Abstract P5-08-06: MDX-124, a novel annexin-A1 antibody, shows anti-tumor efficacy in several preclinical models of triple-negative breast cancer
Authors: Fiona C Dempsey, Hussein Al-Ali, Scott J Crichton, Charlene Fabian, Chris Pepper, Christopher N Parris
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) accounts for 10-15% of all breast cancer cases and is a particularly aggressive form of the disease, with poorer prognosis compared to other breast cancer subtypes. Advances in TNBC treatment have been made with the introduction of checkpoint inhibitors, PARP inhibitors and antibody drug conjugates. However, these therapies still have several limitations including low patient response rates, treatment resistance or relapse, and considerable side effects. Therefore, a significant unmet clinical need remains to develop novel targeted agents to treat TNBC. Annexin-A1 (ANXA1) is a phospholipid binding protein secreted in response to several physiological stimuli where it activates formyl peptide receptors (FPR1/2) triggering multiple oncogenic cell signaling pathways. Overexpression of ANXA1 by TNBC cells has been shown to influence several cancer-related processes including cell growth, cell cycle progression, angiogenesis, migration and invasion. In addition, ANXA1 has been shown to have immunomodulatory effects on T-cells, macrophages and dendritic cells. High ANXA1 expression in TNBC patients correlates with both poor overall survival and progression-free survival, indicating ANXA1 is a therapeutic target in TNBC. MDX-124 is a novel humanized antibody targeting ANXA1, and we have previously demonstrated its significant anti-proliferative activity. Here we present additional data showing the efficacy of MDX-124 in preclinical models of TNBC. Methods: The impact of MDX-124 on cell cycle progression was evaluated by measuring changes in DNA content using flow cytometry and analyzed with FlowJo™ software.The modulation of key oncogenic cell signalling pathways by MDX-124 was assessed using human phospho-kinase and XL Oncology Proteome Profiler™ antibody arrays. The effect of MDX-124 in combination therapy with chemotherapy was studied in-vitro using MTT cell proliferation assays, whilst synergy with anti-PD-1 therapy was evaluated using the EMT6 syngeneic mouse model of TNBC. Results: MDX-124 treatment dramatically decreased the proportion of HCC1806 TNBC cells in S-phase by 29.1% with a concomitant increase in G1 of 33.5% versus untreated cells. This occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest.Treatment of HCC1806 TNBC cells with MDX-124 altered the expression of key oncogenic proteins and the phosphorylation of several kinases that regulate cell signaling pathways involved in proliferation, survival and migration. Notably, MDX-124 substantially reduced ERK and AKT phosphorylation by 84% and 72% respectively versus untreated control cells. In the HCC1806 TNBC cell line, proliferation was significantly reduced after 72 h treatment with MDX-124 and chemotherapy versus control.In the EMT6 syngeneic mouse model of TNBC, the murine analogue of MDX-124 (MDX-001) potentiated mean tumor growth inhibition of single agent anti-PD-1 treatment by 15%. Additionally, 30% of treated mice showed tumor regression in the MDX-001 combination therapy group versus 10% in the single agent anti-PD-1 group. This suggest that anti-ANXA1 antibody therapy acts synergistically with anti-PD-1 immunotherapy.Conclusion: MDX-124 binds to secreted and extracellular ANXA1 disrupting interactions with FPR1/2. This results in altered expression levels of several key cancer-related proteins preventing the activation of oncogenic signaling pathways that promote cancer progression. MDX-124 has demonstrated anti-cancer activity in several TNBC cell line and mouse models, as both a single agent and in combination with other drugs, including anti-PD-1 immunotherapy. Medannex plan to initiate a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies, including TNBC. Citation Format: Fiona C Dempsey, Hussein Al-Ali, Scott J Crichton, Charlene Fabian, Chris Pepper, Christopher N Parris. MDX-124, a novel annexin-A1 antibody, shows anti-tumor efficacy in several preclinical models of triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-06.