Antibody immunogenicity remains one of the inherent therapeutic limitations associated with administration of murine monoclonals to human subjects. In most instances, a single injection of the murine monoclonal will elicit an immune response in 50-80 per cent of patients. Human anti-mouse antibodies (HAMA) will generally be detected within 14 days of antibody administration. Repeated administration of the monoclonal (usually required if the monoclonal is used for therapeutic purposes) will increase the HAMA response significantly. It will also induce an HAMA response in the majority of individuals who display no such response after the initial injection. The HAMA response will effectively and immediately destroy subsequent doses of monoclonal administered. In practice, therefore, therapeutic efficacy of murine monoclonals is limited to the first and, at most, the second dose administered.
An obvious strategy for overcoming the immunogenicity problem would be the generation and use of monoclonal antibodies of human origin. This is possible but difficult. Human antibody-producing lymphocytes can potentially be rendered immortal by:
• transformation by Epstein-Barr virus infection;
• fusion with murine monoclonals;
• fusion with human lymphoblastoid cell lines.
However, a number of technical hurdles remain that prevent routine production of human monoclonal preparations. These include:
• source of antibody-producing cell;
• reliable methods for lymphocyte immortalization;
• stability and antibody-producing capacity of resulting immortalized cells.
Initial stages in the production of murine monoclonals entail administration of the antigen of interest to a mouse. This is followed by sacrifice and recovery of activated B-lymphocytes from the spleen. A similar approach to the production of human monoclonals would be unethical. Administration of some antigens to humans could endanger their health. Although B-lymphocytes could be obtained from the peripheral circulation, the majority of these are unstimulated, and recovery of (stimulated) B-lymphocytes from the spleen is impractical.
Although Epstein-Barr virus is capable of inducing cellular transformation, few antibody-producing B-lymphocytes display the viral cell surface receptor. Most, therefore, are immune to Epstein-Barr virus infection. Even upon successful transformation, most produce low-affinity IgM antibodies, and the cells are often unstable. Having said that, one monoclonal antibody approved for medical use (Humaspect, Table 13.2) is produced by a human lymphoblastoid cell line originally transformed by Epstein-Barr virus.
Fusion of human lymphocytes with human lymphoblastoid cell lines is a very inefficient process. Fusion of human lymphocytes with murine myeloma cells lead to very unstable hybrids. Upon fusion, preferential loss of human genetic elements is often observed. Unfortunately, particularly common is the loss of chromosomes 2, 14 and 22, which encode antibody light and heavy chain loci. The production yields of human monoclonals upon immortalization of the human B-lymphocyte (by whatever means) are also low.
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