1. Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.
- Author
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Battin C, De Sousa Linhares A, Leitner J, Grossmann A, Lupinek D, Izadi S, Castilho A, Waidhofer-Söllner P, Grabmeier-Pfistershammer K, Stritzker J, and Steinberger P
- Subjects
- Mice, Animals, Humans, Immunomodulating Agents, Tumor Necrosis Factor Receptor Superfamily, Member 9 genetics, Receptors, Tumor Necrosis Factor, Killer Cells, Natural, 4-1BB Ligand genetics, CD8-Positive T-Lymphocytes
- Abstract
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-TriXVIII ) is a strong inducer of 4-1BB co-stimulation. Similar to the 4-1BB agonistic antibody urelumab, s4-1BBL-TriXVIII is very potent in inducing CD8+ and CD4+ T cell proliferation. We provide first evidence that s4-1BBL-TriXVIII can be used as an effective immunomodulatory payload in therapeutic viral vectors. Oncolytic measles viruses encoding s4-1BBL-TriXVIII significantly reduced tumor burden in a CD34+ humanized mouse model, whereas measles viruses lacking s4-1BBL-TriXVIII 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).)- Published
- 2023
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