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An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

Author

Listed:
  • Jerod L. Ptacin

    (Synthorx, Inc., a Sanofi Company)

  • Carolina E. Caffaro

    (Synthorx, Inc., a Sanofi Company)

  • Lina Ma

    (Synthorx, Inc., a Sanofi Company)

  • Kristine M. San Jose Gall

    (Synthorx, Inc., a Sanofi Company)

  • Hans R. Aerni

    (Synthorx, Inc., a Sanofi Company)

  • Nicole V. Acuff

    (Synthorx, Inc., a Sanofi Company)

  • Rob W. Herman

    (Synthorx, Inc., a Sanofi Company)

  • Yelena Pavlova

    (Synthorx, Inc., a Sanofi Company)

  • Michael J. Pena

    (Synthorx, Inc., a Sanofi Company)

  • David B. Chen

    (Synthorx, Inc., a Sanofi Company)

  • Lilia K. Koriazova

    (Synthorx, Inc., a Sanofi Company)

  • Laura K. Shawver

    (Synthorx, Inc., a Sanofi Company)

  • Ingrid B. Joseph

    (Synthorx, Inc., a Sanofi Company)

  • Marcos E. Milla

    (Synthorx, Inc., a Sanofi Company)

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.

Suggested Citation

  • Jerod L. Ptacin & Carolina E. Caffaro & Lina Ma & Kristine M. San Jose Gall & Hans R. Aerni & Nicole V. Acuff & Rob W. Herman & Yelena Pavlova & Michael J. Pena & David B. Chen & Lilia K. Koriazova & , 2021. "An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24987-9
    DOI: 10.1038/s41467-021-24987-9
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    Cited by:

    1. Sasha B. Ebrahimi & Devleena Samanta, 2023. "Engineering protein-based therapeutics through structural and chemical design," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Yong Wang & Jingming Zhang & Boyang Han & Linzhi Tan & Wenkang Cai & Yuxuan Li & Yeyu Su & Yutong Yu & Xin Wang & Xiaojiang Duan & Haoyu Wang & Xiaomeng Shi & Jing Wang & Xing Yang & Tao Liu, 2023. "Noncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Elisa I. Rivas & Jenniffer Linares & Melissa Zwick & Andrea Gómez-Llonin & Marc Guiu & Anna Labernadie & Jordi Badia-Ramentol & Anna Lladó & Lídia Bardia & Iván Pérez-Núñez & Carolina Martínez-Ciarpag, 2022. "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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