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Antibody drug conjugates

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https://www.readbyqxmd.com/read/29342352/chemically-defined-antibody-and-small-molecule-drug-conjugates-for-in-vivo-tumor-targeting-applications-a-comparative-analysis
#1
Samuele Cazzamalli, Alberto Dal Corso, Fontaine Widmayer, Dario Neri
We present the first direct comparative evaluation of an antibody-drug conjugate and of a small molecule-drug conjugate for cancer therapy, using chemically-defined products which bind with high-affinity to carbonic anhydrase IX, a marker of tumor hypoxia and of renal cell carcinoma.
January 17, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29341367/development-of-antibody-directed-therapies-quo-vadis
#2
Tiago Rodrigues, Gonçalo J L Bernardes
Less is more: The efficacy of antibody-drug conjugates (ADCs) for cancer therapy is traditionally associated with cleavable linkers for payload release. Evidence now suggests that simpler constructs without cleavable moieties can afford more stable and effective ADCs.
January 17, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29341222/89-zr-immunopet-companion-diagnostics-and-their-impact-in-clinical-drug-development
#3
REVIEW
Brooke N McKnight, Nerissa T Viola-Villegas
Therapeutic monoclonal antibodies (mAbs) have been used in cancer treatment for 30 years, with around 24 mAb and mAb:drug conjugates approved by the FDA to date. Despite their specificity, efficacy has remained limited, which, in part, derails nascent initiatives towards precision medicine. An image-guided approach to reinforce treatment decisions using immune positron emission tomography (immunoPET) companion diagnostic is warranted. This review provides a general overview of current translational research using Zr-89 immunoPET and opportunities for utilizing and harnessing this tool to its full potential...
January 17, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/29337707/induction-chemotherapy-in-acute-myeloid-leukaemia-origins-and-emerging-directions
#4
Vivek A Upadhyay, Amir T Fathi
PURPOSE OF REVIEW: This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. RECENT FINDINGS: We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations...
January 13, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#5
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29333575/a-phase-1-dose-escalation-study-of-pf-06664178-an-anti-trop-2-aur0101-antibody-drug-conjugate-in-patients-with-advanced-or-metastatic-solid-tumors
#6
Gentry T King, Keith D Eaton, Brandon R Beagle, Christopher J Zopf, Gilbert Y Wong, Heike I Krupka, Steven Y Hua, Wells A Messersmith, Anthony B El-Khoueiry
Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity...
January 15, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29333400/brentuximab-vedotin-clinical-updates-and-practical-guidance
#7
REVIEW
Jun Ho Yi, Seok Jin Kim, Won Seog Kim
Brentuximab vedotin (BV), a potent antibody-drug conjugate, targets the CD30 antigen. Owing to the remarkable efficacy shown in CD30-positive lymphomas, such as Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, BV was granted accelerated approval in 2011 by the US Food and Drug Administration. Thereafter, many large-scale trials in various situations have been performed, which led to extensions of the original indication. The aim of this review was to describe the latest updates on clinical trials of BV and the in-practice guidance for the use of BV...
December 2017: Blood Research
https://www.readbyqxmd.com/read/29329556/cancer-immunotherapy-beyond-immune-checkpoint-inhibitors
#8
REVIEW
Julian A Marin-Acevedo, Aixa E Soyano, Bhagirathbhai Dholaria, Keith L Knutson, Yanyan Lou
Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized...
January 12, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29328392/targeting-bladder-cancer-using-activated-t%C3%A2-cells-armed-with-bispecific-antibodies
#9
Juan Ma, Jing Ge, Xin Xue, Weigang Xiu, Pan Ma, Ximing Sun, Man Zhang
In the present study, we aimed to investigate whether EGFR or HER2 may serve as a target for T cell-mediated immunotherapy against human bladder cancer. Expression of EGFR and HER2 was detected on the surface of bladder cancer cells, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. Activated T cells (ATCs) were generated from healthy PBMCs that were stimulated by the combination of anti-CD3 monoclonal antibody and anti‑CD28 monoclonal antibody in the presence of interleukin-2 for 14 days...
January 11, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29319167/antibody-drug-conjugates-promising-and-efficient-tools-for-targeted-cancer-therapy
#10
REVIEW
Hadi Nasiri, Zahra Valedkarimi, Leili Aghebati-Maleki, Jafar Majidi
Over the recent decades, the use of antibody-drug conjugates (ADCs) has led to a paradigm shift in cancer chemotherapy. Antibody-based treatment of various human tumors has presented dramatic efficacy and is now one of the most promising strategies used for targeted therapy of patients with a variety of malignancies, including hematological cancers and solid tumors. Monoclonal antibodies (mAbs) are able to selectively deliver cytotoxic drugs to tumor cells, which express specific antigens on their surface, and has been suggested as a novel category of agents for use in the development of anticancer targeted therapies...
January 10, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29316337/a-novel-enediyne-integrated-antibody-drug-conjugate-shows-promising-anti-tumor-efficacy-against-cd30-lymphomas
#11
Rong Wang, Liang Li, Shenghua Zhang, Yi Li, Xiaofei Wang, Qingfang Miao, Yongsu Zhen
CD30 is a 120-kDa type I trans-membrane glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily. Overexpression of CD30 has been reported in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). CD30-targeted treatment with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. Lidamycin (LDM), consisting of an apoprotein LDP and an active enediyne chromaphore AE, is a member of the enediyne antibiotic family and one of the most potent antitumor agents. AE and LDP can be dissociated and reconstituted under certain conditions in vitro...
