Background. Effective therapeutic options for patients with pancreatic ductal adenocarcinoma (PDAC) remain a critical challenge. It has been found that cell surface localization of syndecan-1 (SDC1) is essential for disease maintenance and progression, where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth1. We hypothesized SDC1 to be an attractive target for theranostics approach suitable for PDAC, as its upregulated expression and rapidly internalizing feature enable cancer cell-selective targeting of radionuclidic payloads. This study aims to evaluate a novel therapeutic strategy using a newly developed monoclonal antibody in combination with radionuclides tailored for both imaging and therapy.
Methods. We have identified the “22B”, a human SDC1-directed monoclonal antibody characterized with high binding affinity and specificity towards human-SDC1 protein and the SDC1-positive PDAC cell line (AsPC-1). The zirconium-89 (89Zr) or terbium-161 (161Tb)-labeled 22B was prepared using a site-selective conjugation approach. Cellular uptake of [89Zr]Zr-DFO-22B was evaluated in AsPC-1 (SDC1+) and AsPC-1 SDC1 knockout (KO; SDC–) cell lines. Tumor uptake, antitumor efficacy, and survival benefit of radiolabeled-22B were investigated in athymic nude mice bearing subcutaneous PDAC cell line xenograft tumors.
Results. [89Zr]Zr-DFO-22B demonstrated rapid internalization in the SDC1+ AsPC-1 cell line and minimal uptake in SDC1– AsPC-1 SDC1 KO cells. In the in vivo microPET/CT imaging study, administration of [89Zr]Zr-DFO-22B resulted in clear and persistent visualization of SDC1+ AsPC-1 tumors up to 120 hours post-injection. The ex vivo quantitative gamma counting revealed significantly greater uptake of [89Zr]Zr-DFO-22B in SDC1+ AsPC-1 tumor than that of [89Zr]Zr-DFO-IgG (IgG=nonspecific isotype control mAb, P < 0.05, Student’s t-test). Encouraged by these findings, we have investigated in vivo profile of the therapeutic counterpart, [161Tb]Tb-DO3A-22B, in the AsPC-1 xenograft mouse model. In line with PET-imaging results, AsPC-1 tumors demonstrated highest [161Tb]Tb-DO3A-22B uptake amongst any other organs when co-injected with optimum amount of carrier protein. We found a > 2-fold increased accumulation of [161Tb]Tb-DO3A-22B in tumor tissue compared to healthy liver, demonstrating the potential of [161Tb]Tb-DO3A-22B for selectively accumulating to liver metastasis with high tumor-to-background contrast. Notably, a single injection of [161Tb]Tb-DO3A-22B at a radioactivity dose of 100 mCi resulted in significant antitumor effects compared to non-treatment control group (P = 0.0004 at day 21, Student’s t-test). The median survival at 40 days post-treatment was undefined for the [161Tb]Tb-DO3A-22B treatment group vs. 28 days for the non-treatment control group (Log-rank test, P = 0.0172).
Conclusions. These results highlight the radiotheranostic potential of site-selectively radiolabeled 22B for the management of PDAC.
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The University of Texas MD Anderson Cancer Center