Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease

Olsan, Erin E.; Matsushita, Tamami; Rezaei, Mina; Weimbs, Thomas

doi:10.1074/jbc.m114.607929

Cited by 16 publications

(21 citation statements)

References 36 publications

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“…Other differences are the timing of disease progression and the extent of dietary treatment between these studies. Warner et al (22) treated the Pkd1 RC/RC mouse model with a more profound level of food reduction (40%) compared with our study (23%) and for a longer duration (from postnatal week 6 to 24) compared with our study (postnatal weeks [5][6][7][8][9][10][11][12]. However, the fact that two independent studies come to very similar conclusions makes a compelling argument that RFI may be beneficial in ADPKD patients as well.…”

Section: Discussionsupporting

confidence: 44%

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease

Kipp

Rezaei

Lin

et al. 2016

American Journal of Physiology-Renal Physiology

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Section: Discussionsupporting

confidence: 44%

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease

Kipp

Rezaei

Lin

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Van Den Berg et al (2002) showed that IL-4 increases intracellular trafficking of proteins in glomerular visceral epithelial cells. Olsan et al (2015), using human autosomal-dominant polycystic kidney disease tissues, showed that STAT6 pathway activation induces an increase in renal pIgR, which is involved in renal cell IgA transport. Our data indicate that IL-4 has a protective effect against the decrease in megalin expression and PT albumin endocytosis induced by higher albumin concentration.…”

Section: Discussionmentioning

confidence: 99%

IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload

et al. 2020

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Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα −/− mice treated with saline; and (4) KO + BSA, IL4Rα −/− mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4 + T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the proinflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.

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“…Prior to our work, only mixtures of recombinantly made monomer and oligomers were used for in vivo experiments studying transcytosis. 10,30 We established a robust expression and purification route allowing the enrichment of dimeric and tetrameric IgA. In particular, modulating the amount of JC DNA used in the transfection or the glycosylation state of the IgA tail region was able to influence the distribution of oligomeric species.…”

Section: Discussionmentioning

confidence: 99%

“…9 Additionally, human IgA dimer (dIgA) could be effectively delivered to the kidney lumen in a polycystic kidney disease mouse model via binding to the polymeric immunoglobulin receptor (pIgR), whereas IgG molecules could not. 10 Harnessing the specific transcytosis activity of IgA could potentially allow access to therapeutic targets within the luminal side of mucosal tissues that are inefficiently targeted by current IgG therapeutics. 2,10,11 Contrary to other human immunoglobulin classes, IgA has the unique ability to naturally exist as both monomeric and polymeric soluble species, whereas only polymeric IgA can bind to pIgR for subsequent transcytosis.…”

Section: Introductionmentioning

confidence: 99%

“…10 Harnessing the specific transcytosis activity of IgA could potentially allow access to therapeutic targets within the luminal side of mucosal tissues that are inefficiently targeted by current IgG therapeutics. 2,10,11 Contrary to other human immunoglobulin classes, IgA has the unique ability to naturally exist as both monomeric and polymeric soluble species, whereas only polymeric IgA can bind to pIgR for subsequent transcytosis. 1 Oligomerization of IgA is facilitated by an 18-residue C-terminal extension of the heavy chain (HC) called the tailpiece and the 137-amino acid joining chain (JC).…”

Section: Introductionmentioning

confidence: 99%

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Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Lombana¹,

Rajan²,

Zorn³

et al. 2019

mAbs

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IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared to traditional IgG-based drugs. However, the transition of IgA into clinical development has been challenged by complex expression and characterization, as well as rapid serum clearance that is thought to be mediated by glycan receptor scavenging of recombinantly produced IgA monomer bearing incompletely sialylated N-linked glycans. Here, we present a comprehensive biochemical, biophysical, and structural characterization of recombinantly produced monomeric, dimeric and polymeric human IgA. We further explore two strategies to overcome the rapid serum clearance of polymeric IgA: removal of all N-linked glycosylation sites creating an aglycosylated polymeric IgA and engineering in FcRn binding with the generation of a polymeric IgG-IgA Fc fusion. While previous reports and the results presented in this study indicate that glycan-mediated clearance plays a major role for monomeric IgA, systemic clearance of polymeric IgA in mice is predominantly controlled by mechanisms other than glycan receptor clearance, such as pIgR-mediated transcytosis. The developed IgA platform now provides the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure.

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Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease

Cited by 16 publications

References 36 publications

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease

A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease

IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

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