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antibody drug conjugate

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https://www.readbyqxmd.com/read/28344991/antibody-directed-glucocorticoid-targeting-to-cd163-in-m2-type-macrophages-attenuates-fructose-induced-liver-inflammatory-changes
#1
Pia Svendsen, Jonas H Graversen, Anders Etzerodt, Henrik Hager, Rasmus Røge, Henning Grønbæk, Erik I Christensen, Holger J Møller, Hendrik Vilstrup, Søren K Moestrup
Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28341790/tumor-associated-macrophages-can-contribute-to-antitumor-activity-through-fc%C3%AE-rmediated-processing-of-antibody-drug-conjugates
#2
Fu Li, Michelle Ulrich, Mechthild Jonas, Ivan J Stone, Germein Linares, Xinqun Zhang, Lori Westendorf, Dennis R Benjamin, Che-Leung Law
The primary mechanism of antibody-drug conjugates (ADCs) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc-FcγR interactions between ADCs and tumor-associated macrophages (TAMs) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors...
March 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28341731/targeting-the-5t4-oncofoetal-glycoprotein-with-an-antibody-drug-conjugate-a1mcmmaf-improves-survival-in-patient-derived-xenograft-models-of-acute-lymphoblastic-leukemia
#3
Owen J McGinn, Shekhar Krishnan, Jean-Pierre Bourquin, Puja Sapra, Clare Dempsey, Vaskar Saha, Peter L Stern
Outcome in childhood acute lymphoblastic leukemia is prognosticated on levels of minimal residual disease after remission induction therapy. Higher minimal residual disease levels are associated with inferior results even with intensification of therapy and suggest identification and targeting of minimal residual disease cells as a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient derived xenografts from patients with high minimal residual disease post induction...
March 24, 2017: Haematologica
https://www.readbyqxmd.com/read/28341549/a-quantitative-method-for-screening-and-identifying-molecular-targets-for-nanomedicine
#4
Peng Guo, Jiang Yang, Diane R Bielenberg, Deborah Dillon, David Zurakowski, Marsha A Moses, Debra T Auguste
Identifying a molecular target is essential for tumor-targeted nanomedicine. Current cancer nanomedicines commonly suffer from poor tumor specificity, "off-target" toxicity, and limited clinical efficacy. Here, we report a method to screen and identify new molecular targets for tumor-targeted nanomedicine based on a quantitative analysis. In our proof-of-principle study, we used comparative flow cytometric screening to identify ICAM-1 as a potential target for metastatic melanoma (MM). We further evaluated ICAM-1 as a MM targeting moiety by characterizing its (1) tumor specificity, (2) expression level, (3) cellular internalization, (4) therapeutic function, and (5) potential clinical impact...
March 21, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28341109/phase-1-2-study-of-the-cd56-targeting-antibody-drug-conjugate-lorvotuzumab-mertansine-imgn901-in-combination-with-carboplatin-etoposide-in-small-cell-lung-cancer-patients-with-extensive-stage-disease
#5
Mark A Socinski, Frederic J Kaye, David R Spigel, Fred J Kudrik, Santiago Ponce, Peter M Ellis, Margarita Majem, Paul Lorigan, Leena Gandhi, Martin E Gutierrez, Dale Nepert, Jesus Corral, Luis Paz Ares
INTRODUCTION: This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors...
January 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28333127/selective-intracellular-vaporisation-of-antibody-conjugated-phase-change-nano-droplets-in-vitro
#6
A Ishijima, K Minamihata, S Yamaguchi, S Yamahira, R Ichikawa, E Kobayashi, M Iijima, Y Shibasaki, T Azuma, T Nagamune, I Sakuma
While chemotherapy is a major mode of cancer therapeutics, its efficacy is limited by systemic toxicities and drug resistance. Recent advances in nanomedicine provide the opportunity to reduce systemic toxicities. However, drug resistance remains a major challenge in cancer treatment research. Here we developed a nanomedicine composed of a phase-change nano-droplet (PCND) and an anti-cancer antibody (9E5), proposing the concept of ultrasound cancer therapy with intracellular vaporisation. PCND is a liquid perfluorocarbon nanoparticle with a liquid-gas phase that is transformable upon exposure to ultrasound...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28330604/stable-and-potent-selenomab-drug-conjugates
#7
Xiuling Li, Christopher G Nelson, Rajesh R Nair, Lori Hazlehurst, Tina Moroni, Pablo Martinez-Acedo, Alex R Nanna, David Hymel, Terrence R Burke, Christoph Rader
Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared with other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions...
