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Increasing ADCC

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https://www.readbyqxmd.com/read/28811973/nk-cell-dysfunction-in-chronic-lymphocytic-leukemia-is-associated-with-loss-of-the-mature-cells-expressing-inhibitory-killer-cell-ig-like-receptors
#1
Alexander W MacFarlane, Mowafaq Jillab, Mitchell R Smith, R Katherine Alpaugh, Marion E Cole, Samuel Litwin, Michael M Millenson, Tahseen Al-Saleem, Adam D Cohen, Kerry S Campbell
A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56(dim) NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death...
2017: Oncoimmunology
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
#2
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/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/28739115/a-recombinant-protein-of-salmonella-typhi-induces-humoral-and-cell-mediated-immune-responses-including-memory-responses
#4
Sayan Das, Rimi Chowdhury, Shubhamoy Ghosh, Santasabuj Das
Gram negative enteric bacteria, Salmonella enterica serovar Typhi (S. Typhi), the etiological agent of typhoid fever is a major public health problem in developing countries. While a permanent solution to the problem would require improved sanitation, food and water hygiene, controlling the infection by vaccination is urgently required due to the emergence of multidrug resistant strains in multiple countries. The currently licensed vaccines are moderately efficacious with limited applicability, and no recommended vaccines exist for younger children...
July 21, 2017: Vaccine
https://www.readbyqxmd.com/read/28727817/immunogenicity-of-a-novel-clade-b-hiv-1-vaccine-combination-results-of-phase-1-randomized-placebo-controlled-trial-of-an-hiv-1-gm-csf-expressing-dna-prime-with-a-modified-vaccinia-ankara-vaccine-boost-in-healthy-hiv-1-uninfected-adults
#5
Susan P Buchbinder, Nicole A Grunenberg, Brittany J Sanchez, Kelly E Seaton, Guido Ferrari, M Anthony Moody, Nicole Frahm, David C Montefiori, Christine M Hay, Paul A Goepfert, Lindsey R Baden, Harriet L Robinson, Xuesong Yu, Peter B Gilbert, M Juliana McElrath, Yunda Huang, Georgia D Tomaras
BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively...
2017: PloS One
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
#6
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/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/28674498/nimotuzumab-induces-nk-cell-activation-cytotoxicity-dendritic-cell-maturation-and-expansion-of-egfr-specific-t-cells-in-head-and-neck-cancer-patients
#8
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/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
#9
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-proteins-from-elite-controllers-sensitizes-hiv-1-infected-cells-to-antibody-dependent-cellular-cytotoxicity
#10
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...
August 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28605680/surrogate-cd16-expressing-effector-cell-lines-for-determining-the-bioactivity-of-therapeutic-monoclonal-antibodies
#11
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
https://www.readbyqxmd.com/read/28598823/preclinical-data-on-the-combination-of-cisplatin-and-anti-cd70-therapy-in-non-small-cell-lung-cancer-as-an-excellent-match-in-the-era-of-combination-therapy
#12
Julie Jacobs, Vanessa Deschoolmeester, Christian Rolfo, Karen Zwaenepoel, Jolien Van den Bossche, Christophe Deben, Karen Silence, Hans de Haard, Christophe Hermans, Sylvie Rottey, Christel Vangestel, Filip Lardon, Evelien Smits, Patrick Pauwels
In contrast to the negligible expression of the immunomodulating protein CD70 in normal tissue, we have demonstrated constitutive overexpression of CD70 on tumor cells in a subset of primary non-small cell lung cancer (NSCLC) biopsies. This can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Early clinical trials of these antibodies have already shown promising results in CD70-positive malignancies.In this study, we explored the potential of cisplatin to induce CD70 expression in NSCLC...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28593989/pentavalent-hiv-1-vaccine-protects-against-simian-human-immunodeficiency-virus-challenge
#13
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/28542350/t0001-a-variant-of-tnfr2-fc-fusion-protein-exhibits-improved-fc-effector-functions-through-increased-binding-to-membrane-bound-tnf%C3%AE
#14
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
https://www.readbyqxmd.com/read/28539449/anti-hiv-1-adcc-antibodies-following-latency-reversal-and-treatment-interruption
#15
Wen Shi Lee, Anne B Kristensen, Thomas A Rasmussen, Martin Tolstrup, Lars Østergaard, Ole S Søgaard, Bruce D Wines, P Mark Hogarth, Arnold Reynaldi, Miles P Davenport, Sean Emery, Janaki Amin, David A Cooper, Virginia L Kan, Julie Fox, Henning Gruell, Matthew S Parsons, Stephen J Kent
There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC...
