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.

Heidelberg Pharma has build up a proprietary ADC technology platform using the active ingredient Amanitin. 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). Heidelberg Pharma wants to make this toxin available for cancer therapy.

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

Heidelberg Pharma's activities focus on establishing and expanding its own ADC technology platforms. In addition to Amanitin, since the 2023 fiscal year the Company has been using additional active ingredients, such as the topoisomerase inhibitor Exatecan or the Toll-like receptor TLR7 with immunostimulatory effects, to develop the best possible ADCs for additional target antigens and areas of application.

Exatecan is a synthetic derivative of the naturally occurring toxin camptothecin. Camptothecin is a cytostatic agent that is obtained from the seeds, roots, bark, wood and (young) leaves of the Chinese “Happy Tree” (Camptotheca acuminata). Camptothecin is a type I topoisomerase inhibitor. A topoisomerase is an enzyme that is responsible for relaxing double-stranded DNA during processes such as DNA replication and transcription. The mode of action used by topoisomerase I inhibitors targets reversible cleavage complexes in the DNA strand. This inhibition of the enzyme results in irregular, irreversible DNA damage such as breaks and cross-linking, which can therefore impair cell growth and cell division, consequently leading to pro­grammed cell death (apoptosis).

In recent years, this drug payload class has achieved positive results in clinical trials with ADCs. For example, the ADC trastuzumab-deruxtecan (Enhertu®), which uses the exatecan derivative Dxd as the payload, was approved by the FDA for HER2-positive metastatic mammary carcinoma in May 2022.

Together with Binghamton University, State University of New York, Heidelberg Pharma develops a novel and proprietary immunostimulatory technology platform, including potent novel immunostimulatory compounds (TLR-7 agonists) and ADC technology for the specific delivery of these compounds to tumor tissue.

The resulting immunostimulatory ADCs have the potential to harness the patient’s own immune system by making the tumor visible to the immune system to thus attack and eliminate malignancies. These immunostimulatory agents could be synergistic with cytotoxic agents, including ADCs generated by Heidelberg Pharma’s ATAC technology.