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https://www.readbyqxmd.com/read/29773864/igg-single-chain-trail-fusion-proteins-for-tumour-therapy
#1
Martin Siegemund, Felix Schneider, Meike Hutt, Oliver Seifert, Ines Müller, Dagmar Kulms, Klaus Pfizenmaier, Roland E Kontermann
Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29771629/brain-uptake-of-multivalent-and-multi-specific-dvd-ig-proteins-after-systemic-administration
#2
Denise Karaoglu Hanzatian, Annette Schwartz, Farid Gizatullin, Jamie Erickson, Kangwen Deng, Ruth Villanueva, Christopher Stedman, Cristina Harris, Tariq Ghayur, Andrew Goodearl
Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would...
May 17, 2018: MAbs
https://www.readbyqxmd.com/read/29769259/novel-therapeutics-for-hemophilia-and-other-bleeding-disorders
#3
Michael U Callaghan, Robert Sidonio, Steven W Pipe
Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment for these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase III trial in people with hemophilia A and inhibitors...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29769244/a-cs1-nkg2d-bispecific-antibody-collectively-activates-cytolytic-immune-cells-against-multiple-myeloma
#4
Wing Keung Chan, Siwen Kang, Youssef Youssef, Erin N Glankler, Emma R Barrett, Alex M Carter, Elshafa H Ahmed, Aman Prasad, Luxi Chen, Jianying Zhang, Don M Benson, Michael A Caligiuri, Jianhua Yu
Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb)...
May 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29766242/inactivation-of-deubiquitinase-cyld-enhances-therapeutic-antibody-production-in-chinese-hamster-ovary-cells
#5
Yafang Lu, Qin Zhou, Qianqian Han, Pengfei Wu, Lanlan Zhang, Lin Zhu, David T Weaver, Changzhi Xu, Buchang Zhang
Chinese hamster ovary (CHO) cells are promising host engineering cells for industry manufacturing of therapeutic antibodies. However, cell death due to apoptosis remains a huge challenge to augment antibody production, and developing CHO cells with enhanced anti-apoptosis and proliferation ability is fundamental for cell line development and high-yielding bioprocesses. Deubiquitinase cylindromatosis (CYLD) has been proved to be a tumor suppressor by negatively regulating NF-κB and Wnt/β-catenin signaling pathways...
May 15, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29764159/emerging-role-of-immunotherapy-for-childhood-cancers
#6
Rupert Handgretinger, Patrick Schlegel
Recent developments in cell and gene therapy have a great impact on the new therapeutic approaches in pediatric cancers. Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukemia have induced significant clinical responses for otherwise chemorefractory patients. Moreover, cellular therapeutic approaches including chimeric antigen receptor (CAR) T-cells as well as natural killer (NK) cells have the potential to cure patients with so far incurable malignancies and are the basis for future new therapies for pediatric cancer...
April 2018: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29763625/unbiased-combinatorial-screening-identifies-a-bispecific-igg1-that-potently-inhibits-her3-signaling-via-her2-guided-ligand-blockade
#7
Cecile A W Geuijen, Camilla De Nardis, David Maussang, Eric Rovers, Tristan Gallenne, Linda J A Hendriks, Therese Visser, Roy Nijhuis, Ton Logtenberg, John de Kruif, Piet Gros, Mark Throsby
HER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibits the HRG/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism...
May 14, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29763554/template-catalyzed-disulfide-conjugation-of-monoclonal-antibodies-using-a-natural-amino-acid-tag
#8
Jeremy D King, Yuelong Ma, Yi-Chui Kuo, Krzysztof P Bzymek, Leah H Goodstein, Kassondra Meyer, Roger E Moore, Desiree Crow, David Colcher, Gagandeep Singh, David A Horne, John C Williams
The high specificity and favorable pharmacological properties of monoclonal antibodies (mAbs) have prompted significant interest in re-engineering this class of molecules to add novel functionalities for enhanced therapeutic and diagnostic potential. Here, we used the high affinity, meditope-Fab interaction to template and drive the rapid, efficient, and stable site-specific formation of a disulfide bond. We demonstrate that this template-catalyzed strategy provides a consistent and reproducible means to conjugate fluorescent dyes, cytotoxins, or "click" chemistry handles to meditope-enabled mAbs (memAbs) and memFabs...