January 9, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29313813/a-phase-ii-study-of-trastuzumab-emtansine-in-her2-positive-non-small-cell-lung-cancer
#12
Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura
Trastuzumab emtansine (T-DM1), an anti-HER2 antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed non-small-cell lung cancer (NSCLC). with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 mutation). This study was terminated early due to limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: age (median: 67 years), sex (male: 47%), performance status (0-1: 80%), and HER2 status (IHC 3+: 33%; IHC 2+/FISH: 20%; mutation: 47%)...
December 4, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29311474/enantioselective-monoclonal-antibodies-for-detecting-ketamine-to-crack-down-on-illicit-use
#13
Izumi Morita, Hiroyuki Oyama, Yui Kanda, Mayumi Yasuo, Aya Ito, Masahiro Toyota, Yoshinori Hayashi, Takeshi Yokoyama, Norihiro Kobayashi
Ketamine (KT) is a chiral anesthetic agent, (R)- and (S)-enantiomers of which differ in their pharmacological properties. KT has become one of the most commonly used illicit drugs in the world, thus, rapid and feasible on-site testing is required to crack down on the illicit use. Although immunochemical approach with specific antibodies is promising for this purpose, in practice anti-KT antibodies are difficult to obtain. We here disclose generation of monoclonal antibodies against KT. Mice were immunized with either (a) commercially-available or (b) in-house-prepared KT-albumin conjugates...
2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29310842/a-regulatory-perspective-on-testing-of-biological-activity-of-complex-biologics
#14
Marianne Saldanha, Prajakta Dandekar, Ratnesh Jain
Antibody-drug conjugates (ADCs) and bispecific antibodies are becoming increasingly popular. However, their complex structures mandate stringent regulatory guidelines to ensure their safety and efficacy. We have briefly reviewed the existing regulatory guidelines and presented our perspectives on refining them to hasten the transition of these drugs from laboratories to market.
January 5, 2018: Trends in Biotechnology
https://www.readbyqxmd.com/read/29302872/control-strategy-for-small-molecule-impurities-in-antibody-drug-conjugates
#15
Hai H Gong, Nathan Ihle, Michael T Jones, Kathleen Kelly, Laila Kott, Thomas Raglione, Scott Whitlock, Qunying Zhang, Jie Zheng
Antibody-drug conjugates (ADCs) are an emerging class of biopharmaceuticals. As such, there are no specific guidelines addressing impurity limits and qualification requirements. The current ICH guidelines on impurities, Q3A (Impurities in New Drug Substances), Q3B (Impurities in New Drug Products), and Q6B (Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products) do not adequately address how to assess small molecule impurities in ADCs. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) formed an impurities working group (IWG) to discuss this issue...
January 4, 2018: AAPS PharmSciTech
https://www.readbyqxmd.com/read/29298756/adct-402-a-pbd-dimer-containing-antibody-drug-conjugate-targeting-cd19-expressing-malignancies
#16
Francesca Zammarchi, Simon Corbett, Lauren Adams, Peter C Tyrer, Konstantinos Kiakos, Narinder Janghra, Teresa Marafioti, Charles E Britten, Carin E G Havenith, Simon Chivers, Francois D'Hooge, David G Williams, Arnaud Tiberghien, Philip W Howard, John A Hartley, Patrick H van Berkel
Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favourable expression profile, CD19 has rapid internalization kinetics and it is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies...
January 3, 2018: Blood
https://www.readbyqxmd.com/read/29290251/prevalence-of-delta-like-protein-3-expression-in-patients-with-small-cell-lung-cancer
#17
Kentaro Tanaka, Kumiko Isse, Tomomichi Fujihira, Mitsuhiro Takenoyama, Laura Saunders, Sheila Bheddah, Yoichi Nakanishi, Isamu Okamoto
OBJECTIVES: Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. MATERIAIS AND METHODS: Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3...
January 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29288033/targeting-renal-fibrosis-mechanisms-and-drug-delivery-systems
#18
Madalina V Nastase, Jinyang Zeng-Brouwers, Malgorzata Wygrecka, Liliana Schaefer
Renal fibrosis is the common outcome of many chronic kidney diseases (CKD) independent of the underlying etiology. Despite a host of promising experimental data, currently available strategies only ameliorate or delay the progression of CKD but do not reverse fibrosis. One of the major impediments of translating novel antifibrotic strategies from bench to bedside is due to the intricacies of the drug delivery process. In this review, we briefly describe mechanisms of renal fibrosis and methods of drug transfer into the kidney...
December 26, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/29287474/practical-considerations-challenges-and-limitations-of-bioconjugation-via-azide-alkyne-cycloaddition
#19
Chad J Pickens, Stephanie N Johnson, Melissa M Pressnall, Martin Leon, Cory Berkland
Interrogating biological systems is often limited by access to biological probes. The emergence of "click chemistry" has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics. One particularly popular version is the copper-catalyzed azide-alkyne cycloaddition (AAC) reaction, which has spawned new alternatives such as the strain-promoted azide-alkyne cycloaddition reaction, among others...
December 29, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29285495/antibody-drug-conjugate-targeting-protein-tyrosine-kinase-7-a-receptor-tyrosine-kinase-like-molecule-involved-in-wnt-and-vascular-endothelial-growth-factor-signaling-effects-on-cancer-stem-cells-tumor-microenvironment-and-whole-body-homeostasis
#20
EDITORIAL
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