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bispecific scFv

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https://www.readbyqxmd.com/read/29213270/nanobodies-and-nanobody-based-human-heavy-chain-antibodies-as-antitumor-therapeutics
#1
REVIEW
Peter Bannas, Julia Hambach, Friedrich Koch-Nolte
Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa) of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL). The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL). VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29186655/engineering-bifunctional-antibodies-with-constant-region-fusion-architectures
#2
Juanjuan Du, Yu Cao, Yan Liu, Ying Wang, Yong Zhang, Guangsen Fu, Yuhan Zhang, Lucy Lu, Xiaozhou Luo, Chan Hyuk Kim, Peter G Schultz, Feng Wang
We report a method to generate bifunctional antibodies by grafting full-length proteins into constant region loops of a full-length antibody or an antigen-binding fragment (Fab). The fusion proteins retain the antigen binding activity of the parent antibody but have an additional activity associated with the protein insert. The engineered antibodies have excellent in-vitro activity, physiochemical properties, and stability. Among these, a Her2×CD3 bispecific antibody (BsAb) was constructed by inserting an anti-Her2 ScFv into an anti-CD3 Fab...
November 29, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29151956/strategies-for-bispecific-single-chain-antibody-in-cancer-immunotherapy
#3
REVIEW
Shu-Juan Zhou, Jia Wei, Shu Su, Fang-Jun Chen, Yu-Dong Qiu, Bao-Rui Liu
Genetic engineering has resulted in more than 50 recombinant bispecific antibody formats over the past two decades. Bispecific scFv antibodies represent a successful and promising immunotherapy platform that retargets cytotoxic T cells to tumor cells, with one scFv directed to tumor-associated antigens and the other to T cells. Based on this antibody construct, strategies for both specific tumor targeting and T cell activation are reviewed here. Three distinct types of tumor antigens are considered to optimize specificity and safety in bispecific scFv based treatment: cancer-testis antigens, neo-antigens and virus-associated antigens...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29139290/decomposing-dynamical-couplings-in-mutated-scfv-antibody-fragments-into-stabilizing-and-destabilizing-effects
#4
Azhagiya Singam Ettayapuram Ramaprasad, Shahid Uddin, Jose Casas-Finet, Donald J Jacobs
Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response...
November 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29107128/targeted-cancer-therapy-through-antibody-fragments-decorated-nanomedicines
#5
REVIEW
Abbas Alibakhshi, Fatemeh Abarghooi Kahaki, Shahrzad Ahangarzadeh, Hajar Yaghoobi, Fatemeh Yarian, Roghaye Arezumand, Javad Ranjbari, Ahad Mokhtarzadeh, Miguel de la Guardia
Active targeting in cancer nanomedicine, for improved delivery of agents and diagnose, has been reviewed as a successful way for facilitating active uptake of theranostic agents by the tumor cells. The application of a targeting moiety in the targeted carrier complexes can play an important role in differentiating between tumor and healthy tissues. The pharmaceutical carriers, as main part of complexes, can be polymeric nanoparticles, micelles, liposomes, nanogels and carbon nanotubes. The antibodies are among the natural ligands with highest affinity and specificity to target pharmaceutical nanoparticle conjugates...
November 3, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28993773/targeting-malignant-brain-tumors-with-antibodies
#6
REVIEW
Rok Razpotnik, Neža Novak, Vladka Čurin Šerbec, Uros Rajcevic
Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood-brain barrier (BBB) makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs), and cell-based approaches...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28937681/primary-t-cells-for-mrna-mediated-immunotoxin-delivery
#7
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/28881778/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#8
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
https://www.readbyqxmd.com/read/28870833/multivalent-interactions-between-streptavidin-based-pretargeting-fusion-proteins-and-cell-receptors-impede-efficient-internalization-of-biotinylated-nanoparticles
#9
Christina L Parker, Qi Yang, Bing Yang, Justin D McCallen, Steven I Park, Samuel K Lai
Pretargeting represents a promising strategy to enhance delivery of nanoparticles. The strategy involves first introducing bispecific antibodies or fusion proteins (BFP) that can bind specific epitopes on target cells with one arm, and use the other arm to capture subsequently administered effector molecules, such as radionuclides or drug-loaded nanoparticles. Nevertheless, it remains unclear whether BFP that bind slowly- or non-internalizing epitopes on target cells can facilitate efficient intracellular delivery...
November 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28864569/modification-of-antibody-function-by-mutagenesis
#10
James R Dasch, Amy L Dasch
The ability to "fine-tune" recombinant antibodies by mutagenesis separates recombinant antibodies from hybridoma-derived antibodies because the latter are locked with respect to their properties. Recombinant antibodies can be modified to suit the application: Changes in isotype, format (e.g., scFv, Fab, bispecific antibodies), and specificity can be made once the heavy- and light-chain sequences are available. After immunoglobulin heavy and light chains for a particular antibody have been cloned, the binding site-namely, the complementarity determining regions (CDR)-can be manipulated by mutagenesis to obtain antibody variants with improved properties...
September 1, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28819027/combination-therapy-with-bispecific-antibodies-and-pd-1-blockade-enhances-the-antitumor-potency-of-t-cells
#11
Chien-Hsing Chang, Yang Wang, Rongxiu Li, Diane L Rossi, Donglin Liu, Edmund A Rossi, Thomas M Cardillo, David M Goldenberg
The DOCK-AND-LOCK (DNL) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL to generate a novel class of trivalent bispecific antibodies (bsAb), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different antitumor Fabs. Here, we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively...
