Back to Search
Start Over
Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2023 Sep; Vol. 72 (9), pp. 3029-3043. Date of Electronic Publication: 2023 Jun 13. - Publication Year :
- 2023
-
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 <superscript>+</superscript> T cells, but also CD4 <superscript>+</superscript> 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 <subscript>XVIII</subscript> ) is a strong inducer of 4-1BB co-stimulation. Similar to the 4-1BB agonistic antibody urelumab, s4-1BBL-Tri <subscript>XVIII</subscript> is very potent in inducing CD8 <superscript>+</superscript> and CD4 <superscript>+</superscript> T cell proliferation. We provide first evidence that s4-1BBL-Tri <subscript>XVIII</subscript> can be used as an effective immunomodulatory payload in therapeutic viral vectors. Oncolytic measles viruses encoding s4-1BBL-Tri <subscript>XVIII</subscript> significantly reduced tumor burden in a CD34 <superscript>+</superscript> humanized mouse model, whereas measles viruses lacking s4-1BBL-Tri <subscript>XVIII</subscript> 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.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 72
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 37310433
- Full Text :
- https://doi.org/10.1007/s00262-023-03474-8