TY  - JOUR
AU  - Fernández-Ulibarri, Inés
AU  - Hammer, Katharina
AU  - Arndt, Michaela
AU  - Kaufmann, Johanna K
AU  - Dorer, Dominik
AU  - Engelhardt, Sarah
AU  - Kontermann, Roland E
AU  - Hess, Jochen
AU  - Allgayer, Heike
AU  - Krauss, Jürgen
AU  - Nettelbeck, Dirk
TI  - Genetic delivery of an immunoRNase by an oncolytic adenovirus enhances anticancer activity.
JO  - International journal of cancer
VL  - 136
IS  - 9
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-02533
SP  - 2228 - 2240
PY  - 2015
AB  - Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase-encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody-fusion protein for targeted bystander killing of tumor cells (viro-antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR-binding scFv antibody fragment fused to the RNase Onconase (ONC(EGFR)) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONC(EGFR) expression by oncolytic adenoviruses is feasible with an optimized, replication-dependent gene expression strategy. Virus-encoded ONC(EGFR) induces potent and EGFR-dependent bystander killing of tumor cells. Importantly, the ONC(EGFR)-encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR-positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONC(EGFR) is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONC(EGFR)-encoding oncolytic adenovirus represents a novel agent for treatment of EGFR-positive tumors. This viro-antibody therapy platform can be further developed for targeted/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof.
KW  - Antibodies, Viral (NLM Chemicals)
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - RNA (NLM Chemicals)
KW  - EGFR protein, human (NLM Chemicals)
KW  - Receptor, Epidermal Growth Factor (NLM Chemicals)
KW  - Ribonucleases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25303768
DO  - DOI:10.1002/ijc.29258
UR  - https://inrepo02.dkfz.de/record/126505
ER  -