Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

Bloomberg Kimmel Institute for Cancer Immunotherapy

Department of Biochemistry Emory University School of Medicine Atlanta Georgia USA

Department of Biochemistry Faculty of Science Charles University Prague Czech Republic

Department of Biology Johns Hopkins University Baltimore Maryland USA

Department of Biomedical Engineering Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Chemical and Biomolecular Engineering and

Department of Chemistry Johns Hopkins University Baltimore Maryland USA

Department of Oncology

Department of Ophthalmology Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Plastic and Reconstructive Surgery Johns Hopkins University School of Medicine Baltimore Maryland USA

Institute of Biotechnology of the Academy of Sciences of the Czech Republic Vestec Czech Republic

Laboratory of Molecular Immunology National Heart Lung and Blood Institute National Institutes of Health Bethesda Maryland USA

Laboratory of Tumor Immunology Institute of Microbiology of the Academy of Sciences of the Czech Republic Prague Czech Republic

Program in Molecular Biophysics Johns Hopkins University School of Medicine Baltimore Maryland USA

Sidney Kimmel Comprehensive Cancer Center; and

Translational Tissue Engineering Center

Vascularized Composite Allotransplantation Laboratory Department of Plastic and Reconstructive Surgery

Před aktualizací

bioRxiv. 2023 May 04:2023.05.03.539272. doi: 10.1101/2023.05.03.539272. PubMed

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