Skip to main content

Tumor Targeting of Oncolytic Adenoviruses Using Bispecific Adapter Proteins

  • Protocol
  • First Online:
Oncolytic Viruses

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2058))

Abstract

Tumor-selectively replicating “oncolytic” adenoviruses based on serotype 5 are promising tools for the treatment of solid tumors. However, their effective delivery to the tumor by systemic administration remains challenging. Several strategies of molecular retargeting have been pursued to equip adenoviruses with molecular features that facilitate their efficient uptake by tumors and to protect healthy tissue from damage. Transductional retargeting can be conveniently achieved using bispecific molecular adapter proteins based on the ectodomain of the coxsackievirus and adenovirus receptor linked to tumor ligands of choice. In this chapter, we describe methods for their design, purification, and application.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Larson C, Oronsky B, Scicinski J, Fanger GR, Stirn M, Oronsky A, Reid TR (2015) Going viral: a review of replication-selective oncolytic adenoviruses. Oncotarget 6:19976–19989

    Article  Google Scholar 

  2. Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, Prabhu SS, Rao G, Fuller GN, Aldape KD et al (2018) Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 36:1419–1427

    Article  CAS  Google Scholar 

  3. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A et al (1996) An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376

    Article  CAS  Google Scholar 

  4. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P, Shi YX, Levin VA, Yung WK, Kyritsis AP (2000) A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 19:2–12

    Article  CAS  Google Scholar 

  5. Ko D, Hawkins L, Yu DC (2005) Development of transcriptionally regulated oncolytic adenoviruses. Oncogene 24:7763–7774

    Article  CAS  Google Scholar 

  6. Aghi M, Martuza RL (2005) Oncolytic viral therapies – the clinical experience. Oncogene 24:7802–7816

    Article  CAS  Google Scholar 

  7. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275:1320–1323

    Article  CAS  Google Scholar 

  8. Shayakhmetov DM, Gaggar A, Ni S, Li ZY, Lieber A (2005) Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol 79:7478–7491

    Article  CAS  Google Scholar 

  9. Kalyuzhniy O, Di Paolo NC, Silvestry M, Hofherr SE, Barry MA, Stewart PL, Shayakhmetov DM (2008) Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. Proc Natl Acad Sci U S A 105:5483–5488

    Article  CAS  Google Scholar 

  10. Douglas JT, Kim M, Sumerel LA, Carey DE, Curiel DT (2001) Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors. Cancer Res 61:813–817

    CAS  PubMed  Google Scholar 

  11. Uusi-Kerttula H, Davies JA, Thompson JM, Wongthida P, Evgin L, Shim KG, Bradshaw A, Baker AT, Rizkallah PJ, Jones R et al (2018) Ad5NULL-A20: a tropism-modified, alphavbeta6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. Clin Cancer Res 24:4215–4224

    Article  Google Scholar 

  12. Wickham TJ, Tzeng E, Shears LL, Roelvink PW, Li Y, Lee GM, Brough DE, Lizonova A, Kovesdi I (1997) Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. J Virol 71:8221–8229

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, Dmitriev I, Krasnykh V, Mikheeva GV, Barnes MN, Alvarez RD et al (2002) Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 62:1266–1270

    CAS  PubMed  Google Scholar 

  14. Magnusson MK, Hong SS, Henning P, Boulanger P, Lindholm L (2002) Genetic retargeting of adenovirus vectors: functionality of targeting ligands and their influence on virus viability. J Gene Med 4:356–370

    Article  CAS  Google Scholar 

  15. Kawakami Y, Li H, Lam JT, Krasnykh V, Curiel DT, Blackwell JL (2003) Substitution of the adenovirus serotype 5 knob with a serotype 3 knob enhances multiple steps in virus replication. Cancer Res 63:1262–1269

    CAS  PubMed  Google Scholar 

  16. Henning P, Lundgren E, Carlsson M, Frykholm K, Johannisson J, Magnusson MK, Tang E, Franqueville L, Hong SS, Lindholm L et al (2006) Adenovirus type 5 fiber knob domain has a critical role in fiber protein synthesis and encapsidation. J Gen Virol 87:3151–3160

    Article  CAS  Google Scholar 

  17. Krasnykh V, Belousova N, Korokhov N, Mikheeva G, Curiel DT (2001) Genetic targeting of an adenovirus vector via replacement of the fiber protein with the phage T4 fibritin. J Virol 75:4176–4183

    Article  CAS  Google Scholar 

  18. Schagen FH, Wensveen FM, Carette JE, Dermody TS, Gerritsen WR, van Beusechem VW (2006) Genetic targeting of adenovirus vectors using a reovirus sigma1-based attachment protein. Mol Ther 13:997–1005

