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Preclinical 89Zr-Immunopet of High Grade Serous Ovarian Cancer and Lymph Node Metastasis Sai Kiran Sharma1,3, Kuntal K

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Preclinical 89Zr-Immunopet of High Grade Serous Ovarian Cancer and Lymph Node Metastasis Sai Kiran Sharma1,3, Kuntal K Journal of Nuclear Medicine, published on February 2, 2016 as doi:10.2967/jnumed.115.167072 Preclinical 89Zr-immunoPET of High Grade Serous Ovarian Cancer and Lymph Node Metastasis Sai Kiran Sharma1,3, Kuntal K. Sevak1, Sebastien Monette2, Sean D. Carlin1, James C. Knight3, Frank R. Wuest3, Evis Sala4, Brian M. Zeglis5,*, Jason S. Lewis1,* 1 Department of Radiology and the Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, NY, USA 2 Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, and The Rockefeller University, NY, USA 3 Department of Oncology, University of Alberta, AB, Canada 4 Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA 5 Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, NY, USA First Author: Sai Kiran Sharma, Department of Radiology, Zuckerman Research Center, 417 East 68th Street, 394, New York, NY, 10065, USA Email: [email protected] Phone: +1.212.896.0484. Fax: +1.646.888.3059 *Co-Corresponding Authors: Brian M. Zeglis, Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, NY, 10021, USA Email: [email protected] Phone: +1.212.896.0443. Fax: +1.212.772.5332 Jason S. Lewis, Department of Radiology, 1275 York Avenue, Memorial Sloan Kettering Cancer Center, NY, 10065, USA Email: [email protected] Phone: +1.646.888.3038. Fax: +1.646.888.3059 1 Financial Support: The authors gratefully acknowledge the MSKCC Small Animal Imaging Core Facility, which is supported in part by NIH grant P30 CA08748. The authors would also like to thank the NIH (R00 CA1440138, BMZ), Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center, the Natural Sciences and Engineering Research Council of Canada, and the Dianne and Irving Kipnes Foundation. Word Count: 4998 Running Title: ImmunoPET of Ovarian Cancer 2 ABSTRACT The elevation of Cancer Antigen 125 (CA125) levels in the serum of asymptomatic patients precedes the radiological detection of high grade serous ovarian cancer (HGSOC) by at least 2 months and the final clinical diagnosis by 5 months. Positron Emission Tomography (PET) imaging of CA125 expression by ovarian cancer cells may enhance the evaluation of the extent of disease and provide a roadmap to surgery, as well as detect recurrence and metastases. Methods: 89Zr-labeled MAb-B43.13 was synthesized to target CA125 and evaluated via PET imaging and biodistribution studies in mice bearing OVCAR3 human ovarian adenocarcinoma xenografts. Ex vivo analysis of tumors and lymph nodes was carried out via autoradiography, histopathology, and immunohistochemistry. Results: PET imaging using 89Zr-DFO-MAb-B43.13 clearly delineated CA125-positive OVCAR3 xenografts as early as 24 h after the administration of the radioimmunoconjugate. Biodistribution studies revealed accretion of 89Zr-DFO-MAb-B43.13 in the OVCAR3 tumors, ultimately reaching 22.3 ± 6.3 %ID/g at 72 h post-injection. Most interestingly, activity concentrations >50 %ID/g were observed in the ipsilateral lymph nodes of the xenograft-bearing mice. Histopathological analysis of the immunoPET-positive lymph nodes revealed the presence of grossly metastasized ovarian cancer cells within the lymphoid tissues. In control experiments, only low-level, non-specific uptake of 89Zr-labeled isotype IgG was observed in OVCAR3 tumors; similarly, low activity concentrations of 89Zr-DFO-MAb-B43.13 accumulated in CA125- negative SKOV3 tumors. Conclusion: ImmunoPET with 89Zr-labeled MAb-B43.13 is a potential strategy for the non- invasive delineation of extent of disease and may add value in treatment planning and treatment monitoring of HGSOC. 3 KEYWORDS: CA125, Zirconium-89, Positron Emission Tomography, Ovarian Cancer 4 INTRODUCTION Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related deaths in women within the United States (1). Owing to the vague symptomatic progression of the disease, most patients present at advanced stages (III-IV) and often recur after primary cytoreductive surgery and platinum-based chemotherapy, yielding a dismal 5-year survival rate of 27% (1,2). HGSOC comprises the major malignant histotype (70%) of epithelial ovarian cancers (EOC) and bears a molecular signature in the overexpression of MUC16/CA125 – a serum biomarker for ovarian cancer (3). Indeed, among EOCs, the frequency of CA125 positivity is higher in serous histotypes than in mucinous or clear cell disease (4). In recurrent HGSOC, the elevation in serum CA125 levels precedes radiological detection by 3 months and predates the clinical presentation of symptoms and diagnosis by a median lag time of 5 months (3). However, elevated serum CA125 levels alone do not qualify as a criterion to initiate treatment in the absence of radiological evidence of recurrent disease. 