The immunobiology of humanized Anti-IL6 receptor antibody: From basic research to breakthrough medicine

The clinical use of monoclonal antibodies is well established in human medicine and has been amongst the most important contributions of basic science to clinical disease. One such antibody, the humanized anti-human IL-6 receptor antibody, is used to treat a variety of autoimmune diseases, particularly rheumatoid arthritis. It is extremely difficult and a laborious process to go from a concept at the research bench, to government approval. Such approval implies not only efficacy but, more importantly, an appropriate safety profile. In this review, the history of anti-human IL-6 receptor antibody is discussed in depth beginning with the author’s experience during a sabbatical visit at the University of California at Davis in 1978. At that time, it was discovered that B cell activation was at least one critical factor in the development of autoimmunity. Approximately six years later, the cDNA encoding for IL-6 was cloned as BSF-2 (B cell stimulatory factor 2) to differentiate B cells to produce antibody. Soon after, it was suggested that this cytokine plays an important role in the development of autoimmune diseases. Based on this evidence, the journey began to search for an IL-6 inhibitor. Although there were numerous obstacles in finding lead compounds, ultimately, basic science developed the methodology for high throughput readouts that would inhibit the biologic function of IL-6. It was finally concluded that a mouse monoclonal antibody against IL-6 receptor would be optimal. In 1991, this antibody was humanized by using CDR-grafting technology in collaboration with the MRC (Medical Research Council). The drug was named tocilizumab and launched as an innovative anti-rheumatic drug in 2008 in Japan. Subsequently, the drug has been used throughout the world and has achieved enormous success in helping patients who suffer from inflammatory arthropathies. The lessons learned in the development of this antibody have application to the study of biologics and their application to other human diseases.