Abstract C033: Preliminary pharmacodynamic evaluation of AU-007 in phase 1 dose escalation trial in patients with advanced solid tumors
Authors: Wyant Timothy , Frentzas Sophia , Ahern Elizabeth , Weickhardt Andrew , Haydon Andrew , Powderly John , Rasco Drew , McKean Meredith , De Souza Paul , Tang Jenny , Richards Lori , Knckerbocker Aron , Ofran Yanay , Amit Inbar , Vasselli James 
Published: December 2023

Abstract
AU-007 is a monoclonal antibody currently being evaluated in a Phase 1/2 clinical trial. In conjunction with evaluation of clinical activity, a pharmacodynamic program has been established to assess the biological activity of AU-007 alone or with low dose subcutaneous aldesleukin in patients with advanced solid cancers. AU-007 binds IL-2 on its CD25-binding epitope, thus inhibiting IL-2’s interaction with CD25 in the trimeric IL-2 receptor (IL-2R) but allowing for IL-2’s binding to the dimeric IL-2R. This effectively inhibits the trimeric IL-2R expressing Tregs without impacting dimer expressing memory T cells, NK cells, NKT cells and naïve T cells. We evaluated the effect of AU-007 +/- aldesleukin on peripheral blood cell populations, IFN-gamma, IL-2 and sCD25. Here we report the interim pharmacodynamic data from the ongoing dose escalation portion of the trial. Peripheral blood samples were collected in Cyto-Chex BCT tubes and phenotyped for T cells, NK cells, B cells, and monocytes. A TruCount system was used to obtain absolute cell numbers. In addition, eosinophils were assessed through standard CBC differentials. Serum collections were done to assess circulating markers using the MSD ECL platform. It was observed that, regardless of AU-007 dose with or without aldesleukin, patients had a reduction in the circulating levels of Treg cells (i.e., based on assay validation, a change greater than +/-10% was considered a real change). This is consistent with the mechanism of action of AU-007, by binding IL-2 such that it prevents the interaction with the trimeric IL-2R, Tregs are affected. There was an increase in the CD8+ to Treg ratio consistent with the overall decrease in Tregs. Trends for increases in NK cells and CD8+ T cells were observed in most patients. Eosinophils express the trimeric IL-2R and are known to increase after IL-2 therapy. To date, no drug related increases in eosinophils with AU-007 +/- aldesleukin were observed, and in most cases the levels of circulating eosinophils decreased. IFN-g is a cytokine released after activation of the inflammatory/cytotoxic arm of the immune system. Twelve of the initial 17 patients for whom data are available demonstrated at least a 2-fold or greater increase in the circulating levels of IFN-g, often occurring within 48 hours after dosing. This was observed regardless of dose given. Higher frequency and amounts of IFN-g expression were observed when subcutaneous low dose aldesleukin was also given (dosed 2 – 24h post AU-007 dosing). A dose dependent trend with single-agent AU-007 was observed, leading to more patients with a &gt;2-fold IFN-g. All patients who received low dose aldesleukin had at least 1 timepoint post dose with a &gt;2-fold increase. Overall, AU-007 has demonstrated pharmacodynamic responses consistent with the mechanism of action, with decreases in the regulatory population of cells and increases in inflammatory cells and markers. The initial pharmacodynamic data support continued dose escalation of AU-007 +/- aldesleukin in patients with advanced cancer.
Citation Format: Timothy Wyant, Sophia Frentzas, Elizabeth Ahern, Andrew Weickhardt, Andrew Haydon, John Powderly, Drew Rasco, Meredith McKean, Paul De Souza, Jenny Tang, Lori Richards, Aron Knckerbocker, Yanay Ofran, Inbar Amit, James Vasselli. Preliminary pharmacodynamic evaluation of AU-007 in phase 1 dose escalation trial in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C033.