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Identification of potent biodegradable adjuvants that efficiently break self-tolerance: a key issue in the development of therapeutic vaccines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2009 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, 48-52 p.Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibodies are used successfully in the treatment of many human disorders. However, these antibodies are expensive and have in many countries put a major strain on the health care economy. Therapeutic vaccines, directed against the same target molecules, may offer a solution to this problem. Vaccines usually involve lower amount of recombinant protein, approximately 10,000-20,000 times less, which is significantly more cost effective. Attempts to develop such therapeutic vaccines have also been made. However, their efficacy has been limited by the lack of potent immunostimulatory compounds, adjuvants, for human use. To address this problem we have conducted a broad screening for adjuvants that can enhance the efficacy of therapeutic vaccines, whilst at the same time being non-toxic and biodegradable. We have now identified adjuvants that show these desired characteristics. A combination of Montanide ISA720 and phosphorothioate stabilized CpG stimulatory DNA, induced similar or even higher anti-self-antibody titers compared to Freund's adjuvant, currently the most potent, but also toxic, adjuvant available. This finding removes one of the major limiting factors in the field and facilitates the development of a broad range of novel therapeutic vaccines.

Place, publisher, year, edition, pages
2009. Vol. 28, no 1, 48-52 p.
Keyword [en]
Adjuvant, Anti-self-response, CpG, Stimulatory DNA, Therapeutic vaccines
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-119720DOI: 10.1016/j.vaccine.2009.09.122ISI: 000274869200007PubMedID: 19835827OAI: oai:DiVA.org:uu-119720DiVA: diva2:300739
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Development of a Cancer Vaccine Targeting Tumor Blood Vessels
Open this publication in new window or tab >>Development of a Cancer Vaccine Targeting Tumor Blood Vessels
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A treatment strategy for cancer is the suppression of tumor growth by directing an immune response to the tumor vessels, which will destroy the tissue.

In this thesis we describe the development of a vaccine that targets antigens expressed around angiogenic vasculature in most solid tumors. These antigens are alternative spliced extra domains of glycoproteins present in the extracellular matrix; e.g. the extra domain-B (ED-B) and extra domain-A (ED-A) of fibronectin and the C-domain of tenascin-C (TNCC).

We show that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Furthermore, tumor growth was inhibited and the changes observed in the tumor tissue were consistent with an attack of the tumor vasculature by the immune system.

For clinical development of therapeutic vaccines, targeting self-molecules like ED-B, a potent but non-toxic biodegradable adjuvant is required. The squalene-based Montanide ISA 720 (M720) in combination with CpG DNA fulfilled these requirements and induced an equally strong anti-self immune response as the preclinical golden standard Freund’s adjuvant. We have further characterized the immune response against ED-B generated with the adjuvant M720/GpG. 

The ED-B vaccine also inhibited tumor growth in a therapeutic setting in a transgenic mouse model of pancreatic insulinoma in which tumorigenesis was already initiated. Furthermore, antibodies against ED-A and TNCC could be induced in mice and rabbits. We analyzed the expression of ED-A in breast tumors of transgenic MMTV-PyMT mice, a metastatic breast cancer model, with the aim to use this model to study the effect of an ED-A vaccine on metastasis. We also detected ED-B in canine mammary tumor tissue. Therefore vascular antigens might also represent potential therapeutic targets in dogs. 

All together our preclinical data demonstrate that a vaccine targeting tumor blood vessels is a promising new approach for cancer treatment. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 85 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 755
Vaccine, Therapeutic, Cancer, Tumor, Angiogenesis, Immunization, Vascular, Extracellular matrix
National Category
Cell and Molecular Biology Immunology in the medical area Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedical Laboratory Science; Medical Cell Biology; Oncology; Medical Science
urn:nbn:se:uu:diva-170887 (URN)978-91-554-8317-3 (ISBN)
Public defence
2012-05-11, B42, Biomedicinsk Centrum (BMC), Husargatan 3, Uppsala, 09:00 (English)
Swedish Research Council
Available from: 2012-04-19 Created: 2012-03-13 Last updated: 2012-08-01Bibliographically approved

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