Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate

Abstract

BackgroundRecombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.MethodsMDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP).ResultsBinding studies with MDNA11 demonstrated increased affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome.ConclusionMDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

“…Specifically, while max PD doses of bempegaldesleukin (0.1 mg/kg) and THOR-707 (0.3 mg/kg) increased ALCs by approximately 5-fold 13 and 4-fold, 40 respectively, TransCon IL-2 β/γ (≥0.3 mg/kg) increased ALCs by an average 24-fold. While nemvaleukin (0.1 mg/kg/day IV× 5, or 0.5 mg/kg SC on Days 1 and 4) increased CD8 + T cells by 6-fold and NK cells by 4-fold, 42 and MDNA11 (0.6 mg/kg) increased CD8 + T cells by ~10-fold and NK cells by ~2.5-fold, 39 TransCon IL-2 β/γ (≥0.3 mg/kg) increased CD8 + T cells and NK cells by on average 19-fold and 26-fold, respectively. In agreement with other IL-2Rβ/γ agonists, 42 higher expansion was observed in effector memory compared with total CD8 + T cells (53-fold vs 19-fold increases at 0.3 mg/kg TransCon IL-2 β/γ, respectively), which aligns with their reported higher IL-2Rβ expression levels.…”

“… 13 20 38 39 Unlike cynomolgus IL-2Rs that bind human IL-2 with similar affinity/potency as the human counterparts, and unlike mouse IL-2Rα which maintains good affinity to human IL-2, mouse IL-2Rβ has substantially lower potency for human IL-2. 39 40 Thus, high doses of TransCon IL-2 β/γ were required in mice, resulting in a narrow therapeutic window for assessing efficacy in mouse models. Additionally, multiple doses of TransCon IL-2 β/γ and higher dose levels were required in mice compared with monkeys to induce robust proliferative responses and increases in CD8 + T cell numbers.…”

Implication of99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells

“… 14 Treg cells highly express IL-2Rαβγ, while naïve CD8 + T cells, CD4 + /CD8 + T cells and NK cells highly express IL-2Rβγ. 15 Wild-type IL-2 shows higher binding affinity to IL-2Rαβγ than IL-2Rβγ (Kd values 10 −11 vs 10 −9 M), therefore, IL-2 preferentially binds to immunosuppressive Treg cells over tumor-killing CD8 + T cells. 16 Sum IL-2 is an artificial variant of IL-2 with six mutations, while L80F, R81D, L85V, I86V and I92F mutations enhance the binding affinity to IL-2Rβ; and F42A mutation reduces the interaction with IL-2Rα.…”

744 Interim single-agent safety and anti-tumor activity from dose escalation phase of ABILITY study on MDNA11, a long-acting beta-only IL-2 agonist

“…MDNA11 is an albuminfused long-acting engineered IL-2 agonist with enhanced affinity for IL-2Rbg with no binding to IL-2Ra, enabling Q2W administration, limiting Treg activation while potentiating antitumor CD8+ T and NK cells and reducing toxicities. 1 Methods The objective of the dose-escalation phase of the ABILITY (A Beta-only IL-2 ImmunoTherapY) study is to determine the safety and tolerability, define the recommended phase-2 dose (RP2D), and assess preliminary tumor response of MDNA11 in patients with advanced solid tumors. In this modified 3+3 dose escalation, patients received a fixed dose of 3 (dose level 1 or DL1), 10 (DL2) or 30 (DL3) ug/kg by intravenous (IV) infusion on a Q2W schedule.…”