Unleashing the Immune System: Targeting Cell Surface Plectin for Pancreatic Cancer Regression

Pancreatic ductal adenocarcinoma (PDA) is recognized as the third leading cause of cancer-related deaths, often diagnosed in later stages, with a low 5-year survival rate of 8%. This highlights an urgent need for innovative treatment strategies to improve the effectiveness of chemotherapy and/or immunotherapy. Our research group has pinpointed a potential therapeutic target in PDA, specifically cell surface plectin 1 (CSP1), which is abnormally expressed on PDA cells, serving as a cancer-associated biomarker. CSP1's presence is evident in high-grade dysplasias and remains elevated throughout the progression of cancer and in metastases.

Our initial human imaging trial with a CSP1-targeted agent in PDA patients showed that CSP is a viable target for binding and could be instrumental in cancer therapy. We have developed a therapeutic monoclonal antibody (mAb), ZB131, which is a pioneering antibody designed to target CSP1 selectively.

ZB131 is a humanized monoclonal antibody that targets human plectin 1 (rhSec8) and also has the ability to bind to murine CSP1. In vitro tests were conducted to assess ZB131's affinity and its impact on cancer cells concerning proliferation, cytotoxicity, and migration. Various pancreatic cell types and normal control cells were utilized for these assays. In vivo studies were performed using mouse models with subcutaneous MiaPACA2 or Yapc PDA cells, as well as a syngeneic KPC-derived tumor model to evaluate the immune response to ZB131 treatment.

The results demonstrated that ZB131 has a high specificity and affinity for CSP1, effectively inducing G0 growth arrest and necrotic cell death in PDA cells. It also showed a synergistic effect with gemcitabine, significantly reducing the IC50 by 50 times. In vivo studies revealed that ZB131 as a monotherapy significantly reduced PDA tumor volume by five times compared to controls. The combination with cisplatin led to sustained tumor reduction and over 85% tumor necrosis. In syngeneic PDA models, ZB131 induced complete tumor regression within 35 days, mediated by an anti-tumor immune response. Upon rechallenge with tumors, complete regression was achieved again without additional ZB131 therapy. Analysis of leukocyte complexity indicated approximately a three-fold increase in effector and central memory T cells in regressing PDA tumors compared to controls.

In conclusion, CSP1 is a novel anti-cancer target found on the cell surface of PDA and other cancers such as ovarian, esophageal, and head and neck. ZB131, an anti-CSP1 monoclonal antibody, not only induces intrinsic cell death in tumor cells but also triggers a strong anti-tumor T cell response, leading to complete tumor regression. This suggests the potential therapeutic effectiveness of ZB131 in treating advanced-stage cancers.