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Antibody-dependent cellular toxicity

Emi Harada, Satoshi Serada, Minoru Fujimoto, Yusuke Takahashi, Tsuyoshi Takahashi, Hisashi Hara, Rie Nakatsuka, Takahito Sugase, Takahiko Nishigaki, Yurina Saito, Kosuke Hiramatsu, Satoshi Nojima, Risa Mitsuo, Tomoharu Ohkawara, Eiichi Morii, Masaki Mori, Yuichiro Doki, Yasufumi Kaneda, Tetsuji Naka
Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite the development of multimodal therapy. Expression of glypican-1 (GPC1) has been reported to be elevated in a subset of patients with ESCC and associated with chemoresistance. This study aimed to determine the association of GPC1 with ESCC growth and potential usefulness of the GPC1 targeted therapy by monoclonal antibody (mAb) in ESCC. Expression of GPC1 was higher in ESCC tumor tissues than in adjacent non-tumoral tissues and normal tissues...
April 11, 2017: Oncotarget
Chun-Tao Yang, Fu-Hui Meng, Li Chen, Xiang Li, Lai-Jian Cen, Yu-Hua Wen, Cai-Chen Li, Hui Zhang
BACKGROUND/AIM: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity...
February 13, 2017: Cellular Physiology and Biochemistry
Lydia Kwast, Tetsuo Aida, Daniëlle Fiechter, Laura Kruijssen, Rob Bleumink, Louis Boon, Irene Ludwig, Raymond Pieters
Immune-mediated drug hypersensitivity reactions (IDHR) may result from immuno-sensitization to a drug-induced neo-antigen. They rarely occur in patients and are usually not predicted preclinically using standard toxicity studies. To assess the potential of a drug to induce T-cell sensitization, trinitrophenyl (TNP)-Ficoll was used here as a bystander antigen in animal experiments. TNP-Ficoll will only elicit TNP-specific IgG antibodies in the presence of non-cognate T-cell help. Therefore, the presence of TNP-specific IgG antibodies after co-injection of drug and TNP-Ficoll was indicative of T-cell sensitization potential...
November 2016: Journal of Immunotoxicology
C Xia, M Ribeiro, S Scott, S Lonial
Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed...
October 2016: Drugs of Today
Alessia Corrado, Paolo Donato, Silvia Maccari, Raffaella Cecchi, Tiziana Spadafina, Letizia Arcidiacono, Simona Tavarini, Chiara Sammicheli, Donatello Laera, Andrea Guido Oreste Manetti, Paolo Ruggiero, Bruno Galletti, Sandra Nuti, Ennio De Gregorio, Sylvie Bertholet, Anja Seubert, Fabio Bagnoli, Giuliano Bensi, Emiliano Chiarot
Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans...
November 30, 2016: Scientific Reports
Xian Li, Hanxian Zeng, Pengfei Wang, Lu Lin, Lin Liu, Pinyi Zhen, Yuanzhe Fu, Panpan Lu, Huanzhang Zhu
BACKGROUND: Current antiretroviral therapy (ART) cannot cure HIV-1 infection due to the presence of latent viral reservoirs. The "shock and kill" strategy is a promising approach to eliminate the viral reservoir. However, there are various limits existing in current latency-reversing agents, searching for new activators are urgently needed. OBJECTIVE: The present study aimed at investigating the ability of hymecromone and scoparone for activating HIV-1 from latent reservoirs...
2016: Current HIV Research
Thomas Peter, Rosi Bissinger, Florian Lang
BACKGROUND/AIMS: The echinocandin antifungal agent caspofungin has been shown to trigger apoptosis of fungal cells. Beyond that, caspofungin is toxic for host mitochondria. Even though lacking mitochondria, erythrocytes may enter apoptosis-like suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, caspase activation and/or activation of p38 kinase, protein kinase C, and casein kinase...
2016: Cellular Physiology and Biochemistry
Lei Zhu, Fan Zhang, Li-Jun Yang, Yang Ge, Qing-Fang Wei, Yu Ou
EPSAH is an exopolysaccharide from Aphanothece halophytica GR02. The present study was designed to evaluate its toxicity and adjuvant potential in the specific cellular and humoral immune responses in ovalbumin (OVA) in mice. EPSAH did not cause any mortality and side effects when the mice were administered subcutaneously twice at the dose of 50 mg·kg(-1). Hemolytic activity in vitro indicated that EPSAH was non-hemolytic. Splenocyte proliferation in vitro was assayed with different concentrations of EPSAH...
July 2016: Chinese Journal of Natural Medicines
Erin M Bertino, Elizabeth L McMichael, Xiaokui Mo, Prashant Trikha, Melanie Davis, Bonnie Paul, Michael Grever, William E Carson, Gregory A Otterson
mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC...
September 2016: Molecular Cancer Therapeutics
S P Koerner, M C André, J S Leibold, P C Kousis, A Kübler, M Pal, S P Haen, H-J Bühring, L Grosse-Hovest, G Jung, H R Salih
Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE)...
February 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
David J M Routledge, Adrian J C Bloor
The last 5 to 10 years have been marked by considerable advances in both our understanding of the biology and treatment of chronic lymphocytic leukaemia (CLL). Fludarabine-based immuno-chemotherapy is the current standard of care for first line therapy in younger fit patients and although this can be highly effective its use in older co-morbid patients is limited by toxicity, and the prognosis for patients with high risk or fludarabine-refractory disease is poor. The introduction of new antibodies has however, facilitated the use of immuno-chemotherapy in co-morbid patients...
