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

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.

• Authors: 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
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 85 (Apr 17 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24741998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Antigens, Neoplasm
• Antineoplastic Agents
• Cell Adhesion Molecules
• EPCAM protein, human
• Epithelial Cell Adhesion Molecule
• Recombinant Fusion Proteins
• Single-Chain Antibodies
• CD40 Ligand
• Rituximab

Topics

• Antibodies, Monoclonal, Murine-Derived (pharmacology)
• Antigens, CD20 (genetics, metabolism)
• Antigens, Neoplasm (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• B-Lymphocytes (drug effects, metabolism, pathology)
• CD40 Ligand (genetics, metabolism)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dendritic Cells (drug effects, metabolism, pathology)
• Epithelial Cell Adhesion Molecule
• Gene Expression
• HEK293 Cells
• Humans
• Molecular Targeted Therapy
• Recombinant Fusion Proteins (genetics, metabolism, pharmacology)
• Rituximab
• Single-Chain Antibodies (genetics, metabolism)