March 9, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28325750/molecular-pathways-evaluating-the-potential-for-b7-h4-as-an-immunoregulatory-target
#8
Heather L MacGregor, Pamela S Ohashi
With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment anti-tumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies...
March 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28325214/antibody-based-cancer-therapy-successful-agents-and-novel-approaches
#9
D Hendriks, G Choi, M de Bruyn, V R Wiersma, E Bremer
Since their discovery, antibodies have been viewed as ideal candidates or "magic bullets" for use in targeted therapy in the fields of cancer, autoimmunity, and chronic inflammatory disorders. A wave of antibody-dedicated research followed, which resulted in the clinical approval of a first generation of monoclonal antibodies for cancer therapy such as rituximab (1997) and cetuximab (2004), and infliximab (2002) for the treatment of autoimmune diseases. More recently, the development of antibodies that prevent checkpoint-mediated inhibition of T cell responses invigorated the field of cancer immunotherapy...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28321813/harnessing-the-immune-system-against-leukemia-monoclonal-antibodies-and-checkpoint-strategies-for-aml
#10
Lucia Masarova, Hagop Kantarjian, Guillermo Garcia-Mannero, Farhad Ravandi, Padmanee Sharma, Naval Daver
Acute myeloid leukemia (AML) is the most common leukemia among adults and is associated with a poor prognosis, especially in patients with adverse prognostic factors, older age, or relapsed disease. The last decade has seen a surge in successful immune-based therapies in various solid tumors; however, the role of immune therapies in AML remains poorly defined. This chapter describes the rationale, clinical data, and toxicity profiles of immune-based therapeutic modalities in AML including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD1/PDL1 or CTLA4...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28319364/a-new-spin-on-antibody-drug-conjugates-trastuzumab-fulvestrant-colloidal-drug-aggregates-target-her2-positive-cells
#11
Ahil N Ganesh, Christopher Mclaughlin, Da Duan, Brian K Shoichet, Molly S Shoichet
While the formation of colloidal aggregates leads to artifacts in early drug discovery, their composition makes them attrac-tive as nanoparticle formulations for targeted drug delivery as the entire nanoparticle is composed of drug. The typical tran-sient stability of colloidal aggregates has inhibited exploiting this property. To overcome this limitation, we investigated a series of proteins to stabilize colloidal aggregates of the chemotherapeutic, fulvestrant, including: bovine serum albumin, a generic human immunoglobulin G, and trastuzumab, a therapeutic anti-human epidermal growth factor receptor 2 anti-body...
March 20, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28318345/novel-agents-in-classical-hodgkin-lymphoma
#12
Sven Borchmann, Bastian von Tresckow
Classical Hodgkin lymphoma (cHL) is the most common hematological malignancy in young adults and can be cured in most cases. However, relapsed and refractory Hodgkin lymphoma, certain patient groups, such as elderly patients, and toxicity of first-line treatment still pose significant challenges. Consequently, new treatment options are needed. Recently, many new treatment concepts have been evaluated in clinical trials. Targeted drug-antibody conjugates and immune checkpoint inhibitors have decisively changed treatment approaches...
March 20, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28316990/diagnostic-and-therapeutic-biomarkers-in-glioblastoma-current-status-and-future-perspectives
#13
REVIEW
Wojciech Szopa, Thomas A Burley, Gabriela Kramer-Marek, Wojciech Kaspera
Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3-5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28315359/antibodies-and-associates-partners-in-targeted-drug-delivery
#14
REVIEW
Patrick J Kennedy, Carla Oliveira, Pedro L Granja, Bruno Sarmento
Monoclonal antibodies (mAbs) are well established in the clinic due to their specificity and affinity to a diverse array of biochemical targets. More recently, mAbs are being exploited as targeting agents in modern drug delivery systems, aiming to bypass normal host tissue and to accumulate a therapeutic agent to a specific tissue or cell for enhanced pharmacology. At sizes ranging from ~10-100nm, antibody-based bioconjugates have opened up a whole new realm of clinical possibilities with several platforms emerging on the market...