August 2016: British Journal of Haematology
Abdullah Norain, Ekaterina Dadachova
An estimated 60,000 individuals in the United States and 132,000 worldwide are yearly diagnosed with melanoma. Until recently, treatment options for patients with stages III-IV metastatic disease were limited and offered marginal, if any, improvement in overall survival. The situation changed with the introduction of B-RAF inhibitors and anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1 immunotherapies into the clinical practice. With only some patients responding well to the immune therapies and with very serious side effects and high costs of immunotherapy, there is still room for other approaches for the treatment of metastatic melanoma...
May 2016: Seminars in Nuclear Medicine
Sonja T H M Kolanowski, Suzanne N Lissenberg-Thunnissen, Diba Emal, S Marieke van Ham, Anja Ten Brinke
OBJECTIVE: To elucidate if TLR4-mediated MyD88 and TRIF signalling by the clinically applicable Lipopolysaccharide (LPS)-derivative monophosphoryl lipid A (MPLA) in primary human dendritic cells requires LPS cofactors LPS-binding protein (LBP) and CD14. METHODS: Cytokine production by monocyte-derived DCs stimulated with MPLA or LPS was determined using ELISA. To investigate involvement of CD14 for action of LPS or MPLA, CD14 was inhibited using blocking antibodies or down-modulated using specific siRNA...
June 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Miriam Reuschenbach, Claudia Pauligk, Julia Karbach, Mohammad-Reza Rafiyan, Matthias Kloor, Elena-Sophie Prigge, Madeleine Sauer, Salah-Eddin Al-Batran, Andreas M Kaufmann, Achim Schneider, Elke Jäger, Magnus von Knebel Doeberitz
BACKGROUND: The cyclin-dependent kinase inhibitor p16(INK4a) is strongly and consistently overexpressed in all human papillomavirus (HPV)-associated cancers. Therefore, the authors hypothesized that p16(INK4a) may be a vaccine target antigen for HPV-associated cancers. To test this hypothesis, the authors performed a phase 1/2a first-in-human trial to evaluate the safety and immunogenicity of a p16(INK4a) -based peptide vaccine. METHODS: A total of 26 patients with different, advanced, p16(INK4a) -overexpressing, HPV DNA-positive cancers were included after the completion of standard treatment...
May 1, 2016: Cancer
Caroline E Rasmussen, Jette Nowak, Julie M Larsen, Anna Bottomley, Alison Rowles, Hanne Offenberg
Nonacog beta pegol is a 40-kDa polyethylene glycosylated (PEGylated) human recombinant coagulation factor IX, intended for the treatment of hemophilia B. Human coagulation factors are immunogenic in animals; therefore, to evaluate the long-term toxicity of nonacog beta pegol, an immune-deficient, athymic rat (Rowett nude; Crl:NIH-Foxn1(rnu)) was used. Rats (n = 216) were given intravenous nonacog beta pegol 0, 40, 150, 600, or 1,200 IU/kg every 5th day for 26 weeks. To avoid infections, the animals were housed in a full-barrier environment with sterilized food and bedding...
July 2016: Toxicologic Pathology
Khalid Al Wadi, Prafull Ghatage
INTRODUCTION: Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. The majority of women are diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, most patients with advanced EOC will relapse with subsequent resistance to conventional chemotherapy and ultimately succumb to their disease. Therefore, new therapeutic agents and strategies are desperately needed to improve the outcomes in patients with advanced EOC...
2016: Expert Opinion on Pharmacotherapy
Rama Pai, Ning Ma, Anu V Connor, Dimitry M Danilenko, Jacqueline M Tarrant, Dany Salvail, Lisa Wong, Dylan P Hartley, Dinah Misner, Eric Stefanich, Yan Wu, Yongmei Chen, Hong Wang, Donna M Dambach
PRO304186, a humanized monoclonal antibody targeting soluble interleukin-17 A and F, was developed for autoimmune and inflammatory disease indications. When administered to cynomolgus monkeys PRO304186 induced unexpected adverse effects characterized by clinical signs of hematemesis, hematochezia, and moribundity. Pathology findings included hemorrhage throughout the gastrointestinal tract without any evidence of vascular wall damage or inflammatory cellular infiltration. Mechanistic investigation of these effects revealed mild elevations of serum MCP-1 and IL-12/23 but without a classical proinflammatory profile in PRO304186-treated animals...
June 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Laurence Booth, Brian Shuch, Thomas Albers, Jane L Roberts, Mehrad Tavallai, Stefan Proniuk, Alexander Zukiwski, Dasheng Wang, Ching-Shih Chen, Don Bottaro, Heath Ecroyd, Iryna O Lebedyeva, Paul Dent
We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins...
March 15, 2016: Oncotarget
Niels W C J van de Donk, Maarten L Janmaat, Tuna Mutis, Jeroen J Lammerts van Bueren, Tahamtan Ahmadi, A Kate Sasser, Henk M Lokhorst, Paul W H I Parren
CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202...
March 2016: Immunological Reviews
Nidhi Nath, Becky Godat, Chad Zimprich, Stephen J Dwight, Cesear Corona, Mark McDougall, Marjeta Urh
Receptor-mediated antibody internalization is a key mechanism underlying several anti-cancer antibody therapeutics. Delivering highly toxic drugs to cancer cells, as in the case of antibody drug conjugates (ADCs), efficient removal of surface receptors from cancer cells and changing the pharmacokinetics profile of the antibody drugs are some of key ways that internalization impacts the therapeutic efficacy of the antibodies. Over the years, several techniques have been used to study antibody internalization including radiolabels, fluorescent microscopy, flow cytometry and cellular toxicity assays...
April 2016: Journal of Immunological Methods
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