Dickopf et al. introduced the concept of Prodrug-Activating Chain Exchange (PACE) to generate antibody functionality only under physiological conditions and target binding. PACE relies on two antibody derivatives with TAA binders, each with one prodrug chain of a two-chain functional binder (such as anti-CD3). Upon encountering each other by binding adjacent TAAs, prodrugs exchange their heavy chains to generate an active functional binder in a TriFab format. TriFab T cell engagers generated against LeY antigen, and a bispecific FOLR1 and EGFR TriFab were therapeutically effective under physiological conditions in cell culture and in an animal model.
Contributed by Shishir Pant
ABSTRACT: Driven by the potential to broaden the target space of conventional monospecific antibodies, the field of multi-specific antibody derivatives is growing rapidly. The production and screening of these artificial proteins entails a high combinatorial complexity. Antibody-domain exchange was previously shown to be a versatile strategy to produce bispecific antibodies in a robust and efficient manner. Here, we show that the domain exchange reaction to generate hybrid antibodies also functions under physiological conditions. Accordingly, we modified the exchange partners for use in therapeutic applications, in which two inactive prodrugs convert into a product with additional functionalities. We exemplarily show the feasibility for generating active T cell bispecific antibodies from two inactive prodrugs, which per se do not activate T cells alone. The two complementary prodrugs harbor antigen-targeting Fabs and non-functional anti-CD3 Fvs fused to IgG-CH3 domains engineered to drive chain-exchange reactions between them. Importantly, Prodrug-Activating Chain Exchange (PACE) could be an attractive option to conditionally activate therapeutics at the target site. Several examples are provided that demonstrate the efficacy of PACE as a new principle of cancer immunotherapy in vitro and in a human xenograft model.
Author Info: (1) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (2) Large Molecule Research (LMR), Roche I
Author Info: (1) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (2) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (3) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (4) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (5) Discovery Oncology, Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (6) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (7) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (8) Pharmaceutical Sciences (PS), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (9) Pharmaceutical Sciences (PS), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (10) Small Molecule Research, Roche Innovation Center Basel, Roche Pharma Research and Early Development (pRED), Basel, Switzerland. (11) Small Molecule Research, Roche Innovation Center Basel, Roche Pharma Research and Early Development (pRED), Basel, Switzerland. (12) Chemical Biology, Roche Innovation Center Basel, Roche Pharma Research and Early Development (pRED), Basel, Switzerland. (13) Center for Cellular Imaging and Nano Analytics, Biozentrum University of Basel, Basel, Switzerland. (14) Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilians University of Munich, German Center for Lung Research (DZL), Munich, Germany. German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany. (15) Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilians University of Munich, German Center for Lung Research (DZL), Munich, Germany. German Center for Translational Cancer Research (DKTK), Partner Site Munich, Munich, Germany. (16) Discovery Oncology, Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland. (17) Large Molecule Research (LMR), Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany.
