title: Improving monoclonal antibody selection and engineering using measurements of colloidal protein interactions.
abstract: A limitation of using mAbs as therapeutic molecules is their propensity to associate with themselves and/or with other molecules via nonaffinity (colloidal) interactions. This can lead to a variety of problems ranging from low solubility and high viscosity to off-target binding and fast antibody clearance. Measuring such colloidal interactions is challenging given that they are weak and potentially involve diverse target molecules. Nevertheless, assessing these weak interactions-especially during early antibody discovery and lead candidate optimization-is critical to preventing problems that can arise later in the development process. Here we review advances in developing and implementing sensitive methods for measuring antibody colloidal interactions as well as using these measurements for guiding antibody selection and engineering. These systematic efforts to minimize nonaffinity interactions are expected to yield more effective and stable mAbs for diverse therapeutic applications. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3356-3363, 2014.
authors.affiliation: Center for Biotechnology & Interdisciplinary Studies, Isermann Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Geng
authors.affiliation: Sterile Product and Analytical Development, Merck Research Laboratories, Kenilworth, New Jersey 07033.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Cheung
authors.affiliation: Sterile Product and Analytical Development, Merck Research Laboratories, Kenilworth, New Jersey 07033.
authors.forename: Chakravarthy
authors.initials: C
authors.lastname: Narasimhan
authors.affiliation: Sterile Product and Analytical Development, Merck Research Laboratories, Kenilworth, New Jersey 07033.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shameem
authors.affiliation: Center for Biotechnology & Interdisciplinary Studies, Isermann Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180. Electronic address: tessier@rpi.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Tessier
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D002626:Chemistry, Pharmaceutical; D003102:Colloids; D003429:Cross Reactions; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D066329:Protein Aggregates; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D003102:Colloids; D066329:Protein Aggregates
keywords: CDR; Fab; IgG; VH; VL; biophysical methods; complementarity-determining region; high throughput technologies; physical stability; protein aggregation; protein formulation; solubility; viscosity