No abstract

In recent years, proteins with aberrant glycosylation patterns have emerged as therapeutic targets in oncology. Along these lines, MUC16 glycoforms have been implicated in the oncogenesis and metastatic progression of high-grade serous ovarian cancer (HGSOC) and pancreatic ductal adenocarcinoma (PDAC). AR9.6 is a therapeutic mAb that binds to MUC16, interferes with the interaction of MUC16 with ErbB receptors on the surface of cancer cells, and thereby attenuates the activation of downstream oncogenic signaling pathways. Here, we report the in vitro, ex vivo, and in vivo validation of [ 89 Zr]Zr-DFO-muAR9.6 and [ 89 Zr]Zr-DFO-huAR9.6 in murine models of MUC16-positive HGSOC and PDAC. Both radioimmunoconjugates displayed excellent tumor-targeting properties in vivo, ultimatelyResearch.

Patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint blockade (ICB) along the PD-1/PD-L1 axis. Variable PD-L1 expression in PDAC indicates a potential access issue of PD-L1–targeted therapy. To monitor target engagement of PD-L1–targeted therapy, we generated a PD-L1–targeted PET tracer labeled with zirconium-89 (89Zr). As the MAPK signaling pathway (MEK and ERK) is known to modulate PD-L1 expression in other tumor types, we used [89Zr]Zr-DFO-anti–PD-L1 as a tool to noninvasively assess whether manipulation of the MAPK signaling cascade could be leveraged to modulate PD-L1 expression and thereby immunotherapeutic outcomes in PDAC. In this study, we observed that the inhibition of MEK or ERK is sufficient to increase PD-L1 expression, which we hypothesized could be leveraged for anti–PD-L1 immune checkpoint therapy. We found that the combination of ERK inhibition and anti–PD-L1 therapy corresponded with a significant improvement of overall survival in a syngeneic mouse model of PDAC. Furthermore, IHC analysis indicates that the survival benefit may be CD8+ T-cell mediated. The therapeutic and molecular imaging tool kit developed could be exploited to better structure clinical trials and address the therapeutic gaps in challenging malignancies such as PDAC.

No abstract