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Development of antibody prodrug conjugates activated by legumain
Published on March 30, 2021 35 min
A selection of talks on Immunology
Inflammation: purposes, mechanisms and development
- Prof. Pietro Ghezzi
- University of Urbino, Italy
Studying immune responses “one cell at a time”
- Dr. Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum, Germany
Ladies and gentlemen, dear colleagues. My name is Hans-Georg Lerchen. I'm Chief Scientist in the Medicine and Chemistry Department in the Pharmaceutical R&D organization, Bayer AG. Today, I would like to invite you to a journey into the world of antibody drug conjugates, an exciting hot topic in oncology research and development.
Antibody drug conjugates are biologics which are composed of three modules: a monoclonal antibody (left-hand side); a toxophore (right-hand side); and the linker in between. The design of antibody drug conjugates follows the vision of magic bullets which Paul Ehrlich formulated about 120 years ago. He envisioned that it would be possible to directly deliver a drug to the target cell without harming the body. Up to the present day, this vision remains a big challenge. Today we talk about the 'therapeutic window' between the minimal dose required for activity and the highest dose which can be administered without causing unacceptable side effects. To increase the therapeutic window, the ADC design follows the goal to combine tumor specificity of a monoclonal antibody-targeting moiety with the high potency of a toxophore moiety, to kill tumor cells.
With the approval of Main Bayer, nine antibody drug conjugates and more than 80 which are in clinical trials, the ADC landscape has evolved rapidly during the last decade. However, in parallel to these success stories, disappointing results in clinical trials also led to a large number of discontinuations of ADC programs, mainly due to the occurrence of dose-limiting toxicities before an efficacious dose was reached. The ADC mode of action is well understood, and shown on this cartoon. The antibody which is stably modified with toxophore moieties, as symbolized by the Ys with the red pellets, binds to its antigen on the cell surface. This antigen has been selected for high expression on the surface of tumor cells, and low (or no) expression on healthy tissues. Upon binding, the ADC is internalized and intracellularly trafficked to the lysosomal compartment. Here the ADC is cleaved and the active metabolite (shown in the red circle) is released. After its release from the antibody, it has to leave the lysosome and find its intracellular target. Target inhibition finally leads to apoptosis. The focus of my talk today is how ADC cleavage and the physico-chemical properties of the active metabolite may contribute to an increased therapeutic window of the ADC.