Macrophage targeted clinical trials

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

It has been reported to stimulate humoral and cellular immune responses in combination with several subunit antigens. It has also been proven safe, and does not cause any major adverse reactions. In clinical trials it has already been used with influenza, HSV or HIV antigens, and has been marketed as part of an enhanced influenza vaccine for the elderly. MF59 does not form a depot at the injection site, but targets macrophages and dendritic cells at the site of injection and in lymph nodes. 

Currently, there is only one formulation of Amikacin in liposomes under clinical trials for treatment of tuberculosis. The antibiotic was found to be twofold to sixfold more active than the free drug in an acute experimental model of murine tuberculosis in which bacteria are located in macrophages. The count of viable bacteria found in the liver and spleen was reduced by a factor of 3-log compared with the untreated mice [158]. However, in human, this formulation was not as active as expected. To explain the disappointed results obtained, it was suggested that the liposomes could target the antibiotics in the macrophages but this was not enough to reach extracellular bacilli, which are clustered in cavity caseum in the human... 

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