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Implications of Fc Neonatal Receptor (FcRn) Manipulations for Transplant Immunotherapeutics

Jordan, Stanley C. MD1; Ammerman, Noriko PharmD1; Vo, Ashley PharmD1

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doi: 10.1097/TP.0000000000002912
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Abstract

INTRODUCTION

Alloimmune injury to allografts is commonly associated with the presence of pathogenic donor-specific alloantibodies (DSAs), usually of the IgG isotype. Currently, a number of strategies exist to reduce DSAs, collectively called desensitization, including plasma exchange (PLEX) + low dose intravenous immunoglobulin (IVIg) and high-dose IVIg.1,2 Anti-CD20 monoclonal antibodies (mAbs), typically rituximab or obinutuzumab, are used to prevent rebound DSA development.3 Despite successes, these treatments are not always effective and can be associated with adverse events, infectious complications, and high cost.4,5

Therapeutic PLEX is often used to remove plasma proteins, including pathogenic IgG molecules.5,6 Disadvantages of PLEX include hypocalcemia, exposure to blood products, reduced circulating plasma concentrations of all immunoglobulins (including IgM and IgA, not just IgG), and removal of complement regulatory proteins.7 The use of PLEX without IVIg and anti-CD20 mAbs results in a strong rebound of the target pathogenic antibody, which can result in disease relapse or intensify allograft rejection.3 An alternative treatment option is immunoadsorption, which specifically removes IgG, without the non-specific removal of all immunoglobulins and complement factors. However, immunoadsorption is not readily available in the U.S. and can be expensive.5,8 Recently, reports detailed the use of the IgG endopeptidase (Imlifidase) that specifically removed all circulating IgG and was successful for desensitization, but treatment was complicated by antibody rebound.3 The complex administration requirements of PLEX and currently utilized infusion therapies can result in the need to treat patients in hospital environments, which increases cost, patient inconvenience, and infection risk.8

IVIg is highly enriched human IgG (95%–99% IgG with trace amounts of IgM, IgA, IgD, IgE) prepared from thousands of healthy donors.9,10 The multiple mechanisms of action of IVIg may include functional blockade of Fc neonatal receptors (FcRn), antibody neutralization through idiotypic/anti-idiotypic interactions, direct inhibition of B cells/plasma cells (through FcγIIb interactions), inhibition of complement activation, and modulation of cytokine and cytokine antagonist production.9,10 Administration of immunomodulatory doses of IVIg (1–2 g/kg), often used for desensitization and treatment of antibody-mediated rejection (AMR), can reduce endogenous total IgG concentrations due to saturation of the FcRn.5,8,11-13 Although the safety profile of IVIg is considered acceptable, adverse reactions can occur in approximately 20% to 50% of patients.14 Unique to the transplant and autoimmunity fields is the volumes of IVIg required for immune modulation. This often requires administration during dialysis or in split doses to avoid severe side effects.15 In addition, many IVIg products contain significant titers of anti-A/B blood group antibodies that may cause severe hemolytic anemia in patients treated with higher doses.15 Thus, there is an unmet medical need for less complex, safer, and less-expensive methods for antibody reduction therapy in allosensitized patients.

Biology of the FcRn

In 1964, Brambell et al postulated the existence of a receptor transporting immunoglobulins from mother to the fetus.16,17 Subsequently, the widely expressed cytosolic receptor, FcRn, was characterized and is now known to be involved in numerous critical biological and immunological functions that extend through an individual’s life span.16,18 The most recognized function of the FcRn is the process of recycling and transcytosis, which contributes to the long-lasting presence of IgG and albumin in human serum, of 21 days.5,19,20Figure 1A shows the biology of the FcRn-IgG interactions that lead to decreased lysosomal degradation and extended half-life of IgG. Figure 1B shows that the absence of the FcRn in FcRn−/− mice results in the rapid degradation of circulating IgG ameliorates autoimmune diseases in mouse models that could have applicability to human diseases.21-23 The FcRn−/− mice exhibit a circulating IgG half-life of only 1–3 days (compared with ≈30 days), with total IgG reduced by 70%–80% (Figure 1B), whereas IgA and IgM levels were unaffected.11,12

