Targeting CD146 with a ⁶⁴ Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas

Abstract

Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ2 = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.

ImmunoPET imaging of tissue factor expression in pancreatic cancer with 89Zr-Df-ALT-836

“…The expression of TF was evaluated by immunofluorescence staining following a previously described methodology [15]. After the terminal imaging timepoint, tissue samples form BXPC-3, PANC-1 tumors, and normal tissues including the liver, kidneys, and spleen were harvested, embedded in optimal cutting temperature (OCT) compound, frozen, and stored for approximately 30 days (10 times 89 Zr decay half-life) at −80 °C.…”

ImmunoPET Imaging of CD146 Expression in Malignant Brain Tumors

“…YY146 was generated and purified as described previously 18 . Chelex 100 resin and p-SCN-Bn-deferoxamine were purchased from Sigma Aldrich and Macrocyclics, Inc., respectively.…”

“…In fact, targeting CD146 with monoclonal antibodies has not only demonstrated value for the determination of CD146 expression in vitro , but also has proven efficacious at inhibiting tumor growth and metastasis in vivo 17 . Recently, the expression of CD146 was described and correlated with aggressiveness in high-grade gliomas 18 .…”

Polyethylenimine-Dermatan Sulfate Complex, a Bioactive Biomaterial with Unique Toxicity to CD146-Positive Cancer Cells

“…22, 24 It was first identified as a melanoma-specific cell-adhesion molecule due to the abundance in malignant melanoma but also implicated in the progression of breast, prostate, and epithelial ovarian cancers. 24 For this reason, CD146 has been pursued as a molecular target for the therapy 25 and imaging 26, 27 of solid tumors.…”