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Human Monoclonal antibodies

Michael Willis, Irmgard Leitner, Klaus Seppi, Maria Trieb, Georg Wietzorrek, Josef Marksteiner, Hans-Günther Knaus
In this study, we investigated the tissue expression levels, alpha subunit composition and distribution of Shaker-related voltage-dependent potassium Kv1 channels in human hippocampus by combining western blotting experiments, toxin autoradiography, in vivo radioligand binding studies, immunoprecipitation and immunohistochemistry. Tissue expression of Kv1.1 and Kv1.2 α-subunits in human post-mortem brain tissue was confirmed in immunoblot analysis using a panel of specific monoclonal and polyclonal antibodies...
March 21, 2018: Brain Structure & Function
Weihsu C Chen, Christopher M Murawsky
Therapeutic molecules derived from antibodies have become a dominant class of drugs used to treat human disease. Increasingly, therapeutic antibodies are discovered using transgenic animal systems that have been engineered to express human antibodies. While the engineering details differ, these platforms share the ability to raise an immune response that is comprised of antibodies with fully human idiotypes. Although the predominant transgenic host species has been mouse, the genomes of rats, rabbits, chickens, and cows have also been modified to express human antibodies...
2018: Frontiers in Immunology
Weon Sup Lee, Sang Ryeol Shim, Seon Young Lee, Jin San Yoo, Sung Kweon Cho
Background: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001) is a fully human IgG1 monoclonal antibody derived from a fully human naïve single-chain variable fragment (ScFv) phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. Methods: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys...
2018: Drug Design, Development and Therapy
Tatiana A Karakasheva, George A Dominguez, Ayumi Hashimoto, Eric W Lin, Christopher Chiu, Kate Sasser, Jae W Lee, Gregory L Beatty, Dmitry I Gabrilovich, Anil K Rustgi
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are a population of immature immune cells with several protumorigenic functions. CD38 is a transmembrane receptor-ectoenzyme expressed by MDSCs in murine models of esophageal cancer. We hypothesized that CD38 could be expressed on MDSCs in human colorectal cancer (CRC), which might allow for a new perspective on therapeutic targeting of human MDSCs with anti-CD38 monoclonal antibodies in this cancer. METHODS: Blood samples were collected from 41 CRC patients and 8 healthy donors, followed by peripheral blood mononuclear cell (PBMC) separation...
March 22, 2018: JCI Insight
Denise C Hsu, Piyanate Sunyakumthorn, Matthew Wegner, Alexandra Schuetz, Decha Silsorn, Jacob D Estes, Claire Deleage, Khamis Tomusange, Samir K Lakhashe, Ruth M Ruprecht, Eric Lombardini, Rawiwan Im-Erbsin, Yanin Kuncharin, Yuwadee Phuang-Ngern, Dutsadee Inthawong, Weerawan Chuenarom, Robin Burke, Merlin L Robb, Lishomwa C Ndhlovu, Jintanat Ananworanich, Victor Valcour, Robert J O'Connell, Serena Spudich, Nelson L Michael, Sandhya Vasan
Studies utilizing highly pathogenic simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) have largely focused on the immunopathology of the central nervous system (CNS) during end-stage neuro AIDS and SIV encephalitis. However, this may not model pathophysiology in earlier stages of infection. In this non-accelerated SHIV model, plasma SHIV RNA levels and peripheral blood and colonic CD4 T+ cell counts mirrored early HIV infection in humans. At 12 weeks post infection, cerebrospinal fluid (CSF) detection of SHIV RNA and elevations in IP-10 and MCP-1 reflected a discrete neurovirologic process...
March 21, 2018: Journal of Virology
Ricardo García-Muñoz, Lorea Aguinaga, Jesus Feliu, Judit Anton-Remirez, Lorena Jorge-Del-Val, Andrea Casajús-Navasal, María José Nebot-Villacampa, Isabel Daroca-Fernandez, Elena Domínguez-Garrido, Pilar Rabasa, Carlos Panizo
AIM: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). METHOD: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy...
March 1, 2018: Immunotherapy
Yongao Xiong, Qiongyu Li, Muchena J Kailemia, Carlito B Lebrilla, Somen Nandi, Karen A McDonald
Kifunensine, a potent and selective inhibitor of class I α-mannosidases, prevents α-mannosidases I from trimming mannose residues on glycoproteins, thus resulting in oligomannose-type glycans. We report for the first time that through one-time vacuum infiltration of kifunensine in plant tissue, N-linked glycosylation of a recombinant protein transiently produced in whole-plants shifted completely from complex-type to oligomannose-type. Fc-fused capillary morphogenesis protein 2 (CMG2-Fc) containing one N -glycosylation site on the Fc domain, produced in Nicotiana benthamiana whole plants, served as a model protein...
March 17, 2018: International Journal of Molecular Sciences
H Peeters, E Louis, F Baert, O Dewit, J C Coche, M Ferrante, G Lambrecht, A Colard, A Van Gossum, P Bossuyt, T Moreels, B Vander Cruyssen, A Gils, M De Vos
BACKGROUND AND STUDY AIMS: Anti-TNF monoclonal antibodies are a cornerstone in the treatment of Crohn's disease. Prospective data on switching from the subcutaneous and human adalimumab (ADM) to the intravenous and chimeric infliximab (IFX) are scarce. PATIENTS AND METHODS: In this prospective, observational, multicentre cohort study we included 21 patients with loss of response to ADM despite at least 4 consecutive weekly injections. Clinical response (CDAI drop≥70 points) and remission (CDAI≤150) were assessed after switching from ADM to IFX after 10 weeks, 6 and 12 months...
January 2018: Acta Gastro-enterologica Belgica
Benjamin B Kasten, Patsy G Oliver, Harrison Kim, Jinda Fan, Soldano Ferrone, Kurt R Zinn, Donald J Buchsbaum
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC...
March 21, 2018: International Journal of Molecular Sciences
Thomas D'huys, Sandra Claes, Tom Van Loy, Dominique Schols
Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry in vitro ...
March 2018: Heliyon
Jean-David Fumet, Aurélie Bertaut, Leila Bengrine, Patricia Lapierre, Julie Vincent, François Ghiringhelli, Nicolas Falvo
Background: Bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody targeting VEGF-A. It is currently used with chemotherapy as the first- or second-line therapy in metastatic colorectal cancer. Previous studies have showed that anti-angiogenic agents decrease capillary density. We evaluated the link between decreased capillary density and the response to bevacizumab-based chemotherapy. Results: Overall, 43 patients with metastatic colorectal cancer treated with first-line bevacizumab-based chemotherapy were enrolled...
February 27, 2018: Oncotarget
David M Hyman, Naiyer A Rizvi, Ronald B Natale, Deborah K Armstrong, Michael J Birrer, Lawrence Recht, Efrat Dotan, Vicky Makker, Thomas J Kaley, Denison Kuruvilla, Matthew Gribbin, Jennifer McDevitt, Dominic W Lai, Mohammed M Dar
PURPOSE: This first-in-human study aimed to determine the maximum tolerated dose (MTD) and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) monoclonal antibody, alone and combined with bevacizumab or cytotoxic chemotherapy. Experimental Design: This phase I/Ib, multicenter, open-label, dose escalation and dose expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy (5-1500 mg every 3 weeks [Q3W]) or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W...
March 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hope S Rugo, Jean-Pierre Delord, Seock-Ah Im, Patrick A Ott, Sarina A Piha-Paul, Phillipe L Bedard, Jasgit Sachev, Christophe Le Tourneau, Emilie M J van Brummelen, Andreea Varga, Roberto Salgado, Sherene Loi, Sanatan Saraf, Dina Pietrangelo, Vassiliki Karantza, Antoinette R Tan
PURPOSE: We investigated the safety and antitumor activity of the anti-programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor‒positive (ER+)/human epidermal growth factor receptor 2-negative (HER2- ) advanced breast cancer with programmed death ligand 1‒positive (PD-L1‒positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study. EXPERIMENTAL DESIGN: Patients with ER+/HER2- advanced breast cancer with PD-L1‒positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity...
March 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qin Wang, Luisette Delva, Paul H Weinreb, Robert B Pepinsky, Danielle Graham, Elvana Veizaj, Anne E Cheung, Weiping Chen, Ivan Nestorov, Ellen Rohde, Robin Caputo, Geoffrey M Kuesters, Tonika Bohnert, Liang-Shang Gan
BACKGROUND: Many studies have focused on the challenges of small molecule uptake across the blood-brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration-time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure...
March 20, 2018: Fluids and Barriers of the CNS
Mariola Śliwińska-Mossoń, Stanisław Milnerowicz, Halina Milnerowicz
The present study was conducted to ascertain how cigarette smoke affects the exocrine-endocrine interactions of the human pancreas with diabetes mellitus secondary to pancreatic diseases (type 3c). Blood has been collected from smoking and non-smoking healthy individuals as well as from patients with diagnosed chronic pancreatitis and diabetes type 3c. The concentrations of interleukin-6, endothelin-1 and insulin in the plasma were determined by enzyme-linked immunosorbent assay (ELISA) tests. The activities of amylase and lipase in the serum, as well as the lipid profile, creatinine, uric acid and urea concentrations, were measured using colorimetric methods...
March 1, 2018: Diabetes & Vascular Disease Research
Hiroki Wakabayashi, Takahiko Hamaguchi, Nobuto Nagao, Sho Kato, Takahiro Iino, Tomoki Nakamura, Akihiro Sudo
BACKGROUND: Interleukin-6 (IL-6) is a potent inflammatory cytokine that appears to play a key role in cancer growth and metastasis. In the present study, the effects of IL-6 receptor (IL-6R) on breast cancer aggressiveness and bone metastases were investigated. METHODS: MDA-MB-231 (MDA-231) cells were treated in the presence or absence of anti-human IL-6 receptor (IL-6R) monoclonal antibody and examined with respect to cell survival. The expressions of signal transducer and activator of transcription 3 (Stat3), vascular endothelial growth factor (VEGF), and receptor activator of NF-κB (RANK) were analyzed by SDS-PAGE and immunoblotting...
March 19, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Takeshi Yuasa, Shinji Urakami, Junji Yonese
Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice...
March 20, 2018: International Journal of Clinical Oncology
Shinji Yamada, Shunsuke Itai, Mika K Kaneko, Yukinari Kato
Programmed cell death-ligand 1 (PD-L1), which is a ligand of programmed cell death-1 (PD-1), is a type I transmembrane glycoprotein that is expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells. There is a strong correlation between human PD-L1 (hPD-L1) expression on tumor cells and negative prognosis in cancer patients. In this study, we produced a novel anti-hPD-L1 monoclonal antibody (mAb), L1 Mab-4 (IgG2b , kappa), using cell-based immunization and screening (CBIS) method and investigated hPD-L1 expression in oral cancers...
March 2018: Biochemistry and Biophysics Reports
Cem Gabay, Jérôme Msihid, Moshe Zilberstein, Caroline Paccard, Yong Lin, Neil M H Graham, Anita Boyapati
Introduction: Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs...
2018: RMD Open
Maria José Costa, Jyothirmayee Kudaravalli, Wen-Hui Liu, Jeffrey Stock, Sophanna Kong, Shu-Hui Liu
The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development...
2018: PloS One
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