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ADCC humans

Leonid Dubrovsky, Elliott Joseph Brea, Dmitry Pankov, Emily Casey, Tao Dao, Cheng Liu, David A Scheinberg
Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A*02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia...
2016: Oncoimmunology
Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Freek Cox, Ted Kwaks, Boerries Brandenburg, Martin H Koldijk, Vincent Klaren, Bastiaan Smal, Hans J W M Korse, Eric Geelen, Lisanne Tettero, David Zuijdgeest, Esther J M Stoop, Eirikur Saeland, Ronald Vogels, Robert H E Friesen, Wouter Koudstaal, Jaap Goudsmit
Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies...
2016: Frontiers in Immunology
Hongmei Wang, Jianmin Liu, Xuemei Hu, Shanshan Liu, Baojun He
BACKGROUND Hepatocellular carcinoma (HCC) causes many deaths worldwide every year, especially in Asia. It is characterized by high malignancy, recurrence, and short survival time. Inflammation is closely related to the initiation and development of HCC. Tumor necrosis factor-α (TNF-α), an essential inflammatory mediator, has been studied as a potential therapy target in many cancers. However, its potential role in HCC diagnosis and therapy is still unclear. MATERIAL AND METHODS In our study, we detected the TNF-α expression in both human HCC tumor tissue and HCC cell lines HepG2 and HuH7...
October 14, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Wei Li, Hongjia Yang, Dimiter S Dimitrov
CD16A (FcγRIIIA) is an activating receptor mostly expressed on natural killer (NK) cells and monocytes/macrophages. It can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) through low-affinity interaction with human immunoglobulin G (IgG) Fc. It can also mediate cell lysis if NK cells are guided by bispecific killer cells engagers (BiKEs). BiKEs showed some success in clinical trials of cancer and are promising candidate therapeutics. However, currently reported BiKEs are based on antibody fragments (scFvs) of relatively large size...
October 3, 2016: Experimental and Molecular Pathology
Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F Choy, Nandhini Ramamoorthi, Erick R Castellanos, Mercedesz Balazs, Min Xu, Wyne P Lee, Marissa L Matsumoto, Jian Payandeh, Joseph R Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D Austin, Karin Reif
Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types...
May 19, 2016: JCI Insight
Capucine L Grandjean, Fabricio Montalvao, Susanna Celli, David Michonneau, Beatrice Breart, Zacarias Garcia, Mario Perro, Olivier Freytag, Christian A Gerdes, Philippe Bousso
Anti-CD20 monoclonal antibodies (mAbs) represent an effective treatment for a number of B cell malignancies and autoimmune disorders. Glycoengineering of anti-CD20mAb may contribute to increased anti-tumor efficacy through enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) as reported by in vitro studies. However, where and how glycoengineered Ab may potentiate therapeutic responses in vivo is yet to be elucidated. Here, we have performed mouse liver transplants to demonstrate that the liver is sufficient to mediate systemic B cells depletion after anti-CD20 treatment...
October 4, 2016: Scientific Reports
Wei Hseun Yeap, Kok Loon Wong, Noriko Shimasaki, Esmeralda Chi Yuan Teo, Jeffrey Kim Siang Quek, Hao Xiang Yong, Colin Phipps Diong, Antonio Bertoletti, Yeh Ching Linn, Siew Cheng Wong
Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16- expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies...
September 27, 2016: Scientific Reports
Aidong Wang, Ming Cui, Hong Qu, Jiabo Di, Zaozao Wang, Jiadi Xing, Fan Wu, Wei Wu, Xicheng Wang, Lin Shen, Beihai Jiang, Xiangqian Su
The epidermal growth factor receptor (EGFR) is overexpressed in several epithelial tumors. Anti-EGFR humanized monoclonal antibodies, cetuximab and panitumumab, in combination with chemotherapy have improved the prognosis for patients with wild-type RAS tumors. To identify mimotopes of EGFR and develop mimotope-based EGFR vaccines, we screened a phage display peptide library with panitumumab. Two EGFR mimotopes P19 and P26, which could be recognized by panitumumab specifically, were isolated. To enhance the immune responses, we generated recombinant proteins of P19 or P26 fused to a heat-shock cognate protein 70 (Hsc70), and evaluated the efficacy of Hsc70-P19 and Hsc70-P26 as vaccines in vivo...
September 21, 2016: Oncotarget
Wei-Wei Deng, Lei Wu, Lin-Lin Bu, Jian-Feng Liu, Yi-Cun Li, Si-Rui Ma, Guang-Tao Yu, Liang Mao, Wen-Feng Zhang, Zhi-Jun Sun
P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2...
