Chimeric antibody, construction

The advent of recombinant DNA technology led to the development of antibodies and fragments that are tailored for optimal behaviour in vivo [7,8]. Humanized and chimeric antibodies can be constructed to circumvent the human anti-mouse antibody response elicited by mouse antibody treatment of patients, which severely hampers the application of these powerful molecules. The treatment of rheumatoid arthritis patients with doses of as high as 10 mg kg cA2 chimeric antibody specific for TNFa [9], emphasizes that at present the production and purification methods for these proteins have been optimized to such extent that clinical studies can be considerably intensified. 

Because of the limitations seen with the fully murine monoclonal antibodies the next generation of antibodies were chimeric antibodies (Table 26.2, Figure 26.2). Chimeric antibodies are constructed from variable regions derived from a murine source and constant regions derived from a human source. The chimeric antibodies show less of an immunogenic response than the fully murine antibodies, but human anti-chimeric antibody (FIACA) rates can still be high with these antibodies. The chimeric antibodies nevertheless have relative long serum half-lives (9.5 days for infliximab) relative to the fully murine antibodies because the Fc portion is human and can therefore bind to human FcRn in a manner similar to that of native antibodies. 

In this chimeric peptide construct the aim was to combine the carrier function and immunstimulatory activity of tuftsin derivatives with an epitope derived from HSV gD to achieve an increased antibody response. Tuftsin is a well-known natural tetrapeptide (TKPR) that has a pronounced effect on the immune system (28,29). Polymerized tuftsin (polytuftsin) is also considered as a carrier molecule that increased antibody levels against attached epitopes in mice (30,31). New, sequential oligopeptides based on repeated tuftsin derivatives (H-[Thr-Lys-Pro-Lys-Gly]n-NH2, where n = 2,4,6,8) were developed in our laboratory to eliminate the drawbacks of tuftsin derivatives produced by polymerization. These new, nontoxic, nonimmunogenic compounds have immunostimulatory activity and a minor chemoattractant effect on monocytes (32). An oligotuftsin derivative was used in this study for the synthesis of a peptide chimera containing an HSV peptide epitope. 

Fig. 2 Diagram of the most important MoAb constructs used clinically (A) antibody fragments (B) chimeric antibody (C) humanized antibody and (D) bispecific antibody. (Adapted from Ref...

Knight, D.M. et al., Construction and initial characterization of mouse human chimeric anti TNF alpha antibody, Molecular Immunol., 30, 1443, 1993. 

An approach for the generation of secondary structure specific abzymes, which utilized a chimeric construction as the hapten, has been described. 98 The hapten was designed to elicit a catalytic antibody which could potentially site-selectively cleave a peptide bond. The synthesis of the hapten 48 is outlined in Scheme 23. 

Monoclonal antibodies can vary tremendously in terms of isotype, construction (animal derived, chimeric, humanized, bound to toxin), ability to activate complement, binding avidity, target specificity, and whether it binds and blocks or binds and activates the receptor. Monoclonal antibodies may be directed toward soluble or membrane bound receptors or receptor ligands, tumor antigens, growth factor or their receptors. Therefore toxicity and side effects are equally variable [68]. 

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