Engineering therapeutic antibodies for improved function

Abstract

The binding sites on human IgG1 for human Fcγ receptor (FcγR) I, FcγRIIa, FcγRIIb, FcγRIIIa and neonatal FcR have been mapped. A common set of IgG1 residues is involved in binding to all FcγRs, while FcγRII and FcγRIII utilize distinct sites outside this common set. In addition to residues which abrogated binding to the FcγR, several positions were found which improved binding only to specific FcγRs or simultaneously improved binding to one type of FcγR and reduced binding to another type. Selected IgG1 variants with improved binding to FcγRIIIa were then tested in an in vitro antibody-dependent cellular cytotoxicity (ADCC) assay and showed an enhancement in ADCC when either peripheral blood mononuclear cells or natural killer cells were used.