Temporal Modulation Of Antigen Availability To Improve Antibody-Tumor Binding And Therapeutic Efficacy.

Abstract Statins are low-cost cholesterol-depleting drugs used to treat patients with hypercholesterolemia. Preclinically, statins modulate caveolae-mediated endocytosis. Membrane receptors defined as tumor biomarkers and therapeutic targets are often internalized by an endocytic pathway. Indeed, receptor endocytosis and recycling are dynamic mechanisms that can affect receptor density at the cell surface. In therapies using monoclonal antibodies, a downregulation in receptor density at the cell surface decreases antibody binding to the extracellular domain of the membrane receptor. Here, we used immunoPET to demonstrate that statins can temporally modulate human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and prostate-specific membrane antigen (PSMA) receptor density at the tumor cell surface for binding therapeutic monoclonal antibodies and antibody-drug conjugates. In xenografts and patient samples, we found that tumors with high CAV1 expression localized less receptor at the cell membrane and these features decreased antibody uptake and efficacy. In cultured cells and tumor xenografts, statins temporally depleted CAV1 expression in ways than enhanced tumors' avidity for anti-HER2, anti-EGFR, and anti-PSMA antibodies. In HER2- and EGFR-expressing xenografts, treating mice with a statin accelerated and increased 89Zr-labeled antibody accumulation at the tumor site. The hydrophilic rosuvastatin demonstrated a lower ability to enhance antibody binding to tumors when compared with the lipophilic lovastatin and simvastatin. 89Zr-labeled huJ591 tumor accumulation was higher in PSMA-expressing tumors of statin-treated mice when compared with tumors of saline-treated mice at later time-points of antibody accumulation (24 h and 48 h), but the values were similar at 4 h and 8 h. These results suggest that treating mice with statins increases, but does not accelerate, anti-PSMA antibody accumulation. Anti-DLL3 antibody accumulation was similar in saline versus statin treated tumors. Retrospective data demonstrated that patients with HER2+/CAV1HIGH(29.4% of total HER2+gastric tumors) have a significantly worse overall survival than those expressing low CAV1. Kaplan-Meier analyses of statin use and HER2+gastric cancer disease outcome in patients treated with trastuzumab suggested that patients without statin treatment have worse survival than patients treated with a statin. Additionally, statins synergize with therapeutic antibodies to decrease oncogenic signaling pathways.Our data suggest that acute statin treatment with appropriate pharmacokinetics/pharmacodynamics are potential adjuvants for specific antibody-targeted therapies. Citation Format: Patricia Pereira, Komal Mandleywala, Ashwin Ragupathi, Marissa Mattar, Sébastien Monette, Yelena Janjigian, Jason Lewis. Temporal modulation of antigen availability to improve antibody-tumor binding and therapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2811.