ImmunoPET of ovarian and pancreatic cancer with AR9.6, a novel MUC16-targeted therapeutic antibody Journal Article


Authors: Sharma, S. K.; Mack, K. N.; Piersigilli, A.; Pourat, J.; Edwards, K. J.; Keinänen, O.; Jiao, M. S.; Zhao, H.; White, B.; Brooks, C. L.; de Stanchina, E.; Madiyalakan, M. R.; Hollingsworth, M. A.; Radhakrishnan, P.; Lewis, J. S.; Zeglis, B. M.
Article Title: ImmunoPET of ovarian and pancreatic cancer with AR9.6, a novel MUC16-targeted therapeutic antibody
Abstract: Purpose: Advances in our understanding of the contribution of aberrant glycosylation to the pro-oncogenic signaling and metastasis of tumor cells have reinvigorated the development of mucin-targeted therapies. Here, we validate the tumor-targeting ability of a novel monoclonal antibody (mAb), AR9.6, that binds MUC16 and abrogates downstream oncogenic signaling to confer a therapeutic response. Experimental Design: The in vitro and ex vivo validation of the binding of AR9.6 to MUC16 was achieved via flow cytometry, radioligand binding assay (RBA), and immunohistochemistry (IHC). The in vivo MUC16 targeting of AR9.6 was validated by creating a Zr-89-labeled radioimmunoconjugate of the mAb and utilizing immunoPET and ex vivo biodistribution studies in xenograft models of human ovarian and pancreatic cancer. Results: Flow cytometry, RBA, and IHC revealed that AR9.6 binds to ovarian and pancreatic cancer cells in an MUC16-dependent manner. The in vivo radiopharmacologic profile of Zr-89-labeled AR9.6 in mice bearing ovarian and pancreatic cancer xenografts confirmed the MUC16-dependent tumor targeting by the radioimmunoconjugate. Radioactivity uptake was also observed in the distant lymph nodes (LNs) of mice bearing xenografts with high levels of MUC16 expression (i.e., OVCAR3 and Capan-2). IHC analyses of these PET-positive LNs highlighted the presence of shed antigen as well as necrotic, phagocytized, and actively infiltrating neoplastic cells. The humanization of AR9.6 did not compromise its ability to target MUC16-expressing tumors. Conclusions: The unique therapeutic mechanism of AR9.6 combined with its excellent in vivo tumor targeting makes it a highly promising theranostic agent. huAR9.6 is poised for clinical translation to impact the management of metastatic ovarian and pancreatic cancers.
Keywords: antigen; immunotherapy; pet; monoclonal-antibodies; cell; muc16; mab-b43.13
Journal Title: Clinical Cancer Research
Volume: 28
Issue: 5
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2022-03-01
Start Page: 948
End Page: 959
Language: English
ACCESSION: WOS:000767325400001
DOI: 10.1158/1078-0432.Ccr-21-1798
PROVIDER: wos
PMCID: PMC8898287
PUBMED: 34907079
Notes: Article -- Source: Wos
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MSK Authors
  1. Brian Zeglis
    120 Zeglis
  2. Jason S Lewis
    461 Lewis
  3. Sai Kiran   Sharma
    25 Sharma
  4. Kimberly Joanna Edwards
    17 Edwards
  5. HuiYong   Zhao
    26 Zhao
  6. Jacob   Pourat
    9 Pourat
  7. Kyeara Mack
    11 Mack