A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors

• Published in: Molecular therapy. Oncolytics 2021-09, Vol.22, p.555-564
• Main Authors: Robb, Ryan, Kuo, Jimmy Chun-Tien, Liu, Yang, Corrales-Guerrero, Sergio, Cui, Tiantian, Hegazi, Ahmad, Nagy, Gregory, Lee, Robert J., Williams, Terence M.
• Format: Article
• Language: English
• Subjects: albumin; caveolin-1; lung cancer; Original; pancreatic cancer; SN-38; SSH20
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2021.07.013

In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors. [Display omitted] In this study, the authors have developed and established a novel albumin-SN-38 conjugate (SSH20) and tested it in pre-clinical models of pancreatic and lung cancer. The advantageous properties inherent to SN-38 conjugation to albumin and targeted delivery make SSH20 an attractive candidate for further preclinical and potential clinical study.