Abstract
Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain.
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References
Di Paolo NC, Shayakhmetov DM . Adenovirus de-targeting from the liver. Curr Opin Mol Ther 2009; 11: 523–531.
Bayo-Puxan N, Cascallo M, Gros A, Huch M, Fillat C, Alemany R . Role of the putative heparan sulfate glycosaminoglycan-binding site of the adenovirus type 5 fiber shaft on liver detargeting and knob-mediated retargeting. J Gen Virol 2006; 87: 2487–2495.
Martin K, Brie A, Saulnier P, Perricaudet M, Yeh P, Vigne E . Simultaneous CAR- and alpha V integrin-binding ablation fails to reduce Ad5 liver tropism. Mol Ther 2003; 8: 485–494.
Kalyuzhniy O, Di Paolo NC, Silvestry M, Hofherr SE, Barry MA, Stewart PL et al. Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. ProcNatl Acad Sci USA 2008; 105: 5483–5488.
Waddington SN, McVey JH, Bhella D, Parker AL, Barker K, Atoda H et al. Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 2008; 132: 397–409.
Gimenez-Alejandre M, Cascallo M, Bayo-Puxan N, Alemany R . Coagulation factors determine tumor transduction in vivo. Hum Gene Ther 2008; 19: 1415–1419.
Kritz AB, Nicol CG, Dishart KL, Nelson R, Holbeck S, Von Seggern DJ et al. Adenovirus 5 fibers mutated at the putative HSPG-binding site show restricted retargeting with targeting peptides in the HI loop. Mol Ther 2007; 15: 741–749.
Rittner K, Schreiber V, Erbs P, Lusky M . Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies. Cancer Gene Ther 2007; 14: 509–518.
Krasnykh V, Dmitriev I, Mikheeva G, Miller CR, Belousova N, Curiel DT . Characterization of an adenovirus vector containing a heterologous peptide epitope in the HI loop of the fiber knob. J Virol 1998; 72: 1844–1852.
Belousova N, Krendelchtchikova V, Curiel DT, Krasnykh V . Modulation of adenovirus vector tropism via incorporation of polypeptide ligands into the fiber protein. J Virol 2002; 76: 8621–8631.
Xia H, Anderson B, Mao Q, Davidson BL . Recombinant human adenovirus: targeting to the human transferrin receptor improves gene transfer to brain microcapillary endothelium. J Virol 2000; 74: 11359–11366.
Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, Dmitriev I et al. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 2002; 62: 1266–1270.
Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol 1998; 72: 9706–9713.
Suzuki K, Fueyo J, Krasnykh V, Reynolds PN, Curiel DT, Alemany R . A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin Cancer Res 2001; 7: 120–126.
Bayo-Puxan N, Gimenez-Alejandre M, Lavilla-Alonso S, Gros A, Cascallo M, Hemminki A et al. Replacement of adenovirus type 5 fiber shaft heparan sulfate proteoglycan-binding domain with RGD for improved tumor infectivity and targeting. Hum Gene Ther 2009; 20: 1214–1221.
Rojas JJ, Guedan S, Searle PF, Martinez-Quintanilla J, Gil-Hoyos R, Alcayaga-Miranda F et al. Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses. Mol Ther 2010; 18: 1960–1971.
Aghi M, Martuza RL . Oncolytic viral therapies-the clinical experience. Oncogene 2005; 24: 7802–7816.
Liu Q, Zaiss AK, Colarusso P, Patel K, Haljan G, Wickham TJ et al. The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther 2003; 14: 627–643.
Cascallo M, Alonso MM, Rojas JJ, Perez-Gimenez A, Fueyo J, Alemany R . Systemic toxicity-efficacy profile of ICOVIR-5, a potent and selective oncolytic adenovirus based on the pRB pathway. Mol Ther 2007; 15: 1607–1615.
Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G et al. Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene 1998; 17: 1969–1978.
Guedan S, Rojas JJ, Gros A, Mercade E, Cascallo M, Alemany R . Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther 2010; 18: 1275–1283.
Acknowledgements
We thank Blanca Luena and Eduard Serra for their technical assistance. This work was supported by BIO2008-04692-C03-01 (RA) from the ‘Ministerio de Ciencia y Tecnología’ and FIS grant PI08/1661 (MC) from the Instituto de Salud Carlos III of the Government of Spain, 2009SGR283 research grant (RA) from the ‘Generalitat de Catalunya’, and by Mutua Madrileña Medical Research Foundation (MC). RA belongs to the Network of Cooperative Research on Cancer (C03-10), ‘Instituto de Salud Carlos III’ of the Government of Spain.
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Rojas, J., Gimenez-Alejandre, M., Gil-Hoyos, R. et al. Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD. Gene Ther 19, 453–457 (2012). https://doi.org/10.1038/gt.2011.106
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DOI: https://doi.org/10.1038/gt.2011.106
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