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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/28820071/antibody-fragments-as-potential-biopharmaceuticals-for-cancer-therapy-success-and-limitations
#2
Roman V Kholodenko, Daniel V Kalinovsky, Igor I Doronin, Eugene D Ponomarev, Irina V Kholodenko
Monoclonal antibodies (mAbs) are an important class of therapeutic agents approved for the therapy of many types of malignancies. However, in certain cases applications of conventional mAbs have several limitations in anticancer immunotherapy. These limitations include insufficient efficacy and adverse effects. The antigen-binding fragments of antibodies have a considerable potential to overcome the disadvantages of conventional mAbs, such as poor penetration into solid tumors and Fc-mediated bystander activation of the immune system...
August 17, 2017: Current Medicinal Chemistry
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/28819070/claudin-5-binders-enhance-permeation-of-solutes-across-the-blood-brain-barrier-in-a-mammalian-model
#4
Yosuke Hashimoto, Keisuke Shirakura, Yoshiaki Okada, Hiroyuki Takeda, Kohki Endo, Maki Tamura, Akihiro Watari, Yoshifusa Sadamura, Tatsuya Sawasaki, Takefumi Doi, Kiyohito Yagi, Masuo Kondoh
A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5, a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies specific to the extracellular domains of CLDN-5...
August 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28818671/incidence-and-risk-of-cardiotoxicity-in-cancer-patients-treated-with-targeted-therapies
#5
REVIEW
Matteo Santoni, Federico Guerra, Alessandro Conti, Alessandra Lucarelli, Silvia Rinaldi, Laura Belvederesi, Alessandro Capucci, Rossana Berardi
BACKGROUND: Cardiotoxicityis a serious side effect of molecularly targeted agents. The purpose of this study was to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade cardiotoxicity in patients with solid tumors receiving targeted agents through a revised meta-analysis of available clinical trials. METHODS: The scientific literature regarding cardiotoxicity was extensively analyzed using MEDLINE, PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL)...
July 28, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28818634/mining-na%C3%A3-ve-rabbit-antibody-repertoires-by-phage-display-for-monoclonal-antibodies-of-therapeutic-utility
#6
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/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/28817087/the-preparation-and-identification-of-a-monoclonal-antibody-against-domoic-acid-and-establishment-of-detection-by-indirect-competitive-elisa
#8
Abdullah F U H Saeed, Sumei Ling, Jun Yuan, Shihua Wang
Domoic acid (DA) is a potent toxin, marine biotoxin, and primarily produced by Pseudo-nitzschia. The DA hapten was coupled with bovine serum albumin (BSA), and ovalbumin (OVA) as carrier proteins. DA-BSA conjugate was used as immunogen and DA-OVA as coating antigen. Cell fusion between spleen cells and sp2/0 myeloma cells developed 1C3 hybridoma clone producing 1C3 monoclonal antibody (mAb). Hybridoma was injected into the mice to produce ascites, and further purified by caprylic acid/ammonium sulfate method...
August 17, 2017: Toxins
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/28815644/role-of-%C3%AE-%C3%AE-t-cells-in-exacerbated-airway-inflammation-during-reinfection-of-neonatally-primed-mice-in-adulthood
#11
Jianqi Wu, Lei Xu, Xu Han, Haiyan Hu, Feifei Qi, Song Bai, Ruonan Chai, Yuee Teng, Beixing Liu
Age at primary infection with respiratory syncytial virus (RSV) is a crucial factor in determining the outcome of reinfection. However, how neonatal RSV infection affects the immune system and renders the host more susceptible to reinfection in later life is poorly understood. In the present study, by using BALB/c mice that were first infected with RSV as neonates, the role of γδ T cells in the development of airway inflammation during reinfection in adulthood was investigated. We found that neonatal RSV infection resulted in an aggravated infiltration of mononuclear cells in bronchoalveolar lavage (BAL) fluids, in parallel with a significant increase in the levels of type 2 cytokines in lungs on day 4 after reinfection...
August 16, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28815409/insulin-like-growth-factor-igf-pathway-targeting-in-cancer-role-of-the-igf-axis-and-opportunities-for-future-combination-studies
#12
Aaron Simpson, Wilfride Petnga, Valentine M Macaulay, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder
Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair...
