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antibody drug conjugate

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https://www.readbyqxmd.com/read/28544534/time-to-event-analysis-of-polatuzumab-vedotin-induced-peripheral-neuropathy-to-assist-in-the-comparison-of-clinical-dosing-regimens
#1
D Lu, W R Gillespie, S Girish, P Agarwal, C Li, J Hirata, Y-W Chu, M Kagedal, L Leon, V Maiya, J Y Jin
Polatuzumab vedotin, an antibody-drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55-72% in patients with indolent non-Hodgkin lymphoma in a phase II study, when dosed 1.8-2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time-to-event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration...
May 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28543395/contact-urticaria-syndrome-with-ige-antibody-against-a-cefotiam-unique-structure-evoked-by-nonapparent-exposure-to-cefotiam
#2
S Takahagi, A Tanaka, K Iwamoto, K Ishii, M Hide
A 26-year-old woman presented with recurrent attacks of widespread urticaria and systemic symptoms. The patient was a nurse, and the attacks occurred only in her workplace, without an apparent trigger. A patch test to cefotiam (CTM) induced an immediate skin reaction. ELISA detected the patient's serum IgE antibody binding to CTM conjugated with human serum albumin (CTM-HSA), and her basophils released histamine in response to CTM-HSA in a histamine release assay (HRA). Both reactions in ELISA and HRA were inhibited by pretreatment of the patient's serum or basophils with cefotiam...
May 22, 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/28541812/engineering-humanized-antibody-framework-sequences-for-optimal-site-specific-conjugation-of-cytotoxins
#3
Jared L Spidel, Earl F Albone, Xin Cheng, Benjamin Vaessen, Sara Jacob, Andrew Z Milinichik, Arielle Verdi, J Bradford Kline, Luigi Grasso
The prevailing techniques used to generate antibody-drug conjugates (ADCs) involve random conjugation of the linker-drug to multiple lysines or cysteines in the antibody. Engineering natural and non-natural amino acids into an antibody has been demonstrated to be an effective strategy to produce homogeneous ADC products with defined drug-to-antibody ratios. We recently reported an efficient residue-specific conjugation technology (RESPECT) where thiol-reactive payloads can be efficiently conjugated to a native unpaired cysteine in position 80 (C80) of rabbit light chains...
May 25, 2017: MAbs
https://www.readbyqxmd.com/read/28540671/multidisciplinary-management-of-mycosis-fungoides-s%C3%A3-zary-syndrome
#4
REVIEW
Sara Berg, Jennifer Villasenor-Park, Paul Haun, Ellen J Kim
PURPOSE OF REVIEW: Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years. RECENT FINDINGS: Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances...
May 24, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28540623/qsp-toolbox-computational-implementation-of-integrated-workflow-components-for-deploying-multi-scale-mechanistic-models
#5
Yougan Cheng, Craig J Thalhauser, Shepard Smithline, Jyotsna Pagidala, Marko Miladinov, Heather E Vezina, Manish Gupta, Tarek A Leil, Brian J Schmidt
Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations...
May 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28536738/selective-targeted-delivery-of-doxorubicin-via-conjugating-to-anti-cd24-antibody-results-in-enhanced-antitumor-potency-for-hepatocellular-carcinoma-both-in-vitro-and-in-vivo
#6
Zhaoxiong Ma, Hua He, Fumou Sun, Yao Xu, Xuequn Huang, Yuexing Ma, Hong Zhao, Yang Wang, Min Wang, Juan Zhang
PURPOSE: Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for clinical application. Cluster of differentiation 24 (CD24) is over-expressed in several human malignancies, especially in hepatocellular carcinoma (HCC). We aimed to develop a new class of CD24-targeted ADCs for HCC. METHODS: DOX was conjugated with G7mAb by a heterobifunctional cross-linker GMBS (N-[gamma-maleimido butyryloxy] succinimide ester) and further analyzed using HPLC...
May 23, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28536381/antibody-drug-conjugates-for-cancer-therapy
#7
REVIEW
Adam C Parslow, Sagun Parakh, Fook-Thean Lee, Hui K Gan, Andrew M Scott
Antibody-drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance...
July 11, 2016: Biomedicines
https://www.readbyqxmd.com/read/28534531/unravelling-the-biology-of-sclc-implications-for-therapy
#8
REVIEW
Joshua K Sabari, Benjamin H Lok, James H Laird, John T Poirier, Charles M Rudin
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints...