August 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28515346/the-novel-complex-combination-of-alum-cpg-odn-and-hh2-as-adjuvant-in-cancer-vaccine-effectively-suppresses-tumor-growth-in-vivo
#16
Yaomei Tian, Meng Li, Chaoheng Yu, Rui Zhang, Xueyan Zhang, Rong Huang, Lian Lu, Fengjiao Yuan, Yingzi Fan, Bailing Zhou, Ke Men, Heng Xu, Li Yang
Single-component adjuvant is prone to eliciting a specific type of Th1 or Th2 response. So, the development of combinatorial adjuvants inducing a robust mixed Th1/Th2 response is a promising vaccination strategy against cancer. Here, we describe a novel combination of aluminum salts (alum), CpG oligodeoxynucleotide (CpG) and innate defense regulator peptide HH2 for improving anti-tumor immune responses. The CpG-HH2 complex significantly enhanced the production of IFN-γ, TNF-α and IL-1β, promoted the uptake of antigen and strengthened the activation of p38, Erk1/2 and NF-κB in vitro, compared to CpG or HH2 alone...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507812/a-barf1-specific-mab-as-a-new-immunotherapeutic-tool-for-the-management-of-ebv-related-tumors
#17
Riccardo Turrini, Anna Merlo, Debora Martorelli, Damiana Antonia Faè, Roberta Sommaggio, Isabella Monia Montagner, Vito Barbieri, Oriano Marin, Paola Zanovello, Riccardo Dolcetti, Antonio Rosato
The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28507799/characterization-of-a-human-anti-tumoral-nk-cell-population-expanded-after-bcg-treatment-of-leukocytes
#18
Eva M García-Cuesta, Gloria Esteso, Omodele Ashiru, Sheila López-Cobo, Mario Álvarez-Maestro, Ana Linares, Mei M Ho, Luis Martínez-Piñeiro, Hugh T Reyburn, Mar Valés-Gómez
Immunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28498953/pathological-role-of-anti-cd4-antibodies-in-hiv-infected-immunologic-nonresponders-receiving-virus-suppressive-antiretroviral-therapy
#19
Zhenwu Luo, Zhen Li, Lisa Martin, Zhuang Wan, Eric G Meissner, Enrique Espinosa, Hao Wu, Xiaocong Yu, Pingfu Fu, Maria Anna Julia Westerink, J Michael Kilby, Jennifer Wu, Lei Huang, Sonya L Heath, Zihai Li, Wei Jiang
Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/μL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/μL) and healthy controls...
July 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28490585/crosslinking-of-a-cd4-mimetic-miniprotein-with-hiv-1-env-gp140-alters-kinetics-and-specificities-of-antibody-responses-against-hiv-1-env-in-macaques
#20
Xiaoying Shen, Willy M Bogers, Nicole L Yates, Guido Ferrari, Antu K Dey, William T Williams, Frederick H Jaeger, Kevin Wiehe, Sheetal Sawant, S Munir Alam, Celia C LaBranche, David C Montefiori, Loic Martin, Indresh Srivastava, Jonathan Heeney, Susan W Barnett, Georgia D Tomaras
Evaluation of the epitope specificities, location (systemic, mucosal) and effector function of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitude, epitope specificity, avidity and function of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4 mimetic miniprotein (gp140-M64U1) in rhesus macaques. Crosslinking of gp140 Env with M64U1 resulted in an earlier increase in both the magnitude and avidity of the IgG binding response compared to Env protein alone...
May 10, 2017: Journal of Virology
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