Strategies for preventing antibody light chain truncation

Monoclonal antibody-based therapeutics are currently the fastest growing class of protein-based drugs. Recombinant antibodies are secreted from the production cell, facilitated by the N-terminal signal peptides, which are removed from the heavy and light chain polypeptides during the secretion process. Mis-cleavage of the signal peptide can occur, resulting in truncation or elongation at the N-terminus of the heavy and/or light chain which is undesirable for antibody manufacturing as it can impact efficacy and result in product heterogeneity. In this work, Gibson et al. demonstrate that a specific N-terminal antibody motif partnered with a specific signal peptide causes light chain truncation leading to product heterogeneity in antibodies of therapeutic interest. They provide a generic and widely applicable strategy to prevent such truncations in any light chain containing this motif through rational design and engineering, resulting in homogeneous recombinant human antibody product. Page 1970