Publications by authors named "Mayumi Sue"

4 Publications

  • Page 1 of 1

Novel anti-EPHA2 antibody, DS-8895a for cancer treatment.

Cancer Biol Ther 2016 11 21;17(11):1158-1167. Epub 2016 Sep 21.

a Biologics & Immuno-Oncology Laboratories , Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo , Japan.

Overexpression of EPHA2 has been observed in multiple cancers and reported to be associated with poor prognosis. Here, we produced an afucosylated humanized anti-EPHA2 monoclonal antibody (mAb), DS-8895a for cancer treatment. The antibody recognizes the extracellular juxtamembrane region of EPHA2 and therefore can bind to both full-length and truncated forms of EPHA2, which are anchored to cell membranes and recently reported to be produced by post-translational cleavage in tumors. DS-8895a exhibited markedly increased antibody dependent cellular cytotoxicity (ADCC) in vitro and also inhibited tumor growth in EPHA2-positive human breast cancer MDA-MB-231 and human gastric cancer SNU-16 xenograft mouse models. Moreover, DS-8895a in combination with cisplatin (CDDP) showed better efficacy than each of the monotherapies did in the human gastric cancer model. These results suggest that a novel antibody, DS-8895a has therapeutic potential against EPHA2-expressing tumors.
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http://dx.doi.org/10.1080/15384047.2016.1235663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137487PMC
November 2016

An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches.

Int Immunopharmacol 2016 Jun 22;35:15-21. Epub 2016 Mar 22.

Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biochemistry, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan; Department of Breast and Endocrine Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan. Electronic address:

Local infiltration of inflammatory cells is regulated by a number of biological steps during which the cells likely penetrate through subendothelial basement membranes that contain heparan sulfate proteoglycans. In the present study, we examined whether administration of heparastatin (SF4), an iminosugar-based inhibitor of heparanase, could suppress local inflammation and degradation of heparan sulfate proteoglycans in basement membranes. In a carrageenan- or formyl peptide-induced dorsal air pouch inflammation model, the number of infiltrated neutrophils and monocytes was significantly lower in mice after topical administration of heparastatin (SF4). The concentration of chemokines MIP-2 and KC in pouch exudates of drug-treated mice was similar to control. In a zymosan-induced peritonitis model, the number of infiltrated cells was not altered in drug-treated mice. To further test how heparastatin (SF4) influences transmigration of inflammatory neutrophils, its suppressive effect on migration and matrix degradation was examined in vitro. In the presence of heparastatin (SF4), the number of neutrophils that infiltrated across a Matrigel-coated polycarbonate membrane was significantly lower, while the number of neutrophils passing through an uncoated membrane was not altered. Lysate of bone marrow-derived neutrophils released sulfate-radiolabeled macromolecules from basement membrane-like extracellular matrix, which was suppressed by heparastatin (SF4). Heparan sulfate degradation activity was almost completely abolished after incubation of lysate with protein G-conjugated anti-heparanase monoclonal antibody, strongly suggesting that the activity was due to heparanase-mediated degradation. Taken together, in a dorsal air pouch inflammation model heparastatin (SF4) potentially suppresses extravasation of inflammatory cells by impairing the degradation of basement membrane heparan sulfate.
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http://dx.doi.org/10.1016/j.intimp.2016.03.017DOI Listing
June 2016

Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mast cells from extracellular matrices.

Biochem J 2014 Mar;458(2):291-9

*Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

Heparanase cleaves macromolecular heparin in the secretory granules of connective tissue-type mast cells. We investigated roles of the cleavage under a microenvironment mimicking where the mast cells physiologically reside. A connective tissue-type mast cell line MST and mouse peritoneal cell-derived mast cells stored macromolecular heparin in the secretory granules. The cells expressing heparanase stored fragmented heparin (~10 kDa) due to heparanase-dependent cleavage of the heparin. We produced an artificial collagen-based extracellular matrix and placed the live cells or glycosaminoglycans purified from the cells in the matrix to measure the release of sulfated macromolecules into the medium. The sulfate-radiolabelled molecules from the degranulating heparanase-expressing cells and the purified glycosaminoglycans showed significantly greater release into the medium than those derived from mock cells, which was not the case in suspension culture. The mast cell granular enzyme chymase, but not β-hexosaminidase, showed significantly greater release from the degranulating heparanase-expressing cells than from mock cells. Purified chymase mixed with fragmented heparin derived from heparanase-expressing cells showed greater release from collagen gels than the enzyme alone or mixed with macromolecular heparin derived from mock cells. We propose that the cleavage of macromolecular heparin by heparanase accelerates the release of heparin and chymase from extracellular matrices.
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http://dx.doi.org/10.1042/BJ20131463DOI Listing
March 2014

Heparanase expression in B16 melanoma cells and peripheral blood neutrophils before and after extravasation detected by novel anti-mouse heparanase monoclonal antibodies.

J Immunol Methods 2008 Feb 27;331(1-2):82-93. Epub 2007 Dec 27.

The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

Degradation of extracellular matrix is associated with extravasation of metastatic tumor cells and inflammatory cells. Heparanase, the heparan sulfate-specific endo-beta-glucuronidase, is a key enzyme for the matrix degradation, yet its involvement in extravasation and invasion during pathological processes was not fully clarified in vivo. In the present study, we examined heparanase expression in mouse experimental models, lung metastasis of melanoma and skin infiltration of neutrophils. Sixteen novel monoclonal antibodies specific for mouse heparanase were established by enzyme-linked immunosorbent assay with a recombinant mouse proheparanase, immunocytochemical staining of B16F10 melanoma cells cultured in vitro, and immunoprecipitation of the lysate of heparanase transfectant cells. Heparanase expression in metastatic nodules of B16F10 melanoma cells and in neutrophils localized in the inflamed skin was immunohistochemically detected using a monoclonal antibody RIO-1 that recognized the C-terminus of mouse heparanase. Homogeneous and strong heparanase staining was observed in 46% of the lung micrometastases of B16F10 melanoma cells. The staining was intensely positive on the invasive front of larger established metastasis nodules, but it was weak or heterogeneous inside the nodules. Heparanase expression in skin-infiltrating neutrophils was examined after inducing local inflammation with croton oil. The monoclonal antibody stained a significant portion of neutrophils inside and along the blood vessels, whereas it did not stain dermal neutrophils located distant from the vasculatures. The present study strongly suggests that both melanoma cells and neutrophils transiently express heparanase before and during the invasive process in vivo.
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http://dx.doi.org/10.1016/j.jim.2007.11.014DOI Listing
February 2008
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