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

Molecular Cancer

Research

Götz U Grigoleit¹  Corinna Strohm²  Harald Wajant²  Daniela Siegmund²  Anna A Rybczynska³  Hans W Nijman⁴  Marloes J Gooden⁴  Marco de Bruyn⁵  Kim L Brunekreeft⁵  Wijnand Helfrich⁶  Edwin Bremer⁶ 

[1]Department of Hematology, Medical Clinic and Polyclinic II, University of Würzburg, Würzburg, Germany

[2]Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Würzburg, Würzburg, Germany

[3]Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[4]Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[5]Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[6]Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Würzburg, Würzburg, Germany

[7]Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

关键词: CD20;    EpCAM;    CD40L;    ScFv;    Targeting;    Fusion protein;   

DOI  :  10.1186/1476-4598-13-85

 received in 2013-12-06, accepted in 2014-04-08,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundStimulation 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.MethodsTo 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.ResultsTargeted 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.ConclusionsTargeted 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.

【 授权许可】

Unknown   
© Brunekreeft et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.