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Saupe, Falk
Publications (6 of 6) Show all publications
Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.-O., Andersson, C. E., . . . Olsson, A.-K. (2017). Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously. The FASEB Journal, 31(3), 1204-1214.
Open this publication in new window or tab >>Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 3, 1204-1214 p.Article in journal (Refereed) Published
Abstract [en]

With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abswere analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinatedmice displayed a 2-to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generatedAbs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.- Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.- O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.- K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.

Keyword
cancer, VLRB, tolerance, ED-A, ED-B
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-320668 (URN)10.1096/fj.201600820R (DOI)000395671200032 ()27993994 (PubMedID)
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2017-06-07Bibliographically approved
Cedervall, J., Dragomir, A., Saupe, F., Zhang, Y., Ärnlöv, J., Larsson, E., . . . Olsson, A.-K. (2017). Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.. Oncoimmunology, 6(8), Article ID e1320009.
Open this publication in new window or tab >>Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, e1320009Article in journal (Refereed) Published
Abstract [en]

Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

Keyword
Cancer, DNase I, GSK484, kidney injury, neutrophil extracellular traps
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-329754 (URN)10.1080/2162402X.2017.1320009 (DOI)000408961700006 ()28919990 (PubMedID)
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2017-12-14Bibliographically approved
Spenle, C., Saupe, F., Midwood, K., Burckel, H., Noel, G. & Orend, G. (2015). Tenascin-C: Exploitation and collateral damage in cancer management. CELL ADHESION & MIGRATION, 9(1-2), 141-153.
Open this publication in new window or tab >>Tenascin-C: Exploitation and collateral damage in cancer management
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2015 (English)In: CELL ADHESION & MIGRATION, ISSN 1933-6918, Vol. 9, no 1-2, 141-153 p.Article, review/survey (Refereed) Published
Abstract [en]

Despite an increasing knowledge about the causes of cancer, this disease is difficult to cure and still causes far too high a death rate. Based on advances in our understanding of disease pathogenesis, novel treatment concepts, including targeting the tumor microenvironment, have been developed and are being combined with established treatment regimens such as surgical removal and radiotherapy. Yet it is obvious that we need additional strategies to prevent tumor relapse and metastasis. Given its exceptional high expression in most cancers with low abundance in normal tissues, tenascin-C appears an ideal candidate for tumor treatment. Here, we will summarize the current applications of targeting tenascin-C as a treatment for different tumors, and highlight the potential of this therapeutic approach.

Keyword
cancer, extracellular matrix, tenascin-C, tumor microenvironment
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-252467 (URN)10.1080/19336918.2014.1000074 (DOI)000351609600014 ()25569113 (PubMedID)
Available from: 2015-05-07 Created: 2015-05-07 Last updated: 2015-05-07Bibliographically approved
Saupe, F., Huijbers, E. J. M., Hein, T., Femel, J., Cedervall, J., Olsson, A.-K. & Hellman, L. (2015). Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters. The FASEB Journal, 29(8), 3253-3262.
Open this publication in new window or tab >>Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters
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2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, 3253-3262 p.Article in journal (Refereed) Published
Abstract [en]

We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wildtype (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.

Keyword
cancer, ED-B of fibronectin, adjuvant, CpG, type I IFN
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-261251 (URN)10.1096/fj.15-271502 (DOI)000358796900014 ()25868727 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2015-09-01 Created: 2015-08-31 Last updated: 2017-12-04Bibliographically approved
Femel, J., Huijbers, E. J. M., Saupe, F., Cedervall, J., Zhang, L., Dimberg, A. & Hellman, L. (2014). Progression of metastatic breast cancer can be attenuated by therapeutic vaccination against the tumor vascular marker ED-A. Angiogenesis, 17(3), 769-769.
Open this publication in new window or tab >>Progression of metastatic breast cancer can be attenuated by therapeutic vaccination against the tumor vascular marker ED-A
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2014 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 17, no 3, 769-769 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Microbiology in the medical area Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-229603 (URN)000338213400175 ()
Available from: 2014-08-12 Created: 2014-08-12 Last updated: 2018-01-11Bibliographically approved
Femel, J., Huijbers, E. J., Saupe, F., Cedervall, J., Zhang, L., Roswall, P., . . . Olsson, A.-K. (2014). Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.. OncoTarget, 5(23), 12418-12427.
Open this publication in new window or tab >>Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
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2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, 12418-12427 p.Article in journal (Refereed) Published
Abstract [en]

Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

Keyword
ED-A, immunization, tumor vasculature, therapeutic, cancer vaccine
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-229544 (URN)000348037700049 ()25360764 (PubMedID)
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2017-12-05Bibliographically approved
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