Abstract
Photoimmunotherapy (PIT) is a new type of tumor‐specific treatment utilizing monoclonal antibody (mAb)‐photosensitizer conjugates and near‐infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly developed humanized anti‐TROP2 mAb conjugated to the photosensitizer IR700 (TROP2‐IR700) for PC and CC. Immunohistochemistry on PC and CC tissue microarrays confirmed that TROP2 is overexpressed in about half of PC and CC specimens. Using cultured PC and CC cells, TROP2‐IR700 localized TROP2‐specific and target‐specific cell killing was observed after NIR light irradiation. In addition, TROP2‐IR700 was localized to mouse xenograft tumors expressing TROP2 after intravenous injection. PC and CC xenograft tumor growth was significantly inhibited by TROP2‐targeted PIT relative to controls. The efficacy of TROP2‐targeted PIT in vitro and against xenografted tumors in vivo suggests promise as a therapy for human PC and CC, both of which currently have dismal prognoses and limited therapeutic options.
Highlights
Photoimmunotherapy (PIT) is a new class of cancer therapy based on conjugation of a monoclonal antibody to a photosensitizing phthalocyanine dye, IRDye 700DX N‐hydroxysuccinimide (NHS) ester (IR700), followed by near‐infrared (NIR) light irradiation guided by molecular‐targeted fluorescence imaging.[1]
TFK‐1 tumor‐bearing mice were randomized into following five groups (n = 10 mice in each group): (a) no treatment (iv injection of PBS without NIR light irradiation); (b) iv injection of PBS followed by NIR light irradiation (30 J/ cm[2] on day 1 and 50 J/cm[2] on day 2); (c) iv injection of 200‐μg unconjugated anti‐TROP2 monoclonal antibody (mAb) without NIR light irradiation; (d) iv injection of 200‐μg isotype control IgG conjugated to IR700 followed by NIR light irradiation (30 J/cm[2] on day 1 and 50 J/cm[2] on day 2); (e) iv injection of 200‐μg TROP2‐ IR700 followed by NIR light irradiation (30 J/cm[2] on day 1 and 50 J/cm[2] on day 2)
High expression of TROP2 was detectable in 40% of pancreatic carcinoma (PC) samples and 46% of CC samples, fairly consistent with previous studies
Summary
Photoimmunotherapy (PIT) is a new class of cancer therapy based on conjugation of a monoclonal antibody (mAb) to a photosensitizing phthalocyanine dye, IRDye 700DX N‐hydroxysuccinimide (NHS) ester (IR700), followed by near‐infrared (NIR) light irradiation guided by molecular‐targeted fluorescence imaging.[1]. Tumor‐associated calcium signal transducer 2 (TROP2) is a 46‐kD glycoprotein initially identified in a trophoblast cancer cell line[5] and is overexpressed in many epithelial cancers including pancreatic cancer (PC) and cholangiocarcinoma (CC).[6-9]. It plays a multifunctional cellular role, including the transducing of cytoplasmic Ca2+ that depends on protein kinase C phosphorylation.[10]. Biliary‐pancreatic cancers are neoplasms with high mortality and a low rate of early diagnosis, with incidences increasing yearly.[15-17]. These tumors are one of the few cancers for which survival rates have not improved substantially over the past few decades. The aim of this study was to investigate the expression rate of TROP2 in PC and CC and evaluate the efficacy of PIT with TROP2‐IR700 in vitro and in vivo for TROP2‐expressing PC and CC cell lines
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