Abstract 3937: MSLN-TTC (BAY 2287411) demonstrates increased activity in comparison to standard of care chemotherapy in models of acquired drug resistance
Authors: Hagemann Urs B. , Zitzmann-Kolbe Sabine , Kristian Alexander , Sperl Carolyn , Schatz Christoph A. , Bjerke Roger M. , Cuthbertson Alan S. , Hennekes Hartwig , Ziegelbauer Karl , Mumberg Dominik 
Published: August 2019

Abstract
Mesothelin (MSLN)-targeted thorium conjugate (MSLN-TTC; BAY 2287411) is a targeted alpha therapy consisting of the MSLN-targeting antibody anetumab, covalently attached to a 3,2-HOPO chelator complexing the alpha-emitter thorium-227. We previously demonstrated the potent in vivo activity of MSLN-TTC in cell line and patient-derived xenograft models, and further, demonstrated its combination potential with DNA damage repair inhibitors. MSLN-TTC is currently in clinical development for the treatment of patients with MSLN-positive mesothelioma and ovarian cancer (NCT03507452). Development of cellular resistance mechanisms are often co-evolutionary to the treatment regimen given to the respective individual. As such, it is well described that ovarian cancer patients have a decreased overall survival when tested positive for markers of acquired drug resistance (ADR), e.g. phospho-glycoprotein (P-gp) (Herzog TJ et al; Oncotarget 2016). However, MSLN-TTC should also be effective independent of P-gp expression, as the major mode of action of MSLN-TTC is the induction of irreparable DNA double-strand breaks upon alpha decay by thorium-227, resulting in apoptotic cell death. To confirm this hypothesis, we first determined the involvement of P-gp in cellular resistance mechanisms in ovarian cancer. To this end, immunohistochemical staining of ovarian cancer patient samples for P-gp was performed. Expression of P-gp was observed in 15% (7/48) primary and relapsing specimens. We then evaluated the potency of MSLN-TTC in MSLN-expressing cell line models in vitro using the isogenic cell line pair OVCAR-8 (P-gp negative) and NCI-RES-ADR (P-gp positive) in comparison to the standard of care (SOC) therapies cisplatin, paclitaxel, doxorubicin and vinorelbine. Whereas paclitaxel and doxorubicin showed a 100- and 10-fold decrease in in vitro potency on the P-gp positive cell line NCI-RES-ADR vs the P-gp negative cell line OVCAR-8, the potency of MSLN-TTC on the two isogenic cell lines remained unaffected.
To further confirm and explore these observations, in vivo xenograft models were conducted. Similar to the in vitro results, the in vivo efficacy of MSLN-TTC was not affected by the P-gp status in the OVCAR-8 vs NCI-RES-ADR xenograft model. In contrast, limited efficacy of paclitaxel and doxorubicin was observed in the P-gp-positive MSLN-expressing NCI-RES-ADR and Hela-MATU-ADR models. Similar, vinorelbine showed no efficacy in the Hela-MATU-ADR xenograft. In summary, these data demonstrate that the efficacy of MSLN-TTC is independent of the P-gp status. Further, these data suggest that MSLN-TTC may be active in patients relapsing after standard therapy.
Citation Format: Urs B. Hagemann, Sabine Zitzmann-Kolbe, Alexander Kristian, Carolyn Sperl, Christoph A. Schatz, Roger M. Bjerke, Alan S. Cuthbertson, Hartwig Hennekes, Karl Ziegelbauer, Dominik Mumberg. MSLN-TTC (BAY 2287411) demonstrates increased activity in comparison to standard of care chemotherapy in models of acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3937.