FIGURE 1
FIGURE 1:
FcRn-IgG recycling and mechanism of current therapies. A, Transport pathways for maintaining half-life of IgG for ≈21 days. IgG is taken up by fluid-phase endocytosis or through binding to Fc neonatal receptor (FcRn) at the apical cell after protonation of the IgG-Fc. This enables active FcRn-mediated transport of IgG across the cell and its subsequent release on the basolateral side at neutral pH. IgGs not bound to FcRn because of levels that exceed FcRn capacity or other serum proteins are destined for lysosomal degradation. B, The importance of FcRn in maintaining IgG and albumin levels in plasma. In FcRn−/− mice, all IgG and albumin are rapidly degraded due to absence of FcRn with half-life of ≈2 days compared with 30 days in animals with intact FcRn. Humans with mutations in FcRn heavy and light chain components exhibit hypercatabolic, hypoproteinemic syndrome with low levels of IgG and albumin.17 C, How saturation of FcRn with high-dose intravenous immunoglobulin (IVIg) accelerates the degradation of ambient IgG, including pathogenic IgG (pIgG) molecules. This represents an important pathway responsible for IVIg’s effect on circulating pathogenic antibodies (pIgG) in sensitized patients.

Exciting new therapeutic manipulations of FcRn are being developed that block IgG recycling to treat IgG-mediated diseases. Other approaches include altering the Fc heavy chain region of therapeutic monoclonals to enhance circulating half-life for treatment of immunologic, infectious, and malignant diseases. Here, we explore aspects of FcRn biology that contribute to its attractiveness as a target for modulation in treatment of human diseases. Readers are also directed to excellent comprehensive reviews regarding basic FcRn biology20,24-30 and for full discussion of structure/function relationships of FcRn, please see Seijsing et al,5 Sockolosky et al,20 Ward et al,22 and Pyzik et al.30

FcRn, the neonatal IgG receptor, is remarkably similar to major histocompatibility complex (MHC) class I molecules in humans. The intact FcRn consist of α1-α2 and α3 domains and β2-microglobulin (β2M).20,21 Briefly, FcRn is responsible for enhancing the half-life of 2 critical human proteins (albumin and IgG). Human serum albumin contacts a binding site spanning the α1-α2 domains of FcRn and β2M, whereas the constant heavy chains (CH3 and CH2) portions of human IgG bind the α1-α2 chain and β2M at a completely different site opposite that of albumin.5,20 The FcRn functions as a bidirectional receptor located primarily in the cytosol that interacts with IgG and albumin that are pinocytosed and subsequently transcytosed from the apical to basolateral membrane of cells containing cytosolic FcRn. Here, transcytosed IgG enters a vesicle and undergoes protonation as H+ is transported into the vesicle. Protonated IgG containing vesicles then fuse with vesicles containing FcRn that binds with high avidity to the protonated IgG-Fc region (CH2, CH3) (Figure 1A).20,30 Normally, IgG binding to FcRn is transported to the basolateral cell membrane and released back into the plasma, intact. The release occurs when pH returns to 7.4 and protonation is reversed. However, if the FcRn is not functional or saturated (ie, with IVIg), endogenous IgG is eliminated by lysosomal degradation with circulating IgG levels declining rapidly. FcRn can also prevent serum albumin from lysosomal degradation, by enhancing binding to a separate site on FcRn (distinct from that for IgG) leading to prolonged half-life for albumin.20 The FcRn heavy chain consists of a single transmembrane helix, cytoplasmic tail, and 3 soluble domains (α1, α2, α3). Despite similarities to MHC Class I molecules, FcRn cannot present antigen to T cells, due to point mutations that interrupt peptide-binding.5,20,22,30

