- search hit 1 of 1
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.…
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: | https://pubmed.ncbi.nlm.nih.gov/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): | CC BY: Creative-Commons-Lizenz: Namensnennung |