Mechanism of Action of ADCs
ADCs are antibody drug conjugates (ADCs) that combine the specificity of antibodies with the efficacy of toxins. Antibodies recognize target structures (antigens) on the surface of cancer cells and bind to them. These specific antibodies are linked to toxins via a chemical compound (linker), and the resulting conjugate carries the toxin directly to the cancer cell, where the toxin is internalized. In the diseased cell, the toxin is released and destroys the cell. Thus, the systemic effects are minimized, and side effects can be avoided.
ADCs promise huge potential for cancer therapy because they can selectively destroy cancer cells. Compared to other types of therapy, ADCs have a more favorable therapeutic index, which is the relation between efficiency and safety. By directly targeting the cancer cell, this highly specific technology can reduce side effects. Moreover, ADCs are able to act on dormant cells and are effective in patients who no longer respond to treatment.
Amanitin as an Innovative Compound for Cancer Therapy
Heidelberg Pharma has been working for some years on a proprietary technology for so called ATACs. ATACs are ADCs that are based on the ATAC technology, and their payload exists of amatoxin molecules. Heidelberg Pharma wants to make Amanitin available for cancer therapy. Amanitin has a unique biological mode of action which could be used as the basis for developing highly effective, innovative drugs. Amanitin is a member of the amatoxin group of natural poisons, which occur in the death cap mushroom (Amanita phalloides).
It works by inhibiting RNA polymerase II, which results in apoptosis. All other chemotherapy drugs used to date, including other ADCs, either function as what are known as “spindle poisons” (tubulin inhibitors) or work via binding to DNA, which makes them dependent on cell division. RNA polymerase II inhibition is a novel principle in cancer therapy and offers the possibility of breaking through drug resistance or destroying dormant tumor cells, which could produce major clinical advances.
ATACs are third generation ADCs characterized by improved efficacy and supposed to be effective also in dormant tumor cells, which are scarcely reached with existing standard therapies and contribute to tumor recurrence and resistance formation. These ATACs will also be used to treat therapy-resistant tumors that no longer respond to standard chemotherapy or anti-tumor antibodies.
YOUTUBE-Video: Prof. Andreas Pahl describes the ATAC technology (2016; in englisch) Link
Efficacy of HER-ATAC in a breast cancer animal model in comparison with Enhertu
An ATAC against the target molecule HER2 on the cancer cell was compared with the already approved HER2-Dxd-ADC (Enhertu®)
The HER2-ATAC showed a complete remission of the tumor
Building a Proprietary ATAC Pipeline
The activities of Heidelberg Pharma are focused on building its own ATAC pipeline. Based on successful in-licensing of antibodies and the data generated from the ATACs produced with these antibodies. The data available so far confirms the hope that the advantages of compounds based on Amanitin can be transferred into specific ATACs for use in different cancer indications. More details on our ATAC candidates can be found here.