Monoclonal antibodies, sepsis treatment with

The majority of the proteins in clinical trials in August 1991 were monoclonal antibodies for treatment of sepsis or neoplasia (see Immunotherapeutic agents). Monoclonal antibodies are derived in most cases from mouse cell lines. This leads to the problem that the antibodies are recognized as foreign by the human immune system. Research efforts are directed toward humanizing antibodies so that these molecules can escape immune surveillance, for example, by the systematic replacement of murine-specific peptide sequences with human homologues while still maintaining the... 

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). 

Pretreatment with monoclonal anti-TNF antibodies prevents mortality (B23, M32) and organ damage (M16) in experimental sepsis. In clinical studies using anti-TNF antibodies, however, the overall benefit of this treatment showed encouraging but no evident results (L22). Recently, the INTERSEPT study suggests a possible role for anti-TNF antibody as an adjunctive therapy, but with no reduction of mortality (C21). There is no plain cause-effect relation between TNF re-... 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

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