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https://www.readbyqxmd.com/read/28938115/a-human-bi-specific-antibody-against-zika-virus-with-high-therapeutic-potential
#1
Jiaqi Wang, Marco Bardelli, Diego A Espinosa, Mattia Pedotti, Thiam-Seng Ng, Siro Bianchi, Luca Simonelli, Elisa X Y Lim, Mathilde Foglierini, Fabrizia Zatta, Stefano Jaconi, Martina Beltramello, Elisabetta Cameroni, Guntur Fibriansah, Jian Shi, Taylor Barca, Isabel Pagani, Alicia Rubio, Vania Broccoli, Elisa Vicenzi, Victoria Graham, Steven Pullan, Stuart Dowall, Roger Hewson, Simon Jurt, Oliver Zerbe, Karin Stettler, Antonio Lanzavecchia, Federica Sallusto, Andrea Cavalli, Eva Harris, Shee-Mei Lok, Luca Varani, Davide Corti
Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28937681/primary-t-cells-for-mrna-mediated-immunotoxin-delivery
#2
R Eggers, A Philippi, M O Altmeyer, F Breinig, M J Schmitt
Immune cells become increasingly attractive as delivery system for immunotoxins in cancer therapy in order to reduce the intrinsic toxicity and severe side effects of chimeric protein toxins. In this study, we investigated the potential of human primary T cells to deliver a secreted immunotoxin through transient mRNA transfection. The chimeric protein toxin was directed towards the neovasculature of cancer cells by fusing a truncated version of Pseudomonas exotoxin A (PE38) to human vascular endothelial growth factor (VEGF) and to the single chain variable fragment (scFv) of anti-Her2/neu...
September 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28935938/an-engineered-bispecific-dna-encoded-igg-antibody-protects-against-pseudomonas-aeruginosa-in-a-pneumonia-challenge-model
#3
Ami Patel, Antonio DiGiandomenico, Ashley E Keller, Trevor R F Smith, Daniel H Park, Stephanie Ramos, Katherine Schultheis, Sarah T C Elliott, Janess Mendoza, Kate E Broderick, Megan C Wise, Jian Yan, Jingjing Jiang, Seleeke Flingai, Amir S Khan, Kar Muthumani, Laurent Humeau, Lily I Cheng, Leslie Wachter-Rosati, C Kendall Stover, Niranjan Y Sardesai, David B Weiner
The impact of broad-spectrum antibiotics on antimicrobial resistance and disruption of the beneficial microbiome compels the urgent investigation of bacteria-specific approaches such as antibody-based strategies. Among these, DNA-delivered monoclonal antibodies (DMAbs), produced by muscle cells in vivo, potentially allow the prevention or treatment of bacterial infections circumventing some of the hurdles of protein IgG delivery. Here, we optimize DNA-delivered monoclonal antibodies consisting of two potent human IgG clones, including a non-natural bispecific IgG1 candidate, targeting Pseudomonas aeruginosa...
September 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28932173/efficient-and-inexpensive-transient-expression-of-multispecific-multivalent-antibodies-in-expi293-cells
#4
Xiaotian T Fang, Dag Sehlin, Lars Lannfelt, Stina Syvänen, Greta Hultqvist
BACKGROUND: Immunotherapy is a very fast expanding field within drug discovery and, hence, rapid and inexpensive expression of antibodies would be extremely valuable. Antibodies are, however, difficult to express. Multifunctional antibodies with additional binding domains further complicate the expression. Only few protocols describe the production of tetravalent bispecific antibodies and all with limited expression levels.. METHODS: Here, we describe a protocol that can produce functional tetravalent, bispecific antibodies at around 22 mg protein/l to a low cost...
2017: Biological Procedures Online
https://www.readbyqxmd.com/read/28931402/recent-advances-of-bispecific-antibodies-in-solid-tumors
#5
REVIEW
Shengnan Yu, Anping Li, Qian Liu, Xun Yuan, Hanxiao Xu, Dechao Jiao, Richard G Pestell, Xinwei Han, Kongming Wu
Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated...
