C
American Journal of Transplantation 2015; 15: 1725–1726 Wiley Periodicals Inc.
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13253
Letter to the Editor
The IVIg Dilemma: A Way Out? To the Editor: In a recent ‘‘AJT Report’’ on The IVIg Dilemma, by Sue Pondrom (1), the current issues on the usage of intravenous immunoglobulin (IVIg) for desensitization of highly-sensitized organ transplant candidates were addressed. Three concerns on IVIg usage were described as follows: 1) its high cost due to IVIg shortage, 2) a perception of inadequate efficacy, and 3) fear of transplantation of high risk patients due to regulatory disincentive. We share these concerns, and here, we would like to suggest novel approaches for tackling the annually-rising high costs of IVIg, which are related to the increasing demand for, and the expected upcoming worldwide shortage of, safe human plasma. Prioritization protocols in organ transplantation will likely not solve this problem, since IVIg is not only used for desensitization of organ transplant candidates, but is indispensable for substitution therapy in immunodeficient patients and immunomodulatory therapy for difficult-to-treat autoimmune diseases. We want to advocate for research on two types of approaches that may help to solve the upcoming IVIg shortage and costs issue. Firstly, we propose to identify molecular targets of IVIg (IVIg-receptors) on the cell surface of human immune cells that mediate the anti-inflammatory pathways activated by IVIg treatment. This approach may enable the development of cheaper compounds (IVIg-mimetics) that target these IVIg-receptors and thereby mimic (some of) the immunomodulatory modes-of-action of IVIg. Secondly, we suggest a more efficient use of IVIg by ‘‘splitting up’’ IVIg into two fractions during manufacturing: one immunomodulatory fraction of IgG that can be used for antiinflammatory therapy whereas the other remaining polyspecific IgG fraction can be used for IgG supplementation of immunodeficient patients. Research in the past decade on the immunomodulatory effects of IVIg, mainly performed in experimental animal models, but also in humans, has shown that IVIg regulates the function of various immune cell types, including B cells, dendritic cells, macrophages and regulatory T cells (2–6). Interestingly in mice, a minor fraction of IgG molecules within IVIg (1–5%) that bear glycan stretches terminating in a2,6-bound sialic acids on the Fc-part was shown to have dominant anti-inflammatory properties (Figure 1). These IgGs bind to the C-type lectin SIGN-R1 and were as effective as conventional IVIg therapy at a 20-fold lower dose in several experimental animal models (2). Similar low doses of
sialylated IVIg induced regulatory T cell expansion in mice, although this was dependent on binding of sialylated IVIg to dendritic cell immunoreceptor (DCIR), and not SIGN-R1 (4). Although some discrepancies on the efficacy of sialylated IgG in animal models need to be resolved, most importantly, it needs to be determined whether sialylated IgG, or other IgG glycoforms, can replace IVIg as immunomodulatory therapy in humans. Interestingly, it has already been shown that sialylated IgGs bind to human DC-SIGN (SIGN-R1 orthologue) (2), and functionally inhibit human B cells in vitro by binding to CD22 (3). As now several molecular binding targets and an immunomodulatory fraction of IVIg have been identified, both our proposed IVIg-saving approaches can be exploited. Of course, it will be quite a challenge to translate these seminal findings to successful alternatives for current conventional IVIg therapy. Firstly, in vitro studies using human dendritic cells, macrophages, B cells and regulatory T cells should be performed to establish whether the current findings, mostly derived from murine studies, are also valid for humans. Such studies will reveal whether sialylated IgG, or other IgG glycoforms, functionally trigger anti-inflammatory responses in these human immune cell types, and whether DC-SIGN, DCIR, CD22 or other IVIg-receptors (identified e.g. by mass spectrometry) are involved. Secondly, after identification of IVIg-receptors in humans, biologicals that bind agonistically to these receptors (IVIg-mimetics) should be synthesized. Thirdly, anti-inflammatory IgG glycoforms purified from IVIg as well as IVIg-mimetics should be tested in clinically relevant experimental disease models of allogeneic organ transplant rejection and auto-immune diseases. Studies using humanized mouse models may be the first step, but should ideally be followed by studies in nonhuman primates if funding allows. Importantly, to save IVIg by splitting it into two fractions, it is essential that the anti-inflammatory fraction will be effective at a much lower dose than conventional IVIg. After the preclinical work has been completed, clinical trials need to be initiated which compare the IVIg-mimetics or an anti-inflammatory IgG fraction to conventional IVIg therapy. To be successful, large multicenter studies are required with homogenous patient cohorts. Moreover, clinical and immunological end-points need to be welldefined of which the latter need to be in conjunction with the preclinical data. These preclinical and clinical studies are extremely costly and can likely only be conducted with full commitment from pharmaceutical partners, either plasma
1725
van Gent and Kwekkeboom
Neu5Ac
Gal
GlcNac
Man GlcNac
Neu5Ac
Gal
GlcNac
Man
Man
GlcNac
Asn297
Fuc
Figure 1: Schematic representation of the IgG Fc-bound glycan structure. The IgG Fc-tail harbours a single N-linked glycan stretch bound to asparagine 297, that can vary in length and composition. Glycans terminating in sialic acids (Neu5Ac; neuraminic acid) have shown to confer anti-inflammatory properties to IgG molecules (2). The residues indicated in italics are variably present in Fc-bound glycan stretches found in human serum IgG. Gal, galactose; GlcNAc, N-acetylglucosamine; Man, Mannose; Fuc, Fucose; Asn297, asparagine 297 of the IgG heavy chain.
