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Recombinant AAV gene therapy for the treatment of EGFR positive lung cancer

Date

10 Oct 2016

Session

Poster display

Presenters

Kam Zaki

Citation

Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362

Authors

K. Zaki1, L. Agundez2, B. Sanchez3, M. Linden2, E. Henckaerts2, Y. Takeuchi4, M. Collins1

Author affiliations

  • 1 Division Of Advanced Therapies, National Institute for Biological Standards and Control, EN6 3QG - Potters Bar/GB
  • 2 Department Of Infectious Diseases, King' College London School of Medicine, London/GB
  • 3 Department Of Tumour Immunology, Center of Molecular Immunology, Havana/CU
  • 4 Division Of Infection And Immunity, UCL - University College London, London/GB
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Resources

Background

Gene therapy using recombinant adeno-associated virus (rAAV) encoding monoclonal antibody (mAb) sequence injected into mice muscle has been shown to produce sustained level of serum antibody level capable of protecting animals from infectious disease in mice models. We aim to develop a protocol to achieve a therapeutic serum level of 7A7, an anti-epidermal growth factor receptor (EGFR) mAb in mouse models for the treatment of EGFR-positive lung cancer.

Methods

rAAV encoding 7A7 light and heavy chains driven by tMCK, a muscle specific promoter (AAV8-7A7) was produced. AAV8-7A7 was administered intra-muscularly to mice in all studies. Serial bleeds were performed at appropriate intervals to monitor 7A7 levels. Detection of serum 7A7 was done by ELISA with human EGFR (hEGFR) antigen. In dose escalation studies, different doses of AAV8-7A7 vector were administered to healthy C57Bl/6 mice. For tumour protection studies, 1x1011 v.g. of AAV8-7A7 were administered followed by tumour inoculation 6 weeks later, either subcutaneously (subcutaneous model) or intravenously (metastatic model). Human A431 luciferase tumour was inoculated in Balb/C nude mice whilst murine 3LL-D122 luciferase tumour was inoculated in C57Bl/6 mice. Tumours were monitored using caliper measurements and in vitro imaging system (IVIS).

Results

ELISA using hEGFR was able to detect serum 7A7 in mice following AAV8-7A7 administration. Higher dose of viral vector results in higher dose of detectable serum 7A7. In Balb/C nude mice with subcutaneous A431 luciferase tumours, smaller tumours with lower luminescence signal were observed in mice administered with AAV8-7A7 compared to mice injected with IM PBS. Bigger tumours with higher luminescence signal were observed in mice given IV 7A7 compared to mice adminstered with AAV8-7A7.

Conclusions

We have developed a protocol to administer AAV8-7A7, a recombinant AAV encoding 7A7, an anti-EGFR antibody that could offer protection against subcutaneous A431 luciferase tumours in Balb/C nude mice compared to PBS control. Similar protection experiments in both subcutaneous and metastatic Lewis lung carcinoma models using murine 3LL-D122 cells as well as in metastatic A431 xenograft model are ongoing and results will be updated.

Clinical trial identification

Legal entity responsible for the study

National Institute for Biological Standards and Control

Funding

National Institute for Biological Standards and Control

Disclosure

All authors have declared no conflicts of interest.

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