Build or destroy technology

Researchers at the University of Zurich have modified a widespread respiratory virus called adenovirus so that it functions like a Trojan horse and transports genes for therapeutic agents directly into tumor cells. In contrast to chemotherapy or radiation therapy, this approach does not harm normal, healthy cells. Once in the tumor cells, the genes supplied serve as templates for therapeutic antibodies, cytokines and other messenger substances that are produced by the cancer cells themselves and eliminate the tumor from within.

Channel adenoviruses undetected by the immune system

"We get the tumor to eliminate itself by causing its cells to produce therapeutic agents," says postdoc Sheena Smith, who led the development of the approach. Research group leader Andreas Plückthun explains: "The active ingredients such as therapeutic antibodies or messenger substances stay in the exact place in the body where they are needed instead of being distributed in the bloodstream where they can damage healthy organs and tissues."

The UZH researchers call their technology SHREAD: for SHielded, REtargeted ADenovirus. It builds on key technologies that the Plückthun working group had already developed in order to guide adenoviruses that no longer carry viral genes past the immune system to specific points in the body.

High levels of antibodies in the tumor, low levels in other tissues

The scientists used the SHREAD system to induce a tumor in the breast of a mouse to produce a clinically approved antibody called trastuzumab (Herceptin®) for the treatment of breast cancer. They found that after a few days, SHREAD produced a greater amount of the clinical antibody in the tumor than when the drug was injected directly. At the same time, the concentration in the bloodstream and in other tissues, in which side effects can occur, was significantly lower. With the help of a sophisticated, high-resolution 3D imaging process and tissue made transparent, they were able to show how the therapeutic antibody produced in the body creates pores in blood vessels in the tumor, destroys cells there and treats it from the inside out.

Use to fight Covid-19 is being investigated

Plückthun, Smith and their colleagues emphasize that the SHREAD technology is not only suitable for the fight against breast cancer. Since healthy tissue no longer comes into contact with significant amounts of medication, the technology can also be used to administer a wide range of so-called biologics - powerful protein-based drugs that would otherwise be too toxic.

The members of the Plückthun Group are currently using their technology in a project funded by the Swiss National Science Foundation, which aims at a Covid-19 therapy. Adenoviral vectors are already used in several Covid vaccines, including those from Johnson & Johnson, AstraZeneca, China's CanSino Biologics and Russia's Sputnik V - but without SHREAD technology. “By administering the SHREAD treatment to the patient via an inhaled aerosol, our approach could allow the targeted production of Covid antibody therapies in lung cells. In other words, where it is needed most, ”explains Smith. "This could reduce costs, increase the accessibility of Covid therapies and, with the inhalation approach, also improve the administration of vaccines."

Literature:

Smith, SN, Schubert, R., Brücher, D., Simic, B., Schmid, M., Kirk, N., Freitag, P., Gradinaru, V. and Plückthun, A. The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody as shown by PACT. PNAS. 17 May 2021. DOI: 10.1073 / pnas.2017925118

Financing:

The work is supported by the Swiss National Science Foundation (Sinergia Grant 170929) and the National Cancer Institute of the NIH (F32CA189372). The ongoing Covid project is supported by the Swiss National Science Foundation (NRP78, 198287).