A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy

Alfredo Quijano-Rubio; Aladdin M Bhuiyan; Huilin Yang; Isabel Leung; Elisa Bello; Lestat R Ali; Kevin Zhangxu; Jilliane Perkins; Jung-Ho Chun; Wentao Wang; Marc J Lajoie; Rashmi Ravichandran; Yun-Huai Kuo; Stephanie K Dougan; Stanley R Riddell; Jamie B Spangler; Michael Dougan; Daniel-Adriano Silva; David Baker

doi:10.1038/s41587-022-01510-z

A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy

Nat Biotechnol. 2023 Apr;41(4):532-540. doi: 10.1038/s41587-022-01510-z. Epub 2022 Oct 31.

Authors

Alfredo Quijano-Rubio^{1

2

3}, Aladdin M Bhuiyan^#^{4

5}, Huilin Yang^#⁶, Isabel Leung^#⁷, Elisa Bello^#^{4

5}, Lestat R Ali^{4

5}, Kevin Zhangxu^{4

5}, Jilliane Perkins¹, Jung-Ho Chun¹, Wentao Wang⁸, Marc J Lajoie^{1

9}, Rashmi Ravichandran¹, Yun-Huai Kuo⁶, Stephanie K Dougan^{4

10}, Stanley R Riddell⁷, Jamie B Spangler^{11

12}, Michael Dougan¹³, Daniel-Adriano Silva^{14

15

16}, David Baker^{17

18}

Affiliations

¹ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
² Department of Bioengineering, University of Washington, Seattle, WA, USA.
³ Monod Bio, Inc., Seattle, WA, USA.
⁴ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA.
⁸ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁹ Outpace Bio, Seattle, WA, USA.
¹⁰ Department of Immunology, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.
¹² Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.
¹³ Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mldougan@partners.org.
¹⁴ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA. dadriano@gmail.com.
¹⁵ Monod Bio, Inc., Seattle, WA, USA. dadriano@gmail.com.
¹⁶ Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China. dadriano@gmail.com.
¹⁷ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹⁸ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.

^# Contributed equally.

Abstract

The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15-Neoleukin-2/15 (Neo-2/15)-both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8⁺ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Cytokines*
Humans
Immunotherapy
Interleukin-2 / therapeutic use
Melanoma* / drug therapy
Mice

Substances

Cytokines
Interleukin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding