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Protein Eng Des Sel. 2016 Oct;29(10):419-426. doi: 10.1093/protein/gzw024. Epub 2016 Jun 21.

Computationally driven antibody engineering enables simultaneous humanization and thermostabilization.

Author information

1
Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA.
2
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.
3
Norris Cotton Cancer Center at Dartmouth, Lebanon, NH 03766, USA.
4
Department of Biological Sciences, Dartmouth, Hanover, NH 03755, USA.

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.

KEYWORDS:

antibody; cetuximab; computational protein design; humanization; thermostability

PMID:
27334453
PMCID:
PMC5036863
DOI:
10.1093/protein/gzw024
[Indexed for MEDLINE]
Free PMC Article

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