title: Computationally driven antibody engineering enables simultaneous humanization and thermostabilization.
abstract: Humanization reduces the immunogenicity risk of therapeutic antibodies of non-human origin. Thermostabilization can be critical for clinical development and application of therapeutic antibodies. Here, we show that the computational antibody redesign method Computationally Driven Antibody Humanization (CoDAH) enables these two goals to be accomplished simultaneously and seamlessly. A panel of CoDAH designs for the murine parent of cetuximab, a chimeric anti-EGFR antibody, exhibited both substantially improved thermostabilities and substantially higher levels of humanness, while retaining binding activity near the parental level. The consistently high quality of the turnkey CoDAH designs, over a whole panel of variants, suggests that the computationally directed approach encapsulates key determinants of antibody structure and function.
authors.affiliation: Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Yoonjoo
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Ndong
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.|Norris Cotton Cancer Center at Dartmouth, Lebanon, NH 03766, USA.|Department of Biological Sciences, Dartmouth, Hanover, NH 03755, USA.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Griswold
authors.affiliation: Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology*; D019295:Computational Biology / Q000379:methods*; D066246:ErbB Receptors / Q000276:immunology; D006801:Humans; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D013696:Temperature
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors
keywords: antibody; cetuximab; computational protein design; humanization; thermostability