Abstract 3036: PEGylated hyaluronidase increases tumor uptake of 89Zr-DFO-HuMab-5B1 (MVT-2163) in a CA19-9 positive hyaluronan-accumulating pancreatic cancer model

Abstract

Abstract Hyaluronan (HA) accumulates in the extracellular matrix of many solid tumors, and is associated with poor prognosis in pancreatic ductal adenocarcinoma. In non-clinical models, enzymatic degradation of HA with PEGylated recombinant human hyaluronidase PH20 (PEGPH20) has been shown to remodel the tumor stroma, reduce tumor interstitial fluid pressure, and expand tumor blood vessels, resulting in enhanced delivery of therapeutic and imaging agents, such as monoclonal antibodies. 89Zr-DFO-HuMab-5B1 (MVT-2163) is a targeted ImmuoPET imaging agent for CA19-9 positive malignancies currently in clinical evaluation. CA19-9 plays a role in tumor adhesion and metastasis, and is an independent prognostic indicator of cancer survival. CA19-9 is expressed in pancreatic and other cancers, including small cell lung and colon. In this study, we aimed to show the effects of PEGPH20 on the biodistribution of MVT-2163 in a CA19-9 positive HA-rich human pancreatic tumor xenograft model. Nude mice were peritibially implanted on the right hind limb with 5x106 human pancreatic tumor cells engineered to overexpress hyaluronan synthase 3 (BxPC3/HAS3). Tumor volumes were measured by MR imaging, and mice were staged when average tumor size reached 320 mm3. The control group received intravenous (IV) vehicle, and the test group received PEGPH20 (IV, 1 mg/kg). Both control and test groups also received MVT-2163 (IV, 3 mg/kg) 24 hours later. PET images were captured from 2 to 120 hours post MVT-2163, and region of interest (ROI) of tumor and liver were analyzed (N=6/group). After the final PET image, tumors and livers were harvested for ex vivo gamma counting. Ex vivo gamma counting demonstrated improved MVT-2163 accumulation in animals treated with PEGPH20, with a 50.9% increase in counts in the excised tumors. ROI analysis of the tumors showed increased tumor SUV of 8.0, 9.4, and 24.1% at 72, 96, and 120 hours post-injection, respectively, with PEGPH20 compared to vehicle. ROI analysis of liver regions showed an 11.4 to 26.4% reduction in SUV in the PEGPH20 group compared to control. Ex vivo counts of liver tissue confirmed the PET signal reduction with PEGPH20. Analysis of tumor-to-liver ratios showed average increases of 34.1, 35.7, and 58.5% at 72, 96, and 120 hours, respectively, post MVT-2163 injection in PEGPH20 treated mice. In summary, as measured by SUV, PEGPH20 increased both the tumor uptake and the tumor-to-liver ratios of MVT-2163 in a CA19-9 positive xenograft mouse model of HA accumulating pancreatic cancer. Ex vivo analysis confirmed in vivo results. Taken together, the increased tumor uptake and the decreased liver uptake support further investigation into the potential clinical utility for the combination of PEGPH20 and MVT-2163. Citation Format: Jonah Rainey, Paul Maffuid, Wolfgang W. Scholz, Jack Ostrowski, H Toni Jun, Paul Resnick, Xiaoming Li, Jesse D. Bahn, Susan Zimmerman, Kelly Chen, Barbara Blouw, Curtis B. Thompson, Daniel C. Maneval, David W. Kang. PEGylated hyaluronidase increases tumor uptake of 89Zr-DFO-HuMab-5B1 (MVT-2163) in a CA19-9 positive hyaluronan-accumulating pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3036.