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Bispecific antibody

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https://www.readbyqxmd.com/read/28932173/efficient-and-inexpensive-transient-expression-of-multispecific-multivalent-antibodies-in-expi293-cells
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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/28900504/platelet-targeted-delivery-of-peripheral-blood-mononuclear-cells-to-the-ischemic-heart-restores-cardiac-function-after-ischemia-reperfusion-injury
#8
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
#9
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
#10
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
#11
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
#12
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/28887948/psoriasis-pathogenesis-and-the-development-of-novel-targeted-immune-therapies
#13
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/28881778/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#14
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/28881627/structural-basis-of-a-novel-heterodimeric-fc-for-bispecific-antibody-production
#15
Hudie Wei, Haiyan Cai, Yuhao Jin, Pilin Wang, Qingqing Zhang, Yihui Lin, Weixiao Wang, Jinke Cheng, Naiyan Zeng, Ting Xu, Aiwu Zhou
Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc for bispecific antibodies production by combining the knob-into-hole and electrostatic steering strategies where a bulky hydrophobic residue Phe405 of the IgG CH3 interface is mutated to a charged residue Lys and Lys409 of the corresponding CH3 domain is mutated to Ala. The crystal structure of this Fc heterodimer solved here at 2.7Å resolution revealed how these two mutations resulted a complementary binding interface and explained why F405K mutation could effectively inhibit Fc homodimer formation during protein expression...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28874545/increasing-the-breadth-and-potency-of-response-to-the-seasonal-influenza-virus-vaccine-by-immune-complex-immunization
#16
Jad Maamary, Taia T Wang, Gene S Tan, Peter Palese, Jeffrey V Ravetch
The main barrier to reduction of morbidity caused by influenza is the absence of a vaccine that elicits broad protection against different virus strains. Studies in preclinical models of influenza virus infections have shown that antibodies alone are sufficient to provide broad protection against divergent virus strains in vivo. Here, we address the challenge of identifying an immunogen that can elicit potent, broadly protective, antiinfluenza antibodies by demonstrating that immune complexes composed of sialylated antihemagglutinin antibodies and seasonal inactivated flu vaccine (TIV) can elicit broadly protective antihemagglutinin antibodies...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28873441/a-fully-humanized-igg-like-bispecific-antibody-for-effective-dual-targeting-of-cxcr3-and-ccr6
#17
Remy Robert, Laurent Juglair, Ee X Lim, Caroline Ang, Carl J H Wang, Gregor Ebert, Olan Dolezal, Charles R Mackay
Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic...
2017: PloS One
https://www.readbyqxmd.com/read/28870833/multivalent-interactions-between-streptavidin-based-pretargeting-fusion-proteins-and-cell-receptors-impede-efficient-internalization-of-biotinylated-nanoparticles
#18
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, which in turn can 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. Here, we investigated the cellular uptake of biotin-functionalized nanoparticles with streptavidin-scFv against TAG-72, a membrane protein on Jurkat T-cell leukemia cell...
September 1, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28864715/opposites-attract-in-bispecific-antibody-engineering
#19
Marit J van Gils, Rogier W Sanders
Bispecific antibodies show great promise as intrinsic combination therapies, but often suffer from poor physiochemical properties, many times related to poor heterodimerization. De Nardis et al. identify specific electrostatic interactions that facilitate efficient heterodimerization, resulting in bispecific antibodies with physiochemical properties very similar to those of naturally occurring antibodies. This provides a new platform for the treatment of an array of diseases from cancer and autoimmune diseases to infectious diseases...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28864569/modification-of-antibody-function-by-mutagenesis
#20
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
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