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bispecific mab

Martin J Scott, Jennifer A Lee, Matthew S Wake, Kelly V Batt, Trevor A Wattam, Ian D Hiles, Thil D Batuwangala, Claire I Ashman, Michael Steward
Bispecific antibodies (BsAbs) are emerging as an important class of biopharmaceutical. The majority of BsAbs are created from conventional antibodies or fragments engineered into more complex configurations. A recurring challenge in their development, however, is the identification of components that are optimised for inclusion in the final format in order to deliver both efficacy and robust biophysical properties. Using a modular BsAb format, the mAb-dAb, we assessed whether an 'in-format' screening approach, designed to select format-compatible domain antibodies, could expedite lead discovery...
October 27, 2016: MAbs
Guido Ferrari, Barton F Haynes, Scott Koenig, Jeffrey L Nordstrom, David M Margolis, Georgia D Tomaras
HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4(+) T cells and thus limit the spread of progeny virus...
October 7, 2016: Nature Reviews. Drug Discovery
Anna Z Wec, Elisabeth K Nyakatura, Andrew S Herbert, Katie A Howell, Frederick W Holtsberg, Russell R Bakken, Eva Mittler, John R Christin, Sergey Shulenin, Rohit K Jangra, Sushma Bharrhan, Ana I Kuehne, Zachary A Bornholdt, Andrew I Flyak, Erica Ollmann Saphire, James E Crowe, M Javad Aman, John M Dye, Jonathan R Lai, Kartik Chandran
There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope...
October 21, 2016: Science
Even Walseng, Christopher G Nelson, Junpeng Qi, Alex R Nanna, William R Roush, Rajib K Goswami, Subhash C Sinha, Terrence R Burke, Christoph Rader
Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART)...
September 9, 2016: Journal of Biological Chemistry
Yajun Zhang, Lingfei Wang, Xiaodan Chong, Xiaojie Yu, Yanchun Meng, Jian Dong, Chao Wang, Huajing Wang, Yang Yang, Tian Xia, Jian Zhao, Bohua Li
The anti-ErbB2 humanized antibody trastuzumab was approved for ErbB2-positive metastatic gastric and gastro-esophageal junction cancer in 2010. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2-targeting therapy. Down-regulation of surface receptors induced by monoclonal antibody (mAb) contributes to its antitumor efficacy. Previous studies have demonstrated that if two anti-ErbB2 mAbs did not compete with each other for binding to ErbB2, the combination of them can enhance ErbB2 internalization...
September 2, 2016: Biochemical and Biophysical Research Communications
Yaoxing Huang, Jian Yu, Anastasia Lanzi, Xin Yao, Chasity D Andrews, Lily Tsai, Mili R Gajjar, Ming Sun, Michael S Seaman, Neal N Padte, David D Ho
While the search for an efficacious HIV-1 vaccine remains elusive, emergence of a new generation of virus-neutralizing monoclonal antibodies (mAbs) has re-ignited the field of passive immunization for HIV-1 prevention. However, the plasticity of HIV-1 demands additional improvements to these mAbs to better ensure their clinical utility. Here, we report engineered bispecific antibodies that are the most potent and broad HIV-neutralizing antibodies to date. One bispecific antibody, 10E8V2.0/iMab, neutralized 118 HIV-1 pseudotyped viruses tested with a mean 50% inhibitory concentration (IC50) of 0...
June 16, 2016: Cell
Michael Hettich, Jayashree Lahoti, Shruthi Prasad, Gabriele Niedermann
T cell-recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell-recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis...
August 15, 2016: Cancer Research
Elodie Picarda, Kim C Ohaegbulam, Xingxing Zang
B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen-presenting cells, B7-H3 plays an important role in the inhibition of T-cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy...
July 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Amita Datta-Mannan, Johnny E Croy, Linda Schirtzinger, Stacy Torgerson, Matthew Breyer, Victor J Wroblewski
Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys...
