Activity of an adeno-associated virus (AAV)-derived anti-Insulin-like Growth Factor 1 Receptor (IGF1R) in vitro and pharmacodynamic activity in an IGF1R+ Human Colon Carcinoma Xenograft Mouse Model
Author: Diego Strianese
Base Hospital / Institution: University of Naples Federico II
ePoster presentation
Abstract ID: 24-358
Purpose
In 2020, the FDA approved the first treatment for thyroid eye disease (TED), Teprotumumab, a fully-human monoclonal antibody that blocks the insulin growth factor 1 receptor (IGF1R). Adverse reactions have been reported with the current treatment regimen, including hearing impairment, hyperglycemia, and muscle spasms. To mitigate the risks while retaining efficacy and durability, we have developed an investigational adeno-associated virus (AAV) gene therapy product engineered to express an anti-IGF1R antibody (AAV.anti-IGF1R). The aims of this study are: (1) to demonstrate in vitro secretion of human IgG1 antibody with anti-IGF1R activity from supernatants of AAV.anti-IGF1R in fibrosarcoma (HT1080) cells, and (2) to compare in vivo pharmacodynamic activity of AAV.anti-IGF1R with weekly teprotumumab administration in a tumor xenograft mouse model.
Methods
Immortalized human embryonic kidney (HEK293) cells were transduced with AAV.anti-IGF1R and harvested supernatants were used for antibody production and pharmacodynamic activity, compared to recombinant Teprotumumab in HT1080 cells. In xenografted nude mice bearing IGF1R+ human colon carcinoma, a single intra-tumoral injection of 7.75e11 vector genomes (vg) of AAV.anti-IGF1R was compared to weekly intraperitoneal injection (IP) of Teprotumumab. At different timepoints post treatment, animals were sacrificed to assess tumors and serum.
Results
A comparable quantity of vectorized antibody and recombinant Teprotumumab bound to IGF1R with similar inhibitory activity in HT1080 cells. A significant and similar decrease of IGF1R levels in tumors was observed in animals treated with one-time AAV.anti-IGF1R or weekly recombinant Teprotumumab.
Conclusion
Our data demonstrate that one-time locally administered AAV.anti-IGF1R generates functional antibody with pharmacodynamic activity equivalent to exogenously administrated Teprotumumab.
Additional Authors
| First name | Last name | Base Hospital / Institution |
|---|---|---|
| Ruth M | Castellanos Rivera | University of Naples Federico II |
| Rachel | Eclov | University of Naples Federico II |
| Angela | Ambakhutwala | University of Naples Federico II |
| Robin | Marjoram | University of Naples Federico II |
| Andrew | Murphy | University of Naples Federico II |
| Brian | Furmanski | University of Naples Federico II |
| Ashlyn | Bassiri | University of Naples Federico II |
| Uma | Karadge | University of Naples Federico II |
| Chris | Lassiter | University of Naples Federico II |
| William | Chappell | University of Naples Federico II |
| Lauren | Parker | University of Naples Federico II |
| Benjamin | Johnson | University of Naples Federico II |
| Jiewu | Liu | University of Naples Federico II |
| Pilar | Prentiss | University of Naples Federico II |
| David | Sutton | University of Naples Federico II |
| Jessica | Raubenolt | University of Naples Federico II |
| Suzanne | Freitag | University of Naples Federico II |
| Michele | Stone | University of Naples Federico II |
