Antibody Humanization by a Single Cycle of CDR-Grafting
Pp. 159-181 (23)
Wei-Gang Hu, Junfei Yin, Damon Chau, Charles C. Hu and John W. Cherwonogrodzky
Murine monoclonal antibodies (mAbs) have great potentials as therapeutics
developed for clinical applications. The major problem with these mAbs, however, is
their immunogenicity due to their foreignness to humans. Humanization, a process to
decease the content of murine residues in mAbs, can make it possible to reduce their
immunogenicity for clinical uses. One of the humanization strategies, complementarity
determining region (CDR)-grafting is well-established and popular, but it generally
needs multiple design cycles, which are time-consuming. A CDR-grafting approach
now described is based on a comprehensive analysis of the antibody sequence, and its
three-dimensional structure from molecular modeling, to identify critical residues in the
murine antibody of interest, which guides the completion of CDR-grafting to a human
antibody template in a single cycle. The single-cycle structure-based method was used
to create the first humanized (>94% human) anti-ricin monoclonal IgG antibody (results
published and patented). The steps used in the successful creation of this antibody, hD9,
are described to assist the researchers in their quest to develop humanized antibodies
against threat agents.
Antibody, humanization, CDR-grafting, molecular modeling.
DRDC, Suffield Research Centre, Box 4000, Station Main, Medicine Hat, Alberta, Canada T1A 8K6.