July 2016: MAbs
Guillaume Terral, Alain Beck, Sarah Cianférani
Over the past 15 years, monoclonal antibodies (mAbs) have emerged as the most successful class of therapeutics. Their specific structural and functional properties make them highly effective treatments for various diseases. Most therapeutic mAbs are based on chimeric, humanized or human G immunoglobulins (IgGs) selected from three isotypes (1, 2 and 4). IgGs are large and highly complex multimeric glycoproteins. They are constituted of a mixture of isoforms including macro and micro-variants that must be extensively characterized prior to their investigation as a drug candidate in clinical trials...
October 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Szabolcs Fekete, Jean-Luc Veuthey, Alain Beck, Davy Guillarme
Hydrophobic interaction chromatography (HIC) is a historical strategy used for the analytical purification and characterization of proteins. Similarly to what can be done in reversed-phase liquid chromatography (RPLC), HIC is able to separate protein species based on their hydrophobicity, but using different conditions. Compared to RPLC, the main benefit of HIC is its ability to perform separations under non denaturing conditions (i.e. physiological pH conditions, ambient mobile phase temperature and no need for organic solvents) and so an orthogonal method...
April 4, 2016: Journal of Pharmaceutical and Biomedical Analysis
Dan Chen, Jianxuan Zou, Yunhui Zong, Huimin Meng, Gangli An, Lin Yang
Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a co-receptor for growth factors and chemokines and is a molecular marker associated with the epithelial-mesenchymal transition during development and carcinogenesis. In this study, we generated two specific mouse anti-human CD138 monoclonal antibodies (mAbs, clone ID: 480CT5.4.3, 587CT7.3.6.5) using hybridoma technology and identified their immunological characteristics. After hybridoma sequencing, the single-chain variable fragments (ScFvs) cloned from two hybridoma cells were combined with anti-CD3 OKT-3 ScFv to generate two recombinant bispecific antibodies (h-STL002, m-STL002) against CD138 and CD3 molecules, respectively...
June 2016: Immunopharmacology and Immunotoxicology
M Tampellini, C Sonetto, G V Scagliotti
INTRODUCTION: Anti-angiogenetic agents are currently the standard of care in metastatic CRC patients. Bevacizumab, aflibercept, regorafenib and recently ramucirumab have significantly improved both progression-free and overall survival in different lines of treatment. Since bevacizumab's approval, a number of novel anti-VEGF agents have been tested in preclinical and clinical models. AREAS COVERED: This review is focused on the most recent clinical results of novel agents targeting VEGF and its receptors with a major focus on those investigated recently in clinical trials...
2016: Expert Opinion on Investigational Drugs
Andrea Zito, Carla Bromuro, Giorgia Mandili, Paola Chiani, Alberto L Horenstein, Fabio Malavasi, Roberto Cauda, Antonio Cassone, Antonella Torosantucci
There is a real medical need of new diagnostic tools for the early recognition of invasive Candida infections. We exploited a rather simple and rapid redox methodology to construct a bispecific monoclonal antibody (bsmAb) that combines a monoclonal antibody (mAb) directed against 1,3-β-D-glucan, a well-known, pan-fungal diagnostic biomarker, with a mAb recognizing MP65, a major immunogenic mannoprotein secreted by C.albicans and other Candida species. The bsmAb (MP65/bglu mAb) was successfully produced and purified at high yields and proved to bind and reveal simultaneously, with high sensitivity, the β-glucan and MP65 antigens in both purified and native forms...
2016: PloS One
J M Lee, S H Lee, J-W Hwang, S J Oh, B Kim, S Jung, S-H Shim, P W Lin, S B Lee, M-Y Cho, Y J Koh, S Y Kim, S Ahn, J Lee, K-M Kim, K H Cheong, J Choi, K-A Kim
Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs...
