uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(gamma-glutamic acid) nanoparticles
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Show others and affiliations
2012 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 26, 6230-6239 p.Article in journal (Refereed) Published
Abstract [en]

Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(gamma-glutamic acid) nanoparticles (gamma-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to gamma-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NP5 induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-alpha in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.

Place, publisher, year, edition, pages
2012. Vol. 33, no 26, 6230-6239 p.
Keyword [en]
Drug delivery, Nanoparticle, Immunostimulation, Protein adsorption, Cell proliferation
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-179895DOI: 10.1016/j.biomaterials.2012.05.011ISI: 000306720400027OAI: oai:DiVA.org:uu-179895DiVA: diva2:547552
Available from: 2012-08-28 Created: 2012-08-27 Last updated: 2014-01-23Bibliographically approved
In thesis
1. Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
Open this publication in new window or tab >>Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer, historically considered a genetic disease, is currently acknowledged to affect the whole body. Our immune system is one key player that can elicit a response against malignant cells but can also promote tumorigenesis. Tumors avoid immune recognition by creating a suppressive microenvironment and inducing tolerance. T-cells are regarded a major effector cell type in tumor immunotherapy. An important ”switch” needed for T-cell activation involves so-called costimulatory and coinhibitory receptors. In this thesis, experimental tumor models were used to investigate the potential of immunomodulatory antibodies to stimulate immune cells and subsequently eliminate tumors.

First, systemic antibody blockade of two negative checkpoint regulators (CTLA-4 and PD-1) present on T-cells was evaluated in combination with local CpG therapy or standard BCG treatment. Indeed, this combinatorial therapy with CpG augmented anti-tumor effects with increased levels of tumor-directed T-cells and reduced tumor-infiltrating Tregs.

Secondly, as these immunomodulatory antibodies elicit severe side effects in patients, a local low-dose delivery regimen was explored as an alternative to systemic bolus treatment. Our results demonstrated that an approximately seven times lower dose of aCTLA-4, compared to systemic delivery, could eradicate both primary and distant tumors.

CD40-expressing APCs are another potential target in antibody-mediated cancer therapy. CD40-stimulated dendritic cells (DCs) have the capability to activate tumor-directed T-cells to kill tumor cells. We next sought to investigate agonistic CD40 antibody efficacy and in vivo biodistribution when delivered locally compared to the equivalent systemic dose. Anti-tumor effects were dependent on CD8+ T-cells, host CD40 expression and the presence of tumor antigen at the injection site. CD40 antibodies were cleared from the circulation and accumulated in lymphoid organs, where, upon repeated aCD40 dosing, target APC populations increased in numbers and upregulated their surface CD40 expression.

Lastly, CD40 agonist antibodies were mixed with nanoparticles to enhance their stimulatory properties. B-cells demonstrated increased proliferative capacity and DCs became more activated when exposed to the cocktail. Further, this combination reduced serum levels of pro-inflammatory cytokines compared to plain antibodies.      

The results herein advocate further exploratory studies of the delivery of monoclonal antibodies at the tumor site in order to improve anti-tumor effects and reduce toxicity.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 953
in situ checkpoint blockade, antibody-mediated tumor immunotherapy, CTLA-4, CD40, monoclonal antibodies, experimental animal model, Fc gamma receptor
National Category
Immunology in the medical area
Research subject
Medical Science
urn:nbn:se:uu:diva-210080 (URN)978-91-554-8806-2 (ISBN)
Public defence
2013-12-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2013-11-22 Created: 2013-10-30 Last updated: 2014-01-23

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Sandin, Linda C.Tötterman, Thomas H.
By organisation
Clinical Immunology
In the same journal
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 214 hits
ReferencesLink to record
Permanent link

Direct link