CDR Repair: A Novel Approach to Antibody Humanization
Hybridoma technology has enabled the rapid production of a large number of monoclonal antibodies with interesting biological properties. Their use in a therapeutic setting, however, can lead to the generation of a human anti-mouse antibody (HAMA) response in patients despite the high degree of sequence similarity shared between human and mouse antibodies. This has prompted efforts to make hybridoma antibodies appear more human through the construction of chimeras, (Morrison et al. 1984) and through a process known as antibody humanization (Riechmann et al. 1988; Verhoeyen et al. 1988).
The modular nature of antibodies makes the swapping of domains a relatively simple process. A chimera consisting of the mouse variable heavy (VH) and variable light (VL) domains recombinantly fused to human heavy and light constant domains is a simple way to reduce HAMA response. Yet, despite 60–75% homology to human, murine variable domains may still elicit a HAMA response.
KeywordsVariable Domain Antigen Binding Variable Light Variable Heavy Parent Antibody
Complementarity determining regions
Antigen binding fragment consisting of the light chain and the variable and first constant domains of the heavy chain
Human anti-mouse antibodies
Variable heavy domain
Variable light domain
I gratefully recognize the contributions made by the oligonucleotide synthesis and DNA sequencing groups at Genentech who have made this work possible. I also thank all current and former members of the Protein Engineering and Antibody Engineering Departments at Genentech for discussions and their contributions to the development of phage display methods, and antibody humanization technologies and especially, Henry Lowman for his support.
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