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Human Monoclonal antibodies

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https://www.readbyqxmd.com/read/28820579/site-specific-conjugation-to-native-and-engineered-lysines-in-human-immunoglobulins-by-microbial-transglutaminase
#1
Jared Spidel, Benjamin Vaessen, Earl Albone, Xin Cheng, Arielle Verdi, J Bradford Kline
The use of microbial transglutaminase (MTG) to produce site-specific antibody-drug conjugates (ADCs) has thus far focused on transamidation of engineered acyl donor glutamine residues in an antibody based on the hypothesis that the lower specificity of MTG for acyl acceptor lysines may result in transamidation of multiple native lysine residues, thereby yielding heterogeneous products. We investigated the utilization of native IgG lysines as acyl acceptor sites for glutamine-based acyl donor substrates. Of the approximately 80 lysines in multiple recombinant IgG monoclonal antibodies (mAbs), none were transamidated...
August 18, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28819723/guselkumab-first-global-approval
#2
Anthony Markham
Guselkumab (Tremfya™) is a human monoclonal IgG1λ antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy...
August 17, 2017: Drugs
https://www.readbyqxmd.com/read/28819703/novel-prostate-cancer-immunotherapy-with-a-dna-encoded-anti-prostate-specific-membrane-antigen-monoclonal-antibody
#3
Kar Muthumani, Liron Marnin, Sagar B Kudchodkar, Alfredo Perales-Puchalt, Hyeree Choi, Sangya Agarwal, Veronica L Scott, Emma L Reuschel, Faraz I Zaidi, Elizabeth K Duperret, Megan C Wise, Kimberly A Kraynyak, Kenneth E Ugen, Niranjan Y Sardesai, J Joseph Kim, David B Weiner
Prostate-specific membrane antigen (PSMA) is expressed at high levels on malignant prostate cells and is likely an important therapeutic target for the treatment of prostate carcinoma. Current immunotherapy approaches to target PSMA include peptide, cell, vector or DNA-based vaccines as well as passive administration of PSMA-specific monoclonal antibodies (mAb). Conventional mAb immunotherapy has numerous logistical and practical limitations, including high production costs and a requirement for frequent dosing due to short mAb serum half-life...
August 17, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28819692/molecular-characterization-of-atypical-antigenic-variants-of-canine-rabies-virus-reveals-its-reintroduction-by-wildlife-vectors-in-southeastern-mexico
#4
Fabiola Garcés-Ayala, Nidia Aréchiga-Ceballos, Joanna M Ortiz-Alcántara, Elizabeth González-Durán, Sandra I Pérez-Agüeros, Alfonso Méndez-Tenorio, Belem Torres-Longoria, Irma López-Martínez, Lucía Hernández-Rivas, José Alberto Díaz-Quiñonez, José Ernesto Ramírez-González
Rabies is an infectious viral disease that is practically always fatal following the onset of clinical signs. In Mexico, the last case of human rabies transmitted by dogs was reported in 2006 and canine rabies has declined significantly due to vaccination campaigns implemented in the country. Here we report on the molecular characterization of six rabies virus strains found in Yucatan and Chiapas, remarkably, four of them showed an atypical reaction pattern when antigenic characterization with a reduced panel of eight monoclonal antibodies was performed...
August 17, 2017: Archives of Virology
https://www.readbyqxmd.com/read/28818634/mining-na%C3%A3-ve-rabbit-antibody-repertoires-by-phage-display-for-monoclonal-antibodies-of-therapeutic-utility
#5
Haiyong Peng, Thomas Nerreter, Jing Chang, Junpeng Qi, Xiuling Li, Pabalu Karunadharma, Gustavo Martinez, Mohammad Fallahi, Jo Soden, Jim Freeth, Roger R Beerli, Ulf Grawunder, Michael Hudecek, Christoph Rader
Owing to their high affinities and specificities, rabbit monoclonal antibodies (mAbs) have demonstrated value and potential primarily as basic research and diagnostic reagents, but in some cases also as therapeutics. To accelerate access to rabbit mAbs bypassing immunization, we generated a large naïve rabbit antibody repertoire represented by a phage display library encompassing >10 billion independent antibodies in chimeric rabbit/human Fab format and validated it by next-generation sequencing. Panels of rabbit mAbs selected from this library against two emerging cancer targets, ROR1 and ROR2, revealed high diversity, affinity, and specificity...
August 14, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28818019/pembrolizumab-in-the-treatment-of-metastatic-non-small-cell-lung-cancer-a-review-of-current-evidence
#6
Karim Rihawi, Francesco Gelsomino, Francesca Sperandi, Barbara Melotti, Michelangelo Fiorentino, Laura Casolari, Andrea Ardizzoni
Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors...
