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Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles.

Broos, Sissela LU ; Sandin, Linda C; Apel, Jenny LU ; Tötterman, Thomas H; Akagi, Takami; Akashi, Mitsuru; Borrebaeck, Carl LU ; Ellmark, Peter and Lindstedt, Malin (2012) In Biomaterials 33(26). p.6230-6239
Abstract
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(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-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-NPs... (More)
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(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-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-NPs 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-α 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell, proliferation, Protein adsorption, Immunostimulation, Drug delivery, Nanoparticle
in
Biomaterials
volume
33
issue
26
pages
6230 - 6239
publisher
Elsevier
external identifiers
  • pmid:22687756
  • wos:000306720400027
  • scopus:84862867187
ISSN
1878-5905
DOI
10.1016/j.biomaterials.2012.05.011
language
English
LU publication?
yes
id
6a73fb51-ff8b-4385-8d92-1520679dab78 (old id 2859534)
date added to LUP
2012-07-06 15:41:07
date last changed
2017-01-22 03:07:27
@article{6a73fb51-ff8b-4385-8d92-1520679dab78,
  abstract     = {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(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-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-NPs 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-α 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.},
  author       = {Broos, Sissela and Sandin, Linda C and Apel, Jenny and Tötterman, Thomas H and Akagi, Takami and Akashi, Mitsuru and Borrebaeck, Carl and Ellmark, Peter and Lindstedt, Malin},
  issn         = {1878-5905},
  keyword      = {Cell,proliferation,Protein adsorption,Immunostimulation,Drug delivery,Nanoparticle},
  language     = {eng},
  number       = {26},
  pages        = {6230--6239},
  publisher    = {Elsevier},
  series       = {Biomaterials},
  title        = {Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles.},
  url          = {http://dx.doi.org/10.1016/j.biomaterials.2012.05.011},
  volume       = {33},
  year         = {2012},
}