    Article  CAS  Google Scholar 

  19. Baker AT, Aguirre-Hernandez C, Hallden G, Parker AL (2018) Designer oncolytic adenovirus: coming of age. Cancers (Basel) 10:pii: E201

    Article  Google Scholar 

  20. Martin NT, Wrede C, Niemann J, Brooks J, Schwarzer D, Kuhnel F, Gerardy-Schahn R (2018) Targeting polysialic acid-abundant cancers using oncolytic adenoviruses with fibers fused to active bacteriophage borne endosialidase. Biomaterials 158:86–94

    Article  CAS  Google Scholar 

  21. Curiel DT (1999) Strategies to adapt adenoviral vectors for targeted delivery. Ann N Y Acad Sci 886:158–171

    Article  CAS  Google Scholar 

  22. Haisma HJ, Grill J, Curiel DT, Hoogeland S, van Beusechem VW, Pinedo HM, Gerritsen WR (2000) Targeting of adenoviral vectors through a bispecific single-chain antibody. Cancer Gene Ther 7:901–904

    Article  CAS  Google Scholar 

  23. Dmitriev I, Kashentseva E, Rogers BE, Krasnykh V, Curiel DT (2000) Ectodomain of coxsackievirus and adenovirus receptor genetically fused to epidermal growth factor mediates adenovirus targeting to epidermal growth factor receptor-positive cells. J Virol 74:6875–6884

    Article  CAS  Google Scholar 

  24. Kashentseva EA, Seki T, Curiel DT, Dmitriev IP (2002) Adenovirus targeting to c-erbB-2 oncoprotein by single-chain antibody fused to trimeric form of adenovirus receptor ectodomain. Cancer Res 62:609–616

    CAS  PubMed  Google Scholar 

  25. Li HJ, Everts M, Pereboeva L, Komarova S, Idan A, Curiel DT, Herschman HR (2007) Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter. Cancer Res 67:5354–5361

    Article  CAS  Google Scholar 

  26. Kloos A, Woller N, Gurlevik E, Ureche CI, Niemann J, Armbrecht N, Martin NT, Geffers R, Manns MP, Gerardy-Schahn R et al (2015) PolySia-specific retargeting of oncolytic viruses triggers tumor-specific immune responses and facilitates therapy of disseminated lung cancer. Cancer Immunol Res 3:751–763

    Article  CAS  Google Scholar 

  27. Li HJ, Everts M, Yamamoto M, Curiel DT, Herschman HR (2009) Combined transductional untargeting/retargeting and transcriptional restriction enhances adenovirus gene targeting and therapy for hepatic colorectal cancer tumors. Cancer Res 69:554–564

    Article  CAS  Google Scholar 

  28. Kim J, Smith T, Idamakanti N, Mulgrew K, Kaloss M, Kylefjord H, Ryan PC, Kaleko M, Stevenson SC (2002) Targeting adenoviral vectors by using the extracellular domain of the coxsackie-adenovirus receptor: improved potency via trimerization. J Virol 76:1892–1903

    Article  CAS  Google Scholar 

  29. Kuhnel F, Schulte B, Wirth T, Woller N, Schafers S, Zender L, Manns M, Kubicka S (2004) Protein transduction domains fused to virus receptors improve cellular virus uptake and enhance oncolysis by tumor-specific replicating vectors. J Virol 78:13743–13754

    Article  Google Scholar 

  30. van Beusechem VW, Mastenbroek DC, van den Doel PB, Lamfers ML, Grill J, Wurdinger T, Haisma HJ, Pinedo HM, Gerritsen WR (2003) Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Ther 10:1982–1991

    Article  Google Scholar 

  31. Hemminki A, Wang M, Hakkarainen T, Desmond RA, Wahlfors J, Curiel DT (2003) Production of an EGFR targeting molecule from a conditionally replicating adenovirus impairs its oncolytic potential. Cancer Gene Ther 10:583–588

    Article  CAS  Google Scholar 

  32. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 95:2509–2514

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Else-Kröner-Fresenius-Stiftung and Deutsche Forschungsgemeinschaft (DFG).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Florian Kühnel .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Niemann, J., Kühnel, F. (2020). Tumor Targeting of Oncolytic Adenoviruses Using Bispecific Adapter Proteins. In: Engeland, C. (eds) Oncolytic Viruses. Methods in Molecular Biology, vol 2058. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9794-7_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9794-7_3

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9793-0

  • Online ISBN: 978-1-4939-9794-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics