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https://www.readbyqxmd.com/read/28802255/simultaneous-targeting-of-two-distinct-epitopes-on-met-effectively-inhibits-met-and-hgf-driven-tumor-growth-by-multiple-mechanisms
#1
Michael M Grandal, Serhiy Havrylov, Thomas Tuxen Poulsen, Klaus Koefoed, Anna Dahlman, Gunther R Galler, Paolo Conrotto, Sara Collins, Karsten W Eriksen, Dafna Kaufman, George F Vande Woude, Helle J Jacobsen, Ivan D Horak, Michael Kragh, Johan Lantto, Thomas Bouquin, Morag Park, Mikkel Wandahl Pedersen
Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against non-overlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo Sym015 was found to exert its activity via multiple mechanisms...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28794022/potent-in-vivo-nk-cell-mediated-elimination-of-hiv-1-infected-cells-mobilized-by-a-gp120-bispecific-and-hexavalent-broadly-neutralizing-fusion-protein
#2
Ariola Bardhi, Yanling Wu, Weizao Chen, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C Kappes, Dimiter S Dimitrov, Tianlei Ying, Harris Goldstein
Antibodies bound to HIV-1 envelope protein expressed by infected cells mobilize antibody dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to functional HIV-1 cure...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28790065/gsk-3-inhibition-drives-maturation-of-nk-cells-and-enhances-their-antitumor-activity
#3
Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey K Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart E Abbot, Daniel Shoemaker, Yenan T Bryceson, Bruce R Blazar, Scott Wolchko, Sarah Cooley, Jeffrey S Miller
Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57(+) NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation...
August 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28778085/investigation-of-factors-affecting-the-efficacy-of-3c23k-a-human-monoclonal-antibody-targeting-misiir
#4
Sarah E Gill, Qing Zhang, Gary L Keeney, William A Cliby, S John Weroha
MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28771513/a-modified-vaccinia-ankara-vaccine-vector-expressing-a-mosaic-h5-hemagglutinin-reduces-viral-shedding-in-rhesus-macaques
#5
Nicholas W Florek, Attapon Kamlangdee, James P Mutschler, Brock Kingstad-Bakke, Nancy Schultz-Darken, Karl W Broman, Jorge E Osorio, Thomas C Friedrich
The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a "mosaic" hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus...
2017: PloS One
https://www.readbyqxmd.com/read/28762488/a-real-time-cytotoxicity-assay-as-an-alternative-to-the-standard-chromium-51-release-assay-for-measurement-of-human-nk-and-t-cell-cytotoxic-activity
#6
Julien Fassy, Kyriaki Tsalkitzi, Maria Goncalves-Maia, Véronique M Braud
This unit describes the monitoring and quantification of cellular cytotoxicity using a non-radioactive and real-time cytotoxic assay. The extent of target-cell lysis is monitored over time by imaging and quantifying live fluorescent target cells using a cell-imaging multimode reader. This assay is performed in a 96 well plate in optimized culture conditions at 37°C in the presence of 5% CO2 . The basic protocol describes natural killer cell-mediated cytotoxic assay that can be adapted to include antibodies blocking inhibitory NK receptors or triggering antibody-dependent cell-mediated cytotoxicity (ADCC)...
August 1, 2017: Current Protocols in Immunology
https://www.readbyqxmd.com/read/28710915/potent-therapeutic-activity-against-peritoneal-dissemination-and-malignant-ascites-by-the-novel-anti-folate-receptor-alpha-antibody-khk2805
#7
Munetoshi Ando, Keiko Nagata, Kaito Nihira, Yui Suzuki, Yutaka Kanda, Maiko Adachi, Tsuguo Kubota, Naoya Kameyama, Mariko Nakano, Hiroshi Ando, Kazuya Yamano, Toshihiko Ishii, Ryuichiro Nakai, Kazuyasu Nakamura
Many ovarian cancer patients often show peritoneal metastasis with malignant ascites. However, unmet medical needs remain regarding controlling these symptoms after tumors become resistant to chemotherapies. We developed KHK2805, a novel anti-folate receptor α (FOLR1) humanized antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The primary aim of the present study was to evaluate whether the anti-tumor activity of KHK2805 was sufficient for therapeutic application against peritoneal dissemination and malignant ascites of platinum-resistant ovarian cancer in preclinical models...
July 11, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28701403/monoclonal-antibodies-derived-from-humans-vaccinated-with-the-rv144-hiv-vaccine-containing-the-hvem-binding-domain-of-herpes-simplex-virus-hsv-glycoprotein-d-neutralize-hsv-infection-mediate-adcc-and-protect-mice-from-ocular-challenge-with-hsv-1
#8
Kening Wang, Georgia D Tomaras, Sinthujan Jegaskanda, M Anthony Moody, Hua-Xin Liao, Kyle Goodman, Phillip W Berman, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Barton F Haynes, Jeffrey I Cohen
The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus (HSV-1) glycoprotein D (gD), such that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection as well as antibodies to HSV...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28679958/fc-functional-antibodies-in-humans-with-severe-h7n9-and-seasonal-influenza
#9
Hillary A Vanderven, Lu Liu, Fernanda Ana-Sosa-Batiz, Thi Ho Nguyen, Yanmin Wan, Bruce Wines, P Mark Hogarth, Danielle Tilmanis, Arnold Reynaldi, Matthew S Parsons, Aeron C Hurt, Miles P Davenport, Tom Kotsimbos, Allen C Cheng, Katherine Kedzierska, Xiaoyan Zhang, Jianqing Xu, Stephen J Kent
BACKGROUND: Both seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection. METHODS: Serum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16)...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28679766/sym015-a-highly-efficacious-antibody-mixture-against-met-amplified-tumors
#10
Thomas Tuxen Poulsen, Michael M Grandal, Niels Jørgen Ø Skartved, Rikke Hald, Lene Alifrangis, Klaus Koefoed, Trine Lindsted, Camilla Fröhlich, Sofie Ellebæk Pollmann, Karsten W Eriksen, Anna Dahlman, Helle J Jacobsen, Thomas Bouquin, Mikkel Wandahl Pedersen, Ivan D Horak, Johan Lantto, Michael Kragh
<span style="text-decoration: underline;">Purpose:</span> Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized monoclonal antibodies directed against non-overlapping epitopes of MET. <p><span style="text-decoration: underline;">Experimental Design/Results:</span> We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28674297/characterization-of-therapeutic-monoclonal-antibodies-by-using-fc%C3%AE-r-expressing-reporter-cell-lines
#11
Minoru Tada, Akiko Ishii-Watabe
 Fcγ receptors (FcγRs), which bind to the Fc regions of antibodies, play an important role in antibody effector functions. In humans, there are four types of activating FcγRs: FcγRI, FcγRIIa, FcγRIIIa, and FcγRIIIb. These are expressed on various effector cells such as natural killer (NK) cells, neutrophils and macrophages. FcγRIIIa expressed on NK cells is known to play a pivotal role in antibody-dependent cellular cytotoxicity (ADCC) by therapeutic monoclonal antibodies (mAbs). To assess the ADCC activity of mAbs, the killing of target cells is often measured using human peripheral mononuclear blood cells (hPBMCs) or isolated primary NK cells as effector cells...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28664668/human-papillomavirus-related-carcinoma-with-adenoid-cystic-like-features-a-series-of-5-cases-expanding-the-pathologic-spectrum
#12
Jen-Fan Hang, Min-Shu Hsieh, Wing-Yin Li, Jo-Yu Chen, Shih-Yao Lin, Shih-Hao Liu, Chin-Chen Pan, Ying-Ju Kuo
AIMS: Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype, and molecular testing to identify potentially helpful features in distinguishing it from classical adenoid cystic carcinoma (AdCC). METHODS AND RESULTS: We retrospectively collected 5 HPV-related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract...
June 30, 2017: Histopathology
https://www.readbyqxmd.com/read/28624584/antibody-dependent-nk-cell-degranulation-as-a-marker-for-assessing-antibody-dependent-cytotoxicity-against-pandemic-2009-influenza-a-h1n1-infection-in-human-plasma-and-influenza-vaccinated-transchromosomic-bovine-intravenous-immunoglobulin-therapy
#13
Brian J Morrison, Jessica A Roman, Thomas C Luke, Nishith Nagabhushana, Kanakatte Raviprakash, Maya Williams, Peifang Sun
This study describes an antibody-dependent NK cell degranulation assay, as a biomarker to assess antibody-dependent cellular cytotoxicity (ADCC) response in influenza plasma and for antibody therapies against influenza infection. The concentration of neutralizing antibodies (NAbs) against the hemagglutinin receptor of influenza viruses is a current determinant in protection against infection, particularly following receipt of the seasonal influenza vaccine. However, this is a limited assessment of protection, because: (i) NAb titers that incur full protection vary; and (ii) NAb titers do not account for the entire breadth of antibody responses against viral infection...
June 15, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28623459/blockade-of-cd112r-and-tigit-signaling-sensitizes-human-natural-killer-cell-functions
#14
Feng Xu, Alexander Sunderland, Yue Zhou, Richard D Schulick, Barish H Edil, Yuwen Zhu
Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity...
June 16, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28593989/pentavalent-hiv-1-vaccine-protects-against-simian-human-immunodeficiency-virus-challenge
#15
Todd Bradley, Justin Pollara, Sampa Santra, Nathan Vandergrift, Srivamshi Pittala, Chris Bailey-Kellogg, Xiaoying Shen, Robert Parks, Derrick Goodman, Amanda Eaton, Harikrishnan Balachandran, Linh V Mach, Kevin O Saunders, Joshua A Weiner, Richard Scearce, Laura L Sutherland, Sanjay Phogat, Jim Tartaglia, Steven G Reed, Shiu-Lok Hu, James F Theis, Abraham Pinter, David C Montefiori, Thomas B Kepler, Kristina K Peachman, Mangala Rao, Nelson L Michael, Todd J Suscovich, Galit Alter, Margaret E Ackerman, M Anthony Moody, Hua-Xin Liao, Georgia Tomaras, Guido Ferrari, Bette T Korber, Barton F Haynes
The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian-human immunodeficiency virus (SHIV) challenge...
