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https://www.readbyqxmd.com/read/28100833/follicular-cd8-t-cells-accumulate-in-hiv-infection-and-can-kill-infected-cells-in-vitro-via-bispecific-antibodies
#1
Constantinos Petrovas, Sara Ferrando-Martinez, Michael Y Gerner, Joseph P Casazza, Amarendra Pegu, Claire Deleage, Arik Cooper, Jason Hataye, Sarah Andrews, David Ambrozak, Perla M Del Río Estrada, Eli Boritz, Robert Paris, Eirini Moysi, Kristin L Boswell, Ezequiel Ruiz-Mateos, Ilias Vagios, Manuel Leal, Yuria Ablanedo-Terrazas, Amaranta Rivero, Luz Alicia Gonzalez-Hernandez, Adrian B McDermott, Susan Moir, Gustavo Reyes-Terán, Fernando Docobo, Giuseppe Pantaleo, Daniel C Douek, Michael R Betts, Jacob D Estes, Ronald N Germain, John R Mascola, Richard A Koup
Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals...
January 18, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28100773/targeted-fc%C3%AE-r-mediated-clearance-by-a-biparatopic-bispecific-antibody
#2
Srinath Kasturirangan, G Jonah Rainey, Linda Xu, Xinwei Wang, Alyse Portnoff, Tracy Chen, Christine Fazenbaker, Helen Zhong, Jared Bee, Zhutian Zeng, Craig Jenne, Herren Wu, Changshou Gao
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. While monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6 mediated signaling...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28077575/effector-attenuating-substitutions-that-maintain-antibody-stability-and-reduce-toxicity-in-mice
#3
Megan Lo, Hok Seon Kim, Raymond K Tong, Travis W Bainbridge, Jean-Michel Vernes, Yin Zhang, Yuwen Linda Lin, Shan Chung, Mark S Dennis, Y Joy Yu Zuchero, Ryan J Watts, Jessica A Couch, Y Gloria Meng, Jasvinder K Atwal, Randall J Brezski, Christoph Spiess, James A Ernst
The antibody Fc region regulates antibody cytotoxic activities and serum half-life. In a therapeutic context however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor-antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies. These earlier studies focused primarily on the interaction of human antibodies with human Fc-Gamma; receptors, and it remains largely unknown how such changes to the Fc might translate in the context of a murine antibody...
January 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28075428/balanced-secretion-of-anti-cea-x-anti-cd3-diabody-chains-using-the-2a-self-cleaving-peptide-maximizes-diabody-assembly-and-tumor-specific-cytotoxicity
#4
K Mølgaard, M Compte, N Nuñez-Prado, S L Harwood, L Sanz, L Alvarez-Vallina
Adoptive transfer of genetically engineered human cells secreting bispecific T cell engagers has shown encouraging therapeutic effects in preclinical models of cancer. However, reducing the toxicity and improving the effectiveness of this emerging immunotherapeutic strategy will be critical to its successful application. We have demonstrated that for gene-based bispecific antibody strategies, two-chain diabodies have a better safety profile than single-chain tandem scFvs, because their reduced tendency to form aggregates reduces the risk of inducing antigen-independent T cell activation...
January 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28071970/the-making-of-bispecific-antibodies
#5
Ulrich Brinkmann, Roland E Kontermann
During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The 'zoo' of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties...
January 10, 2017: MAbs
https://www.readbyqxmd.com/read/28069541/a-bispecific-tribody-pet-radioligand-for-visualization-of-amyloid-beta-protofibrils-a-new-concept-for-neuroimaging
#6
Stina Syvänen, Xiaotian T Fang, Greta Hultqvist, Silvio R Meier, Lars Lannfelt, Dag Sehlin
Antibodies are highly specific for their target molecules, but their poor brain penetrance has restricted their use as PET ligands for imaging of targets within the CNS. The aim of this study was to develop an antibody-based radioligand, using the Tribody(TM) format, for PET imaging of soluble amyloid-beta (Aβ) protofibrils, which are suggested to cause neurodegeneration in Alzheimer's disease. Antibodies, even when expressed in smaller engineered formats, are large molecules that do not enter the brain in sufficient amounts for imaging purposes...
