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T cell dependent bispecific antibody

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https://www.readbyqxmd.com/read/28895560/tyrosine-kinase-inhibition-increases-the-cell-surface-localization-of-flt3-itd-and-enhances-flt3-directed-immunotherapy-of-acute-myeloid-leukemia
#1
K Reiter, H Polzer, C Krupka, A Maiser, B Vick, M Rothenberg-Thurley, K H Metzeler, D Dörfel, H R Salih, G Jung, E Nößner, I Jeremias, W Hiddemann, H Leonhardt, K Spiekermann, M Subklewe, P A Greif
The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28881778/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#2
Yanyu Bi, Hua Jiang, Peng Wang, Bo Song, Huamao Wang, Xianming Kong, Zonghai Li
There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28873441/a-fully-humanized-igg-like-bispecific-antibody-for-effective-dual-targeting-of-cxcr3-and-ccr6
#3
Remy Robert, Laurent Juglair, Ee X Lim, Caroline Ang, Carl J H Wang, Gregor Ebert, Olan Dolezal, Charles R Mackay
Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic...
2017: PloS One
https://www.readbyqxmd.com/read/28834699/t-cell-engaging-bispecific-antibody-t-bsab-from-technology-to-therapeutics
#4
REVIEW
Z Wu, N V Cheung
Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials...
August 20, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28794022/potent-in-vivo-nk-cell-mediated-elimination-of-hiv-1-infected-cells-mobilized-by-a-gp120-bispecific-and-hexavalent-broadly-neutralizing-fusion-protein
#5
Ariola Bardhi, Yanling Wu, Weizao Chen, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C Kappes, Dimiter S Dimitrov, Tianlei Ying, Harris Goldstein
Antibodies bound to HIV-1 envelope protein expressed by infected cells mobilize antibody dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to functional HIV-1 cure...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28674296/next-generation-antibody-therapeutics-using-bispecific-antibody-technology
#6
Tomoyuki Igawa
 Nearly fifty monoclonal antibodies have been approved to date, and the market for monoclonal antibodies is expected to continue to grow. Since global competition in the field of antibody therapeutics is intense, we need to establish novel antibody engineering technologies to provide true benefit for patients, with differentiated product values. Bispecific antibodies are among the next generation of antibody therapeutics that can bind to two different target antigens by the two arms of immunoglobulin G (IgG) molecule, and are thus believed to be applicable to various therapeutic needs...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28596941/highly-specific-and-effective-targeting-of-egfrviii-positive-tumors-with-tandab-antibodies
#7
Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Stefan Knackmuss, Michael Weichel, Thorsten Gantke, Vera Molkenthin, Eugene A Zhukovsky, Michael Tesar, Martin Treder
To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28588218/a-semi-high-throughput-method-for-screening-small-bispecific-antibodies-with-high-cytotoxicity
#8
Aruto Sugiyama, Mitsuo Umetsu, Hikaru Nakazawa, Teppei Niide, Tomoko Onodera, Katsuhiro Hosokawa, Shuhei Hattori, Ryutaro Asano, Izumi Kumagai
Small bispecific antibodies that induce T-cell-mediated cytotoxicity have the potential to damage late-stage tumor masses to a clinically relevant degree, but their cytotoxicity is critically dependent on their structural and functional properties. Here, we constructed an optimized procedure for identifying highly cytotoxic antibodies from a variety of the T-cell-recruiting antibodies engineered from a series of antibodies against cancer antigens of epidermal growth factor receptor family and T-cell receptors...
June 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28572527/treatment-of-hepatocellular-carcinoma-with-a-gpc3-targeted-bispecific-t-cell-engager
#9
Yanyu Bi, Hua Jiang, Peng Wang, Bo Song, Huamao Wang, Xianming Kong, Zonghai Li
There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404865/dual-angiopoietin-2-and-vegfa-inhibition-elicits-antitumor-immunity-that-is-enhanced-by-pd-1-checkpoint-blockade
#10
Martina Schmittnaegel, Nicolò Rigamonti, Ece Kadioglu, Antonino Cassará, Céline Wyser Rmili, Anna Kiialainen, Yvonne Kienast, Hans-Joachim Mueller, Chia-Huey Ooi, Damya Laoui, Michele De Palma
Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma...
April 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28262555/membrane-proximal-epitope-facilitates-efficient-t-cell-synapse-formation-by-anti-fcrh5-cd3-and-is-a-requirement-for-myeloma-cell-killing
#11
Ji Li, Nicola J Stagg, Jennifer Johnston, Michael J Harris, Sam A Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R James, Teemu T Junttila
The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28257797/bispecific-t-cell-engaging-antibody-constructs-targeting-a-universally-conserved-part-of-the-viral-m2-ectodomain-cure-and-prevent-influenza-a-virus-infection
#12
Jochen Pendzialek, Kenny Roose, Anouk Smet, Bert Schepens, Peter Kufer, Tobias Raum, Patrick A Baeuerle, Markus Muenz, Xavier Saelens, Walter Fiers
The ectodomain of the influenza A matrix protein 2 (M2e) is highly conserved amongst all influenza virus A subtypes. M2e is present on the surface of influenza A virus-infected cells, and therefore a suitable target for broadly protective therapies. We designed bispecific T cell engaging (BiTE(®)) antibody constructs specific for M2e by genetically fusing a single chain variable fragment (scFv) derived from an M2e-specific murine monoclonal antibody with a CD3ɛ-specific scFv. These so-called FLU BiTE(®) antibody constructs selectively mediate T cell dependent lysis of M2-expressing and influenza A virus infected cells and protect BALB/c mice against challenge with different influenza A virus subtypes...
