作者: Chen, Zian ; Chen, Xiangyi ; Hu, Ping ; Li, Weida ; Zhang, Jingzhi ; Sheng, Zhejin ; Yang, Kaijiang ; Wang, Gaowei ; Sun, Jingyu ; Wang, Hong ; Huang, Feier ; Su, Yajuan ; Zhang, Zhen-Ning ; Qin, Duran ; Pei, Yu ; Gong, Mengting ; Le, Rongrong ; Gao, Shaorong ; He, Qing ; Dong, Yu ; Wang, Zhaoyue ; Deng, Qiaolin ; Kong, Yunhui ; Li, Xiaobo ; Xu, Minglu

CD47-blocking antibody is a well-known potential antibody drug for tumor immunotherapy. However, it is unclear whether CD47-blocking antibody can protect against metabolic disorders. We report that high-fat diet (HFD)-induced obesity increases CD47 expression, while exercise downregulates it in skeletal muscle. Administration of CD47-blocking antibody in mice prevents HFD-induced weight gain and glucose intolerance, enhances exercise capacity, and improves body composition and skeletal muscle mitochondrial function. Mechanistically, the protective effects conferred by CD47-blocking antibody are mediated through activation of AMP-activated protein kinase (AMPK) in skeletal muscle. Consistently, muscle-specific CD47-knockout mice show similar metabolic improvements, indicating a direct muscle-specific role of CD47 in regulating AMPK activation in vivo. Furthermore, the CD47-blocking antibody reduces the phosphorylation of heat shock protein 90α (HSP90α) to activate AMPK in skeletal muscle. In conclusion, CD47-blocking antibody confers metabolic benefits by activating the AMPK pathway in skeletal muscle.

2024-02-01·Clinical and Translational Medicine

Tolerating CD47

Review

作者: Isenberg, Jeffrey S ; Montero, Enrique

AbstractCluster of differentiation 47 (CD47) occupies the outer membrane of human cells, where it binds to soluble and cell surface receptors on the same and other cells, sculpting their topography and resulting in a pleiotropic receptor‐multiligand interaction network. It is a focus of drug development to temper and accentuate CD47‐driven immune cell liaisons, although consideration of on‐target CD47 effects remain neglected. And yet, a late clinical trial of a CD47‐blocking antibody was discontinued, existent trials were restrained, and development of CD47‐targeting agents halted by some pharmaceutical companies. At this point, if CD47 can be exploited for clinical advantage remains to be determined. Herein an airing is made of the seemingly conflicting actions of CD47 that reflect its position as a junction connecting receptors and signalling pathways that impact numerous human cell types. Prospects of CD47 boosting and blocking are considered along with potential therapeutic implications for autoimmune diseases and cancer.

2021-09-23·Nature

Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Article

作者: Banuelos, Allison M ; Jerby-Arnon, Livnat ; Spees, Kaitlyn ; Yao, David ; Kamber, Roarke A ; Nishiga, Yoko ; Seoane, Jose A ; Fernandez, Daniel ; Bassik, Michael C ; Weissman, Irving L ; Morton, Bhek ; Sage, Julien ; Lin, Sijie ; Liu, Katherine ; Barkal, Amira A ; Gu, Mingxin ; Vences-Catalán, Felipe ; Curtis, Christina

Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells^1-7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

100 项与 CD47-blocking Antibody(Tongji University) 相关的药物交易

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