6VWU

X-ray structure of ALKS 4230, a fusion of circularly permuted human Interleukin-2 and Interleukin-2 Receptor alpha

Summary for 6VWU

• Entry DOI: 10.2210/pdb6vwu/pdb
• Descriptor: Interleukin-2,Interleukin-2 receptor subunit alpha (1 entity in total)
• Functional Keywords: circular permutation, alks 4230, cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 34464.32

Authors

Losey, H.C. (deposition date: 2020-02-20, release date: 2020-04-29, Last modification date: 2024-11-20)

Primary citation

Lopes, J.E.,Fisher, J.L.,Flick, H.L.,Wang, C.,Sun, L.,Ernstoff, M.S.,Alvarez, J.C.,Losey, H.C.
ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy.
J Immunother Cancer, 8:-, 2020

PubMed Abstract: Interleukin-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 (T). 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 (γ), preferentially expressed on T. Higher concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, composed of IL-2Rβ and γ, 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 T. 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.

PubMed: 32317293
DOI: 10.1136/jitc-2020-000673

Experimental method

X-RAY DIFFRACTION (3.4 Å)