Biologic drugs, including monoclonal antibodies (mAbs), are widely used to treat cancers and chronic diseases such as autoimmune and metabolic disorders. Unlike small-molecule drugs, biologics are large, structurally complex proteins that require parenteral administration due to their instability in the gastrointestinal tract. Most biologics are formulated for intravenous (IV) infusion; however, there is growing interest in subcutaneous (SC) administration as a patient-preferred and cost-effective alternative.
SC administration offers multiple benefits, including the potential for self-administration, reduced healthcare costs, and improved patient adherence. However, it poses significant formulation challenges, particularly for high-concentration antibody products (HCAPs). These challenges include increased viscosity, instability, and higher risks of immunogenicity, which must be carefully managed through robust formulation strategies.
Key Trends in Antibody Formulations
1. Lowering of Formulation pH:
One of the most notable trends in monoclonal antibody formulation is a reduction in average pH. Between 1986 and 2023, the pH of commercial antibody formulations dropped by over 0.5 units, reaching an average of 5.8. This shift improves colloidal stability, reduces aggregation, and mitigates chemical degradation risks, such as deamidation and oxidation. Interestingly, this trend extends across formulation types, including low-concentration liquid formulations, high-concentration liquid formulations, and lyophilized products.
The trend aligns with broader efforts to optimize developability attributes and ensure stability across different routes of administration, including SC and IV. Particularly, SC products often require low pH to manage viscosity and ensure injectability, especially in high-concentration formulations.
2. Increased Adoption of Platform Formulations:
Commercial antibody formulations increasingly follow platform approaches. These formulations typically consist of a histidine buffer, sucrose as a stabilizing sugar, and polysorbate as a surfactant. From 2021 to 2023, histidine and sucrose were present in 63% and 53% of commercial antibody formulations, respectively. This trend reflects the industry’s preference for low-risk, versatile formulations that balance stability, safety, and manufacturability.
Polysorbates—mainly polysorbate-20 and polysorbate-80—are used in over 97% of formulations to prevent aggregation caused by mechanical stresses. This consistency reflects a cautious approach, given the complexity of biologics and the risks associated with introducing novel excipients.
High-concentration antibody products (≥100 mg/mL) present unique challenges related to physical and chemical instability, viscosity, and immunogenicity. These challenges require careful consideration of the following factors:
Formulation Composition:
Excipients such as arginine, methionine, and sucrose are increasingly used to enhance stability and reduce viscosity in HCAPs. Arginine, for example, reduces protein-protein interactions, improving injectability at high concentrations.
Dosage Form:
Liquid formulations dominate the market, comprising approximately 75% of approved biologics. However, lyophilized formulations remain essential for more complex modalities, such as antibody-drug conjugates (ADCs).
Packaging and Delivery Systems:
SC delivery increasingly relies on advanced devices, including OBDS, to support larger injection volumes. These devices enable the use of lower-concentration formulations, reducing the viscosity and instability challenges associated with traditional high-concentration SC biologics.
Addressing Developability with Technology and Innovation
The evolution of monoclonal antibody formulations has been driven by advancements in developability assessment and computational tools. High-throughput screening technologies, such as dynamic light scattering (DLS) and affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS), allow for the early identification of molecules with optimal colloidal and conformational stability.
Computational tools further enhance this process, enabling the prediction of aggregation propensity, viscosity, and other stability attributes. The integration of artificial intelligence (AI) and machine learning is expected to further streamline these efforts, making it possible to evaluate thousands of candidates rapidly.
Biointron provides antibody products for in vivo research at Abinvivo, where we have a wide range of Benchmark Positive Antibodies, Isotype Negative Antibodies, Anti-Mouse Antibodies, Bispecific Antibodies, and Antibody-Drug Conjugates. Contact us to find out more at info@biointron.com or +86 400-828-8830 / +1(732)790-8340.
References:
Mieczkowski, C. A. (2023). The Evolution of Commercial Antibody Formulations. Journal of Pharmaceutical Sciences, 112(7), 1801-1810. https://doi.org/10.1016/j.xphs.2023.03.026
Desai, M., Kundu, A., Michiel G.J.S. Hageman, Lou, H., & Boisvert, D. (2023). Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume. MAbs, 15(1). https://doi.org/10.1080/19420862.2023.2285277
Ghosh, I., Gutka, H., Krause, M. E., Clemens, R., & Kashi, R. S. (2023). A systematic review of commercial high concentration antibody drug products approved in the US: Formulation composition, dosage form design and primary packaging considerations. MAbs, 15(1), 2205540. https://doi.org/10.1080/19420862.2023.2205540
