The relatively recent expansion in the use of antibodies as therapeutic agents has extended their function from targeting pathogens to targeting components of the immune system itself in order to achieve a specific regulatory result. For example, the potential of antibodies to eliminate unwanted lymphocytes is demonstrated by anti-lymphocyte globulin, a preparation of polyclonal immunoglobulin from rabbits (and previously horses) immunized with human lymphocytes, which has been used for many years to treat episodes of acute graft rejection. Anti-lymphocyte globulin does not, however, discriminate between useful lymphocytes and those responsible for the unwanted responses and therefore leads to global immunosuppression. Foreign immunoglobulins are also highly antigenic in humans, and the large doses of anti-lymphocyte globulin used in therapy often cause a condition called serum sickness, resulting from the formation of immune complexes of the animal immunoglobulin and human antibodies against it (see Section 14-15).
Anti-lymphocyte globulin is nevertheless still used to treat acute rejection, and this has stimulated the quest for monoclonal antibodies (see Appendix I, Section A-7) that would achieve more specifically targeted effects. One such antibody is alemtuzumab (marketed as Campath-1H), which is directed at the cell-surface protein CD52 expressed by most lymphocytes. It has similar actions to anti-lymphocyte globulin, causing long-standing lymphopenia. It is also used to eliminate cancer cells in the treatment of chronic lymphocytic leukemia.
Immunosuppressive monoclonal antibodies act by one of two general mechanisms. Some, such as alemtuzumab, trigger the destruction of lymphocytes in vivo and are referred to as depleting antibodies, whereas others are nondepleting and act by blocking the function of their target protein without killing the cell that bears it. Depleting monoclonal IgG antibodies bind to lymphocytes and target them to macrophages and NK cells, which bear Fc receptors and kill the lymphocytes by phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC), respectively. Complement-mediated lysis may also play a part in lymphocyte destruction.
16-5 Antibodies can be engineered to reduce their immunogenicity in humans.
A major impediment to therapy with monoclonal antibodies in humans has been that these antibodies are most readily made by immunizing nonhuman species, such as the mouse, to generate antibodies of the desired specificity (see Appendix I, Section A-7). Humans may develop an antibody response against such nonhuman antibodies, since aggregated forms of foreign antibodies can be immunogenic. Such a reaction not only interferes with the therapeutic actions of the antibodies, but also leads to allergic reactions, and, if treatment is continued, may result in anaphylaxis (see Section 14-10). Once a patient has made a response to an antibody, it can no longer be used for future treatment. This problem can, in principle, be avoided by making antibodies that are not recognized as foreign by the human immune system, a process called humanization.
Various approaches have been tried to humanize antibodies. The variable regions encoding the antigen-recognition determinants from a murine antibody can be spliced onto the Fc regions of human IgG by gene manipulation. Antibodies of this type are called chimeric antibodies. However, this approach leaves regions within the murine variable regions that could potentially induce