IgG Fc engineering to modulate antibody effector functions

Abstract

Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss proposed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.

Keywords: Fc engineering; Fc gamma receptor; antibody-dependent cell-mediated cytotoxicity; antibody-dependent cellular phagocytosis; complement-dependent cytotoxicity; monoclonal antibody; neonatal Fc receptor.

Figure 1

The Fc domain of human IgG1 is shown (PDBID:3AVE). The positions of amino acids described in Table 1 are shown. Key sequence motifs for FcRn interactions are shown in green (L251-S254; L309-Q311; N434-H435) (Oganesyan et al., 2014). Amino acids 5 angstroms proximal to the FcγR:Fc interface for FcγRI (PDBID:4W4O) (Kiyoshi et al., 2015), FcγRIIa (PDBID:3RY6) (Ramsland et al., 2011), FcγRIIb (PDBID:3WJJ) (Mimoto et al., 2013b), and FcγRIIIb (PDBID:1E4K) (Sondermann et al., 2000) as determined with PyMOL are shown in red (P232-S239; D265-D270; Y296-T299; N325-I332). The amino acids that are critical for interactions with C1q are shown in blue (D270, K322, P329, P331) (Idusogie et al., 2000). Amino acids depicted in black were not identified as critical for interactions with FγRs, FcRn, or C1q. Figure 1 was generated with PyMOL.