May 23, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28534292/development-and-characterization-of-a-neutralizing-anti-idiotype-antibody-against-mirvetuximab-for-analysis-of-clinical-samples
#9
Sven Loebrich, Mingfang Shen, Erika Cohen, Gillian Payne, Ying Chen, Megan Bogalhas, Yiwei Zhao
Antibody-drug-conjugates (ADCs) are an emerging class of biological therapeutics. Mirvetuximab soravtansine is a novel folate receptor alpha (FRα)-targeting ADC which represents a potential new treatment for patients with ovarian and other FRα-positive cancers. Since patient immune responses to biological therapeutics may negatively affect drug efficacy and patient safety, regulatory authorities require rigorous monitoring of patient samples. Taking advantage of the immune system's ability to generate highly specific antibodies, the field has turned to anti-idiotype antibodies as powerful tools for the development of sensitive and specific bioassays...
May 22, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28528212/targeted-co-delivery-of-polypyrrole-and-rapamycin-by-trastuzumab-conjugated-liposomes-for-combined-chemo-photothermal-therapy
#10
Hanh Thuy Nguyen, Tuan Hiep Tran, Raj Kumar Thapa, Cao Dai Phung, Beom Soo Shin, Jee-Heon Jeong, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
Trastuzumab is a therapeutic monoclonal antibody that selectively recognizes HER2/neu receptor for targeting breast cancers. In this study, we aimed to present a strategy to combine chemo and phototherapy and targeted delivery via monoclonal antibody for enhanced anticancer effects. We co-loaded a chemotherapeutic agent, rapamycin, and a photosensitizer, polypyrrole, in trastuzumab-conjugated liposomes (LRPmAb) for combined chemo-photothermal therapy. LRPmAb had small size (172.2±9.6nm), narrow distribution, and negative ζ-potential (-12...
May 17, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28527133/a-phase-ii-study-of-antibody-drug-conjugate-tak-264-mln0264-in-previously-treated-patients-with-advanced-or-metastatic-pancreatic-adenocarcinoma-expressing-guanylyl-cyclase-c
#11
Khaldoun Almhanna, David Wright, Teresa Macarulla Mercade, Jean-Luc Van Laethem, Antonio Cubillo Gracian, Carmen Guillen-Ponce, Jason Faris, Carolina Muriel Lopez, Richard A Hubner, Johanna Bendell, Alain Bols, Jaime Feliu, Naureen Starling, Peter Enzinger, Devalingham Mahalingham, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic
Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)])...
May 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#12
Carl U Bialucha, Scott D Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno LaFont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P Wagner, GiNell Elliott, Artur Veloso, Jessica C Piel, Meghan M Flaherty, Keith G Mansfield, Emily K Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J Meyer, Jason E Faris, Mary J Janatpour, Vivien W Chan, Nicholas C Yoder, Kalli C Catcott, Molly A McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A Engelman, Seth A Ettenberg, William R Sellers, Emma Lees
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development...
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526536/trastuzumab-emtansine-versus-capecitabine-plus-lapatinib-in-patients-with-previously-treated-her2-positive-advanced-breast-cancer-emilia-a-descriptive-analysis-of-final-overall-survival-results-from-a-randomised-open-label-phase-3-trial
#13
Véronique Diéras, David Miles, Sunil Verma, Mark Pegram, Manfred Welslau, José Baselga, Ian E Krop, Kim Blackwell, Silke Hoersch, Jin Xu, Marjorie Green, Luca Gianni
BACKGROUND: The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. METHODS: EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane...
