Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.

Autor: Battin C; Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.; Loop Lab Bio GmbH, Vienna, Austria., De Sousa Linhares A; Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.; Loop Lab Bio GmbH, Vienna, Austria., Leitner J; Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Grossmann A; Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.; Loop Lab Bio GmbH, Vienna, Austria., Lupinek D; Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.; Loop Lab Bio GmbH, Vienna, Austria., Izadi S; Department of Applied Genetics and Cell Biology, Institute for Plant Biotechnology and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria., Castilho A; Department of Applied Genetics and Cell Biology, Institute for Plant Biotechnology and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria., Waidhofer-Söllner P; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Grabmeier-Pfistershammer K; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Stritzker J; Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. jochen.stritzker@looplabbio.com.; Loop Lab Bio GmbH, Vienna, Austria. jochen.stritzker@looplabbio.com., Steinberger P; Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology, Institute of Immunology, Medical University of Vienna, Vienna, Austria. peter.steinberger@meduniwien.ac.at.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2023 Sep; Vol. 72 (9), pp. 3029-3043. Date of Electronic Publication: 2023 Jun 13.
DOI: 10.1007/s00262-023-03474-8
Abstrakt: Targeting co-stimulatory receptors promotes the activation and effector functions of anti-tumor lymphocytes. 4-1BB (CD137/TNFSF9), a member of the tumor necrosis factor receptor superfamily (TNFR-SF), is a potent co-stimulatory receptor that plays a prominent role in augmenting effector functions of CD8 + T cells, but also CD4 + T cells and NK cells. Agonistic antibodies against 4-1BB have entered clinical trials and shown signs of therapeutic efficacy. Here, we have used a T cell reporter system to evaluate various formats of 4-1BBL regarding their capacity to functionally engage its receptor. We found that a secreted 4-1BBL ectodomain harboring a trimerization domain derived from human collagen (s4-1BBL-Tri XVIII ) is a strong inducer of 4-1BB co-stimulation. Similar to the 4-1BB agonistic antibody urelumab, s4-1BBL-Tri XVIII is very potent in inducing CD8 + and CD4 + T cell proliferation. We provide first evidence that s4-1BBL-Tri XVIII can be used as an effective immunomodulatory payload in therapeutic viral vectors. Oncolytic measles viruses encoding s4-1BBL-Tri XVIII significantly reduced tumor burden in a CD34 + humanized mouse model, whereas measles viruses lacking s4-1BBL-Tri XVIII were not effective. Natural soluble 4-1BB ligand harboring a trimerization domain might have utility in tumor therapy especially when delivered to tumor tissue as systemic administration might induce liver toxicity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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