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Antibody-dependent cellular toxicity

Masafumi Taniwaki, Mihoko Yoshida, Yosuke Matsumoto, Kazuho Shimura, Junya Kuroda, Hiroto Kaneko
Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity...
2018: Mediterranean Journal of Hematology and Infectious Diseases
Michael J Robertson, Christopher W Stamatkin, David Pelloso, Jill Weisenbach, Nagendra K Prasad, Ahmad R Safa
Interleukin-18 (IL-18) is an immunostimulatory cytokine that augments antibody-dependent cellular cytotoxicity mediated by human natural killer cells against antibody-coated lymphoma cells in vitro and that has antitumor activity in animal models. Ofatumumab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with ofatumumab was undertaken in patients with CD20 lymphoma who had undergone high-dose chemotherapy and autologous peripheral blood stem cell transplantation...
April 2018: Journal of Immunotherapy
Christopher T Laird, Wessam Hassanein, Natalie A O'Neill, Beth M French, Xiangfei Cheng, William E Fogler, John L Magnani, Dawn Parsell, Arielle Cimeno, Carol J Phelps, David Ayares, Lars Burdorf, Agnes M Azimzadeh, Richard N Pierson
BACKGROUND: Alongside the need to develop more effective and less toxic immunosuppression, the shortage of human organs available for organ transplantation is one of the major hurdles facing the field. Research into xenotransplantation, as an alternative source of organs, has unveiled formidable challenges. Porcine lungs perfused with human blood rapidly sequester the majority of circulating neutrophils and platelets, which leads to inflammation and organ failure within hours, and is not significantly attenuated by genetic modifications to the pig targeted to diminish antibody binding and complement and coagulation cascade activation...
January 23, 2018: Xenotransplantation
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
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
Despoina Goniotaki, Asvin K K Lakkaraju, Amulya N Shrivastava, Pamela Bakirci, Silvia Sorce, Assunta Senatore, Rajlakshmi Marpakwar, Simone Hornemann, Fabrizio Gasparini, Antoine Triller, Adriano Aguzzi
Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices...
November 2017: PLoS Pathogens
Kelly A Shipkowski, Christopher M Sheth, Matthew J Smith, Michelle J Hooth, Kimber L White, Dori R Germolec
Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function...
December 2017: Journal of Immunotoxicology
Kenneth H Mayer, Kelly E Seaton, Yunda Huang, Nicole Grunenberg, Abby Isaacs, Mary Allen, Julie E Ledgerwood, Ian Frank, Magdalena E Sobieszczyk, Lindsey R Baden, Benigno Rodriguez, Hong Van Tieu, Georgia D Tomaras, Aaron Deal, Derrick Goodman, Robert T Bailer, Guido Ferrari, Ryan Jensen, John Hural, Barney S Graham, John R Mascola, Lawrence Corey, David C Montefiori
BACKGROUND: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. METHODS AND FINDINGS: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens...
November 2017: PLoS Medicine
Thomas A Waldmann
Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints...
November 3, 2017: Cold Spring Harbor Perspectives in Biology
Áquila S B Portela, Lourena E Costa, Beatriz C S Salles, Mariana P Lima, Thaís T O Santos, Fernanda F Ramos, Daniela P Lage, Vívian T Martins, Rachel B Caligiorne, Daniela R Lessa, Fabiana R Silva, Amanda S Machado, Guilherme F Nascimento, Isabela S Gama, Miguel A Chávez-Fumagalli, Antonio L Teixeira, Manoel O C Rocha, Regina L Rocha, Eduardo A F Coelho
Visceral leishmaniasis (VL) is a potentially fatal disease, in which the treatment based on chemotherapy is considered toxic. The cure of disease is associated with the life-long Th1-type immunity against the infection. The Th1-related cytokines production by peripheral blood mononuclear cells (PBMCs) seems to be crucial for host control of parasite load and clinical cure. In the current study, we used five proteins (IgE-dependent histamine-releasing factor [HRF], LiHyD, LiHyV, LiHyT and LiHyp6) recently shown to be antigenic and/or immunogenic in the canine VL, aiming to evaluate the antigen-specific antibody levels and cytokine production in PBMCs culture supernatants collected from VL patients before and after anti-VL treatment...
