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https://www.readbyqxmd.com/read/27913998/immunotherapy-for-breast-cancer-past-present-and-future
#1
Alison Spellman, Shou-Ching Tang
Immunotherapy has shown promise in many solid tumors including melanoma and non-small cell lung cancer with an evolving role in breast cancer. Immunotherapy encompasses a wide range of therapies including immune checkpoint inhibition, monoclonal antibodies, bispecific antibodies, vaccinations, antibody-drug conjugates, and identifying other emerging interventions targeting the tumor microenvironment. Increasing efficacy of these treatments in breast cancer patients requires identification of better biomarkers to guide patient selection; recognizing when to initiate these therapies in multi-modality treatment plans; establishing novel assays to monitor immune-mediated responses; and creating combined systemic therapy options incorporating conventional treatments such as chemotherapy and endocrine therapy...
December 2, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/27913544/treatment-of-rare-factor-deficiencies-in-2016
#2
Flora Peyvandi, Marzia Menegatti
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913530/cytokine-release-syndrome-with-novel-therapeutics-for-acute-lymphoblastic-leukemia
#3
Noelle V Frey, David L Porter
T-cell-engaging immunotherapies are exciting new approaches to treat patients with acute lymphoblastic leukemia (ALL). These unique agents, which include blinatumomab, a CD3/CD19 bispecific antibody, and chimeric antigen receptor (CAR) modified T cells targeted to CD19 have shown unprecedented remission rates in the relapsed, refractory ALL setting. Cytokine release syndrome (CRS), resulting from the high magnitude of immune activation by these therapies, is the most significant treatment-related toxicity. CRS manifests with fever and malaise and can progress to life-threatening capillary leak with hypoxia and hypotension...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#4
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 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, pharmacological 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...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27896591/design-and-in-vitro-evaluation-of-bispecific-complexes-and-drug-conjugates-of-anticancer-peptide-lyp-1-in-human-breast-cancer
#5
Selin Seda Timur, Prashant Bhattarai, Reyhan Neslihan Gürsoy, İmran Vural, Ban-An Khaw
PURPOSE: LyP-1, a nine-amino-acid tumor homing peptide, selectively binds to its cognate receptor, p32. Overexpression of p32 in certain tumors should allow use of LyP-1 as a targeting agent for the delivery of therapeutic or diagnostic agents. Peptide conjugates are developed for enhanced pre-targeting of MDA-MB-231 breast cancer cells with peptide-antibody bispecific complexes and targeting with multiple-drug/-fluorophore-conjugated nano-polymers. METHODS: LyP-1-anti-DTPA bispecific antibody complexes (LyP-1-bsAbCx) were generated by conjugation of anti-DTPA antibody and LyP-1...
November 28, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27895507/fc-gamma-receptors-glycobiology-and-therapeutic-prospects
#6
REVIEW
Jerrard M Hayes, Mark R Wormald, Pauline M Rudd, Gavin P Davey
Therapeutic antibodies hold great promise for the treatment of cancer and autoimmune diseases, and developments in antibody-drug conjugates and bispecific antibodies continue to enhance treatment options for patients. Immunoglobulin (Ig) G antibodies are proteins with complex modifications, which have a significant impact on their function. The most important of these modifications is glycosylation, the addition of conserved glycans to the antibody Fc region, which is critical for its interaction with the immune system and induction of effector activities such as antibody-dependent cell cytotoxicity, complement activation and phagocytosis...
2016: Journal of Inflammation Research
https://www.readbyqxmd.com/read/27885373/a-new-era-of-treatment-for-patients-with-haemophilia-a
#7
Robert Klamroth
Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII...
November 25, 2016: Hämostaseologie
https://www.readbyqxmd.com/read/27881685/generation-of-camelid-vhh-bispecific-constructs-via-in-cell-intein-mediated-protein-trans-splicing
#8
Yuki Shibuya, Natsuki Haga, Ryutaro Asano, Hikaru Nakazawa, Takamitsu Hattori, Daisuke Takeda, Aruto Sugiyama, Reiko Kurotani, Izumi Kumagai, Mitsuo Umetsu, Koki Makabe
Production of various combinations of bispecific variable domain of heavy chain of heavy chain-only antibody (VHH) constructs to evaluate their therapeutic potential usually requires several gene-engineering steps. Here, we present an alternative method of creating bispecific VHH constructs in vivo through protein trans-splicing (PTS) reaction; this method may reduce the number of gene manipulation steps required. As a proof-of-concept, we constructed a bispecific antibody (bsAb) containing an anti-epidermal growth factor receptor VHH and anti-green fluorescent protein VHH, and we evaluated and confirmed its bispecificity...
November 23, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27873237/estimating-long-term-survival-of-adults-with-philadelphia-chromosome-negative-relapsed-refractory-b-precursor-acute-lymphoblastic-leukemia-treated-with-blinatumomab-using-historical-data
#9
Arie Barlev, Vincent W Lin, Aaron Katz, Kuolung Hu, Ze Cong, Beth Barber
INTRODUCTION: Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years. METHODS: The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset...
November 21, 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27870103/role-of-immunotherapy-in-targeting-the-bone-marrow-microenvironment-in-multiple-myeloma-an-evolving-therapeutic-strategy
#10
Clement Chung
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor...
November 21, 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27869733/antiviral-therapy-by-hiv-1-broadly-neutralizing-and-inhibitory-antibodies
#11
REVIEW
Zhiqing Zhang, Shaowei Li, Ying Gu, Ningshao Xia
Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1...