August 1, 2017: Therapeutic Advances in Respiratory Disease
https://www.readbyqxmd.com/read/28817679/increased-half-life-and-enhanced-potency-of-fc-modified-human-pcsk9-monoclonal-antibodies-in-primates
#7
Yijun Shen, Hua Li, Li Zhao, Gang Li, Ben Chen, Qingsong Guo, Bei Gao, Jinsong Wu, Tong Yang, Li Jin, Yong Su
Blocking proprotein convertase subtilisin kexin type 9 (PCSK9) binding to low-density lipoprotein receptor (LDLR) can profoundly lower plasma LDL levels. Two anti-PCKS9 monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved by the FDA in 2015. The recommended dose is 75 mg to 150 mg every two weeks for alirocumab and 140mg every two weeks or 420 mg once a month for evolocumab. This study attempted to improve the pharmacokinetic properties of F0016A, an IgG1 anti-PCKS9 mAb, to generate biologically superior molecules...
2017: PloS One
https://www.readbyqxmd.com/read/28817103/a-review-of-anti-angiogenic-targets-for-monoclonal-antibody-cancer-therapy
#8
REVIEW
Deok-Hoon Kong, Mi Ra Kim, Ji Hye Jang, Hee-Jun Na, Sukmook Lee
Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis...
August 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28816583/mammalian-cell-surface-display-for-monoclonal-antibody-based-facs-selection-of-viral-envelope-proteins
#9
Tim-Henrik Bruun, Veronika Grassmann, Benjamin Zimmer, Benedikt Asbach, David Peterhoff, Alexander Kliche, Ralf Wagner
The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation...
August 17, 2017: MAbs
https://www.readbyqxmd.com/read/28815933/an-%C3%AE-iib-%C3%AE-3-antagonist-prevents-thrombosis-without-causing-fc%C3%AE-riia-mediated-thrombocytopenia
#10
Yu-Ju Kuo, Ying-Ru Chen, Chun-Chieh Hsu, Hui-Chin Peng, Tur-Fu Huang
BACKGROUND: Thrombocytopenia, a common side effect of Arg-Gly-Asp (RGD)-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin αIIb β3 . OBJECTIVE: To explore the correlation between αIIb β3 binding epitopes and induction of DDAb binding to conformation-altered αIIb β3 , we examined whether two purified disintegrins TMV-2 and TMV-7 with distinct binding motifs that have different effects on induction of αIIb β3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory monoclonal antibody (mAb) raised against αIIb β3 ...
August 16, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28815913/metastatic-triple-negative-breast-cancer-optimizing-treatment-options-new-and-emerging-targeted-therapies
#11
REVIEW
Parham Khosravi-Shahi, Luis Cabezón-Gutiérrez, Sara Custodio-Cabello
Triple negative breast cancer (TNBC) is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. It also has a distinct epidemiology. TNBCs are frequently of high histologic grade, typically more aggressive and difficult to treat than hormone receptor-positive tumors, and they are associated with a higher risk of early relapse with visceral metastasis after surgery, chemotherapy and/or radiotherapy. The lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression precludes the use of targeted therapies in advanced stages, and the only approved systemic treatment option is chemotherapy with or without bevacizumab...
August 16, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28814758/targeted-insertion-of-an-anti-cd2-monoclonal-antibody-transgene-into-the-ggta1-locus-in-pigs-using-foki-dcas9
#12
Mark B Nottle, Evelyn J Salvaris, Nella Fisicaro, Stephen McIlfatrick, Ivan Vassiliev, Wayne J Hawthorne, Philip J O'Connell, Jamie L Brady, Andrew M Lew, Peter J Cowan
Xenotransplantation from pigs has been advocated as a solution to the perennial shortage of donated human organs and tissues. CRISPR/Cas9 has facilitated the silencing of genes in donor pigs that contribute to xenograft rejection. However, the generation of modified pigs using second-generation nucleases with much lower off-target mutation rates than Cas9, such as FokI-dCas9, has not been reported. Furthermore, there have been no reports on the use of CRISPR to knock protective transgenes into detrimental porcine genes...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813171/anti-edar-agonist-antibody-therapy-resolves-palate-defects-in-pax9-mice
#13
S Jia, J Zhou, Y Wee, M L Mikkola, P Schneider, R N D'Souza
To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans...
August 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28813164/pembrolizumab-in-patients-with-extensive-stage-small-cell-lung-cancer-results-from-the-phase-ib-keynote-028-study
#14
Patrick A Ott, Elena Elez, Sandrine Hiret, Dong-Wan Kim, Anne Morosky, Sanatan Saraf, Bilal Piperdi, Janice M Mehnert
Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry...