Manipulation of the FcRn in Treatment of Pathogenic Antibodies

Recent data support the development of strategies to block FcRn-IgG recycling as effective approaches to treat IgG-mediated autoimmune diseases.12,13,23 Lessons learned from FcRn−/− mice demonstrated complete protection from autoimmune arthritis, which supports this approach. In addition, defects in the FcRn gene recognized in humans result in increased catabolism of IgG and albumin characterized by hypogammaglobulinemia, hypoproteinemia, and edema.31 Thus, strategies to block the FcRn/IgG interaction are desirable, to increase IgG catabolism to treat pathogenic autoantibodies and potentially alloantibodies. Current approaches are described in Figure 1C. IVIg is now recognized as the prototype treatment to enhance FcRn/IgG blockade by saturating FcRn which results in degradation of other serum IgG molecules (including pathogenic antibodies). This is likely important for the known effects of IVIg on lowering anti-HLA antibodies and for treatment of antibody-mediated autoimmune diseases such as Guillain-Barré Syndrome and myasthenia.11-13,20,22 The ability of IVIg to saturate the rescue/recycle pathway leads to an increased degradation of pathogenic IgG by blocking IgG-mediated rescue by FcRn. Unfortunately, IVIg treatment requires large amounts of protein, is costly and because it is derived from a limited human donor source, requires extensive filtration and anti-infective treatments. Another concern would be the potential impact high-dose IVIg has on the half-life of concomitantly administered mAbs often used in desensitization, treatment of AMR, and growing numbers of autoimmune diseases. Here, high-dose IVIg could negate the therapeutic benefits of administered mAbs by blocking the FcRn recycling, thus limiting half-life.

Novel Approaches to Inhibition of the IgG-Fc/FcRn Interaction

Multiple IgG derived therapies have been developed to interrupt the endogenous IgG-FcRn interaction (Figure 3), including FcRn or β2M directed mAbs. From rat models, it was noted that 1G3 mAb binds the rat FcRn heavy chain in vitro and inhibits IgG-FcRn binding, accelerating endogenous serum IgG clearance. 1G3 was shown to reduce the severity of myasthenia gravis.20,23,32 An anti-rat β2M antibody also inhibits the IgG-FcRn interaction, accelerating clearance of rat IgG autoantibodies, with ≈50-fold higher potency than IVIg.20,23,33 However, targeting β2M, which is a component of all MHC class I molecules, would likely result in an unacceptable adverse event risk profile and possible AMR in transplant recipients.19,20

Another novel approach to alter FcRn recycling of endogenous IgG is to alter the Fc-domain of IgG aimed at developing high affinity for FcRn at pH 6 and 7.4. These engineered antibodies are referred to as antibodies that enhance IgG degradation (Abdegs) and enhance IgG degradation (Figure 3). In an in vitro mice model, Abdegs impede FcRn recycling of endogenous IgG and result in reduced concentrations and increased clearance of circulating IgG.20,30,34 Abdegs have shown efficacy in a murine model of arthritis, at 25- to 50-times lower doses versus IVIg.20,35 These data suggest Abdegs are potent inhibitors of the IgG-FcRn interaction and are likely to have benefits as alternative therapeutic agents in autoimmunity and transplantation. As clinical experience with these agents evolves, it is imperative to carefully monitor treated patients because treatment regimens for autoimmunity and transplantation require the use of immunosuppressive drugs. One will always need to remain cognizant that the combination of immunosuppression and endogenous IgG clearance could predispose to infection as can be seen with PLEX. Here, use of IVIg will need to be considered in at-risk patients, preferentially used in doses of 0.5 gm/kg traditionally used in patients with humoral immune deficiency that should have minimal effect on blocking the FcRn.

Synthetic FcRn-binding peptides (FcBP) were recently discovered from a phage library. The FcBPs compete with IgG-FcRn binding at the same position as the Fc-domain of IgG, with high affinity for human and monkey FcRn.20,36,37 The FcBP binds FcRn with micromolar affinity at pH 6 and 7.4, which inhibits IgG-FcRn–binding in vitro. Small molecule IgG-FcRn interaction inhibitors have also been reported, which could be developed as oral agents, although less potent than IgG- and peptide-based inhibitors (Figures 3 and 4).20,38

