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Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death.
- Source :
- Molecular Cancer; 2014, Vol. 13 Issue 1, p1-25, 24p, 2 Diagrams, 5 Graphs
- Publication Year :
- 2014
-
Abstract
- 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 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 ~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. [ABSTRACT FROM AUTHOR]
- Subjects :
- T cells
CANCER cells
BIOMOLECULES
IMMUNOLOGY
LYMPHOCYTES
Subjects
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 13
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Molecular Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 96042836
- Full Text :
- https://doi.org/10.1186/1476-4598-13-85