ADC technology (antibody drug conjugates)
WILEX‘ subsidiary Heidelberg Pharma has focused on the development of a proprietary ADC technology in the last few years. Heidelberg Pharma was the first company to start on the research and development of the active substance Amanitin for treatment of cancer
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 favourable 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 on 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
The activities of Heidelberg Pharma besides improving the ATAC technology are focused on building its own pipeline. This move stems from the successful in-licensing of antibodies and the data generated from the ATACs produced from these. The data available so far confirm our hope that the advantages of products based on Amanitin can be transferred also to specific ATACs for use in different cancer indications. Find more details regarding our ATAC candidates here.
Licensing model for toxin linker technology: Heidelberg Pharma’s business model comprises the granting of ATAC technology licenses and its application on antibodies provided by customers. Heidelberg Pharma also offers customers the preclinical work necessary related to designing, optimizing, profiling and manufacturing new ATACs. Integrated into license agreements, toxin linker prototypes are made available and cross-linked to antibodies developed by partners, and tested biologically.
Product partnerships: In this model, Heidelberg Pharma contributes the toxin linker technology to the cooperative partnership as a contribution in kind, while other biotechnology companies contribute antibodies or innovative antibody formats. Together, novel ATACs will be developed up to the preclinical stage, in which their efficacy and tolerability can be meaningfully assessed. A decision will later be taken with the partner in question as to whether joint clinical development is possible or whether direct licensing or sale of the product to third parties is preferable.
Funding projects: The ADC research approach is to be applied to peptides, for example, in a research programme of the European Union. Link to PR
Collaboration with institutions: Study results achieved in cooperation with the well-known MD Anderson Cancer Center in Texas, USA, showed exceptionally good efficacy of an ATAC therapeutic in a colorectal cancer subpopulation with changes in the status of the tumor suppressor gene TP53. In a clinical setting, selecting patients based on their TP53 or POLR2A gene status could broaden the therapeutic window of ATACs and ensure high efficacy while minimizing side effects. These data were published in Nature in April 2016.