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基本情報
登録情報 | データベース: PDB / ID: 8il3 | ||||||||||||||||||||||||||||||||||||
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タイトル | Cryo-EM structure of CD38 in complex with FTL004 | ||||||||||||||||||||||||||||||||||||
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![]() | HYDROLASE / monoclonal antibody | ||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / Nicotinate metabolism / artery smooth muscle contraction / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ metabolic process / NAD+ nucleosidase activity, cyclic ADP-ribose generating / long-term synaptic depression / negative regulation of bone resorption / response to hydroperoxide ...2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / Nicotinate metabolism / artery smooth muscle contraction / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ metabolic process / NAD+ nucleosidase activity, cyclic ADP-ribose generating / long-term synaptic depression / negative regulation of bone resorption / response to hydroperoxide / 加水分解酵素; 糖加水分解酵素; N-グリコシル化合物加水分解酵素 / positive regulation of vasoconstriction / B cell proliferation / response to retinoic acid / positive regulation of B cell proliferation / response to interleukin-1 / response to progesterone / B cell receptor signaling pathway / apoptotic signaling pathway / female pregnancy / positive regulation of insulin secretion / response to estradiol / negative regulation of neuron projection development / transferase activity / positive regulation of cytosolic calcium ion concentration / positive regulation of cell growth / nuclear membrane / basolateral plasma membrane / response to hypoxia / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / cell surface / signal transduction / extracellular exosome / identical protein binding / membrane / plasma membrane 類似検索 - 分子機能 | ||||||||||||||||||||||||||||||||||||
生物種 | ![]() | ||||||||||||||||||||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.86 Å | ||||||||||||||||||||||||||||||||||||
![]() | Yang, J. / Wang, Y. / Zhang, G. | ||||||||||||||||||||||||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma. 著者: Guangbing Zhang / Cuiyu Guo / Yan Wang / Xianda Zhang / Shuang Liu / Wen Qu / Chunxia Chen / Lingli Yan / Zhouning Yang / Zhixiong Zhang / Xiaohua Jiang / Xiaofeng Chen / Hong Liu / Qinhuai ...著者: Guangbing Zhang / Cuiyu Guo / Yan Wang / Xianda Zhang / Shuang Liu / Wen Qu / Chunxia Chen / Lingli Yan / Zhouning Yang / Zhixiong Zhang / Xiaohua Jiang / Xiaofeng Chen / Hong Liu / Qinhuai Lai / Xian Wei / Ying Lu / Shengyan Zhao / Han Deng / Yuxi Wang / Lin Yu / Hongbin Yu / Yu Wu / Zhaoming Su / Pengyu Chen / Ziqing Ren / Meng Yu / Feng Qu / Yong Luo / Lantu Gou / Qing Li / Ying Huang / Fanxin Ma / Jinliang Yang / ![]() 要旨: Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve ...Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma. | ||||||||||||||||||||||||||||||||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 141.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 107.2 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.5 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.5 MB | 表示 | |
XML形式データ | ![]() | 31.4 KB | 表示 | |
CIF形式データ | ![]() | 45.1 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 35526MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: 抗体 | 分子量: 23929.572 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#2: 抗体 | 分子量: 22817.510 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
#3: タンパク質 | 分子量: 26834.471 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: P28907, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase |
Has protein modification | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Cryo-EM structure of CD38 in complex with FTL004 / タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.2 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 200 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 |
急速凍結 | 凍結剤: ETHANE / 湿度: 100 % |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2826 nm / 最小 デフォーカス(公称値): 752 nm |
撮影 | 電子線照射量: 60 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 QUANTUM (4k x 4k) |
画像スキャン | 動画フレーム数/画像: 5 |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.15.2_3472: / 分類: 精密化 | ||||||||||||||||||||||||
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EMソフトウェア | 名称: PHENIX / カテゴリ: モデル精密化 | ||||||||||||||||||||||||
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.86 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 34435 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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