Radiopharmacologic screening of antibodies to the unshed ectodomain of MUC16 in ovarian cancer identifies a lead candidate for clinical translation Journal Article

Authors: Nemieboka, B.; Sharma, S. K.; Rao, T. D.; Edwards, K. J.; Yan, S.; Wang, P.; Ragupathi, A.; Piersigilli, A.; Spriggs, D. R.; Lewis, J. S.
Article Title: Radiopharmacologic screening of antibodies to the unshed ectodomain of MUC16 in ovarian cancer identifies a lead candidate for clinical translation
Abstract: Introduction: Despite its limitations, CA125 remains the most widely used biomarker for the diagnosis and treatment monitoring of ovarian cancer. Targeting the unshed portion of serum biomarkers such as CA125/MUC16 may afford more specific imaging and targeting of MUC16-positive tumors in High Grade Serous Ovarian Cancer (HGSOC) patients. Methods: Six monoclonal antibodies raised against the 58 amino acid sequence between the extracellular cleavage site and the transmembrane region of MUC16 were radiolabeled with [89Zr]Zr4+. The radioimmunoconjugates were evaluated in vitro for molar activities, target binding affinity, cellular internalization and serum stability. In vivo characterization was performed via longitudinal positron emission tomography (PET) imaging and ex vivo biodistribution studies in mice bearing subcutaneous xenografts of SKOV3 cells transfected with the proximal 114 amino-acids of MUC16 carboxy-terminus (SKOV3+). Results: In vitro screening identified 9C9 and 4H11 as the lead antibody candidates based on their comparable binding affinities, serum stability and cellular internalization profiles. Despite an identical molecular footprint for binding to MUC16, [89Zr]Zr-DFO-4H11 yielded a more favorable in vivo radiopharmacologic profile. Furthermore, a humanized variant of 4H11 capable of binding MUC16 in vitro also yielded excellent in vivo profile in subcutaneous xenograft models of SKOV3+, OVCAR3 tumors and a patient-derived xenograft model representative of HGSOC. Conclusion: Radiopharmacologic screening of antibodies early during their development can provide crucial information pertinent to the in vitro characterization and in vivo pharmacokinetics. The favorable in vivo profile demonstrated by humanized 4H11 combined with the use of its murine predecessor for immunohistochemical staining of biopsied tumor tissues from HGSOC patients makes a unique pair of antibodies that is poised for clinical translation. © 2018 Elsevier Inc.
Keywords: immunohistochemistry; controlled study; unclassified drug; human cell; nonhuman; positron emission tomography; binding affinity; ovarian cancer; mouse; animal tissue; ovary cancer; animal experiment; animal model; immunoreactivity; enzyme linked immunosorbent assay; monoclonal antibody; amino acid sequence; isotope labeling; radiopharmaceutical agent; drug half life; protein structure; antigen binding; antibody detection; ex vivo study; ca125; zirconium-89; zirconium 89; protein cleavage; concentration response; internalization; mucin; molecular stability; mucin 16; human; female; article; 4h11; muc16 carboxy-terminus domain; monoclonal antibody 29g9; monoclonal antibody 4a2; monoclonal antibody 4a5; monoclonal antibody 4c7; monoclonal antibody 4h11; monoclonal antibody 9c9; sk-ov-3 cell line
Journal Title: Nuclear Medicine and Biology
Volume: 86-87
ISSN: 0969-8051
Publisher: Elsevier Science Inc.  
Date Published: 2020-07-01
Start Page: 9
End Page: 19
Language: English
DOI: 10.1016/j.nucmedbio.2020.04.006
PUBMED: 32403071
PROVIDER: scopus
Notes: Article -- Export Date: 1 June 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Dharmarao Thapi
    35 Thapi
  2. David R Spriggs
    323 Spriggs
  3. Jason S Lewis
    304 Lewis
  4. Sai Kiran   Sharma
    17 Sharma
  5. Kimberly Joanna Edwards
    12 Edwards