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Antibody drug conjugates

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https://www.readbyqxmd.com/read/29775731/targeted-and-controlled-drug-delivery-by-multifunctional-mesoporous-silica-nanoparticles-with-internal-fluorescent-conjugates-and-external-polydopamine-and-graphene-oxide-layers
#1
Anh-Vy Tran, KyuHwan Shim, Thu-Thao Vo Thi, Jeong-Keun Kook, Seong Soo A An, Sang-Wha Lee
This study demonstrated the targeted delivery and controlled release of cisplatin drug molecules from doubly decorated mesoporous silica nanoparticles (MSNs), which were internally grafted with fluorescent conjugates and externally coated with polydopamine (PDA) and graphene oxide (GO) layers. The brush-like internal conjugates conferred fluorescent functionality and high capacity of cisplatin loading into MSNs, as well as contributing to a sustained release of the cisplatin through a porous channel with the assistance of external PDA layer...
May 15, 2018: Acta Biomaterialia
https://www.readbyqxmd.com/read/29772094/quantifying-biomolecular-binding-constants-using-video-paper-analytical-devices
#2
Benjamin S Miller, Claudio Parolo, Valerian Turbé, Candice E Keane, Eleanor R Gray, Rachel McKendry
We report a novel ultralow-cost biochemical analysis platform to quantify protein dissociation binding constants and kinetics using paper microfluidics. Our approach marries video imaging with one of humankind's oldest materials - paper, requiring no large, expensive laboratory equipment, complex microfluidics or external power. Temporal measurements of nanoparticle-antibody conjugates binding on paper is found to follow the Langmuir Adsorption Model. This is exploited to measure a series of antibody-antigen dissociation constants on paper, showing excellent agreement with a gold-standard benchtop interferometer...
May 17, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29771109/the-therapeutic-pipeline-for-pseudomonas-aeruginosa-infections
#3
Lori L Burrows
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen, designated by the World Health Organization as a critical priority for development of new therapeutics due to high levels of intrinsic and acquired antibiotic resistance. Other challenges include its versatility (it can persist in the environment and most strains are capable of causing disease in compromised hosts), robust efflux mechanisms that limit drug penetration, and the propensity to form antimicrobial-tolerant biofilms. Novel therapeutics in development to prevent or treat P...
May 17, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29768576/recent-advances-and-perspectives-in-cancer-drug-design
#4
Luma G Magalhaes, Leonardo L G Ferreira, Adriano D Andricopulo
Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments...
May 14, 2018: Anais da Academia Brasileira de Ciências
https://www.readbyqxmd.com/read/29765526/esophageal-cancer-cells-resistant-to-t-dm1-display-alterations-in-cell-adhesion-and-the-prostaglandin-pathway
#5
Juliette Sauveur, Eva-Laure Matera, Kamel Chettab, Philippe Valet, Jerome Guitton, Ariel Savina, Charles Dumontet
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged in vitro exposure of the gastroesophageal junction cancer cell line OE-19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764866/lrrc15-is-a-novel-mesenchymal-protein-and-stromal-target-for-antibody-drug-conjugates
#6
James W Purcell, Sonia G Tanlimco, Jonathan A Hickson, Melvin Fox, Mien Sho, Lisa Durkin, Tamar Uziel, Rick Powers, Kelly D Foster-Duke, Thomas McGonigal, Subashri Kumar, Josue Samayoa, Dong Zhang, Joann P Palma, Sasmita Mishra, Diane Hollenbaugh, Kurt Gish, Susan E Morgan-Lappe, Eric D Hsi, Debra T Chao
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29764854/preclinical-antitumor-activity-of-a-novel-anti-c-kit-antibody-drug-conjugate-against-mutant-and-wild-type-c-kit-positive-solid-tumors
#7
Tinya J Abrams, Anu Connor, Christie P Fanton, Steven B Cohen, Thomas Huber, Kathy Miller, E Erica Hong, Xiaohong Niu, Janine Kline, Marjorie Ison-Dugenny, Sarah Harris, Dana B Walker, Klaus R Krauser, Francesco Galimi, Zhen Wang, Majid Ghoddusi, Keith G Mansfield, Si Tuen Lee-Hoeflich, Jocelyn Holash, Nancy Pryer, William Kluwe, Seth A Ettenberg, William R Sellers, Emma Lees, Paul Kwon, Judith A Abraham, Siew Schleyer
PURPOSE: c-KIT overexpression is well-recognized in cancers such as GIST, SCLC, melanoma, NSCLC and AML. Treatment with the small molecule inhibitors imatinib, sunitinib and regorafenib result in resistance (c-KIT mutant tumors) or limited activity (c-KIT wildtype tumors). We selected an anti-c-KIT ADC approach to evaluate the anti-cancer activity in multiple disease models. EXPERIMENTAL DESIGN: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a non-cleavable linker (SMCC)...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29761078/novel-immunotherapy-options-for-extranodal-nk-t-cell-lymphoma
#8
REVIEW
Boyu Hu, Yasuhiro Oki
Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein-Barr virus (EBV) and specific ethnic-genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29758590/interobserver-variation-in-cd30-immunohistochemistry-interpretation-consequences-for-patient-selection-for-targeted-treatment
#9
Lianne Koens, Peter M van de Ven, Nathalie J Hijmering, Marie José Kersten, Arjan Diepstra, Martine Chamuleau, Daphne de Jong
CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 IHC staining is required. We conducted a 3-round reproducibility assessment of CD30 scoring for categorized frequency and intensity, including a technical validation, a "live polling" pre- and post-instruction scoring round, and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice...
May 14, 2018: Histopathology
https://www.readbyqxmd.com/read/29758393/phase-i-trial-of-brentuximab-vedotin-for-steroid-refractory-chronic-graft-versus-host-disease-after-allogeneic-hematopoietic-cell-transplantation
#10
Zachariah DeFilipp, Shuli Li, Maria E Kempner, Jami Brown, Candice Del Rio, Betsy Valles, Chrisa Hunnewell, Meredith Saylor, Julie Vanderklish, Bimalangshu R Dey, Areej El-Jawahri, Steven L McAfee, Thomas R Spitzer, Yi-Bin Chen
We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3+3 study design was used with the primary endpoint to determine the maximum tolerated dose (MTD) of BV in this population. Escalating doses of BV were planned, starting with 0.6 mg/kg q3weeks (dose level 0) and increasing by 0.3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy...
May 11, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29757698/prediction-of-non-linear-pharmacokinetics-in-humans-of-an-antibody-drug-conjugate-adc-when-evaluation-of-higher-doses-in-animals-is-limited-by-tolerability-case-study-with-an-anti-cd33-adc
#11
Isabel Figueroa, Doug Leipold, Steve Leong, Bing Zheng, Montserrat Carrasco-Triguero, Aimee Fourie-O'Donohue, Katherine R Kozak, Keyang Xu, Melissa Schutten, Hong Wang, Andrew G Polson, Amrita V Kamath
For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design...
May 14, 2018: MAbs
https://www.readbyqxmd.com/read/29757658/a-macropinocytosis-intensifying-albumin-domain-based-scfv-antibody-and-its-conjugate-directed-against-k-ras-mutant-pancreatic-cancer
#12
Xiaofei Wang, Weijin Sheng, Yangyang Wang, Liang Li, Yi Li, Shenghua Zhang, Xiujun Liu, Shuzhen Chen, Yongsu Zhen
Enhanced macropinocytosis has been found in K-Ras mutant pancreatic cancer cells and through which albumin can massively enter into the K-Ras driven cancer cells suggesting its role serving as micropinocytosis-intensifying drug delivery carrier. In the present study, a novel recombinant protein Fv-LDP-D3 and its reconstituted analogue Fv-LDP-D3-AE were designed and prepared. In which, Fv is the fragment of an anti-EGFR antibody, D3 is the domain III of HSA, LDP is the apoprotein of the antitumor antibiotic lidamycin (LDM), and AE is an extremely cytotoxic enediyne derived from LDM...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29757653/metabolism-of-an-oxime-linked-antibody-drug-conjugate-ags62p1-and-characterization-of-its-identified-metabolite
#13
Josh T Snyder, Maria-Christina Malinao, Julien Dugal-Tessier, John E Atkinson, Banmeet S Anand, Akihiro Okada, Brian A Mendelsohn
AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29752104/antibody-fragment-conjugated-gemcitabine-and-paclitaxel-based-liposome-for-effective-therapeutic-efficacy-in-pancreatic-cancer
#14
Wentao Yang, Qian Hu, Yanmei Xu, Hailang Liu, Lin Zhong
In this study, we have developed an antibody fragment (AF)-conjugated gemcitabine (GEM) and paclitaxel (PTX)-loaded liposome (AF-GPL) to enhance the therapeutic efficacy in pancreatic cancer treatment. The maleimide-thiol chemistry was utilized to conjugate AF on the liposome surface. The dual-drug loaded liposome was nanosized and exhibited a controlled release of both the drugs. Importantly, two drugs have different release pattern over a period of time. The AF-conjugated liposome showed enhanced cellular uptake in pancreatic cancer cells compared to that of non-targeted liposome...