Other molecules binding Fc at the CH2-CH3 binding site, (blocking the IgG-FcRn interaction) include a 13-amino acid cyclic peptide (FcIII) selected by phage display, an endogenous Fc receptor, tripartite motif 21 (TRIM21), and a computer-designed IgG-Fc binding protein (FcBP6.1).20,39 FcIII and TRIM21 bind Fc with nanomolar affinity at pH 6 and 7.4. FcBP6.1 binds with micromolar and nanomolar affinities at pH 6 and 7.4, respectively. There are numerous human and nonhuman ligands binding at the CH2-CH3 domain on Fc, indicating the human CH2-CH3 domain of IgG favors interaction with molecules exhibiting different affinities, binding mechanisms and likely have varying efficacy in FcRn function modulation.39 This would seem to suggest that additional endogenous human proteins binding Fc at the CH2-CH3 domain interface will be identified.20 (Figure 4)

FIGURE 2
FIGURE 2:
Dynamics of monoclonal antibody performance pre- and post-IgG modification to enhance efficacy and half-life. A, Fc neonatal receptor (FcRn)–mediated recycling of humanized monoclonal therapeutic antibodies. Monoclonal IgG binds to target antigen (ie, C5) and is transcytosed from apical to basolateral membrane through binding to FcRn at the apical cell after protonation of the IgG-Fc. This enables active FcRn-mediated transport of monoclonal bound to antigen across the cell and its subsequent release on the basolateral side at neutral pH. IgGs not bound to FcRn because of levels that exceed FcRn capacity or use of concomitant intravenous immunoglobulin (IVIg) are destined for lysosomal degradation. Recirculation of monoclonal IgG with bound antigen results in rapid loss of efficacy of monoclonal requiring frequent dosing. B, How genetic alterations of the Fc fragments enhance FcRn binding extending half-life of the monoclonal. In addition, alterations of the amino acid structure of the Fab binding regions of the monoclonal allows release of target antigen (ie, C5) at pH 6.5 with lysosomal degradation and release of intact IgG back into the circulation. This allows for repeat binding, delivery, and digestion of target antigen via the FcRn system, enhancing efficacy and half-life of the monoclonal.
FIGURE 3
FIGURE 3:
Inhibitors of the Fc neonatal receptor (FcRn)–IgG-Fc interaction. A, since high-dose intravenous immunoglobulin (IVIg) saturates FcRn, it accelerates the clearance of endogenous IgG (Figure 1), (B) anti-FcRn heavy chain antibodies and (C) anti–β2-microglobulin (β2m) light chain antibodies bind FcRn epitopes, inhibiting FcRn function and accelerating degradation of circulating IgG (D) Fc-engineered IgGs that have increased pH-independent affinity for FcRn (antibodies that enhance IgG degradation [Abdegs]) and (E), peptides and (F) small molecules that compete with IgG for binding to FcRn. To date, anti-FcRn and synthetic peptides that block IgG-Fc/FcRn interactions are now in clinical trials (Figure 2). Reproduced with permission from Brambell et al.17
FIGURE 4
FIGURE 4:
Various domains derived from human IgG1 that can block IgG-Fc/Fc neonatal receptor (FcRn) interactions. A, This drawing shows full-length human IgG1. Here, for example, intravenous immunoglobulin (IVIg) can saturate the FcRn by constant heavy chain (CH)2-CH2 domain binding to FcRn and (B) albumin can also bind to FcRn but not at the same domain that binds IgG. C, The Fc-domain of IgG1 can be used to construct dimeric and monomeric Fc-fusion proteins that bind to FcRn through CH2-CH3 interactions. Fc-fusions are often used to enhance half-life of attached drugs or proteins (ie, belatacept). D, Fc-domain residues are mutated to generate mono-Fc-fusions. E, Monomeric CH2 and CH3 derived from IgG1-Fc. F, Engineered FcRn-binding affibody5 and (G) Fc binding protein fusion molecules. FcBP, FcRn-binding peptides. Reproduced with permission from Brambell et al.17

Currently available IgG-FcRn inhibitors have a short half-life which requires frequent dosing. Abdegs and IVIg can also exert immunomodulatory functions through Fcγ receptors and complement interactions. Whether inhibition of the IgG-FcRn interaction alone with peptide or small molecule FcRn antagonists is effective in producing a therapeutic benefit in IgG-mediated autoimmune disease and AMR warrants further investigation.20,30

