High resolution mapping of the binding site on human IgG1 for Fc gamma RI,Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R

Immunoglobulin G (IgG) Fc receptors play a critical role in linking IgG ant ibody-mediated immune responses with cellular effector functions. A high re solution map of the binding site on human IgG1 for human Fc gamma RI, Fc ga mma RIIA, Fc gamma RIIB, Fc gamma RIIIA, and FcRn receptors has been determ ined. A common set of IgG1 residues is involved in binding to all Fc gammaR ; Fc gamma RII and Fc gamma RIII also utilize residues outside this common set. In addition to residues which, when altered, abrogated binding to one or more of the receptors, several residues were found that improved binding only to specific receptors or simultaneously improved binding to one type of receptor and reduced binding to another type. Select IgG1 variants with improved binding to Fc gamma RIILA exhibited up to 100% enhancement in anti body-dependent cell cytotoxicity using human effector cells; these variants included changes at residues not found at the binding interface in the IgG /Fc gamma RIIIA co-crystal structure (Sondermann, P., Huber, R., Oosthuizen , V., and Jacob, U. (2000) Nature 406, 267-273). These engineered antibodie s may have important implications for improving antibody therapeutic effica cy.