Concentration-Dependent Diffusion of Monoclonal Antibodies: Underlying Mechanisms of Anomalous Diffusion.
Mol Pharm
; 21(5): 2212-2222, 2024 May 06.
Article
en En
| MEDLINE
| ID: mdl-38572979
ABSTRACT
The development, storage, transport, and subcutaneous delivery of highly concentrated monoclonal antibody formulations pose significant challenges due to the high solution viscosity and low diffusion of the antibody molecules in crowded environments. These issues often stem from the self-associating behavior of the antibody molecules, potentially leading to aggregation. In this work, we used a dissipative particle dynamics-based coarse-grained model to investigate the diffusion behavior of IgG1 antibody molecules in aqueous solutions with 15 and 32 mM NaCl and antibody concentrations ranging from 10 to 400 mg/mL. We determined the coarse-grained interaction parameters by matching the calculated structure factor with the computational and experimental data from the literature. Our results indicate Fickian diffusion for antibody concentrations of 10 and 25 mg/mL and anomalous diffusion for concentrations exceeding 50 mg/mL. The anomalous diffusion was observed for â¼0.33 to 0.4 µs, followed by Fickian diffusion for all antibody concentrations. We observed a strong linear correlation between the diffusion behavior of the antibody molecules (diffusion coefficient D and anomalous diffusion exponent α) and the amount of aggregates present in the solution and between the amount of aggregates and the Coulomb interaction energy. The investigation of underlying mechanisms for anomalous diffusion revealed that in crowded environments at high antibody concentrations, the attractive interaction between electrostatically complementary regions of the antibody molecules could further bring the neighboring molecules closer to one another, ultimately resulting in aggregate formation. Further, the Coulomb attraction can continue to draw more molecules together, forming larger aggregates.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Inmunoglobulina G
/
Anticuerpos Monoclonales
Idioma:
En
Revista:
Mol Pharm
/
Mol. pharm
/
Molecular pharmaceutics
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos