MUC16 Targeted Antibodies for PET Imaging of Epithelial Ovarian Carcinoma

Objectives The CA-125 antigen is the most widely used serum biomarker to monitor epithelial ovarian carcinoma (EOC) and for the differential diagnosis of pelvic masses. To date, the majority of antibodies against MUC16 have targeted the tandem repeat region of the protein, which is shed into circulation following cleavage. Using synthetic MUC16 peptides, high affinity antibodies (9C9, 19C11, 7B12, 18C6) were raised against the portion of MUC16 retained by the cell [1, 2]. Imaging modalities currently used for EOC are generally viewed as inadequate and as such, the goal of this study is to evaluate these three antibodies to determine the best candidate to be used as a PET imaging agent for EOC [3].

Methods The antibodies were conjugated with desferrioxamine-isothiocyanate and radiolabelled with 89Zr. Using a MUC16-positive cell line (SKOV3-MUC16c114), in vitro studies were performed to confirm immunoreactivity and binding affinities of the radiolabeled antibodies. In addition, in vitro internalization studies were conducted which demonstrated similar uptake among the tracers. Subcutaneous EOC tumors were established in athymic, nude mice for the in vivo characterization of the MUC16 antibodies for imaging and biodistribution studies.

Results Biodistribution data for 89Zr-9C9 revealed an accumulation of the tracer in the tumor tissue at 24 hours post-injection of 9.41 ± 1.98 %ID/g. Kidney uptake of this tracer, although washing out over time, was extremely high at 24 hours (37.02 ± 1.35 %ID/g). The liver and spleen uptake of the tracer at 24 hours post-injection were 9.74 ± 0.76 and 4.76 ± 0.55 %ID/g, respectively. For 89Zr-19C11, despite in vitro data that demonstrated active internalization, biodistribution data for 89Zr-19C11 revealed minimal tumor uptake in vivo 24 hours post-injection (3.12 ± 0.68 %ID/g). Kidney uptake of this tracer was 4.84 ± 0.98 %ID/g and liver and spleen uptake were high 24 hours post-injection (34.73 ± 4.39 and 9.25 ± 0.90 %ID/g, respectively) indicating potential aggregation or stability issues in vivo. For 89Zr-7B12, biodistribution data revealed modest tumor uptake 24 hours post-injection (8.54 ± 0.95 %ID/g), kidney uptake of 7.19 ± 0.75 %ID/g, and liver and spleen uptake of 6.24 ± 0.83 and 7.22 ± 1.26 %ID/g, respectively.

Conclusions Although the 24-hour 89Zr-7B12 biodistribution data appeared promising, serial PET imaging studies through 120 hours revealed limited additional accumulation of the tracer beyond what is believed to be due to the EPR effect. Biodistribution and imaging studies of humanized 18C6 antibodies are currently being conducted. Research funded, in part, by the Center to Reduce Cancer Health Disparities of the National Cancer Institute (3R01CA176671-02S1) and 1PO1CA190174-01A1.