Abstract 3356: Annexin-A1 as a potential therapeutic target for solid tumors

Abstract

Abstract Significant challenges persist in developing novel, less toxic, more effective therapies for clinically challenging cancers with relatively low response rates to treatment. Moreover, additional treatment options for refractory and drug resistant cancers are urgently required. Annexin-A1 (ANXA1), a member of a protein superfamily that binds acidic phospholipids in a calcium-dependent manner, is normally localized in cell cytoplasm or plasma membrane. However, ANXA1 can be secreted in response to cell activation and can then modulate the behaviors of nearby cells by binding to the formyl peptide receptor 2 (FPR2). Current literature strongly suggests that ANXA1 can act as a tumor suppressor or an oncogene dependent on cancer indication/subtype, playing a significant role in many upstream signalling pathways that direct cancer proliferation, angiogenesis, drug resistance, invasion and metastasis. Our hypothesis was that annexin-A1 would be a novel target for anti-cancer therapy. We have developed a humanized antibody targeting ANXA1 (MDX-124) and here we present data showing its cytotoxic effect on a panel of cancer cell lines and in a mouse model of triple negative breast cancer. Results: Incubation of a selected panel of breast, colorectal, pancreatic and ovarian cancer cell lines with MDX-124 (0-10 µM) for 72h resulted in a statistically significant reduction in cell survival compared to incubation with an IgG isotype control which binds in a non-specific manner or a commercially available anti-ANXA1 polyclonal antibody. MDX-124 has been assessed for binding affinity to ANXA1 by Biacore and found to have a low nM KD, whilst the potency of MDX-124 was evaluated to be in the low nM range using MCF-7 cells in the CellTiter-Glo® luminescent cell viability assay. ANXA1 localization was also assessed across the panel of cell lines using imaging flow cytometry to quantitate ANXA1 in different cellular compartments. We found the cytotoxic effect of MDX-124 correlated with strong ANXA1 membrane staining. Further in-vivo studies utilized MDX-124 (1 mg/kg) in the syngeneic orthotopic 4T1-luc triple negative breast cancer model. Following dosing once a week we identified a statistically significant reduction in the rate of increase in tumor volume compared to the vehicle control which was not associated with any significant change in body weight. Therefore, our results demonstrate that cancer cell growth is suppressed by inhibition of ANXA1 and indicate that MDX-124 is a promising targeted antibody therapeutic against cancers overexpressing ANXA1. Further studies are under way to determine the mechanism of cell kill by MDX-124. Citation Format: Fiona C. Dempsey, Henry C. Hays, Scott J. Crichton, Hussein Al-Ali, Christopher N. Parris. Annexin-A1 as a potential therapeutic target for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3356.