99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma

Abstract

Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (p < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

“…MSLN plays a critical role in the development of pancreatic cancer, especially at an early stage, and in peritoneal metastasis by binding with its single ligand MUC16; however, the intracellular mechanism remains unclear [88]. Furthermore, overexpression of MSLN is associated with poor outcomes for PDAC patients [89]. Several preclinical and clinical trials of MSLN-targeted mAb-based therapy have been summarized by several reviews [90][91][92].…”

Carbohydrate 3′-sialyllactose as a novel target for theranostics in pancreatic ductal adenocarcinoma

“…Understanding the molecular basis of antigen binding and recognition by antibodies helps to facilitate the production of better and more potent antibodies for diagnosis, therapy, and various other applications. 20,21 The variable domains of antibody heavy and light chains of antibodies contain three hypervariable loops, named CDRs, and together six CDR loops form the antigen binding site. CDR3 of the heavy chain often forms the most significant contact with antigen, is longer than the other CDRs, and usually plays a prominent role in antigen binding.…”

Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics

“…Pant et al ( 26 ) developed a novel implementation of anti-EGFR-nanobody-dendritic polyglycerols (dPGs), demonstrating enhanced accumulation in vivo . 99m Tc-EGFR ( 27 ), 99m Tc-EGFR-cartilage oligomeric matrix protein (COMP) ( 28 ), 99m Tc-dipeptidyl-peptidase-like protein 6 (DPP6) ( 29 ), 99m Tc-mesothelin ( 30 ), and 131 I-HER2 ( 31 ) nanobodies nanobody probes have also demonstrated high T/B ratios. Additionally, anti-EGFR nanobody probes have been utilized in dual-isotope SPECT ( 32 ) and optical imaging ( 33 ), with an enhanced T/B ratio vs. mAb-based probes ( 32 , 33 ).…”