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Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM
H J Haisma1, H M Pinedo, A Rijswijk
1Gene Therapy Program, Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Abstract:
The utility of adenoviral vectors for cancer therapy is limited due to their lack of specificity for tumor cells. In order to target adenovirus to tumor, the natural tropism of the adenovirus should be ablated and replaced by a tumor-specific binding domain. To this end, a neutralizing anti-fiber antibody conjugated to an anti-EpCAM antibody was created that targets the adenovirus to the EpCAM antigen present on tumor cells. The EpCAM antigen was chosen as the target because this antigen is highly expressed on a variety of adenocarcinomas of different origin such as breast, ovary, colon and lung, whereas EpCAM expression is limited in normal tissues. In these studies, the EpCAM-targeted adenovirus was shown to infect specifically cancer cell lines of different origin expressing EpCAM such as ovary, colon and head and neck. Gene transfer was blocked by excess anti-EpCAM antibody and dramatically reduced in EpCAM negative cell lines, thus showing the specificity of the EpCAM-targeted adenovirus. Importantly, infection with targeted adenovirus was independent of CAR, which is the natural receptor for adenovirus binding, since blocking of CAR with recombinant fiber knob did not affect infection with targeted adenovirus. Apart from the cancer cell lines, the efficacy of targeted viral infection was studied in freshly isolated primary human colon cancer cells. As colon cancer predominantly metastasizes to liver, and adenovirus has a high tropism for hepatocytes, we also sought to determine if the EpCAM-targeted adenovirus showed reduced infectivity of human liver cells. The bispecific antibody could successfully mediate gene transfer to primary human colon cancer cells, whereas it almost completely abolished infection of liver cells. This work thus demonstrates that EpCAM-targeted adenoviral vectors can be specifically directed to a wide variety of adenocarcinomas. This approach may prove to be useful for selective gene therapy of cancer.
Insights
Adenoviral vectors were engineered to target EpCAM-expressing tumors using a bispecific antibody, enhancing cancer gene therapy specificity. This approach successfully targeted adenocarcinomas while sparing healthy liver cells, showing promise for selective cancer treatment.
Area of Science:
- Oncolytic Virotherapy
- Molecular and Cellular Oncology
- Gene Therapy
Background:
- Adenoviral vectors are promising for cancer therapy but lack tumor specificity.
- Natural adenovirus tropism limits their targeted application in oncology.
- Engineering adenovirus tropism is crucial for effective and safe cancer gene therapy.
Purpose of the Study:
- To develop an EpCAM-targeted adenoviral vector for specific cancer cell targeting.
- To ablate natural adenovirus tropism and replace it with tumor-specific binding.
- To evaluate the efficacy and specificity of EpCAM-targeted adenovirus in various cancer models.
Main Methods:
- Conjugation of a neutralizing anti-fiber antibody with an anti-EpCAM antibody to create a bispecific antibody.
- Targeting adenovirus to EpCAM antigen highly expressed on adenocarcinomas.
- Assessing gene transfer specificity in EpCAM-positive and EpCAM-negative cancer cell lines.
- Evaluating infectivity in primary human colon cancer cells and human liver cells.
Main Results:
- EpCAM-targeted adenovirus specifically infected EpCAM-expressing cancer cell lines (ovary, colon, head and neck).
- Gene transfer was blocked by anti-EpCAM antibody and reduced in EpCAM-negative cells.
- Infection was independent of the natural coxsackie and adenovirus receptor (CAR).
- Targeted adenovirus mediated gene transfer to primary colon cancer cells while sparing liver cells.
Conclusions:
- EpCAM-targeted adenoviral vectors demonstrate high specificity for a range of adenocarcinomas.
- This strategy offers a potential method for selective gene therapy in cancer treatment.
- The approach shows reduced infectivity in non-target tissues like the liver.