August 16, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28815043/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#13
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28814603/single-nucleotide-polymorphisms-of-the-high-affinity-igg-receptor-fc%C3%AE-ri-reduce-immune-complex-binding-and-downstream-effector-functions
#14
Arianne M Brandsma, Toine Ten Broeke, Evelien van Dueren den Hollander, Thomas G Caniels, Tineke Kardol-Hoefnagel, Jürgen Kuball, Jeanette H W Leusen
Binding of IgG Abs to FcγRs on immune cells induces FcγR cross-linking that leads to cellular effector functions, such as phagocytosis, Ab-dependent cellular cytotoxicity, and cytokine release. However, polymorphisms in low affinity FcγRs have been associated with altered avidity toward IgG, thereby substantially impacting clinical outcomes of multimodular therapy when targeting cancer or autoimmune diseases with mAbs as well as the frequency and severity of autoimmune diseases. In this context, we investigated the consequences of three nonsynonymous single nucleotide polymorphisms (SNPs) for the high affinity receptor for IgG, FcγRI...
August 16, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28812232/introgression-of-heat-shock-protein-hsp70-and-shsp-genes-into-the-malaysian-elite-chilli-variety-kulai-capsicum-annuum-l-through-the-application-of-marker-assisted-backcrossing-mab
#15
Magaji G Usman, Mohd Y Rafii, Mohammad Y Martini, Oladosu A Yusuff, Mohd R Ismail, Gous Miah
Backcrossing together with simple sequence repeat marker strategy was adopted to improve popular Malaysian chilli Kulai (Capsicum annuum L.) for heat tolerance. The use of molecular markers in backcross breeding and selection contributes significantly to overcoming the main drawbacks such as increase linkage drag and time consumption, in the ancient manual breeding approach (conventional), and speeds up the genome recovery of the recurrent parent. The strategy was adopted to introgress heat shock protein gene(s) from AVPP0702 (C...
August 15, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28811971/preclinical-immunopet-ct-imaging-using-zr-89-labeled-anti-pd-l1-monoclonal-antibody-for-assessing-radiation-induced-pd-l1-upregulation-in-head-and-neck-cancer-and-melanoma
#16
Masahiro Kikuchi, David A Clump, Raghvendra M Srivastava, Lingyi Sun, Dexing Zeng, Julio A Diaz-Perez, Carolyn J Anderson, W Barry Edwards, Robert L Ferris
Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28810552/anti-cxcl4-monoclonal-antibody-accelerates-telogen-to-anagen-transition-and-attenuates-apoptosis-of-the-hair-follicle-in-mice
#17
Wen Guan, Xiaolan Yu, Jingjing Li, Qing Deng, Yang Zhang, Jing Gao, Peng Xia, Yunsheng Yuan, Jin Gao, Liang Zhou, Wei Han, Yan Yu
Although hair loss or alopecia is a common disease, its exact mechanisms are not yet well understood. The present study investigated the hypothesis that the homeostatic regulation of genes during hair regeneration may participate in hair loss, based on the cyclicity of hair growth. A cluster of such genes was identified by an expression gene-array from the dorsal skin in a depilated mouse model, and CXCL4 was identified as a significantly regulated gene during the hair regeneration process. To elucidate the function of CXCL4 in hair growth, CXCL4 activity was blocked by the administration of an anti-CXCL4 monoclonal antibody (mAb)...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28810082/therapeutic-monoclonal-antibodies-and-clinical-laboratory-tests-when-why-and-what-is-expected
#18
Zhanhu Zhang, Wenjie Hu, Linlin Li, Hongxia Ding, Haibo Li
BACKGROUND: We herein provide an overview of the clinical laboratory tests that should be performed before, during and after using therapeutic monoclonal antibodies (mAbs) and the clinical laboratory tests that may be affected by mAbs. METHODS: The labels of FDA-approved therapeutic mAbs were downloaded from DailyMed (the official website for drug labels) and were used as the sources of data for this review. RESULTS: It was found that most of the labels provided information relevant to the clinical laboratory tests, including the tests needed before mAbs treatment to check the patients' background status and to identify potentially sensitive patients, the tests needed during or after the treatment to evaluate the patients' response, and the mAbs that may lead to false positive or negative results for clinical laboratory tests...
August 15, 2017: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/28807287/an-elisa-for-the-early-diagnosis-of-acute-canine-babesiosis-detecting-circulating-antigen-of-large-babesia-spp
#19
Ramon M Eichenberger, Saša Štefanić, Torsten J Naucke, Mindaugas Šarkūnas, Gintaras Zamokas, Felix Grimm, Peter Deplazes
Babesia canis is the predominant Babesia species in dogs in Europe and is responsible for a severe and fatal disease. An increase in global pet tourism and a widening of the geographic distribution of the tick vector has led to the emergence of infections in areas where previously only imported cases have been reported. Due to the potential for rapid and serious disease progression, direct parasite detection by stained blood smears and light microscopy or DNA-based methods have traditionally been used for the diagnosis of acute infections...
August 30, 2017: Veterinary Parasitology
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#20
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
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