Targeted 'click-to-release' chemotherapy leads to potent antitumor activity in mice

May 4 2018

Antibody Drug Conjugates (ADCs) are relatively new anti-cancer drugs. They consist of an antibody to which a cell-killing molecule (chemotherapy) is attached. Antibodies can recognize and bind to certain receptors (the 'hands' on the outside of a cell) in a very targeted way. The antibody in an ADC is designed to adhere exclusively to receptors that are characteristic of a tumor cell. The chemotherapy drug is not released until the receptor has brought the entire structure into the cell, and then the chemotherapy drug can do its job.

ADCs are currently already used for the treatment of lymphoma and metastatic breast cancer. "These ADCs work very well," says Marc Robillard of Tagworks Pharmaceuticals, a company based at Radboud university medical center. "But for many other tumors, including colon cancer and ovarian cancer, this method is not yet applicable. The problem is that there are not many suitable cancer-specific receptors that automatically drag such an ADC into the cell, and if the ADC gets stuck on the outside, the chemotherapy drug will not be released and therefore can't do its job."

Chemotherapy drug released

It is vital to ensure that the chemotherapy drug is also released if the ADC remains on the outside of the tumor cells. To achieve this objective, Tagworks has designed a smart variant of the ADCs. The ADC is injected and then binds to the receptors on the tumor cells. After a day or two, the tumor is filled with these ADCs. So far, this is nothing new. Robillard: "Our innovation is that we inject a second component that 'click-releases' the chemotherapy drug from the ADC. As a result, a large quantity of chemotherapy is released very quickly, attacking the tumor. This method will hopefully enable us to treat many more types of cancer."

Effective in mice

The first results of this new 'click-to-release' method in mice have now been published in Nature Communications. Robillard: "We studied ovarian cancer and an aggressive form of colon cancer. In both cases we observed a pronounced anticancer effect. For control purposes, we also applied a 'traditional' ADC, i.e., without the second component that causes the chemotherapy drug to release, but this approach had no therapeutic effect in these forms of cancer."

Cooperation

In Nijmegen, Tagworks collaborates with a variety of research groups, Technology Centers and Research Facilities, which have been specifically set up for cooperation with the business community, including the Radboudumc Technology Center for Mass Spectrometry. In addition, Tagworks cooperates with specialized small and medium-sized enterprises that are also co-authors of the publication. According to Robillard, this illustrates the importance of cooperation. "Developing new drugs for cancer is very complex and requires the expertise of specialists. No party can do this by itself. I believe this result is a fine example of how you can maximize the innovative power of small and medium-sized businesses by joining forces and connecting with the advanced facilities and high-quality knowledge of institutions such as Radboud university medical center and Radboud University."