5TZ2

Crystal structure of human CD47 ECD bound to Fab of C47B222

Summary for 5TZ2

• Entry DOI: 10.2210/pdb5tz2/pdb
• Related: 5TZT 5TZU
• Descriptor: C47B222 Fab Heavy Chain, C47B222 Fab Light Chain, Leukocyte surface antigen CD47, ... (7 entities in total)
• Functional Keywords: antigen-fab complex, immunoglobulin, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 64418.74

Authors

Cardoso, R.M.F. (deposition date: 2016-11-21, release date: 2017-03-15, Last modification date: 2023-10-04)

Primary citation

Pietsch, E.C.,Dong, J.,Cardoso, R.,Zhang, X.,Chin, D.,Hawkins, R.,Dinh, T.,Zhou, M.,Strake, B.,Feng, P.H.,Rocca, M.,Santos, C.D.,Shan, X.,Danet-Desnoyers, G.,Shi, F.,Kaiser, E.,Millar, H.J.,Fenton, S.,Swanson, R.,Nemeth, J.A.,Attar, R.M.
Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies.
Blood Cancer J, 7:e536-e536, 2017

PubMed Abstract: CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα 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 IgG2σ 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.

PubMed: 28234345
DOI: 10.1038/bcj.2017.7

Experimental method

X-RAY DIFFRACTION (2.302 Å)