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bispecific monoclonal

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https://www.readbyqxmd.com/read/29158380/anti-sirp%C3%AE-antibody-immunotherapy-enhances-neutrophil-and-macrophage-antitumor-activity
#1
Nan Guo Ring, Dietmar Herndler-Brandstetter, Kipp Weiskopf, Liang Shan, Jens-Peter Volkmer, Benson M George, Melanie Lietzenmayer, Kelly M McKenna, Tejaswitha J Naik, Aaron McCarty, Yunjiang Zheng, Aaron M Ring, Richard A Flavell, Irving L Weissman
Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-α (SIRPα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPα with high affinity and disrupts its binding to CD47...
November 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29129068/structural-and-functional-characterization-of-a-hole-hole-homodimer-variant-in-a-knob-into-hole-bispecific-antibody
#2
Hui-Min Zhang, Charlene Li, Ming Lei, Victor Lundin, Ho Young Lee, Milady Ninonuevo, Kevin Lin, Guanghui Han, Wendy Sandoval, Dongsheng Lei, Gang Ren, Jennifer Zhang, Hongbin Liu
Bispecific antibodies have great potential to be the next-generation biotherapeutics due to their ability to simultaneously recognize two different targets. Compared to conventional monoclonal antibodies, knob-into-hole bispecific antibodies face unique challenges in production and characterization due to the increase in variant possibilities, such as homodimerization in covalent and non-covalent forms. In this study, a storage- and pH-sensitive hydrophobic interaction chromatography (HIC) profile change was observed for the hole-hole homodimer, and the multiple HIC peaks were explored and shown to be conformational isomers...
November 12, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29082835/efficacy-and-safety-of-bispecific-t-cell-engager-blinatumomab-and-the-potential-to-improve-leukemia-free-survival-in-b-cell-acute-lymphoblastic-leukemia
#3
Josep-Maria Ribera
Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19(+) target B cells of ALL inducing their serial lysis. Areas covered: This review focuses on the efficacy and safety of blinatumomab used for the treatment of relapsed/refractory (R/R) ALL and minimal residual disease (MRD)-positive B-cell precursor (BCP) ALL in adults and children, as well as the future prospects of this drug in the treatment of ALL...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29042366/emicizumab-a-bispecific-antibody-recognizing-coagulation-factors-ix-and-x-how-does-it-actually-compare-to-factor-viii
#4
Peter J Lenting, Cécile V Denis, Olivier D Christophe
During the last decade, the development of improved and novel approaches for the treatment of hemophilia A has expanded tremendously. These approaches include factor VIII (FVIII) with extended half-life (e.g. FVIII-Fc and PEGylated FVIII), monoclonal antibodies targeting tissue factor pathway inhibitor, si-RNA to reduce antithrombin expression and the bispecific antibody ACE910/Emicizumab. Emicizumab is a bispecific antibody recognizing both the enzyme factor IXa (FIXa) and the substrate factor X (FX). By simultaneously binding enzyme and substrate, Emicizumab mimics some part of the function exerted by the original cofactor FVIII, in that it promotes co-localization of the enzyme/substrate complex...
October 17, 2017: Blood
https://www.readbyqxmd.com/read/29037466/the-use-of-a-groel-bli-biosensor-to-rapidly-assess-pre-aggregate-populations-for-antibody-solutions-exhibiting-different-stability-profiles
#5
Samantha E Pace, Sangeeta B Joshi, Reza Esfandiary, Robert Stadelman, Steven M Bishop, C R Middaugh, Mark Fisher, David B Volkin
An automated method using biotinylated GroEL-streptavidin biosensors with Bio-Layer Interferometry (GroEL-BLI) was evaluated to detect the formation of transiently formed, pre-aggregate species in various pharmaceutically relevant monoclonal antibody (mAb) samples. The relative aggregation propensity of various IgG1 and IgG4 mAbs was rank-ordered using the GroEL-BLI biosensor method, and the least stable IgG4 mAb was subjected to different stresses including elevated temperatures, acidic pH, and addition of guanidine-HCl...
October 13, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28990505/biological-therapy-of-hematologic-malignancies-toward-a-chemotherapy-free-era
#6
Pavel Klener, Tomas Etrych, Pavel Klener
Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short...
October 6, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28985411/tethered-variable-cl-bispecific-igg-an-antibody-platform-for-rapid-bispecific-antibody-screening
#7
Hok Seon Kim, Diana Ronai Dunshee, Angie Yee, Raymond K Tong, Ingrid Kim, Farzam Farahi, Jo-Anne Hongo, James A Ernst, Junichiro Sonoda, Christoph Spiess
Bispecific antibodies offer a clinically validated platform for drug discovery. In generating functionally active bispecific antibodies, it is necessary to identify a unique parental antibody pair to merge into a single molecule. However, technologies that allow high-throughput production of bispecific immunoglobulin Gs (BsIgGs) for screening purposes are limited. Here, we describe a novel bispecific antibody format termed tethered-variable CLBsIgG (tcBsIgG) that allows robust production of intact BsIgG in a single cell line, concurrently ensuring cognate light chain pairing and preserving key antibody structural and functional properties...
