The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy

Abstract

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5–93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.

Preliminary Development and Testing of C595 Radioimmunoconjugates for Targeting MUC1 Cancer Epitopes in Pancreatic Ductal Adenocarcinoma

“…The utility of radioimmunotherapy can be improved by developing complementary imaging radioimmunoconjugates which allow for the informed selection of patients who have optimal expression of the target receptor for radioimmunotherapy [9,12]. We have previously identified MUC1-CE as an ideal target receptor given its expression is correlated with advanced PDAC and it is overexpressed on up to 90% of PDAC cells yet minimally expressed on normal cells [20][21][22]. Effective targeting of MUC1-CE is feasible using the C595 antibody and provides an avenue for radioimmunoconjugate development.…”

“…To evaluate the binding capacity of the radioimmunoconjugates to MUC1-CE, separate cell binding assays were performed using 177 Lu-DOTA-C595 and 64 Cu-DOTA-C595. Our previous work has identified that 93.1% of PANC-1 cells express MUC1-CE compared to only 11.5% of AsPC-1 cells (Supplementary Figure S2) [22]. Due to the variable MUC1-CE expression, these cell lines were used to evaluate for binding differences relative to MUC1-CE expression.…”

“…This hypoglycosylation exposes the variable number tandem repeat region (VNTR) which holds a number of cancer-specific MUC1 epitopes (MUC1-CE). Several studies have identified these MUC1-CE as having an optimal expression profile for targeted therapy of PDAC [20][21][22][23]. The expression of MUC1-CE has also been correlated with more advanced PDAC, suggesting these epitopes could be used to characterise and treat late-stage disease [24].…”

“…Of note is the Arg-Pro-Ala-Pro MUC1-CE which can be targeted by C595, an IgG3 murine mAb [25][26][27]. Over 90% of PDAC overexpress the C595-reactive MUC1-CE yet expression on normal tissues is minimal [20][21][22]. This expression profile is ideal for targeted therapy as it allows for specific targeting of only cancer cells to optimise the therapeutic efficacy and minimise normal-tissue toxicities [28].…”

ImmunoPET: Antibody-Based PET Imaging in Solid Tumors

“…Mucins are transmembrane glycoproteins highly expressed on several epithelial cancers, usually with an altered glycosylation pattern ( 37 , 298 ). MUC1 or cancer antigen 15-3 (CA 15-3) may have a role in the management of PDAC ( 299 ). Also, carbohydrate antigen 125 (CA125), an extracellular domain of MUC16, is a well-known ovarian cancer biomarker ( 38 ).…”