Address of Corresponding Author

Tumor Biol 2005;26:31-43 (DOI: 10.1159/000084184)

  Key Words

• Complementarity-determining region grafting
• Human anti-murine antibody
• Humanized antibodies
• Immunogenicity
• Specificity-determining residue
• Serum reactivity
• Surface plasmon resonance

  Abstract

The clinical utility of murine monoclonal antibodies has been greatly limited by the human anti-murine antibody responses they effect in patients. To make them less immunogenic, murine antibodies have been genetically engineered to progressively replace their murine content with that of their human counterparts. This review describes the genetic approaches that have been used to humanize murine antibodies, including the generation of mouse-human chimeric antibodies, veneering of the mouse variable regions, and the grafting of murine complementarity-determining regions (CDRs) onto the variable light (V_L) and variable heavy (V_H) frameworks of human immunoglobulin molecules, while retaining only those murine framework residues deemed essential for the integrity of the antigen-binding site. To minimize the anti-idiotypic responses that could still be evoked by the murine CDRs in humanized antibodies, two approaches have also been described. These are based on grafting onto the human frameworks the 'abbreviated' CDRs or only the specificity-determining residues (SDRs), the CDR residues that are involved in antigen interaction. The SDRs are identified through the help of the database of three-dimensional structures of antibody:antigen complexes or by mutational analysis of the antibody-combining site. In addition, we also describe the use of in vitro affinity maturation to enhance the binding affinity of humanized antibodies, as well as the manipulation of framework residues to maximize their human content and minimize their immunogenic potential.

Copyright © 2005 S. Karger AG, Basel

  Author Contacts

Syed V.S. Kashmiri
10 Center Drive, Bldg 10, Rm 5B38
Bethesda, MD 20892 (USA)
Tel. +1 301 496 0418, Fax +1 301 496 2756
E-Mail sk85f@nih.gov

  Article Information

Number of Print Pages : 13
Number of Figures : 2, Number of Tables : 3, Number of References : 51