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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications - Monoclonal Antibodies: From Structure to Therapeutic Application

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Murine, Chimeric, Humanized and Fully Humanized mAbs - Antibody Structure and Classes

With the advancement of technology early murine mAbs have been engineered further to chimeric (mouse CDR human Fc), humanized and fully human mAbs (Fig. 2).

Murine, Chimeric, Humanized and Fully Humanized mAbs

 

With the advancement of technology early murine mAbs have been engineered further to chimeric (mouse CDR human Fc), humanized and fully human mAbs (Fig. 2). Murine mAbs, chimeric mAbs, huma-nized mAbs and fully humanized mAbs have 0%, ~60% to ~70%, ~90% to ~95% and ~100% sequencesthat are similar to human mAbs, respectively. Decreasing the xenogenic portion of the mAb poten-tially reduces the immunogenic risks of generating anti-therapeutic antibodies (ATAs). The first thera-peutic mAbs were murine mAbs produced via hybridomas, however, these murine antibodies easily elicited formation of neutralizing human anti-mouse antibodies (HAMA) (Kuus-Reichel et al., 1994). Muromonab-CD3 (Orthoclone OKT3), a first genera-tion mAb of murine origin, has shown efficacy in the treatment of acute transplant rejection and was the first mAb licensed for use in humans. It is reported that 50% of the patients who received OKT3 produced HAMA after the first dose. HAMA interfered with OKT3’s binding to T-cells, thus decreasing the therapeutic efficacy of the mAb (Norman et al., 1993). Later, molecular cloning and the expression of the variable region genes of IgGs have facilitated the generation of engineered antibodies. A second gen-eration of mAbs, chimeric mAbs consist of human constant regions and mouse variable regions. The antigen specificity of chimeric mAb is the same as the parental mouse antibodies; however, the human Fc region renders a longer in vivo half-life than the parent murine mAb and similar effector functions as the human Ab. Currently, there are five chimeric antibodies and fragments on the market (abciximab, basiliximab, cetuximab, infliximab, and rituximab). These antibodies can still induce human anti-chimeric antibodies (HACA). For example, about 61% of patients who received infliximab had HACA response associated with shorter duration of therapeutic effi-cacy and increased risk of infusion reactions (Baert et al., 2003). The development of ATA is currently not predictable, as 6 of 17 patients with systemic lupus erythematosus receiving rituximab developed high-titer HACA (Looney et al., 2004), whereas only 1 of 166 lymphoma patients developed HACA (McLaughlin et al., 1998). Humanized mAbs contain significant portions of human sequence except the CDR which is still of murine origin. There are 10 marketed humanized antibodies on the market (alemtuzumab, bevacizumab, daclizumab, efalizu-mab, gemtuzumab, natalizumab, omalizumab, palivi-zumab, ranibizumab and trastuzumab). The incidence rate of anti-drug antibody [i.e., human anti-human antibody (HAHA)] was greatly decreased for these humanized mAbs. Trastuzumab has a reported HAHA incidence rate of only 0.1% (1 of 903 cases) (Herceptin, 2006), but daclizumab had a HAHA rate as high as 34% (Zenapax, 2005). Another way to achieve biocompatibility of mAbs is to develop fully humanized antibodies, which can be produced by two approaches: through phage display library and by using transgenic XenoMouse with human heavy and light chain gene fragments (Weiner, 2006).


CH2 domain or the hinge region joining CH1 and CH2 have been identified as the crucial regions for binding to FcγR (Presta et al., 2002). Engineered mAbs with enhanced or decreased ADCC and CDC activity have been produced by manipulation of the critical Fc regions. Umana et al. (1999) engineered an anti-neuroblastomal IgG1 with enhanced ADCC activity compared with wild-type (WT). Shields et al. (2001) demonstrated that selected IgG1 variants with im-proving binding to FcγRIIIA showed an enhancement in ADCC for peripheral blood monocyte cells or natural killer cells. These findings indicate that Fc-engineered antibodies may have important applica-tions for improving therapeutic efficacy. It was found that the FcγRIIIA gene dimorphism generates two allotypes: FcγRIIIa-158V and FcγRIIIa-158F and the polymorphism in FcγRIIIA is associated with favorable clinical response following rituximab

administration in non-Hodgkin’s lymphoma patients (Cartron et al., 2004; Dall’Ozzo et al., 2004). Currently, several anti-CD20 mAbs with increased binding affinity to FcγRIIIA are in clinical trials. The efficacy of antibody-interleukin-2 fusion protein (Ab-IL-2) was improved by reducing its interaction with Fcγ receptors (Gillies et al., 1999). In addition, the Fc portion of mAbs also binds to the FcRn receptor (FcRn- named based on discovery in neonatal rats as neonatal Fc receptor), an Fc receptor belonging to the major histocompatibility complex structure, which is involved in IgG transport and clearance (Junghans, 1997). Engineered mAbs with a decreased or in-creased FcRn binding affinity have been investigated for the potential of modifying the PK behavior of mAb (see section “Antibody clearance” for detail).

 

 

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