Humanization of Monoclonal Antibodies

Initial studies of monoclonal antibody therapies were complicated by significant infusion-related toxicity owing to host recognition of xenotropic sequences in the murine monoclonal antibodies. The formation of human anti-mouse antibodies (HAMAs) limited the clinical utility of initial monoclonal antibodies, and patients also developed serum sickness (35,36). However, recombinant DNA technology has allowed the generation of chimeric and "humanized" murine monoclonal IgG antibodies in which murine sequences have been replaced with the human Fc fragment. It is now technologically possible to generate humanized IgG molecules whose Fab portions contain only the murine sequences necessary to recognize the tumor-specific antigen of interest. These chimeric and humanized antibodies have proved to be less immunogenic, resulting in reduced infusion-related toxicity (37-39). In addition, incorporation of the human Fc fragment allows activation of patients' host immune systems through induction of ADCC and CDC. Thus, recombinant DNA technology has allowed the production of monoclonal antibodies that are better tolerated by patients and more effective clinically. Although technical problems must be addressed with each new individual monoclonal antibody, several antibodies have entered clinical practice or are undergoing active clinical investigation in CLL.

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