May 16, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28522588/a-potential-mechanism-for-adc-induced-neutropenia-role-of-neutrophils-in-their-own-demise
#14
Hui Zhao, Sara Gulesserian, Maria Christina Malinao, Sathish Kumar-Ganesan, James Song, Mi Sook Chang, Melissa M Williams, Zhilan Zeng, Michael Mattie, Brian A Mendelsohn, David R Stover, Fernando Doñate
Neutropenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs) and we aimed to elucidate the potential mechanism of this toxicity. To investigate if ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSCs) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADCs) or MMAF via a non-cleavable maleimidocaproyl linker (mcMMAF-ADCs), and their cytotoxicity was tested in the neutrophil differentiation assay...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28522587/preclinical-evaluation-of-medi0641-a-pyrrolobenzodiazepine-conjugated-antibody-drug-conjugate-targeting-5t4
#15
Jay Harper, Christopher Lloyd, Nazzareno Dimasi, Dorin Toader, Rose Marwood, Leeanne Lewis, David Bannister, Jelena Jovanovic, Ryan Fleming, Francois d'Hooge, Shenlan Mao, Allison M Marrero, Martin Korade, Patrick Strout, Linda Xu, Cui Chen, Leslie Wetzel, Shannon Breen, Lilian van Vlerken-Ysla, Sanjoo Jalla, Marlon Rebelatto, Helen Zhong, Elaine M Hurt, Mary Jane Hinrichs, Keven Huang, Philip W Howard, David A Tice, Robert E Hollingsworth, Ronald Herbst, Adeela Kamal
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28516982/colorimetric-and-electrochemical-quantification-of-global-dna-methylation-using-a-methyl-cytosine-specific-antibody
#16
Md Hakimul Haque, Ripon Bhattacharjee, Md Nazmul Islam, Vinod Gopalan, Nam-Trung Nguyen, Alfred K Lam, Muhammad J A Shiddiky
We report a simple colorimetric (naked-eye) and electrochemical method for the rapid, sensitive and specific quantification of global methylation levels using only 25 ng of input DNA. Our approach utilises a three-step strategy; (i) initial adsorption of the extracted, purified and denatured bisulfite-treated DNA on a screen-printed gold electrode (SPE-Au), (ii) immuno-recognition of methylated DNA using a horseradish peroxidase (HRP)-conjugated methylcytosine (HRP-5mC) antibody and (iii) subsequent colorimetric detection by the enzymatic oxidation of 3,3',5,5'-tetramethylbenzidin (TMB)/H2O2 which generated a blue-coloured product in the presence of methylated DNA and HRP-5mC immunocomplex...
May 18, 2017: Analyst
https://www.readbyqxmd.com/read/28515253/strategies-for-management-of-relapsed-or-refractory-hodgkin-lymphoma
#17
Leo I Gordon
The advent of effective therapies has improved outcomes for those with newly diagnosed Hodgkin lymphoma (HL), with a resulting cure rate of at least 80%. However, with limited data on therapeutic options in the setting of advanced disease, individualized treatment is recommended, and potential long-term effects of therapy remain a key consideration. At the NCCN 22nd Annual Conference, Dr. Leo I. Gordon explored strategies for systemic therapy in the relapsed or refractory setting, focusing primarily on the standard of high-dose therapy/autologous stem cell rescue, the CD30-targeted antibody drug conjugate brentuximab vedotin, and checkpoint inhibition...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28513851/population-pharmacokinetics-of-brentuximab-vedotin-in-patients-with-cd30-expressing-hematologic-malignancies
#18
Hong Li, Tae H Han, Naomi N Hunder, Graham Jang, Baiteng Zhao
Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for treating certain patients with CD30-expressing hematologic malignancies. Its primary mechanism of action is the targeted delivery of a microtubule-disrupting agent, monomethyl auristatin E (MMAE), to CD30-expressing cells. A population pharmacokinetic (PopPK) analysis was conducted to characterize the PK of ADC and unconjugated MMAE in patients with CD30-expressing hematologic malignancies by compartmental analysis and to evaluate the effects of covariates on PK of the ADC...
May 17, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28513744/high-affinity-recognition-of-the-human-c-reactive-protein-independent-of-phosphocholine
#19
Jie Yang, Anna-Lena Gustavsson, Martin Haraldsson, Göran Karlsson, Thomas Norberg, Lars Baltzer
A high-affinity polypeptide conjugate 4-C25L22-DQ, has been developed for the molecular recognition of the human C-reactive protein, CRP, a well-known inflammation biomarker. CRP is one of the most frequently quantified targets in diagnostic applications and a target in drug development. With the exception of antibodies, most molecular constructs take advantage of the known affinity for CRP of phosphocholine that depends on Ca(2+) for its ability to bind. 4-C25L22-DQ which is unrelated to phosphocholine binds in the absence of Ca(2+) with a dissociation constant of 760 nM, an order of magnitude lower than that of phosphocholine, the KD of which is 5 μM...
May 17, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28513142/12-13-aziridinyl-epothilones-stereoselective-synthesis-of-trisubstituted-olefinic-bonds-from-methyl-ketones-and-heteroaromatic-phosphonates-and-design-synthesis-and-biological-evaluation-of-potent-antitumor-agents
#20
K C Nicolaou, Derek Rhoades, Yanping Wang, Ruoli Bai, Ernest Hamel, Monette Aujay, Joseph Sandoval, Julia Gavrilyuk
The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess-Kürti-Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations...
May 17, 2017: Journal of the American Chemical Society
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