Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease.
Autosomal-dominant polycystic kidney disease (ADPKD) is a common life-threatening genetic disease that leads to renal failure. No treatment is available yet to effectively slow disease progression. Renal cyst growth is, at least in part, driven by the presence of growth factors in the lumens of renal cysts, which are enclosed spaces lacking connections to the tubular system. We have shown previously shown that IL13 in cyst fluid leads to aberrant activation of STAT6 via the IL4/13 receptor. Although antagonistic antibodies against many of the growth factors implicated in ADPKD are already available, they are IgG isotype antibodies that are not expected to gain access to renal cyst lumens. Here we demonstrate that targeting antibodies to renal cyst lumens is possible with the use of dimeric IgA (dIgA) antibodies. Using human ADPKD tissues and polycystic kidney disease mouse models, we show that the polymeric immunoglobulin receptor (pIgR) is highly expressed by renal cyst-lining cells. pIgR expression is, in part, driven by aberrant STAT6 pathway activation. pIgR actively transports dIgA from the circulation across the cyst epithelium and releases it into the cyst lumen as secretory IgA. dIgA administered by intraperitoneal injection is preferentially targeted to polycystic kidneys whereas injected IgG is not. Our results suggest that pIgR-mediated transcytosis of antagonistic antibodies in dIgA format can be exploited for targeted therapy in ADPKD.
From the Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106-9610.
Erin E
EE
Olsan
From the Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106-9610.
Tamami
T
Matsushita
From the Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106-9610.
Mina
M
Rezaei
From the Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106-9610. Electronic address: weimbs@lifesci.ucsb.edu.
Thomas
T
Weimbs
D000818:Animals; D003560:Cysts / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053660:Receptors, Interleukin-13 / Q000235:genetics / Q000378:metabolism; D019056:Receptors, Polymeric Immunoglobulin / Q000096:biosynthesis* / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D057900:Transcytosis
C508181:IL13RA1 protein, human; D007070:Immunoglobulin A; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053660:Receptors, Interleukin-13; D019056:Receptors, Polymeric Immunoglobulin; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse
IgA; STAT transcription factor; STAT6; antibody; dimeric IgA; drug development; drug targeting; genetic disease; polycystic kidney disease; polymeric immunoglobulin receptor