TY - JOUR
T1 - ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody
AU - Sharma, Sai Kiran
AU - Mack, Kyeara N.
AU - Piersigilli, Alessandra
AU - Pourat, Jacob
AU - Edwards, Kimberly J.
AU - Keinänen, Outi
AU - Jiao, Maria S.
AU - Zhao, Huiyong
AU - White, Brandy
AU - Brooks, Cory L.
AU - de Stanchina, Elisa
AU - Madiyalakan, Madi R.
AU - Hollingsworth, Michael A.
AU - Radhakrishnan, Prakash
AU - Lewis, Jason S.
AU - Zeglis, Brian M.
N1 - Funding Information:
C.L. Brooks reports grants from Quest PharmaTech Inc. during the conduct of the study and grants from Quest PharmaTech Inc. outside the submitted work. R. Madiyalakan reports personal fees from Quest PharmaTech Inc during the conduct of the study; personal fees from OncoQuest Inc outside the submitted work; and has a patent 17048119 pending to Quest PharmaTech. M.A. Hollingsworth reports grants from the NCI during the conduct of the study; other support from OncoCare Therapeutics outside the submitted work; and has a patent 62669058 issued. P. Radhakrishnan reports grants from the NCI during the conduct of the study; other support from OncoCare Therapeutics outside the submitted work; and has a patent 62669058 issued. J.S. Lewis reports grants from NIH, Emerson
Funding Information:
We gratefully acknowledge Dr. Sebastien Monette for help with ex vivo histopathologic examination and Dr. Eric E. Gardner for providing the luciferase-transfected Capan-2 cell line that was used for the development of the orthotopic pancreatic cancer xenograft model. This work was supported by the MSKCC Small Animal Imaging Core Facility (funded in part by the NIH Small-Animal Imaging Research Program Grant R24 CA83084 and NIH Center Grant P30 CA08748) as well as the Radiochemistry and Molecular Imaging Probe core and the Tri-Institutional Laboratory of Comparative Pathology, which are also funded in part by NIH grant P30 CA08748. This work was also supported by the funds awarded to J.S. Lewis from the NIH (R35CA232130), the Emerson Collective Cancer Research Fund, the Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center. S.K. Sharma acknowledges the Tow Foundation for a Postdoctoral Fellowship Award and funding to support this work. B.M. Zeglis, C.L. Brooks, P. Radhakrishnan, and M.A. Hollingsworth also acknowledge the NIH for support (B.M. Zeglis: R01CA240963, U01CA221046, R01CA204167, R21EB030275, and R01CA244327; C.L. Brooks: R15CA242349; P. Radhakrishnan and M.A. Hollings-worth: CA208108, P01CA217798, and U01CA237629).
Publisher Copyright:
© 2021 The Authors.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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 mucintargeted 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 89Zr-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 89Zr-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.
AB - 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 mucintargeted 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 89Zr-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 89Zr-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.
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U2 - 10.1158/1078-0432.CCR-21-1798
DO - 10.1158/1078-0432.CCR-21-1798
M3 - Article
C2 - 34907079
AN - SCOPUS:85123498235
VL - 28
SP - 948
EP - 959
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -