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Antibody dependent cellular cytotoxicity

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https://www.readbyqxmd.com/read/28723675/tumor-antigen-ca125-suppresses-antibody-dependent-cellular-cytotoxicity-adcc-via-direct-antibody-binding-and-suppressed-fc-%C3%AE-receptor-engagement
#1
J Bradford Kline, Rina P Kennedy, Earl Albone, Qimin Chao, Shawn Fernando, Jennifer M McDonough, Katherine Rybinski, Wenquan Wang, Elizabeth B Somers, Charles Schweizer, Luigi Grasso, Nicholas C Nicolaides
Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28710915/potent-therapeutic-activity-against-peritoneal-dissemination-and-malignant-ascites-by-the-novel-anti-folate-receptor-alpha-antibody-khk2805
#2
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
#3
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/28701402/increased-durable-b-cell-and-adcc-responses-associated-with-t-helper-responses-to-hiv-1-envelope-in-macaques-vaccinated-with-gp140-occluded-at-the-cd4-receptor-binding-site
#4
Willy M J M Bogers, Susan W Barnett, Herman Oostermeijer, Ivonne G Nieuwenhuis, Niels Beenhakker, Daniella Mortier, Petra Mooij, Gerrit Koopman, Edmund Remarque, Gregoire Martin, Rachel Pei-Jen Lai, Antu K Dey, Yide Sun, Brian Burke, Guido Ferrari, David Montefiori, Loic Martin, David Davis, Indresh Srivastava, Jonathan L Heeney
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens for more long lived, efficacious HIV-1 vaccine induced B-cell responses. HIV-1 Env gp140 (native or un-cleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells may result in anergic effects on T-cell recruitment and consequently a lack of strong robust and durable B-memory responses. To test this hypothesis we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3kD CD4 miniprotein mimetic serving to block ligation of gp140 on CD4+T-cells while preserving CD4 inducible (CDi) neutralizing and epitopes targeted by antibody dependent cellular cytotoxic (ADCC) effector responses...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28701393/hiv-1-env-and-vpu-specific-antibody-dependent-cellular-cytotoxicity-responses-associated-with-elite-control-of-hiv
#5
Vijaya Madhavi, Bruce D Wines, Janaki Amin, Sean Emery, Ester Lopez, Anthony Kelleher, Rob J Center, P Mark Hogarth, Amy W Chung, Stephen J Kent, Ivan Stratov
Studying HIV-infected individuals who control HIV replication (elite controllers, ECs) enable exploration of effective anti-HIV immunity. HIV Env- and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env- and Vpu-specific ADCC responses were studied in sera using a novel ELISA-based dimeric recombinant soluble (rs) FcγRIIIa-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays and ADCC-mediated killing assays...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28699800/towards-the-improvement-in-stability-of-an-anti-a%C3%AE-single-chain-variable-fragment-scfv-h3d6-as-a-way-to-enhance-its-therapeutic-potential
#6
Laia Montoliu-Gaya, Javier Murciano-Calles, Jose C Martinez, Sandra Villegas
ScFv-h3D6 is a single-chain variable fragment derived from the monoclonal antibody bapineuzumab that prevents Aβ-induced cytotoxicity by capturing Aβ oligomers. The benefits of scFv-h3D6 treatment in Alzheimer's disease are known at the behavioural, cellular and molecular levels in the 3xTg-AD mouse model. Antibody-based therapeutics are only stable in a limited temperature range, so their benefit in vivo depends on their capability for maintaining the proper fold. Here, we have stabilized the scFv-h3D6 folding by introducing the mutation VH-K64R and combining it with the previously described elongation of the VL domain (C3)...
July 12, 2017: Amyloid: the International Journal of Experimental and Clinical Investigation
https://www.readbyqxmd.com/read/28679958/fc-functional-antibodies-in-humans-with-severe-h7n9-and-seasonal-influenza
#7
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/28679774/syd985-a-novel-duocarmycin-based-her2-targeting-antibody-drug-conjugate-shows-antitumor-activity-in-uterine-and-ovarian-carcinosarcoma-with-her2-neu-expression
#8
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan D Black, Federica Predolini, Francesca Pettinella, Alice Masserdotti, Luca Zammataro, Gary Altwerger, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
Purpose: Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985, (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to Trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS. <p>Experimental Design: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28679766/sym015-a-highly-efficacious-antibody-mixture-against-met-amplified-tumors
#9
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/28674498/nimotuzumab-induces-nk-cell-activation-cytotoxicity-dendritic-cell-maturation-and-expansion-of-egfr-specific-t-cells-in-head-and-neck-cancer-patients
#10
Zaima Mazorra, Anabel Lavastida, Fernando Concha-Benavente, Anet Valdés, Raghvendra M Srivastava, Tatiana M García-Bates, Esperanza Hechavarría, Zuyen González, Amnely González, Martha Lugiollo, Iván Cuevas, Carlos Frómeta, Braulio F Mestre, Maria C Barroso, Tania Crombet, Robert L Ferris
Survival benefit and long-term duration of clinical response have been seen using the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody (mAb) nimotuzumab. Blocking EGFR signaling may not be the only mechanism of action underlying its efficacy. As an IgG1 isotype mAb, nimotuzumab's capacity of killing tumor cells by antibody dependent cellular cytotoxicity (ADCC) and to induce an immune response in cancer patients have not been studied. ADCC-induced by nimotuzumab was determined using a (51)Cr release assay...
2017: Frontiers in Pharmacology
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/28630095/antibody-dependent-nk-cell-activation-differentially-targets-ebv-infected-cells-in-lytic-cycle-and-bystander-b-lymphocytes-bound-to-viral-antigen-containing-particles
#12
María López-Montañés, Elisenda Alari-Pahissa, Jordi Sintes, José E Martínez-Rodríguez, Aura Muntasell, Miguel López-Botet
NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV(+) individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation...
June 19, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28628770/a-comparative-analysis-between-proteasome-and-immunoproteasome-inhibition-in-cellular-and-humoral-alloimmunity
#13
Theodoros Eleftheriadis, Georgios Pissas, Georgia Antoniadi, Vassilios Liakopoulos, Ioannis Stefanidis
Triggered by the successful administration of the proteasome inhibitor bortezomib in kidney transplant recipients with acute or chronic antibody-mediated rejection, we evaluated the effect of the proteasome inhibitor CEP-18770 and of the selective immunoproteasome inhibitor ONX-0914 on cellular and humoral alloimmunity. Cellular alloimmunity was assessed by cell proliferation in a two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method, where humoral alloimmunity was induced in one-way MLR...
June 16, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28628042/a-therapeutic-t-cell-receptor-mimic-antibody-targets-tumor-associated-prame-peptide-hla-i-antigens
#14
Aaron Y Chang, Tao Dao, Ron S Gejman, Casey A Jarvis, Andrew Scott, Leonid Dubrovsky, Melissa D Mathias, Tatyana Korontsvit, Victoriya Zakhaleva, Michael Curcio, Ronald C Hendrickson, Cheng Liu, David A Scheinberg
Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive cancer target. PRAME is an intracellular protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells...
June 30, 2017: Journal of Clinical Investigation
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
#15
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
#16
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/28618063/papillary-thyroid-carcinoma-expressing-cd20
#17
Yuya Sasaki, Masao Seto, Hiroaki Miyoshi, Shinya Okada, Shintaro Yokoyama, Akira Ohshima, Koichi Ohshima
We identified a case of lymphadenopathy of metastatic papillary thyroid carcinoma (PTC) with CD20 expression, which was also expressed by the primary tumor. CD20 expression was identified using immunohistochemistry (IHC) in metastatic PTC biopsy samples from a 58-year-old woman. CD20 expression was initially determined using a CD20-recognizing L26 clone. To validate this phenomenon, we performed IHC with another antibody that recognizes the N-terminus of CD20 and fluorescent double staining using anti-TTF-1 and anti-CD20 antibodies...
June 15, 2017: Pathology International
https://www.readbyqxmd.com/read/28615419/dimeric-fc%C3%AE-receptor-enzyme-linked-immunosorbent-assay-to-study-hiv-specific-antibodies-a-new-look-into-breadth-of-fc%C3%AE-receptor-antibodies-induced-by-the-rv144-vaccine-trial
#18
Milla R McLean, Vijaya Madhavi, Bruce D Wines, P Mark Hogarth, Amy W Chung, Stephen J Kent
Ab-dependent cellular cytotoxicity (ADCC) responses are of growing interest in the HIV vaccine field but current cell-based assays are usually difficult to reproduce across laboratories. We developed an ELISA and multiplex assay to model the cross-linking of Fcγ receptors (FcγR) by Abs, which is required to initiate an ADCC response. Our FcγR dimer ELISA readily detected Abs in samples from two separate cohorts of the partially efficacious Thai RV144 HIV vaccine efficacy trial. The FcγR dimer-binding Abs induced by the RV144 regimen correlated well with a functional measure of ADCC as well as IgG subclasses...
June 14, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28615199/impaired-downregulation-of-nkg2d-ligands-by-nef-protein-from-elite-controllers-sensitizes-hiv-1-infected-cells-to-adcc
#19
Nirmin Alsahafi, Jonathan Richard, Jérémie Prévost, Mathieu Coutu, Nathalie Brassard, Matthew S Parsons, Daniel E Kaufmann, Mark Brockman, Andrés Finzi
HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4+ T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors...
June 14, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28605680/surrogate-cd16-expressing-effector-cell-lines-for-determining-the-bioactivity-of-therapeutic-monoclonal-antibodies
#20
Shalom A Gurjar, Jeremy P Derrick, Rebecca J Dearman, Robin Thorpe, Simon Hufton, Ian Kimber, Meenu Wadhwa
Traditional antibody dependent cellular cytotoxicity (ADCC) assays use donor derived natural killer (NK) or peripheral blood mononuclear cells, but donor genetic variability and the technically challenging nature of the assay means that alternative in vitro assay formats are required. We explored the utility of two reporter gene cell lines, the J2 and J9, as surrogate effector cells for ADCC assays. Both express the ADCC relevant Fcγ receptor CD16, crosslinking of which leads to firefly luciferase expression...
September 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
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