Antibodydependent immunotherapy

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The capacity to use antibodies for immunotherapy has been reported by a number of groups, and provides a very flexible and specific approach. This approach has been used in a wide spectrum of diseases, in transplantation and cancer, as well as autoimmunity. One of the virtues of antibody-mediated therapy is its molecular specificity, which, unlike the case with organic chemical drugs, is precisely known. Thus, cross-reactions can be readily monitored and therapeutic trials offer insight into pathophysiology.

The murine monoclonal antibody OKT3 developed by Patrick Kung was the first antibody to reach the market for transplant rejection episodes, and is still in use. Because murine antibodies are highly immunogenic in humans, repeated administration was not likely to be practical in the treatment of chronic disease, unless the effect was permanent.

Subsequent developments have altered the structure of murine antibodies so that they more closely resemble human antibodies in order to reduce immunogenicity. Replacement of the Fc and hinge regions leads to 'chimeric' antibodies, retaining the murine Fv, and more recently only the murine hyper-variable regions have been 'grafted' on to a human Ig backbone, forming 'humanized' antibodies. With the generation of transgenic mice with a considerable part of the functional human Ig gene locus in place, the goal of developing fully human antibodies is also close to becoming realized. Phage display technology has been used to construct recombinations of human heavy and light chains. These immunoglobulins can be selected to bind molecular targets, and can be used for antibody. Whether these strategics will prevent immune responses to neoepitopes in the idiotypic (hypervariable) region is unclear.

One of the most studied antibodies is anti-CD4. It has been shown by H. Waldmann in animal models that this promotes the development of immunological tolerance. The mechanism of this is not fully understood, and probably several mechanisms exist. Both lytic (depleting) and nondepleting antibodies can be protolerogenic, the latter more so. The mechanism of tolerance involves the generation of regulatory T cells and takes several weeks to reach optimal effects. Since such tolerance is capable ot being transferred by T cells, the induced tolerance is 'infectious'. In humans anti-CD4 has been used extensively. Initial trials with lytic anti-CD4 in rheumatoid arthritis were not effective, but current trials of non-lytic anti-CD performed by SmithKline Beecham and Glaxo-Wellcome are more encouraging, reflecting the animal model experience.

Immunotherapy with anti-CD7 and with anti-CD.5 (the latter conjugated to ricin) have not been effective in rheumatoid arthritis. CAMPATH-1H reacting with CD52 present on T, B and monocytic cells is a very lytic antibody, and may be effective in rheumatoid arthritis, although its apparent toxicity has prevented its use in randomized placebo-controlled trials. Nevertheless, it has had dramatic success in vasculitis and in lymphomas and some success in multiple sclerosis.

Antibodies to cytokines have been used for immunotherapy. The most widely studied is anti-tumor necrosis factor a (TNFa), which was initially used in sepsis, without clearcut success. Subsequent open and placebo-controlled clinical trials in rheumatoid arthritis and Crohn's disease have been highly successful and reproducible using two different antibodies, first with cA2 from Centocor Inc. and subsequently CDP571 from Celltech. In addition, two immunoglobulin (Ig) Fc-TNF receptor fusion pro-

reins produced by Immunex (p75) and Roche (p53) have both been shown to be effective.

Antibodies to IL-6 and I1-6R have been reported to be beneficial in very small open studies in rheumatoid arthritis.

Fusion proteins, comprising the IgG Fc region coupled to a receptor, have been used for two reasons: in order to prolong half-life in the blood and to augment avidity due to the presence of two combining sites. In addition to the above-mentioned TNFR Ig proteins, another which has entered trials is CTLA4-Ig (Bristol Myers Squibb). This protein binds to the CD80 and CD86 costimulatory ligands on antigen-presenting cells for CD28, and is very effective in animal models.

Cytokines with immunoregulatory properties have been used for immunotherapy and clinical trials. These include IL-10 for Crohn's disease and rheumatoid arthritis (Schering Plough), IL-11 for Crohn's disease (Genetics Institute) and IL-4 for rheumatoid arthritis (Schering Plough). The clinical trials are based on the effectiveness of these cytokines in relevant animal models, but of these only IL-10 in Crohn's disease has yet reached the clinical trial stage where its effectiveness has been successfully assessed.

Interleukin 1 receptor antagonist has been used in sepsis without success, but recent trials in rheumatoid arthritis by Amgen Inc. have shown a trend to some benefit, not so much in reducing inflammation, but in reducing the rate of joint destruction as assessed by serial X-rays of the hands.

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