March 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28315346/inhibition-of-osteoporosis-by-the-%C3%AE-v%C3%AE-3-integrin-antagonist-of-rhodostomin-variants
#15
Tzu-Hung Lin, Rong-Sen Yang, Huang-Ju Tu, Houng-Chi Liou, Yen-Ming Lin, Woie-Jer Chuang, Wen-Mei Fu
Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvβ3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvβ3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvβ3 integrin have been shown to inhibit bone resorption in vitro and in vivo...
March 14, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28303026/strategies-and-challenges-for-the-next-generation-of-antibody-drug-conjugates
#16
REVIEW
Alain Beck, Liliane Goetsch, Charles Dumontet, Nathalie Corvaïa
Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody...
March 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28296511/targeted-delivery-of-doxorubicin-into-tumor-cells-by-nanostructured-lipid-carriers-conjugated-to-anti-egfrviii-monoclonal-antibody
#17
Saeideh Abdolahpour, Tayebeh Toliyat, Kobra Omidfar, Helmout Modjtahedi, Albert J Wong, Mohammad Javad Rasaee, Susan Kashanian, Maliheh Paknejad
Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the EGF receptor in many human tumors. This variant is tumor specific and highly immunogenic, thus, it can be used as a target for targeted drug delivery toward tumor cells. The major aim of this study was to develop an EGFRvIII-mediated drug delivery system by anti-EGFRvIII monoclonal antibody (MAb) conjugated to doxorubicin (Dox)-loaded nanostructured lipid carriers (NLC) to enhance the targeting specificity and cytotoxic effect of Dox on EGFRvIII-overexpressing cell line...
March 15, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/28292941/preclinical-anti-tumor-efficacy-of-bay-1129980-a-novel-auristatin-based-anti-c4-4a-lypd3-antibody-drug-conjugate-for-the-treatment-of-non-small-cell-lung-cancer
#18
Jörg Willuda, Lars Linden, Hans-Georg Lerchen, Charlotte Kopitz, Beatrix Stelte-Ludwig, Carol Pena, Claudia Lange, Sven Golfier, Christoph Kneip, Patricia E Carrigan, Kirk Mclean, Joachim Schuhmacher, Oliver von Ahsen, Jörg Müller, Frank Dittmer, Rudolf Beier, Sherif El-Sheikh, Jan Tebbe, Gabriele Leder, Heiner Apeler, Rolf Jautelat, Karl Ziegelbauer, Bertolt Kreft
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292243/injectable-drug-loaded-nanocarriers-for-lung-cancer-treatments
#19
Huang-Ping Yu, Ibrahim A Aljuffali, Jia-You Fang
Different types of injectable nanoparticles, including metallic nanoparticles, polymeric nanocarriers, dendrimers, liposomes, niosomes, and lipid nanoparticles, have been employed to load drugs for lung delivery. Nanoparticles used for lung delivery offer some benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tumor targeting, and minimal side effects. In recent years, the concept of using injectable nanocarriers as vehicles for drug delivery has attracted increasing attention...
2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28291390/efficacy-and-safety-of-anti-trop-2-antibody-drug-conjugate-sacituzumab-govitecan-immu-132-in-heavily-pretreated-patients-with-metastatic-triple-negative-breast-cancer
#20
Aditya Bardia, Ingrid A Mayer, Jennifer R Diamond, Rebecca L Moroose, Steven J Isakoff, Alexander N Starodub, Nikita C Shah, Joyce O'Shaughnessy, Kevin Kalinsky, Michael Guarino, Vandana Abramson, Dejan Juric, Sara M Tolaney, Jordan Berlin, Wells A Messersmith, Allyson J Ocean, William A Wegener, Pius Maliakal, Robert M Sharkey, Serengulam V Govindan, David M Goldenberg, Linda T Vahdat
Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival...
March 14, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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