title: Weak interactions govern the viscosity of concentrated antibody solutions: high-throughput analysis using the diffusion interaction parameter.
abstract: Weak protein-protein interactions are thought to modulate the viscoelastic properties of concentrated antibody solutions. Predicting the viscoelastic behavior of concentrated antibodies from their dilute solution behavior is of significant interest and remains a challenge. Here, we show that the diffusion interaction parameter (k(D)), a component of the osmotic second virial coefficient (B(2)) that is amenable to high-throughput measurement in dilute solutions, correlates well with the viscosity of concentrated monoclonal antibody (mAb) solutions. We measured the k(D) of 29 different mAbs (IgG(1) and IgG(4)) in four different solvent conditions (low and high ion normality) and found a linear dependence between k(D) and the exponential coefficient that describes the viscosity concentration profiles (|R| ≥ 0.9). Through experimentally measured effective charge measurements, under low ion normality where the electroviscous effect can dominate, we show that the mAb solution viscosity is poorly correlated with the mAb net charge (|R| ≤ 0.6). With this large data set, our results provide compelling evidence in support of weak intermolecular interactions, in contrast to the notion that the electroviscous effect is important in governing the viscoelastic behavior of concentrated mAb solutions. Our approach is particularly applicable as a screening tool for selecting mAbs with desirable viscosity properties early during lead candidate selection.
authors: Pharmaceutical Development, Genentech, Inc., South San Francisco, California, USA.
authors: Brian D
authors: BD
authors: Connolly
authors: Chris
authors: C
authors: Petry
authors: Sandeep
authors: S
authors: Yadav
authors: Barthélemy
authors: B
authors: Demeule
authors: Natalie
authors: N
authors: Ciaccio
authors: Jamie M R
authors: JM
authors: Moore
authors: Steven J
authors: SJ
authors: Shire
authors: Yatin R
authors: YR
authors: Gokarn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004058:Diffusion; D057166:High-Throughput Screening Assays; D009994:Osmolar Concentration; D012997:Solvents; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D012997:Solvents