Silver et al. fused vWF collagen binding domain (CBD) to F10 – a fusion comprising human IL-2 and an anti-IL-2 Ab that blocks IL-2/IL-2Rα and boosts IL-2/IL-2Rβ binding to bias TEFF over Treg cell activation – to create F10 IC-CBD. Compared to controls, intratumoral (i.t.) injection of F10 IC-CBD exhibited increased/prolonged bioavailability and bioactivity in situ, minimal systemic exposure, a wider safety margin, and enhanced/potent efficacy in tumor-bearing mice. This was due to collagen binding and TEFF bias. I.t. injection of F10 IC-CBD also elicited systemic immunity, as evidenced by an abscopal response, and its antitumor efficacy was potentiated by systemic PD-1 blockade.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Translational Tissue Engineering Cent
Author Info: (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.