October 20, 2017: Immunobiology
Zahra Payandeh, Masoumeh Rajabibazl, Yousef Mortazavi, Azam Rahimpour, Amir Hossein Taromchi
Background: Ofatumumab, an anti-CD20 mAb, was approved in 2009 for the treatment of chronic lymphocytic leukemia. This mAb acts through immune-mediated mechanisms, in particular complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by natural killer cells as well as antibody-dependent phagocytosis by macrophages. Apoptosis induction is another mechanism of this antibody. Computational docking is the method of predicting the conformation of an antibody-antigen from its separated elements...
October 10, 2017: Iranian Biomedical Journal
Mohammad Y Ansari, Nazir M Khan, Tariq M Haqqi
BACKGROUND/OBJECTIVE: Osteoarthritis (OA) is a leading cause of joint dysfunction, disability and poor quality of life in the affected population. The underlying mechanism of joint dysfunction involves increased oxidative stress, inflammation, high levels of cartilage extracellular matrix degrading proteases and decline in autophagy-a mechanism of cellular defense. There is no disease modifying therapies currently available for OA. Different parts of the Butea monosperma (Lam.) plant have widely been used in the traditional Indian Ayurvedic medicine system for the treatment of various human diseases including inflammatory conditions...
October 4, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jessica R Ingram, Olga S Blomberg, Jonathan T Sockolosky, Lestat Ali, Florian I Schmidt, Novalia Pishesha, Camilo Espinosa, Stephanie K Dougan, K Christopher Garcia, Hidde L Ploegh, Michael Dougan
CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47-SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
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
Dina Popova, Jessica Karlsson, Stig O P Jacobsson
BACKGROUND: Exposure to chemicals might be toxic to the developing brain. There is a need for simple and robust in vitro cellular models for evaluation of chemical-induced neurotoxicity as a complement to traditional studies on animals. In this study, neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) were compared with human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells for their ability to detect toxicity of methylmercury (MeHg), okadaic acid and acrylamide...
June 5, 2017: BMC Pharmacology & Toxicology
Bei Wu, Alex J McDonald, Kathleen Markham, Celeste B Rich, Kyle P McHugh, Jörg Tatzelt, David W Colby, Glenn L Millhauser, David A Harris
PrP(C), the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrP(Sc), the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrP(C) functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain...
May 20, 2017: ELife
Theodoros Eleftheriadis, Georgios Pissas, Maria Sounidaki, Georgia Antoniadi, Nikolaos Antoniadis, Vassilios Liakopoulos, Ioannis Stefanidis
PURPOSE: Acute cellular rejection is the major cause of immune-mediated graft failure early in the course of kidney transplantation, whereas chronic antibody-mediated rejection is a major contributor to graft loss in the late post-transplant phase. Based mainly on the results of short-term studies, the calcineurin inhibitor tacrolimus prevails over the mammalian target of rapamycin (mTOR) inhibitors. However, the toxicity profile of the two drug categories differs, making the interchange between them appealing...
September 2017: International Urology and Nephrology
Austin G Duffy, Chi Ma, Susanna V Ulahannan, Osama E Rahma, Oxana Makarova-Rusher, Liang Cao, Yunkai Yu, David E Kleiner, Jane Trepel, Min-Jung Lee, Yusuke Tomita, Seth M Steinberg, Theo Heller, Baris Turkbey, Peter L Choyke, Cody J Peer, William D Figg, Brad J Wood, Tim F Greten
Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child-Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily...
August 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Howard A Burris, Jeffrey R Infante, Stephen M Ansell, John J Nemunaitis, Geoffrey R Weiss, Victor M Villalobos, Branimir I Sikic, Matthew H Taylor, Donald W Northfelt, William E Carson, Thomas R Hawthorne, Thomas A Davis, Michael J Yellin, Tibor Keler, Timothy Bullock
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors...
June 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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
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