An engineered immunocytokine with collagen affinity improves the tumor bioavailability, tolerability, and therapeutic efficacy of IL-2

Aliyah B Silver; Stephany Y Tzeng; Mallory Lager; Jeremy Wang; Jun Ishihara; Jordan J Green; Jamie B Spangler

doi:10.1016/j.xcrm.2023.101289

An engineered immunocytokine with collagen affinity improves the tumor bioavailability, tolerability, and therapeutic efficacy of IL-2

Cell Rep Med. 2023 Nov 21;4(11):101289. doi: 10.1016/j.xcrm.2023.101289.

Authors

Aliyah B Silver¹, Stephany Y Tzeng², Mallory Lager³, Jeremy Wang⁴, Jun Ishihara⁵, Jordan J Green⁶, Jamie B Spangler⁷

Affiliations

¹ Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.
⁴ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.
⁵ Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
⁶ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical and Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jamie.spangler@jhu.edu.

Abstract

The clinical utility of human interleukin-2 (hIL-2) is limited by its short serum half-life, preferential activation of regulatory T (T_Reg) over immune effector cells, and dose-limiting toxicities. We previously engineered F10 immunocytokine (IC), an intramolecularly assembled cytokine/antibody fusion protein that linked hIL-2 to an anti-IL-2 antibody (denoted F10) that extended IL-2 half-life and augmented the immune effector to T_Reg ratio. Here, we leveraged molecular engineering to improve the anti-tumor therapeutic efficacy and tolerability of F10 IC by developing an iteration, denoted F10 IC-CBD (collagen binding domain), designed for intratumoral administration and in situ retention based on collagen affinity. F10 IC-CBD retained IL-2 bioactivity exclusively in the tumor and eliminated IL-2-associated toxicities. Furthermore, F10 IC exhibited potent single-agent therapeutic efficacy and synergy with systemic immune checkpoint blockade and elicited an abscopal response in mouse tumors models. This engineered fusion protein presents a prototype for the design of intratumoral therapies.

Keywords: antibody; cancer; collagen affinty; immunocytokine; immunotherapy; interleukin-2; intratumoral administration.

Publication types

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

MeSH terms

Animals
Biological Availability
Collagen
Humans
Interleukin-2* / genetics
Interleukin-2* / pharmacology
Interleukin-2* / therapeutic use
Mice
Neoplasms*

Substances

Interleukin-2
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding