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Antibody dependent cellular cytotoxicity

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https://www.readbyqxmd.com/read/29448044/safety-evaluation-of-a-human-chimeric-monoclonal-antibody-that-recognizes-the-extracellular-loop-domain-of-claudin-2
#1
Yosuke Hashimoto, Tomoyuki Hata, Minoru Tada, Manami Iida, Akihiro Watari, Yoshiaki Okada, Takefumi Doi, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
Claudin-2 (CLDN-2), a pore-forming tight-junction protein with a tetra-transmembrane domain, is involved in carcinogenesis and the metastasis of some cancers. Although CLDN-2 is highly expressed in the tight junctions of the liver and kidney, whether CLDN-2 is a safe target for cancer therapy remains unknown. We recently generated a rat monoclonal antibody (mAb, clone 1A2) that recognizes the extracellular domains of human and mouse CLDN-2. Here, we investigated the safety of CLDN-2-targeted cancer therapy by using 1A2 as a model therapeutic antibody...
February 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29438058/assessment-of-antibody-dependent-cellular-cytotoxicity-by-flow-cytometry
#2
Thomas D Duensing, Susan R Watson
A useful feature of therapeutic antibodies is the ability to kill the cells to which they bind. Antibodies are capable of mediating cell killing in a variety of ways. Apoptosis, complement-mediated mechanisms, and antibody-dependent cellular cytotoxicity (ADCC) are all effects that can be assayed to characterize lead antibody candidates. Extensive, multidose characterizations of a series of candidates can be performed in a short amount of time using assays developed for high-throughput flow cytometry systems...
February 1, 2018: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/29438057/complement-dependent-cytotoxicity-assay
#3
Thomas D Duensing, Susan R Watson
A useful feature of therapeutic antibodies is the ability to kill the cells to which they bind. Antibodies are capable of mediating cell killing in a variety of ways. Apoptosis, complement-mediated mechanisms, and antibody-dependent cellular cytotoxicity are all effects that can be assayed to characterize lead antibody candidates. Extensive, multidose characterizations of a series of candidates can be performed in a short amount of time using assays developed for high-throughput flow cytometry systems. Antibodies that contain the Fc portion of the human IgG1 can activate complement-mediated cell death...
February 1, 2018: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/29434980/augmentation-of-antibody-dependent-cellular-cytotoxicity-with-defucosylated-monoclonal-antibodies-in-patients-with-gi-tract-cancer
#4
Takahiro Nakajima, Hirokazu Okayama, Mai Ashizawa, Masaru Noda, Keita Aoto, Motonobu Saito, Tomoyuki Monma, Shinji Ohki, Masahiko Shibata, Seiichi Takenoshita, Koji Kono
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs)...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434844/oxaliplatin-and-infliximab-synergize-to-induce-regression-of-colon-cancer
#5
Di Huang, Jun Xue, Shuguang Li, Dongdong Yang
There is currently a lack of therapeutic options for patients with advanced colon cancer. Although certain chemotherapies are able to suppress the progression slightly, the response rate is low, and side effects of treatment and tumor recurrence continue to present problems for clinicians. Tumor necrosis factor-α (TNF-α) has been identified to possess tumor-promoting properties. In the present study, the effect of anti-TNF-α treatment (infliximab) in combination with chemotherapy on colon cancer was investigated...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29428821/recombinant-igg1-fc-hexamers-block-cytotoxicity-and-pathological-changes-in-experimental-in-vitro-and-rat-models-of-neuromyelitis-optica
#6
Lukmanee Tradtrantip, Christian M Felix, Rolf Spirig, Adriana Baz Morelli, A S Verkman
Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments...
February 8, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29416099/generation-and-characterization-of-a-igg-monoclonal-antibody-specific-for-gm3-neugc-ganglioside-by-immunizing-%C3%AE-3gn-t5-knockout-mice
#7
Dongwei He, Xiaoyan Fan, Boyi Liu, Yiqing Tian, Xiangmei Zhang, Lin Kang, Yan Tai, Shuzhen Liu, Qian Wang, Qingxia Li, Jianhui Cai
A murine monoclonal antibody (MAb-1) specific for GM3 has been generated by immunizing β3Gn-T5 knockout mice with purified GM3 ganglioside. The binding specificity of MAb-1 (IgG3 subclass) was established by an enzyme-linked immunosorbent assay (ELISA) and FACS and the antibody showed high binding specificity with GM3. Cell viability assay showed that MAb-1 significantly suppressed cell growth. Immunohistochemistry analysis revealed that MAb-1 was strongly expressed in human ovarian cancer tissues, whereas it was hardly expressed in normal tissues...
February 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29400603/a-novel-bicistronic-gene-design-couples-stable-cell-line-selection-with-a-fucose-switch-in-a-designer-cho-host-to-produce-native-and-afucosylated-glycoform-antibodies
#8
Gargi Roy, Tom Martin, Arnita Barnes, Jihong Wang, Rod Brian Jimenez, Megan Rice, Lina Li, Hui Feng, Shu Zhang, Raghothama Chaerkady, Herren Wu, Marcello Marelli, Diane Hatton, Jie Zhu, Michael A Bowen
The conserved glycosylation site Asn297 of a monoclonal antibody (mAb) can be decorated with a variety of sugars that can alter mAb pharmacokinetics and recruitment of effector proteins. Antibodies lacking the core fucose at Asn297 (afucosylated mAbs) show enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and increased efficacy. Here, we describe the development of a robust platform for the manufacture of afucosylated therapeutic mAbs by engineering a Chinese hamster ovary (CHO) host cell line to co-express a mAb with GDP-6-deoxy-D-lyxo-4-hexulose reductase (RMD), a prokaryotic enzyme that deflects an intermediate in the de novo synthesis of fucose to a dead-end product, resulting in the production of afucosylated mAb (GlymaxX™ Technology, ProBioGen)...
February 5, 2018: MAbs
https://www.readbyqxmd.com/read/29388200/phase-i-clinical-trial-of-adoptive-transfer-of-expanded-natural-killer-cells-in-combination-with-igg1-antibody-in-patients-with-gastric-or-colorectal-cancer
#9
Takeshi Ishikawa, Tetsuya Okayama, Naoyuki Sakamoto, Mitsuko Ideno, Kaname Oka, Tatsuji Enoki, Junichi Mineno, Naohisa Yoshida, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Tomohisa Takagi, Hideyuki Konishi, Satoshi Kokura, Kazuko Uno, Yuji Naito, Yoshito Itoh
Natural killer (NK) cells exhibit strong cytotoxic activity against tumor cells without prior sensitization, and have the potential to exert antibody-dependent cellular cytotoxicity (ADCC). In this clinical trial, we examined the safety and efficacy of the use of NK cells, generated using a novel expansion system, in combination with IgG1 antibodies for the treatment of advanced gastric or colorectal cancers. Treatment consisted of trastuzumab- or cetuximab-based chemotherapy, plus adoptive NK cell therapy...
January 31, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29363526/nitric-oxide-production-by-myeloid-derived-suppressor-cells-plays-a-role-in-impairing-fc-receptor-mediated-natural-killer-cell-function
#10
Andrew Stiff, Prashant Trikha, Bethany L Mundy-Bosse, Elizabeth L McMichael, Thomas A Mace, Brooke Benner, Kari Kendra, Amanda Campbell, Shalini Gautam, David Abood, Ian Landi, Vincent Hsu, Megan C Duggan, Robert Wesolowski, Matthew Old, John H Howard, Lianbo Yu, Nancy Stasik, Thomas Olencki, Natarajan Muthusamy, Susheela Tridandapani, John C Byrd, Michael A Caligiuri, William E Carson
PURPOSE: Monoclonal antibodies (mAb) are used to treat solid and hematological malignancies, and work in part through Fc receptors (FcR) on natural killer cells (NK). However, FcR mediated functions of NK cells from cancer patients are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.  Experimental Design: Co-cultures of autologous NK cells and MDSC from cancer patients were used to study the effect of MDSC on NK cell FcR mediated functions including antibody dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro...
January 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29359992/fc%C3%AE-rii-binding-centyrins-mediate-agonism-and-antibody-dependent-cellular-phagocytosis-when-fused-to-an-anti-ox40-antibody
#11
Di Zhang, Brian Whitaker, Mehabaw G Derebe, Mark L Chiu
Immunostimulatory antibodies against the tumor necrosis factor receptors (TNFR) are emerging as promising cancer immunotherapies. The agonism activity of such antibodies depends on crosslinking to Fc gamma RIIB receptor (FcγRIIB) to enable the antibody multimerization that drives TNFR activation. Previously, Fc engineering was used to enhance the binding of such antibodies to Fcγ receptors. Here, we report the identification of Centyrins as alternative scaffold proteins with binding affinities to homologous FcγRIIB and FcγRIIA, but not to other types of Fcγ receptors...
January 23, 2018: MAbs
https://www.readbyqxmd.com/read/29350566/abp-501-for-the-treatment-of-rheumatoid-arthritis
#12
Eleftherios Pelechas, Paraskevi V Voulgari, Alexandros A Drosos
Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor. Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity...
January 19, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29339750/a-single-dose-of-modified-vaccinia-ankara-expressing-ebola-virus-like-particles-protects-nonhuman-primates-from-lethal-ebola-virus-challenge
#13
Arban Domi, Friederike Feldmann, Rahul Basu, Nathanael McCurley, Kyle Shifflett, Jackson Emanuel, Michael S Hellerstein, Farshad Guirakhoo, Chiara Orlandi, Robin Flinko, George K Lewis, Patrick W Hanley, Heinz Feldmann, Harriet L Robinson, Andrea Marzi
Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013-2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV)...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29339550/relative-target-affinities-of-t-cell-dependent-bispecific-antibodies-determine-biodistribution-in-a-solid-tumor-mouse-model
#14
Danielle Mandikian, Nene Takahashi, Amy A Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B Joseph, Mark S Dennis, Saileta Prabhu, Teemu T Junttila, C Andrew Boswell
Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29325416/igy-reduces-afb1-induced-cytotoxicity-cellular-dysfunction-and-genotoxicity-in-human-l-02-hepatocytes-and-swan-71-trophoblasts
#15
Taotao Qiu, Xing Shen, Zhen Tian, Riming Huang, Xiangmei Li, Juan Wang, Rong Wang, Yuanming Sun, Yiguo Jiang, Huidong Zhang, Hongtao Lei
Aflatoxin B1 (AFB1) causes hepatotoxic, genotoxic, and immuno¬toxic effects in a variety of species. Although various neutralizing agents of AFB1 toxicity have been studied, the egg yolk immunoglobulins (IgY) detoxification of small molecular toxins and the mechanisms underlying such effects have not yet been reported. In this investigation, anti-AFB1 IgY against AFB1 was successfully raised, and a competitive indirect enzyme-linked immunosorbent assay was established with a sensitive half-maximal inhibitory concentration (IC50, 2...
January 11, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29323175/functional-antibody-response-against-v1v2-and-v3-of-hiv-gp120-in-the-vax003-and-vax004-vaccine-trials
#16
Preetha Balasubramanian, Constance Williams, Mariya B Shapiro, Faruk Sinangil, Keith Higgins, Arthur Nádas, Maxim Totrov, Xiang-Peng Kong, Andrew J Fiore-Gartland, Nancy L Haigwood, Susan Zolla-Pazner, Catarina E Hioe
Immunization with HIV AIDSVAX gp120 vaccines in the phase III VAX003 and VAX004 trials did not confer protection. To understand the shortcomings in antibody (Ab) responses induced by these vaccines, we evaluated the kinetics of Ab responses to the V1V2 and V3 regions of gp120 and the induction of Ab-mediated antiviral functions during the course of 7 vaccinations over a 30.5-month period. Plasma samples from VAX003 and VAX004 vaccinees and placebo recipients were measured for ELISA-binding Abs and for virus neutralization, Ab-dependent cellular phagocytosis (ADCP), and Ab-dependent cellular cytotoxicity (ADCC)...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29317395/the-role-of-elotuzumab-in-the-treatment-of-relapsed-or-refractory-multiple-myeloma
#17
REVIEW
Jill M Comeau, Katherine Kelly, Gary W Jean
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy and safety, cost, and place in therapy of elotuzumab for treatment of relapsed or refractory multiple myeloma (MM) are reviewed. SUMMARY: Elotuzumab is a humanized monoclonal antibody that targets the signaling lymphocytic activation molecule (SLAM) protein SLAMF7 and facilitates an antibody-dependent cellular cytotoxicity interaction between myeloma cells and natural killer cells. Elotuzumab has U.S...
January 15, 2018: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/29315477/enrichment-of-high-affinity-subclasses-and-glycoforms-from-serum-derived-igg-using-fc%C3%AE-rs-as-affinity-ligands
#18
Boesch Aw, Kappel Jh, Mahan Ae, Chu Th, Crowley Ar, Osei-Owusu Ny, Alter G, Ackerman Me
As antibodies continue to gain predominance in drug discovery and development pipelines, efforts to control and optimize their activity in vivo have matured to incorporate sophisticated abilities to manipulate engagement of specific Fc binding partners. Such efforts to promote diverse functional outcomes include modulating IgG-Fc affinity for FcγRs to alternatively potentiate or reduce effector functions, such as antibody-dependent cellular cytotoxicity and phagocytosis. While a number of natural and engineered Fc features capable of eliciting variable effector functions have been demonstrated in vitro and in vivo, elucidation of these important functional relationships has taken significant effort through use of diverse genetic, cellular and enzymatic techniques...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29305595/frequency-analysis-of-the-g-7081t-g-a-and-g-10872t-g-polymorphisms-in-the-fcgr3a-gene-cd16a-using-nested-pcr-and-their-functional-specific-effects
#19
Camilo Andrés Pérez-Romero, Isaura Pilar Sánchez, Laura Naranjo-Piedrahita, Julio Cesar Orrego-Arango, Carlos Enrique Muskus-López, Winston Rojas-Montoya, Jose Luis Franco Restrepo, Claudia Milena Trujillo-Vargas
Polymorphic variants p.66L>R/H (g.7081T>G/A; rs10127939) and p.176F>V (g.10872T>G; rs396991) in FCGR3A (CD16A) have been associated with defects in cytotoxic function of natural killer (NK) cells in humans. Genotyping of these variants in genomic DNA has been ambiguous because of high degree of homology between FCGR3A and FCGR3B. We designed a strategy to genotype these polymorphisms and to evaluate their effects on NK cells' cytotoxic activity. One hundred and fifteen individuals from different geographical regions of Colombia were included...
January 5, 2018: Genes and Immunity
https://www.readbyqxmd.com/read/29296857/effects-of-daratumumab-on-natural-killer-cells-and-impact-on-clinical-outcomes-in-relapsed-or-refractory-multiple-myeloma
#20
Tineke Casneuf, Xu Steven Xu, Homer C Adams, Amy E Axel, Christopher Chiu, Imran Khan, Tahamtan Ahmadi, Xiaoyu Yan, Sagar Lonial, Torben Plesner, Henk M Lokhorst, Niels W C J van de Donk, Pamela L Clemens, A Kate Sasser
Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed...
October 24, 2017: Blood Advances
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