9-positive (BxPC3) and -negative (MIAPaCa-2) human pancreatic cancer cell lines. Each construct showed exceptional uptake and contrast in antigen-positive tumors with negligible nonspecific uptake in antigen-negative tumors. Additionally, the dual-modal construct was evaluated in an orthotopic murine pancreatic cancer model, using the human pancreatic cancer cell line, Suit-2. The ssdual-5B1 demonstrated a remarkable capacity to delineate metastases and to map the sentinel lymph nodes via tandem PET-computed tomography (PET/CT) and NIRF imaging. Fluorescence microscopy, histopathology, and autoradiography were performed on representative sections of excised tumors to visualize the distribution of the constructs within the tumors. These imaging tools have tremendous potential for further preclinical research and for clinical translation.
Keywords: unclassified drug; human cell; nonhuman; pancreas cancer; positron emission tomography; sentinel lymph node; pancreas; mouse; spleen; ca 19-9 antigen; fluorescence; animal experiment; cancer cell culture; in vitro study; molecular imaging; immunoreactivity; monoclonal antibody; liver; kidney; drug distribution; computer assisted emission tomography; bone; lung; radiopharmaceutical agent; pet imaging; pancreatic cancer; dye; small intestine; heart; deferoxamine; autoradiography; stomach; polyacrylamide gel electrophoresis; muscle; antibody conjugate; glycan; large intestine; human; priority journal; article; ca19.9; deferoxamine 5b1 zr 89; near infrared fluorescence
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 112
Issue: 52
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2015-12-29
Start Page: 15850
End Page: 15855
Language: English
DOI: 10.1073/pnas.1506542112
PROVIDER: scopus
PMCID: PMC4702985
PUBMED: 26668398
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Brian Zeglis
    92 Zeglis
  2. Jason S Lewis
    382 Lewis