Antibody-drug Conjugates or ADCs are relatively new anti-cancer drugs.

Consisting of an antibody linked to a cell-killing, chemotherapeutic agent, these agents are designed to target specif cancers without harming the surrounding tissue. In other words, the antibodies part of an ADC recognizes and bind to certain receptors, using the target-specificity of monoclonal antibodies or antibody fragments, and adhere exclusively to specific membrane receptors that are characteristic of a tumor cell.

The potent, small molecule, chemotherapeutic drug is not released until the receptor has brought the entire structure into the cell. Only after the linker is cleaved do these cell-killing drugs become active. In turn, this creates an excellent control mechanism of drug activation, resulting in an increase of the therapeutic window and, thereby, increasing the use of the anti-cancer drugs.

Antibody-drug Conjugates are currently used for the treatment of lymphoma and metastatic breast cancer. Today, four Antibody-drug Conjugates have been approved by the U.S. Food and Drug Administration (FDA).  These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.

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“These ADCs work very well,” explained Marc Robillard of Tagworks Pharmaceuticals, a company based at the Radboud University Medical Center (RUMC) compound in Nijmegen, The Netherlands.

“[However],” Robillard noted, “for many other tumors, including colon cancer and ovarian cancer, this method is not yet applicable. The problem is that there are not [enough] 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.”

Drug release
It is vital to ensure that the chemotherapy drug is also released if the antibody-drug conjugate remains on the outside of the tumor cells. To achieve this objective, scientists at Tagworks have designed a smart variant of an antibody-drug conjugate.

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.

Following this step, scientists at Tagworks, focusing on chemically triggered release mechanisms for antibody-drug conjugates, succeeded in modifying a fast and highly selective click reaction, known as an inverse-electron-demand-Diels-Alder (IEDDA) reaction, in such a way that a selective bioorthogonal release, a chemical reaction that occurs inside of living systems without interfering with native biochemical processes.  When successful, this approach makes it possible to expand the scope of suitable targets for antibody-drug conjugates with slow- or non-internalizing targets and extracellular-matrix constituents that are not suitable for biological cleavage mechanisms. [1][2]

Figure 1.0: Existing antibody-drug conjugate technologies rely on a process in which an ADC bind to a tumor cell-specific membrane receptor and subsequently is internalized. Following internalization, the small-cell, cytotoxic, chemotherapeutic agents is activated. However, because the number of tumor-specific receptors ensuring efficient internalization is limited, especially in solid tumors, a wide range of cancer-targets remains out of reach for antibody-drug conjugates. Scientists at Tagworks Pharmaceuticals have developed a proprietary solution based on chemically triggered release mechanisms called the inverse-electron-demand-Diels-Alder or IEDDA reaction. Using this approach, thes scientists achieved selective bioorthogonal release. According to the scientists, this approach holds great promise for using chemically triggered release of a drug from a tumor-bound antibody-drug conjugate. Courtesy: © 2010 – 2018. Tagworks Pharmaceuticals, Nijmegen, The Netherlands. Used with permission.

“Our innovation is that we inject a second component that ‘click-releases’ the chemotherapy drug from the Antibody-drug Conjugate. 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,” Robillard summarized.

Effective in mice
The first results of this new ‘click-to-release’ method in mice have now been published in Nature Communications.[3]

“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,” Robillard said.

Ongoing cooperation
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, which offers high-level expertise in bioanalytical mass spectrometry combined with in-depth knowledge on biomedical and clinical applications, embedded in a cutting-edge clinical and fundamental research environment.

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.”

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