Human clinical applications, antibodies

Following recent advances in antibody engineering, it is now possible to s)mthesize humanized antibodies [35]. Because of clinical applicability, antibody-based medicines are one of the biopharmaceutical categories that have attracted close attention in recent years [36]. IgG has been most frequently used for the prevention and treatment of various diseases. The CH2 region of IgG has A-linked carbohydrates (usually complex type double stranded chains) in diverse manners (O Scheme 14). It has recently been revealed that differences in the carbohydrate structure affect the effecter activity of antibodies such as antibody-dependent cellular cytotoxicity (ADCC) and their half-life in blood, inviting close attention from the viewpoint of improving the responses to antibody-based medicines [37,38,39]. 

The advent of recombinant DNA technology led to the development of antibodies and fragments that are tailored for optimal behaviour in vivo [7,8]. Humanized and chimeric antibodies can be constructed to circumvent the human anti-mouse antibody response elicited by mouse antibody treatment of patients, which severely hampers the application of these powerful molecules. The treatment of rheumatoid arthritis patients with doses of as high as 10 mg kg cA2 chimeric antibody specific for TNFa [9], emphasizes that at present the production and purification methods for these proteins have been optimized to such extent that clinical studies can be considerably intensified. 

More than twenty years of rodent monoclonal antibody generation by the classical hybridoma technology has yielded a number of promising therapeutic candidates and their humanization compares well to the de novo generation and characterization of human antibodies for accessing clinical applications in the coming years. 

Numerous investigators have reported and reviewed the chnical application of monoclonal antibodies in various areas, including organ transplantation, neoplastic diseases, severe sepsis, and chronic inflammatory diseases. Collectively, these antibodies generally did not produce major adverse effects. The rapid development of antibodies against murine monoclonal antibodies is one of the most important clinical hmitations to their therapeutic use, but the development of humanized (chimeric human/ murine) monoclonal antibodies has improved their safety. Monoclonal antibodies have also been used in non-immune mediated diseases, such as cancer, septic shock, reperfusion, and as antiplatelet drugs. Treatment of neoplastic diseases with monoclonal antibodies is theoretically attractive. Unfortunately none of the monoclonal antibodies available at present has been demonstrated to be strictly tumor-specific, and binding of antibody to normal cells has been shown to be the major unknown factor for toxicity (6). 

Laroche-Traineau J., Clofent-Sanchez G. and Santarelli X. 2000. Three-step purification of bacterially expressed human single-chain Fv antibodies for clinical applications, J. Chro-matogr. B Biomed. Sci. AppL, 737, 107. 

However, direct inhibition of the action of IL-8 might be the most effective and beneficial therapy considering clinical application. This novel intervention therapy inhibits specific types of leukocytes, neutrophils, and thus can be applied to neutrophil-mediated acute inflammatory diseases in any organ and/or tissue injury. This approach does not accelerate the spread of unexpected bacterial infection because there is no inhibitory action against monocyte/macrophages. Moreover, because IL-8 is involved relatively downstream of the cytokine network in acute inflanunation, and anti-IL-8 therapy is expected to have few side effects compared with other anticytokine therapies. Furthermore, this therapy not only inhibits neutrophil infiltration but also neutrophil-associated tissue injury. Thus, at present, humanized monoclonal antibodies to human IL-8 is expected to be one of the most promising clinical applications of novel intervention therapy for acute inflammatory diseases. 

---