June 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28592534/comprehensive-cross-clade-characterization-of-antibody-mediated-recognition-complement-mediated-lysis-and-cell-mediated-cytotoxicity-of-hiv-1-envelope-specific-antibodies-toward-eradication-of-the-hiv-1-reservoir
#16
Shariq Mujib, Jun Liu, A K M Nur-Ur Rahman, Jordan A Schwartz, Phil Bonner, Feng Yun Yue, Mario A Ostrowski
Immunotherapy with passive administration of broadly neutralizing HIV-1 envelope-specific antibodies (bnAbs) in the setting of established infection in vivo has yielded mixed results. The contribution of different antibodies toward the direct elimination of infected cells is poorly understood. In this study, we determined the ability of 12 well-characterized anti-HIV-1 neutralizing antibodies to recognize and eliminate primary CD4 T cells infected with HIV-1 belonging to clades A, B, C, and D, via antibody-dependent complement-mediated lysis (ADCML) and antibody-dependent cell-mediated cytotoxicity (ADCC), in vitro We further tested unique combinations of these antibodies to determine the optimal antibody cocktails to be tested in future clinical trials...
August 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28576848/identification-of-fc-gamma-receptor-glycoforms-that-produce-differential-binding-kinetics-for-rituximab
#17
Jerrard M Hayes, Asa Frostell, Robert Karlsson, Steffen Müller, Silvia Millan-Martin, Martin Pauers, Franziska Reuss, Eoin Cosgrave, Cecilia Anneren, Gavin P Davey, Pauline M Rudd
Fc gamma receptors (FcyR) bind the Fc region of antibodies and therefore play a prominent role in antibody-dependent cell-based immune responses such as ADCC, CDC and ADCP. The immune effector cell activity is directly linked to a productive molecular engagement of FcyRs where both the protein and glycan moiety of antibody and receptor can affect the interaction and in the present study we focus on the role of the FcyR glycans in this interaction. We provide a complete description of the glycan composition of Chinese hamster ovary (CHO) expressed human Fcy receptors RI (CD64), RIIa Arg131/His131 (CD32a), RIIb (CD32b) and RIIIa Phe158/Val158 (CD16a) and analyze the role of the glycans in the binding mechanism with IgG...
June 2, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28574482/immunologic-and-virologic-mechanisms-for-partial-protection-from-intravenous-challenge-by-an-integration-defective-siv-vaccine
#18
Chu Wang, Chunlai Jiang, Nan Gao, Kaikai Zhang, Donglai Liu, Wei Wang, Zhe Cong, Chuan Qin, Vitaly V Ganusov, Guido Ferrari, Celia LaBranche, David C Montefiori, Wei Kong, Xianghui Yu, Feng Gao
The suppression of viral loads and identification of selection signatures in non-human primates after challenge are indicators for effective human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccines. To mimic the protective immunity elicited by attenuated SIV vaccines, we developed an integration-defective SIV (idSIV) vaccine by inactivating integrase, mutating sequence motifs critical for integration, and inserting the cytomegalovirus (CMV) promoter for more efficient expression in the SIVmac239 genome...
June 2, 2017: Viruses
https://www.readbyqxmd.com/read/28542406/human-igg3-with-extended-half-life-does-not-improve-fc-gamma-receptor-mediated-cancer-antibody-therapies-in-mice
#19
Rens Braster, Simran Grewal, Remco Visser, Helga K Einarsdottir, Marjolein van Egmond, Gestur Vidarsson, Marijn Bögels
BACKGROUND: Current anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models...
2017: PloS One
https://www.readbyqxmd.com/read/28542350/t0001-a-variant-of-tnfr2-fc-fusion-protein-exhibits-improved-fc-effector-functions-through-increased-binding-to-membrane-bound-tnf%C3%AE
#20
Yijun Shen, Gang Li, Chunying Gu, Ben Chen, Aihua Chen, Hua Li, Bei Gao, Chencai Liang, Jingsong Wu, Tong Yang, Li Jin, Yong Su
T0001 is a recombinant human TNFR-Fc fusion protein mutant; it exhibits higher affinity to TNFα than etanercept and is now being tested in a Phase 1 study in China (ClinicalTrials.gov Identifier: NCT02481180). T0001 can inhibit the binding of soluble TNFα (sTNFα) or membrane-bound TNFα (mTNFα) to TNF receptors. When bound to mTNFα, the Fc-bearing TNFα antagonists have the potential to induce Fc-mediated effects, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) as well as outside-to-inside signals (apoptosis mainly)...
2017: PloS One
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