Chimaeric and humanized antibodies

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. 

It was hoped that such chimaeric antibodies, when compared with murine antibodies, would be  

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. 

Humanization has overcome many of the major factors that limited the therapeutic effectiveness of first-generation (murine) monoclonals as therapeutic agents. Several such humanized products have now gained marketing authorization (Table 13.2), and one such product is featured in Box 13.3. 

Avastin (tradename, also known as bevacizumab) is a 149 kDa recombinant humanized monoclonal IgGl antibody first approved for medical use in the USA in 2004, and subsequently in the EU in 2005. It is indicated for first-line treatment of patients with metastatic colorectal cancer, in combination with specified (5-fluorouricil-based) small molecule chemotherapeutic drugs. 

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Chimaeric and humanized antibodies Rendering murine antibodies more human in sequence, thereby decreasing their immunogenicity and increasing their serum half-life 13... 

G. L. Boulianne, N. Hozumi, and M. J. Schuhnan, Production of functional chimaeric mouse/human antibody region domains. Nature 312 643-646 (1984). 

The first strategy entails production of chimaeric antibodies, consisting of mouse variable regions and human constant regions (Figure 13.9). The chimaeric antibody would display the specificity of the original murine antibody, but would largely be human in sequence. 

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...

It is a chimaeric antibody containing murine light and heavy chain variable sequences and human constant region sequences. It is produced by genetically transformed CHO cells. 

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