August 25, 2016: Oncogene
Tao Dao, Dmitry Pankov, Andrew Scott, Tatyana Korontsvit, Victoriya Zakhaleva, Yiyang Xu, Jingyi Xiang, Su Yan, Manuel Direito de Morais Guerreiro, Nicholas Veomett, Leonid Dubrovsky, Michael Curcio, Ekaterina Doubrovina, Vladimir Ponomarev, Cheng Liu, Richard J O'Reilly, David A Scheinberg
Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cell-based therapies, but there has been little progress in developing small-molecule drugs or antibodies directed to these antigens. Here we describe a bispecific T-cell engager (BiTE) antibody derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1 presented on HLA-A*02:01. Despite the very low density of the complexes at the cell surface, ESK1-BiTE selectively activated and induced proliferation of cytolytic human T cells that killed cells from multiple leukemias and solid tumors in vitro and in mice...
October 2015: Nature Biotechnology
Kapil Gadkar, Cinthia V Pastuskovas, Jennifer E Le Couter, J Michael Elliott, Jianhuan Zhang, Chingwei V Lee, Sarah Sanowar, Germaine Fuh, Hok Seon Kim, T Noelle Lombana, Christoph Spiess, Makia Nakamura, Phil Hass, Whitney Shatz, Y Gloria Meng, Justin M Scheer
PURPOSE: To design and select the next generation of ocular therapeutics, we performed a comprehensive ocular and systemic pharmacokinetic (PK) analysis of a variety of antibodies and antibody fragments, including a novel-designed bispecific antibody. METHODS: Molecules were administrated via intravitreal (IVT) or intravenous (IV) injections in rabbits, and antibody concentrations in each tissue were determined by ELISA. A novel mathematical model was developed to quantitate the structure-PK relationship...
August 2015: Investigative Ophthalmology & Visual Science
Grace Chan, Gwen Jordaan, Robert N Nishimura, Richard H Weisbart
TP53 is a tumor suppressor gene that is mutated in 50% of cancers, and its function is tightly regulated by the E3 ligase, Mdm2. Both p53 and Mdm2 are localized in the cell nucleus, a site that is impervious to therapeutic regulation by most antibodies. We identified a cell-penetrating lupus monoclonal anti-DNA antibody, mAb 3E10, that targets the nucleus, and we engineered mAb 3E10 to function as an intranuclear transport system to deliver therapeutic antibodies into the nucleus as bispecific single chain Fv (scFv) fragments...
January 1, 2016: International Journal of Cancer. Journal International du Cancer
George J Weiner
For 20 years, monoclonal antibodies (mAbs) have been a standard component of cancer therapy, but there is still much room for improvement. Efforts continue to build better cancer therapeutics based on mAbs. Anticancer mAbs function through various mechanisms, including directly targeting the malignant cells, modifying the host response, delivering cytotoxic moieties and retargeting cellular immunity towards the malignant cells. Characteristics of mAbs that affect their efficacy include antigen specificity, overall structure, affinity for the target antigen and how a mAb component is incorporated into a construct that can trigger target cell death...
June 2015: Nature Reviews. Cancer
Michele Merli, Andrea Ferrario, Margherita Maffioli, Luca Arcaini, Francesco Passamonti
INTRODUCTION: The advent of the anti-CD20 mAb rituximab has opened a new era in the treatment of non-Hodgkin's lymphomas (NHL), markedly altering standard treatment strategies. Moreover, the proof-of-concept that targeting a specific lymphocyte surface antigen may induce a highly effective and safe targeted killing of malignant cells has opened the door to the development of a plethora of novel mAbs directed towards different B- and T-cell-specific antigens. AREAS COVERED: This review discusses the recent available clinical data about new-generation anti-CD20 mAbs characterized by increased antibody- (obinutuzumab) or complement-dependent cyotoxicity (ofatumumab) as well as novel investigational agents targeting other lymphocyte antigens (e...
2015: Expert Opinion on Investigational Drugs
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