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Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.ORCID-id: 0000-0001-6120-2683
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
Alligator Bioscience AB, Lund, Sweden.
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2014 (Engelska)Ingår i: Cancer Immunology Research, ISSN 2326-6066, Vol. 2, nr 1, s. 80-90Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment for advanced solid tumors and hematological cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events such as cytokine release syndrome and liver toxicity and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity and biodistribution in the experimental MB49 bladder cancer model. Anti-tumor effects were confirmed in the B16 model. In terms of anti-tumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T-cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in tumor-draining lymph nodes and spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in liver and blood compared to local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates anti-tumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic.

Ort, förlag, år, upplaga, sidor
2014. Vol. 2, nr 1, s. 80-90
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:uu:diva-209738DOI: 10.1158/2326-6066.CIR-13-0067ISI: 000340030900010PubMedID: 24778163OAI: oai:DiVA.org:uu-209738DiVA, id: diva2:659313
Tillgänglig från: 2013-10-25 Skapad: 2013-10-25 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Ingår i avhandling
1. Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
Öppna denna publikation i ny flik eller fönster >>Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.  

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 953
Nyckelord
in situ checkpoint blockade, antibody-mediated tumor immunotherapy, CTLA-4, CD40, monoclonal antibodies, experimental animal model, Fc gamma receptor
Nationell ämneskategori
Immunologi inom det medicinska området
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-210080 (URN)978-91-554-8806-2 (ISBN)
Disputation
2013-12-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-11-22 Skapad: 2013-10-30 Senast uppdaterad: 2018-01-11

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