half-life and supporting its recycling capacity. However, despite the earlier description of the complex structure, the molecular mechanism underlying these dependencies has remained elusive. Here, we further explored the crystal structure of the empasiprubart fragment antigen-binding (Fab) complexed to a C2 fragment, and provide a molecular rationale for its unique properties, while recognizing that not all contributing factors have been fully elucidated. Our observations indicate that the pH-dependent target release is rooted in a subtle intramolecular complementarity-determining region (CDR) destabilization, rather than direct modulation of the binding interface, and highlight the interplay between framework residues and CDRs. Collectively, our results not only lead to a better understanding of the mode of action of empasiprubart but also demonstrate the pivotal role of framework residues in the orchestration of antibody CDR function for non-trivial target binding.
Bracke et al. (Mon,) studied this question.