Formulation Strategies for Next-Generation Bispecific Antibodies: Design Considerations and Stability Implications

Abstract

Bispecific antibodies (BsAbs) represent a transformative class of next-generation biologics, enabling simultaneous binding to two targets and offering mechanisms of action beyond conventional monoclonal antibodies. Their growing clinical success, particularly in T-cell–redirecting therapies, has increased the need for robust formulation and Chemistry, Manufacturing, and Controls (CMC) strategies to support complex molecular designs, high potency, and multiple delivery routes. However, BsAbs present unique challenges due to structural heterogeneity, asymmetric domain interfaces, aggregation propensity, and sensitivity to physical and chemical stresses. This review provides a structured overview of formulation strategies for BsAbs, integrating molecular design considerations, developability assessment, and Quality by Design (QbD) principles. It highlights the impact of domain architecture on conformational and colloidal stability and outlines rational selection of excipients including buffers, sugars, amino acids, and surfactants based on (Fragment crystallizable) Fc-containing versus fragment based formats. Key challenges in high-concentration formulations for subcutaneous delivery, such as viscosity control and device compatibility, are also discussed. Critical degradation pathways, including oxidation, chain mispairing, and interfacial stress, are addressed with practical mitigation strategies. The review further describes analytical and stability study approaches to monitor critical quality attributes such as arm specific activity, heterodimer integrity, and stress-induced degradation. Emerging tools, including machine learning and predictive modeling, are also considered to enhance formulation development. Case study understandings identify common risks, including arm-specific potency loss, interface-driven aggregation, and high-viscosity limitations. Overall, this review presents a unified framework to guide the development of stable, manufacturable, and clinically reliable BsAb therapeutics.