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Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death

Please always quote using this URN: urn:nbn:de:bvb:20-opus-116682
  • Background: Stimulation of CD40 can augment anti-cancer T cell immune responses by triggering effective activation and maturation of antigen-presenting cells (APCs). Although CD40 agonists have clinical activity in humans, the associated systemic activation of the immune system triggers dose-limiting side-effects. Methods: To increase the tumor selectivity of CD40 agonist-based therapies, we developed an approach in which soluble trimeric CD40L (sCD40L) is genetically fused to tumor targeting antibody fragments, yielding scFv: CD40L fusionBackground: Stimulation of CD40 can augment anti-cancer T cell immune responses by triggering effective activation and maturation of antigen-presenting cells (APCs). Although CD40 agonists have clinical activity in humans, the associated systemic activation of the immune system triggers dose-limiting side-effects. Methods: To increase the tumor selectivity of CD40 agonist-based therapies, we developed an approach in which soluble trimeric CD40L (sCD40L) is genetically fused to tumor targeting antibody fragments, yielding scFv: CD40L fusion proteins. We hypothesized that scFv: CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L-like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain. Results: Targeted delivery of CD40L to the carcinoma marker EpCAM on carcinoma cells induced dose-dependent paracrine maturation of DCs similar to 20-fold more effective than a non-targeted control scFv: CD40L fusion protein. Similarly, targeted delivery of CD40L to the B cell leukemia marker CD20 induced effective paracrine maturation of DCs. Of note, the CD20-selective delivery of CD40L also triggered loss of cell viability in certain B cell leukemic cell lines as a result of CD20-induced apoptosis. Conclusions: Targeted delivery of CD40L to cancer cells is a promising strategy that may help to trigger cancer-localized activation of CD40 and can be modified to exert additional anti-cancer activity via the targeting domain.show moreshow less

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Metadaten
Author: Kim L. Brunekreeft, Corinna Strohm, Marloes J. Gooden, Anna A. Rybczynska, Hans W. Nijman, Götz U. Grigoleit, Wijnand Helfrich, Edwin Bremer, Daniela Siegmund, Harald Wajant, Marco de Bruyn
URN:urn:nbn:de:bvb:20-opus-116682
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik II
Language:English
Parent Title (English):Molecular Cancer
ISSN:1476-4598
Year of Completion:2014
Volume:13
Issue:85
Source:Molecular Cancer 2014 13:85. doi:10.1186/1476-4598-13-85
DOI:https://doi.org/10.1186/1476-4598-13-85
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24741998
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:CD20; CD40L; EpCAM; ScFv; T-cells; autologous tumor; dendritic cells; immune modulation; monoclonal-antibodies; targeting
Release Date:2015/08/03
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung