Monoclonal antibody murine

Ricin [9009-86-3], a phytotoxin found in the seeds of the castor oil plant Acinus communis, conjugated to murine monoclonal antibody (Immunogen Corp.), has been approved by the U.S. Food and Dmg Administration (FDA) for the treatment of patients with B-ceU leukemia and lymphoma (59). 

Muronomab-CD3 is a murine monoclonal antibody directed against the CD3 complex of the T-lymphocyte antigen receptor. This drug selectively diminishes the T-lymphocyte pool resulting in a strong lymphopenia. Similar to other nonhuman antibodies the generation of human antimurine antibodies (HAMA) limits its long-term use. 

Murine monoclonal antibodies reacting with CD4, which is solely located on T-helper lymphocytes and monocytes/macrophages, may also be suited for immunosuppression. 

Muronomab-CD3 (OKT-3) is a murine monoclonal antibody that targets the CD3 receptor. The CD3 receptor is only found on activated T cells and medullary thymocytes.10,11,14 After binding with the CD3 receptor, complement-mediated T cell lysis occurs rapidly. This agent is dosed at 5 mg/day. This dose is given daily for 10 to 14 days. Lower doses have been used successfully in liver transplant recipients.14... 

Mundegar RR, Franke E, Schafer R, et al. Reduction of high background staining by heating unfixed mouse skeletal muscle tissue sections allows for detection of thermostable antigens with murine monoclonal antibodies./. Histochem. Cytochem. 2008 56 969-975. 

Ghetie, V., Ghetie, M.-A., Uhr, J.W., and Vitetta, E.S. (1988) Large scale preparation of immunotoxins constructed with the Fab fragment of IgGl murine monoclonal antibodies and chemically deglyco-sylated ricin A chain./. Immunol. Meth. 112, 267-277. 

Immunogenicity. Many, if not most, therapeutic proteins are potentially immunogenic when administered to humans. The likelihood that non-human proteins (e.g. murine monoclonal antibodies Chapter 13) are immunogenic in humans is an obvious one. However, human proteins can also be potentially immunogenic, as discussed in Box 4.1. Antibodies raised in this way can bind the therapeutic protein, neutralizing its activity and/or affecting its serum half-life. 

Zevalin (Ibritumomab Tiuxetan murine monoclonal antibody, produced in a CHO cell line, targeted against the CD20 antigen) IDEC Pharmaceuticals Non-Hodgkin s lymphoma... 

NeutroSpec (murine monoclonal antibody raised against CD15 surface antigen of selected leukocytes) Palatin Technologies/ Mallinckrodt Inc. Imaging of equivocal appendicitis... 

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. 

Recombinant DNA technology has provided an alternative (and successful) route of reducing the innate immunity of murine monoclonals. The genes for all human immunoglobulin sub-types have been cloned, and this has allowed generation of various hybrid antibody structures of reduced immunogenicity. 

Figure 13.9 Production of chimaeric (a) and humanized (b) antibodies (via recombinant DNA technology). Chimaeric antibodies consist of murine monoclonal VH and VL domains grafted onto the Fc region of a human antibody. Humanized antibody consists of murine CDR regions grafted into a human antibody...

When compared with human monoclonals (half-life 14-21 days), murine monoclonals administered to humans display a relatively short half-life (30-40 h). Chimaerization increased serum half-life by fivefold, with typical values of 230 h being recorded (Table 13.4). A prolonged half-life is desirable if the antibody is to be used therapeutically, as it decreases the required frequency of product administration. Chimaeric antibodies also allow activation of Fc-mediated functions (e.g. activation of complement, etc.), as this domain displays human sequence. 

The first monoclonals were murine (mouse) antibodies, because the early experiments involved injecting mice with an antigen, harvesting their B cells, and then fusing a harvested B cell with an immortal tumor cell line. There were immediate ahempts to make therapeutic drugs from murine monoclonal antibodies. Scientists at Harvard Medical School tried to apply murine monoclonal antibodies for heahnenf of tumors as early as 1980. But with a very few exceptions, murine antibodies failed as drugs in humans. 

Vandamme, A.M., Bulens, R, Bemar, H., Nelles, L., Lijnen, R.H., and Collen, D., Construction and characterization of recombinant murine monoclonal antibody directed against human fibrin fragment-D dimer, Eur. ]. Biochem., 192, 767-775, 1990. 

Factor IX may also be purified by immuno-alfinity chromatography, using immobilized anti-IX murine monoclonals. Purification to homogeneity is particularly important in the case of recombinant products. At least one monoclonal antibody has been raised that specifically binds only to factor IX, which contains pre-bound Ca + (i.e. the Ca +-dependent conformation of factor IX). Immobilization of this antibody allowed the development of an immuno-alfinity system in which factor IX binds to the column in the presence of a Ca -containing bufier. Subsequent elution is promoted simply by inclusion of a chelating agent (e.g. EDTA) in the elution buffer. 

CEA-scan (Arcitumomab, murine monoclonal antibody (Mab) fragment (Fab), directed against human carcinoembryonic antigen, CEA)... 

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