2016: American Journal of Translational Research
Alba Matas-Céspedes, Anna Vidal-Crespo, Vanina Rodriguez, Neus Villamor, Julio Delgado, Eva Giné, Heleia Roca-Ho, Pablo Menéndez, Elias Campo, Armando López-Guillermo, Dolors Colomer, Gaël Roué, Adrian Wiestner, Paul Whi Parren, Parul Doshi, Jeroen J Lammerts-van Bueren, Patricia Perez-Galan
PURPOSE: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ CLL subtype. EXPERIMENTAL DESIGN: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP) or human serum to analyze complement-dependent cytotoxicity (CDC)...
September 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jonathan Richard, Beatriz Pacheco, Neelakshi Gohain, Maxime Veillette, Shilei Ding, Nirmin Alsahafi, William D Tolbert, Jérémie Prévost, Jean-Philippe Chapleau, Mathieu Coutu, Manxue Jia, Nathalie Brassard, Jongwoo Park, Joel R Courter, Bruno Melillo, Loïc Martin, Cécile Tremblay, Beatrice H Hahn, Daniel E Kaufmann, Xueling Wu, Amos B Smith, Joseph Sodroski, Marzena Pazgier, Andrés Finzi
Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to "push" Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera...
September 9, 2016: EBioMedicine
Akira Iizuka, Ryota Kondou, Chizu Nonomura, Tadashi Ashizawa, Keiichi Ohshima, Masatoshi Kusuhara, Mitsuhiro Isaka, Yasuhisa Ohde, Ken Yamaguchi, Yasuto Akiyama
Tumor immune regulation has been demonstrated in clinical studies using antibodies targeted to the B7/CD28 family. B7 homolog 4 (B7-H4) negatively regulates immune responses and is overexpressed in many types of human cancer, indicating that B7-H4 may be a potential target of cancer therapy. B7-H4 expression is affected by the microenvironment, and its presence has been reported in cancer tissues and immune cells. We found an upregulation of B7-H4 expression using comprehensive whole exome sequencing and gene expression profiling (project HOPE) launched by the Shizuoka Cancer Center based on tumor tissue samples from 1,058 cancer patients...
September 12, 2016: Oncology Reports
Matthew Costa, Justin Pollara, Regina Whitney Edwards, Michael Seaman, Miroslaw K Gorny, David Montefiori, Hua-Xin Liao, Guido Ferrari, Shan Lu, Shixia Wang
: HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years' infection and, therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with ADCC activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities...
September 14, 2016: Journal of Virology
Shanshan Chen, Xuechun Li, Rongming Chen, Mingang Yin, Qiuhong Zheng
Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported...
September 2016: Oncology Letters
Aneta Schieferdecker, Ofer Shoshani, Benedikt Westner, Dov Zipori, Boris Fehse, Nicolaus Kröger, Francis Ayuk
INTRODUCTION: Multiple myeloma is still incurable in most cases. Polyclonal anti T lymphocyte globulins (ATG) have been reported to kill human myeloma cells in vitro and in mouse models. METHODS: Anti-human-myeloma globulins (AMG) were produced by immunizing rabbits with human myeloma cell lines RPMI-8226 (AMG-8226) or KMS-12-BM (AMG-12-BM). Cytotoxicity of the polyclonal antibodies was analyzed in vitro and in a xenograft NOD-SCID mouse model. RESULTS: Both AMG had stronger cytotoxicity against myeloma cells compared to ATG...
August 22, 2016: Oncotarget
Han Xiao, Elliot C Woods, Petar Vukojicic, Carolyn R Bertozzi
Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody-sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Swati Khanna, Anish Thomas, Daniel Abate-Daga, Jingli Zhang, Betsy Morrow, Seth M Steinberg, Augusto Orlandi, Patrizia Ferroni, Jeffrey Schlom, Fiorella Guadagni, Raffit Hassan
INTRODUCTION: The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. METHODS: Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry and its prognostic significance. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1(+) and PD-L1(+) infiltrating lymphocytes and their role in inducing tumor cell PD-L1 expression...
August 17, 2016: Journal of Thoracic Oncology
Elizabeth L McMichael, Alena C Jaime-Ramirez, Kristan D Guenterberg, Eric Luedke, Lakhvir S Atwal, Amanda Campbell, Zhiwei Hu, Armika S Tatum, Sri Vidya Kodadasula, Xiaokui Mo, Susheela Tridandapani, Mark Bloomston, E Christopher Ellison, Terence M Williams, Tanios Bekaii-Saab, William E Carson
PURPOSE: Alternative strategies to EGFR blockage by mAbs is necessary in order to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status...
July 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
S P Koerner, M C André, J S Leibold, P C Kousis, A Kübler, M Pal, S P Haen, H-J Bühring, L Grosse-Hovest, G Jung, H R Salih
Antibody-dependent cellular cytotoxicity (ADCC) of NK cells largely contributes to the success of mAb treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (ML), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against ML. When comparing different available CD133 mAb, no difference was observed with regard to binding to primary CML cells. However, clone 293C3 recognized AML cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wildtype Fc-part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE)...
July 20, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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