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

Autor: Edwin Bremer, Hans W. Nijman, Harald Wajant, Daniela Siegmund, Anna A. Rybczynska, Wijnand Helfrich, Götz Ulrich Grigoleit, Corinna Strohm, Kim L Brunekreeft, Marloes J. M. Gooden, Marco de Bruyn
Přispěvatelé: Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL)
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Cancer Research
medicine.medical_treatment
Gene Expression
Antibodies
Monoclonal
Murine-Derived

immune system diseases
LYMPHOMA
CD40L
Molecular Targeted Therapy
B-Lymphocytes
biology
Cell Death
hemic and immune systems
Epithelial Cell Adhesion Molecule
medicine.anatomical_structure
PHASE-I
Oncology
Molecular Medicine
IMMUNE MODULATION
Fusion protein
Cell Survival
T cell
Recombinant Fusion Proteins
CD40 Ligand
Antineoplastic Agents
chemical and pharmacologic phenomena
DENDRITIC CELLS
ScFv
Antigen
Antigens
Neoplasm

Cell Line
Tumor

medicine
Humans
CD20
ddc:610
RITUXIMAB
IMMUNOTHERAPY
Antigen-presenting cell
B cell
Targeting
CD40
Research
Immunotherapy
Antigens
CD20

HEK293 Cells
EpCAM
Cancer cell
biology.protein
Cancer research
T-CELLS
AUTOLOGOUS TUMOR
MONOCLONAL-ANTIBODIES
LIGAND
Cell Adhesion Molecules
Single-Chain Antibodies
Zdroj: Molecular Cancer
Molecular Cancer, 13:85. BMC
ISSN: 1476-4598
DOI: 10.1186/1476-4598-13-85
Popis: 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.
Databáze: OpenAIRE