Emerging Therapies That Leverage FcRn/IgG Interactions for Antibody Removal

Degradation of pathogenic IgG autoantibodies by FcRn/IgG inhibition may constitute an attractive target in the treatment of autoantibody- and alloantibody-mediated diseases.5,22,30 A more refined, less invasive approach to antibody depletion likely would limit many of the side effects and expense associated with immunosuppressive and high-dose IVIg protocols. To this end, recent reports described the use of a novel engineered alternative scaffold protein (affibody molecule, ZFcRn) with high specificity for the human FcRn (compared with mice FcRn), which is enhanced when ZFcRn is albumin-bound.5 Repeated intravenous administration of ZFcRn to mice resulted in a 40% reduction in the total IgG serum concentrations after 5 days. The authors concluded proteins such as ZFcRn-albumin binding domain may have therapeutic benefits in IgG-driven autoimmune diseases, and further investigation of ZFcRn in animal models are warranted.5

Another group recently reported data generated in clinical trials of a novel humanized high-affinity anti-human FcRn mAb (Rozanolixizumab).8,40 In cynomolgus monkeys, rozanolixizumab decreased IgG (maximum 75 to 90% by day 10) and was well tolerated without an observed increased infection risk. The authors reported a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous, or subcutaneous rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability; secondary objectives were to assess pharmacokinetics and pharmacodynamics of rozanolixizumab and effects on circulating IgG. Rozanolixizumab demonstrated specificity to IgG, without changes in circulating IgM, IgD, IgE, IgA, complement, or other immune biomarker concentrations. In healthy subjects, serum IgG levels were reduced by up to 50%, similar to reductions seen with PLEX (50%–60%). B and T cells were unaffected, suggesting rozanolixizumab will not decrease the potential of the immune system to generate de novo or rebound antibody response.8

Reductions in serum IgG concentrations from rozanolixizumab administration persisted for weeks. Maximum decreases occurred by 7 to 10 days, followed by a gradual recovery to baseline by day 57. These sustained reductions may be attributed to the rapid inhibition of FcRn by rozanolixizumab and the continued suppression of IgG recycling. This rate of IgG recovery after a single treatment is comparable to that observed with PLEX. After one single PLEX treatment, plasma IgG returns to baseline within 2 weeks. Following initial reductions with PLEX, IgG and autoantibody rebound has been observed due to renewed IgG synthesis and prompt redistribution from extravascular to intravascular compartments. The most frequent adverse events with rozanolixizumab were headache in 38.9% of patients (n = 14 of 36), more frequently observed in the intravenous group and was dose dependent. Serious adverse events of headache (n = 3) and back pain (n = 1) occurred in the group receiving the highest intravenous dose.3,8

Data reported in this study demonstrate clinical support for the use of rozanolixizumab as a potential new therapy for autoimmune diseases and possibly alloimmunity as well. Rozanolixizumab provides a means of selective inhibition of IgG-FcRn binding without impacts on albumin, reduced IgG recycling, and potentially pathogenic IgG in the serum. Because subcutaneous rozanolixizumab administration was better tolerated than intravenous, the investigators are now beginning phase 2 studies with subcutaneous rozanolixizumab dosing in patients with primary immune thrombocytopenic purpura (NCT02718716) and myasthenia gravis (NCT03052751).

Engineering Fc to Increase Half-Life and Retain Efficacy of Therapeutic Antibodies

