Electrostatic Interactions of Monoclonal Antibodies With Subcutaneous Tissue

Abstract

Aim: The majority of the subcutaneously injected monoclonal antibodies already on the market achieve 50–65% bioavailability, yet the fate of the portion that is lost remains unknown. This consistently incomplete systemic absorption affects the efficacy, safety and overall cost of the drug product. There are many potential factors that might influence the absorption, such as charge, hydrophobicity, formulation variables and the depth and volume of the injection. Materials & methods: To explore the possibility that the charge of the injected protein and/or formulation components is partially responsible for drug retention at the subcutaneous site, an ex vivo study, where the monoclonal antibodies were exposed to homogenized rat subcutaneous tissue, was performed. Results & conclusion: It was found that positively charged monoclonal antibodies bind to subcutaneous tissue in a manner that is dependent on ionic strength and pH, suggesting the electrostatic nature of the interaction. As expected, saturation of both nonspecific and electrostatic subcutaneous binding sites was observed after incubation with highly concentrated monoclonal antibody solutions. Additionally, it was demonstrated using model proteins that electrostatic effects of buffer components depend on ionic strength of ions bearing opposite charge rather than total ionic strength of the solution. These results suggest that electrostatic interactions may play a role in absorption processes of positively charged therapeutic proteins after subcutaneous administration.

Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics

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Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

“…This is indicated by the kinetics of subcutaneously injected soluble protein (Noe et al, 2010) and further supported by pharmacokinetic studies with subcutaneously injected monoclonal antibodies showing significant retention of protein at the site of injection (Joshi et al, 2006; Xu et al, 2010). In vitro experiments suggests that a variable but significant portion of monoclonal antibodies is retained at the injection site via electrostatic interactions with the extracellular matrix (Mach et al, 2011). This is also likely to happen with certain vaccine antigens.…”

Colloidal interactions between monoclonal antibodies in aqueous solutions

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