title: Measurements of Monoclonal Antibody Self-Association Are Correlated with Complex Biophysical Properties.
abstract: Successful development of monoclonal antibodies (mAbs) for therapeutic applications requires identification of mAbs with favorable biophysical properties (high solubility and low viscosity) in addition to potent bioactivities. Nevertheless, mAbs can also display complex, nonconventional biophysical properties that impede their development such as formation of soluble aggregates and subvisible particles as well as nonspecific interactions with various types of surfaces such as nonadsorptive chromatography columns. Here we have investigated the potential of using antibody self-interaction measurements obtained via affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) at dilute concentrations (0.01 mg/mL) for ranking a panel of 12 mAbs in terms of their expected biophysical properties at higher concentrations (1-30 mg/mL). Several mAb properties (solubility, % monomer, size-exclusion elution time and % recovery) displayed modest correlation with each other, as some mAbs with deficiencies in one or more properties (e.g., solubility) failed to show deficiencies in other properties (e.g., % monomer). The ranking of mAbs in terms of their level of self-association was correlated with their solubility ranking. However, the correlation was even stronger between the average ranking of the four biophysical properties and the AC-SINS measurements. This finding suggests that weak self-interactions detected via AC-SINS can manifest themselves in different ways and lead to complex biophysical properties. Our findings highlight the potential for using high-throughput self-interaction measurements to improve the identification of mAbs that possess a collection of excellent biophysical properties without the need for cumbersome analysis of each individual property during early candidate selection.
authors.affiliation: Center for Biotechnology & Interdisciplinary Studies, Isermann Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute , Troy, New York 12180, United States.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Geng
authors.affiliation: Contrafect Corporation, Yonkers, New York 10701, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Wittekind
authors.affiliation: Contrafect Corporation, Yonkers, New York 10701, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Vigil
authors.affiliation: Center for Biotechnology & Interdisciplinary Studies, Isermann Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute , Troy, New York 12180, United States.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Tessier
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001703:Biophysics / Q000379:methods; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D012995:Solubility; D013057:Spectrum Analysis / Q000379:methods; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal
keywords: aggregation; mAb; self-association; size-exclusion chromatography; solubility; viscosity