We also briefly describe the improvements in aglycosylated mAb development

We also briefly describe the improvements in aglycosylated mAb development. Loss of the antibody Fc region dramatically shortens its serum half-life and weakens its anticancer effects. Given the essential roles that this Fc region plays in the modulation of the efficacy of mAb in malignancy treatment, Fc engineering has been extensively analyzed in the past years. This review focuses on the recent advances in therapeutic Fc engineering that modulates its related effector functions and serum half-life. We also discuss the progress made in aglycosylated mAb development that may substantially reduce the cost of manufacture but maintain comparable efficacies as standard glycosylated mAb. Finally, we spotlight several Fc engineering-based mAbs under clinical trials. Keywords: antibody Fc region, ADCC, CDC, ADCP, serum half-life, aglycosylated antibody, FcRn, malignancy therapy Introduction Monoclonal antibodies (mAbs) can target tumors through specific acknowledgement of tumor-associated antigens and subsequent recruitment of effector elements including macrophages, dendritic cells, natural killer (NK) cells, T-cells, and the match pathway components (1). Such recruitments are achieved by interactions among the immunoglobulin gamma (IgG)-crystallizable fragment (Fc) and the immune cell receptors like Fc receptors (FcRs) and the match protein C1q of the match system (2C4). These interactions lead to the activation of immune cells for enhanced antibody-dependent cellular cytotoxicity (ADCC)/antibody-dependent cell-mediated phagocytosis?(ADCP), formation of the membrane attack complex, and more efficient presentation of antigen to the dendritic cells (1). Through a recycling mechanism, the neonatal Fc receptor (FcRn) prolongs the half-life of mAbs in a pH-dependent conversation with the Fc region (5). The schematic of overall IgG structure and its binding regions with FcRs, C1q, and FcRn is usually depicted in Physique ?Figure11. Open in a separate window Physique 1 Schematics of immunoglobulin gamma overall structure and its binding regions with FcRs, C1q, and FcRn. The constituent heavy [VH, CH1, hinge, CH2, and CH3 (gray)] and light chains [VL and CL (gray)] linked by inter-chain disulfide bonds are shown. The site at which FcRs/C1q interacts with the crystallizable fragment (Fc) region is located in the lower hinge-upper CH2 (green rectangle); the site at which FcRn interacts with the Fc region is located in the interface of CH2CCH3 (yellow rectangle). The FcRs, consisting of FcRI (CD64), FcRII (CD32), and FcRIII (CD16) classes, are heterogeneous in terms Mouse monoclonal to WDR5 of their cellular expression and Fc binding affinities (1, 6). FcRI binds to the Fc region with FcRIII engagement by up to 50-fold (30, 46). However, mAb-associated glycan heterogeneity poses several key difficulties (30, 33, 45C51) including (1) troubles in developing therapeutic mAbs with glycan composition similar to naturally occurring human IgG1, (2) troubles in controlling glycan Myrislignan heterogeneity, (3) lengthier development time to construct cell lines generating glycan homogeneity, (4) lengthier IgG production time and higher developing cost in mammalian cells as compared to that in or yeast-based expression systems, (5) dominance of particular glycoforms that can affect effector functions of IgG molecules, and (6) troubles in separating numerous glycoforms generated from mammalian cells. Alternatively, development of aglycosylated mAbs with comparable efficacy as glycosylated counterpart but lower developing cost has drawn great efforts in the past decade. In this review, we focus on the recent progress in therapeutic Fc engineering-associated effector functions (ADCC, ADCP, and CDC) and pharmacokinetics. The mutations known to induce profound effects on Fc conversation with FcRs, C1q, and FcRn are summarized (observe Table ?Table1).1). We also briefly describe the improvements in aglycosylated mAb development. Finally, we spotlight clinical trials of several mAbs developed from relevant Fc engineering. Table 1 Tabulation of the Fc mutations known to mediate a profound effect on antibody effector functions and immunoglobulin gamma homeostasis. compared to WT IgG (6). The same Fc mutations also Myrislignan enhanced ADCC/ADCP activity against lymphoma cell lines and directly translated into a more effective treatment of lymphoproliferative diseases when incorporated into anti-CD19/CD40 mAbs (53, 54). Furthermore, it was shown that a change from glycine to alanine at residue 236 can shift the immune balance toward activating FcRIIa relative to inhibitory FcRIIb (56). The coupling of G236A to either I332E or Myrislignan S239D/I332E experienced dual beneficial effect as these mutants not only improve FcRIIa:FcRIIb ratio but also enhance binding to FcRIIIa by ~6- to 31-fold (56). These mutants experienced significantly improved NK cell-mediated ADCC and macrophage-mediated ADCP activity (56). In addition, shuffled variants of anti-CD20/CD57 antibody were constructed by grafting the CH1/hinge and CH3 carboxyl-terminal of IgG1 into the Fc of IgG3 to maintain both the ADCC activity from IgG1 and the CDC activity from IgG3 (72)..