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CD47 monoclonal antibody

Akanksha Chhabra, Aaron M Ring, Kipp Weiskopf, Peter John Schnorr, Sydney Gordon, Alan C Le, Hye-Sook Kwon, Nan Guo Ring, Jens Volkmer, Po Yi Ho, Serena Tseng, Irving L Weissman, Judith A Shizuru
Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice...
August 10, 2016: Science Translational Medicine
Zhenyu Xiao, Babak Banan, Min Xu, Jianluo Jia, Pamela T Manning, Ronald R Hiebsch, Muthukumar Gunasekaran, Gundumi A Upadhya, William A Frazier, Thalachallour Mohanakumar, Yiing Lin, William C Chapman
BACKGROUND: Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling...
July 2016: Transplantation
Michael Zhang, Gregor Hutter, Suzana A Kahn, Tej D Azad, Sharareh Gholamin, Chelsea Y Xu, Jie Liu, Achal S Achrol, Chase Richard, Pia Sommerkamp, Matthew Kenneth Schoen, Melissa N McCracken, Ravi Majeti, Irving Weissman, Siddhartha S Mitra, Samuel H Cheshier
Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts...
2016: PloS One
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
Thomas Höfner, Corinna Klein, Christian Eisen, Teresa Rigo-Watermeier, Axel Haferkamp, Martin R Sprick
The long-term propagation of basal prostate progenitor cells ex vivo has been very difficult in the past. The development of novel methods to expand prostate progenitor cells in vitro allows determining their cell surface phenotype in greater detail. Mouse (Lin(-)Sca-1(+) CD49f(+) Trop2(high)-phenotype) and human (Lin(-) CD49f(+) TROP2(high)) basal prostate progenitor cells were expanded in vitro. Human and mouse cells were screened using 242 anti-human or 176 antimouse monoclonal antibodies recognizing the cell surface protein profile...
April 2016: Journal of Cellular and Molecular Medicine
F Kong, F Gao, H Li, H Liu, Y Zhang, R Zheng, Y Zhang, J Chen, X Li, G Liu, Y Jia
The relationship between the immune system and cancer growth and aggravation has been discussed over a century. A number of molecules have been shown to participate in this process. CD47, a normal universally expressed member of the immunoglobulin superfamily, plays multiple functions in immune system. Researches demonstrated that CD47 was also highly expressed on the surface of tumor cells as well as cancer stem cells (CSCs). Whether the highly expressed CD47 was associated with tumor growth, metastasis, recurrence, or drug resistance has become the hotspot...
February 1, 2016: Clinical & Translational Oncology
Jie Liu, Lijuan Wang, Feifei Zhao, Serena Tseng, Cyndhavi Narayanan, Lei Shura, Stephen Willingham, Maureen Howard, Susan Prohaska, Jens Volkmer, Mark Chao, Irving L Weissman, Ravindra Majeti
CD47 is a widely expressed cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, SIRP-alpha, which in turn delivers an inhibitory signal for phagocytosis. We previously found increased expression of CD47 on primary human acute myeloid leukemia (AML) stem cells, and demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML, non-Hodgkin's lymphoma (NHL), and many solid tumors in xenograft models...
2015: PloS One
Jessica Lo, Eunice Yuen Ting Lau, Francis Tak Yuk So, Ping Lu, Vera Sau Fong Chan, Vincent Chi Ho Cheung, Rachel Hiu Ha Ching, Bowie Yik Ling Cheng, Mark Kin Fai Ma, Irene Oi Lin Ng, Terence Kin Wah Lee
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with metastasis and recurrence leading to a poor prognosis. Therefore, development of novel treatment regimens is urgently needed to improve the survival of HCC patients. In this study, we aimed to investigate the in vitro and in vivo effects of anti-CD47 antibody alone and in combination with chemotherapy in HCC. METHODS: In this study, we examined the functional effects of anti-CD47 antibody (B6H12) on cell proliferation, sphere formation, migration and invasion, chemosensitivity, macrophage-mediated phagocytosis and tumourigenicity both in vitro and in vivo...
May 2016: Liver International: Official Journal of the International Association for the Study of the Liver
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
Kazumichi Yoshida, Hironori Tsujimoto, Kouji Matsumura, Manabu Kinoshita, Risa Takahata, Yusuke Matsumoto, Shuichi Hiraki, Satoshi Ono, Shuhji Seki, Junji Yamamoto, Kazuo Hase
CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied...
