Trial in progress: A phase 1-2, first-in-human, open label, dose escalation and expansion study of AU-007, a monoclonal antibody that binds to IL-2 and inhibits IL-2Rα binding, in patients with advanced solid tumors.

Abstract

TPS2671 Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant “non-CD25” IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Methods: This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an escalating single aldesleukin dose in sequential escalation cohorts. In Arm C, AU-007 is evaluated in combination with aldesleukin, both given Q2w. AU-007 is administered at a fixed dose with an escalating dose of aldesleukin in sequential cohorts. The Phase 2 cohort expansion portion of the study evaluates the initial efficacy at the RP2D defined in escalation cohorts A, B, and C in 3 matching expansion cohorts of up to 20 patients each. Patients with advanced melanoma, RCC and other tumors including, but not limited to, Merkel Cell Carcinoma, NSCLC, and urothelial cancer are eligible. Enrolment to the study commences in Australia, with US sites planned to open later in 2022. Clinical trial information: CT-2021-CTN-03938-1.

Cytokine Biopharmaceuticals with “Activity-on-Demand” for Cancer Therapy

“…XTX202 is another investigational protease-activable, βγ biased, engineered IL2-based compound that has shown promising preclinical activity 84 and that is under evaluation in Phase I/II clinical studies in patients with advanced melanoma and renal cell carcinoma (NCT05052268). 85 Xilio Therapeutics has disclosed other conditionally activated cytokines for IL12 (XTX301 in Phase 1; NCT05684965) 86 and IL15 (XTX401 in discovery).…”

Engineering cytokines for cancer immunotherapy: a systematic review

“…Interestingly, AU-007 shows a different mechanism of action than other IL-2 therapies being developed, as it leverages the body’s own IL-2 to increase its innate antitumor immune effects. This increased effect was achieved by preventing IL-2 secreted from effector T cells from binding to trimeric receptors on Treg cells while still allowing IL-2 to bind to and induce the expansion of the effector T cells ( 52 ). A Phase I/II dose-escalation and expansion trial of AU-007 in participants with unresectable locally advanced or metastatic cancer is ongoing (NCT05267626) ( 52 ).…”

“…This increased effect was achieved by preventing IL-2 secreted from effector T cells from binding to trimeric receptors on Treg cells while still allowing IL-2 to bind to and induce the expansion of the effector T cells (52). A Phase I/II dose-escalation and expansion trial of AU-007 in participants with unresectable locally advanced or metastatic cancer is ongoing (NCT05267626) (52).…”