R. van Gent and J. Kwekkeboom* Department of Gastroenterology Hepatology, Erasmus MC-University Medical Centre, Rotterdam the Netherlands * Corresponding author: Jaap Kwekkeboom, [email protected]
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References manufacturers or biotech companies. Importantly, in the case of splitting up IVIg into immunomodulatory and supplementary fractions, their industrial scale production needs to be designed accordingly to enable that both fractions are produced in a single procedure instead of the one at the expense of the other. Likely, a successful alternative to conventional IVIg treatment will require at least a decade to develop. Nevertheless, despite many hurdles that need to be taken, we believe that, when successful, these approaches will lead to a new era in which patients in need of IVIg can be treated with a (combination of) substitute(s) that may be as effective as the current conventional IVIg treatment. Of course, whether these substitutes are superior for all treatment indications, including organ transplantation and autoimmune diseases, only time will tell.
1726
1. Pondrom S. The AJT Report: The IVIg dilemma. Am J Transplant 2014; 14: 2195–2196. 2. Anthony RM, Wermeling F, Ravetch JV. Novel roles for the IgG Fc glycan. Ann Ny Acad Sci 2012; 1253: 170–180. 3. Seite JF, Cornec D, Renaudineau Y, Youinou P, Mageed RA, Hillion S. IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood 2010; 116: 1698–1704. 4. Massoud AH, Yona M, Xue D, et al. Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 2014; 133: 853–863, e855. 5. Tjon AS, Tha-In T, Metselaar HJ, et al. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells. Clin Exp Immunol 2013; 173: 259–267. 6. Tjon AS, van Gent R, Jaadar H, et al. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J Immunol 2014; 192: 5625–5634.
American Journal of Transplantation 2015; 15: 1725–1726
Copyright of American Journal of Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
American Journal of Transplantation 2015; 15: 1725–1726 Wiley Periodicals Inc.
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13253
Letter to the Editor
The IVIg Dilemma: A Way Out? To the Editor: In a recent ‘‘AJT Report’’ on The IVIg Dilemma, by Sue Pondrom (1), the current issues on the usage of intravenous immunoglobulin (IVIg) for desensitization of highly-sensitized organ transplant candidates were addressed. Three concerns on IVIg usage were described as follows: 1) its high cost due to IVIg shortage, 2) a perception of inadequate efficacy, and 3) fear of transplantation of high risk patients due to regulatory disincentive. We share these concerns, and here, we would like to suggest novel approaches for tackling the annually-rising high costs of IVIg, which are related to the increasing demand for, and the expected upcoming worldwide shortage of, safe human plasma. Prioritization protocols in organ transplantation will likely not solve this problem, since IVIg is not only used for desensitization of organ transplant candidates, but is indispensable for substitution therapy in immunodeficient patients and immunomodulatory therapy for difficult-to-treat autoimmune diseases. We want to advocate for research on two types of approaches that may help to solve the upcoming IVIg shortage and costs issue. Firstly, we propose to identify molecular targets of IVIg (IVIg-receptors) on the cell surface of human immune cells that mediate the anti-inflammatory pathways activated by IVIg treatment. This approach may enable the development of cheaper compounds (IVIg-mimetics) that target these IVIg-receptors and thereby mimic (some of) the immunomodulatory modes-of-action of IVIg. Secondly, we suggest a more efficient use of IVIg by ‘‘splitting up’’ IVIg into two fractions during manufacturing: one immunomodulatory fraction of IgG that can be used for antiinflammatory therapy whereas the other remaining polyspecific IgG fraction can be used for IgG supplementation of immunodeficient patients. Research in the past decade on the immunomodulatory effects of IVIg, mainly performed in experimental animal models, but also in humans, has shown that IVIg regulates the function of various immune cell types, including B cells, dendritic cells, macrophages and regulatory T cells (2–6). Interestingly in mice, a minor fraction of IgG molecules within IVIg (1–5%) that bear glycan stretches terminating in a2,6-bound sialic acids on the Fc-part was shown to have dominant anti-inflammatory properties (Figure 1). These IgGs bind to the C-type lectin SIGN-R1 and were as effective as conventional IVIg therapy at a 20-fold lower dose in several experimental animal models (2). Similar low doses of