September 20, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28927784/safety-and-efficacy-of-blinatumomab-in-combination-with-a-tyrosine-kinase-inhibitor-for-the-treatment-of-relapsed-philadelphia-chromosome-positive-leukemia
#6
Rita Assi, Hagop Kantarjian, Nicholas J Short, Naval Daver, Koichi Takahashi, Guillermo Garcia-Manero, Courtney DiNardo, Jan Burger, Jorge Cortes, Nitin Jain, William Wierda, Salim Chamoun, Marina Konopleva, Elias Jabbour
OBJECTIVE: The treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia has been revolutionized with the introduction of tyrosine kinase inhibitors (TKIs) and the combination of these agents with chemotherapy. Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed setting and independent of BCR-ABL1 mutational status, including T315I. The combination of blinatumomab with a TKI may further improve outcomes for this high-risk population, including higher eradication of minimal residual disease and minimize the use of chemotherapy...
August 18, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28922593/cysteine-silac-mass-spectrometry-enables-the-identification-and-quantitation-of-scrambled-inter-chain-disulfide-bonds-preservation-of-native-heavy-light-chain-pairing-in-bispecific-iggs-generated-by-controlled-fab-arm-exchange
#7
Ewald T J van den Bremer, Aran F Labrijn, Ramon van den Boogaard, Patrick Priem, Kai Scheffler, Joost P M Melis, Janine Schuurman, Paul Parren, Rob N de Jong
Bispecific antibodies (bsAbs) are one of the most versatile and promising pharmaceutical innovations for countering heterogeneous and refractory disease by virtue of their ability to bind two distinct antigens. One critical quality attribute of bsAb formation requiring investigation is the potential randomization of cognate heavy chain (H)/light (L) chain pairing, which could occur to a varying extent dependent on bsAb format and the production platform. To assess the content of such HL chain-swapped reaction products with high sensitivity, we developed cysteine-SILAC, a method that facilitates the detailed characterization of disulfide-bridged peptides by mass-spectrometry...
September 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28921818/blinatumomab-activity-in-a-patient-with-down-syndrome-b-precursor-acute-lymphoblastic-leukemia
#8
Aman Wadhwa, Matthew A Kutny, Ana C Xavier
Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP-ALL, it is likely that MRD levels are also of prognostic significance in DS BP-ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL...
September 17, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28919896/vhh-based-bispecific-antibodies-targeting-cytokine-production
#9
Maxim A Nosenko, Kamar-Sulu N Atretkhany, Vladislav V Mokhonov, Grigory A Efimov, Andrey A Kruglov, Sergei V Tillib, Marina S Drutskaya, Sergei A Nedospasov
Proinflammatory cytokines, such as TNF, IL-6, and IL-1, play pathogenic roles in multiple diseases and are attractive targets for biologic drugs. Because proinflammatory cytokines possess non-redundant protective and immunoregulatory functions, their systemic neutralization carries the potential for unwanted side effects. Therefore, next-generation anti-cytokine therapies would seek to selectively neutralize pathogenic cytokine signaling, leaving normal function intact. Fortunately, the biology of proinflammatory cytokines provides several such opportunities...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28918646/depletion-of-gut-resident-ccr5-cells-for-hiv-cure-strategies
#10
David Patrick Merriam, Connie Chen, Gema Mendez-Lagares, Kenneth Rogers, Anthony Michaels, Jiangli Yan, Paul Casaz, Keith Reimann, Francois Villenger, Dennis J Hartigan-O'Connor
The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5+ cells, because these cells are the targets of transmissible virus. Restriction of the CCR5+ reservoir, particularly in gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5+ cells have been described, but none have been tested in vivo in non-human primates and the extent of achievable depletion from tissues is not known. Here we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5+ cells in young rhesus macaques...
September 17, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28902983/solid-tumor-immunotherapy-with-t-cell-engager-armed-oncolytic-viruses
#11
REVIEW
Eleanor M Scott, Margaret R Duffy, Joshua D Freedman, Kerry D Fisher, Leonard W Seymour
Oncolytic viruses (OVs) are novel anticancer agents that combine direct cancer cell killing with the stimulation of antitumor immunity. In addition, OVs can be engineered to deliver biological therapeutics directly to tumors, offering unique opportunities to design multimodal anticancer strategies. Here, a case for arming OVs with bispecific T cell engagers (BiTEs) is put forward. BiTEs redirect the cytotoxicity of polyclonal T cells to target cells of choice, and have demonstrated efficacy against a number of hematological cancers...
