Monoclonal origin

Figure 12.2 Monoclonal origin of cancer with the selection of cells with multiple mutations in critical genes. X designates the occurrence of a mutation in a critical gene.

Monoclonal origin of crypts in an XO/XY mosaic individual. Staining using in situ hybridization for a Y chromo-some-specific probe demonstrates an XO crypt (left) and an XY crypt (right). 

Bioprocess plants are an essential part of food, fine chemical and pharmaceutical industries. Use of microorganisms to transform biological materials for production of fermented foods, cheese and chemicals has its antiquity. Bioprocesses have been developed for an enoimous range of commercial products, as listed in Table 1.1. Most of the products originate from relatively cheap raw materials. Production of industrial alcohols and organic solvents is mostly originated from cheap feed stocks. The more expensive and special bioprocesses are in the production of antibiotics, monoclonal antibodies and vaccines. Industrial enzymes and living cells such as baker s yeast and brewer s yeast are also commercial products obtained from bioprocess plants. 

Originator First Introduction Novartis US Type monoclonal antibody Fully human IgGl,... 

Country of Origin Germany Class Trifunctional monoclonal... 

The antibody preparations could be administered unaltered or (more commonly) after their conjugation to radioisotopes or toxins. Binding of unaltered monoclonal antibodies to a tumour surface alone should facilitate increased destruction of tumour cells (Figure 13.4). This approach, however, has yielded disappointing results, as the monoclonal antibody preparations used to date have been murine in origin. The Fc region of such mouse antibodies is a very poor activator of human immune function. Technical advances, allowing the production of human/humanized monoclonals (see later) may render this therapeutic approach more attractive in the future. 

Figure 13.5 Outline of the production strategy of CEA-SCAN. The antibody-producing hybridoma cell line was originally obtained by standard methods of hybridoma generation. Spleen-derived murine B-lymphocytes were fused with murine myeloma calls. The resulting stable hybridomas were screened for the production of anti-CEA monoclonals. The clone chosen produces an IgG anti-CEA antibody. Note that the finished product outlined above is not radiolabelled. The freeze-dried antibody preparation (which has a shelf life of 2 years at 2-8 °C) is reconstituted immediately prior to its medical use. The reconstituting solution contains 99mTc, and is formulated to facilitate direct conjugation of the radiolabel to the antibody fragment...

Despite the scientific elegance of the antibody-mediated approach to tumour detection/destruc-tion, initial clinical trials proved disappointing. A number of factors contributed to their poor therapeutic performance, particularly against solid tumours. Most such factors relate directly/ indirectly to the fact that the first generation of such drugs utilized whole monoclonal antibody preparations of murine origin. These factors include ... 

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 ... 

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