Monoclonal antilymphocyte antibodies

Although the polyspecific ALS (shown to contain antibodies to a great number of T lymphocyte surface antigens) is still very useful, with the advent of monoclonal antibodies to various surface molecules on lymphocytes, more specific tools are available. Antibodies specific for epitopes on molecules such as CD2, CD3/TCR components, CD4, CD6, CD8, IL-2R (CD25), LFA-1, and HLA class II have been tried. OKT3 (anti-CD3), which is by far the most commonly used mAb to lymphocytes, has been used for immunosuppression in clinical practice for about 15 years. It has a half-life after injection of 18 h. As with ALS, such mAbs will be used for depletion of lymphocyte populations, but may also be used to modulate the function of lymphocytes by way of interacting with the respective surface molecules. Many studies have compared the therapeutic use of OKT3 and ALS, and in many cases they were found to be equivalent. OKT3 has been effective in cases where graft rejection was both steroid and ALS resistant. Many factors influence the effectiveness of lymphocyte-specific mAbs, such as the properties of preparation itself, the pharmacokinetics, the rate of production of the target molecules, the presence of blocking antibodies, etc. Advantages with mAbs are that they are uniform in immunoglobulin subclass and have a better defined specificity and more repro ducible effects. A problem is the production of anti-antibodies which counteract the effect of the administered mAb (Figure 1). It is a smaller problem when using polyclonal ALS, and is to some extent prevented by the use of concomitant immunosuppression. The problem with antiantibodies may be circumvented by changing to a mAb against a different epitope or by using mAbs with a human type of molecular structure. In an experimental system, pretreat-ment with ALS was found to suppress formation of neutralizing antiantibody to a mAb administered later. Only mAbs against CD4 seem to avoid stimulating the production of antiantibodies by the recipient. This may reflect the unique ability of CD4-spe-cific mAbs to induce tolerance. A humanized CD4-specific mAb has been used in clinical trials on patients with autoimmune disease. The effect of mAbs may be modified by removing the Fc fragment, which is of importance for the elimination of the target cells by phagocytes. Thus, CD3-specific mAbs which lack the Fc part cause immune activation rather than immunosuppression. Antibodies may be raised against the antigen-binding epitope of the T cell receptor. This will probably become of value in the treatment of autoimmune disease. In the comparison between ordinary, polyclonal ALS and mAbs, contradictory opinions have been published regarding the effectiveness and severity of side-effects.

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