Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles.
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.
Department of Immunotechnology, BMC D13, Lund University, SE-221 84 Lund, Sweden.
Sissela
S
Broos
Linda C
LC
Sandin
Jenny
J
Apel
Thomas H
TH
Tötterman
Takami
T
Akagi
Mitsuru
M
Akashi
Carl A K
CA
Borrebaeck
Peter
P
Ellmark
Malin
M
Lindstedt
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid