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antibody-drug conjugates

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https://www.readbyqxmd.com/read/29055044/anti-glypican-1-antibody-drug-conjugate-exhibits-potent-preclinical-antitumor-activity-against-glypican-1-positive-uterine-cervical-cancer
#1
Satoko Matsuzaki, Satoshi Serada, Kosuke Hiramatsu, Satoshi Nojima, Shinya Matsuzaki, Yutaka Ueda, Tomoharu Ohkawara, Seiji Mabuchi, Minoru Fujimoto, Eiichi Morii, Kiyoshi Yoshino, Tadashi Kimura, Tetsuji Naka
Glypican-1 (GPC1) is highly expressed in solid tumors, especially squamous cell carcinomas (SCCs), and is thought to be associated with disease progression. We explored the use of a GPC1-targeted antibody-drug conjugate (ADC) as a novel treatment for uterine cervical cancer. On immunohistochemical staining, high expression levels of GPC1 were detected in about 50% of uterine cervical cancer tissues and also in a tumor that had relapsed after chemoradiotherapy. Novel anti-GPC1 monoclonal antibodies were developed, and clone 01a033 was selected as the best antibody for targeted delivery of the cytotoxic agent monomethyl auristatin F (MMAF) into GPC1-positive cells...
October 21, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29054985/caveolae-mediated-endocytosis-as-a-novel-mechanism-of-resistance-to-trastuzumab-emtansine-t-dm1
#2
Matthew Sung, Xingzhi Tan, Bingwen Lu, Jonathan Golas, Christine Hosselet, Fang Wang, Laurie Tylaska, Lindsay King, Dahui Zhou, Russell Dushin, Jeremy S Myers, Edward Rosfjord, Judy Lucas, Hans-Peter Gerber, Frank Loganzo
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer, however its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance utilizing a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1 resistant population was generated...
October 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29052674/egfr-targeting-plga-peg-nanoparticles-as-a-curcumin-delivery-system-for-breast-cancer-therapy
#3
Hua Jin, Jiang Pi, Yue Zhao, Jinhuan Jiang, Ting Li, Xueyi Zeng, Peihui Yang, Colin E Evans, Jiye Cai
Poor bioavailability and non-specificity of chemotherapeutic agents are major challenges in breast cancer treatment. Antibodies and small molecules that block cell signaling pathways have shown promise in the clinic, but their application is also limited by the high costs and treatment dosages required. Novel therapies that aim to rapidly and specifically target malignant cells with long-lasting impact in the tumor microenvironment may ultimately improve clinical outcome in cancer patients. Here, we demonstrate that epidermal growth factor receptor (EGFR)-targeting GE11 peptides conjugated with PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles can be used to effectively deliver an anti-cancer agent, curcumin, into EGFR-expressing MCF-7 cells in vitro and in vivo...
October 20, 2017: Nanoscale
https://www.readbyqxmd.com/read/29052423/streamlined-total-synthesis-of-trioxacarcins-and-its-application-to-the-design-synthesis-and-biological-evaluation-of-analogues-thereof-discovery-of-simpler-designed-and-potent-trioxacarcin-analogues
#4
K C Nicolaou, Pengxi Chen, Shugao Zhu, Quan Cai, Rohan D Erande, Ruofan Li, Hongbao Sun, Kiran Kumar Pulukuri, Stephan Rigol, Monette Aujay, Joseph Sandoval, Julia Gavrilyuk
A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described...
October 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29051180/midostaurin-enasidenib-cpx-351-gemtuzumab-ozogomycin-and-venetoclax-bring-new-hope-to-aml
#5
Andrew H Wei, Ing S Tiong
In 2017, four new drugs have so far received FDA marketing approval for the treatment of acute myeloid leukemia (AML), including targeted therapies for mutant FLT3 (midostaurin) and IDH2 (enasidenib), a novel liposomal cytarabine-daunorubicin formulation (CPX-351) for therapy-related AML and AML with myelodysplasia-related changes and finally, resurgence of an antibody-drug conjugate designed to target CD33 (gemtuzumab ozogomycin; GO). Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients with AML unfit for intensive chemotherapy...
October 19, 2017: Blood
https://www.readbyqxmd.com/read/29050691/philadelphia-chromosome-negative-b-cell-acute-lymphoblastic-leukemia-in-older-adults-current-treatment-and-novel-therapies
#6
REVIEW
Kristen M O'Dwyer, Jane L Liesveld
Older adults with Philadelphia chromosome negative (Ph-),-B-cell acute lymphoblastic leukemia (ALL) have the highest rates of treatment failure and treatment complications with current therapy, and, thus, there is no standard treatment for these patients. Approximately 16 percent of patients with newly diagnosed Ph- B-cell ALL are aged 60 years or older [1]. The five-year overall survival for this older cohort of patients is approximately 20 percent, and there has been no improvement in their survival in decades [2]...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#7
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29046337/cathepsin-b-is-dispensable-for-cellular-processing-of-cathepsin-b-cleavable-antibody-drug-conjugates
#8
Niña G Caculitan, Josefa Dela Cruz Chuh, Yong Ma, Donglu Zhang, Katherine R Kozak, Yichin Liu, Thomas H Pillow, Jack Sadowsky, Tommy K Cheung, Qui Phung, Benjamin Haley, Byoung-Chul Lee, Robert Akita, Mark X Sliwkowski, Andrew G Polson
Antibody-drug conjugates (ADCs) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline (VC(S)) linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload...
October 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/29045509/the-antibody-drug-conjugate-target-landscape-across-a-broad-range-of-tumour-types
#9
K L Moek, D J A de Groot, E G E de Vries, R S N Fehrmann
Background: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Since ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods: PubMed and ClinicalTrials...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29043411/population-pharmacokinetics-of-trastuzumab-emtansine-in-previously-treated-patients-with-her2-positive-advanced-gastric-cancer-agc
#10
Shang-Chiung Chen, Matts Kagedal, Yuying Gao, Bei Wang, Marie-Laurence Harle-Yge, Sandhya Girish, Jin Jin, Chunze Li
PURPOSE: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC). METHODS: Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling...
October 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29042604/placenta-specific1-plac1-is-a-potential-target-for-antibody-drug-conjugate-based-prostate-cancer-immunotherapy
#11
Mohammad-Reza Nejadmoghaddam, Amir-Hassan Zarnani, Ramin Ghahremanzadeh, Roya Ghods, Jafar Mahmoudian, Maryam Yousefi, Mahboobeh Nazari, Mohammad Hossein Ghahremani, Maryam Abolhasani, Ali Anissian, Morteza Mahmoudi, Rassoul Dinarvand
Our recent findings strongly support the idea of PLAC1 being as a potential immunotherapeutic target in prostate cancer (PCa). Here, we have generated and evaluated an anti-placenta-specific1 (PLAC1)-based antibody drug conjugate (ADC) for targeted immunotherapy of PCa. Prostate cancer cells express considerable levels of PLAC1. The Anti-PLAC1 clone, 2H12C12, showed high reactivity with recombinant PLAC1 and selectivity recognized PLAC1 in prostate cancer cells but not in LS180 cells, the negative control. PLAC1 binding induced rapid internalization of the antibody within a few minutes which reached to about 50% after 15 min and almost completed within an hour...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042337/plga-peg-nanoparticles-for-targeted-delivery-of-the-mtor-pi3kinase-inhibitor-dactolisib-to-inflamed-endothelium
#12
Shima Gholizadeh, Jan A A M Kamps, Wim E Hennink, Robbert J Kok
Dactolisib (NVP-BEZ235, also referred to as: 'BEZ235' or 'BEZ') is a dual mTOR/PI3K inhibitor that is of potential interest in the treatment of inflammatory disorders. This work focuses on formulation of BEZ-loaded polymeric nanoparticles composed of a blend of poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide-co-glycolide)-poly(ethylene glycol)-2000 (PLGA-PEG). The nanoparticles were prepared by an oil/water emulsion solvent evaporation method, and were subsequently characterized for yield, encapsulation efficiency, morphology, particle size, drug-polymer interaction and in vitro drug release profiles...
October 14, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29039459/bc-02-eradicates-liver-cancer-stem-cells-by-upregulating-the-ros-dependent-dna-damage
#13
Chunhui Dou, Chunyan Fang, Yan Zhao, Xiaoyan Fu, Yufei Zhang, Dongqi Zhu, Huina Wu, Huijie Liu, Jian Zhang, Wenfang Xu, Zhijun Liu, Hongyan Wang, Daqi Li, Xuejian Wang
Cancer stem cells (CSCs) are responsible for chemoresistance, tumor recurrence and metastasis. Reportedly, aminopeptidase N (APN, also known as CD13) is a marker for semi-quiescent CSCs and a therapeutic target in human liver CSCs. In the present study, the effect of BC-02, a compound obtained by conjugating a CD13 inhibitor bestatin and fluorouracil (5-FU), was investigated toward liver CSCs. Tumor spheres formed in serum-free culture conditions have been successfully used to enrich CSCs. In this study, the sphere cells were shown to have several characteristics of CSCs, including drug resistance, high tumorigenicity, epithelial-mesenchymal transition (EMT) phenotype, lower reactive oxygen species (ROS) levels, greater colony-forming efficiency and increased proliferation capacity in vitro...