The observation that FcRn contributes significantly to the half-life of IgG has stimulated interest in macromolecular engineering techniques to modulate the IgG-FcRn interaction.41 IgG1 Fc-domain amino acid residue mutations (proximal to FcRn-binding sites) has been the primary strategy utilized to date; several groups have reported the identification of amino acid residues involved in IgG transcytosis and catabolism regulation. Here, there is a strong association between increased serum half-life and FcRn affinity at pH 6.42 This work led to the idea that manipulation of FcRn/IgG binding at pH 6.0 could enhance the half-life of therapeutic monoclonals, possibly enhancing efficacy and reducing cost of therapy. Ghetie and Ward28 were the first to demonstrate this. They randomly mutated 3 amino acid residues proximal to the IgG-FcRn–binding interface and utilized phage display technology to select Fc variants binding FcRn. This seminal study demonstrated Fc site mutations that increase affinity for FcRn at pH 6 result in an increased persistence of Fc, and likely IgG. Importantly, Fc mutations of human IgG1 also increased half-life of IgG in healthy adults.43 The significance of this work cannot be overstated because it has the potential to improve the efficacy and therapeutic range of mAbs used in multiple therapeutic areas. It is a major validation of engineering efforts to increase IgG-FcRn affinity at pH 6 as a means of increasing therapeutic IgG persistence in humans.20

To this end, recent data published regarding one of the first Fc-engineered monoclonals aimed at enhancing Fc/FcRn interactions at pH 6.0 demonstrated a marked improvement in half-life and therapeutic efficacy.44,45 Ravulizumab is a novel Fc-engineered anti-C5 developed from eculizumab that allows for increased binding to the FcRn at pH 6.0. The investigators recently reported on 2 phase 1b/2 studies in paroxysmal nocturnal hemoglobinuria. Ravulizumab at varying doses resulted in remission of this disease for up to 12 weeks after a single dose. This is remarkable considering that the non–Fc-engineered eculizumab has a half-life of <1 week, requiring weekly dosing to maintain therapeutic efficacy. Here, the cost and convenience of dosing every 1–2 months to control a disease process is a significant advancement in anticomplement therapy and has implications for treatment of complement-mediated antibody rejection in humans. Another important advancement in IgG mAb engineering is the alteration of the amino acid constitution of F(ab) antigen-binding sites to allow antigen release into lysosomal vesicles when pH 6.5 is obtained. Once antigen is released, the monoclonal is recycled to the basolateral membrane and returned to the circulation. In the case of ravulizumab, IgG-Fc/FcRn interactions prolong therapeutic antibody half-life and result in disposal of the ligand (C5) allowing a continuous shuttling to the endothelium for disposal. This contrasts with eculizumab which irreversibly binds C5 and when recycled through FcRn is returned to the circulation with C5 in the F(ab) binding sites (Figure 2A and B).

CONCLUSIONS

FcRn is a nonclassical MHC Class I receptor which is emerging as a novel target to significantly reduce the half-life of pathogenic antibodies or extend the half-life of therapeutic monoclonals well beyond current ranges. It is now apparent that FcRn is involved in a broad range of biological and immunological functions. FcRn receptors are widely distributed in virtually all tissues of the body, especially the liver. IgG and albumin binding to FcRn is pH-dependent, which results in a significant prolongation of the half-life of these 2 important proteins. Recent findings suggest manipulation of IgG-Fc/FcRn interactions may have implications for a wide range of therapeutic strategies. The interaction of IgG or albumin with FcRn is currently being exploited as a mechanism to manipulate the FcRn transcytotic capacity to extend the half-life of therapeutic antibodies. The use of monoclonals directed at the FcRn and β2M can rapidly enhance the turnover of total IgG, including pathogenic IgG molecules. Other strategies such as the use of IVIg or Fc-engineered IgG molecules that have high-affinity binding to the FcRn at pH 7.40 and pH 6.5, so-called Abdegs also have the potential to treat autoimmune and alloimmune disorders by enhancing IgG turnover.8,20,30