October 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28765298/creation-of-recombinant-antibodies-using-degenerate-oligonucleotides-to-amplify-heavy-and-light-chain-sequences
#12
James R Dasch, Amy L Dasch
Recombinant antibodies can be modified to suit the application: Changes in isotype, format (e.g., scFv, Fab, bispecific antibodies), and specificity can be made once the heavy- and light-chain sequences are available. However, Ig gene families are large and the variable region gene segments are, indeed, variable, precluding the use of polymerase chain reaction (PCR) with two simple primers to amplify the heavy and light chain gene segments. A wide variety of approaches have been taken to obviate the complexity of the variable region gene segments, including using "universal" or degenerate primers...
August 1, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/28680755/bispecific-antibody-does-not-induce-t-cell-death-mediated-by-chimeric-antigen-receptor-against-disialoganglioside-gd2
#13
Sayed Shahabuddin Hoseini, Konstantin Dobrenkov, Dmitry Pankov, Xiaoliang L Xu, Nai-Kong V Cheung
Chimeric antigen receptors (CAR) and bispecific antibodies (BsAb) are two powerful immunotherapy approaches for retargeting lymphocytes toward cancer cells. Despite their success in lymphoblastic leukemia, solid tumors have been more recalcitrant. Identifying therapeutic barriers facing CAR-modified (CART) or BsAb-redirected T (BsAb-T) cells should facilitate their clinical translation to solid tumors. Novel lentiviral vectors containing low-affinity or high-affinity 4-1BB second-generation anti-GD2 (disialoganglioside) CARs were built to achieve efficient T cell transduction...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28669053/efficient-targeting-of-cd13-on-cancer-cells-by-the-immunotoxin-scfv13-eta-and-the-bispecific-scfv-13xds16
#14
Elena Grieger, Gerrit Gresch, Judith Niesen, Mira Woitok, Stefan Barth, Rainer Fischer, Rolf Fendel, Christoph Stein
PURPOSE: Treatment of cancer using standard chemotherapy still offers a poor prognosis combined with severe side effects. Novel antibody-based therapies have been shown to overcome low efficiency and lack of selectivity by targeting cancer-associated antigens, such as aminopeptidase CD13. METHODS: We isolated a high-affinity CD13-specific single-chain fragment variable (scFv13) from a phage display library of V-genes from mice immunized with soluble antigen. An immunotoxin comprising the scFv13 and a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA', scFv13-ETA') and a bispecific scFv targeting CD13 and CD16 simultaneously (bsscFv[13xds16]) was generated and investigated for their therapeutic potential...
November 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28605874/the-pharmacological-efficacy-of-the-anti-il17-scfv-and-stnfr1-bispecific-fusion-protein-in-inflammation-mouse-stimulated-by-lps
#15
Yongbi Yang, Teng Zhang, Hongxue Cao, Dan Yu, Tong Zhang, Shaojuan Zhao, Xiaohui Jing, Liying Song, Yunye Liu, Ruixiang Che, Xin Liu, Deshan Li, Guiping Ren
Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our study found that a bispecific fusion protein treatment can ameliorate the lung injury induced by LPS. However, the molecular mechanisms which bispecific fusion protein ameliorates acute lung injury remain unclear. In this study, we found that the bispecific fusion protein treatment inhibited the nuclear transcription of NF-κB in confocal laser scanning fluorescence microscopy, the bispecific fusion protein exert protective effects in the cell model of ALI induced by lipopolysaccharide (LPS) via inhibiting the nuclear factor κB (NF-κB) signaling pathway and mediate inflammation...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28596941/highly-specific-and-effective-targeting-of-egfrviii-positive-tumors-with-tandab-antibodies
#16
Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Stefan Knackmuss, Michael Weichel, Thorsten Gantke, Vera Molkenthin, Eugene A Zhukovsky, Michael Tesar, Martin Treder
To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28584141/multimechanistic-monoclonal-antibodies-mabs-targeting-staphylococcus-aureus-alpha-toxin-and-clumping-factor-a-activity-and-efficacy-comparisons-of-a-mab-combination-and-an-engineered-bispecific-antibody-approach
#17
C Tkaczyk, S Kasturirangan, A Minola, O Jones-Nelson, V Gunter, Y Y Shi, K Rosenthal, V Aleti, E Semenova, P Warrener, D Tabor, C K Stover, D Corti, G Rainey, B R Sellman
Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant S...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28572527/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#18
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...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28500232/nkg2d-ligand-targeted-bispecific-t-cell-engagers-lead-to-robust-antitumor-activity-against-diverse-human-tumors
#19
Claire Godbersen, Tiffany A Coupet, Amelia M Huehls, Tong Zhang, Michael B Battles, Jan L Fisher, Marc S Ernstoff, Charles L Sentman
Two new bispecific T-cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3ε binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3ε on human T cells...
July 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28450393/immunoglobulin-domain-interface-exchange-as-a-platform-technology-for-the-generation-of-fc-heterodimers-and-bispecific-antibodies
#20
Darko Skegro, Cian Stutz, Romain Ollier, Emelie Svensson, Paul Wassmann, Florence Bourquin, Thierry Monney, Sunitha Gn, Stanislas Blein
Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains...
June 9, 2017: Journal of Biological Chemistry
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