ADC drug development
ADCs (Antibody Drug Conjugates) 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.
Mechanism of Action of ADCs
The basis of ADC technology is the conjugation of specific antibodies to a toxin via a chemical linker. These antibodies transport the toxin selectively to the cancer cell, which internalizes the toxin. In the diseased cell, the toxin can maximize its effect and destroy the cell. This way, systemic effects are minimized and side effects can be avoided.
Amanitin as an Innovative Compound for Cancer Therapy
Heidelberg Pharma has for some years been working on a proprietary technology for so called ATACs (Antibody Targeted Amanitin Conjugates). ATACs are ADCs that are based on the compound Amanitin as a toxin. 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.
While they are a promising approach, ATACs are also complex structures that require constant further development and improvement. Selecting an appropriate antibody, optimizing the linker and also chemical Amanitin synthesis are challenges that still need to be addressed.
Efficacy of Anti-CD269 ATAC in a Multiple Myeloma Animal Model
- Development of several ATAC variants against the target molecule CD269 in the cancer cell
- Anti-CD269 ATACs were administered in single doses specified above
- Anti-CD269 ATACs cause a complete regression of the tumors
- No hepatic toxicity observed in the animal model
Building a Proprietary ATAC Pipeline
Besides improving the ATAC technology, the activities of Heidelberg Pharma are focused on building its own ATAC pipeline. This move stems from the 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.