sialylated IVIg induced regulatory T cell expansion in mice, although this was dependent on binding of sialylated IVIg to dendritic cell immunoreceptor (DCIR), and not SIGN-R1 (4). Although some discrepancies on the efficacy of sialylated IgG in animal models need to be resolved, most importantly, it needs to be determined whether sialylated IgG, or other IgG glycoforms, can replace IVIg as immunomodulatory therapy in humans. Interestingly, it has already been shown that sialylated IgGs bind to human DC-SIGN (SIGN-R1 orthologue) (2), and functionally inhibit human B cells in vitro by binding to CD22 (3). As now several molecular binding targets and an immunomodulatory fraction of IVIg have been identified, both our proposed IVIg-saving approaches can be exploited. Of course, it will be quite a challenge to translate these seminal findings to successful alternatives for current conventional IVIg therapy. Firstly, in vitro studies using human dendritic cells, macrophages, B cells and regulatory T cells should be performed to establish whether the current findings, mostly derived from murine studies, are also valid for humans. Such studies will reveal whether sialylated IgG, or other IgG glycoforms, functionally trigger anti-inflammatory responses in these human immune cell types, and whether DC-SIGN, DCIR, CD22 or other IVIg-receptors (identified e.g. by mass spectrometry) are involved. Secondly, after identification of IVIg-receptors in humans, biologicals that bind agonistically to these receptors (IVIg-mimetics) should be synthesized. Thirdly, anti-inflammatory IgG glycoforms purified from IVIg as well as IVIg-mimetics should be tested in clinically relevant experimental disease models of allogeneic organ transplant rejection and auto-immune diseases. Studies using humanized mouse models may be the first step, but should ideally be followed by studies in nonhuman primates if funding allows. Importantly, to save IVIg by splitting it into two fractions, it is essential that the anti-inflammatory fraction will be effective at a much lower dose than conventional IVIg. After the preclinical work has been completed, clinical trials need to be initiated which compare the IVIg-mimetics or an anti-inflammatory IgG fraction to conventional IVIg therapy. To be successful, large multicenter studies are required with homogenous patient cohorts. Moreover, clinical and immunological end-points need to be welldefined of which the latter need to be in conjunction with the preclinical data. These preclinical and clinical studies are extremely costly and can likely only be conducted with full commitment from pharmaceutical partners, either plasma
1725
van Gent and Kwekkeboom
Neu5Ac
Gal
GlcNac
Man GlcNac
Neu5Ac
Gal
GlcNac
Man
Man
GlcNac
Asn297
Fuc
Figure 1: Schematic representation of the IgG Fc-bound glycan structure. The IgG Fc-tail harbours a single N-linked glycan stretch bound to asparagine 297, that can vary in length and composition. Glycans terminating in sialic acids (Neu5Ac; neuraminic acid) have shown to confer anti-inflammatory properties to IgG molecules (2). The residues indicated in italics are variably present in Fc-bound glycan stretches found in human serum IgG. Gal, galactose; GlcNAc, N-acetylglucosamine; Man, Mannose; Fuc, Fucose; Asn297, asparagine 297 of the IgG heavy chain.
R. van Gent and J. Kwekkeboom* Department of Gastroenterology Hepatology, Erasmus MC-University Medical Centre, Rotterdam the Netherlands * Corresponding author: Jaap Kwekkeboom, [email protected]
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References manufacturers or biotech companies. Importantly, in the case of splitting up IVIg into immunomodulatory and supplementary fractions, their industrial scale production needs to be designed accordingly to enable that both fractions are produced in a single procedure instead of the one at the expense of the other. Likely, a successful alternative to conventional IVIg treatment will require at least a decade to develop. Nevertheless, despite many hurdles that need to be taken, we believe that, when successful, these approaches will lead to a new era in which patients in need of IVIg can be treated with a (combination of) substitute(s) that may be as effective as the current conventional IVIg treatment. Of course, whether these substitutes are superior for all treatment indications, including organ transplantation and autoimmune diseases, only time will tell.
1726
1. Pondrom S. The AJT Report: The IVIg dilemma. Am J Transplant 2014; 14: 2195–2196. 2. Anthony RM, Wermeling F, Ravetch JV. Novel roles for the IgG Fc glycan. Ann Ny Acad Sci 2012; 1253: 170–180. 3. Seite JF, Cornec D, Renaudineau Y, Youinou P, Mageed RA, Hillion S. IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood 2010; 116: 1698–1704. 4. Massoud AH, Yona M, Xue D, et al. Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 2014; 133: 853–863, e855. 5. Tjon AS, Tha-In T, Metselaar HJ, et al. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells. Clin Exp Immunol 2013; 173: 259–267. 6. Tjon AS, van Gent R, Jaadar H, et al. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J Immunol 2014; 192: 5625–5634.
American Journal of Transplantation 2015; 15: 1725–1726
Copyright of American Journal of Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
