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 |
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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 |
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