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Anti CD47 Therapy

Gizem Bener, Alex J Félix, Cristina Sánchez de Diego, Isabel Pascual Fabregat, Carlos J Ciudad, Véronique Noé
BACKGROUND: In the context of tumor immunology, tumor cells have been shown to overexpress CD47, an anti-phagocytic signal directed to macrophages to escape from phagocytosis by interacting with Signal Regulatory Protein α SIRPα. In the present work, we designed Polypurine reverse Hoogsteen hairpins, PPRHs, to silence the expression of CD47 in tumor cells and SIRPα in macrophages with the aim to eliminate tumor cells by macrophages in co-culture experiments. METHODS: THP-1 cells were differentiated to macrophages with PMA...
September 26, 2016: BMC Immunology
Michael Ngo, Arum Han, Anita Lakatos, Debashis Sahoo, Stephanie J Hachey, Kipp Weiskopf, Andrew H Beck, Irving L Weissman, Alexander D Boiko
The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts...
August 9, 2016: Cell Reports
Kipp Weiskopf, Nadine S Jahchan, Peter J Schnorr, Sandra Cristea, Aaron M Ring, Roy L Maute, Anne K Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T Poirier, Eric E Gardner, Linde A Miles, Elisa de Stanchina, Shane M Lofgren, Hannes Vogel, Monte M Winslow, Caroline Dive, Roman K Thomas, Charles M Rudin, Matt van de Rijn, Ravindra Majeti, K Christopher Garcia, Irving L Weissman, Julien Sage
Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture...
July 1, 2016: Journal of Clinical Investigation
Viktor H Koelzer, Katharina Canonica, Heather Dawson, Lena Sokol, Eva Karamitopoulou-Diamantis, Alessandro Lugli, Inti Zlobec
Tumor-associated macrophages (TAM) play a controversial role in epithelial-mesenchymal transition (EMT) and prognosis of colorectal cancer (CRC). In particular, the microlocalization, polarization and prognostic impact of TAM in the immediate environment of invading CRC cells has not yet been established. To address this clinically relevant question, intraepithelial (iCD68) and stromal macrophages (sCD68), M1-macrophages (iNOS), M2-macrophages (CD163), cytokeratin-positive cancer cells (tumor buds) and expression of the anti-phagocytic marker CD47 were investigated in primary tumors of 205 well-characterized CRC patients...
April 2016: Oncoimmunology
Jonathan T Sockolosky, Michael Dougan, Jessica R Ingram, Chia Chi M Ho, Monique J Kauke, Steven C Almo, Hidde L Ploegh, K Christopher Garcia
Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xiaojuan Liu, Yang Pu, Kyle Cron, Liufu Deng, Justin Kline, William A Frazier, Hairong Xu, Hua Peng, Yang-Xin Fu, Meng Michelle Xu
Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses...
October 2015: Nature Medicine
Chao-Chih Wu, Yuh-Cheng Yang, Yun-Ting Hsu, T-C Wu, Chien-Fu Hung, Jung-Tang Huang, Chih-Long Chang
Hyperthermic intraperitoneal chemotherapy is effective in treating various intra-abdominal malignancies. However, this therapeutic modality can only be performed during surgical operations and cannot be used repeatedly. We propose repeatedly noninvasive hyperthermia mediated by pegylated silica-core gold nanoshells (pSGNs) in vivo with external near-infrared (NIR) laser irradiation. This study demonstrated that repeated photothermal treatment can effectively eliminate intraperitoneal tumors in mouse ovarian cancer models without damage of normal tissues...
September 29, 2015: Oncotarget
Y Wang, C Yin, L Feng, C Wang, G Sheng
Leukemia stem cells (LSCs) are regarded as the origin of leukemia and its recurrence. Side population (SP) cells possess some intrinsic stem cell properties and contain numerous LSCs. In this study, we examined the prognostic significance of cluster differentiation 47 (CD47) and identified the appropriate target for eliminating LSCs. We determined the percentage of SP cells in a THP-1 cell population and analyzed CD47 expression in different cell subsets. We then explored whether CD47 affected the phagocytic ability of macrophages to LSCs in vitro...
