Minimizing the immunogenicity of antibodies for clinical application.
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 (VL) and variable heavy (VH) 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.
Gonzales
Noreen R
NR
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
De Pascalis
Roberto
R
Schlom
Jeffrey
J
Kashmiri
Syed V S
SV
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000918:Antibody Specificity; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D019151:Peptide Library; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D022801:Complementarity Determining Regions; D019151:Peptide Library; D011993:Recombinant Fusion Proteins