October 16, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29037986/antibody-drug-conjugates-can-the-payload-improve-activity-in-her2-expressing-cancers
#14
Manish A Shah
No abstract text is available yet for this article.
October 13, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29037983/safety-pharmacokinetics-and-antitumour-activity-of-trastuzumab-deruxtecan-ds-8201-a-her2-targeting-antibody-drug-conjugate-in-patients-with-advanced-breast-and-gastric-or-gastro-oesophageal-tumours-a-phase-1-dose-escalation-study
#15
Toshihiko Doi, Kohei Shitara, Yoichi Naito, Akihiko Shimomura, Yasuhiro Fujiwara, Kan Yonemori, Chikako Shimizu, Tatsunori Shimoi, Yasutoshi Kuboki, Nobuaki Matsubara, Atsuko Kitano, Takahiro Jikoh, Caleb Lee, Yoshihiko Fujisaki, Yusuke Ogitani, Antoine Yver, Kenji Tamura
BACKGROUND: Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours...
October 13, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29028806/a-novel-immunotoxin-reveals-a-new-role-for-cd321-in-endothelial-cells
#16
Takeshi Fukuhara, Jia Kim, Shintaro Hokaiwado, Makiko Nawa, Hayato Okamoto, Tomohiko Kogiso, Tetsuro Watabe, Nobutaka Hattori
There are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes, and which provided toxin delivery capability. Accordingly, we generated the 90G4 antibody, which induced DT3C-dependent cytotoxicity in endothelial cells. Molecular analysis revealed that 90G4 recognized CD321, a protein localized at tight junctions...
2017: PloS One
https://www.readbyqxmd.com/read/29027591/clinical-toxicity-of-antibody-drug-conjugates-a-meta-analysis-of-payloads
#17
REVIEW
Joanna C Masters, Dana J Nickens, Dawei Xuan, Ronald L Shazer, Michael Amantea
Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type...
October 13, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29026164/production-and-evaluation-of-parathyroid-hormone-receptor1-ligands-with-intrinsic-or-assembled-peroxidase-domains
#18
Xavier Charest-Morin, Patrice E Poubelle, François Marceau
Parathyroid hormone (PTH) can be C-terminally extended without significant affinity loss for the PTH1 receptor (PTHR1). We developed fusion protein ligands with enzymatic activity to probe PTHR1s at the cell surface. Two fusion proteins were generated by linking PTH to the N-terminus of either horseradish peroxidase (PTH-HRP) or the genetically modified soybean peroxidase APEX2 (PTH-APEX2). Alternatively, myc-tagged PTH (PTH-myc) was combined with antibodies, some of which HRP-conjugated, in the extracellular fluid...
October 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29025987/preclinical-development-of-cd38-targeted-89-zr-zr-dfo-daratumumab-for-imaging-multiple-myeloma
#19
Anchal Ghai, Dolonchampa Maji, Michael Rettig, Chantiya Chanswangphuwana, John DiPersio, Walter Akers, Samuel Achilefu, Farrokh Dehdashti, Ravi Vij, Monica Shokeen
Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein over-expressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is US Food and Drug Administration approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [(89)Zr]Zr-DFO-daratumumab positron emission tomography/computed tomography (PET/CT) imaging in MM tumor models...
October 12, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29025292/-brentuximab-vedotin-treatment-in-patients-with-relapsed-or-refractory-hodgkin-lymphoma-a-hungarian-retrospective-study
#20
Zsuzsa Molnár, László Imre Pinczés, Klára Piukovics, Ildikó Istenes, Krisztina Wolf, Zoltán Csukly, Árpád Szomor, Árpád Illés, Zsófia Miltényi
INTRODUCTION: The treatment of relapsed or refractory Hodgkin lymphoma is still a major therapeutic challenge. The use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, represents a promising approach for these patients, however clinical outcomes have not yet been evaluated in Hungary. AIM: Our aim was to assess the efficacy, safety and outcome of brentuximab vedotin treatment in Hungarian Hodgkin lymphoma patients. METHOD: In this retrospective case note review we enrolled patients at 6 clinical sites countrywide who were diagnosed with Hodgkin lymphoma and received brentuximab vedotin between 1 January 2013 and 31 December 2016...
October 2017: Orvosi Hetilap
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