5tz2 | pdb_00005tz2
Crystal structure of human CD47 ECD bound to Fab of C47B222
Structural highlights
Function[CD47_HUMAN] Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.[1] [2] [3] Publication Abstract from PubMedCD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPalpha. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPalpha blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2sigma C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices. Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies.,Pietsch EC, Dong J, Cardoso R, Zhang X, Chin D, Hawkins R, Dinh T, Zhou M, Strake B, Feng PH, Rocca M, Santos CD, Shan X, Danet-Desnoyers G, Shi F, Kaiser E, Millar HJ, Fenton S, Swanson R, Nemeth JA, Attar RM Blood Cancer J. 2017 Feb 24;7(2):e536. doi: 10.1038/bcj.2017.7. PMID:28234345[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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