Comparison of Huggins Coefficients and Osmotic Second Virial Coefficients of Buffered Solutions of Monoclonal Antibodies

Abstract

The Huggins coefficient kH is a well-known metric for quantifying the increase in solution viscosity arising from intermolecular interactions in relatively dilute macromolecular solutions, and there has been much interest in this solution property in connection with developing improved antibody therapeutics. While numerous kH measurements have been reported for select monoclonal antibodies (mAbs) solutions, there has been limited study of kH in terms of the fundamental molecular interactions that determine this property. In this paper, we compare measurements of the osmotic second virial coefficient B22, a common metric of intermolecular and interparticle interaction strength, to measurements of kHfor model antibody solutions. This comparison is motivated by the seminal work of Russel for hard sphere particles having a short-range “sticky” interparticle interaction, and we also compare our data with known results for uncharged flexible polymers having variable excluded volume interactions because proteins are polypeptide chains. Our observations indicate that neither the adhesive hard sphere model, a common colloidal model of globular proteins, nor the familiar uncharged flexible polymer model, an excellent model of intrinsically disordered proteins, describes the dependence of kH of these antibodies on B22. Clearly, an improved understanding of protein and ion solvation by water as well as dipole–dipole and charge–dipole effects is required to understand the significance of kH from the standpoint of fundamental protein–protein interactions. Despite shortcomings in our theoretical understanding of kH for antibody solutions, this quantity provides a useful practical measure of the strength of interprotein interactions at elevated protein concentrations that is of direct significance for the development of antibody formulations that minimize the solution viscosity.

Predictive modeling of concentration-dependent viscosity behavior of monoclonal antibody solutions using artificial neural networks

“…PPI are complex especially at high concentration and influence viscosity in nonlinear fashion. Pathak, 2021 29 3 mAbs at max 90 mg/mL, pH 5.8–6.8 in diverse buffers; plus excipients arginine-HCl, NaCl, sorbitol, sucrose, polysorbate 80 B2 (SLS), hydrated protein molecular volume (simulation) The Huggins coefficient (kH), derived from viscosity, can serve as a measure of PPIs in relation to the increase of solution viscosity, it can be used to identify solution conditions minimizing the increment of viscosity increase with protein concentration. The table contains a selection of studies in chronological order which describe for monoclonal antibodies the correlation of factors derived from experimental data with their solution viscosity.…”

Obtaining and Microstructural Study of a Multifunctional Highly Phosphorylated Starch

“…This quantity, which had the dimensions of the inverse of a concentration, will give an idea of the hydrophilicity and degree of hydration of the polymer. Relative viscosity 𝜂∕𝜂 0 could be expressed as a limited virial expansion (Equation ( 2)) describing the variation of a quantity (viscosity, osmometry) as a function of the concentration for dilute macromolecular solutions: [29] 𝜂∕𝜂 With 𝜂 and 𝜂 0 denoted the viscosity of the polymeric solution and that of the solvent, respectively. k H was the second hydrodynamic virial coefficient also known as the Huggins constant.…”

New Facet in Viscometry of Charged Associating Polymer Systems in Dilute Solutions

“…In dilute polymer solutions, viscometry serves to determine the characteristics of an isolated macromolecule, following Staudinger [ 34 ]. The macromolecules of amphiphilic polymers manifest their peculiar behavior already in dilute solutions, and, as a rule, demonstrate high values of the Huggins parameter [ 35 , 36 , 37 , 38 ].…”