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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/28935938/an-engineered-bispecific-dna-encoded-igg-antibody-protects-against-pseudomonas-aeruginosa-in-a-pneumonia-challenge-model
#2
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
#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/28898162/modulation-of-protein-a-binding-allows-single-step-purification-of-mouse-bispecific-antibodies-that-retain-fcrn-binding
#4
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
#5
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/28874545/increasing-the-breadth-and-potency-of-response-to-the-seasonal-influenza-virus-vaccine-by-immune-complex-immunization
#6
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/28870833/multivalent-interactions-between-streptavidin-based-pretargeting-fusion-proteins-and-cell-receptors-impede-efficient-internalization-of-biotinylated-nanoparticles
#7
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/28852148/semi-synthetic-vnar-libraries-screened-against-therapeutic-antibodies-primarily-deliver-anti-idiotypic-binders
#8
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
#9
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
#10
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
#11
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...
August 14, 2017: MAbs
https://www.readbyqxmd.com/read/28726352/computational-design-of-a-specific-heavy-chain-%C3%AE%C2%BA-light-chain-interface-for-expressing-fully-igg-bispecific-antibodies
#12
K J Froning, A Leaver-Fay, X Wu, S Phan, L Gao, F Huang, A Pustilnik, M Bacica, K Houlihan, Q Chai, J R Fitchett, J Hendle, B Kuhlman, S J Demarest
The use of bispecific antibodies (BsAbs) to treat human diseases is on the rise. Increasingly complex and powerful therapeutic mechanisms made possible by BsAbs are spurring innovation of novel BsAb formats and methods for their production. The long-lived in vivo pharmacokinetics, optimal biophysical properties and potential effector functions of natural IgG monoclonal (and monospecific) antibodies has resulted in a push to generate fully IgG BsAb formats with the same quaternary structure as monoclonal IgGs...
July 20, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28722325/polymer-mediated-flocculation-of-transient-cho-cultures-as-a-simple-high-throughput-method-to-facilitate-antibody-discovery
#13
Matthew G Schmitt, Yashas Rajendra, Maria D Hougland, Jeffrey S Boyles, Gavin C Barnard
Most biopharmaceutical drugs, especially monoclonal antibodies (mAbs), bispecific antibodies (BsAbs) and Fc-fusion proteins, are expressed using Chinese Hamster Ovary (CHO) cell lines. CHO cells typically yield high product titers and high product quality. Unfortunately, CHO cell lines also generate high molecular weight (HMW) aggregates of the desired product during cell culture along with CHO host cell protein (HCP) and CHO DNA. These immunogenic species, co-purified during Protein A purification, must be removed in a multi-step purification process...
July 19, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28692328/fabs-in-tandem-immunoglobulin-is-a-novel-and-versatile-bispecific-design-for-engaging-multiple-therapeutic-targets
#14
Shiyong Gong, Fang Ren, Danqing Wu, Xuan Wu, Chengbin Wu
In recent years, the development of bispecific antibody (bsAb) has become a major trend in the biopharmaceutical industry. By simultaneously engaging two molecular targets, bsAbs show unique mechanisms of action that could lead to clinical benefits unattainable by conventional monoclonal antibodies. Various bsAb generation formats have been described, and several are being investigated in clinical development. However, some bsAb constructs have proven to be problematic due to their unfavorable physicochemical and pharmacokinetic properties, as well as poor manufacturing efficiencies...
July 10, 2017: MAbs
https://www.readbyqxmd.com/read/28679475/cik-as-therapeutic-agents-against-tumors
#15
REVIEW
M Introna
Cytokine Induced Killer (CIK) cells are ex vivo expanded and activated T lymphocytes obtained by sequential incubation of Peripheral Blood Mononuclear cells (PBMNC) with Interferon γ (IFNG), anti CD3 monoclonal antibody OKT3 and IL2. These cells, while retaining few characteristics of the Effector memory T cells subpopulation, acquired during culture CD56 expression, as well as non specific, Natural Killer like, anti tumoral cytotoxicity. CIK cells from human are equivalent to expanded NKT cells in mouse...
July 2, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28674296/next-generation-antibody-therapeutics-using-bispecific-antibody-technology
#16
Tomoyuki Igawa
 Nearly fifty monoclonal antibodies have been approved to date, and the market for monoclonal antibodies is expected to continue to grow. Since global competition in the field of antibody therapeutics is intense, we need to establish novel antibody engineering technologies to provide true benefit for patients, with differentiated product values. Bispecific antibodies are among the next generation of antibody therapeutics that can bind to two different target antigens by the two arms of immunoglobulin G (IgG) molecule, and are thus believed to be applicable to various therapeutic needs...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28664386/novel-therapies-for-acute-myeloid-leukemia-are-we-finally-breaking-the-deadlock
#17
REVIEW
Maximilian Stahl, Benjamin Y Lu, Tae Kon Kim, Amer M Zeidan
Acute myeloid leukemia (AML) is one of the best studied malignancies, and significant progress has been made in understanding the clinical implications of its disease biology. Unfortunately, drug development has not kept pace, as the '7+3' induction regimen remains the standard of care for patients fit for intensive therapy 40 years after its first use. Temporal improvements in overall survival were mostly confined to younger patients and driven by improvements in supportive care and use of hematopoietic stem cell transplantation...
August 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28655766/a-new-approach-for-generating-bispecific-antibodies-based-on-a-common-light-chain-format-and-the-stable-architecture-of-human-immunoglobulin-g1
#18
Camilla De Nardis, Linda J A Hendriks, Emilie Poirier, Tudor Arvinte, Piet Gros, Alexander B H Bakker, John de Kruif
Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G1 We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28604239/continuing-challenges-and-current-issues-in-acute-lymphoblastic-leukemia
#19
Ankit Kansagra, Saurabh Dahiya, Mark Litzow
Conventional cytotoxic chemotherapy used to treat acute lymphoblastic leukemia (ALL) has resulted into high cure rates for pediatric patients, however outcomes for adult patients remain suboptimal. The 5-year overall survival is only 30-40% in adults and elderly patients with ALL compared to 90% in children. We have seen major advances in our understanding and management of ALL related to identification of new cytogenetic and molecular abnormalities and development of novel targeted agents for the treatment of ALL...
June 11, 2017: Leukemia & Lymphoma
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
#20
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
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