Heidelberg Pharma is working on the development of third generation ADCs based on the toxin Amanitin derived from the green death cap mushroom Amanita Phalloides. 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, i.e. the relation between efficiency and safety. The basis of ADC technology is the conjugation of specific antibodies to a toxin via a chemical linker.

Heidelberg Pharma’s so called ATACs (Antibody Targeted Amanitin Conjugates) are ADCs that are 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. They will also be used to treat therapy-resistant tumors that no longer respond to standard chemotherapy or anti-tumor antibodies. Amanitin has a unique biological mode of action by inhibiting RNA polymerase II, which drives cells into apoptosis. 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 advances effective for patients who no longer respond to treatment.

In the frame of the project offered by Heidelberg Pharma, new ADCs will be generated that allow targeting structures specific to pancreatic cancer cells. Several structures have been identified to be suitable targets for targeted therapy of PDAC: CAIX, NBCn1, KV10.1, KV11.1. Appropriate antibodies are available within the consortium. The first generation of PDAC specific ADCs will use the proprietary payload amanitin of HDP. ADCs will be generated using chemical linkers with different release mechanisms, e.g. protease cleavable or pH-sensitive. For the second generation of PDAC specific ADCs small molecules interfering with PDAC processes will be used as payloads: channel modulators (Senicapoc, Englerin), inhibitors of proton pumps or NHE1-inhibitors.

A prerequisite for an effective ADC is the conjugation of the drug moiety to the Ab by a chemical linker group that provides high stability in circulation and substantial drug release after internalization into tumor cells. HDP has extensive expertise of the ADC technology at all levels facilitating the production and examination of the new ADCs. The newly generated ADCs will be tested for their activity in various in vitro and in vivo models. The most active ADCs will be tested in vivo in advanced PDX models of PDAC established at different partners. This includes preclinical profiling of ADCs in PDAC models at UBa (humanized 3D models), MPG (orthotopic PDAC mouse models) and CAU (clinically adapted tumor models).