May 15, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29762173/a-defucosylated-bispecific-multivalent-molecule-exhibits-broad-hiv-1-neutralizing-activity-and-enhanced-adcc-against-reactivated-hiv-1-latently-infected-cells
#9
Desheng Kong, Yan Wang, Ping Ji, Wei Li, Tianlei Ying, Jinghe Huang, Chen Wang, Yanling Wu, Yanping Wang, Weizao Chen, Yanling Hao, Kunxue Hong, Yiming Shao, Dimiter S Dimitrov, Shibo Jiang, Liying Ma
OBJECTIVE: Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody-dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the non-defucosylated molecule LSEVh-LS...
May 11, 2018: AIDS
https://www.readbyqxmd.com/read/29754509/-new-and-traditional-directions-in-the-biology-and-management-of-childhood-acute-lymphoblastic-leukemia
#10
Bálint Egyed, Gábor Kovács, Nóra Kutszegi, Andrea Rzepiel, Judit Csányiné Sági, Dániel János Erdélyi, Judit Müller, Ágnes Félné Semsei
Owing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy...
May 2018: Orvosi Hetilap
https://www.readbyqxmd.com/read/29754163/inhibition-of-autophagy-potentiated-the-anti-tumor-effects-of-vegf-and-cd47-bispecific-therapy-in-glioblastoma
#11
Xuyao Zhang, Shaofei Wang, Yanyang Nan, Jiajun Fan, Wei Chen, Jingyun Luan, Yichen Wang, Yanxu Liang, Song Li, Wenzhi Tian, Dianwen Ju
Glioblastoma, characterized by extensive microvascular proliferation and invasive tumor growth, is one of the most common and lethal malignancies in adults. Benefits of the conventional anti-angiogenic therapy were only observed in a subset of patients and limited by diverse relapse mechanism. Fortunately, recent advances in cancer immunotherapy have offered new hope for patients with glioblastoma. Herein, we reported a novel dual-targeting therapy for glioblastoma through simultaneous blockade of VEGF and CD47 signaling...
May 12, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29743205/preclinical-development-of-a-bispecific-antibody-that-safely-and-effectively-targets-cd19-and-cd47-for-the-treatment-of-b-cell-lymphoma-and-leukemia
#12
Vanessa Buatois, Zoë Johnson, Susana Salgado-Pires, Anne Papaïoannou, Eric Hatterer, Xavier Chauchet, Françoise Richard, Leticia Barba, Bruno Daubeuf, Laura Cons, Lucile Broyer, Matilde D'Asaro, Thomas Matthes, Simon LeGallou, Thierry Fest, Karin Tarte, Robert K Clarke Hinojosa, Eulàlia Genescà Ferrer, José María Ribera, Aditi Dey, Katharine Bailey, Adele K Fielding, Linda Eissenberg, Julie Ritchey, Michael Rettig, John F DiPersio, Marie H Kosco-Vilbois, Krzysztof Masternak, Nicolas Fischer, Limin Shang, Walter G Ferlin
CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often up-regulated by hematological and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to co-engage CD47 and CD19 selectively on B cells...
May 9, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29743179/a-cd19-cd3-bispecific-antibody-for-effective-immunotherapy-of-chronic-lymphocytic-leukemia-in-the-ibrutinib-era
#13
Hannah R Robinson, Junpeng Qi, Erika M Cook, Cydney Nichols, Eman L Dadashian, Chingiz Underbayev, Sarah E M Herman, Nakhle S Saba, Keyvan Keyvanfar, Clare Sun, Inhye E Ahn, Sivasubramanian Baskar, Christoph Rader, Adrian Wiestner
The Bruton's tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE® format, is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29742077/philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-adults-current-treatments-and-future-perspectives
#14
Musa Yilmaz, Hagop Kantarjian, Farhad Ravandi-Kashani, Nicholas J Short, Elias Jabbour
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately one-fourth of cases of adult ALL. It typically presents with an aggressive clinical course, responds poorly to standard chemotherapy, and carries a high risk for relapse. The landscape of Ph+ ALL therapy has changed favorably since the development of tyrosine kinase inhibitors (TKIs). With the successful incorporation of TKIs into chemotherapy regimens, remissions occur more frequently and patients live longer...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29740424/modulation-of-dengue-zika-virus-pathogenicity-by-antibody-dependent-enhancement-and-strategies-to-protect-against-enhancement-in-zika-virus-infection
#15
REVIEW