November 18, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27863175/modeling-longitudinal-preclinical-tumor-size-data-to-identify-transient-dynamics-in-tumor-response-to-antiangiogenic-drugs
#12
L G Hutchinson, H-J Mueller, E A Gaffney, P K Maini, J Wagg, A Phipps, C Boetsch, H M Byrne, B Ribba
Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27858101/a-novel-three-dimensional-heterotypic-spheroid-model-for-the-assessment-of-the-activity-of-cancer-immunotherapy-agents
#13
Sylvia Herter, Laura Morra, Ramona Schlenker, Jitka Sulcova, Linda Fahrni, Inja Waldhauer, Steffi Lehmann, Timo Reisländer, Irina Agarkova, Jens M Kelm, Christian Klein, Pablo Umana, Marina Bacac
The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor-host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB)...
November 17, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27846146/identification-and-validation-of-novel-subtype-specific-protein-biomarkers-in-pancreatic-ductal-adenocarcinoma
#14
Laura Kuhlmann, Wiebke M Nadler, Alexander Kerner, Sabrina A Hanke, Elisa M Noll, Christian Eisen, Elisa Espinet, Vanessa Vogel, Andreas Trumpp, Martin R Sprick, Christoph P Roesli
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has been subclassified into 3 molecular subtypes: classical, quasi-mesenchymal, and exocrine-like. These subtypes exhibit differences in patient survival and drug resistance to conventional therapies. The aim of the current study is to identify novel subtype-specific protein biomarkers facilitating subtype stratification of patients with PDAC and novel therapy development. METHODS: A set of 12 human patient-derived primary cell lines was used as a starting material for an advanced label-free proteomics approach leading to the identification of novel cell surface and secreted biomarkers...
November 11, 2016: Pancreas
https://www.readbyqxmd.com/read/27836687/integrated-bio-affinity-nano-platform-into-a-microfluidic-immunosensor-based-on-monoclonal-bispecific-trifunctional-antibodies-for-the-electrochemical-determination-of-epithelial-cancer-biomarker
#15
Karina Bravo, Francisco G Ortega, Germán A Messina, María I Sanz, Martín A Fernández-Baldo, Julio Raba
BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is a biomarker that is highly overexpressed on the surface of epithelial carcinoma cells. In this study, silver nanoparticles covered with polyvinyl alcohol (AgNPs-PVA) were synthesized, characterized and used in a microfluidic immunosensor based on the use of anti-EpCAM recombinant antibodies as a trapping agent. METHODS: The concentration of trapped EpCAM is then electrochemically quantified by HRP-conjugated anti-EpCAM-antibody...
November 9, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/27820973/emerging-biological-therapies-to-treat-acute-lymphoblastic-leukemia
#16
Françoise Huguet, Suzanne Tavitian
Various settings of acute lymphoblastic leukemia (ALL) represent unmet medical needs: first remission at high risk of relapse, such as persistent minimal residual disease (MRD); relapse/refractoriness (R/R); elderly patients. Biological therapies targeting widely-shared antigens of blast cells have entered the clinic in B-cell precursor (BCP)-ALL. Area covered. Results of phase II/III trials of monoclonal antibodies (MoAbs) and phase I/II trials of adoptive cell therapy by chimeric antigen receptor-engineered T cells (CAR-T cells) are presented...
November 8, 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27802782/treatment-of-human-b-cell-lymphomas-using-minicircle-dna-vector-expressing-anti-cd3-cd20-in-a-mouse-model
#17
Xiaojuan Pang, Fei Ma, Peifa Zhang, Yujian Zhong, Jing Zhang, Tianyan Wang, Gang Zheng, Xiaohu Hou, Jing Zhao, Cheng-Yi He, Zhi-Ying Chen
Bispecific antibodies (BsAbs), capable of directing T cells to kill specific cancer cells by transiently binding the two cell types, have emerged as one class of promising cancer immunotherapies. However, their wide clinical application might be hampered by two deficiencies: high cost and inconvenience in drug administration. We present concept-proving data that these problems could be bypassed by using an enhanced nonviral DNA vector minicircle (MC) to produce BsAb in vivo. We found that the anti-CD3/CD20 produced from the minicircle (MC...
November 1, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27795538/trends-in-novel-treatments-for-hemophilia
#18
Midori Shima
The principle of hemophilia treatment is replacement therapy with factor VIII and factor IX concentrates. Recently, extended half-life factor VIII and factor IX concentrates have been developed. With these concentrates, improvements in patient QOL can be expected. More recently, a novel hemophilia therapy based on a very new concept was developed. ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function. The half-life is reportedly 4-5 weeks and remarkably decreased annual bleeding rates have been achieved with subcutaneous weekly injections in the phase 1 clinical trial...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27792681/distinct-hiv-1-neutralization-potency-profiles-of-ibalizumab-based-bispecific-antibodies
#19
Ruijiang Song, Craig Pace, Michael S Seaman, Qing Fang, Ming Sun, Chasity D Andrews, Amos Wu, Neal N Padte, David D Ho
BACKGROUND: Preexposure prophylaxis using antiretroviral agents has been shown to effectively prevent human immunodeficiency virus type 1 (HIV-1) acquisition in high-risk populations. However, the efficacy of these regimens is highly variable, which is thought to be largely due to the varying degrees of adherence to a daily intervention in the populations. Passive immunization using broadly neutralizing antibodies (bNAbs) against HIV-1, with their relatively long half-life and favorable safety profile, could provide an alternative to daily preexposure prophylaxis...
December 1, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/27787607/cytokine-neutralization-at-specific-cellular-source-a%C3%A2-new-therapeutic-paradigm
#20
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...
October 27, 2016: Zeitschrift Für Rheumatologie
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