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ISSUES SPECIFICALLY RELATED TOMONOCLONAL ANTIBODIES
The thinking about the immunogenicity of mono-clonal antibodies went through the same paradigm shift as occurred with therapeutic proteins in general. The first generation of monoclonal antibodies was of murine origin. They induced an immune response in the majority of patients as foreign proteins should trigger a classical vaccine-type immune response. This so-called human antimurine antibodies (HAMA) response was a major restriction in the clinical success of these murine antibodies. Over the years, however, methods were introduced to humanize monoclonal antibodies in different stages . Recombinant DNA technology was used to exchange the murine constant parts of the immune globulin chains with their human counterparts resulting in chimeric monoclonal antibodies. The next step was to graft murine complementarity determining regions (CDRs), which determine the specificity, into a human immune globulin backbone creating humanized monoclonal antibodies. And the final step was the development of transgenic ani-mals, phage display technologies, and other devel-opments allowing the production of human monoclonal antibodies.
However, the assumption that human mono-clonal antibodies would have no immunogenicity proved to be wrong. Although humanization has reduced the immunogenicity, even completely human monoclonal antibodies have been shown to induce antibodies. The introduction of chimeric antibodies by the exchange of the murine constant regions with their human counterparts has resulted in a substantial reduction of the induction of antibodies. Whether further humanization has resulted in an additional decrease is less clear. As discussed, the presence of aggregates has been identified as a major cause of immunogenicity of human therapeutic proteins. It is likely that with human monoclonal antibodies aggre-gates are also responsible for antibody induction. In fact in the classical studies of B-cell tolerance done more than 40 years ago aggregated immuno-globulin preparations were used to break tolerance (Weigle, 1971).
Monoclonal antibodies have properties, which may contribute to their immunogenicity. They can activate T-cells by themselves and may boost the immune response by their Fc functions such as macrophage activation and complement activation. Indeed removal of N-linked glycosyl chains from the Fc part of the immunoglobulin may reduce Fc function and lead to a diminished immunogenicity.
What the antibodies are binding is also influen-cing their immunogenicity. Monoclonal antibodies targeting cell-bound antigens induce a higher level of antibody formation than those with circulating targets. Monoclonal antibodies directed to antigens on immune cells with the purpose of inducing immune suppression also suppress an immunogenic response.
Although more injections and higher doses are associated with a higher immune response, in some cases chronic treatment and higher doses were reported to be less immunogenic than episodic treatment and lower doses. The interpretation of these data is difficult because under these treatment conditions the level of circulating product is higher and more persistent and the presence of circulating monoclonal antibodies during the time of blood sampling may mask the detection of induced anti-bodies. Only a few studies were performed in which the subcutaneous and intravenous route of adminis-tration of monoclonal antibodies were compared showing little difference in immunogenicity.
The immune status of the patients influences the antibody response as with other protein therapeutics. Many of the patients receiving monoclonal antibodies are immune compromised by diseases such as cancer or by immune suppressive treatment and are less likely to produce antibodies than patients with a normal immune status. Sometimes immune suppres-sive agents such as methotrexate are given to patients with the purpose of inhibiting an antibody response.
Another important aspect when studying the immunogenicity of monoclonal antibodies is timing of the blood sampling of patients. These products have a relative long half-life (several weeks) and the circulat-ing product may interfere with the detection of induced antibodies and may lead to false-negative results. Sampling sera up to 20 weeks after the patient has received the last injection may be necessary to avoid the interference of circulating monoclonal antibodies. Also natural antibodies, soluble receptors, and immune complexes may interfere with assays and lead to either false-positive or false-negative results (as explained above).
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