title: In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability.
abstract: For mAbs to be viable therapeutics, they must be formulated to have low viscosity, be chemically stable, and have normal in vivo clearance rates. We explored these properties by observing correlations of up to 60 different antibodies of the IgG1 isotype. Unexpectedly, we observe significant correlations with simple physical properties obtainable from antibody sequences and by molecular dynamics simulations of individual antibody molecules. mAbs viscosities increase strongly with hydrophobicity and charge dipole distribution and decrease with net charge. Fast clearance correlates with high hydrophobicities of certain complementarity determining regions and with high positive or high negative net charge. Chemical degradation from tryptophan oxidation correlates with the average solvent exposure time of tryptophan residues. Aspartic acid isomerization rates can be predicted from solvent exposure and flexibility as determined by molecular dynamics simulations. These studies should aid in more rapid screening and selection of mAb candidates during early discovery.
authors.affiliation: Early Stage Pharmaceutical Development Department.
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Early Stage Pharmaceutical Development Department.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Patapoff
authors.affiliation: Early Stage Pharmaceutical Development Department.
authors.forename: Bruce
authors.initials: B
authors.lastname: Kabakoff
authors.affiliation: Early Stage Pharmaceutical Development Department.
authors.forename: Satyan
authors.initials: S
authors.lastname: Pai
authors.affiliation: Early Stage Pharmaceutical Development Department.
authors.forename: Eric
authors.initials: E
authors.lastname: Hilario
authors.affiliation: Protein Analytical Chemistry, and.
authors.forename: Boyan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Protein Analytical Chemistry, and.
authors.forename: Charlene
authors.initials: C
authors.lastname: Li
authors.affiliation: Protein Analytical Chemistry, and.
authors.forename: Oleg
authors.initials: O
authors.lastname: Borisov
authors.affiliation: Drug Delivery, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kelley
authors.affiliation: Simprota Corp., San Francisco, CA 94158; and.
authors.forename: Ilya
authors.initials: I
authors.lastname: Chorny
authors.affiliation: Simprota Corp., San Francisco, CA 94158; and.
authors.forename: Joe Z
authors.initials: JZ
authors.lastname: Zhou
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794 dill@laufercenter.org swartz.trevor@gene.com.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Dill
authors.affiliation: Early Stage Pharmaceutical Development Department, dill@laufercenter.org swartz.trevor@gene.com.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Swartz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000627:therapeutic use; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011994:Recombinant Proteins
keywords: degradation; monoclonal antibodies; pharmacokinetics; prediction; viscosity