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Immunotoxin SS1P is rapidly removed by proximal tubule cells of kidney, whose damage contributes to albumin loss in urine

Xu Liu,Junxia Wei,Qi Zhou,B. Molitoris,R. Sandoval,Hisataka Kobayashi,Ryuhei Okada,T. Nagaya,Baktiar O Karim,D. Butcher,I. Pastan

Published 2020 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance This paper shows that the major pathway of degradation of immunotoxins in mice is rapid filtration through the glomerulus of the kidney and degradation by proximal tubular cells. It also shows that SS1P treatment damages proximal tubular cells and enhances loss of albumin in the urine, which can contribute to capillary leak syndrome, a major side effect of immunotoxin therapy. Because lysine administration diminishes kidney uptake of SS1P, it could also protect against SS1P-induced capillary leak syndrome. Recombinant immunotoxins (RITs) are chimeric proteins composed of an Fv and a protein toxin being developed for cancer treatment. The Fv brings the toxin to the cancer cell, but most of the RITs do not reach the tumor and are removed by other organs. To identify cells responsible for RIT removal, and the pathway by which RITs reach these cells, we studied SS1P, a 63-kDa RIT that targets mesothelin-expressing tumors and has a short serum half-life. The major organs that remove RIT were identified by live mouse imaging of RIT labeled with FNIR-Z-759. Cells responsible for SS1P removal were identified by immunohistochemistry and intravital two-photon microscopy of kidneys of rats. The primary organ of SS1P removal is kidney followed by liver. In the kidney, SS1P passes through the glomerulus, is taken up by proximal tubular cells, and transferred to lysosomes. In the liver, macrophages are involved in removal. The short half-life of SS1P is due to its very rapid filtration by the kidney followed by degradation in proximal tubular cells of the kidney. In mice treated with SS1P, proximal tubular cells are damaged and albumin in the urine is increased. SS1P uptake by kidney is reduced by coadministration of l-lysine. Our data suggests that l-lysine administration to humans might prevent SS1P-mediated kidney damage, reduce albumin loss in urine, and alleviate capillary leak syndrome.

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