September 13, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28900504/platelet-targeted-delivery-of-peripheral-blood-mononuclear-cells-to-the-ischemic-heart-restores-cardiac-function-after-ischemia-reperfusion-injury
#12
Melanie Ziegler, Xiaowei Wang, Bock Lim, Ephraem Leitner, Franco Klingberg, Victoria Ching, Yu Yao, Dexing Huang, Xiao-Ming Gao, Helen Kiriazis, Xiao-Jun Du, Jody J Haigh, Alex Bobik, Christoph E Hagemeyer, Ingo Ahrens, Karlheinz Peter
One of the major hurdles in intravenous regenerative cell therapy is the low homing efficiency to the area where these cells are needed. To increase cell homing toward areas of myocardial damage, we developed a bispecific tandem single-chain antibody (Tand-scFvSca-1+GPIIb/IIIa) that binds with high affinity to activated platelets via the activated glycoprotein (GP)IIb/IIIa receptor, and to a subset of peripheral blood mononuclear cells (PBMC) which express the stem cell antigen-1 (Sca-1) receptor. Methods: The Tand-scFvSca-1+GPIIb/IIIa was engineered, characterized and tested in a mouse model of ischemia-reperfusion (IR) injury applying left coronary artery occlusion for 60 min...
2017: Theranostics
https://www.readbyqxmd.com/read/28898214/blood-feud-erupts-over-roche-s-bispecific-antibody-for-hemophilia
#13
Elie Dolgin
No abstract text is available yet for this article.
September 11, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28898162/modulation-of-protein-a-binding-allows-single-step-purification-of-mouse-bispecific-antibodies-that-retain-fcrn-binding
#14
Adam Zwolak, Anthony A Armstrong, Susan H Tam, Jose R Pardinas, Dennis R Goulet, Songmao Zheng, Kerry Brosnan, Eva Emmell, Jeffrey Luo, Gary L Gilliland, Mark L Chiu
The increased number of bispecific antibodies (BsAb) under therapeutic development has resulted in a need for mouse surrogate BsAbs. Here, we describe a one-step method for generating highly pure mouse BsAbs suitable for in vitro and in vivo studies. We identify two mutations in the mouse IgG2a and IgG2b Fc region: one that eliminates protein A binding and one that enhances protein A binding by 8-fold. We show that BsAbs harboring these mutations can be purified from the residual parental monoclonal antibodies in one step using protein A affinity chromatography...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#15
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28895560/tyrosine-kinase-inhibition-increases-the-cell-surface-localization-of-flt3-itd-and-enhances-flt3-directed-immunotherapy-of-acute-myeloid-leukemia
#16
K Reiter, H Polzer, C Krupka, A Maiser, B Vick, M Rothenberg-Thurley, K H Metzeler, D Dörfel, H R Salih, G Jung, E Nößner, I Jeremias, W Hiddemann, H Leonhardt, K Spiekermann, M Subklewe, P A Greif
The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28894181/rigidly-connected-multispecific-artificial-binders-with-adjustable-geometries
#17
Yufan Wu, Alexander Batyuk, Annemarie Honegger, Fabian Brandl, Peer R E Mittl, Andreas Plückthun
Multivalent binding proteins can gain biological activities beyond what is inherent in the individual binders, by bringing together different target molecules, restricting their conformational flexibility or changing their subcellular localization. In this study, we demonstrate a method to build up rigid multivalent and multispecific scaffolds by exploiting the modular nature of a repeat protein scaffold and avoiding flexible linkers. We use DARPins (Designed Ankyrin Repeat Proteins), synthetic binding proteins based on the Ankyrin-repeat protein scaffold, as binding units...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28887948/psoriasis-pathogenesis-and-the-development-of-novel-targeted-immune-therapies
#18
REVIEW
Jason E Hawkes, Tom C Chan, James G Krueger
Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition...
September 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28887049/an-fda-oncology-analysis-of-cd3-bispecific-constructs-and-first-in-human-dose-selection
#19
Haleh Saber, Pedro Del Valle, Tiffany K Ricks, John K Leighton
We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab...
September 5, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28881778/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#20
Yanyu Bi, Hua Jiang, Peng Wang, Bo Song, Huamao Wang, Xianming Kong, Zonghai Li
There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells...
August 8, 2017: Oncotarget
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