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bispecific monoclonal

Tong Wang, Fumou Sun, Yang Wang, Jiahao Jiang, Mingzhu Pan, Minne Yuan, Hang Zhang, Xiaodian Du, Kamal Hezam, Kai Song, Min Wang, Juan Zhang
Colorectal carcinoma (CRC) is one of the most common malignant cancers worldwide. The poor response of CRC to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies for its potential efficiency. However, cetuximab, as one of the first-line targeted drugs in the treatment of CRC, has drug resistance and poor prognosis in clinic. To address this, a novel bispecific protein with CRC targeting and natural killer (NK) cell triggering was used for treatment. NK cell-mediated immunosurveillance is normally activated by the activating receptor natural killer cell receptor NK group 2, member D (NKG2D), which binds its key ligand major histocompatibility complex (MHC) class I-related chain A (MICA) expressed on the tumor cells...
April 2018: Journal of Immunotherapy
Elisabeth K Nyakatura, Samantha E Zak, Anna Z Wec, Daniel Hofmann, Sergey Shulenin, Russell R Bakken, M Javad Aman, Kartik Chandran, John M Dye, Jonathan R Lai
Filoviruses (family Filoviridae ) include five ebolaviruses and Marburg virus. These pathogens cause a rapidly progressing and severe viral disease with high mortality rates (generally 30%-90%). Outbreaks of filovirus disease are sporadic and, until recently, were limited to less than 500 cases. However, the 2013-2016 epidemic in western Africa, caused by Ebola virus (EBOV), illustrated the potential of filovirus outbreaks to escalate to a much larger scale (over 28,000 suspected cases). Monoclonal antibodies (mAbs) against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections...
March 2, 2018: Journal of Biological Chemistry
Alexey Teplyakov, Galina Obmolova, Jinquan Luo, Gary L Gilliland
CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or other tissues, which makes it an attractive target for monoclonal antibody-mediated immunotherapy. Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab, that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia. To gain insight into the mechanism of action of the antibody, the crystal structure of B43 Fab was determined in complex with CD19 and in the unbound form...
February 28, 2018: Proteins
Archana Thakur, Manley Huang, Lawrence G Lum
Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent...
February 20, 2018: Blood Reviews
Yesim Dargaud, Anne Lienhart, Maissaa Janbain, Sandra LeQuellec, Nathalie Enjolras, Claude Negrier
Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that bridges activated factor IX and factor X to restore the function of deficient factor VIII. Treatment of bleeding in patients with hemophilia and inhibitors involves the use of bypassing agents (BPA).These molecules are also used for the management of breakthrough bleeds in patients on prophylaxis with emicizumab, with increased concerns about the risks of combining two procoagulant drugs. Using thrombin generation assay, we tailored the dosage of activated prothrombin complex concentrate (APCC) and successfully treated an acute spontaneous arterial bleeding in a patient on prophylaxis with emicizumab 1...
February 22, 2018: Haematologica
Mahiuddin Ahmed, Andres Lopez-Albaitero, Dmitry Pankov, Brian H Santich, Hong Liu, Su Yan, Jingyi Xiang, Pei Wang, Aisha N Hasan, Annamalai Selvakumar, Richard J O'Reilly, Cheng Liu, Nai-Kong V Cheung
EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-like) monoclonal antibodies with exquisite specificity for the LMP2A-derived nonamer peptide, C426LGGLLTMV434 (CLG), as presented on HLA-A*02:01...
February 22, 2018: JCI Insight
Andrew D Tustian, Linus Laurin, Henrik Ihre, Travis Tran, Robert Stairs, Hanne Bak
There is strong interest in the production of bispecific monoclonal antibodies that can simultaneously bind two distinct targets or epitopes to achieve novel mechanisms of action and efficacy. Regeneron's bispecific technology, based upon a standard IgG, consists of a heterodimer of two different heavy chains, and a common light chain. Coexpression of two heavy chains leads to the formation of two parental IgG impurities, the removal of which is facilitated by a dipeptide substitution in the Fc portion of one of the heavy chains that ablates Fc Protein A binding...
February 21, 2018: Biotechnology Progress
Sergey E Sedykh, Victor V Prinz, Valentina N Buneva, Georgy A Nevinsky
Antibodies (Abs) containing two different antigen-binding sites in one molecule are called bispecific. Bispecific Abs (BsAbs) were first described in the 1960s, the first monoclonal BsAbs were generated in the 1980s by hybridoma technology, and the first article describing the therapeutic use of BsAbs was published in 1992, but the number of papers devoted to BsAbs has increased significantly in the last 10 years. Particular interest in BsAbs is due to their therapeutic use. In the last decade, two BsAbs - catumaxomab in 2009 and blinatumomab in 2014, were approved for therapeutic use...
2018: Drug Design, Development and Therapy
T Annecke, A Hohn, B Böll, M Kochanek
Cancer is one of the leading causes of death worldwide. New targeted and individualized therapies and drugs provide a survival benefit for an increasing number of patients, but can also cause severe side effects. An increasing number of oncology patients are admitted to intensive care units (ICU) because of cancer-related complications or treatment-associated side effects. Postoperative care, respiratory distress and sepsis are the leading causes for admission. Tumor mass syndromes and tumor lysis may require urgent treatment...
January 24, 2018: Der Anaesthesist
Lesley J Scott, Esther S Kim
Emicizumab-kxwh (Hemlibra®) is a bispecific humanized monoclonal antibody that restores the function of missing activated FVIII by bridging activated FIX and FX to facilitate effective haemostasis in patients with haemophilia A. Subcutaneous emicizumab-kxwh is approved in the USA for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients with haemophilia A (congenital FVIII deficiency) with FVIII inhibitors. Subcutaneous emicizumab-kxwh is awaiting approval in several countries worldwide, including in the EU and Japan, and is undergoing phase 3 development in haemophilia A without FVIII inhibitors...