August 16, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28811604/multimerization-is-required-for-antigen-binding-activity-of-an-engineered-igm-igg-chimeric-antibody-recognizing-a-skin-related-antigen
#15
Kwesi Teye, Koji Hashimoto, Sanae Numata, Kunihiro Ohta, Marek Haftek, Takashi Hashimoto
Monoclonal antibodies offer great tools for research. We encountered a potentially useful mouse IgM monoclonal antibody whose antigen is expressed in normal skin but lost in human skin cancer. Because IgM is difficult to work with and the antigen was unknown, we decided to convert the IgM (µ) to IgG (γ) version. After cDNA for the antibody was obtained by RACE PCR, we made a series of molecules with different combinations of IgM and IgG domains. Whereas VH-Cµ1-Cµ2-Cγ3 and VH-Cµ1-Cµ2-Hinge-Cγ2-Cγ3 functionally bound to the antigen, VH-Cγ1-Hinge-Cγ2-Cγ3, VH-Cµ1-Hinge-Cγ2-Cγ3, and VH-Cµ1-Cµ2-Cγ2-Cγ3 did not...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811514/differential-epitope-recognition-in-the-immunodominant-staphylococcal-antigen-a-of-staphylococcus-aureus-by-mouse-versus-human-igg-antibodies
#16
Dennis G A M Koedijk, Francisco Romero Pastrana, Hedzer Hoekstra, Sanne van den Berg, Jaap Willem Back, Carolien Kerstholt, Rianne C Prins, Irma A J M Bakker-Woudenberg, Jan Maarten van Dijl, Girbe Buist
The immunodominant staphylococcal antigen A (IsaA) is a potential target for active or passive immunization against the important human pathogen Staphylococcus aureus. Consistent with this view, monoclonal antibodies against IsaA were previously shown to be protective against S. aureus infections in mouse models. Further, patients with the genetic blistering disease epidermolysis bullosa (EB) displayed high IsaA-specific IgG levels that could potentially be protective. Yet, mice actively immunized with IsaA were not protected against S...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28810837/phase-i-dose-escalation-study-of-pazopanib-combined-with-bevacizumab-in-patients-with-metastatic-renal-cell-carcinoma-or-other-advanced-tumors
#17
Sylvie Négrier, David Pérol, Rastislav Bahleda, Antoine Hollebecque, Etienne Chatelut, Helen Boyle, Philippe Cassier, Séverine Metzger, Ellen Blanc, Jean-Charles Soria, Bernard Escudier
BACKGROUND: Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors...
August 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28809993/adalimumab-in-chronic-plaque-psoriasis-a-clinical-guide
#18
Jashin J Wu, W C Valdecantos
<p>Psoriasis is a common, inflammatory disease that manifests itself as lesions on the skin, which greatly impacts the physical and psychological wellbeing of those affected. The current goal of treatment in psoriasis is to improve the signs and symptoms of disease, whilst minimizing the burden of disease on patient health-related quality of life. Psoriasis can also be associated with other comorbidities such as joint disease, cardiovascular disease, and depression, which can add to the complexity of treatment...
August 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28808918/idarucizumab-in-dabigatran-treated-patients-with-acute-ischemic-stroke-receiving-alteplase-a-systematic-review-of-the-available-evidence
#19
REVIEW
Slaven Pikija, Laszlo K Sztriha, J Sebastian Mutzenbach, Stefan M Golaszewski, Johann Sellner
BACKGROUND AND PURPOSE: Current guidelines do not recommend the use of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who receive direct oral anticoagulants. While the humanized monoclonal antibody idarucizumab can quickly reverse the anticoagulant effects of the thrombin inhibitor dabigatran, safety data for subsequent tissue plasminogen activator treatment are sparse. Here, we review current knowledge about dabigatran reversal prior to systemic reperfusion treatment in acute ischemic stroke...
August 14, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28807912/safety-and-efficacy-of-mhaa4549a-a-broadly-neutralizing-monoclonal-antibody-in-a-human-influenza-a-challenge-model-a-phase-2-randomized-trial
#20
Jacqueline M McBride, Jeremy J Lim, Tracy Burgess, Rong Deng, Michael A Derby, Mauricio Maia, Priscilla Horn, Omer Siddiqui, Daniel Sheinson, Haiyin Chen-Harris, Elizabeth M Newton, Dimitri Fillos, Denise Nazzal, Carrie M Rosenberger, Maikke B Ohlson, Rob Lambkin-Williams, Hosnieh Fathi, Jeffrey M Harris, Jorge A Tavel
BACKGROUND: MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. Safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV-challenge model. METHODS: One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24-36 hours later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1200, or 3600 mg) or a standard oral dose of oseltamivir...
August 14, 2017: Antimicrobial Agents and Chemotherapy
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