2015: Genetics and Molecular Research: GMR
Ji-Feng Xu, Xiao-Hong Pan, Shui-Jun Zhang, Chen Zhao, Bin-Song Qiu, Hai-Feng Gu, Jian-Fei Hong, Li Cao, Yu Chen, Bing Xia, Qin Bi, Ya-Ping Wang
Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues...
September 15, 2015: Oncotarget
Emily C Piccione, Silvia Juarez, Jie Liu, Serena Tseng, Christine E Ryan, Cyndhavi Narayanan, Lijuan Wang, Kipp Weiskopf, Ravindra Majeti
Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20...
2015: MAbs
Ga Bin Park, Si Ra Bang, Hyun-Kyung Lee, Daejin Kim, Seonghan Kim, Jin Kyoung Kim, Yeong Seok Kim, Dae Young Hur
CD47 is expressed in normal activated cells as well as in several tumors. It also has been implicated as having antiangiogenic and antimetastatic properties, but its roles in Epstein-Barr virus (EBV)-transformed B cells are still not fully understood. Herein, we report that EBV infection induced CD47 surface expression on B cells, and CD47 ligation with anti-CD47 mAb (B6H12) reduced cell proliferation and induced G1 arrest. CD47-induced G1 arrest was mediated through increased cyclin-dependent kinase inhibitors (CDKi) and a simultaneously decreased CDK/cyclins, and p38 MAPK/JNK activation preceded binding of CDKi-CDK...
July 2014: Journal of Immunotherapy
Cindy Fevre, Jovanka Bestebroer, Mirjam M Mebius, Carla J C de Haas, Jos A G van Strijp, J Ross Fitzgerald, Pieter-Jan A Haas
In order to cause colonization and invasive disease, pathogenic bacteria secrete proteins that modulate host immune defences. Identification and characterization of these proteins leads to a better understanding of the pathological processes underlying infectious and inflammatory diseases and is essential in the development of new strategies for their prevention and treatment. Current techniques to functionally characterize these proteins are laborious and inefficient. Here we describe a high-throughput functional selection strategy using phage display in order to identify immune evasion proteins...
November 2014: Cellular Microbiology
Hiroki Goto, Yuki Kojima, Kouki Matsuda, Ryusho Kariya, Manabu Taura, Kazuhiko Kuwahara, Hirokazu Nagai, Harutaka Katano, Seiji Okada
BACKGROUND: Recently, the critical role of CD47 on the surface of resistant cancer cells has been proposed in their evasion of immunosurveillance. Primary effusion lymphoma (PEL) is a subtype of aggressive non-Hodgkin lymphoma that shows serous lymphomatous effusion in body cavities, especially in advanced acquired immunodeficiency syndrome (AIDS). PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect of anti-CD47 antibody (Ab) on PEL in vitro and in vivo...
July 2014: European Journal of Cancer
Ying-Chao Wang, Lei Feng, Chu-Yun Yin, Li-Na Ma, Yong-Wei Wei, Chun-Mei Wang, Guang-Yao Sheng
OBJECTIVE: To study the prognostic significance of CD47 in a NOD/SCID mouse model of acute myeloid leukemia (AML) and the best strategy for targeted therapy for this disease. METHODS: CD34(+)CD38(-) leukemia stem cells (LSCs) were separated and transplanted into NOD/SCID mice to establish a mouse model of acute monocytic leukemia (AMoL). Anti-human CD47 antibody, alone or combined with cytosine arabinoside (Ara-C), was used to treat the mice with AMoL for 7-14 days, and therapeutic efficacy was assessed...