10% of HGSOCs are reported to be biochemically silent (i.e. have normal serum CA125 levels), and 50% of patients with normal serum CA125 levels at the completion of chemotherapy are found to have active small volume disease during second-look surgery (5,6). At present, serum CA125 levels are quantified via immunoassays, which are often limited in their sensitivity and capability to provide information regarding the rate of antigen shedding and tumor growth in vivo (7). To complicate matters further, metastatic ovarian cancer cells are prone to spread to other parts of the body through the lymphatic system (8). To wit, lymph node (LN) involvement in HGSOC patients is observed in up to 25% of cases of early stage disease (I-II) and 75% of cases of late stage disease (III-IV) (9,10). Interestingly, the frequency of lymph node metastases at recurrence is found to be higher, even in patients with complete pathologic response to 5 chemotherapy (9). Not surprisingly, the degree of lymph node involvement strongly influences clinical care decisions: for example, stage I patients with metastatic LNs get upstaged to stage IIIC (11,12). Thus, the accurate evaluation of the site and status of lymph node involvement in addition to peritoneal carcinomatosis is critical for the treatment planning of HGSOC patients (13). In light of the limitations of CA125 as a serum biomarker and the importance of lymph node involvement in HGSOC, we propose that a method for the non-invasive visualization of CA125 expression by neoplastic cells could provide a valuable clinical tool for the initial mapping of the disease, as well as treatment planning and treatment monitoring of recurrent disease. Such a methodology could bridge the gap between the observation of elevated serum CA125 levels and the subsequent radiological detection of the disease. In the investigation at hand, we have leveraged our experience with in vivo targeting of CA125 and developed an immunoPET probe for the molecular imaging of HGSOC (14). We have synthesized a 89Zr-labeled variant of the B43.13 antibody — 89Zr-DFO-MAb-B43.13 — that targets CA125 with high affinity (KD = 1.2 nM) and evaluated the radioimmunoconjugate in murine models of HGSOC. In doing so, we have created a ‘theranostic’ variant of MAb B43.13, an antibody previously used for the immunotherapy of ovarian cancer (15,16). The ability of 89Zr-DFO-MAb-B43.13 to track lymph node metastases of HGSOC via PET is a highlight of this study. This is the first report of a CA125-targeting 89Zr-labeled antibody for the non-invasive visualization of HGSOC. 6 MATERIALS AND METHODS PET Imaging PET imaging experiments were conducted on a microPET Focus rodent scanner (Concorde Microsystems). Mice bearing subcutaneous OVCAR3 (right shoulder) xenografts (150-200 mm3) were administered 89Zr-DFO-MAb-B43.13 (10.2 – 12.0 MBq in 200 µL 0.9% sterile saline, 40- 50 μg) via intravenous tail vein injection (t = 0). Approximately 5 minutes prior to PET imaging, mice were anesthetized by inhalation of 2% isoflurane (Baxter Healthcare)/oxygen gas mixture and placed on the scanner bed; anesthesia was maintained using 1% isoflurane/gas mixture. PET data for each mouse were recorded via static scans at time points between 24 and 120 h. Images were analyzed using ASIPro VMTM software (Concorde Microsystems). Statistical Analysis All data are expressed as means ± SEM. Where applicable, statistical differences were analyzed by an unpaired student’s T-test using GraphPad Prism 6 software. Comparisons with p values <0.05 were considered significant. RESULTS Synthesis and Characterization MAb-B43.13 was conjugated to desferrioxamine (DFO) using p-SCN-Bn-DFO and subsequently radiolabeled with 89Zr4+ to yield 89Zr-DFO-MAb-B43.13 in >99% radiochemical purity and a specific activity of 203.5 ± 29.6 MBq/mg (5.5 ± 0.8 mCi/mg) (Supp. Figs. S1, S2). In vitro immunoreactivity experiments using CA125-expressing OVCAR3 epithelial ovarian cancer cells revealed an average immunoreactive fraction of approximately 0.92, and in vitro 7 serum stability assays demonstrated that 89Zr-DFO-MAb-B43.13 is >96% stable to decomposition over 7 days at 37 °C in human serum (Supp. Figs. S3-S5). PET Imaging and Acute Biodistribution Experiments Small animal PET imaging experiments facilitated the visualization of the in vivo performance of 89Zr-DFO-MAb-B43.13. In preliminary experiments, mice (n = 5) bearing bilateral OVCAR3 (CA125-positive) and SKOV3 (CA125-negative) ovarian cancer xenografts were administered 89Zr-DFO-MAb-B43.13 [10.2-12.0 MBq] intravenously and subsequently imaged daily from 24-120 h post-injection. The images clearly illustrate the selective targeting of 89Zr-DFO-MAb-B43.13 to the CA125-expressing OVCAR3 tumors, with high levels of the radioimmunoconjugate accumulating in the antigen-bearing tissue. In contrast, the CA125- negative SKOV3 tumors were characterized by low uptake of the tracer, likely due to the non- specific enhanced permeability and retention effect (Fig.
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