August 1, 2018: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/29751334/treatment-of-advanced-her2-positive-breast-cancer-2018-and-beyond
#15
REVIEW
Noam Pondé, Mariana Brandão, Georges El-Hachem, Emilie Werbrouck, Martine Piccart
In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer - HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed...
May 2, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29748524/high-affinity-promotes-internalization-of-engineered-antibodies-targeting-fgfr1
#16
Łukasz Opaliński, Jakub Szymczyk, Martyna Szczepara, Marika Kucińska, Daniel Krowarsch, Małgorzata Zakrzewska, Jacek Otlewski
Fibroblast growth factor receptor 1 (FGFR1) is a plasma membrane protein that transmits signals from the extracellular environment, regulating cell homeostasis and function. Dysregulation of FGFR1 leads to the development of human cancers and noncancerous diseases. Numerous tumors overproduce FGFR1, making this receptor a perspective target for cancer therapies. Antibody-drug conjugates (ADCs) are highly potent and selective anticancer agents. ADCs are composed of antibodies (targeting factors) fused to highly cytotoxic drugs (warheads)...
May 10, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29748443/a-phase-2-multicenter-study-of-the-anti-cd19-antibody-drug-conjugate-coltuximab-ravtansine-sar3419-in-patients-with-relapsed-or-refractory-diffuse-large-b-cell-lymphoma-previously-treated-with-rituximab-based-immunotherapy
#17
Marek Trněný, Gregor Verhoef, Martin Js Dyer, Dina Ben Yehuda, Caterina Patti, Miguel Canales, Andrés Lopez, Farrukh T Awan, Paul G Montgomery, Andrea Janikova, Anna M Barbui, Kazimierz Sulek, Maria J Terol, John Radford, Anna Guidetti, Massimo Di Nicola, Laure Siraudin, Laurence Hatteville, Sandrine Schwab, Corina Oprea, Alessandro M Gianni
This phase 2, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥ lesion >5 cm) at trial entry...
May 10, 2018: Haematologica
https://www.readbyqxmd.com/read/29742077/philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-adults-current-treatments-and-future-perspectives
#18
Musa Yilmaz, Hagop Kantarjian, Farhad Ravandi-Kashani, Nicholas J Short, Elias Jabbour
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately one-fourth of cases of adult ALL. It typically presents with an aggressive clinical course, responds poorly to standard chemotherapy, and carries a high risk for relapse. The landscape of Ph+ ALL therapy has changed favorably since the development of tyrosine kinase inhibitors (TKIs). With the successful incorporation of TKIs into chemotherapy regimens, remissions occur more frequently and patients live longer...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29741878/detection-and-identification-of-the-vibrational-markers-for-the-quantification-of-methionine-oxidation-in-therapeutic-proteins
#19
Gurusamy Balakrishnan, Gregory V Barnett, Sambit R Kar, Tapan K Das
Methionine oxidation is a major degradation pathway in therapeutic proteins which can impact the structure and function of proteins as well as risk to drug product quality. Detecting Met oxidation in proteins by peptide mapping followed by liquid chromatography with mass spectrometry (LC-MS) is the industry standard but is also labor intensive and susceptible to artifacts. In this work, vibrational difference spectroscopy in combination with 18 O isotopic shift enabled us to demonstrate the application of Raman and FTIR techniques for the detection and quantification of Met oxidation in various therapeutic proteins, including, mAbs, fusion proteins and antibody drug conjugate...
May 9, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29738555/fn3-proteins-engineered-to-recognize-tumor-biomarker-mesothelin-internalize-upon-binding
#20
Allison R Sirois, Daniela A Deny, Samantha R Baierl, Katia S George, Sarah J Moore
Mesothelin is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of mesothelin has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker CA125. Therefore, molecules that specifically bind to mesothelin have potential therapeutic and diagnostic applications. However, no mesothelin-targeting molecules are currently approved for routine clinical use. While antibodies that target mesothelin are in development, some clinical applications may require a targeting molecule with an alternative protein fold...
2018: PloS One
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