Developing a Minimally Immunogenic Humanized Antibody by SDR Grafting

Since the advent of hybridoma technology a quarter century ago, a large number of murine monoclonal antibodies (MAbs) have been developed that are potentially useful clinical reagents against human infectious diseases and cancers. However, the clinical value of murine antibodies is limited because of the human anti-murine antibody (HAMA) response they evoke in patients (1 –4 ). Early attempts to reduce the HAMA response led to the development of mouse-human chimeric MAbs that are generated by replacing the constant regions of the heavy and light chains of the murine antibodies with those of the human antibodies (5 ). Another approach to reducing the immunogenicity of a murine antibody is to resurface or veneer its variable domains. This is accomplished by replacing the exposed residues in the framework region of the murine antibody with the residues that are present in the corresponding positions of human antibodies (6 ). A more commonly used procedure for the reduction of HAMA response involves grafting of the complementarity-determining regions (CDRs) of the xenogeneic antibody onto the human antibody frameworks, while retaining those residues of the xenogeneic framework regions that are considered essential for antibody reactivity to its antigen (7 ) (see Chapter 7 ). Following this approach, several xenogeneic antibodies have been successfully humanized (8 ).