September 1, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28984651/new-anti-her2-agents-from-second-generation-tyrosine-kinases-inhibitors-to-bifunctional-antibodies
#8
Joseph Gligorov, Sandrine Richard, Vladimir Todorovic
PURPOSE OF REVIEW: HER2-positive breast cancers have benefited since the end of the twentieth century, not only from the improvement of biological knowledge, but also from major technological advances. The latter allowed the synthesis of the first generation of enzymatic inhibitors of the HER receptor family such as lapatinib, but above all, monoclonal antibodies such as trastuzumab or pertuzumab having profoundly modified the management of these cancers. However, despite outstanding progresses, there are still patients who are not cured with these first-generation treatments, and they will need new approaches to improve disease control and impact patients' survival...
November 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28955654/the-role-of-novel-immunotherapies-in-non-hodgkin-lymphoma
#9
Allyson Pishko, Sunita D Nasta
Immunotherapy is an evolving modality in the treatment of non-Hodgkin lymphoma. Vaccinations with patient-specific tumor-derived antigens have been developed to strengthen immune response to tumor. The success of rituximab, a monoclonal antibody for CD20 on malignant B-cells, fueled further immunotherapy research. The power of the immune system to fight hematologic malignancies is seen in allogeneic stem cell transplant, where donor T cells attack residual malignant cells in the recipient. Now, three innovative therapeutic immunotherapy classes (I) adoptive cellular therapy; (II) immune-checkpoint inhibitors; and (III) novel antibody therapies show promising results in non-Hodgkin lymphoma...
February 2017: Translational Cancer Research
https://www.readbyqxmd.com/read/28938115/a-human-bi-specific-antibody-against-zika-virus-with-high-therapeutic-potential
#10
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/28935938/an-engineered-bispecific-dna-encoded-igg-antibody-protects-against-pseudomonas-aeruginosa-in-a-pneumonia-challenge-model
#11
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/28927784/safety-and-efficacy-of-blinatumomab-in-combination-with-a-tyrosine-kinase-inhibitor-for-the-treatment-of-relapsed-philadelphia-chromosome-positive-leukemia
#12
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/28898162/modulation-of-protein-a-binding-allows-single-step-purification-of-mouse-bispecific-antibodies-that-retain-fcrn-binding
#13
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...
November 2017: MAbs
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#14
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...
November 2017: MAbs
https://www.readbyqxmd.com/read/28874545/increasing-the-breadth-and-potency-of-response-to-the-seasonal-influenza-virus-vaccine-by-immune-complex-immunization
#15
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 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28870833/multivalent-interactions-between-streptavidin-based-pretargeting-fusion-proteins-and-cell-receptors-impede-efficient-internalization-of-biotinylated-nanoparticles
#16
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/28852148/semi-synthetic-vnar-libraries-screened-against-therapeutic-antibodies-primarily-deliver-anti-idiotypic-binders
#17
Doreen Könning, Laura Rhiel, Martin Empting, Julius Grzeschik, Carolin Sellmann, Christian Schröter, Stefan Zielonka, Stephan Dickgießer, Thomas Pirzer, Desislava Yanakieva, Stefan Becker, Harald Kolmar
Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark-derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3-randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28834699/t-cell-engaging-bispecific-antibody-t-bsab-from-technology-to-therapeutics
#18
REVIEW
Z Wu, N V Cheung
Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials...
August 20, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28821272/novel-immunotherapies-for-adult-patients-with-b-lineage-acute-lymphoblastic-leukemia
#19
REVIEW
Guoqing Wei, Jiasheng Wang, He Huang, Yanmin Zhao
The past decade witnessed the rapid development of adult B-lineage acute lymphoblastic leukemia (ALL) treatment. Beyond the development of chemotherapy regimens, immunotherapy is starting a new era with unprecedented complete remission (CR) rate. Targeting B-lineage-specific surface markers such as CD19, CD20, CD22, or CD52, immunotherapy has been demonstrating promising clinical results. Among the immunotherapeutic methods, naked monoclonal antibodies (mAbs), antibody-drug conjugate (ADC), bispecific T cell engager (BiTE), and chimeric antigen receptor (CAR) T cells are the main types...
August 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28805498/gingiskhan%C3%A2-protease-cleavage-allows-a-high-throughput-antibody-to-fab-conversion-enabling-direct-functional-assessment-during-lead-identification-of-human-monoclonal-and-bispecific-igg1-antibodies
#20
Jörg Moelleken, Manuel Endesfelder, Christian Gassner, Sabine Lingke, Simone Tomaschek, Oksana Tyshchuk, Stefan Lorenz, Ulrike Reiff, Michael Mølhøj
The determination of the binding strength of immunoglobulins (IgGs) to targets can be influenced by avidity when the targets are soluble di- or multimeric proteins, or associated to cell surfaces, including surfaces introduced from heterogeneous assays. However, for the understanding of the contribution of a second drug-to-target binding site in molecular design, or for ranking of monovalent binders during lead identification, affinity-based assessment of the binding strength is required. Typically, monovalent binders like antigen-binding fragments (Fabs) are generated by proteolytic cleavage with papain, which often results in a combination of under- and over-digestion, and requires specific optimization and chromatographic purification of the desired Fabs...
October 2017: MAbs
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