TY - GEN AB - Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5–2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants. AD - Bristol Myers Squibb AD - Pharma Solutions R&D AD - Pharma Solutions R&D AD - Pharma Solutions R&D AD - Bristol Myers Squibb AD - Bristol Myers Squibb AD - Bristol Myers Squibb AD - Bristol Myers Squibb AD - University of Chicago AD - University of Chicago AD - University of Chicago AD - The City College of New York AD - The City College of New York AU - Kanthe, Ankit D. AU - Carnovale, Miriam R. AU - Katz, Joshua S. AU - Jordan, Susan AU - Krause, Mary E. AU - Zheng, Songyan AU - Ilott, Andrew AU - Ying, William AU - Bu, Wei AU - Bera, Mrinal K. AU - Lin, Binhua AU - Maldarelli, Charles AU - Tu, Raymond S. DA - 2022-07-26 ID - 13407 JF - Molecular Pharmaceutics KW - novel surfactants KW - protein formulations KW - protein aggregation KW - polysorbate 80 (PS80) KW - FM1000 KW - monoclonal antibody (mAb) KW - X-ray reflectivity KW - pendant bubble tensiometry KW - surface tension KW - air/water interface KW - silicone oil/liquid interface L1 - https://knowledge.uchicago.edu/record/13407/files/kanthe-et-al-2022-differential-surface-adsorption-phenomena-for-conventional-and-novel-surfactants-correlates-with.pdf L1 - https://knowledge.uchicago.edu/record/13407/files/mp2c00152_si_001.pdf L2 - https://knowledge.uchicago.edu/record/13407/files/kanthe-et-al-2022-differential-surface-adsorption-phenomena-for-conventional-and-novel-surfactants-correlates-with.pdf L2 - https://knowledge.uchicago.edu/record/13407/files/mp2c00152_si_001.pdf L4 - https://knowledge.uchicago.edu/record/13407/files/kanthe-et-al-2022-differential-surface-adsorption-phenomena-for-conventional-and-novel-surfactants-correlates-with.pdf L4 - https://knowledge.uchicago.edu/record/13407/files/mp2c00152_si_001.pdf LA - eng LK - https://knowledge.uchicago.edu/record/13407/files/kanthe-et-al-2022-differential-surface-adsorption-phenomena-for-conventional-and-novel-surfactants-correlates-with.pdf LK - https://knowledge.uchicago.edu/record/13407/files/mp2c00152_si_001.pdf N2 - Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5–2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants. PY - 2022-07-26 T1 - Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization TI - Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization UR - https://knowledge.uchicago.edu/record/13407/files/kanthe-et-al-2022-differential-surface-adsorption-phenomena-for-conventional-and-novel-surfactants-correlates-with.pdf UR - https://knowledge.uchicago.edu/record/13407/files/mp2c00152_si_001.pdf Y1 - 2022-07-26 ER -