What are the clinical implications of the advancements in our recent understanding of FcRn biology for transplantation? From our standpoint, there are many current and emerging considerations that need to be discussed. One of the most prescient is the impact of IVIg on circulating levels of concomitantly administered therapeutic monoclonals. Although suspected, there is little data from humans to confirm the impact of high-dose IVIg on therapeutic mAbs. This clearly has relevance to the efficacy and half-life of the monoclonal. We first suspected that IVIg might play a role in enhancing the degradation of therapeutic monoclonals in a patient receiving anti–tumor necrosis factor (TNF)-α therapy for inflammatory bowel disease. The patient was stable on monthly anti–TNF-α therapy until IVIg was administered for hypogammaglobulinemia. We noted a rapid onset of gastrointestinal bleeding 2 weeks after the anti–TNF-α was given in close proximity to IVIg. Subsequently, we performed a study using a novel anti-C5 monoclonal that was given immediately after IVIg administration (2 g/kg) or alone in highly HLA sensitized patients undergoing desensitization (NCT02878616). Initial observations in this controlled study revealed that concomitantly administered IVIg significantly reduced the circulating levels of anti-C5 >50% and decreased half-life of anti-C5 from 30 days to 11 days (unpublished observations). Thus, IVIg exerts important effects on the FcRn system to enhance turnover of target monoclonals. This may also represent an important therapeutic pathway for decreasing pathogenic anti-HLA antibodies. Newer agents that are more specific and with higher affinity to block the FcRn will likely find applications in desensitization and treatment of AMR but also must be administered with consideration for the impact they may have on other nonpathogenic and therapeutic antibodies. It is also apparent that the reverse is true. IgG-Fc/FcRn interactions can be manipulated to enhance the half-life of therapeutic monoclonals. Here, Fc mutations that enhance the monoclonal IgG binding to FcRn at pH 6.5 preferentially allows these antibodies to continually recirculate through the cytosol carrying their target antigens that are released at pH 6.5 and degraded in the lysosome while the monoclonal is shuttled to the cell surface and released to the plasma with clean F(ab)’2 antigen-binding sites. This allows for a higher capacity of antigen-binding (clearance) and extended half-life of the monoclonal. Ravulizumab (anti-C5) is the first example of a therapeutic monoclonal engineered from eculizumab to have enhanced pH-dependent binding to FcRn. One would expect we will see similar Fc-engineered monoclonals that should help us have more proficient and less-expensive therapies in the future.44,45

ACKNOWLEDGMENTS

The authors acknowledge the team members of the Kidney Transplant Program, Transplant Immunology Laboratory, and HLA Laboratory at Cedars-Sinai Medical Center for their commitment to improving lives through transplantation.

