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bispecific mab

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https://www.readbyqxmd.com/read/28981753/designing-fcabs-well-expressed-and-stable-high-affinity-antigen-binding-fc-fragments
#1
Gordana Wozniak-Knopp, Gerhard Stadlmayr, Jan Walther Perthold, Katharina Stadlbauer, Maximilian Woisetschläger, Haijun Sun, Florian Rüker
Fc fragment with antigen-binding (Fcab) is a novel construct which can be selected to recognize specifically a wide variety of target proteins. We describe the selection and affinity maturation of Fcab clones targeting VEGF, an important pro-angiogenesis factor. To investigate the extent of engineering permissible to Fcabs we applied targeted mutagenesis to all three C-terminal loop structures and the C-terminus of the CH3 domain to isolate high-affinity binders by directed evolution and yeast display. The matured clone, CT6, binds to VEGF with low nanomolar affinity and inhibits VEGF-stimulated proliferation of human umbilical vein endothelial cells in vitro...
August 1, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28938115/a-human-bi-specific-antibody-against-zika-virus-with-high-therapeutic-potential
#2
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/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#3
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/28887948/psoriasis-pathogenesis-and-the-development-of-novel-targeted-immune-therapies
#4
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/28827777/efficient-generation-of-bispecific-igg-antibodies-by-split-intein-mediated-protein-trans-splicing-system
#5
Lei Han, Junsheng Chen, Kai Ding, Huifang Zong, Yueqing Xie, Hua Jiang, Baohong Zhang, Huili Lu, Weihan Yin, John Gilly, Jianwei Zhu
Many methods have been developed to produce bispecific antibodies (BsAbs) for industrial application. However, huge challenges still remain in synthesizing whole length BsAbs, including their assembly, stability, immunogenicity, and pharmacodynamics. Here we present for first time a generic technology platform of generating bispecific IgG antibodies, "Bispecific Antibody by Protein Trans-splicing (BAPTS)". Different from published methods, we assembled two parental antibody fragments in the hinge region by the protein trans-splicing reaction of a split intein to generate BsAbs without heavy/heavy and light/heavy chain mispairing...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827403/targeting-anti-tgf-%C3%AE-therapy-to-fibrotic-kidneys-with-a-dual-specificity-antibody-approach
#6
Steve McGaraughty, Rachel A Davis-Taber, Chang Z Zhu, Todd B Cole, Arthur L Nikkel, Meha Chhaya, Kelly J Doyle, Lauren M Olson, Gregory M Preston, Christine M Grinnell, Katherine M Salte, Anthony M Giamis, Yanping Luo, Victor Sun, Andrew D Goodearl, Murali Gopalakrishnan, Susan E Lacy
Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney...
August 21, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28821272/novel-immunotherapies-for-adult-patients-with-b-lineage-acute-lymphoblastic-leukemia
#7
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/28722325/polymer-mediated-flocculation-of-transient-cho-cultures-as-a-simple-high-throughput-method-to-facilitate-antibody-discovery
#8
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/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
#9
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/28463232/bispecific-antibody-targets-multiple-pseudomonas-aeruginosa-evasion-mechanisms-in-the-lung-vasculature
#10
Ajitha Thanabalasuriar, Bas Gj Surewaard, Michelle E Willson, Arpan S Neupane, Charles K Stover, Paul Warrener, George Wilson, Ashley E Keller, Bret R Sellman, Antonio DiGiandomenico, Paul Kubes
Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. aeruginosa has evolved numerous evasion and subversion mechanisms that work in concert to overcome immune recognition and effector functions in hospitalized and immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy to monitor the blood-borne stage in a murine bacteremic model of P. aeruginosa infection. P. aeruginosa adhered avidly to lung vasculature, where patrolling neutrophils and other immune cells were virtually blind to the pathogen's presence...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28407743/new-drugs-new-toxicities-severe-side-effects-of-modern-targeted-and-immunotherapy-of-cancer-and-their-management
#11
REVIEW
Frank Kroschinsky, Friedrich Stölzel, Simone von Bonin, Gernot Beutel, Matthias Kochanek, Michael Kiehl, Peter Schellongowski
Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity...
April 14, 2017: Critical Care: the Official Journal of the Critical Care Forum
https://www.readbyqxmd.com/read/28315359/antibodies-and-associates-partners-in-targeted-drug-delivery
#12
REVIEW
Patrick J Kennedy, Carla Oliveira, Pedro L Granja, Bruno Sarmento
Monoclonal antibodies (mAbs) are well established in the clinic due to their specificity and affinity to a diverse array of biochemical targets. More recently, mAbs are being exploited as targeting agents in modern drug delivery systems, aiming to bypass normal host tissue and to accumulate a therapeutic agent to a specific tissue or cell for enhanced pharmacology. At sizes ranging from ~10-100nm, antibody-based bioconjugates have opened up a whole new realm of clinical possibilities with several platforms emerging on the market...
March 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28269762/cloning-and-molecular-characterization-of-the-cdnas-encoding-the-variable-regions-of-an-anti-cd20-monoclonal-antibody
#13
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
BACKGROUND: CD20-based targeting of B-cells in hematologic malignancies and autoimmune disorders is associated with outstanding clinical outcomes. Isolation and characterization of VH and VL cDNAs encoding the variable regions of the heavy and light chains of monoclonal antibodies (MAb) is necessary to produce next generation MAbs and their derivatives such as bispecific antibodies (bsAb) and single-chain variable fragments (scFv). OBJECTIVE: This study was aimed at cloning and characterization of the VH and VL cDNAs from a hybridoma cell line producing an anti-CD20 MAb...
