Shigeyuki Iijima

A defucosylated anti-CD317 antibody exhibited enhanced antibody-dependent cellular cytotoxicity against primary myeloma cells in the presence of effectors from patients

The humanized monoclonal antibody (mAb) against CD317 antigen (anti‐HM1.24 antibody; AHM), which is highly expressed on multiple myeloma (MM), induces antibody‐dependent cellular cytotoxicity (ADCC). However, the antitumor activity of AHM in the clinical setting has not been clearly demonstrated. In this study, we produced defucosylated AHM and evaluated its potency for clinical application by performing autologous ADCC assays against primary MM cells from patients. Defucosylated AHM that was produced in rat myeloma YB2/0 cells expressing a low level of fucosyltransferase (FUT8) showed significant ADCC activity against three out of six primary MM cells in the presence of autologous PBMC, whereas conventional AHM did not. The results indicate that the potency of AHM to induce ADCC against primary MM cells was insufficient, but was significantly augmented by defucosylation. To generate more homogenous defucosylated monoclonal antibodies (mAb) for fermentation, we disrupted the GFT gene that encodes a GDP‐fucose transporter in a CHO/DXB11 cell line by sequential homologous recombination. Analysis of the N‐linked oligosaccharide in the defucosylated AHM produced by the established GFT(−/−)CHO cell line showed that a majority (93.4%) of the oligosaccharide was fucose free. The GFT(−/−) cells stably produced defucosylated mAb over passages. These results demonstrate that GTF(−/−)CHO‐produced defucosylated AHM (GFTKO‐AHM) will be a promising new therapeutic antibody against MM in the clinical setting. (Cancer Sci 2010)

Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis.

Novel vitamin D(3) analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3β-hydroxy group of 1α,25-dihydroxyvitamin D(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.