Casales, E. (Erkuden)

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2013 - 20192

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    Short-term local expression of a PD-L1 blocking antibody from a self-replicating RNA vector induces potent antitumor responses
    (2019) Kochan, G. (Grazyna); Mancheño, U. (Uxua); Sanchez-Paulete, A.R. (Alfonso R.); Smerdou, C. (Cristian); Galindo, J. (Javier); Ballesteros-Briones, M.C. (María Cristina); Hervas-Stubbs, S. (Sandra); Melero, I. (Ignacio); Casales, E. (Erkuden); Prieto, J. (Jesús); Martisova, E. (Eva); Gorraiz, M. (Marta); Escors, D. (David); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María); Silva-Pilipich, N.R. (Noelia Romina); Lasarte, J.J. (Juan José)
    Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFVaPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and s
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    A simple and efficient method for the production of human glycosylated glial cell line-derived neurotrophic factor using a Semliki Forest virus expression system
    (Elsevier, 2013) Blanco-Prieto, M.J. (María José); Smerdou, C. (Cristian); Aymerich-Soler, M.S. (María Soledad); Tamayo, E. (Esther); Ansorena-Artieda, E. (Eduardo); Casales, E. (Erkuden); Garbayo, E; Aranda, A. (Alejandro)
    Human glial cell line-derived neurotrophic factor (hGDNF) is a very promising protein for the treatment of Parkinson's disease and other neurodegenerative disorders. The present work describes a quick and simple method to obtain a high amount of purified hGDNF using a mammalian cell-derived system. The method is based on the high expression level provided by a Semliki Forest virus vector and its ability to induce a strong shut-off of host-cell protein synthesis in mammalian cells. As a result, hGDNF is the only protein present in the supernatant and can be efficiently purified by a single chromatographic step. Using this system it was possible to eliminate other secreted proteins from the culture medium, like insulin-like growth factor-5, which are hard to remove using other hGDNF production methods. Purified hGDNF presents a complex glycosylation pattern typical of mammalian expression systems and is biologically active. This protocol could be extended to other secreted proteins and could be easily scaled up for industrial purposes.