Updated results of a phase 1/2 study of AU-007, a monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, in patients with advanced solid tumors.

2527 Background: AU-007 is a computationally designed human mAb that binds interleukin-2 (IL-2) on its CD25 binding epitope. AU-007 bound IL-2 cannot bind trimeric (CD25, CD122, CD132) IL-2 receptors (IL-2R) on regulatory T cells (Tregs), vascular endothelium, or eosinophils, but IL-2’s binding to dimeric IL-2R (CD122, CD132) on effector T (T eff) and NK cells is unhindered. AU-007 thus redirects IL-2 towards T eff and NK cell activation, while diminishing Treg activation and vascular leak. AU-007 uniquely redirects IL-2 generated from T eff cell expansion, converting a Treg-mediated autoinhibitory loop into an immune stimulating loop. Methods: The study consists of three dose escalation arms followed by cohort expansion. Arm 1A evaluates escalating doses (0.5 – 12 mg/kg) of AU-007 (IV every 2 weeks Q2W). Arm 1B evaluates AU-007 Q2W + escalating doses (15K – 270K IU/kg) of one aldesleukin subcutaneous (SC) dose. Arm 1C evaluates AU-007 + escalating doses of SC aldesleukin, both Q2W. Nineteen solid tumor types are allowed in escalation. Cohort expansion Arm 2B evaluates 9 mg/kg AU-007 + one 135K IU/kg aldesleukin dose. Results: Fifty-three patients were enrolled as of 23 January 2024: 15 in Arm 1A, 12 in Arm 1B, 25 in Arm 1C, and 1 in cohort expansion. AU-007 (+/- aldesleukin) was well-tolerated, with no dose limiting toxicities through all Arm 1A and 1B cohorts and the 3 rd cohort (of 4) in 1C. Enrollment is ongoing in the final Arm 1C cohort and Arm 2B expansion. All drug related adverse events (AE) were Grade 1 or 2 except for 4 patients with transient lymphopenia (Grade 3 and 4) and 1 patient with Grade 3 anemia. The most common drug-related AEs were pyrexia (18%), fatigue (16%), nausea (14%), lymphopenia (8%), and chills (6%). Two patients had transient Grade 2 drug-related serious AEs: pyrexia Arm 1B and cytokine release syndrome Arm 1C; both patients continued therapy. A confirmed partial response (32% decrease) occurred in a nasopharyngeal carcinoma patient in Arm 1C who progressed on anti-PD-1 therapy. Tumor shrinkage occurred in patients with non-small cell lung, bladder, head and neck, colorectal (CRC), and renal cancer. A melanoma patient (Arm 1B) who progressed on anti-CTLA-4 + anti-PD-1 therapy had a 48% decrease in target tumors; a small brain metastasis was found and irradiated at week 16 and the patient remains on treatment. A patient with microsatellite stable CRC had a 26% tumor shrinkage after the first cycle (Arm 1C). Serum Tregs and eosinophils decreased in patients while NK and CD8 cell counts trended upwards. The CD8:Treg ratio trends upward in all cohorts. Conclusions: The mild toxicity profile and promising early efficacy observed in dose escalation across multiple tumor types in heavily pretreated patients, along with initial pharmacodynamic data, warrant continued evaluation of AU-007 + low dose SC aldesleukin in the Phase 2 expansion cohorts of the study. Clinical trial information: NCT05267626 .