LAUSR

Multispecifics are increasingly being evaluated in the pharmaceutical industry due to their unique mechanisms of action, enabled by their multiple antigen‐binding capabilities. The complexity of these molecules can make production challenging, prompting the development of various generation approaches. This study employs an electrostatic‐steering generation method, where charge‐based differences between two parental homodimer antibodies drive correct heterodimerization during a redox reaction of the partially purified parental homodimers. This strategy can achieve high conversion to the heterodimer with minimal product‐related impurities. However, it also necessitates separate bioreactors for each parental homodimer, leading to complex manufacturing campaigns. This work introduces a novel bioprocess for electrostatic‐steering‐based multispecifics, combining two unique components. First, two separate cell lines are cocultured, leading to the simultaneous production of both parental homodimers in a single bioreactor. The second component involves a column‐based redox reaction, where the homodimers are captured, and their disulfide bonds are reduced while bound to the protein A resin using a reductant wash. The column is then eluted and neutralized, allowing the reduced parental homodimers to heterodimerize. Finally, the addition of an oxidant enables the reformation of disulfide bonds, completing the formation of the multispecific. This new process is robust and efficient across both the lab bench and manufacturing scales, maintaining well‐controlled impurity profiles. Homodimer harvest ratios were consistently within 10%–15% of the target across various cocultured cell lines. Conversions from homodimers to heterodimers exceeded 90%, and multispecific percentages in all tested drug substance pools were above 95%. This strategy aligns the new multispecific bioprocess with typical antibody‐like processes, optimizing clinical and commercial manufacturing resources while producing complex multispecific molecules with minimal impurities.