Septic shock monoclonal antibodies

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. 

T4. Taylor, F. B., Jr., Chang, A. C., Ruf, W., Morrissey, J. H., Hinshaw, L., Catlett, R Blick, K. and Edgington, T. S., Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ. Shock 33,127-134 (1991). 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

V. Monoclonal Antibody Therapy in Infectious Diseases A. Septic Shock... 

Reinhart, K., Wiegand-Lohnert, C., Grimminger, F., Kaul, M., Withington, S., Treacher, D., Eckart, J. et al. (1996). Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock A multicenter, randomized, placebo-controlled, doseranging study. Crit. Care Med. 24, 733-742. 

Ziegler, E.J., Fisher, C.J.Jr, Sprung, C. L. etal. (1991). Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin A randomized, double-blind, placebo-controlled trial. N. Eng.]. Med. 324, 429-436. 

McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M., and Smith, C. R. (1994). CHESS Trial Study Group. Treatment of septic shock with human monoclonal antibody HA-1A. Ann. Intern. Med. 121, 1-5. 

Derkx, B., Wittes, J., McCloskey R. et al. (1999). Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. Clin. Infect. Dis. 28, 770-777. 

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). 

ND-STAT brompheniramine, nebacumab [ban, inn. usan) (HA-1A) is a monoclonal antibody (MW c. 1,000,000) that has immunomodulator/ IMMUNOSUPPRESSANT activity. It has been used for treatment of Gram-negative sepsis and septic shock. Withdrawn from European market in 1994. 

Hopken U, Mohr M, Struber A, et al. Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies. Eur ) Immuno 1996 26 1103-9. 

Silva, A. T., Bayston, K. F., and Cohen, J. (1990). Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative septic shock. J. Infect. Dis. 162, 421-427. 

Tracey K J, Fong Y, Hesse D G, et al. (1987). Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 330 662-664. 

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