Mp65-19 Therapy of Advanced Bladder Cancer by Targeting Hyal2 With Antibody-Drug Conjugate: Preclinical Study

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III (MP65)1 May 2024MP65-19 THERAPY OF ADVANCED BLADDER CANCER BY TARGETING HYAL2 WITH ANTIBODY-DRUG CONJUGATE: PRECLINICAL STUDY Padraic O'Malley, William Donelan, Meng-Lun Hsieh, Shiwu Li, Brianna Nguyen, Paul Crispen, and Sergei Kusmartsev Padraic O'MalleyPadraic O'Malley , William DonelanWilliam Donelan , Meng-Lun HsiehMeng-Lun Hsieh , Shiwu LiShiwu Li , Brianna NguyenBrianna Nguyen , Paul CrispenPaul Crispen , and Sergei KusmartsevSergei Kusmartsev View All Author Informationhttps://doi.org/10.1097/01.JU.0001008756.24343.22.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There is an unmet need to develop novel approaches to overcome immune suppression and resistance to bladder cancer immunotherapy, including resistance to checkpoint inhibitors. Hyaluronidase 2 (Hyal2), a membrane-bound enzyme expressed by both myeloid-derived suppressor cells (MDSCs) and epithelial tumor cells that degrades hyaluronan (HA) in the extracellular matrix of the tumor stroma, increases small HA fragments in the tumor microenvironment that promote inflammation, tumor-associated immune suppression, and angiogenesis. For targeting Hyal2 we developed monoclonal antibodies that recognize both human and mouse Hyal2 and developed antibody-drug conjugate (ADC) Hyal2-ADC. METHODS: Hyal2 expression in bladder cancer tissues was assessed using immunohistochemistry and western blotting. The in vitro effects of Hyal2-ADC on tumor cells and MDSCs were evaluated using MTT assay and immunofluorescence. Single-cell RNA sequencing was utilized for transcriptomic analysis of Hyal2-expressing myeloid cells. Syngeneic mouse models with established bladder tumors were used to examine the in vivo anti-tumor activity of Hyal2-ADC. RESULTS: In vitro, Hyal2-ADC efficiently inhibited the proliferation of both mouse and human tumor cell lines. Administration of Hyal2-ADC alone led to inhibition of tumor growth in a dose-dependent manner and was associated with remodeling of the tumor microenvironment, reduction of immunosuppressive myeloid cells, and influx of immune T cells. Combination of Hyal2-ADC with anti-PD1 therapy resulted in complete tumor eradication in 100% of mice with established tumors (initial volume <200 mm3) and 80% with large, advanced established tumors (>200 mm3), and demonstrated long-term protection from tumor re-challenge. CONCLUSIONS: Hyal2-ADC targets Hyal2-expressing cells, modulates the immunosuppressive tumor microenvironment, and induces efficient immune memory in murine models suggesting that Hyal2-ADC alone or in combination with anti-PD1 therapy could be used as therapy for solid tumors associated with deregulated HA metabolism, including bladder cancer. Eliminating Hyal2-expressing cells normalizes HA metabolism, counters tumor-associated immune suppression, and mediates anti-tumor immune responses offering a new therapeutic approach for patients. Download PPT Source of Funding: 1923 Fund (SK, PC); UF Health Cancer Center, American Cancer Society Institutional Research Grant (WD) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1084 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Padraic O'Malley More articles by this author William Donelan More articles by this author Meng-Lun Hsieh More articles by this author Shiwu Li More articles by this author Brianna Nguyen More articles by this author Paul Crispen More articles by this author Sergei Kusmartsev More articles by this author Expand All Advertisement PDF downloadLoading ...