September 2015: Cancer Medicine
Chia Chi M Ho, Nan Guo, Jonathan T Sockolosky, Aaron M Ring, Kipp Weiskopf, Engin Özkan, Yasuo Mori, Irving L Weissman, K Christopher Garcia
CD47 is a cell surface protein that transmits an anti-phagocytic signal, known as the "don't-eat-me" signal, to macrophages upon engaging its receptor signal regulatory protein α (SIRPα). Molecules that antagonize the CD47-SIRPα interaction by binding to CD47, such as anti-CD47 antibodies and the engineered SIRPα variant CV1, have been shown to facilitate macrophage-mediated anti-tumor responses. However, these strategies targeting CD47 are handicapped by large antigen sinks in vivo and indiscriminate cell binding due to ubiquitous expression of CD47...
May 15, 2015: Journal of Biological Chemistry
Zhenyu Xiao, Haniee Chung, Babak Banan, Pamela T Manning, Katherine C Ott, Shin Lin, Benjamin J Capoccia, Vijay Subramanian, Ronald R Hiebsch, Gundumi A Upadhya, Thalachallour Mohanakumar, William A Frazier, Yiing Lin, William C Chapman
Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα...
May 1, 2015: Cancer Letters
Zhen-Yu Xiao, Babak Banan, Jianluo Jia, Pamela T Manning, Ronald R Hiebsch, Muthukumar Gunasekaran, Gundumi A Upadhya, William A Frazier, Thalachallour Mohanakumar, Yiing Lin, William C Chapman
Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant...
April 2015: Liver Transplantation
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No abstract text is available yet for this article.
August 2014: Cancer Discovery
Katsuto Takenaka, Koichi Akashi
Human acute myeloid leukemia is organized as a hierarchy initiated and maintained by "leukemia stem cells(LSC)" which possesses self-renewal capacity. LSCs are therapeutic targets and must be eliminated to cure the patients. Recent advances in LSC research provided insights into the cell surface antigens preferentially expressed on AML-LSCs compared with normal hematopoietic stem cells and the signaling pathways defining the LSC characteristics. These molecules are potential targets to eradicate LSCs. Especially, monoclonal antibodies targeting surface antigens expressed on LSCs, including CD123, CD44, TIM-3 and CD47 have been shown its efficacy against AML-LSCs in xenotransplant models...
June 2014: Nihon Rinsho. Japanese Journal of Clinical Medicine
Yiing Lin, Pamela T Manning, Jianluo Jia, Joseph P Gaut, Zhenyu Xiao, Benjamin J Capoccia, Chun-Cheng Chen, Ronald R Hiebsch, Gundumi Upadhya, Thalachallour Mohanakumar, William A Frazier, William C Chapman
BACKGROUND: Ischemia-reperfusion injury (IRI) significantly contributes to delayed graft function and inflammation, leading to graft loss. Ischemia-reperfusion injury is exacerbated by the thrombospondin-1-CD47 system through inhibition of nitric oxide signaling. We postulate that CD47 blockade and prevention of nitric oxide inhibition reduce IRI in organ transplantation. METHODS: We used a syngeneic rat renal transplantation model of IRI with bilaterally nephrectomized recipients to evaluate the effect of a CD47 monoclonal antibody (CD47mAb) on IRI...
August 27, 2014: Transplantation
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
Cord Naujokat
Cancer stem cells (CSCs) are a subpopulation of tumor cells that display self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to modern cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Various cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, CD123, EpCAM (CD326), CD133, IGF receptor I, and proteins of the Notch and Wnt signaling pathways have been identified...
2014: Immunotherapy
Alexander Zheleznyak, Oluwatayo F Ikotun, Julie Dimitry, William A Frazier, Suzanne E Lapi
CD47 functions as a marker of "self" by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET) in both human xenograft and murine allograft tumor models. Anti-CD47 antibodies were conjugated with p-isothiocyanatobenzyldesferrioxamine (Df-Bz-NCS) and labeled with 89Zr. We employed xenograft and allograft small-animal models of cancer in biodistribution and PET imaging studies to investigate the specificity and PET imaging robustness of CD47...
November 2013: Molecular Imaging
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