Rekha Khandia, Ashok Munjal, Kuldeep Dhama, Kumaragurubaran Karthik, Ruchi Tiwari, Yashpal Singh Malik, Raj Kumar Singh, Wanpen Chaicumpa
Antibody-dependent enhancement (ADE) is a phenomenon in which preexisting poorly neutralizing antibodies leads to enhanced infection. It is a serious concern with mosquito-borne flaviviruses such as Dengue virus (DENV) and Zika virus (ZIKV). In vitro experimental evidences have indicated the preventive, as well as a pathogenicity-enhancing role, of preexisting DENV antibodies in ZIKV infections. ADE has been confirmed in DENV but not ZIKV infections. Principally, the Fc region of the anti-DENV antibody binds with the fragment crystallizable gamma receptor (FcγR), and subsequent C1q interactions and immune effector functions are responsible for the ADE...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29734520/routine-measurements-of-factor-viii-activity-and-inhibitor-titer-in-the-presence-of-emicizumab-utilizing-anti-idiotype-monoclonal-antibodies
#16
Keiji Nogami, Tetsuhiro Soeda, Tomoko Matsumoto, Yoshiki Kawabe, Takehisa Kitazawa, Midori Shima
BACKGROUND: Emicizumab is an anti-factor (F)IXa/X bispecific monoclonal antibody (mAb), mimicking the Factor (F)VIIIa cofactor activity. Emicizumab does not require activation by thrombin and its shortening effect on the activated partial prothrombin time (aPTT) is more pronounced than that of Factor (F)VIII. aPTT-based FVIII activity (FVIII:C) and FVIII inhibiter titer measurements are influenced by the presence of emicizumab. AIM: To establish a reliable aPTT-based assay to measure FVIII in the presence of emicizumab...
May 7, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29728897/translational-pk-pd-modeling-analysis-of-mcla-128-a-her2-her3-bispecific-monoclonal-antibody-to-predict-clinical-efficacious-exposure-and-dose
#17
Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model...
May 5, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29725336/tribody-her2-2-xcd16-is-more-effective-than-trastuzumab-in-enhancing-%C3%AE-%C3%AE-t-cell-and-natural-killer-cell-cytotoxicity-against-her2-expressing-cancer-cells
#18
Hans H Oberg, Christian Kellner, Daniel Gonnermann, Susanne Sebens, Dirk Bauerschlag, Martin Gramatzki, Dieter Kabelitz, Matthias Peipp, Daniela Wesch
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29720517/antiviral-activity-of-hiv-gp120-targeting-bispecific-t-cell-engager-bite%C3%A2-antibody-constructs
#19
Johannes Brozy, Erika Schlaepfer, Christina K S Mueller, Mary-Aude Rochat, Silvana K Rampini, Renier Myburgh, Tobias Raum, Peter Kufer, Patrick A Baeuerle, Markus Muenz, Roberto F Speck
Today's gold standard in HIV therapy is the combined antiretroviral therapy (cART). It requires strict adherence by patients and life-long medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency, but cannot cure patients. The bispecific T cell engaging (BiTE®) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. We here generated BiTE® antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1+2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ϵ scFv...
May 2, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29718725/bispecific-antibodies-anti-mpeg-anti-her2-for-active-tumor-targeting-of-docetaxel-dtx-loaded-mpegylated-nanocarriers-to-enhance-the-chemotherapeutic-efficacy-of-her2-overexpressing-tumors
#20
Chia-Yu Su, Michael Chen, Ling-Chun Chen, Yuan-Soon Ho, Hsiu-O Ho, Shyr-Yi Lin, Kuo-Hsiang Chuang, Ming-Thau Sheu
Anti-mPEG/anti-human epidermal growth factor receptor 2 (HER2) bispecific antibodies (BsAbs) non-covalently bound to a docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micellar drug delivery system (Lsb MDDs) were endowed with active targetability to improve the chemotherapeutic efficacy of DTX. DTX-loaded mPEGylated Lsb MDDs formulations were prepared using lecithin/DSPE-PEG(2K or 5K) nanosuspensions to hydrate the thin film, and then they were subjected to ultrasonication. Two BsAbs (anti-mPEG/anti-DNS or anti-HER2) were simply mixed with the Lsb MDDs to form BsAbs-Lsb MDDs formulations, respectively, referred as the DNS-Lsb MDDs and HER2-Lsb MDDs...
November 2018: Drug Delivery
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