Antibodies for Neoplastic Disease
The ease with which polyclonal, monoclonal, and engineered antibody fragments can be prepared allows access to a series of reagents with high selectivity and affinity. These reagents therefore have long held promise as a means of influencing the growth an
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6 Antibodies for Neoplastic Disease Solid Tumors Ian T. W. Matthews 1. Introduction The ease with which polyclonal, monoclonal, and engineered antibody fragments can be prepared allows access to a series of reagents with high selectivity and affinity. These reagents therefore have long held promise as a means of influencing the growth and spread of malignant disease. Over a number of decades therapeutic antibodies have been developed either as single entities or conjugated to a variety of potential disease-ameliorating agents. Single entity antibodies can have their effects either through antigen- or nonantigen-binding site interactions leading to, for instance, complement fixation or T cell activation. Conjugates of antibodies have been prepared both by chemistry and by molecular biology, leading to a range of reagents conjugated to protein toxins, organic toxins, chelating agents, radioisotopes, enzymes, and photosensitizers. This chapter will be restricted to some modern clinical experiences with a variety of antibodies with and without toxic passengers in the most difficult area of cancer therapy, the solid tumor. 2. Immunotoxins The word “toxin” can be applied to a number of low- and high-mol wt agents either directly antitumor-progressive, or as in the case of photodynamic therapy and prodrugs, indirectly antitumor progressive. The clinical use of immunotoxins has found success in the therapy of lymphoma (1) and leukemia (2) but has been spectacularly unsuccessful in the treatment of solid tumors. The apparent ease with which xenograft-bearing mice could be cured spurred on a number of clinical trials, the conclusions of which were far from positive. From: Methods in Molecular Medicine, Vol. 40: Diagnostic and Therapeutic Antibodies Edited by: A. J. T. George and C. E. Urch © Humana Press Inc., Totowa, NJ
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Recently, for instance, a monoclonal antibody (mAb) (791T) that recognizes a 72 kDa glycoprotein on colorectal and ovarian carcinomas and an osteogenic sarcoma was conjugated to ricin A chain (XMMCO-791/RTA) and administered as a Phase I trial to 12 patients with metastatic colorectal carcinoma. The conclusion (3) of this trial was that a number of severe toxic side effects were seen but no antitumor effect was apparent. In a further study (4), eight patients with leptomeningeal neoplasia (although not a classical solid tumor) were treated by intraventricular administration of an antitransferrin antibody (454A12) linked to recombinant ricin A chain. Admin-istered doses of
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