7M2G

INTERLEUKIN-2 (human) mutant P65K, C125S

7M2G の概要

• エントリーDOI: 10.2210/pdb7m2g/pdb
• 分子名称: Interleukin-2, SULFATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: cytokine il-2 mutein human, cytokine
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15640.14

構造登録者

Ptacin, J.L.,Milla, M.E.,Steinbacher, S.,Maskos, K.,Thomsen, M. (登録日: 2021-03-16, 公開日: 2021-08-04, 最終更新日: 2024-10-30)

主引用文献

Ptacin, J.L.,Caffaro, C.E.,Ma, L.,San Jose Gall, K.M.,Aerni, H.R.,Acuff, N.V.,Herman, R.W.,Pavlova, Y.,Pena, M.J.,Chen, D.B.,Koriazova, L.K.,Shawver, L.K.,Joseph, I.B.,Milla, M.E.
An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism.
Nat Commun, 12:4785-4785, 2021

PubMed Abstract: The implementation of applied engineering principles to create synthetic biological systems promises to revolutionize medicine, but application of fundamentally redesigned organisms has thus far not impacted practical drug development. Here we utilize an engineered microbial organism with a six-letter semi-synthetic DNA code to generate a library of site-specific, click chemistry compatible amino acid substitutions in the human cytokine IL-2. Targeted covalent modification of IL-2 variants with PEG polymers and screening identifies compounds with distinct IL-2 receptor specificities and improved pharmacological properties. One variant, termed THOR-707, selectively engages the IL-2 receptor beta/gamma complex without engagement of the IL-2 receptor alpha. In mice, administration of THOR-707 results in large-scale activation and amplification of CD8 T cells and NK cells, without Treg expansion characteristic of IL-2. In syngeneic B16-F10 tumor-bearing mice, THOR-707 enhances drug accumulation in the tumor tissue, stimulates tumor-infiltrating CD8 T and NK cells, and leads to a dose-dependent reduction of tumor growth. These results support further characterization of the immune modulatory, anti-tumor properties of THOR-707 and represent a fundamental advance in the application of synthetic biology to medicine, leveraging engineered semi-synthetic organisms as cellular factories to facilitate discovery and production of differentiated classes of chemically modified biologics.

PubMed: 34373459
DOI: 10.1038/s41467-021-24987-9

実験手法

X-RAY DIFFRACTION (1.79 Å)