2017: Human Antibodies
https://www.readbyqxmd.com/read/28262952/mirna-engineering-of-cho-cells-facilitates-production-of-difficult-to-express-proteins-and-increases-success-in-cell-line-development
#14
Simon Fischer, Kim F Marquart, Lisa A Pieper, Juergen Fieder, Martin Gamer, Ingo Gorr, Patrick Schulz, Harald Bradl
In recent years, coherent with growing biologics portfolios also the number of complex and thus difficult-to-express (DTE) therapeutic proteins has increased considerably. DTE proteins challenge bioprocess development and can include various therapeutic protein formats such as monoclonal antibodies (mAbs), multi-specific affinity scaffolds (e.g., bispecific antibodies), cytokines, or fusion proteins. Hence, the availability of robust and versatile Chinese hamster ovary (CHO) host cell factories is fundamental for high-yielding bioprocesses...
July 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28249243/a-recombinant-igg-like-bispecific-antibody-acting-as-interleukin-1%C3%AE-and-interleukin-17a-inhibitor-exhibits-a-promising-efficacy-for-rheumatoid-arthritis
#15
Yunxin Wang, Qiang Wu, Zhihang Liu, Xiaochen Guo, Lijiao Zhou, Yuyang Wang, Liying Song, Nan Wang, Qi Zheng, Wenfei Wang, Guiping Ren, Deshan Li
Recently, targeting inflammatory cytokines in the pathogenic process of rheumatoid arthritis is now performed as a feasible biological method in therapy. However, treatments against single cytokine are often difficult to achieve the ideal therapeutic effect. Multi-target drugs permit more effective suppression of inflammation. In this study, we constructed an IgG-like bispecific antibody targeting IL-1β and IL-17A and expressed it in mammalian cells. The therapeutic efficacy was studied in CIA (collagen-induced arthritis) mice, which were administrated with either FL-BsAb1/17 (IgG-like bispecific antibody targeting IL-1β and IL-17A) or monovalent IL-1β Mab or IL-17A Mab (anti-IL-1β/IL-17A monoclonal antibody)...
May 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28188692/bioreactor-scale-up-and-protein-product-quality-characterization-of-piggybac-transposon-derived-cho-pools
#16
Yashas Rajendra, Sowmya Balasubramanian, Robert B Peery, James R Swartling, Neil A McCracken, Dawn L Norris, Christopher C Frye, Gavin C Barnard
Chinese hamster ovary (CHO) cells remain the most popular host for the production of biopharmaceutical drugs, particularly monoclonal antibodies (mAbs), bispecific antibodies, and Fc-fusion proteins. Creating and characterizing the stable CHO clonally-derived cell lines (CDCLs) needed to manufacture these therapeutic proteins is a lengthy and laborious process. Therefore, CHO pools have increasingly been used to rapidly produce protein to support and enable preclinical drug development. We recently described the generation of CHO pools yielding mAb titers as high as 7...
February 11, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28067257/enhanced-tumor-targeting-selectivity-by-modulating-bispecific-antibody-binding-affinity-and-format-valence
#17
Yariv Mazor, Kris F Sachsenmeier, Chunning Yang, Anna Hansen, Jessica Filderman, Kathy Mulgrew, Herren Wu, William F Dall'Acqua
Bispecific antibodies are considered attractive bio-therapeutic agents owing to their ability to target two distinct disease mediators. Cross-arm avidity targeting of antigen double-positive cancer cells over single-positive normal tissue is believed to enhance the therapeutic efficacy, restrict major escape mechanisms and increase tumor-targeting selectivity, leading to reduced systemic toxicity and improved therapeutic index. However, the interplay of factors regulating target selectivity is not well understood and often overlooked when developing clinically relevant bispecific therapeutics...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28067179/cd20-based-immunotherapy-of-b-cell-derived-hematologic-malignancies
#18
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
CD20 is a surface antigen which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/relapsed disease...
January 9, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28035914/antibody-mimicry-receptors-and-clinical-applications
#19
Alberto L Horenstein, Antonella Chillemi, Valeria Quarona, Andrea Zito, Valentina Mariani, Angelo C Faini, Fabio Morandi, Ilaria Schiavoni, Clara Maria Ausiello, Fabio Malavasi
This review focuses on the concept of antibodies acting as receptor agonists and antagonists, and on the potential relevance of this notion in applied medicine. Antibodies are composed of three functional units: two antigen-binding fragments (Fabs) that confer antigen specificity and one constant fragment (Fc) linking antibodies to immune effector functions. The proof-of-concept that large amounts of highly specific and homogeneous antibodies could be produced was provided in 1975 by César Milstein and Georges Köhler...
2017: Human Antibodies
https://www.readbyqxmd.com/read/27977915/transient-and-stable-cho-expression-purification-and-characterization-of-novel-hetero-dimeric-bispecific-igg-antibodies
#20
Yashas Rajendra, Robert B Peery, Maria D Hougland, Gavin C Barnard, Xiufeng Wu, Jonathan R Fitchett, Michael Bacica, Stephen J Demarest
IgG bispecific antibodies (BsAbs) represent one of the preferred formats for bispecific antibody therapeutics due to their native-like IgG properties and their monovalent binding to each target. Most reported studies utilized transient expression in HEK293 cells to produce BsAbs. However, the expression of biotherapeutic molecules using stable CHO cell lines is commonly used for biopharmaceutical manufacturing. Unfortunately, limited information is available in the scientific literature on the expression of BsAbs in CHO cell lines...
March 2017: Biotechnology Progress
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