Huyghe, Van Parys, and Cauwels et al. engineered mCD13-AFR, a VHH-CD13-targeted, weakly active, mutant TNF(AFR) that rescued TNF activity when bound to endothelial cells. In mice, perilesional mCD13-AFR treatment upregulated endothelial cell adhesion molecules and delayed B16B16 tumor growth without systemic toxicity. mCD13-AFR potentiated hCD70 CAR T cell activity, increasing infiltration into hCD70+ tumors and inducing tumor stasis, and synergized with CD13 targeted IFNγ in B16B16 and huRL models to induce endothelial apoptosis, necrosis, and total tumor regression.
Contributed by Samuel Goldman
Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity-on-Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF-based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T-cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8-targeted type I interferon AcTakine. Co-treatment with a CD13-targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible.
Author Info: (1) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (2) Cytokine Receptor Laboratory, VIB
Author Info: (1) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (2) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (3) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (4) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (5) Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. (6) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (7) Orionis Biosciences, Boston, MA, USA. (8) Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (9) Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (10) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (11) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (12) CNRS UMR 5235, University of Montpellier, Montpellier, France. (13) Orionis Biosciences, Boston, MA, USA. (14) VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (15) Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium. (16) Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (17) Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Orionis Biosciences, Boston, MA, USA.
