TY  - JOUR
A1  - Brunekreeft, Kim L.
A1  - Strohm, Corinna
A1  - Gooden, Marloes J.
A1  - Rybczynska, Anna A.
A1  - Nijman, Hans W.
A1  - Grigoleit, Götz U.
A1  - Helfrich, Wijnand
A1  - Bremer, Edwin
A1  - Siegmund, Daniela
A1  - Wajant, Harald
A1  - de Bruyn, Marco
T1  - Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death
JF  - Molecular Cancer
N2  - 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 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.
KW  - CD20
KW  - EpCAM
KW  - CD40L
KW  - ScFv
KW  - targeting
KW  - dendritic cells
KW  - T-cells
KW  - monoclonal-antibodies
KW  - immune modulation
KW  - autologous tumor
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116682
SN  - 1476-4598
VL  - 13
IS  - 85
ER  - 
TY  - JOUR
A1  - Oehler, Beatrice
A1  - Kloka, Jan
A1  - Mohammadi, Milad
A1  - Ben-Kraiem, Adel
A1  - Rittner, Heike L.
T1  - D-4F, an ApoA-I mimetic peptide ameliorating TRPA1-mediated nocifensive behaviour in a model of neurogenic inflammation
JF  - Molecular Pain
N2  - Background
High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model.

Results
Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell–Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue H2O2 or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F.

Conclusions
D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.
KW  - TRPA1
KW  - capsaicin
KW  - reactive oxygen species
KW  - oxidised lipids
KW  - pain
KW  - targeting
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236061
VL  - 16
ER  -