Bispecific antibodies present numerous challenges to the development of robust manufacturing processes. Low titers resulting from low cell line productivity, difficulties achieving product quality targets, and degradation of the antibody often lead to long development timelines and delays in delivering material to the clinic. As a contract development and manufacturing organization (CDMO), we have evolved a platform process over five years with more than 20 bispecific antibodies. Refinement of seed train, production, and harvest processes was undertaken for two families of bispecific molecules consisting of at least four molecules each, and for a wide array of other bispecific formats. Early implementation of the platform often required extensive screening and optimization studies to achieve acceptable performance, particularly for the production process. These adjustments to the process were necessary to achieve high titers and to modulate product quality targets such as homodimer levels. The introduction of remediation strategies in the harvest process has successfully prevented degradation of the product that occurred with multiple molecules. Strategies have also been introduced in the overall workflow to uncover the unique aspects and challenges for each new molecule early in the development timeline. Utilization of stable pools of clones provide an initial performance baseline and early testing of the harvest process. Conducting clone selection in parallel with other process development activities ensures that the final clone performs well with the final process. Overall, incremental improvements to the platform process have made it more robust and enabled development efforts to be more targeted for each new molecule.

Overcoming manufacturability challenges for bispecific antibodies through evolution of a platform process

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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