February 2018: Drugs
Juan Ma, Jing Ge, Xin Xue, Weigang Xiu, Pan Ma, Ximing Sun, Man Zhang
In the present study, we aimed to investigate whether EGFR or HER2 may serve as a target for T cell-mediated immunotherapy against human bladder cancer. Expression of EGFR and HER2 was detected on the surface of bladder cancer cells, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. Activated T cells (ATCs) were generated from healthy PBMCs that were stimulated by the combination of anti-CD3 monoclonal antibody and anti‑CD28 monoclonal antibody in the presence of interleukin-2 for 14 days...
March 2018: Oncology Reports
Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Ryu Kasai, Koichiro Yoneyama, Hiroki Yoshida, Keiji Nogami
Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33...
October 10, 2017: Blood Advances
Rodrigo Vazquez-Lombardi, Damien Nevoltris, Ansha Luthra, Peter Schofield, Carsten Zimmermann, Daniel Christ
Recombinant expression of antibody molecules in mammalian cells offers important advantages over traditionally utilized bacterial expression, including glycosylation required for antibody functionality and markedly reduced levels of endotoxin contamination. Advances in transient mammalian expression systems enable high yields (>100 mg/liter) that now allow for effective recombinant antibody production at a reasonable cost. Here, we provide step-by-step protocols for the design and recombinant expression of full-length IgG antibodies and antibody-derived constructs (including Fab, Fc-fusions and bispecifics) in mammalian cells...
January 2018: Nature Protocols
Wentong Deng, Jiayu Liu, Haitao Pan, Li Li, Changhua Zhou, Xiaojuan Wang, Rui Shu, Bin Dong, Donglin Cao, Qing Li, Zhong Wang
Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed and activated in metastatic breast cancers. Monoclonal antibodies targeting Her2, such as trastuzumab and pertuzumab, have become important targeted therapies for patients with HER2-positive breast cancer. Both trastuzumab and pertuzumab can reduce Her2 positive tumor burden by inhibiting Her2 signaling and inducing ADCC activities (antibody dependent cell-mediated cytotoxicity). In this study, we have generated a bispecific antibody, Her2(Per)-S-Fab, by linking the pertuzumab Fab to an anti-CD16 single domain antibody...
January 2018: Journal of Immunotherapy
Thomas Van Blarcom, Kevin Lindquist, Zea Melton, Wai Ling Cheung, Chris Wagstrom, Dan McDonough, Cendy Valle Oseguera, Sheng Ding, Andrea Rossi, Shobha Potluri, Purnima Sundar, Steven Pitts, Marina Sirota, Meri Galindo Casas, Yu Yan, Jeffrey Jones, Zygy Roe-Zurz, Surabhi Srivatsa Srinivasan, Wenwu Zhai, Jaume Pons, Arvind Rajpal, Javier Chaparro-Riggers
The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large scale manufacturing purposes. Bispecific IgG (BsIgG) based on two antibodies that use an identical common light chain can be combined with a minimal set of Fc mutations to drive heavy chain heterodimerization in order to address these challenges. However, the facile generation of common light chain antibodies with properties similar to traditional monoclonal antibodies has not been demonstrated and they have only been used sparingly...
February 2018: MAbs
Dag Sehlin, Xiaotian T Fang, Silvio R Meier, Malin Jansson, Stina Syvänen
Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab')2 fragment of the amyloid-beta (Aβ) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB...
December 8, 2017: Scientific Reports
Lewis B Silverman
With current available therapies, the prognosis for most children and adolescents with acute lymphoblastic leukemia (ALL) is favorable. However, the multiagent chemotherapy regimens used to treat newly diagnosed patients are associated with many acute and long-term complications, and therapy for relapsed disease is intensive and suboptimally effective. Over the last decade, several nonchemotherapeutic approaches have been evaluated, with the goal of identifying more effective, less toxic therapies that can be used in conjunction with, or even replace, current regimens...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
Peter Bannas, Julia Hambach, Friedrich Koch-Nolte
Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa) of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL). The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL). VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv)...
2017: Frontiers in Immunology
Shengnan Yu, Qian Liu, Xinwei Han, Shuang Qin, Weiheng Zhao, Anping Li, Kongming Wu
HER2-targeted immunotherapy consists of monoclonal antibodies (e.g. trastuzumab, pertuzumab), bispecific antibodies (e.g. MM-111, ertumaxomab) and activated T cells armed with anti-HER2 bispecific antibody (HER2Bi-aATC). Trastuzumab is a classic drug for the treatment of HER2 positive metastatic breast cancer. The combined application of pertuzumab, trastuzumab and paclitaxel has been suggested as a standard therapy for HER2 positive advanced breast cancer. The resistance to anti-HER2 antibody has resulted in disease progression...
2017: Experimental Hematology & Oncology
Rita Assi, Hagop Kantarjian, Farhad Ravandi, Naval Daver
PURPOSE OF REVIEW: This review discusses the rationale, efficacy, and toxicity of a variety of immune approaches being evaluated in the therapy of acute myeloid leukemia (AML) including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, and immune checkpoint blockade via antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1). RECENT FINDINGS: The stellar success of immune therapies that harness the power of T cells in solid tumors and an improved understanding of the immune system in patients with hematologic malignancies have resulted in major efforts to develop immune therapies for the treatment of patients with AML...
March 2018: Current Opinion in Hematology
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