Journal
JOURNAL OF BIOTECHNOLOGY
Volume 290, Issue -, Pages 53-58Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jbiotec.2018.12.007
Keywords
Tumor targeting; Antibody-fusion proteins; Calreticulin; ED-A(+) fibronectin
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Funding
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [670603]
- Swiss National Science Foundation [310030B_163479/1]
- Swiss National Science Foundation (SNF) [310030B_163479] Funding Source: Swiss National Science Foundation (SNF)
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We report the design and characterization of novel fusion proteins, consisting of the F8 antibody and of murine calreticulin (Calr). The F8 antibody recognizes the alternatively-spliced ED-A domain of fibronectin, an extra-cellular matrix component found in most tumor types, while calreticulin has previously been described as an eat-me signal for dendritic cells and phagocytes. Four fusion proteins, differing in antibody formats and peptide linkers, were produced in mammalian cells, purified to homogeneity and tested in vitro and in vivo. A quantitative biodistribution in F9 tumor-bearing mice revealed that the homobivalent F8-F8-Calr format, featuring a tandem diabody structure, had the best tumor-homing properties and, for this reason, this protein was studied in therapy experiments in CT26 tumor-bearing mice. Intravenous administration of F8-F8-Calr led to a tumor growth retardation, which could be further improved by combination with anti-PD1 antibody treatment. Immunohistochemical analysis revealed an increased density of CD8(+) T cells, CD11c(+) dendritic cells and F4/80(+) macrophages in tumor tissue. Even though F8-F8-Calr did not lead to cancer cures at the doses tested, the excellent tolerability profile and the ability to favor a leukocyte infiltration into the neoplastic mass suggests that the targeted delivery of calreticulin may be considered for combination therapy approaches.
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