REFERENCES

1. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008; 3593242–251
2. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011; 3654318–326
3. Jordan SC, Lorant T, Choi J, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med. 2017; 3775442–453
4. Kerr J, Quinti I, Eibl M, et al. Is dosing of therapeutic immunoglobulins optimal? a review of a three-decade long debate in Europe. Front Immunol. 2014; 5:629
5. Seijsing J, Yu S, Frejd FY, et al. In vivo depletion of serum IgG by an affibody molecule binding the neonatal Fc receptor. Sci Rep. 2018; 815141
6. Kawano T, Matsuse H, Obase Y, et al. Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone. Int Arch Allergy Immunol. 2002; 1283240–243
7. Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am J Transplant. 2016; 16123468–3478
8. Kiessling P, Lledo-Garcia R, Watanabe S, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: a randomized phase 1 study. Sci Transl Med. 2017; 9414eaan1208
9. Jordan SC, Toyoda M, Kahwaji J, et al. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011; 112196–202
10. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012; 367212015–2025
11. Bleeker WK, Teeling JL, Hack CE. Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect. Blood. 2001; 98103136–3142
12. Li N, Zhao M, Hilario-Vargas J, et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest. 2005; 115123440–3450
13. Hansen RJ, Balthasar JP. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost. 2002; 886898–899
14. Yong PL, Boyle J, Ballow M, et al. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. Clin Immunol. 2010; 1352255–263
15. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly HLA sensitized patients. Clin J Am Soc Nephrol. 2009; 4121993–1997
16. Brambell FW. The transmission of immune globulins from the mother to the foetal and newborn young. Proc Nutr Soc. 1969; 28135–41
17. Brambell FW, Hemmings WA, Morris IG. A theoretical model of gamma-globulin catabolism. Nature. 1964; 203:1352–1354
18. Borvak J, Richardson J, Medesan C, et al. Functional expression of the MHC class I-related receptor, FcRn, in endothelial cells of mice. Int Immunol. 1998; 1091289–1298
19. Andersen JT, Sandlie I. The versatile MHC class I-related FcRn protects IgG and albumin from degradation: implications for development of new diagnostics and therapeutics. Drug Metab Pharmacokinet. 2009; 244318–332
20. Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Adv Drug Deliv Rev. 2015; 91:109–124
21. Huang X, Zheng F, Zhan CG. Binding structures and energies of the human neonatal Fc receptor with human Fc and its mutants by molecular modeling and dynamics simulations. Mol Biosyst. 2013; 9123047–3058
22. Ward ES, Devanaboyina SC, Ober RJ. Targeting FcRn for the modulation of antibody dynamics. Mol Immunol. 2015; 672 Pt A131–41
23. Raghavan M, Chen MY, Gastinel LN, et al. Investigation of the interaction between the class I MHC-related Fc receptor and its immunoglobulin G ligand. Immunity. 1994; 14303–315
24. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007; 79715–725
25. Challa DK, Velmurugan R, Ober RJ, et al. FcRn: from molecular interactions to regulation of IgG pharmacokinetics and functions. Curr Top Microbiol Immunol. 2014; 382:249–272
26. Rath T, Kuo TT, Baker K, et al. The immunologic functions of the neonatal Fc receptor for IgG. J Clin Immunol. 2013; 33(Suppl 1)S9–17
27. Junghans RP. Finally! The brambell receptor (Fcrb). Mediator of transmission of immunity and protection from catabolism for IgG. Immunol Res. 1997; 16129–57
28. Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu Rev Immunol. 2000; 18:739–766
29. Rath T, Baker K, Dumont JA, et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol. 2015; 352235–254
30. Pyzik M, Rath T, Lencer WI, et al. FcRn: the architect behind the immune and nonimmune functions of IgG and albumin. J Immunol. 2015; 194104595–4603
31. Kaminsky P, Lesesve JF, Jonveaux P, et al. IgG deficiency and expansion of CTG repeats in myotonic dystrophy. Clin Neurol Neurosurg. 2011; 1136464–468
32. Liu L, Garcia AM, Santoro H, et al. Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol. 2007; 17885390–5398
33. Vaccaro C, Zhou J, Ober RJ, et al. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005; 23101283–1288
34. Getman KE, Balthasar JP. Pharmacokinetic effects of 4C9, an anti-FcRn antibody, in rats: implications for the use of FcRn inhibitors for the treatment of humoral autoimmune and alloimmune conditions. J Pharm Sci. 2005; 944718–729
35. Patel DA, Puig-Canto A, Challa DK, et al. Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol. 2011; 18721015–1022
36. Mezo AR, McDonnell KA, Hehir CA, et al. Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci USA. 2008; 10572337–2342
37. Mezo AR, Sridhar V, Badger J, et al. X-ray crystal structures of monomeric and dimeric peptide inhibitors in complex with the human neonatal Fc receptor, FcRn. J Biol Chem. 2010; 2853627694–27701
38. Wang Z, Fraley C, Mezo AR. Discovery and structure-activity relationships of small molecules that block the human immunoglobulin G-human neonatal Fc receptor (hIgG-hFcRn) protein-protein interaction. Bioorg Med Chem Lett. 2013; 2351253–1256
39. Strauch EM, Fleishman SJ, Baker D. Computational design of a pH-sensitive IgG binding protein. Proc Natl Acad Sci U S A. 2014; 1112675–680
40. Smith B, Kiessling A, Lledo-Garcia R, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. Mabs. 2018; 1071111–1130
41. Liu L. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell. 2018; 9115–32
42. Martins JP, Kennedy PJ, Santos HA, et al. A comprehensive review of the neonatal Fc receptor and its application in drug delivery. Pharmacol Ther. 2016; 161:22–39
43. Robbie GJ, Criste R, Dall’acqua WF, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013; 57126147–6153. doi: 10.1128/AAC.01285-13
44. Sheridan D, Yu ZX, Zhang Y, et al. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. Plos One. 2018; 134e0195909
45. Röth A, Rottinghaus ST, Hill A, et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2018; 2172176–2185
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