8ZCA

Crystal structure of human CD47 ECD bound to Fab of Hu1C8

8ZCA の概要

• エントリーDOI: 10.2210/pdb8zca/pdb
• 分子名称: 1C8 Fab light chain, 1C8 Fab heavy chain, Leukocyte surface antigen CD47, ... (7 entities in total)
• 機能のキーワード: cd47, antibody, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 126122.35

構造登録者

Chen, Z.,Ding, J. (登録日: 2024-04-29, 公開日: 2025-05-07, 最終更新日: 2025-08-06)

主引用文献

Lu, X.,Chen, Z.,Yi, C.,Ling, Z.,Ye, J.,Chen, K.,Cong, Y.,Sonam, W.,Cheng, S.,Wang, R.,Zhang, D.,Xu, J.,Yang, J.,Ma, L.,Duan, Q.,Sun, X.,Ding, J.,Sun, B.
An anti-CD47 antibody binds to a distinct epitope in a novel metal ion-dependent manner to minimize cross-linking of red blood cells.
J.Biol.Chem., 301:110420-110420, 2025

PubMed Abstract: Cluster of differentiation 47 (CD47) is a widely expressed transmembrane protein that plays a crucial role in immune self-recognition. Cancer cells upregulate CD47 expression to promote immune escape through activating the "don't eat me" signal via interactions with signal regulatory protein α (SIRPα) on macrophages. The effectiveness of anti-CD47 antibodies has been demonstrated in multiple tumor models. However, since CD47 is also expressed in human red blood cells (RBCs) and platelets, the clinical application of anti-CD47 antibodies requires careful consideration of blood toxicity. One major obstacle to the clinical application of CD47 antibodies is the hemagglutination caused by RBCs cross-linking. In this study, we generated Hu1C8, a humanized anti-CD47 monoclonal antibody that demonstrated increased selectivity for binding to CD47 on cancer cells and lacked hemagglutination activity. Epitope mapping and the crystal structure of the Hu1C8 Fab-CD47 extracellular domain (ECD) complex revealed that Hu1C8 binds to a distinct epitope of CD47 in a Ca-dependent manner. The unique recognition and binding mode allowed Hu1C8 to bind CD47 on RBCs with reduced hemagglutination activity while still maintaining effective antitumor activity. These findings demonstrate a feasible strategy for developing CD47 antibodies with high antitumor activity but low RBC hemagglutination activity. Our study elucidates how epitope-specific antibody influences antibody-induced cell cross-linking, offering innovative strategies for antibody design to either leverage or avoid cell cross-linking effects.

PubMed: 40578556
DOI: 10.1016/j.jbc.2025.110420

実験手法

X-RAY DIFFRACTION (2.5 Å)