January 6, 2017: NeuroImage
https://www.readbyqxmd.com/read/28067257/enhanced-tumor-targeting-selectivity-by-modulating-bispecific-antibody-binding-affinity-and-format-valence
#7
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
#8
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/28062646/generation-of-human-bispecific-common-light-chain-antibodies-by-combining-animal-immunization-and-yeast-display
#9
Simon Krah, Christian Schröter, Carla Eller, Laura Rhiel, Nicolas Rasche, Jan Beck, Carolin Sellmann, Ralf Günther, Lars Toleikis, Björn Hock, Harald Kolmar, Stefan Becker
Bispecific antibodies (bsAbs) pave the way for novel therapeutic modes of action along with potential benefits in several clinical applications. However, their generation remains challenging due to the necessity of correct pairings of two different heavy and light chains and related manufacturability issues. We describe a generic approach for the generation of fully human IgG-like bsAbs. For this, heavy chain repertoires from immunized transgenic rats were combined with either a randomly chosen common light chain or a light chain of an existing therapeutic antibody and screened for binders against tumor-related targets CEACAM5 and CEACAM6 by yeast surface display...
January 5, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28058501/-cytokine-neutralization-at-specific-cellular-source-a%C3%A2-new-therapeutic-paradigm-german-version
#10
A A Kruglov, S A Nedospasov
BACKGROUND: Currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. This approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine. METHODS: Techniques of reverse genetics, such as conditional gene targeting, were employed to uncover the contributions of two proinflammatory and immunomodulatory cytokines, tumour necrosis factor (TNF) and interleukin 6 (IL-6), in various disease states...
January 5, 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/28055299/guiding-bispecific-monovalent-antibody-formation-through-proteolysis-of-igg1-single-chain
#11
Nazzareno Dimasi, Ryan Fleming, Kris F Sachsenmeier, Binyam Bezabeh, Carl Hay, Jincheng Wu, Erin Sult, Saravanan Rajan, Li Zhuang, Peter Cariuk, Andrew Buchanan, Michael A Bowen, Herren Wu, Changshou Gao
We developed an IgG1 domain-tethering approach to guide the correct assembly of two light and two heavy chains, derived from two different antibodies, to form bispecific monovalent antibodies in IgG1 format. We show here that assembling two different light and heavy chains by sequentially connecting them with protease-cleavable polypeptide linkers results in the generation of monovalent bispecific antibodies that have IgG1 sequence, structure and functional properties. This approach was used to generate a bispecific monovalent antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor that: 1) can be produced and purified using standard IgG1 techniques; 2) exhibits stability and structural features comparable to IgG1; 3) binds both targets simultaneously; and 4) has potent anti-tumor activity...
January 5, 2017: MAbs
https://www.readbyqxmd.com/read/28054091/constrained-evolution-of-a-bispecific-enzyme-lessons-for-biocatalyst-design
#12
E Sugrue, C Scott, C J Jackson
One of the central goals of protein design and engineering is to be able to accurately predict the effects of a mutation on stability and activity. However, the genetic context into which mutations are introduced can lead to complex interactions between the mutation and other amino acids and unpredictable, non-additive, effects. This phenomenon is known as intramolecular epistasis and has been shown to restrict evolutionary paths through laboratory directed evolution experiments and ancestral protein reconstruction, but has rarely been studied at a quantitative level in naturally evolving enzymes...
January 5, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28049295/-64-cu-labeled-trastuzumab-fab-peg24-egf-radioimmunoconjugates-bispecific-for-her2-and-egfr-pharmacokinetics-biodistribution-and-tumor-imaging-by-pet-in-comparison-to-monospecific-agents
#13
Luke Yongkyu Kwon, Deborah A Scollard, Raymond M Reilly
Heterodimerization of EGFR with HER2 coexpressed in breast cancer (BC) promotes tumor growth, and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct (64)Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab, which binds HER2 linked through a polyethylene glycol (PEG24) spacer to EGF, and to compare their pharmacokinetic, biodistribution, and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking maleimide modified trastuzumab Fab with thiolated EGF through a thioether bond...