March 1, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28184223/fc-engineering-for-developing-therapeutic-bispecific-antibodies-and-novel-scaffolds
#13
REVIEW
Hongyan Liu, Abhishek Saxena, Sachdev S Sidhu, Donghui Wu
Therapeutic monoclonal antibodies have become molecules of choice to treat autoimmune disorders, inflammatory diseases, and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (T cell, natural killer cell, or macrophage cell) toward target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas to antibody fragments...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28157217/acute-myeloid-leukemia-targets-for-bispecific-antibodies
#14
REVIEW
S S Hoseini, N K Cheung
Despite substantial gains in our understanding of the genomics of acute myelogenous leukemia (AML), patient survival remains unsatisfactory especially among the older age group. T cell-based therapy of lymphoblastic leukemia is rapidly advancing; however, its application in AML is still lagging behind. Bispecific antibodies can redirect polyclonal effector cells to engage chosen targets on leukemia blasts. When the effector cells are natural-killer cells, both antibody-dependent and antibody-independent mechanisms could be exploited...
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/27966460/potent-cd4-t-cell-associated-antitumor-memory-responses-induced-by-trifunctional-bispecific-antibodies-in-combination-with-immune-checkpoint-inhibition
#15
Nina Deppisch, Peter Ruf, Nina Eißler, Horst Lindhofer, Ralph Mocikat
Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#16
Steven R Leong, Siddharth Sukumaran, Maria Hristopoulos, Klara Totpal, Shannon Stainton, Elizabeth Lu, Alfred Wong, Lucinda Tam, Robert Newman, Brian R Vuillemenot, Diego Ellerman, Chen Gu, Mary Mathieu, Mark S Dennis, Allen Nguyen, Bing Zheng, Crystal Zhang, Genee Lee, Yu-Waye Chu, Rodney A Prell, Kedan Lin, Steven T Laing, Andrew G Polson
Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML...
February 2, 2017: Blood
https://www.readbyqxmd.com/read/27712994/identification-of-high-affinity-anti-cd16a-allotype-independent-human-antibody-domains
#17
Wei Li, Hongjia Yang, Dimiter S Dimitrov
CD16A (FcγRIIIA) is an activating receptor mostly expressed on natural killer (NK) cells and monocytes/macrophages. It can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) through low-affinity interaction with human immunoglobulin G (IgG) Fc. It can also mediate cell lysis if NK cells are guided by bispecific killer cells engagers (BiKEs). BiKEs showed some success in clinical trials of cancer and are promising candidate therapeutics. However, currently reported BiKEs are based on antibody fragments (scFvs) of relatively large size...
October 2016: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/27708227/t-cell-responses-against-cd19-pediatric-acute-lymphoblastic-leukemia-mediated-by-bispecific-t-cell-engager-bite-are-regulated-contrarily-by-pd-l1-and-cd80-cd86-on-leukemic-blasts
#18
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
November 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27406985/mor209-es414-a-novel-bispecific-antibody-targeting-psma-for-the-treatment-of-metastatic-castration-resistant-prostate-cancer
#19
Gabriela Hernandez-Hoyos, Toddy Sewell, Robert Bader, Jeannette Bannink, Ruth A Chenault, Mollie Daugherty, Maria Dasovich, Hang Fang, Rebecca Gottschalk, John Kumer, Robert E Miller, Padma Ravikumar, Jennifer Wiens, Paul A Algate, David Bienvenue, Catherine J McMahan, Sateesh K Natarajan, Jane A Gross, John W Blankenship
Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen)...
September 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27322989/trikes-and-bikes-join-cars-on-the-cancer-immunotherapy-highway
#20
Szun Szun Tay, Hernan Carol, Maté Biro
Unprecedented clinical success has recently been achieved in cancer immunotherapy using cytotoxic T cells armed with activating tumor-specific Chimeric Antigen Receptors (CARs). Natural killer (NK) cells, potent cytotoxic effectors, also hold potential to be effectively harnessed for immunotherapy. The anti-tumor efficacy of NK cell therapies has been limited by a lack of antigen specificity and the poor persistence of NK cells in vivo. To address these limitations, Vallera and colleagues developed novel Trispecific Killer cell Engagers (TriKEs), reported in the Feb...
November 2016: Human Vaccines & Immunotherapeutics
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