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https://www.readbyqxmd.com/read/29113954/an-improved-method-to-quantify-human-nk-cell-mediated-antibody-dependent-cell-mediated-cytotoxicity-adcc-per-igg-fcr-positive-nk-cell-without-purification-of-nk-cells
#1
Alexander P Sung, Jennifer J-J Tang, Michael J Guglielmo, Doug Redelman, Julie Smith-Gagen, Lucinda Bateman, Dorothy Hudig
Natural killer (NK) lymphocyte ADCC supports anti-viral protection and monoclonal antibody (mAb) anti-tumor therapies. To predict in vivo ADCC therapeutic responses of different individuals, measurement of both ADCC cellular lytic capacity and their NK cellular receptor recognition of antibodies on 'target' cells are needed, using clinically available amounts of blood. Twenty ml of blood provides sufficient peripheral blood mononuclear cells (PBMCs) for the new assay for lytic capacity described here and for an antibody EC50 assay for Fc-receptor recognition...
November 4, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/29104875/a-novel-system-for-the-quantification-of-the-adcc-activity-of-therapeutic-antibodies
#2
Christophe Lallemand, Feifei Liang, Flore Staub, Maud Simansour, Benoit Vallette, Lue Huang, Rosa Ferrando-Miguel, Michael G Tovey
Novel ADCC effector cells expressing the V-variant or F-variant of FcγRIIIa (CD16a) and firefly luciferase under the control of a chimeric promoter incorporating recognition sequences for the principal transcription factors involved in FcγRIIIa signal transduction, together with novel target cells overexpressing a constant high level of the specific antigen recognized by rituximab, trastuzumab, cetuximab, infliximab, adalimumab, or etanercept, confer improved sensitivity, specificity, and dynamic range in an ADCC assay relative to effector cells expressing a NFAT-regulated reporter gene and wild-type target cells...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/29100408/a-novel-fc-engineered-human-icam-1-cd54-antibody-with-potent-anti-myeloma-activity-developed-by-cellular-panning-of-phage-display-libraries
#3
Katja Klausz, Michael Cieker, Christian Kellner, Hans-Heinrich Oberg, Dieter Kabelitz, Thomas Valerius, Renate Burger, Martin Gramatzki, Matthias Peipp
To identify antibodies suitable for multiple myeloma (MM) immunotherapy, a cellular screening approach was developed using plasma cell lines JK-6L and INA-6 and human synthetic single-chain fragment variable (scFv) phage libraries. Isolated phage antibodies were screened for myeloma cell surface reactivity. Due to its binding characteristics, phage PIII-15 was selected to generate the scFv-Fc fusion protein TP15-Fc with an Fc domain optimized for FcγRIIIa binding. Various MM cell lines and patient-derived CD138-positive malignant plasma cells, but not granulocytes, B or T lymphocytes from healthy donors were recognized by TP15-Fc...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29067686/association-between-gm-hla-and-killer-immunoglobulin-like-receptors-and-the-natural-course-of-hcmv-infection-a-pilot-study-performed-in-sicilian-population
#4
Danilo Di Bona, Giulia Accardi, Anna Aiello, Massimo Bilancia, Giuseppina Candore, Claudia Colomba, Calogero Caruso, Giovanni Duro, Caterina M Gambino, Luigi Macchia, Janardan P Pandey
Natural killer (NK) cells provide a major defence against cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. Also GM allotypes, able to influence the NK antibody-dependent cell-mediated cytotoxicity (ADCC), appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA...
October 25, 2017: Immunology
https://www.readbyqxmd.com/read/29056481/targeting-the-late-stage-of-hiv-1-entry-for-antibody-dependent-cellular-cytotoxicity-structural-basis-for-env-epitopes-in-the-c11-region
#5
William D Tolbert, Neelakshi Gohain, Nirmin Alsahafi, Verna Van, Chiara Orlandi, Shilei Ding, Loïc Martin, Andrés Finzi, George K Lewis, Krishanu Ray, Marzena Pazgier
Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal "eighth strand" of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment...
November 7, 2017: Structure
https://www.readbyqxmd.com/read/29046448/in-vitro-neutralization-is-not-predictive-of-prophylactic-efficacy-of-broadly-neutralizing-monoclonal-antibodies-cr6261-and-cr9114-against-lethal-h2-influenza-virus-challenge-in-mice
#6
Troy C Sutton, Elaine W Lamirande, Kevin W Bock, Ian N Moore, Wouter Koudstaal, Muniza Rehman, Gerrit Jan Weverling, Jaap Goudsmit, Kanta Subbarao
Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, anti-viral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1, and H1N1, H3N2, and influenza B viruses, respectively...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29041009/fcgr2a-and-fcgr3a-genotypes-correlate-with-farletuzumab-response-in-patients-with-first-relapsed-ovarian-cancer-exhibiting-low-ca125
#7
Wenquan Wang, Elizabeth B Somers, Erin N Ross, J Bradford Kline, Daniel J O'Shannessy, Charles Schweizer, Susan Weil, Luigi Grasso, Nicholas C Nicolaides
Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha and elicits an anti-tumor response via immune effector activity. Recent studies from a global phase 3 trial in ovarian cancer patients treated with carboplatin/taxane plus farletuzumab found that the tumor-produced CA125 protein can suppress farletuzumab function via perturbing its engagement to the activating Fc-γ receptors CD32a (FCGR2A) and CD16a (FCGR3A). Previous reports have indicated that naturally occurring polymorphisms in both of these receptors may play a role in their ability to engage therapeutic antibodies and elicit an optimal immune response via antibody-dependent cellular cytotoxicity (ADCC)...
October 18, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29021394/hiv-1-gp120-protein-and-mvagp140-boost-immunogens-increase-immunogenicity-of-a-dna-mva-hiv-1-vaccine
#8
Xiaoying Shen, Rahul Basu, Sheetal Sawant, David Beaumont, Sue Fen Kwa, Celia LaBranche, Kelly E Seaton, Nicole L Yates, David C Montefiori, Guido Ferrari, Linda S Wyatt, Bernard Moss, S Munir Alam, Barton F Haynes, Georgia D Tomaras, Harriet L Robinson
An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia Ankara (MVA) expressing HIV-1 Env on virus like particles. Here we evaluated whether the addition of a gp120 protein in alum or MVA expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime - MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26 and 40...
October 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28983766/hersintuzumab-a-novel-humanized-anti-her2-monoclonal-antibody-induces-potent-tumor-growth-inhibition
#9
Mohammad Mehdi Amiri, Forough Golsaz-Shirazi, Tahereh Soltantoyeh, Reza Hosseini-Ghatar, Tannaz Bahadori, Jalal Khoshnoodi, Shadi Sadat Navabi, Samira Farid, Mohammad Hossein Karimi-Jafari, Mahmood Jeddi-Tehrani, Fazel Shokri
Humanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells...
October 6, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28982260/immunization-with-clinical-hiv-1-env-proteins-induces-broad-antibody-dependent-cellular-cytotoxicity-mediating-antibodies-in-a-rabbit-vaccination-model
#10
Ingrid Karlsson, Marie Borggren, Sanne Skov Jensen, Leo Heyndrickx, Guillaume Stewart-Jones, Gabriella Scarlatti, Anders Fomsgaard
The induction of both neutralizing antibodies and non-neutralizing antibodies with effector functions, for example, antibody-dependent cellular cytotoxicity (ADCC), is desired in the search for effective vaccines against HIV-1. In the pursuit of novel immunogens capable of inducing an efficient antibody response, rabbits were immunized with selected antigens using different prime-boost strategies. We immunized 35 different groups of rabbits with Env antigens from clinical HIV-1 subtypes A and B, including immunization with DNA alone, protein alone, and DNA prime with protein boost...
November 17, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28959256/functionally-active-fc-mutant-antibodies-recognizing-cancer-antigens-generated-rapidly-at-high-yields
#11
Kristina M Ilieva, Judit Fazekas-Singer, Daniela Y Achkova, Tihomir S Dodev, Silvia Mele, Silvia Crescioli, Heather J Bax, Anthony Cheung, Panagiotis Karagiannis, Isabel Correa, Mariangela Figini, Rebecca Marlow, Debra H Josephs, Andrew J Beavil, John Maher, James F Spicer, Erika Jensen-Jarolim, Andrew N Tutt, Sophia N Karagiannis
Monoclonal antibodies find broad application as therapy for various types of cancer by employing multiple mechanisms of action against tumors. Manipulating the Fc-mediated functions of antibodies that engage immune effector cells, such as NK cells, represents a strategy to influence effector cell activation and to enhance antibody potency and potentially efficacy. We developed a novel approach to generate and ascertain the functional attributes of Fc mutant monoclonal antibodies. This entailed coupling single expression vector (pVitro1) antibody cloning, using polymerase incomplete primer extension (PIPE) polymerase chain reaction, together with simultaneous Fc region point mutagenesis and high yield transient expression in human mammalian cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28952147/genetic-variation-of-human-neutrophil-fc%C3%AE-receptors-and-sirp%C3%AE-in-antibody-dependent-cellular-cytotoxicity-towards-cancer-cells
#12
Louise W Treffers, Xi Wen Zhao, Joris van der Heijden, Sietse Q Nagelkerke, Dieke J van Rees, Patricia Gonzalez, Judy Geissler, Paul Verkuijlen, Michel van Houdt, Martin de Boer, Taco W Kuijpers, Timo K van den Berg, Hanke L Matlung
The efficacy of cancer therapeutic antibodies varies considerably among patients. Anti-cancer antibodies act through different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) triggered via Fcγ receptors (FcγR). This phagocyte ADCC can be promoted by interference with CD47-SIRPα interactions, but the magnitude of this enhancement also varies among individuals. Both FcγR and SIRPα display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC...
September 27, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28932638/the-anti-slamf7-antibody-elotuzumab-mediates-nk-cell-activation-through-both-cd16-dependent-and-independent-mechanisms
#13
Tatiana Pazina, Ashley M James, Alexander W MacFarlane, Natalie A Bezman, Karla A Henning, Christine Bee, Robert F Graziano, Michael D Robbins, Adam D Cohen, Kerry S Campbell
Elotuzumab is a humanized therapeutic monoclonal antibody directed to the surface glycoprotein SLAMF7 (CS1, CRACC, CD319), which is highly expressed on multiple myeloma (MM) tumor cells. Improved clinical outcomes have been observed following treatment of MM patients with elotuzumab in combination with lenalidomide or bortezomib. Previous work showed that elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), via Fc-domain engagement with FcγRIIIa (CD16). SLAMF7 is also expressed on NK cells, where it can transmit stimulatory signals...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28928627/a-novel-truncation-mutation-in-crybb1-associated-with-autosomal-dominant-congenital-cataract-with-nystagmus
#14
Yan Rao, Sufang Dong, Zuhua Li, Guohua Yang, Chunyan Peng, Ming Yan, Fang Zheng
PURPOSE: To identify the potential candidate genes for a large Chinese family with autosomal dominant congenital cataract (ADCC) and nystagmus, and investigate the possible molecular mechanism underlying the role of the candidate genes in cataractogenesis. METHODS: We combined the linkage analysis and direct sequencing for the candidate genes in the linkage regions to identify the causative mutation. The molecular and bio-functional properties of the proteins encoded by the candidate genes was further explored with biophysical and biochemical studies of the recombinant wild-type and mutant proteins...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28928215/influenza-virus-hemagglutinin-stalk-specific-antibodies-in-human-serum-are-a-surrogate-marker-for-in-vivo-protection-in-a-serum-transfer-mouse-challenge-model
#15
Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A Brokstad, Rebecca J Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant, it has been shown that hemagglutination inhibition titers do not always accurately predict protection from disease. In addition, several novel influenza virus vaccines that are currently under development do not target the hemagglutinin head domain, but rather more conserved sites, including the hemagglutinin stalk...
September 19, 2017: MBio
https://www.readbyqxmd.com/read/28883824/natural-killer-nk-cell-education-differentially-influences-hiv-antibody-dependent-nk-cell-activation-and-antibody-dependent-cellular-cytotoxicity
#16
REVIEW
Nicole F Bernard, Zahra Kiani, Alexandra Tremblay-McLean, Sanket A Kant, Christopher E Leeks, Franck P Dupuy
Immunotherapy using broadly neutralizing antibodies (bNAbs) endowed with Fc-mediated effector functions has been shown to be critical for protecting or controlling viral replication in animal models. In human, the RV144 Thai trial was the first trial to demonstrate a significant protection against HIV infection following vaccination. Analysis of the correlates of immune protection in this trial identified an association between the presence of antibody-dependent cellular cytotoxicity (ADCC) mediated by immunoglobulin G (IgG) antibodies (Abs) to HIV envelope (Env) V1/V2 loop structures and protection from infection, provided IgA Abs with competing specificity were not present...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28881644/engineering-a-high-affinity-humanized-anti-cd24-antibody-to-target-hepatocellular-carcinoma-by-a-novel-cdr-grafting-design
#17
Fumou Sun, Tong Wang, Jiahao Jiang, Yang Wang, Zhaoxiong Ma, Zhaoting Li, Yue Han, Mingzhu Pan, Jialing Cai, Min Wang, Juan Zhang
Cluster of differentiation 24 (CD24) is a specific surface marker involved in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, all reported anti-CD24 antibodies are murine ones with inevitable immunogenicity. To address this, a method using both molecular structure and docking-based complementarity determining region (CDR) grafting was employed for humanization. After xenogeneic CDR grafting into a human antibody, three types of canonical residues (in the VL/VH interface core, in the loop foundation, and interaction with loop residues) that support loop conformation and residues involved in the antigen-binding interface were back-mutated...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28877934/identification-of-senescent-cell-surface-targetable-protein-dpp4
#18
Kyoung Mi Kim, Ji Heon Noh, Monica Bodogai, Jennifer L Martindale, Xiaoling Yang, Fred E Indig, Sandip K Basu, Kei Ohnuma, Chikao Morimoto, Peter F Johnson, Arya Biragyn, Kotb Abdelmohsen, Myriam Gorospe
Senescent cell accumulation in aging tissues is linked to age-associated diseases and declining function, prompting efforts to eliminate them. Mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts. Importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies. Moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells...
August 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28877251/identification-of-a-novel-gja3-mutation-in-a-large-chinese-family-with-congenital-cataract-using-targeted-exome-sequencing
#19
Yihua Yao, Xuedong Zheng, Xianglian Ge, Yanghui Xiu, Liu Zhang, Weifang Fang, Junzhao Zhao, Feng Gu, Yihua Zhu
Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified...
2017: PloS One
https://www.readbyqxmd.com/read/28873441/a-fully-humanized-igg-like-bispecific-antibody-for-effective-dual-targeting-of-cxcr3-and-ccr6
#20
Remy Robert, Laurent Juglair, Ee X Lim, Caroline Ang, Carl J H Wang, Gregor Ebert, Olan Dolezal, Charles R Mackay
Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic...
2017: PloS One
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