BackgroundInterleukin-2 (IL-2) plays a pivotal role in immune homeostasis due to its ability to stimulate numerous lymphocyte subsets including natural killer (NK) cells, effector CD4+and CD8+T cells, and regulatory T cells (Tregs). Low concentrations of IL-2 induce signaling through the high-affinity IL-2 receptor (IL-2R) comprised of IL-2Rα, IL-2Rβ, and common γ chain (γc), preferentially expressed on Tregs. Higher concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, composed of IL-2Rβ and γc, expressed on memory CD8+T cells and NK cells. Recombinant human IL-2 (rhIL-2) is approved for treatment of metastatic melanoma and renal cell carcinoma (RCC), but adverse events including capillary leak syndrome, potentially mediated through interaction with the high-affinity IL-2R, limit its therapeutic use. Furthermore, antitumor efficacy of IL-2 may also be limited by preferential expansion of immunosuppressive Tregs. ALKS 4230 is an engineered fusion protein comprised of a circularly-permuted IL-2 with the extracellular domain of IL-2Rα, designed to selectively activate effector lymphocytes bearing the intermediate-affinity IL-2R.ResultsALKS 4230 was equipotent to rhIL-2 in activating human cells bearing the intermediate-affinity IL-2R, and less potent than rhIL-2 on cells bearing the high-affinity IL-2R. As observed in vitro with primary human cells from healthy donors and advanced cancer patients, ALKS 4230 induced greater activation and expansion of NK cells with reduced expansion of Tregsrelative to rhIL-2. Similarly, in mice, ALKS 4230 treatment stimulated greater expansion of NK cells and memory-phenotype CD8+T cells at doses that did not expand or activate Tregs. ALKS 4230 treatment induced significantly lower levels of proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and interferon gamma relative to rhIL-2. Furthermore, ALKS 4230 exhibited superior antitumor efficacy in the mouse B16F10 lung tumor model, where ALKS 4230 could be administered via multiple routes of administration and dosing schedules while achieving equivalent antitumor efficacy.ConclusionsALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties resulting in both improved antitumor efficacy and lower indices of toxicity relative to rhIL-2 in mice. These data highlight the potential of ALKS 4230 as a novel cancer immunotherapy, and as such, the molecule is being evaluated clinically.
Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel cytokine, created by the fusion of circularly permuted interleukin-2 (IL-2) to the IL-2Rα subunit of the IL-2 receptor (IL-2R) complex, that confers selectivity for the intermediate-affinity IL-2R expressed on CD8 + T cells and natural killer (NK) cells. The pharmacokinetics and selective pharmacodynamic properties of nemvaleukin have been demonstrated using in vitro and in vivo mouse models. The pharmacokinetic/pharmacodynamic effects of nemvaleukin on immune cell subtypes were evaluated in cynomolgus monkeys following intravenous (i.v.) and subcutaneous (s.c.) administration to inform dose selection and predict pharmacodynamic effects in humans. Male drug-naïve cynomolgus monkeys (N = 15) were administered either single-dose (i.v. 0.3 mg/kg; s.c. 0.3 mg/kg or 1.0 mg/kg) or repeated-doses (i.v. 0.1 mg/kg on days 1-5 or s.c. 0.5 mg/kg on days 1 and 4) of nemvaleukin. Serial blood samples were collected for pharmacokinetic assessment, immunophenotyping by flow cytometry, and profiling of serum cytokines. Repeat-dose s.c. administration of nemvaleukin with less frequent dosing resulted in total systemic exposure and trough serum concentrations comparable to those seen with i.v. administration, with lower peak serum concentrations. Transient elevation of interferon-γ and IL-6 peaked at 2 and 8 hours after i.v. and s.c. administration, respectively. Selective expansion of immunoprotective central memory, effector memory, and terminal effector CD8 + T cells and CD56 + NK cells, and minimal expansion of immunosuppressive CD4 + CD25 + FoxP3 + regulatory T cells was observed following both i.v. and s.c. administration. These data support the ongoing clinical evaluation of i.v. and s.c. nemvaleukin.
RDB 1450 is an engineered fusion protein which selectively activates the intermediate-affinity IL-2 receptor present on NK cells and memory CD8 T cells. In rodents, RDB 1450 has a half-life of 6-8 hours, compared to a half-life of minutes for recombinant human IL-2 (rhIL-2). Repeat daily dosing (QD) of RDB 1450 in mice results in marked expansion of NK cells and CD8+CD44high T cells, with minimal expansion of CD4+ regulatory T cells (Tregs). Higher QD doses elicit more pronounced effector cell expansion with modest pulmonary edema. TID delivery of the same total daily dose of RDB 1450 enhances the immunological responses in the absence of pulmonary edema. These results suggest that prolonged delivery of reduced concentrations of RDB 1450 drive the desired immune responses with improved tolerability. In contrast, high circulating concentrations of rhIL-2 are required to stimulate effector cells due to its preferential activation of Tregs at lower concentrations. The selectivity profile and favorable pharmacokinetics of RDB 1450 highlight its potential as a novel, differentiated immunotherapeutic agent for the treatment of cancer. Citation Format: Heather C. Losey, Jared E. Lopes, Reginald L. Dean, Heather Flick, Madison Gomes, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Chunhua Wang, Julie F. Waters, Juan C. Alvarez. Utilizing a selective agonist of the intermediate-affinity IL-2 receptor with an improved pharmacokinetic profile leads to an enhanced immunostimulatory response With reduced toxicity in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4280. doi:10.1158/1538-7445.AM2015-4280
ALKS 4230 is a selective agonist of the intermediate-affinity IL-2 receptor (IL-2R). A phase 1 study is ongoing to evaluate the safety and tolerability of ALKS 4230 in the treatment of patients with refractory solid tumors. The selectivity of ALKS 4230 is achieved through the stable fusion of circularly permuted IL-2 to the extracellular portion of the IL-2Rα chain, CD25. The resulting fusion protein is sterically prevented from binding to the high-affinity IL-2R complex, comprised of IL-2Rα, IL-2Rβ, and common gamma chain, expressed preferentially on CD4+ FOXP3+ regulatory T cells (CD4+ Tregs) yet retains full ability to signal through the intermediate-affinity IL-2R complex, comprised of IL-2Rβ and common gamma chain, expressed on memory CD8+ T cells and NK cells. Repeated dosing of ALKS 4230 drives the significant expansion of various CD8+ T cell and NK cell populations without activation and minimal expansion of CD4+ Tregs in mice and non-human primates (NHP). The kinetics of the immunological responses in mice and NHP demonstrate that the pharmacodynamic effects persist beyond systemic exposure of ALKS 4230. Data demonstrating the effects of ALKS 4230 on tumor-infiltrating lymphocyte populations in syngeneic tumor models will also be presented. Citation Format: Jared E. Lopes, Heather C. Losey, Reginald L. Dean, Heather L. Flick, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Juan C. Alvarez. Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2017-2663
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