July 2013: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Yuhua Wang, Zhenghong Xu, Shutao Guo, Lu Zhang, Arati Sharma, Gavin P Robertson, Leaf Huang
CD47 is a "self marker" that is usually overexpressed on the surface of cancer cells to enable them to escape immunosurveillance. Recognition of CD47 by its receptor, signal regulatory protein α (SIRPα), which is expressed in the macrophages, inhibits phagocytic destruction of cancer cells by the macrophages. In this study, we have first shown that clinical isolates of human melanoma significantly upregulate CD47, possibly as a mechanism to defend themselves against the macrophages. We then exploited RNA interference (RNAi) technology to test the hypothesis that knocking down CD47 in the tumor cells will render them targets for macrophage destruction; hence, creating a novel anti-cancer therapy...
October 2013: Molecular Therapy: the Journal of the American Society of Gene Therapy
Wojciech Kalas, Ewelina Swiderek, Marta Switalska, Joanna Wietrzyk, Janusz Rak, Leon Strzadala
BACKGROUND: The anti-angiogenic activity of thrombospondin-1 (TSP-1) is suppressed in cancer cells, fact which has generated considerable interest in generating the respective therapeutic mimetics. These efforts were almost exclusively centered on peptides targeting CD36, the known TSP-1 receptor. Since the effects of these agents were less dramatic than those of full-length. TSP-1 questions could be raised about the cancer-related roles of additional TSP-1 domains and receptors, such as CD47, which bind the C-terminal sequences of this protein...
April 2013: Anticancer Research
Yuantao Wang, Hui Wang, Roderick Bronson, Yaowen Fu, Yong-Guang Yang
CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days)...
March 2014: Cell Transplantation
D Kim, J Wang, S B Willingham, R Martin, G Wernig, I L Weissman
Multiple myeloma is a plasma cell neoplasm residing in bone marrow. Despite advances in myeloma therapies, novel therapies are required to improve patient outcomes. CD47 is highly expressed on myeloma cells and a potential therapeutic candidate for myeloma therapies. Flow cytometric analysis of patient bone marrow cells revealed that myeloma cells overexpress CD47 when compared with non-myeloma cells in 73% of patients (27/37). CD47 expression protects cells from phagocytosis by transmitting an inhibitory signal to macrophages...
December 2012: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Badreddin Edris, Kipp Weiskopf, Anne K Volkmer, Jens-Peter Volkmer, Stephen B Willingham, Humberto Contreras-Trujillo, Jie Liu, Ravindra Majeti, Robert B West, Jonathan A Fletcher, Andrew H Beck, Irving L Weissman, Matt van de Rijn
Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-α, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells. Leiomyosarcoma (LMS) is a tumor of smooth muscle that can express varying levels of colony-stimulating factor-1 (CSF1), the expression of which correlates with the numbers of tumor-associated macrophages (TAMs) that are found in these tumors...
April 24, 2012: Proceedings of the National Academy of Sciences of the United States of America
Stephen B Willingham, Jens-Peter Volkmer, Andrew J Gentles, Debashis Sahoo, Piero Dalerba, Siddhartha S Mitra, Jian Wang, Humberto Contreras-Trujillo, Robin Martin, Justin D Cohen, Patricia Lovelace, Ferenc A Scheeren, Mark P Chao, Kipp Weiskopf, Chad Tang, Anne Kathrin Volkmer, Tejaswitha J Naik, Theresa A Storm, Adriane R Mosley, Badreddin Edris, Seraina M Schmid, Chris K Sun, Mei-Sze Chua, Oihana Murillo, Pradeep Rajendran, Adriel C Cha, Robert K Chin, Dongkyoon Kim, Maddalena Adorno, Tal Raveh, Diane Tseng, Siddhartha Jaiswal, Per Øyvind Enger, Gary K Steinberg, Gordon Li, Samuel K So, Ravindra Majeti, Griffith R Harsh, Matt van de Rijn, Nelson N H Teng, John B Sunwoo, Ash A Alizadeh, Michael F Clarke, Irving L Weissman
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected...
April 24, 2012: Proceedings of the National Academy of Sciences of the United States of America
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