January 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28045502/legomedicine-a-versatile-chemo-enzymatic-approach-for-the-preparation-of-targeted-dual-labeled-llama-antibody-nanoparticle-conjugates
#14
Sanne A M van Lith, Sander M J van Duijnhoven, Anna C Navis, Edward Dolk, Jos W H Wennink, Cornelus F van Nostrum, Jan C M van Hest, William P J Leenders, Sanne A M van Lith, Sander M J van Duijnhoven, Anna C Navis, William P J Leenders, Edward Dolk, Jos W H Wennink, Cornelus F van Nostrum, Jan C M van Hest
Conjugation of llama single domain antibody fragments (Variable Heavy chain domains of Heavy chain antibodies, VHHs) to diagnostic or therapeutic nanoparticles, peptides, proteins, or drugs offers many opportunities for optimized targeted cancer treatment. Currently, mostly nonspecific conjugation strategies or genetic fusions are used that may compromise VHH functionality. In this paper we present a versatile modular approach for bioorthogonal VHH modification and conjugation. First, sortase A mediated transPEGylation is used for introduction of a chemical click moiety...
January 18, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28036020/bispecific-antibodies-as-a-development-platform-for-new-concepts-and-treatment-strategies
#15
REVIEW
Fa Yang, Weihong Wen, Weijun Qin
With the development of molecular cloning technology and the deep understanding of antibody engineering, there are diverse bispecific antibody formats from which to choose to pursue the optimal biological activity and clinical purpose. The single-chain-based bispecific antibodies usually bridge tumor cells with immune cells and form an immunological synapse because of their relatively small size. Bispecific antibodies in the IgG format include asymmetric bispecific antibodies and homodimerized bispecific antibodies, all of which have an extended blood half-life and their own crystalline fragment (Fc)-mediated functions...
December 28, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28035914/antibody-mimicry-receptors-and-clinical-applications
#16
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...
December 23, 2016: Human Antibodies
https://www.readbyqxmd.com/read/28028314/redirecting-t-cells-to-eradicate-b-cell-acute-lymphoblastic-leukemia-bispecific-t-cell-engagers-and-chimeric-antigen-receptors
#17
REVIEW
I Aldoss, R C Bargou, D Nagorsen, G R Friberg, P A Baeuerle, S J Forman
Recent advances in antibody technology to harness T-cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed or refractory acute lymphoblastic leukemia (r/r ALL), has led to innovative methods for directing cytotoxic T-cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T-cells and cancer cells. Another approach infuses ex vivo-engineered T-cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR)...
December 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28028054/fluorescence-based-atg8-sensors-monitor-localization-and-function-of-lc3-gabarap-proteins
#18
Alexandra Stolz, Mateusz Putyrski, Ivana Kutle, Jessica Huber, Chunxin Wang, Viktória Major, Sachdev S Sidhu, Richard J Youle, Vladimir V Rogov, Volker Dötsch, Andreas Ernst, Ivan Dikic
Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mATG8s). We used phage display to isolate peptides that possess bona fide LIR (LC3-interacting region) properties and are selective for individual mATG8 isoforms. Sensitivity of the developed sensors was optimized by multiplication, charge distribution, and fusion with a membrane recruitment (FYVE) or an oligomerization (PB1) domain...
December 27, 2016: EMBO Journal
https://www.readbyqxmd.com/read/28025583/a-novel-bcma-cd3-bi-specific-t-cell-engager-for-the-treatment-of-multiple-myeloma-induces-selective-lysis-in-vitro-and-in-vivo
#19
S Hipp, Y-T Tai, D Blanset, P Deegen, J Wahl, O Thomas, B Rattel, P J Adam, K Anderson, M Friedrich
B cell maturation antigen (BCMA) is a highly plasma cell selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T cell redirecting therapies. We developed a bispecific T cell engager (BiTE(®)) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T cell proliferation; whereas BCMA-negative cells were not affected...
December 27, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28001485/optimizing-assembly-and-production-of-native-bispecific-antibodies-by-codon-de-optimization
#20
Giovanni Magistrelli, Yves Poitevin, Florence Schlosser, Guillemette Pontini, Pauline Malinge, Soheila Josserand, Marie Corbier, Nicolas Fischer
When production of bispecific antibodies requires the co-expression and assembly of three or four polypeptide chains, low expression of one chain can significantly limit assembly and yield. κλ bodies, fully human bispecific antibodies with native IgG structure, are composed of a common heavy chain and two different light chains, one kappa and one lambda. No engineering is applied to force pairing of the chains, thus both monospecific and bispecific antibodies are secreted in the supernatant. In this context, stoichiometric expression of the two light chains allows for maximal assembly of the bispecific antibody...
December 21, 2016: MAbs
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