Constant region

Biologicals. Figure 3 Fusion protein construction combination of the molecular component of interest with the constant region (Fc) of an antibody molecule, usually immunoglobulin (lg)G1 Fc, imparts the Fc function on to the molecularcomponentfortherapeutic use. The example given is ofCTLA4-lg, derivatives of which have shown clinical efficacy in the treatment of rheumatoid arthritis and transplant rejection. 

The Constant Regions Determine Class-Specific Effector Functions... 

The constant regions of the immunoglobulin molecules, particularly the C 2 and 0 3 (and C 4 of IgM and IgE), which constitute the Fc fragment, are responsible for the class-specific effector functions of the different immunoglobulin molecules (Table 50-7, bottom part), eg, complement fixation or transplacental passage. 

The four hypervariable regions are indicated by the bars. The constant regions in this disanalog family include a 50 AA N-terminal region (not shown) and the 6 cysteine residues. 

Binding of IFN-y to its surface receptor on polymorphonuclear neutrophils induces increased expression of the gene coding for a neutrophil cell surface protein capable of binding the Fc portion (i.e. the constant region see also Box 13.2) of IgG. This greatly increases the phagocytotic and cytotoxic activities of these cells. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

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. 

H. Mayer, S. A. Campos-Portuguez, M. Busch, T. Urbanik-Sypniewska, and U. R. Bhat, in A. Nowotny, J. J. Spitzer, and E. J. Ziegler (Eds.), Endotoxin Research Series, Vol. 1, Cellular and Molecular Aspects of Endotoxin Reactions Lipid A Variants—Or, How Constant Are the Constant Regions in Lipopolysaccharides p. 111. Elsevier, Amsterdam, 1990. 

Figure 1.10. Generalised structure of the variable and constant domains within antibodies. The variable regions (dark shading) of either the light or heavy chains are indicated as VL or VH, respectively. The light chains also possess one constant region (CL), whereas the heavy chains possess either three or four constant regions (Ch)-Ch4). depending upon the class of immunoglobulin (see text for details).

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